Lymphoma - treatment options

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Updated - April 5, 2026

There are dozens of types of lymphoma. Not every type responds to every therapy, and a therapy may even be counterproductive for a certain type of lymphoma.

On the one hand, this overview is intended to support a solid diagnosis, and on the other hand, it is also intended to discuss specific - herbal - therapy options that are suitable depending on the type and subtype of lymphoma.

Where clinical studies on an adjuvant form of therapy exist, these are linked in the text. In vitro results are theoretically possible approaches or are based on laboratory tests that are not necessarily directly transferable to humans: What works in the Petri dish, in which the active substance comes into direct contact with a pathogen, may also cause different results due to different bioavailability in the organism.

However, since medicine is generally not primarily interested in purely herbal active substances and their thorough research in the context of randomized, double-blind and peer-reviewed studies - dependent on appropriate funding - in the absence of possible patenting, the theoretical approach is an opportunity for interested physicians to offer their patients evidence-based herbal alternatives, which therefore - demonstrably - have their justification as adjuvants.

A differentiated presentation is given for each type of lymphoma, which includes the following aspects:

• Clinical features
• Differential diagnostics
• Diagnostic methods
• (Standard) therapy and prognosis
• Alternative therapy option(s)

All the information provided here has been carefully researched to the best of our current knowledge, but is not a substitute for a consultation with a specialist.

How do lymphoma diseases develop?

Lymphomas arise from a malignant transformation of lymphocytes, the white blood cells of the immune system. These cells, which normally fight infections, are altered by Stochastic processes in the genome, mostly through genetic changes such as chromosomal translocations or mutations. These changes cause the cells to uncontrolled proliferation, no longer die off and displace healthy tissue. 

Although the exact cause of most lymphomas is not fully understood, certain factors play a role, which increase the risk of illness:

• SleeveThe risk increases with age, especially from the age of 60. 
• Weakened immune systemLymphomas occur more frequently in people with immunosuppression (e.g., after organ transplantation, HIV, or autoimmune diseases). 
• InfectionsSome viruses (like Epstein-Barr virus) or bacteria (like Helicobacter pylori) can favor certain types of lymphoma. 
• Environmental factorsRadiation (e.g., X-rays, radioactivity) and chemical pollutants (e.g., pesticides, benzene) can promote its development. 

Introduction

Lymphoma diseases are non-heritable, non-contagious, rarely, – however, good prognoses for an uncomplicated recovery are even rarer.
Even if the prognosis is initially very positive, successful radiation therapies cause damage that may only appear years or a decade later.
Even expedient and therapeutically sensible stem cell transplants (like organ transplants) can cause lymphomas in immunosuppressed patients in the first few years, or in a second attempt after about 5-10 years.

Even though chemotherapeutic agents attack target cells more or less „selectively,“ they must also act systemically, meaning throughout the entire organism, due to systemic infestation. Therefore, the known side effects of chemotherapy are always relevant to the patient in their impact.

Therefore, everything must be done that is suitable to strengthen the organism with regard to the necessarily systemically damaging effects of chemotherapy and radiation therapy.

This can be done by a suitable Dietary changebut also Use of adjuvant herbal active ingredients occur, which have an immune-boosting and immune-regulating effect.

A strong (!) immune system can't be easily intimidated and resists den — unwanted — manipulations of chemo- and radiotherapy measures significantly better.
And yes, the With an area of around 260-300 m, the intestine represents² around 70-80 % of the human immune system:

The majority of these immune cells are located in the intestinal mucosa and form the gut-associated lymphoid tissue (GALT). 
This is where immune cells are educated, trained and activated to distinguish between harmless substances (such as food and intestinal bacteria) and dangerous intruders (such as bacteria or viruses).

However, the worst strategy in every respect is the ostrich policy! It is definitely essential to adhere precisely to examination intervals., because lymphomas can change (transform) and, with omitted, late (follow-up) diagnostics or as a result of incorrect therapy, this usually leads to a significant disadvantage for the patient.
Those who act vigilantly and proactively are clearly at an advantage!

Overview of lymphoma types

Lymphomas are classified according to WHO classification (2022) are divided into two main groups with various subspecies:

Hodgkin's lymphoma (approx. 10-15% of all lymphomas)

Classical Hodgkin's lymphoma (cHL)

• Nodular sclerosis (NS) (60-70%) - most common form
• Chimerism (MC) (15-20%)
• Lymphocyte-rich (LR) (5%)
• Lymphocyte-poor (cHL) (5%)

Nodular lymphocyte-dominant HL (NLPHL)

• Rarer variant with better prognosis

Non-Hodgkin's lymphomae (NHL, approx. 85-90%)

B-cell lymphomas (80% of all NHL)

Indolent (low-malignant) B-cell lymphomas:

• Follicular lymphoma (FL) - Most common indolent form
• Lymphoplasmocytic lymphoma / Waldenström's macroglobulinemia
• Small lymphocytic leukemia/lymphoma (SLL/CLL)
• Nodal marginal zone lymphoma (NMZL)
• Splenic marginal zone lymphoma (SMZL)
• Primary cutaneous lymphoma (Mycosis fungoides/Sézary syndrome)
• Primary duodenal B-cell lymphoma (MALT type)

Aggressive B-cell lymphomas:

• Diffuse large B-cell lymphoma (DLBCL) - Most common aggressive form
  – NOS (Not Otherwise Specified)
  - Primary mediastinal DLBCL (pMBCL)
  — Highly transformed lymphoma
• Burkitt's lymphoma - very aggressive, fast growth
• Lymphoblastic lymphoma
• Primary cutaneous large cell lymphoma (centrotaximal variant)

Gray areas/borderline cases:

• B-cell lymphoma, unclassifiable (between DLBCL and Burkitt)

Special extranodal lymphomas:

• Hepatosplenic lymphoma (HSTL)
• Intravascular large B-cell lymphoma
• Primary efflusion lymphoma (PEL)
• HHV8-associated lymphomas
• MALT lymphoma (stomach, intestines, other organs)
• Nodal/extranodal marginal zone lymphoma

T-cell and NK-cell lymphomas (20% of all NHL)

Peripheral T-cell lymphomas (PTCL):

• Peripheral T-cell lymphoma, NOS - most common T-cell form
• Angioimmunoblastic T-cell lymphoma (AITL)
• Follicular helper T-cell lymphoma (PTFCL)
• Hepatosplenic T-cell lymphoma (γδ-type)
• Enteropathy-associated T-cell lymphoma
• Anaplastic large cell lymphoma (ALCL)
  – ALK-positive (better prognosis)
  – ALK-negative
  – Primary cutaneous variant

Cutaneous T-cell lymphomas:

• Mycosis fungoides (most common cutaneous T-cell form)
• Sézary syndrome (blood involvement of MF)
• Primary cutaneous anaplastic large cell lymphoma
• Cutaneous marginal zone lymphoma
• Cutaneous lymphoma with granular middle finger tattoo

Lymphoblastic lymphomas:

• B-lymphoblastic lymphoma/leukemia (B-ALL)
  more often
• T-lymphoblastic lymphoma/leukemia (T-ALL)
  rarer (and T-cell lymphoma)

Note: If >25% blasts in the BM (bone marrow) or blood, then rather Leukemia-Diagnosis

NK cell lymphomas:

• Extranodal NK cell lymphoma (associated with EBV)
• Aggressive NK-cell leukemia (ANKL)
• Chronic NK cell leukemia

Hodgkin's lymphoma - Related diseases

• Nodular lymphocyte-dominant HL
• EBV-positive large B-cell lymphoma (post-transplant lymphoproliferative disorder)

Immunoproliferative diseases & borderline cases

• MALT lymphomas (Mucosa-Associated Lymphoid Tissue)
• Lymphomatoid granulomatosis
• Granulomatosis with organ-preserving vasculitis (GANZL)
• EBV-associated B-cell lymphoproliferations

Epidemiological overview

Lymphoma type	Frequency	Median age	5-Y. Survival
Total non-Hodgkin's lymphomas (NHL)	85-90%	65-70 J.	70%
Total Hodgkin's lymphoma (HL)	10-15%	40 J.	90%+
Most important NHL subtypes:
Follicular lymphoma (FL)	20% (from NHL)	65 J.	85-90%
DLBCL	35% (from NHL)	70 J.	65-75%
Small lymphocytic leukemia/lymphoma (CLL/SLL)	15% (from NHL)	70 J.	75%+
Burkitt's lymphoma	2-3% (from NHL)	50 J.	80-90%
Angioimmunoblastic T-cell lymphoma (AITL)	2-3% (from NHL)	75 J.	32%
MALT lymphoma	5-10% (from NHL)	60 J.	80-90%

Classification according to biology (prognosis)

Indolent (slow growth, poorer chances of recovery, but long survival times)

• Follicular lymphoma, CLL/SLL, MALT

Aggressive (rapid growth, better chances of recovery with modern chemotherapy)

• DLBCL, Burkitt's lymphoma, Hodgkin's lymphoma

Differential Representation – Non-Hodgkin lymphomae

Follicular lymphoma (FL)

The current WHO classification (WHO-HAEM-5) divides follicular lymphomas into:

• Classic type (cFL)
  Corresponds to former grades 1, 2, 3A (indolent)
• Follicular large B-cell lymphoma (FLBL)
  Corresponds to former grade 3B (aggressive)
• FL with unusual characteristics (uFL)
  new provisional entity

Genetic subtypes: 90% have t(14;18)* with BCL2 rearrangement; less frequently t(8;14) with MYC translocation (poor prognosis); 70% major breakpoint region (MBR)**, 10-15% minor breakpoint region (mbr)***.

* t(14;18) - indicates (in simplified form) a translocation between chromosome 8 and chromosome 14. Written out in full, it would read t(8;14)(q24;q32), the translocation supplemented by the band positions, which are Precise cytogenetic localization q, which breaks the band q24 of chromosome 8 (MYC gene) and band q32 of chromosome 14 (IGH locus).

** The MBR is located in the Switch-μ range (Sμ) of the IGH locus, just upstream of the constant region gene Cμ. This region is a target of the class-specific recombination (Class Switch Recombination, CSR) in B cells, which indicates a misdirected physiological process as the cause of the translocation.

*** The mbr is also in the Sμ range, but somewhat upstream (5′) to the MBR and with approx. 10-15 % is involved in the t(8;14) translocation. This region is also attacked during CSR, but less frequently than the MBR.

In both cases (MBR and mbr), the translocation results in the MYC gene (8q24) under the control of the strong enhancers of the IGH-Lokus which leads to a constitutive overexpression of MYC and thus leads to uncontrolled cell proliferation. 

The remaining cases have breakpoints in other switch regions (e.g. Sα, Sγ) or in the JH region, which also results in the MYC gene (8q24) comes under the control of strong regulatory elements of the IGH locus, which constitutive overexpression of MYC and thus causes tumor development.

Lymphoplasmocytic lymphoma - Waldenström's macroglobulinemia

The Lymphoplasmocytic lymphoma (LPL)also Waldenström's disease-macroglobulinemia (WM) is a rare, chronic lymphoproliferative disease that belongs to the group of mature B-cell neoplasms. 

It is characterized by a Lymphoplasmocytic infiltration of the bone marrow, the production of a monoclonal IgM antibody (paraprotein) and a mostly indolent, slowly progressing form. 

The disease occurs predominantly in older adults (mean age of diagnosis: 65-72 years), with men being affected twice as often as women.

Clinical-morphological features

• Histological the lymphoma shows a dense, diffuse or follicular infiltrate of small lymphocytes, plasmacytoid lymphocytes and plasma cells in the bone marrow and other organs
• The tumor cells are CD19+, CD20+, CD22+ (weak), CD5-, CD10-, CD23-, CD103-, CD27+, FMC7+, CD38+, CD52+ and IgM+
• BCL2 is expressed in approx. 98 % cases and represents a therapeutic target
• The Increase in the IgM level leads to increased blood viscosity, which can result in symptoms such as headaches, dizziness, impaired vision and hearing, nosebleeds and Raynaud's phenomenon
• Characteristic symptoms include: B-symptoms (fever, night sweats, weight loss), anemia (pallor, weakness), thrombocytopenia (bleeding tendency), polyneuropathy (tingling, pain in extremities) and cryoglobulinemia/cold agglutinin disease with cold dependence of IgM aggregation
• Complications can be light chain amyloidosis (organ damage), organ infiltration (spleen, liver enlargement), infections due to immunosuppression

Differential diagnosistic

The differential diagnosis includes other diseases with monoclonal IgM production or lymphoplasmocytic infiltration:

• IgM monoclonal gammopathy of unknown significance (IgM-MGUS)
  IgM < 30 g/l, < 10 % plasma cells in the bone marrow, no symptoms
  Progression rate: 1.5-2 % per year
• Other non-Hodgkin's lymphomas:
  - Marginal zone lymphoma (MZL)
  Can be IgM- or IgG-secreting, but usually without bone marrow involvement
  - Chronic lymphocytic leukemia (B-CLL)
  CD5+, CD23+, CD20+, IgM-positive, but mostly without IgM paraprotein
  - Diffuse large B-cell lymphoma (DLBCL)
  Aggressive course, different immunophenotype
• Multiple myeloma (plasmacytoma)
  Osteolytic lesions, hypercalcemia, only rarely IgM secretion
• Hepatitis, HIV, rheumatoid arthritis
  can secondarily increase IgM
• Other IgM-LPL without bone marrow involvement (non-Morbus Waldenström LPL): e.g. IgG/IgA LPL, non-secretory LPL (WHO 2022)

Diagnostic methods

Diagnosis is based on a combination of clinical, laboratory and molecular genetic tests:

• Serum and urine electrophoresis + Immunofixation
  Detection of a monoclonal IgM protein
• Bone marrow biopsy
  Confirmation of lymphoplasmocytic infiltration (>10 % clonal cells)
• Cytomorphology
  Assessment of the blood and bone marrow smear
• Immunophenotyping (flow cytometry)
  CD19+, CD20+, CD22+, CD27+, CD38+, CD52+, IgM+, CD5-, CD23-
• Chromosome analysis
  Deletion of the long arm of chromosome 6 (del(6q)) at ~50 %, gain of 6p, gains of chromosomes 4, 8, 3, 18, deletions in the long arm of chromosome 13
• FISH (fluorescence in situ hybridization)Detection of del(6q), del(11q) (ATM), del(17p) (TP53) - the latter with unfavorable progression
• Molecular genetics (NGS)
  - MYD88 L265P mutationWith ~90-95 % of the WM patients - diagnostically highly specific
  - CXCR4-S338X (WHIM variant)
  With ~30 % - associated with poorer response to ibrutinib, more aggressive course

Therapy

The therapy depends on symptoms, risk, age, general condition and genotype:

• Asymptomatic WM (Waldenström's macroglobulinemia)
  Observation („watch and wait“), life expectancy comparable to age group
• Symptomatic WM - First-line therapy
  Chemoimmunotherapy (CIT)
  - DRC (dexamethasone-rituximab-cyclophosphamide): For elderly or frail patients
  - BR (Bendamustine-Rituximab): For fit patients, rapid disease control
  BTK inhibitors (BTKi)
  - Ibrutinib, Zanubrutinib: First-line indication, especially in patients with MYD88 L265P
  Not suitable for MYD88 WT / CXCR4 WT
  - High response rates (>80 %), good tolerability, continuous therapy
• Bortezomib-based therapies
  (e.g. bortezomib-rituximab) - Rapid control, for patients with high disease burden
• Stem cell transplantation
  In young, agile patients with recurrent disease (rare)

Forecast

• Median overall survival
  >10 years (in asymptomatic patients even close to the normal population)
• Prognostic factors
  InexpensiveMYD88 L265P mutation, CXCR

Small lymphocytic leukemia / lymphoma (CLL/SLL)

This is a homogeneous entity (not a subtype in the classical sense), but with prognostic subcategories:

• Mutated IGHV (~50%)
  Better prognosis
• Unmutated IGHV (~50%)
  Poorer prognosis
• Del(13q)
  favorable risk factor
• Del(11q) / TP53 mutation
  unfavorable risk factors
• Del(17p) / TP53 mutation
  Very unfavorable prognosis
• Complex Karyotype (≥3 aberrations)
  worse

The Chronic lymphocytic leukemia (CLL) and that small cell B-cell lymphoma (SLL) are considered a common entity of indolent B-cell lymphomas according to the WHO 2022 classification. 

Both diseases have an identical immunophenotypic and histologic profile, but differ clinically in the site of involvement: In the CLL dominates the leukemic infiltration of the peripheral blood and bone marrow, while the SLL the Extramedullary involvement of lymph nodes, spleen or other organs is in the foreground (blood lymphocytes < 5 × 10⁹/L).

Clinical features

• Frequency
  CLL is the most common leukemic disease in Germany with a new case rate of approx. 5,600/year
• Median age of onset
  72 years (men), 76 years (women)
• Symptoms
  Many patients are asymptomatic at the time of diagnosis. With advanced disease B symptoms (fever, night sweats, weight loss), Lymphadenopathy, Hepato- and splenomegaly, Cytopenias (anemia, thrombocytopenia) or Autoimmune cytopenias on
• Blood smear
  Dominance of small, mature lymphocytes with dense, cloddy chromatin, narrow cytoplasmic rim and Gumprecht's core shadow (typical, but not pathognomonic)
• Bone marrow
  Infiltration by small lymphocytes, often with loss of the germinal centers

Differential diagnostics

Diagnostic criteria (according to IWCLL)

• Permanent lymphocytosis (> 3 months) with ≥ 5 × 10⁹/L monoclonal B cells in the peripheral blood
• Morphologically: predominance of small, mature lymphocytes in the blood smear
• Immunophenotype: CD5+, CD19+, CD23+, CD20(dim), CD79b(dim), CD200+, ROR1+; weak/sIg, no CD10, none FMC7
• MonoclonalityDetection of light chain restriction (kappa or lambda) using CD19/Igκ or CD19/Igγ

Differential diagnoses

Disease	Criteria for differentiation
Monoclonal B-cell lymphocytosis (MBL)	< 5 × 10⁹/L monoclonal B cells, No symptoms, No lymph node enlargement, no cytopenias
Mantle cell lymphoma (MCL)	t(11;14)(q13;q32), CD5+, but CD23-, cyclin D1+, CD5+ prolymphocytes > 15% (for prolymphocytic progression)
B-cell prolymphocytic leukemia (B-PLL)	> 55% Prolymphocytes in the blood, CD5-, CD23-, CD20+, CD200-
Hairy cell leukemia (HCL)	„Hair cells“ with an irregular cytoplasmic structure, CD103+, CD123+, CD25+, TRAP+, reticular fibrosis in the bone marrow
Richter transformation (CLL → DLBCL)	Extramedullary lymphoma progression (2-5% of cases), Aggressive course, DLBCL type (centroblastic/immunoblastic), CD30+, CD10+, BCL6+, BCL2-

Diagnostic methods

• Cytomorphology
  EDTA blood, obligatory
• Immunophenotyping
  EDTA or heparin
  Matutes score Classification
• FISH
  Standard panel
  del(13q), del(11q), +12, del(17p), IGH rearrangements (e.g. t(11;14), t(14;18))
• Chromosome analysis
  Heparin-blood; Complex karyotype (≥3 aberrations) is prognostically unfavorable
• Molecular genetics
  IGHV mutation status (unmutated = unfavorable), TP53, ATM, NOTCH1, SF3B1-mutations
• MRD detection
  Sensitivity ≥ 10-⁴; important for therapy monitoring

Forecast

The prognosis is highly heterogeneous and is determined by several factors:

• IGHV mutation status: Unmutated (U-CLL) = unfavorable
• Hypermutated (H-CLL) = favorable
• Chromosomal aberrations (FISH):
  - del(17p): Unfavorable, TP53 change → Resistance to therapy.
  - del(11q)Unfavorable, often with lymphadenopathy.
• Complex karyotype
  Independent prognostic factor (unfavorable). 
• Molecular genetics
  NOTCH1, SF3B1, BIRC3-mutations → unfavorable, especially in recurrence
• CLL-IPI (International Prognostic Index)
  Takes into account age, Binet stage, β₂ microglobulin, IGHV, del(17p), TP53 mutation
  Valuable for PFS (progression-free survival), less for O.S (overall survival) under targeted therapy

Therapy

The therapy depends on the Need for treatment, Prognostic factors and Patient profile. 

Indication for therapy (according to iwCLL/Onkopedia)

• SymptomsB-symptoms, cytopenias, progression of lymphadenopathy
• Laboratory criteria: Lymphocytes > 30 × 10⁹/L, Cell doubling time < 12 months, progressive cytopenias

Treatment options

• Targeted therapies (primary therapy)
  - Ibrutinib (BTK inhibitor)
  Standard for TP53 alterations or unmutated IGHV
  - Venetoclax (BCL-2 inhibitor)
  Combination with Obinutuzumab
  especially with del(17p) or TP53 mutation
• Combination therapy (for fitter patients)
  - Obinutuzumab + chlorambucil or FCR (fludarabine, cyclophosphamide, rituximab)
  only for favorable risk (hypermutated, no TP53 alteration)

Marginal zone lymphomas

Marginal zone lymphoma (MZL) are a group of indolent B-cell lymphomas that can be divided into three main subtypes according to their primary localization:

• extranodal MZL (MALT lymphoma)
• nodal MZL (nMZL)
• Splenic MZL (SMZL)

All three subtypes originate from mature B-cell tissue, but show different clinical, genetic and therapeutic characteristics. 

Extranodal marginal zone lymphoma (MALT lymphoma)

• Origin
  Primarily in non-lymphatic organs (e.g. stomach, salivary glands, eye, skin, lungs)
• Frequency
  approx. 8% of all lymphomas, with stomach as the most frequent localization (30-35%)
• Pathogenesis
  Frequently associated with chronic antigen stimulation by Helicobacter pylori-Infection (stomach)
  or autoimmune diseases (e.g. Sjögren's syndrome, Hashimoto's thyroiditis)

Differential diagnostics

• To be distinguished from diffuse large B-cell lymphoma (DLBCL), follicular lymphoma and chronic lymphocytic leukemia (CLL)
• Classic lymphoepithelial lesions with invasion of the epithelium by clonal B cells are characteristic

Diagnostic methodology

• Histological examination of the affected organ (e.g. stomach biopsy)
• Gastroscopy, Colonoscopy, Ultrasound, PET-CT (for staging)
• Immunohistochemistry: CD20+, CD79a+, CD10-, CD5-, CD23-

Therapy and prognosis

• First line: Antibiotic eradication of H. pylori (remission rates up to 80%)
• In case of non-response or extragastric MALT lymphoma: Radiotherapy (24 Gy) or System therapy (e.g.  Rituximab + bendamustine, Rituximab + chlorambucil)
• Zanubrutinib (BTK inhibitor) as a new approach for recurrence or refractory disease

Nodal marginal zone lymphoma (nMZL)

The Nodal marginal zone lymphoma is a rare, indolent B-cell lymphoma, accounting for approximately 0.5-1% of all lymphomas and 10% of all MZL. Lymph nodes, without extranodal or splenic infestation.
It belongs to the group of marginal zone lymphomas (MZL), which also includes extranodal (MALT lymphoma) and splenic marginal zone lymphoma.

Clinical features

• Similar to the follicular lymphoma
  Advanced stage at diagnosis, lymph node enlargement, bone marrow involvement (approx. 30%)

Differentiation between splenic and extranodal MZL

• nMZL
  The primary infestation affects only the lymph nodes
  It lies No infestation of the spleen (splenic) and No extranodal infestation (e.g. stomach, salivary gland, eye) before
• Splenic MZL
  Infestation of the Spleen, often with Bone marrow infiltration and leukemic involvement of the peripheral blood
• Extranodal MZL (MALT lymphoma)
  Starts in non-lymphatic organs (e.g. stomach, salivary gland, eye) and often shows an association with chronic inflammation (e.g. Helicobacter pylori, Sjögren's syndrome)

Differentiation from other indolent B-cell lymphomas

• Follicular lymphoma (FL)
  Similar clinical picture and treatment approach, but histologically different cell structure (follicular architecture in FL, marginal zone-like structure in nMZL)
• Lymphoplasmacytic lymphoma
  May have clinically and histologically overlapping features; differentiation by specific immunophenotypes (e.g. absence of CD5, CD10, CD23 in nMZL, but expression of plasma cell markers in LPL)
• Mature B-cell lymphomas
  Differentiation using immunohistochemistry (e.g. CD20+, CD5-, CD10-, CD23-, typical for nMZL)

Diagnostic methodology

• Histological diagnosis by Lymph node biopsy (diagnosis of exclusion)
• Staging according to Ann Arbor Classification
• PET-CT, Bone marrow biopsy, Blood count, Pulmonary function tests, ECG/heart echo (before therapy)

Therapy

• First line
  Rituximab + chemotherapy (e.g.  Bendamustine, CVP, CHOP)
• Rituximab maintenance therapy (2 years) shows prolonged progression-free survival
• In case of recurrence: 
  renewed rituximab/chemotherapy, High-dose therapy with autologous stem cell transplantation (for early relapses)
• For refractory disease
  BTK inhibitors (ibrutinib, zanubrutinib) or PI3K inhibitors (idelalisib, copanlisib)

Splenic marginal zone lymphoma (SMZL)

The Splenic marginal zone lymphoma (SMZL) is one with approx. 1-2% of all lymphomas; and approx.  2% all MZL, rare, indolent B-cell neoplasia that manifests primarily in the spleen and is often accompanied by involvement of the bone marrow and peripheral blood. 
The differential diagnosis is difficult due to the lack of specific cellular markers and requires multimodal diagnostics.

Clinical features

• Typical are Splenomegaly, Bone marrow infiltration and variable leukemic involvement of the peripheral blood
  Generalized lymphadenopathy is rare

Cytomorphology

• The peripheral blood contains lymphatic cells with short, polar villi, plasmacytoid lymphocytes and inconspicuous lymphocytes. The cells show a mature, villous morphology

Histology

• The spleen shows involvement of the white and red pulp, with the white pulp typically being enlarged. The bone marrow shows micronodular infiltrates of atypical lymphocytes

Immunophenotype

The tumor cells express Pan B cell antigens (CD19, CD20, CD22, CD79a), sIgM/IgD and FMC7, but are negative for CD5, CD10, CD23, CD43, CD103, Cyclin D1 and Annexin A1. 
The Misexpression of CD5 is crucial for differentiating between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL)

Cytogenetics and molecular markers

• Deletion 7qIn approx. 30-40% of the cases detectable - a characteristic but not specific feature
• Trisomy 3q and Gains of 1q, 8q, 12q, 18 are often
• Molecular genetic changes: Mutations in NOTCH2 (10-25%), KLF2 (10-40%), TP53 and MYD88 are frequent and associated with a less favorable course.
• No characteristic translocation as in follicular lymphoma (t(14;18)) or mantle cell lymphoma (t(11;14))

Differential diagnostics

• Splenic B-cell lymphoma/leukemia with prominent nucleoli (SBLPN)Mutations in MAP2K1, specific cell morphology
• Chronic lymphocytic leukemia (CLL)CD5-positive, CD23-positive, cell morphology different
• Mantle cell lymphoma (MCL)CD5-positive, cyclin D1-positive, t(11;14) present
• Hairy cell leukemia (HZL)BRAF V600E mutation, „hair cells“ in the blood, CD11c-positive
• Lymphoplasmocytic lymphoma (LPL)MYD88 L265P mutation, CXCR4 mutation, IgM macroglobulinemia
• Splenic diffuse small B-cell lymphoma of the red pulp (SDRPL): Histologically different, more frequent involvement of the red pulp

Diagnostic methodology

• Peripheral lymphocyte typing, Bone marrow biopsy, Splenectomy preparation (rare)
• Immunophenotype: CD20+, CD79a+, sIgM/IgD+, CD5-, CD10-, CD23-, CD43-, Annexin A1-, Cyclin D1-.
• Ki67 staining: Targetoid pattern (characteristic)
• Molecular genetics: NOTCH2- (10-25%) and KLF2- (10-40%) mutations → less favorable course
• Spleen histology

Therapy and forecast

• Indication for therapy
  Only in case of cytopenia (Hb <10 g/dl, platelets <80,000, neutrophils <1000) or symptomatic splenomegaly
• Therapy options
  - Splenectomy (equivalent option).
  - Rituximab monotherapy
  - or Rituximab + bendamustine.
• Median overall survival >10 years
  POD24 (progression within 24 months) → median survival 3-5 years

Primary cutaneous lymphomas (CL)

Primary cutaneous lymphomas (CL) are a heterogeneous group of lymphoproliferative diseases of the skin characterized by isolated skin involvement without systemic involvement. They account for about 70 % of cutaneous lymphomas (T-cell lymphomas) and 25 % (B-cell lymphomas), with the remaining 5 % including rare forms. The disease occurs predominantly in middle to old age, with an annual incidence of around 1,000 new cases in Germany. 

Clinical-morphological features

• Most common form: Mycosis fungoides (MF)
  typically begins with erythematous plaques that develop into scaly, thickened lesions („cigarette paper“ plaques)
  Later, tumor nodules and generalized involvement may occur
• Primary cutaneous B-cell lymphoma (CBCL)
  - Follicular lymphomaSolitary or few, smooth, red to brown-red plaques on the trunk, face or head. Clinically often asymptomatic
  - Marginal zone lymphomaMultiple papules or plaques, often on the leg
  - Sézary syndromeGeneralized erythroderma, lymphadenopathy, pruritus, pseudopapillomas, CD4+/CD56+-cells in the blood

Differential diagnosis

• Clinical
  Psoriasis, atopic eczema, chronic contact dermatitis, lichen planus, lupus erythematosus, skin tuberculosis, mycosis fungoides vs. pityriasis rubra pilaris
• Histological
  Pseudolymphomas (e.g. Lymphadenosis cutis benigna), benign lymphocyte infiltrate, reactive lymphadenopathy, cutis laxa, granulomatous slack skin, subcutaneous panniculitis-like lymphoma
• Specific differential diagnoses for CBCL
  Primary cutaneous follicular lymphoma vs. reactive germinal centers, Marginal zone lymphoma vs. chronic inflammation, diffuse large cell lymphoma vs. malignant melanoma, Hodgkin's lymphoma, carcinoma

Diagnostic methods

• Clinical examination
  Detailed medical history, skin and lymph node examination
• Histology
  Biopsy with several levels, preferred for non-eroded lesions
• Immunohistochemistry
  CD20, CD79a (B cells), CD3, CD4, CD5, CD7 (T cells), CD30 (for CD30+ diseases), Bcl-2, Bcl-6, CD10
• Molecular biology
  - PCR for clonal immunoglobulin genes (IGK, IGH) - Detection of a clonal tumor cell population
  - FISH or cytogenetics
  t(14;18)(q32;q21) in follicular lymphoma (only in approx. 30-50 % of primary cutaneous cases)
• Staging - TNM classification (ISCL/EORTC):
  - T - Size and extent of the skin lesions (T1-T4)
  - N - Lymph node involvement (N0-N3)
  - M - Systemic infestation (M0-M1)
• Imaging
  PET/CT for the detection of subclinical infestation (recommended for higher stages)
• Bone marrow biopsy
  If systemic spread is suspected (e.g. diffuse large cell lymphoma)

Therapy

• Localized lesions (stage I/II)
  - Radiotherapy: Permanent local tumor control for 90-100 % the CTCL and 95-100 % of CBCL cases
  - Topical therapy: Nitrogen mustard (mechlorethamine), Bexarotene gel (for MF), Imiquimod, Corticosteroids
• Multiplying or locally advanced lesions
  - PhototherapyUVB, PUVA (for MF)
• Systemic therapy
  - Rituximab (anti-CD20 antibody): Standard for B-cell lymphomas (R-CHOP, R-CVP)
  - CHOP scheme (cyclophosphamide, doxorubicin, vincristine, prednisone) or R-CHOP for aggressive forms
  - Brentuximab vedotin (CD30+)
• Prophylaxis for Sézary syndromeSystemic therapy, e.g. Methotrexate, Bexarotene, Alemtuzumab. 
• Study-based therapy: For early lesions („low burden“) a „wait and see“ strategy with Rituximab (RESORT study) to be superior to observation

Forecast

• Good prognosis (>5 years survival time)
  - Mycosis fungoides (early stages), primarily cutaneous follicular B-cell lymphoma, Marginal zone lymphoma, Lymphomatoid papulosis, Pagetoid reticulosis.
  - 5-year survival rate: up to 95 % for follicular lymphoma without bone marrow involvement
• Medium forecast (2-5 years)
  Sézary syndrome, folliculotropic MF, diffuse large B-cell lymphoma (other types)
• Poor prognosis (<2 years)
  Intravascular large B-cell lymphoma, gamma/delta T-cell lymphoma, CD4+/CD56+-neoplasia, NK/T-cell lymphoma
• Prognostic factors
  Localization on the leg (poorer prognosis), bone marrow infiltration, Bcl-2 expression, t(14;18)-negativity, high LDH, CD56 positivity

NoticeThe prognosis has improved thanks to modern therapies (e.g. Rituximab, Immunotherapies), but there is a lack of up-to-date, large-scale statistics that fully reflect these developments. The Clonality analysis is an important prognostic factor that has not yet been taken into account in older studies.

Primary duodenal B-cell lymphoma (MALT type)

A primary duodenal B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma) is a rare form of malignant non-Hodgkin lymphoma that develops in the duodenum. It originates from B-cells and grows at the expense of mucosal lymphoid tissue.
Although rare, it is one of the more common extranodal lymphomas, with the stomach being the most frequent location, followed by the duodenum and other gastrointestinal regions.

MALT lymphomas are overall rarely and do about 7–8 % all newly diagnosed non-Hodgkin lymphomas. The The stomach is the most common location (30–60 % der MALT-Lymphome), während das Duodenum is clearly less commonly affected is. 

According to current guidelines and studies, MALT lymphomas are found in entire gastrointestinal tract only approximately 5 % der Fälle, with the vast majority being localized in the stomach.

Specific incidence data for the duodenum are not available, but it is considered Rarest location in the small intestine regarded. Estimates suggest that only about 3 % of all MALT lymphomas in the intestinal tract, and the duodenal portion of that is minimal. 

The Incidence of all MALT lymphomas is about 1 case per 313,000 people per year, with a median age of illness of 65 years.

A light Female dominance is described, in contrast to stomach lymphomas, which tend to affect men.

primary duodenal MALT lymphoma is a Indolent, mostly localized disease, which by H. pyloriEradication can be treated. The Diagnosis requires histological and immunohistochemical confirmation, supplemented by molecular biology and imaging techniques.

Clinical features

• Symptoms
  Often unspecific, like Fatigue, weight loss, abdominal pain, nausea, or bleeding from the upper gastrointestinal tract
  In some cases, it may lead to obstructive symptoms occur if the lymphoma infiltrates the intestinal wall or causes stenosis
• Clinical pictureThe disease usually progresses lazy, but with progression it can lead to a Transformation into diffuse large B-cell lymphoma (DLBCL) come. This is considered a clinically unfavorable development.

Differential diagnostics

Differential diagnoses include:

• Benign inflammatory diseases of the duodenum (e.g., chronic enteritis, Crohn's disease)
• Malignant Tumors of the duodenum (e.g., adenocarcinoma, GIST)
• Other non-Hodgkin's lymphomas (e.g., DLBCL, follicular lymphoma)
• Infections (e.g. Helicobacter pylori-associated gastritis, also relevant for duodenal MALT lymphomas)
• Autoimmune diseases (e.g., Celiac disease, autoimmune enteritis) 

Diagnostic methods

• Endoscopy with biopsy
  The Histology shows a infiltrating lymphocyte population in the mucosa and submucosa, often with Mantle zone-like structure
• Immunohistochemistry
  Confirms B-cell genesis: CD20+, CD79a+, PAX5+, CD10–, BCL2+, MUM1-.  CD5- and CD23- help differentiate from CLL/SLL
• Clonality analysis
  Proof of B-cell clonality (e.g., via PCR for IgH gene rearrangements)
• Molecular biological investigations
  - FISH
  Exclusion of translocations such as t(11;18)(q21;q21) (BIRC3-MALT1), which are associated with therapy resistance
  - Gene expression profile:
  Subclassification by Cell of Origin (COO) – GCB-like or ABC-like – has prognostic relevance
• Imaging
  - CT or MRI abdomen for staging
  - FDG-PET/CT is recommended when advanced stage or transformation is suspected, as MALT lymphomas often low FDG uptake exhibit

Therapy

• First choice in isolated duodenal involvement and evidence of H. pylori: Antibiotic therapy for eradication, up to 50–70% der Fälle leads to complete remission 
• Regarding negative H. pylori- Status or therapy resistance
  - Radiotherapy very effective for localized lesions (e.g., in the duodenum) with high remission rates
  Chemotherapy in advanced stage or transformation to DLBCL: R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone).
  - New therapies in case of a relapsed or refractory course: 
  – – BTK inhibitors (e.g., Ibrutinib)
  – – BCL2 inhibitors (e.g., Venetoclax), especially with H. pylori-negative or t(11;18)-positive cases. 
• Surgery Only indicated in complications such as bleeding or perforation, not as curative therapy. 

Forecast

The Prognosis is good with early diagnosis and treatment., but is unfavorable for transformation or specific genetic markers.

• Inexpensive with isolated, H. pyloripositive lesion 10-year survival rate > 75%.
• Unfavorable in transformation to DLBCL – Significantly worsens; requires aggressive therapy. 
• Factors for unfavorable prognosis:
  • t(11;18)(q21;q21)Translocation
  • CD5 expression
  • Location outside the stomach (e.g., Duodenum)
  • Stage III/IV
  • Elevated LDH
  • Number of extranodal organs (after IPI) 

Clinical-morphological features

• Morphology
  Infiltration of the mucosa and submucosa by small to medium lymphocytes with centrocentric nuclear shape, good differentiation, low proliferation rate (Ki-67 < 10%)
• Immunophenotype
  CD20+, CD79a+, CD10–, BCL2+, MUM1–, CD5–, CD23–
• Genetics
  t(11;18)(q21;q21) in 20–40% of cases, t(1;14)(p22;q32) rarely, BCL10 Translocations possible

Diffuse large B-cell lymphoma (DLBCL)

The Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma in adults and is characterized by an aggressive clinical course. 
It develops from mature B cells and is classified in the current WHO classification (WHO-HAEM5) and the International Consensus Classification (ICC) as DLBCL, NOS (not elsewhere classified) is defined, whereby a subdivision into molecular subtypes is recommended.

Molecular subtypes (Cell of Origin, COO)

• GCB-DLBCL (germinal center B-cell-like)
  Similar to the development of B cells in the germinal center
  Has a better prognosis with a 5-year progression-free survival of 70-80%
• ABC-DLBCL (activated B-cell-like)
  Similar to activated B cells outside the germinal center
  Characterized by a less favorable prognosis with a 5-year progression-free survival of 40-50%
• 10-15% of the cases cannot currently be assigned to a subtype

Clinical features

• Main places of manifestation
  Lymph nodes, spleen, bone marrow, extranodal organs (e.g. gastrointestinal tract, skin)
• B symptoms (fever, night sweats, weight loss) are common
• Prognostic factors
  Age >60 years, advanced stage (III-IV), elevated LDH, high IPI score, large tumor mass (bulk >7.5 cm), bone marrow infiltration, male gender, vitamin D deficiency

Differential diagnosis

DLBCL, NOS must be differentiated from other large B-cell lymphomas, including:

• Highly malignant B-cell lymphomas (HGBL) with MYC and BCL2 and/or BCL6 rearrangements
  („double-hit“ or „triple-hit“ lymphomas), which are considered independent entities
• Large B-cell lymphoma with IRF4 rearrangement (definitive entity)
• Primary DLBCL of the central nervous system, of the testicle or the Vitroretina
• EBV-positive DLBCL, KSHV/HHV8-positive DLBCL, fibrin-associated DLBCL and HGBL with 11q aberration

Diagnostic criteria

The standard diagnostics include:

• Histopathological examination of a lymph node biopsy
• Immunohistochemistry with marker panel (CD20, CD10, BCL6, MUM1, CD5, CD30, MYC, BCL2)
• Gene expression analysis to determine the COO subtype (gold standard, but not a standard service provided by health insurance companies)
• Cytogenetics and molecular genetic analyses (MYC, BCL2, BCL6 translocations, mutations in EZH2, MYD88, CARD11, CREBBP)
• Imaging (CT, PET-CT) and Bone marrow examination to the staging

Therapy and forecast

• First-line therapy
  R-CHOP scheme (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) for patients with low to intermediate risk
• Alternatives
  Pola-R-CHP (with polatuzumab vedotin) for intermediate to high risk
• Recurrent/refractory
  CAR-T cell therapy (e.g. tisagenlecleucel, axicabtagen-ciloleucel), Bispecific antibodies (epcoritamab, glofitamab, odronextamab), Loncastuximab tesirine or autologous stem cell transplantation

If left untreated, DLBCL quickly becomes lethal, but with modern therapies, up to 70% of patient healing.

Primary mediastinal B-cell lymphoma (pMBCL)

Primary mediastinal B-cell lymphoma (PMBCL) is a rare, aggressive subtype of non-Hodgkin's lymphoma (NHL), which affects approx.  2-4 accounts for % of all NHLs and above all young women aged 30-40 on average (median age of onset around 35 years).

Originally classified as a subtype of diffuse large B-cell lymphoma (DLBCL), it has been listed as an independent entity in the WHO classification since 2001, as it is distinguished by specific clinical, pathological and molecular characteristics. 

Clinical presentation

PMBCL is created in the anterior mediastinum (between the lungs, behind the sternum) and leads to typical symptoms such as the local invasive growth:

• Upper influence accumulation (e.g. visible vein in the thoracic wall),
• Airway compression or obstruction,
• Esophageal constriction,
• Pericardial tamponade,
• Thrombosis of the cervical veins,
• Pleural effusions,
• Tumor lysis syndrome (rare).

Laboratory chemistry often shows a Increased lactate dehydrogenase (LDH) and B symptoms (fever, night sweats, weight loss) in about half of the patients. 

Pathogenesis and diagnostics

PMBCL differs significantly from other DLBCL subtypes at the molecular level:

• Constitutive activation of the NF-κB and JAK/STAT signaling pathway
• Frequent amplification of the 9p24.1 locus with overexpression of PD-L1 and PD-L2 - a central reason for the effectiveness of PD-1 inhibitors like Pembrolizumab and Nivolumab
• CD30 positivity (similar to classic Hodgkin's lymphoma)
• No immunoglobulins (in contrast to other B-cell lymphomas)
• Similarity to Reed-Sternberg cells of classical Hodgkin's lymphoma (cHL), which makes diagnosis more difficult

The diagnosis is based on a Lymph node biopsy with histological, immunohistochemical and molecular biological analysis.
Circulating tumor DNA (ctDNA) is being investigated as a new biomarker in diagnostics and follow-up. 

Therapy and prognosis

• First-line therapy
  Combination of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and Irradiation of the mediastinum
  often supplemented by Etoposide (e.g. R-CHOP-Plus reference programs).
• Recurrent/refractory
  PD-1 inhibitors (e.g. Pembrolizumab, Nivolumab) are established and ready for approval
  Brentuximab vedotin (anti-CD30 antibody-drug conjugate) and CAR T-cell therapies (e.g.  Axicabtagen Ciloleucel) offer promising options in the second and third lines
• Long-term remission
  With initial therapy, the Survival rate over 90 %
  Poor prognosis in case of recurrence or refractoriness 

Differential diagnostics

Important differential diagnoses are

• Classical Hodgkin's lymphoma (similar molecular profiles, but different cell types)
• Diffuse large B-cell lymphoma (DLBCL, NOS)
• High-grade B-cell lymphoma (HGBL) with MYC and BCL2 rearrangement („double-hit lymphoma“)
• Thymus carcinoma or Thymoma (especially in the mediastinum)
• Lymph node metastases from other tumors (e.g. bronchial carcinoma)

The demarcation is made by Immunohistochemistry, cytogenetic examinations (e.g. FISH for 9p24.1 amplification) and Transcriptome analyses.

PMBCL is a rare, but well-treatable, aggressive B-cell lymphoma with a characteristic localization in the mediastinum, typical clinical symptoms and a specific molecular profile that Targeted therapies like PD-1 inhibitors and CAR-T cells makes it possible.

Burkitt's lymphoma (BL)

Burkitt's lymphoma (BL) is a highly malignant, aggressive B-cell non-Hodgkin's lymphoma with extraordinarily high cell division rate and a proliferation rate of almost 100 1TP3.

Clinical features

Morphologically it shows a Diffuse, purely blastic infiltrate from medium-sized cells with round, basophilic nuclei, several Nucleoli and a characteristic, basophilic cytoplasm with vacuolization. A typical histological feature is the „Starry sky“ pattern, generated by light-colored macrophages, which phagocytose apoptotic tumor cells. Clinically, a distinction is made between three variants:

• Endemic BLCommon in Africa, Brazil and Papua New Guinea; mostly in the Jaw or facial bones manifested, mostly in children.  >95 % EBV-associated
• Sporadic BL: Worldwide, especially in children and young adults; typical abdominal manifestation (ileocecal valve, mesentery), can lead to intestinal obstruction.  ~20 % EBV-associated
• Immunodeficiency-associated BLCommon in HIV infection (AIDS-defining illness), with nodal participation and Bone marrow infiltration

Differential diagnosistic

• High-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 translocations
  („double-hit“ lymphoma)
  overlaps clinically and biologically with BL
  Poorer prognosis
• Acute lymphoblastic leukemia (ALL) L3 form
  (Burkitt's leukemia), if bone marrow involvement >25 % is present
• Diffuse large B-cell lymphoma (DLBCL)
  especially with MYC rearrangement, but without the typical genetics and morphology of BL
• Lymphoproliferative diseases in immunocompromised patients 
  (e.g. after transplantation)
  may show similar EBV-associated patterns

Diagnostic methods

• Cytomorphology
  Bone marrow smear and tissue biopsy show characteristic blastic cells with a „starry sky“ pattern
• Immunophenotyping
  Positive for CD19, CD20, CD10, CD38, CD43, CD81, FMC-7, MYC
  Negative for BCL2, CD44, TdT, CD34
• Chromosome analysis
  Proof of the Translocation t(8;14)(q24;q32) (85 %), more rarely t(2;8) or t(8;22)
• FISH
  By default MYC rearrangement (with IGH::MYC* or MYC-independent probe).  11q23/11q24 probe helps to differentiate against HGBL11q
  * Molecular genetic notation „::“ to indicate a Gene fusion or rearrangement to symbolize;
  here the fusion of the MYC oncogene with the IGH gene
• Molecular genetics: Mutations in ID3, MYC, TP53, FOXO1 (especially with EBV-negative BL)
• Imaging: PET-CT (high FDG uptake), MRI with CNS involvement
• Cerebrospinal fluid examination: Mandatory due to high probability of CNS involvement
• LDH level: >500 U/L is a risk factor

Therapy

The treatment is emergency to initiate:

• First-line therapy
  Intensive, short chemotherapy with Rituximab
  (e.g.  R-CODOX-M/R-IVAC or GMALL-B-ALL/NHL protocol)
• Prophylaxis of the CNS
  Intrathecal and systemic Methotrexate
• Tumor lysis syndrome prophylaxis
  Intravenous hydration, Allopurinol or rasburicase (contraindicated for G6PD deficiency!)
• Salvage therapy
  In the event of recurrence or treatment failure autologous stem cell transplantation (limited prospects of success)
• Rare indications
  Radiotherapy or surgical intervention for complicated symptoms (e.g. bowel obstruction). 

Forecast

• In resource-rich countries
  Overall survival >80 % in adults, >90 % in children under modern immunochemotherapies (e.g. with rituximab)
• In countries with low resources
  Prognosis significantly worse due to delays in diagnosis and treatment
• BL-IPI (International Prognostic Index)
  Helps with risk assessment (e.g. LDH, stage, age, CNS involvement)
• Molecular genetic subgroups
  (e.g. with TP53, ID3 or FOXO1 mutations) influence the course of the disease

Lymphoblastic lymphoma (BL)

The differential diagnosis of lymphoblastic lymphoma (BL) requires careful differentiation from other B-cell neoplasms, particularly Burkitt's lymphoma (BL), dem diffuse large B-cell lymphoma (DLBCL) and the B-cell acute lymphoblastic leukemia (B-ALL).

The clinico-morphological, immunophenotypic, and molecular genetic characteristics are crucial for correct classification. 

Clinical-morphological features

• Cytomorphology
  At the Burkitt's lymphoma show the cells medium-sized, blastular forms with deep basophilic cytoplasm, characteristic vacuolization, round cores and multiple basophilic nucleoli
  The cell division rate is extremely high.
• Cell size and cell cytoplasm
  Unlike B-ALL, the cells in BL not small, but medium-sized, and show No significant changes in cell cytoplasm like at the ALL
• Proliferation Index
  Ki67 > 95%% – a central marker for high cell proliferation in BL

Differential diagnostics

• Facing B-ALL
  – Missing expression of immature markersBL is CD34- and TdT-negative,
  during B-ALL CD34+ and TdT+ is
• - Light chain expressionBL shows Concentrated light chain expression (kappa/lambda),
  what is missing in B-ALL
• Opposite DLBCL
  - MYC rearrangementOn the BL is MYC Translocation (t(8;14), t(8;22), t(2;8)) central,
  but not specific – it also occurs in DLBCL
  - KaryotypeBL shows less complex karyotypes as DLBCL
  - Immunophenotype
  BL is CD10+, CD19+, CD20+, CD38+++, CD81+++, CD43+, MYC+++, but BCL2-, CD5-, CD44-, CD138-
• Opposite HGBL with 11q aberrations
  The entity HGBL with 11q aberration (HGBL11q) was redefined by the WHO in 2022 and is characterized by 11q23/11q24 changes from
  It differs molecularly from classic BL (e.g., through mutations in ID3, TP53, FOXO1)

Diagnostic methods

• Cytomorphology Mandatory
• Immunophenotyping (Flow Cytometry)
  EDTA or heparin as an anticoagulant. Detection of CD19+, CD20+, CD10+, CD38++, CD81+++, CD43+, MYC+++, BCL2-
• FISH Mandatory
  Proof of MYC Rearrangements (IG::MYC-Probe) and 11q-aberrations (11q23/24 Probe)
  Distinction between BL, HGBL11q, and DLBCL/HGBL-MYC/BCL2
• Molecular genetics
  Analyses of ID3, TP53, FOXO1, MYC. Missing BCL2 rearrangement at BL
  unlike HGBL
• Chromosome analysis
  Heparin (Recommended as an anticoagulant for cultivation), confirmation of complex changes

Therapy

• Standard therapy
  Intensive Immunochemotherapy (e.g.  R-CODOX-M/IVAC, DA-EPOCH-R) with Rituximab
• CNS prophylaxis
  Necessary due to high CNS involvement
• Targeted therapies
  Investigated in clinical studies: BCL2 inhibitors (Venetoclax), BTK Inhibitors (Ibrutinib), BCL6 Inhibitors, PI3K inhibitors
• Stem cell transplantation
  In case of recurrence or high-risk cases

Forecast

• Adults
  Overall survival > 80% with modern therapy in resource-rich countries.
• Children
  Over 90% 5-year survival. 
• Prognostic factors:
  - BL-IPI (Burkitt Lymphoma International Prognostic Index)Considers age, stage, LDH, general condition, extranodal involvement
  - Molecular subgroups - EBV-negative BL with TP53 or ID3 mutations shows a poorer prognosis
  - CNS involvement and high LDH are unfavorable factors

The correct diagnosis requires a integrated approach from Morphology, Immunophenotyping, FISH, and Molecular Genetics, to differentiate Burkitt lymphoma from other aggressive B-cell lymphomas and enable precise therapy.

Primary cutaneous diffuse large B-cell lymphoma, leg type (DLBCL, LT)

The Primary cutaneous diffuse large B-cell lymphoma, leg type (DLBCL, LT) is a aggressive primary cutaneous lymphoma with poor prognosis, which by specific clinical, histological, and molecular biological features is characterized and primarily manifests in the legs.

The diagnosis requires a comprehensive staging diagnostics, and the therapy is based on R-CHOP as default.

The prognosis is moderate despite therapy, which is why early and intensive treatment is crucial.

It differs significantly from indolent forms such as primary cutaneous marginal zone lymphoma (PCMZL) or primary cutaneous follicle center lymphoma (PCFCL) in terms of clinical, histological, and prognostic features.

Clinical features

• Localization
  Typically individually or in groups on one or both legs
• Appearance
  Dark erythematous to livid, hard, indurated tumors, which present as plaques or nodules
• Course
  Aggressive, with faster growth rate and high risk of recurrence
• Systemic symptoms
  In advanced stages, B symptoms (fever, night sweats, weight loss) may occur

Clinical-morphological features

• Histology
  Diffuse infiltrate of large, mature B-cells with nuclear features such as large cell size, large nucleoli, and numerous mitoses. 
• Immunohistochemistrye
  - Positive for CD20, CD79a, CD10 (in part), Bcl-6, MUM1/IRF4
  - Negative for CD5, CD10 (typically), Bcl-2 (typically negative, in contrast to systemic DLBCL) 
• Molecular biology
  Common mutations in Bcl-2, MYD88, MALT-1, Myc, and INK4, promotes cell death resistance and cell cycle dysregulation.
  However, the pathogenesis is not yet fully understood

Differential diagnostics

The differential diagnosis is crucial, as DLBCL, LT can be confused clinically and histologically with other skin tumors or lymphoproliferative disorders:

• Reactive B-cell pseudolymphoma
  Similar histological images, but no clonal immunoglobulin rearrangement, no systemic involvement
• Systemic DLBCL with primary cutaneous involvement
  Must go through Spread diagnostics (CT, PET-CT, bone marrow) can be ruled out
• Other cutaneous lymphomas
  DLBCL, PT must PCFCL, PCMZL and intravascular large B-cell lymphoma to be delimited
• Other malignant skin tumors
  Melanoma, carcinoma, and sarcoma are differentiated by immunohistochemistry (e.g., S100, HMB-45, desmin)

Diagnostic methods

• Biopsy
  Atraumatic, sufficiently large punch biopsy for histological, immunohistochemical, and molecular biological investigations
• Immunohistochemistry
  Proof of CD20, CD79a, Bcl-6, MUM1/IRF4, Exclusion of CD5, CD10
• Molecular biology
  Proof of Clonal immunoglobulin heavy chain rearrangement
• Spread diagnostics
  - Lab chemistry – Blood count, liver and kidney function, LDH
  - Imaging - PET-CT or CT of the thorax, abdomen, and pelvis
  - Bone marrow biopsy - Mandatory for DLBCL, LT due to the aggressive course
  - Lymph node examination Cervical and axillary lymph nodes 

Therapy

• First-line therapy
  R-CHOP scheme (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone)
• alternative
  Other polychemotherapies with rituximab, if applicable Stem cell transplantation in case of relapse or refractory disease
• Local therapy
  In the case of solitary lesions – Radiation therapy or Total excision, but only as Adjunction, not only in DLBCL, LT
• Systemic therapy
  In cases of multiple or disseminated lesions – Intravenous rituximab in combination with chemotherapy

Forecast

• 5-year survival rate
  approx. 55 % – clearly worse than with indolent forms
• Factors with an unfavorable prognosis
  Over 60 years old, high LDH, bone marrow involvement, high tumor stage (T3/T4), absent CD10 expression
• Recurrence rate
  High, 40-50 % of patients suffer relapses
• Follow-up care
  Regular check-ups (e.g., every 3 months in the first 3 years, then every 6 months) with clinical examination, laboratory tests, and imaging as needed

Gray areas/borderline cases

Diffuse large B-cell lymphoma, NOS (DLBCL, NOS) and Burkitt's lymphoma (BL)

The Diffuse large B-cell lymphoma, NOS and Burkitt's lymphoma (BL) are both aggressive B-cell lymphomas with overlapping morphological and immunophenotypic features, making precise differentiation necessary.

The current WHO classification 2022 has clarified differentiation by defining specific genetic markers as crucial for classification. 

Clinical and Morphological Picture

• DLBCL, NOS
  Typically, it shows a diffuse, large-cell infiltration with centroblastic, immunoblastic, or anaplastic cells
  The cells are medium to large, with loose chromatin and prominent nucleoli. Necrosis are often
  The clinical picture includes lymph node involvement, spleen and bone marrow infiltration, as well as B symptoms (fever, night sweats, weight loss).
  Extranodal manifestations are not uncommon
• Burkitt's lymphoma
  Characterized by a extremely high proliferation rate (Ki67 >95 %), an „Starry-sky pattern due to macrophages in the tumor mass and small, homogeneous blasts with little cytoplasm
  It often occurs extranodally (e.g., in the abdominal cavity, bone marrow, CNS) and is associated with a rapid, life-threatening course.

Differential Diagnosis and Methodology

The differentiation is based on a multimodal diagnostics, as there are morphological similarities:

• Cytomorphology & Histology
  The Cytomorphology is the first step.
  BL typically shows small, homogeneous blasts, while DLBCL, NOS shows larger, heterogeneous cells.
  The Bone marrow cytology is essential, as infiltrations can be discordant with lymph node involvement. 
• Immunophenotyping (Immunohistochemistry)
  - DLBCL, NOS
  Positive for CD20, CD19, CD79a, PAX5, CD10 (30–50 %), BCL6 (75–89 %), MUM1/IRF4 (17–42 %)
  BCL2 and MYC are expressed in many cases („double-expresser“ phenotype)
  - Burkitt's lymphoma
  Positive for CD20, CD19, CD79a, PAX5, CD10, BCL6, CD56, LMO2
  BCL2 negative
  MYC highly expressed
  TdT positive in up to 2 % of cases
• Genetic and Molecular Diagnostics
  - FISH (fluorescence in situ hybridization)
  the crucial difference:
  – – DLBCL, NOS
  – – – No MYC-BCL2 rearrangement
  – – – MYC rearrangement alone (up to 14 %) is possible, but no indication of BL
  – – Burkitt's lymphoma
  – – – Typical translocation t(8;14)(q24;q32) → MYC translocation with IGH
  – – – Additionally, a double translocation (t(8;14);t(2;8)) appearance
  - Gene expression analysis (gold standard for COO)
  Is used to determine the Cell of Origin-Subtypes (GCB vs. ABC), however no statutory benefits from health insurance providers
  GCB subtype shows similar genes to germinal center B cells, ABC subtype resembles activated B cells
  - Molecular genetics
  BL shows typical mutations in ID3, CCND3, TP53
  DLBCL, NOS often shows CREBBP, EZH2, KMT2D, TP53 on
• Differentiation of High-Grade B-Cell Lymphomas (HGBL)
  - HGBL with MYC and BCL2 rearrangement („double-hit“)
  Is no longer part of DLBCL, NOS, but rather a separate entity.
  Prognosis unfavorable
  requires intensive therapy
  - HGBL with 11q aberration
  MYC-Rearrangement negative, but 11q23.3 gain and 11q24.1-qter loss
  Morphology and immunophenotype are similar to BL, but BCL2 negative

A experienced hematopathologist and Reference pathology are recommended!

Therapy

• DLBCL, NOS
  Standard therapy is R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone)
  With Recurrence or refractoriness are CAR T-cell therapies (e.g., Axicabtagene ciloleucel) approved
• Burkitt's lymphoma
  Requires intensive, short chemotherapies (e.g.  CODOX-M/IVACas the tumor cells proliferate very rapidly
  Rituximab is integrated (R-CODOX-M/IVAC)
  CNS prophylaxis is mandatory

Forecast

• DLBCL, NOS
  5-year survival rate
  – at 70–80 % (GCB subtype)
  - 40–50 % (ABC subtype)
  Double-Expresser Phenotype (MYC+BCL2) is an unfavorable factor. 
• Burkitt's lymphoma
  With intensive therapy is reached Healing rates of up to 80-90 %, despite an aggressive course. 

Extranodal lymphomas

Hepatosplenic lymphoma (HSTL)

Hepatosplenic T-cell lymphoma (HSTL) is a rare, aggressive form of peripheral T-cell lymphoma (PTCL) characterized by pronounced involvement of the liver and spleen. It usually occurs in adulthood and shows a typical clinical triad of 

• Hepatosplenomegaly
• Cytopenias
• persistent fever

The diagnosis requires differentiation from other diseases with similar clinical and laboratory findings. 

Clinical features

• Clinical picture
  HSTL presents itself with Acute, severe course, often with fever, weight loss, hepatosplenomegaly and multi-organ involvement (e.g. liver dysfunction, haemorrhagic diathesis)
• Cytomorphology
  The lymphoma cells are small to medium-sized, with irregular nuclei and little cytoplasm. They show diffuse infiltration in the bone marrow or spleen
• Immunophenotype
  The cells express pan-T-cell antigens (CD2, CD3, CD5, CD7) and are CD4+ or CD8+, often with double positivity (CD4+/CD8+). A loss of T-cell antigens can occur. The detection of a Clonality through T-cell receptor gene rearrangements (TZR) is helpful

Differential diagnostics

• Primary hemophagocytic lymphohistiocytosis (HLH)
  Fever, hepatosplenomegaly, cytopenias and hyperferritinemia are also found here. Hemophagocytosis in the bone marrow is characteristic of HLH, but not specific. This is usually missing in HSTL. The Diagnostic criteria for HLH (e.g. 5 of 8 criteria) must be fulfilled in order to exclude HLH. 
• Infectious systemic diseases
  Sepsis, viral infections (e.g. EBV, HIV), tuberculosis or other infections can cause similar symptoms. EBV-PCR and EBER-ISH are important for differentiation, as HSTL is not EBV-associated. 
• Other lymphomas with liver and spleen involvement:
  • Diffuse large B-cell lymphoma (DLBCL)
    mostly CD20+, CD10+, BCL6+
    Usually no CD4+/CD8+ phenotype
  • Nodal T-follicular helper cell lymphomas (nTFH lymphomas)
    similar clinical involvement, but with CD10+, BCL6+, PD1+, CXCL13+ and CD4+ Phenotype
    In contrast to HSTL, nTFH lymphoma is often CD8-
  • Anaplastic large cell lymphoma (ALCL)
    Can be CD30+, often with ALK-positive or ALK-negative course
    Less liver and spleen involvement
• Hemophagocytic syndromes in autoimmune diseases
  In the case of Systemic Lupus Erythematosus (SLE) or Juvenile Rheumatoid Arthritis (JRA), a Macrophage activation syndrome (MAS) differentiated by clinical and laboratory criteria. 

Diagnostic methods

• Cytomorphology and immunophenotyping
  Mandatory for identification of the T-cell phenotype
• FISH and molecular genetics
  Detection of TZR rearrangements
  Mutations in TP53, NOTCH2, KLF2
• EBER-ISH
  to exclude EBV-associated lymphomas (e.g. NK/T-cell lymphoma) 
• Biopsy
  Bone marrow, spleen or lymph nodes
  to confirm infiltration and hemophagocytosis if present

Therapy and prognosis

• Therapy
  HSTL is usually associated with immunochemotherapeutic protocols treated, e.g.  CHOP or EPOCH.
  In relapsing or refractory cases, the following are used Stem cell transplants under consideration
• Forecast
  Aggressive course, median survival less than 2 years with inadequate therapy, worse than many other PTCL subtypes

The differential diagnosis of HSTL is crucial, as treatment and prognosis depend on the exact entity. Close collaboration between hematologists, pathologists and immunologists is necessary.

Intravascular large B-cell lymphoma

Intravascular large B-cell lymphoma (IVBZL) is a rare, aggressive form of diffuse large B-cell lymphoma (DLBCL), characterized by a pure intravascular proliferation of malignant B lymphocytes in small and medium-sized blood vessels of various organs, without significant lymph node infiltration or circulating tumor cells. 

Clinical features

• Skin manifestations
  Frequent, blurred, reticular or homogeneous erythema, indurated plaques, subcutaneous nodules (sometimes panniculitic), telangiectasia or petechial foci
  Skin changes are often asymptomatic, but can be painful
• Systemic symptoms (B symptoms)
  Fever, night sweats, weight loss, fatigue - occur in the majority of patients, especially those of Asian origin or with advanced disease
• CNS involvement
  Common in Caucasian patients: subacute encephalopathies, epileptic seizures, neurological deficits, cerebral infarctions, myelopathies, peripheral neuropathies
• Organ infestation
  Bone marrow, spleen, liver (especially in people of Asian descent), lungs, heart - leads to organ-related symptoms (e.g. shortness of breath, heart failure)

Diagnostics

• Histology
  Strictly intravascular, pleomorphic, highly pleomorphic B-cell lymphocytes with round/oval, chromatin-tight cores
  Vessels are dilated, often with thrombi and fibrinous deposits
• Immunohistochemistry
  Positive for CD20, CD79a, CD19, high proliferation rate (Ki-67: 70-80 %).  Negative for endothelial markers (e.g. CD31, CD34)
  No clonal T-cell or NK-cell expression
• Laboratory
  Frequent anemia (80-90 %), increased LDH, increased beta-2-microglobulin, thrombocytopenia (65 %), leukopenia (25 %), increased erythrocyte sedimentation rate (43 %). Liver, kidney and thyroid values pathological at 15-20 %. 
• Imaging
  MRI shows non-specific lesions (e.g. multiple cerebral infarcts), which are often misinterpreted
  PET-CT can be helpful, but no specificity
• Histological confirmation by tissue biopsy of an affected organ (e.g. skin, brain, bone marrow)

Differential diagnostics

• Cutaneous B-cell lymphomas (e.g. primary large B-cell lymphoma of the skin)
• Reactive angioendotheliomatosis (benign, non-clonal proliferation)
• Intravascular T-cell lymphoma (rare, similar morphology, but T-cell phenotype)
• Primary effusion lymphoma
• Kaposi's sarcoma
• Vasculitides (e.g. polyarteritis nodosa)
• Thrombotic microangiopathies (e.g. HUS/TTP)

Therapy and prognosis

• Standard therapy
  R-CHOP protocol (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone), often 6 cycles
• Additive therapies
  With CNS involvement: CNS prophylaxis (e.g. methotrexate intrathecal), possibly Rituximab intensive therapy or Autologous stem cell transplantation on response
• Forecast
  Unfavorable, especially in the case of CNS or multi-organ infestation
  Early diagnosis and treatment improve the survival rate
  The 5-year survival rate is around 30-50 %, depending on the severity of the infection and response to treatment

NoticeThe disease is extremely rare and often difficult to diagnose. The differential diagnosis must be made carefully, as the clinical and radiological findings are non-specific. A multidisciplinary team (dermatology, hematology, neurology, pathology) is crucial for a correct diagnosis and therapy.

Primary effusion lymphoma (PEL)

Primary effusion lymphoma (PEL) is a rare, aggressive type of B-cell lymphoma that typically manifests as lymphomatous effusions in body cavities (pleura, peritoneum, pericardium) without forming a recognizable tumorous mass.
It is invariable with human herpesvirus 8 (HHV-8, also KSHV) and occurs almost exclusively in immunocompromised patients, especially in HIV-positive people with advanced AIDS.
The disease shows a Plasmablastic differentiation with expression of markers such as CD38, CD138, MUM1/IRF4 and LANA-1 (latent-associated nuclear antigen-1), but lacking expression of pan-B-cell markers such as CD19, CD20 and CD79a. 

Differential diagnostics

• Diffuse large B-cell lymphoma (DLBCL)
  May also be associated with effusions, but differs by the lack of HHV-8 association and the expression of B-cell markers
  DLBCL often shows c-myc gene rearrangements that are absent in PEL
• Burkitt's lymphoma
  Can rarely occur with effusions, but is characterized by a MYC rearrangement and typically shows a small-cell, homogeneous cytomorphology.
  MYC rearrangement is common in HHV-8-negative PEL cases with Burkitt-like morphology
• Anaplastic large cell lymphoma (ALCL)
  May be associated with effusions, but is characterized by the expression of CD30 and ALK (in ALK-positive ALCL)
  PEL is typically ALK-negative and shows plasmablastic differentiation
• Pyothorax-associated lymphoma (BAL)
  Develops in chronic pleural periods, usually in patients with pre-existing inflammation
  It is not associated with HHV-8, often shows B-cell phenotyping and occurs in a different clinical context
• HHV-8-negative, PEL-like lymphomas (type II PEL)
  A rare subgroup without HHV-8 infection that occurs in older, immunocompetent patients with underlying diseases (e.g. liver cirrhosis, kidney failure, heart failure)
  These cases show a B-cell phenotyping (CD19, CD20 positive), Frequent MYC rearrangements and a Better prognosis as classic PEL

Clinical and immunophenotypic differentiation

Feature	Classic PEL (Type I)	HHV-8-negative PEL-like lymphomas (type II)
HHV-8	Positive (obligatory)	Negative
HIV status	Mostly positive (advanced AIDS)	Mostly negative, older patients
Immunosuppression	Strongly pronounced	Rare, often due to age-related weakness (immunosenescence)
Cell morphology	Plasmablastic, immunoblastic	Plasmablastic, immunoblastic, also Burkitt-like
B-cell marker	Negative (CD19, CD20, CD79a)	Positive (CD19, CD20, CD79a)
Plasma cell markers	Positive (CD38, CD138, MUM1)	Negative
MYC rearrangement	Rare (3%)	Frequent (29%)
EBV association	High (65-80%)	Low (13-30%)
Forecast	Very poor (median survival <6 months)	Better (1-year survival rate 47%)

The Diagnosis from PEL sets the Detectability of HHV-8 (via LANA-1 immunohistochemistry) ahead.

If HHV-8-negative effusion lymphomas are suspected, a differentiated analysis of cytomorphology, immunophenotyping, genotyping (MYC, BCL2, BCL6) and clinical background is crucial.

A multidisciplinary approach combining cytology, flow cytometry, molecular biology and immunohistochemistry methods is necessary to correctly differentiate PEL and its differential diagnoses.

HHV8-associated lymphoma

HHV-8-associated lymphoma is a rare neoplasia caused by the human herpesvirus 8 (HHV-8), which mainly occurs in HIV-infected patients. It belongs to a group of lymphoproliferative diseases associated with HHV-8, including the primary effusion lymphoma (PEL)which multicentric Castleman's disease (MCD) and that MCD-associated plasmoblastic lymphoma. 

Differential diagnostics

The differential presentation of HHV-8-associated lymphoma includes the following diseases:

• Primary effusion lymphoma (PEL)
  Characterized by fluid-filled cavities (pleural, peritoneal or pericardial effusions) with plasmablastic cells that are HHV-8-positive and EBV-positive
  It usually occurs in HIV-positive patients and shows no typical lymph node involvement
• Multicentric Castleman's disease (MCD)
  A systemic disease with multiple lymph node enlargement, accompanied by fever, weight loss, hepato- and splenomegaly and elevated cytokines such as IL-6
  In HHV-8-associated MCD, the virus is detectable in the plasma cells and there is a close association with HIV infection
• MCD-associated plasmoblastic lymphoma
  A highly malignant, plasmablastic lymphoma that often occurs in the liver, abdomen or lymph nodes
  It shows HHV-8 positivity in the tumor cells and may be related to a PEL 

Clinical and histological features

• Cytology
  Plasmablasts with large, irregular nuclei, prominent nucleoli and basophilic cytoplasmata
• Immunohistochemistry
  Positive for CD45, CD79a, CD138, MUM1, λ or κ chains, but negative for CD20 and CD30
• Virus detection
  HHV-8 by in situ hybridization (EBER) and detection of the viral interleukin (vIL-6) in tumor cells

Differential diagnosis to other lymphomas

• Non-Hodgkin's lymphoma (NHL)
  Especially plasmablastic lymphomas without HHV-8 association
• Kaposi's sarcoma
  Also HHV-8-associated, but histologically characterized by spindle cells and vascular proliferation
• Reactive lymphadenopathies
  In infectious or autoimmune diseases, which can also cause lymph node enlargement and cytokine release

Differential diagnosis requires a combination of clinical findings, histological analysis and molecular biological detection of HHV-8.

T-cell and NK-cell lymphomas

Peripheral T-cell lymphoma (PTCL-NOS)

Peripheral T-cell lymphomas (PTCL-NOS) are a heterogeneous group of rare, mostly aggressive T-cell lymphomas that arise from the umbrella term „PTCL“ when no specific subtyping is possible.

The diagnosis of PTCL-NOS requires a multimodal diagnostics (Histology, IHC, Gene analysis). The differential diagnosis is complex, especially against AITL and ALCL.

The prognosis is poor, but survival varies significantly by molecular subgroup. Therapy should be administered whenever possible in clinical studies take place.

Clinical-morphological features

• Clinical symptoms
  Common manifestations include painless lymph node enlargement, B symptoms (fever, night sweats, weight loss), Hepatosplenomegaly and extranodal lesions (e.g., skin, gastrointestinal tract).
  One polyclonal hypergammaglobulinemia or Coombs-positive hemolytic anemia can occur in AITL-like courses. 
• Morphology
  Histologically, PTCL-NOS show variable architecture:
  - Pattern 1 (partial paracortical infiltration around hyperplastic germinal centers)
  - Pattern 2 (extensive paracortical infiltration around regressive germinal centers)
  - Pattern 3 (completely abrogated architecture). An epithelioid cell-rich, histiocyte-rich infiltration requires differential diagnosis against granulomatous disease or Lennert's lymphoma. 

Differential diagnostics

The Differential diagnosis from other lymphomas is crucial:

• Angioimmunoblastic T-cell lymphoma (AITL)
  PTCL-NOS can be AITL-like. Differentiation by immunohistochemical markers (CD10, PD-1, BCL6, CXCL13) and Gene expression analysis
  AITL typically shows strong expression of TFH markers and clonal T-cell receptor gene rearrangement
• ALK-negative large cell anaplastic lymphoma (ALCL)
  Characterized by strong, uniform CD30 expression, cytotoxic immunophenotype (CD8+, granzyme B+, TIA-1+) and T-cell receptor gene rearrangement
  The t(2;5)(p23;q35)Translocation with an NPM-ALK fusion gene is typical in ALCL, not in PTCL-NOS
• Reactive lymph node changes
  Kikuchi's lymphadenitis (speckled necrosis, lack of clonality) or chronic inflammation can mimic PTCL-NOS
  Clonality detection (TCR gene rearrangement PCR) is crucial
• Nodal peripheral T-cell lymphomas with T-follicular helper phenotype
  A newly defined entity (WHO 2017) that previously belonged to PTCL-NOS
  She has a CD4+/BCL6+/PD-1+-Expression and Mutations in TET2, IDH2, DNMT3A on.

Diagnostic methods

• Immunohistochemistry (IHC)
  – Key markers are CD3, CD4, CD5, CD2, CD7 (often reduced).
  - CD30 Expression is heterogeneous (CD30+ vs. CD30−), where CD30+ shows a better prognosis and similarity to ALCL
• Gene expression analysis
  Distinction into two main groups:
  - GATA3 group low 5-year survival: 19 %)
  - TBX21 group higher 5-year survival: 38 %)
• Molecular genetics
  - Mutations in epigenetic regulators (TET2, DNMT3A, IDH2, MLL2, KDM6A) in ca. 25 %
  - t(5;9)(q33;q22) with ITK/SYK fusion gene (approx. 10 %)
  - VAV1 fusion products (11 %)
• Microarray technology
  Differentiation of AITL, ALCL, and PTCL-NOS with up to 98 % accuracy

Therapy

• Primary therapy
  - CHOP or CHOP-like anthracycline-based chemotherapy is standard.
  Brentuximab Vedotin (anti-CD30) is used in CD30+ PTCL-NOS, and response has also been observed in CD30-negative cases
• Consolidation
  With good response to induction therapy
  autologous stem cell transplantation (auto-SCT)
• Recurrent/refractory
  Allogeneic stem cell transplantation (allo-SCT), Romidepsin, Belinostat, Pralatrexate
• Targeted therapies
  – Hypomethylating agents (e.g., azacitidine) in TET2 mutations
  - JAK/STAT inhibitors in STAT3-activating mutations

Forecast

• Median overall survival
  10.5 months for PTL-NOS-CD30−
  19-38 % 5-year survival rate depending on the gene signature (GATA3 vs. TBX21)
• Prognostic factors
  CD30 Expression, Transcription factor signature (GATA3/TBX21), Age group, Disease stage, Recurrence status
• Therapy claim
  Primarily curative, but no therapeutic breakthrough for years.
  Clinical studies are recommended.

Angioimmunoblastic T-cell lymphoma (AITL)

The Angioimmunoblastic T-cell lymphoma (AITL) is a rare, aggressive peripheral T-cell lymphoma that originates from follicular T helper cells (TFH) goes out and about 1–2 % of Non-Hodgkin lymphoma It primarily affects older patients in their 6th to 7th decade of life and is characterized by a complex, often unspecific clinical presentation. 

Clinical features and morphological signs

• Common Symptoms
  - B symptomsFever, night sweats, weight loss, fatigue
  - Generalized lymphadenopathy (Neck, armpit, groin)
  - Hepatosplenomegaly
  - Anemia, Thrombocytopenia, Lymphopenia
  - Polyclonal hypergammaglobulinemia and Hypereosinophilia (in 30-40 %)
  - Payment (e.g., facial edema, ascites, pulmonary edema)
  - Arthralgia, Susceptibility to infection, neurological disorders (e.g., polyneuropathy)
• Skin manifestations (in up to 50 % of patients)
  - Maculopapular rash (frequent first symptoms)
  - itching Itching
  - Macular and nodular rash with „deck chair sign“ (excision of skin folds)
  - Nodular or plaque-like lesions, which to Mycosis fungoides can remember
  - RareAssociation with Linear IgA dermatosis 

Differential diagnosis

The AITL is often mistakenly referred to as infectious or drug-induced disease diagnosed, as the symptoms heavily overlap:

• DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms)
  – Similar symptoms: fever, rash, lymphadenopathy, eosinophilia, hypergammaglobulinemia
  – Distinction by Medical History (Medication Use), Negative EBV detection in serum, missing clonal T cell proliferation
  - AITL: EBV-positive, clonal T-cell genome alteration
• Infectious diseases
  - Viruses – EBV, HIV, HCV, HHV-6, Hantaviruses
  - bacteria - Klebsiella pneumoniae, Mycoplasma, Borrelia
  - Parasites Leishmania
  - Differential - PCR, serology, blood cultures, clinical context analysis 
• Other lymphomas
  - Peripheral T-cell lymphomas, NOS (not otherwise classified)
  - Mycosis fungoides (continuous skin infiltration, CD4+/CD8- phenotype)
  - Classical Hodgkin's lymphoma Reed-Sternberg cells, CD15+/CD30+
  - Lennert's Lymphoma (Epithelioid cell infiltrate, strong histiocytic pattern) 
• Autoimmune diseases
  - Stiff-person syndrome, SLE, Sjögren's Syndrome
  - Differential – Autoantibodies (ANA, ENA), clinical criteria

Diagnostic Methodology

1. Clinical examination
   – Palpation of lymph nodes, liver, spleen
   – Assessment of skin lesions, edema, enanthems 
2. Laboratory tests
   - Blood count Anemia, thrombocytopenia, lymphopenia, hypereosinophilia
   - Inflammation markers – CRP increased, ESR increased
   - Functional testing – LDH ↑, Beta-2-Microglobulin ↑
   - Electrophoresis Hypergammaglobulinemia
   - PCR – EBV-DNA in serum (positive in 80–90 % of cases)
3. Imaging
   - Ultrasound/CT/MRIEnlarged lymph nodes (multiloculated), hepato-/splenomegaly, ascites
4. Biopsy
   - Lymph node biopsy (not peripheral blood or bone marrow biopsy)
   - Pathohistology
   – Disrupted architecture, polymorphous infiltrate of lymphocytes, histiocytes, eosinophils, plasma cells
   – – Proliferated, branched venules
   – – Perivascular and paracortical infiltrates
   – – EBV-positive B-immunoblasts (not in T-cells)
   – – Reed-Sternberg-like cells possible
5. Immunohistochemistry
   - Positive – CD3, CD4, CD5, CD10, PD-1, ICOS, BCL6, CXCL13, CD20 (in B cells)
   - NegativeCD8, CD30 (not in typical Hodgkin cells)
   - CXCL13 and CD10 – highest specificity for AITL 
6. Flow cytometry
   - sCD3–/CD4+ T cells in peripheral blood: high positive predictive value 
7. Molecular biology
   - Clonal T-cell receptor gene arrangement (70–90 %)
   - Mutations: RHOA (G17V), TET2, IDH2, DNMT3A
   - CTLA4-/CD28-Fusion in 50 % der Fälle 

Therapy

• First line
  - Anthracycline-based chemotherapy
  – – CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone)
  – – R-CHOP (with Rituximab)
  – – CHOP (with Etoposide)
  – – Addition of Pegfilgrastim for granulocyte prophylaxis
• Second-line – High-risk / Relapsed
  - Stem cell transplantation (autologous or allogeneic) after remission
  - New Drugs in Clinical Trials
  – – Brentuximab vedotin (CD30-targeted)
  – – Brentuximab vedotin (CD30-targeted)
  – – Lenalidomide (immunomodulatory)
• Palliative therapy for insufficient response
  - Glucocorticoids Prednisone 80–100 mg/day, decreasing
  - CytostaticsChlorambucil, Cyclophosphamide
  - ImmunomodulatorsCyclosporine

Forecast

The forecast of Angioimmunoblastic T-cell lymphoma (AITL) is overall unfavorable, with a 5-year survival rate of about 30-32 % and one Median survival time of 18–29 months. 

Several prognostic scores are used for risk stratification:

• International Prognostic Index (IPI)
  Unfavorable factors:
  – Over 60 years old
  – ECOG Performance Status ≥ 2
  – Elevated LDH
  – Ann-Arbor-Stadium ≥ III
  1 extranodal spread
• Prognostic Index for T-cell Lymphoma (PIT)
  Taking into account:
  – Over 60 years old
  – ECOG Performance Status ≥ 2
  – Elevated LDH
  - Bone marrow involvement
• Modified PIT (mPIT)
  – Replaces bone marrow infiltration by Ki-67 Proliferation Index > 75 %

When applying the PIT Scores Here are the 5-year survival rates for PTCL (including AITL):

• Low risk: 75 %
• Low-intermediate risk: 30 %
• High-intermediate risk: 15 %
• High risk: 0 % 

A highly unfavorable outcome will be Stage IVB, Bone marrow infiltration (as in the case study with 10 %) and Lack of remission after initial therapy expected.

Cutaneous T-cell lymphoma

The Follicular T-cell lymphoma (FTCL) is the same entity and is also known by these synonyms PTFCL, F-PTCL, nTFHL managed, a very rare, aggressively progressing T-cell lymphoma type that originates from follicular T helper cells (TFH) derived and listed as a distinct entity in the current WHO classification (2017). Previously assigned to the PTCL-NOS group.

Follicular lymphoma is a tumor with characteristic TFH phenotype, which through Differential diagnosis of AITL, Hodgkin lymphoma, and follicular B-cell lymphoma must be delimited.
The diagnosis requires careful histological and immunohistochemical evaluation.

Therapy is Symptomatic and empirical, Forecast unfavorable.

Clinical-morphological features

• Age and gender
  Primarily affected are Middle-aged to older adults (33–88 years), with a slight preference for men
• Clinical presentation
  Resembles the Angioimmunoblastic T-cell lymphoma (AITL)
  Common symptoms include generalized lymphadenopathy, splenomegaly, B symptoms (fever, night sweats, weight loss) and Skin lesions in about one-third of patients
  These are not typical for MF (no scaly, firm papules/plaques)
• Histology
  The lymph nodes show a Nodular/follicular proliferation of medium-sized, monomorphic lymphoid cells with partial or complete infiltration of the lymph follicles
  The The mantle zone is reduced or missing.
  In contrast to reactive changes and B-cell lymphomas (e.g., follicular lymphoma), the Differentiation difficult without immunohistochemistry
• Immunophenotype
  Neoplastic cells express T-cell antigens (CD2, CD3, CD5), are CD4+, CD8–, show CD7 Deficiency and one characteristic TFH phenotype with expression of PD-1, CXCL13, BCL6, CD10, and ICOS
  CD20-positive immunoblasts are often EBV-positive and can even Hodgkin/Reed-Sternberg-like cells form

Differential diagnosis and methodology

• Key differential diagnoses
  - Angioimmunoblastic T-cell lymphoma (AITL)
  Similar clinical symptoms and TFH phenotype, but FTCL lacks typical AITL features such as vascular proliferates, FD cells, and inflammatory background
  - Hodgkin lymphoma (classic)
  EBV-positive, CD30+/CD15+ cells can exhibit the phenotype of Hodgkin cells. Differentiation by Immunophenotype and cell morphology
  - Follicular lymphoma (FL)
  Similar morphological pattern (follicular growth), but FL is a B-cell lymphoma with CD20+, CD5–, BCL6+, and BCL2+ Cells
  CD4+ TFH phenotype in FTCL is critical
  - Marginal zone lymphoma or nodular lymphocyte-predominant Hodgkin lymphoma
  Differentiation through Immunophenotyping and molecular analyses
• Diagnostics
  - Lymph node biopsy with pronounced histological and immunohistochemical evaluation by an experienced pathologist
  - Immunohistochemistry Proof of CD4, PD-1, CXCL13, BCL6, CD10, ICOS and Absence of CD7
  - Molecular biology - t(5;9)(q33;q22)-Translocation (ITK-SYK-fusion gene) approximately 20 % of the cases.
  Mutations in RHOA, TET2, IDH2, DNMT3A are also described
  - Clonality analysis – Demonstration of a clonal T-cell receptor genome

Therapy

• No established standard therapy due to low case numbers
• First-line therapy
  CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone)
  or Cheops
• Second-line therapy
  In appropriate patients autologous or allogeneic stem cell transplantation. 
• Clinical studies
  Testing new therapies (e.g. immunotherapeutic approaches, Targeted therapies). 

Forecast

• Aggressive clinical course with poor prognosis. 
• Approximately 50 % of patients die within the first 24 months after diagnosis.. 
• The Survival rate is significantly worse as with most other PTCL subtypes.

Hepatosplenic T-cell lymphoma (γδ-type)

Hepatosplenic T-cell lymphoma (HSTCL) is a very rare, clinically aggressive, systemic T-NHL (<1% of non-Hodgkin lymphomas), which mostly originates from γδ T cells descends.

It is characterized by a exclusive involvement of spleen, liver, and bone marrow as, where Lymphadenopathy or leukemic infiltration are usually absent.

The disease occurs primarily in Adolescent to young adult age at (average age: 38 years), men are significantly more affected. A significant proportion of cases is associated with chronic immunosuppression associated. 

Clinical and clinicomorphological characteristics

Patients typically present with B-symptoms (fever, night sweats, weight loss), hepatosplenomegaly, and pancytopenia, that can be reminiscent of acute leukemia.
A Hemophagocytic syndrome also occurs.

• Laboratory
  - elevated lactate dehydrogenase (71.4 %
  - Liver dysfunction (42.9 %
  - reduced fibrinogen (35.7 %)
• Histology
  Morphologically, the lymphoma shows a Sinusoidal, monomorphic infiltrate of medium-sized cells with pale cytoplasm.
• Immunophenotype
  The immune phenotype is characteristic: CD3+, CD5-, CD8-, CD4-, CD56+, TCR γδ+, Granzyme B+, mostly TCR αβ negative
• Molecular biology
  Genetically Isochromosome 7q and trisomy 8 the most common chromosomal aberrations
  Mutations in STAT3/STAT5B (JAK-STAT signaling pathway) and SETD2, IN080, ARID1 (Chromatin modification) are frequent and potentially therapeutically relevant 

Differential diagnosis and methodology

The differential diagnosis includes:

• Acute leukemia (especially in pancytopenia and leukocytosis in peripheral blood) 
• Other T-cell lymphomas (e.g. T-cell prolymphocytic leukemia (T-PLL), Angioimmunoblastic T-cell lymphoma (AITL), NK/T-cell lymphoma)
• Hemophagocytic Lymphohistiocytosis can be triggered by infectious, autoimmune, or malignant causes
• Other extranodal lymphomas with liver/spleen involvement

For a safe diagnosis, obligated The following methods are required:

• Cytomorphology (peripheral blood, bone marrow, spleen biopsy)
• Immunophenotyping (Flow cytometry) with detection of the γδ T cell phenotype
• Chromosome analysis and FISH for the detection of 7q and trisomy 8
• Molecular genetics (PCR for TCR gene rearrangements, sequencing for mutation detection in STAT3, SETD2, etc.)

Therapy

There are no uniform treatment standard. Currently, the Allogene hematopoietic stem cell transplantation (HSCT) the only approach with proven clinical efficacy and is used in first-line treated patients with remission Recommended for consolidation.

Chemotherapies (e.g. CHOP, EPOCH) show limited success, and recurrences are common.  

Forecast

The The prognosis is poor
– The median survival time is under three years
the 5-year survival rate is less than 20 %

The The disease is associated with a high risk of recurrence. and low therapeutic response connected. 

NoticeThe diagnosis requires an interdisciplinary work-up by oncologists, hematologists, and pathologists. Current data is limited as HSTCL is a very rare disease.

Enteropathy-associated T-cell lymphoma (EATL)

The Enteropathy-associated T-cell lymphoma (EATL) is an aggressive non-Hodgkin lymphoma of the gastrointestinal tract that develops from intestinal intraepithelial cytotoxic T-cells.

The current WHO classification (2017) uses the term EAT exclusively for the EATL Type 1, associated with gluten-sensitive enteropathy (celiac disease).

The gamma-delta type is a rare but clinically relevant subtype characterized by a $\gamma\delta$ T-cell phenotype and requires special attention in the differential diagnosis.

Clinical picture

• Most common infestationSmall intestine (especially jejunum), mesentery; rarer localizations in the gastrointestinal tract. 
• Clinical symptomsAbdominal pain (most common symptom), steatorrhea, weight loss, malabsorption, gastrointestinal bleeding, anemia, B symptoms, intestinal obstruction, or intestinal perforation.

Morphological characteristics

• EATL Type 1 (Classic)Associated with celiac disease; CD56-negative, CD8+, CD56-negative; clonal T-cell proliferation with cytotoxic morphology
• EATL-Type 2 (new nomenclature: Monomorphic epitheliotropic intestinal T-cell lymphoma, MEITL): CD56-positive, no association with celiac disease, more common in older patients, aggressive course
• gamma delta T cell subtypeRare, characterized by Gamma Delta T Cell Receptor Expression, CD3+, CD56+, CD4, CD8–; often with pronounced epitheliotropism and distinct morphology. The differentiation of Indolent T-cell lymphoproliferations (e.g., indolent T-cell lymphoproliferative disorder of the gastrointestinal tract) is crucial, as this can benign, slow-progressing disease with low proliferation rate (10–15%) and superficial infiltrate represent.

Differential diagnostics

• Refractory Celiac Disease (RCD) Type IIClonal intraepithelial T lymphocytes with aberrant phenotype (e.g., CD8–, CD56+, TCRγδ+), high transformation rate into EATL
• Indolent T-cell lymphoproliferations of the gastrointestinal tractSuperficial, non-destructive infiltrate, low proliferation rate, no massive tumorous process, mixed cytology, persistent lesions without progression
• Indolent NK-cell enteropathy/gastropathyCD3+, CD56+, CD4–, CD8–, atypical medium-sized cells, no T-cell genre arrangements
• Extranodal NK/T-cell lymphomasAssociated with Epstein-Barr virus (EBV), not with celiac disease, CD56+, TIA1+, granzyme B+, EBV-LMP1+
• Gastrointestinal lymphomas of other genesisB-cell lymphomas (e.g., diffuse large B-cell lymphoma), follicular lymphoma, marginal zone lymphoma

Diagnostic Methodology

• Endoscopy with small bowel biopsy
  Macroscopic: multiple ulcers, perforations possible
• Histology
  Proof of T-cell clonality (PCR for TCR genre arrangements), 
  immunohistochemical profiles (CD3, CD4, CD8, CD56, TCRαβ/γδ, CD57, granzyme B)
• Molecular biology
  proof recurrent mutations in the JAK/STAT signaling pathway (e.g. STAT3, JAK1),
  chromosomal gains (9q33-q34).
• DUSP22-Rearrangements
  Rare in EATL, can occur in cutaneous CD30+ lymphoproliferations, broaden the differential diagnosis. 

Therapy

• Consistent gluten-free diet
  Prophylaxis, can prevent development. 
• Chemotherapy
  CHOP scheme (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone), possibly with Etoposide in patients < 60 years old
• Autologous stem cell transplantation
  Option for younger patients with relapsed or refractory disease
• Corticosteroids
  For refractory celiac disease symptoms
• Watch & Wait Strategy
  Only in indolent lymphoproliferative disorders, not in EATL. 

Forecast

• Aggressive course, high metastatic rate (liver, spleen, skin)
• Bowel perforation as a typical complication
• Median survival time from diagnosis 10 months
• Prognostic factors
  Age, Stadium, clonal T-cell proliferation, mutations in the JAK/STAT pathway, CD56 status, therapy response. 

SummaryThe differential diagnosis of gamma delta T-cell enteropathy-associated T-cell lymphoma requires a close combination of clinical, endoscopic, histological, and molecular biological analysis.

The Exclusion diagnosis of indolent lymphoproliferative disorders is crucial to avoid excessive, harmful chemotherapy.

The therapy is aggressive, the prognosis is poor, early diagnosis and treatment are vital.

Anaplastic large cell lymphoma (ALCL)

The Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, CD30-positive Non-Hodgkin Lymphoma, which primarily originates from T-cells and is found frequently in Childhood and early adulthood performance.

It is divided into two main groups: ALK-positive (ALK+ ALCL) and ALK-negative (ALK– ALCL), whereby ALK expression causes crucial clinical-pathological and prognostic differences. 

Clinical picture

• Systemic ALCL
  Typically wears B symptoms (Fever, night sweats, weight loss), mostly in advanced stages (III/IV)
  Common extranodal infiltrates affect the skin, liver, lungs, soft tissues, bones, and bone marrow (approx. 15 %).
• Primary cutaneous ALCL (cALCL)
  It mostly occurs in older men and presents as solitary, ulcerated skin tumors with cheaper forecast (10-year survival rate >90 %)
  Unlike systemic ALCL, cALCL ALK-negative and EMA-negative
• Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL)
  A rare but documented form that occurs years to decades after implantation in the serous cavity (e.g., around breast implants) manifests
  Clinically as serous exudate with lymphocytic infiltration. Mostly ALK-negative, CD30-positive, EMA negative

Morphology

• Characteristic are „Hallmark Cells“, large, anaplastic cells with eccentrically located, horseshoe-shaped nuclei and perinuclear eosinophilic halo.
• Morphological Variants common, lymphohistiocytic, Hodgkin-like, small cell (often misdiagnosed) and Combination types

Differential diagnostics

The diagnosis is based on a combination of morphological, immunohistochemical, and molecular biological analysis:

• Immunohistochemistry (IHC)
  - positiveCD30 (constant), CD2, CD3, CD5, CD7, CD45RO, Granzyme B, Perforin, TIA-1, EMA (only in ALK+).
  - ALK Expression – Core-positive in ALK+ ALCL; central differentiation from ALK– ALCL
• Molecular biology
  - FISH and PCRProof of t(2;5)(p23;q35)-Translocation (NPM-ALK) in ALK+ ALCL
  - Next-generation sequencingIdentifies prognostically relevant rearrangements
  – – DUSP22/IRF4 Rearrangement → better prognosis
  – – TP63 Rearrangement worse prognosis
• Differential diagnoses
  - Hodgkin's lymphomaCD30+ and CD15+; but CD20+, CD30- in Reed-Sternberg cells, ALK-negative.
  - Anaplastic large cell lymphoma (ALCL)CD20+ (compared to CD30+ in ALCL), CD30-, ALK-negative
  - Primary cutaneous CD30-positive lymphomas
  – – ALK-negative, EMA-negative, More favorable forecast
  - Angioimmunoblastic T-cell lymphoma (AITL)
  – – T-follicle helper phenotype, TET2/RHOA/IDH2 mutations, Coombs-positive, Polyclonal hypergammaglobulinemia

Therapy

• Systemic ALCL (ALK+)
  - default: CHOP therapy (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone)
  - Combination with Brentuximab Vedotin (BV): high response rate (86 %), improved Disease-free and overall survival (ECHELON-2 Study)
• ALK-ALCL
  – Less sensitive to CHOP; BV combination is a central therapeutic option
  New approaches:
  - 5-Azacytidine Demethylation
  - CAR-T cells against CD30
• BIA-ALCL
  - Implant and capsule removal; chemotherapy aftercare during spread (e.g., CHOP + BV)

Forecast

• ALK+ ALCL
  Inexpensive – 5-year survival rate 70–90 %
• ALK-ALCL
  Unfavorable – 5-year survival rate 40-60 %
• CALCL
  Very good – 10-year survival rate >90% %
• BIA-ALCL
  Inexpensive, if detected and treated early (implant removal)

The molecular subclassification (ALK, DUSP22, TP63) is crucial for prognosis and treatment planning.

Mycosis fungoides

Mycosis fungoides is the most common primary cutaneous T-cell lymphoma, a form of non-Hodgkin lymphoma that primarily affects the skin.

It is characterized by clonal proliferation of atypical T-lymphocytes in the skin and belongs to the cutaneous T-cell lymphomas, which account for approximately 70 % of all primary cutaneous lymphomas. 

Clinical picture and clinical-morphological features

The illness typically progresses through three stages:

• Eczema stage
  Chronic, itchy, sharply demarcated, erythematous-scaling patches that can persist for years to decades
• Infiltration stadium
  Ingrowth of brownish, raised plaques into existing lesions, often with preserved areas of healthy skin 
• Tumor stage
  Training of hemispherical, ulcerating tumors that tend to superinfection and can lead to a generalization process with lymph node and organ involvement (liver, spleen, lungs, CNS). 

Variations:

• Folliculotropic Mycosis Fungoides (FMF)
  Characterized by follicularly prominent, cone-shaped, skin-colored horny papules, often with alopecia (e.g., eyebrows, hairline), acne-like lesions, and cysts in the facial and neck area. The epidermis usually remains unaffected („smooth surface epidermis“).
• Pagetoid reticulosis
  Localized, demarcated lesions with marked intraepidermal proliferation of neoplastic T-cells, mostly on the extremities.
• Granulomatous lax skin (GLS)
  Rare form with flaccid, dangling skin in the large skin folds, accompanied by granulomatous tissue changes and loss of elastic fibers. Poorer prognosis than classic MF.
• Hypopigmented mycosis fungoidesPoikilodermatous variant with good prognosis. 

Differential diagnosis and methodology

The diagnosis is challenging, as the clinical picture is often atypical and the average duration between initial manifestation and diagnosis is 3–4 years. Crucial is the histopathologic evidence:

• Characteristic histological features
  Bandlike lymphocytic infiltrate in the upper dermis and Pautrier microabscesses in the epidermis
• Immunohistology
  CD3+, CD4+, CD8–, CD45Ro+, CD45Ra– (memory T helper phenotype). CD30 may be positive in advanced stages
• Molecular biology
  Clonal T-cell receptor gene rearrangement (may be absent in early lesions)
• Imaging
  CT, MRI, PET-CT for staging (especially for suspected extracutaneous involvement)

Differential diagnoses:

• Sézary syndrome
  Erythroderma (>80% % body surface area), lymphadenopathy, Sézary cells in peripheral blood.
• Urticaria pigmentosa
  Gray-brown spots with urticarial reaction (missing in MF)
• Ringworm
  Edema, desquamation, mycological culture
• Other cutaneous T-cell lymphomas
  No staged progression, mostly primary nodule formation
• Primary cutaneous B-cell lymphomas
  The phased progression is also missing here; histologically proven

Therapy

The therapy is guided by the stage of the disease:

• Early stage (patches/plaques)
  Local therapy with PUVA, Narrowband UVB, Glucocorticoid external or Aggressive topical radiotherapy (especially with FMF)
• Advanced stage
  Combination of PUVA + Retinoids (e.g., Acitretin >10 mg/day), Interferon-α, local radiation therapy (3–5 Gy). 
• Stage IIb and beyond
  Chemotherapy (CHOP, Doxorubicin, Gemcitabine)
  experimental: Allogene stem cell transplant
• Palliative therapy in tumor stage
  Chlorambucil or polychemotherapy

Forecast

• Early stage
  Good prognosis, remission possible, average life expectancy 7–10 years after diagnosis
• Advanced stage
  Prognosis significantly worse; 5-year survival rate for stage IIA FMF: 87 %, for IIb: 83 %
• GSS*
  5-year survival rate about 60 %
  *Granulomatous Slack Skin – a very rare variant of mycosis fungoides (MF), which is classified as a primary cutaneous T-cell lymphoma
• Transformation into large cell lymphoma (approx. 25 % of cases)
  Significantly worsens the prognosis

Prognostic factors
Stage at diagnosis, extent of skin involvement, lymph node involvement, extracutaneous manifestations.

Early and aggressive therapy improves quality of life and slows disease progression.

Sézary syndrome

The Sézary Syndrome (SS) is an aggressive form of primary cutaneous T-cell lymphoma (CTCL) and is characterized by the classic Triad of erythroderma, generalized lymphadenopathy, and circulating atypical T lymphocytes (Sézary cells) in the peripheral blood.

It represents the leukemic variant of cutaneous T-cell lymphomas and typically occurs in the fifth decade of life, more commonly in men. The disease progresses more rapidly than mycosis fungoides and has an unfavorable prognosis. 

Clinical picture

• Skin manifestations: Include a scaling, generalized erythroderma with severe itching (pruritus), often accompanied by Alopecia hair loss, Nail malformations (onychodystrophy), Palmoplantar hyperkeratosis and Ectropion (Eyelid displacement). The skin can Lion face (lion-like face). 
• Systemic symptomsCommon complaints include general fatigue, feeling cold, and shivering. Other signs are Hepatosplenomegaly and lymph node enlargement. 

Morphology

Morphological features of Sézary cells
Characterized by cerebriform (convoluted) nuclei, are typically CD4-positive, CD7-negative, and CD26-negative.

The circulating cells are detected in the blood, with a Count of ≥1000 Sézary cells/mm³ is considered diagnostic. 

Differential diagnostics

The differential diagnosis of Sézary syndrome is crucial, as it can be confused with other conditions clinically and histologically.
Important differential diagnoses:

• Mycosis fungoides (most common form of CTCL)
  The distinction is made primarily by Blood involvement (in late stages, not in early MF stages)
• Inflammatory dermatoses
  - Atopic Dermatitis (Eczema),
  - Psoriasis
  - Pityriasis rubra pilaris
• Other cutaneous lymphomas
  Other primary CTCL subtypes such as folliculotropic MF, pagetoid reticulosis. 
• Medication side effects and systemic diseases with erythrodermic manifestations

Diagnostic Methodology

• Clinical examination with a focus on skin changes, lymph nodes, and blood count.
• Histopathology of skin biopsy
  often shows a non-specific „pseudo-dermatitis“ picture in the early stage; in the advanced stage are cerebriform nuclei and band-shaped infiltrates visible
• Flow cytometry of peripheral blood
  Proof of CD4+/CD8– T cells with CD7 and CD26 negativity and CD4/CD8 ratio ≥10
• Molecular biology analyses
  Clonality detection (T-cell receptor gene PCR) in blood and skin, as clonal T-cell expansion a central feature is
• Imaging procedures
  Sonography, CT, PET-CT for staging and detection of extracutaneous involvement. 

Therapy

The therapy is stage-dependent and usually palliative, with the goal of symptom control and delaying progression. 

• First line
  - PUVA therapy (Psoralen + UV-A)
  - Extracorporeal Photopheresis (ECP) especially effective in pregnancy
  - Topical corticosteroids or retinoids (e.g., Bexarotene)
  - Combination therapy ECP with low-dose methotrexate, Interferon-Alpha or Bexarotene 
• Second line (advanced / refractory)
  - Chemotherapy with Liposomal Doxorubicin, Gemcitabine, Alemtuzumab
  - Monoclonal antibodies - Mogamulizumab (anti-CCR4) approved in the EU since 2018
• Radical therapy options
  - Allogeneic stem cell transplantation in younger patients with a refractory course
  - Whole-skin electron beam therapy in case of local progression

Forecast

The prognosis for Sézary syndrome is unfavorable:

• Median survival approximately 5 years
• The survival time is determined by Initial symptoms, blood involvement, and disease progression influences
• The The 5-year survival rate is about 50 % 
• One Poorer prognosis compared to mycosis fungoides, especially in advanced stages and with a high number of Sezary cells in the blood

The diagnosis of Sézary syndrome requires a multimodal approach with clinical, histological, flow cytometry, and molecular biology clonality analysis.

The therapy is multifaceted and stage-dependent, with new approaches like mogamulizumab and stem cell transplantation expanding treatment options.

The prognosis remains limited despite progress.

Primary cutaneous anaplastic large cell CD30-positive lymphoma (cALCL)

Primary cutaneous anaplastic large cell CD30-positive lymphoma (cALCL) is a rare but clinically benign form of cutaneous lymphoma that is significantly different from systemic ALCL.

It occurs primarily in men over 60 and is through rapidly growing, often solitary or grouped nodules or plaques characterized that often ulcerate can.

In some cases, a spontaneous regression possible. The prognosis is very good, with a 10-year survival rate of over 90% %. 

Clinical and Morphological Picture

• Clinical
  Red, brownish-red, or bluish-red, smooth nodules or plaques, often on the head, neck, or body. 
• Histological
  Diffuse infiltrate in the dermis and upper subcutis, epidermis mostly free
  The tumor cells show typical Anaplastic features:
  eccentrically located, horseshoe-shaped nucleus, eosinophilic perinuclear zone in the cytoplasm
• Immunophenotype
  - CD30-positive (constant)
  - ALK-negative
  - EMA-negative
  - CD2, CD3, CD5, CD7, CD45RO positive (T-cell phenotype)
  - No expression of ALK protein, which differentiates systemic ALCL

Differential diagnosis and methodology

The differential diagnosis is crucial, as there can be clinical and histological overlaps.

Important differential diagnoses:

• Systemic anaplastic large cell lymphoma (sALCL)
  Distinction is made by Absence of extracutaneous manifestations (Bone marrow, lymph nodes, organs) in cALCL
  ALK Status is crucial: sALCL is often ALK-positive, cALCL ALK-negative
• Diffuse large B-cell lymphoma (DLBCL)
  Clinically similar lesions. Differentiation by negative B-cell phenotype (CD20-, CD79a-, CD10-), positive CD30 at CALCL
  Molecular detection of Clonal immunoglobulin heavy chain rearrangement helps with DLBCL
• Reactive B-cell pseudolymphomas (B-PSL)
  Histologically similar infiltrates, but non-clonal, CD30-negative, no anaplasia
• Mycosis fungoides (MF)
  Can be associated with CD30-positive cells.
  Differentiation through T-cell phenotype (CD4+, CD5-, CD7-)
  no CD30 expression in classic MF
• Cutaneous lymphoma with CD30-positive pseudolymphoma (LPE)
  Clinically and histologically similar images.
  Diagnosis requires Combination of clinical picture, histological morphology, and immunophenotyping. 

Therapy

• Primary
  Irradiation (individually or localized) or Excision in solitary lesions
• Alternative
  Rituximab monoclonal anti-CD20 antibodies, Interferon-alfa (low dose)
• Polychemotherapy (e.g., CHOP regimen) only in case of multiple or recurrent lesions, rarely necessary
• None Systemic chemotherapy for isolated cutaneous involvement

Forecast

• Very good – 10-year survival rate > 90 %
• Extracutaneous metastases are extremely rare
• Relapse can occur, but mostly locally and well treatable
• Transformation into highly malignant forms is very rare

The diagnosis requires a multimodal approach: Clinical assessment, histological examination, immunohistochemistry (especially CD30, ALK, CD20, CD3, CD45RO) and where applicable molecular biological analyses (e.g., clonal immunoglobulin rearrangement).

Differentiation from systemic ALCL is crucial for therapy and prognosis.

Cutaneous marginal zone lymphoma

The Primary cutaneous marginal zone lymphoma (PCMZL) is a low-grade B-cell lymphoma that primarily occurs in the skin and is characterized by a slow-growing, benign course.

It represents a cutaneous equivalent of MALT lymphomas (mucosa-associated lymphoid tissue) and is therefore occasionally also referred to as SALT Lymphoma (skin-associated lymphoid tissue). 

Clinical picture and clinical-morphological features

• Presentation
  Typically as multiple, single, or grouped papules, plaques, or nodular infiltrates to the limbs, torso, or neck
• Clinical presentation
  Reddish-brown, sharply demarcated, often slightly scaly or indurated skin lesions with slow progression in size
• Histological features
  Knotty to diffuse infiltrates small to medium lymphocytes, which are primarily located in the dermis.
  The tumor cells are bcl-2-positive, show no epidermotropism and exhibit characteristic Mantle zone-like structures on.
  In the immunostaining, CD20+, CD79a+, CD5-, CD10-, CD23- and Membrane immunoglobulins expresses

Differential diagnosis and methodology

The differential diagnosis is difficult due to the morphological similarity with reactive processes and other cutaneous lymphomas.

Important differential diagnoses include:

• Reactive B-cell pseudolymphomas (B-PSL)
  Clinically and histologically often difficult to differentiate
  Crucial is the clinicopathological correlation and the Clonality detection (e.g., by PCR for clonal immunoglobulin heavy chain rearrangements)
• Follicular Lymphoma (PCFCL)
  Can be morphologically similar
  Differentiation by immunohistochemistry (e.g., BCL6 expression, CD10)
• Diffuse large B-cell lymphoma (DLBCL)
  Shows a more aggressive growth pattern, larger cells, a higher proliferation index (Ki-67), and is CD20+, but often BCL2-positive and MYC-positive Double-hit lymphoma
• Reactive germinal centers in inflammatory diseases
  Through Immunohistochemistry (e.g., CD10, BCL6, MUM1) and Clonality analysis to differentiate

Diagnostics

• Atraumatic, large-area punch biopsy (at least 4–6 mm) for adequate histological and immunohistochemical assessment
• Immunohistochemistry
  CD20, CD79a, CD5, CD10, CD23, BCL6, MUM1, bcl-2, CD21 (for FDC network)
• Molecular biological clonality test
  PCR or Southern Blot for Immunoglobulin Genes
• Staging
  Imaging procedures (CT, PET-CT) to rule out extracutaneous involvement, as PCMZL is primarily cutaneous

Therapy

• Asymptomatic, limited lesions
  „Watch-and-wait strategy (watchful waiting, no immediate therapy)
• Local therapy
  Excision individual lesions or local radiotherapy (e.g. 20–30 Gy).
• Multifocal involvement
  Local therapy in combination with systemic options such as Rituximab (CD20 antibody), Immunomodulators (e.g., interferon-α) or Oral chemotherapy (e.g., chlorambucil)
• Rare necessary – With progression or spread systemic chemotherapy (e.g. R-CHOP)

Forecast

• Very good Five-year survival rates 90 %
• The disease progresses slowly progressive, with rare, localized recurrences
• Metastases to lymph nodes or internal organs are rare.
• Secondary lymphoma (e.g., Hodgkin lymphoma) can in up to 1/3 of cases occur and indirectly influence the prognosis

The diagnosis requires a exact clinicopathological correlation And is not solely based on molecular biological findings.

The current S2k guideline (2021) emphasizes the central role of clinical presentation in the classification of cutaneous lymphomas.

Cutaneous lymphoma with granular middle finger tattoo

The Cutaneous lymphoma is a heterogeneous group of malignant diseases that primarily manifest in the skin and arise from T or B lymphocytes.

The clinical presentation can vary widely and is often nonspecific, making diagnosis difficult.

One Gritty middle finger tattoo could indicate a local skin change in the context of cutaneous lymphoma, especially if associated with a slowly growing, reddish to brownish plaque or nodule.

This change can develop over months to years and is typically not painful, but often itchy. 

Clinical picture and clinical-morphological features

• Mycosis fungoides (MF)
  the most common form of cutaneous T-cell lymphoma (approx. 75–80 %) typically progresses in three stages:
  - Patch stadium
  Flat, sharply demarcated, erythematous, slightly scaly macules (similar to eczema), mostly on the trunk, flexural surfaces of the extremities, or body parts without sun exposure
  - Plaquestadium
  Elevated, reddish-livid to brownish plaques with scales, crusts, and lichenification; often persists for 2-5 years
  - Tumor stage
  Hemispherical or lobed tumors, possibly with ulceration and superinfection; occurs in 10–20 %
• Sézary Syndrome (SS)
  Leukemic equivalent of MF with generalized erythroderma, intense itching, lymph node enlargement, nail dystrophy, and detection of atypical lymphoid cells (Sézary cells) in the blood.
• Lymphomatoid Papulosis (LyP)
  Characterized by grouped, spontaneously regressing papules and nodules that disappear within weeks
  Histologically, various types show overlap with aggressive CTCL, which is why clinicopathological correlation is crucial
• Primary cutaneous anaplastic large cell lymphoma (cALCL)
  Solitary erythematous to brownish nodules, possibly with ulceration
  CD30-positive, but mostly ALK-negative
  Spontaneous regression possible (approx. 20 %)
• Primary cutaneous CD8-positive acral T-cell lymphoma (CD8+ ATCL)
  Solitary or bilateral nodules in acral locations (e.g., face, ears, feet)
  histologically dense infiltrates of small to medium-sized atypical lymphocytes without epidermotropism
  excellent prognosis. 

Differential diagnosis and diagnostics

The differential diagnosis is crucial, as cutaneous lymphomas can often be mistaken for inflammatory or benign skin diseases:

• Inflammatory skin diseases
  Psoriasis, atopic dermatitis, contact dermatitis, lichen planus
• Benign lymphoproliferations
  Pseudolymphoma, lymphomatoid papulosis (LyP)
• Other malignant diseases
  Melanoma, cutaneous Merkel cell carcinoma, cutaneous diffuse large B-cell lymphoma (aggressive course)
• Infectious diseases
  Tuberculosis, leprosy, fungal infections

Diagnostic Methodology

• Medical history and physical examination
  Long-term course, localization, symptoms (itching, pain)
• Skin biopsy with histological and immunohistochemical analysis
  Detection of tumor cells (CD3, CD4, CD8, CD30, TCR-genes), epidermotropism, clonality
• Clonality analysis (PCR for TCR-gamma or IgH genes)
  Confirmation of neoplastic proliferation
• Imaging procedures
  CT, PET-CT, MRI for staging examination (lymph nodes, organs)
• Blood test
  Detection of Sézary cells in blood (in SLE), LDH, serum protein electrophoresis

Therapy

The therapy is stage and entity dependent:

• Early stages (patch/plaque)
  Topical therapy (glucocorticoids class III–IV), Phototherapy (UVB, PUVA), local radiotherapy
• Advanced Stages (Tumor Stage, SS)
  Systemic therapies (retinoids, interferon-α, cytostatics), Targeted therapies Mogamulizumab (CCR4), Brentuximab Vedotin (CD30), Histone deacetylase inhibitors
• Aggressive forms (e.g., cutaneous gamma-delta T-cell lymphoma)
  Polychemotherapy, hematopoietic stem cell transplantation
• CD8+ acral T-cell lymphoma
  Surgical excision or radiation therapy are sufficient; no systemic therapy required

Forecast

• Mycosis fungoides
  5-year survival rate 20–60 %; extracutaneous dissemination possible
• Sézary syndrome
  Poor prognosis, median survival time under 3 years
• Lymphomatoid Papulosis
  Excellent prognosis, 5- and 10-year survival rate close to 100 %
• CD8+ acral T-cell lymphoma
  Excellent forecast, no deaths from the disease known
• Primary cutaneous anaplastic large cell lymphomaFavorable prognosis, spontaneous regression possible

The clinicopathological correlation is crucial for correct diagnosis and treatment planning.

In therapy-refractory, eczematous lesions, a cutaneous lymphoma should be considered early on.

B-lymphoblastic lymphoma/leukemia (B-ALL)

The B-lymphoblastic lymphoma/leukemia (B-ALL) is an aggressive, acute neoplasm of B-cell precursor cells that can clinically manifest as leukemia or lymphoma.

The differential diagnosis includes other lymphoid neoplasms, particularly diffuse large B-cell lymphoma (DLBCL), the Burkitt's lymphoma and Acute T-cell leukemia (T-ALL).

Differentiated diagnostics are crucial, as therapy and prognosis strongly depend on the exact classification. 

Clinical picture and clinical-morphological features

• Symptoms
  Bone marrow failure with anemia (fatigue, dyspnea), neutropenia (infections), thrombocytopenia (bleeding), B symptoms (fever, night sweats, weight loss). Extramedullary manifestations such as lymphadenopathy, hepato- and splenomegaly, mediastinal masses (especially in T-ALL) or CNS involvement (5-8% at diagnosis) are possible.
• Cytomorphology
  Lymphoblasts with large nuclei, finely dispersed chromatin, multiple nucleoli, and scant cytoplasm. The cells show high proliferative activity (high Ki67 index).
• Immunophenotype
  Positive for CD19, CD20, CD22, CD79a, TdT Terminal deoxynucleotidyl transferase, CD34 (frequently), HLA-DR
  Negative for myeloid markers (CD13, CD33) and T-cell markers (CD2, CD3, CD5)
• Genetic markers
  Typical translocations such as t(9;22) BCR-ABL1, t(12;21) ETV6-RUNX1, t(1;19) (E2A-PBX1), IGH::IL3, TCF3::PBX1, as well as BCR::ABL1-like Variants with activation of JAK/STAT or ABL kinase signaling pathways.
  IKZF1 Deletions are frequent and associated with an unfavorable prognosis.

Differential diagnostics

• Differential diagnosis
  • DLBCL (diffuse large B-cell lymphoma)Cell size and morphology similar, but TdT-negative, CD10 positive (at GCB type), BCL2 positive, BCL6 positive, MYC negative.No leukemia or bone marrow failure
  • Burkitt's lymphomaSimilar morphology (blasts), MYC translocation (t(8;14)), high Ki67 index (>95%), CD10 positive, BCL2 negative.Mostly extranodal (abdomen, CNS)
  • T-ALLCD3+, CD7+, TdT+, absent B-cell markers, often mediastinal lymphadenopathy
  • B-cell lymphoblastic lymphomaClinically similar to B-ALL, but without significant blood count changes, primarily lymphatic involvement

Diagnostic methods

• Cytomorphology (peripheral blood, bone marrow, lymph node biopsy).
• Immunophenotyping (Flow Cytometry, Immunohistochemistry).
• Cytogenetics Karyotyping.
• FISH (for translocations: t(9;22), t(12;21), t(1;19), IGH::IL3, CRLF2).
• Molecular genetics (NGS) for the identification of mutations (e.g.  IKZF1, PAX5, EBF1, JAK/STAT, RAS signaling pathway).
• Cerebrospinal fluid examination for suspected CNS involvement.

Therapy

• First-line therapy
  Intensive chemotherapy regimens, e.g. Blinatumomab (BiTE antibodies) or Inotuzumab ozogamicin (Antibody-drug conjugate) in combination with chemotherapy
  In adults: Hyper-CVAD (Cyclophosphamide, Vincristine, Doxorubicin, Dexamethasone) or Blinatumomab
• Allogeneic stem cell transplantation
  In patients with unfavorable genetics (e.g.,. BCR::ABL1, IKZF1 Deletion, Low white blood cell count), high risk or recurrence
• CNS prophylaxis
  Methotrexate (intrathecal), corticosteroid therapy, often combined with systemic chemotherapy

Forecast

• Inexpensive
  T-ALL with t(12;21), BCR::ABL1-negative, Older patients with low risk
• Unfavorable
  BCR-ABL1-positive, BCR::ABL1-like Variations, IKZF1 Deletion, Low white blood cell count, older patients, CNS involvement
  The 5-year survival rate is about 60–70% in children, significantly lower in adults (approx.  40-50%), especially with unfavorable genetic profiles

Modern diagnostics using NGS and FISH enables precise risk stratification and personalized therapeutic approaches.

T-lymphoblastic lymphoma/leukemia (T-ALL)

The T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) are malignant diseases of lymphatic precursor cells, characterized by uncontrolled proliferation of immature T-lymphocytes (lymphoblasts).

The disease can occur primarily in the bone marrow (leukemia) or in lymph nodes and extranodal organs (lymphoma), with the distinction being made based on the proportion of blasts in the bone marrow (usually >20–25%).

T-ALL occurs less frequently in children and adolescents than B-ALL (approx. 15 %of all ALL cases), but is more common in adults (approx. 25 %).
The disease shows two incidence peaks: in childhood (under 5 years of age) and in adulthood (from 50 years of age).

Clinically, T-ALL typically manifests with symptoms of bone marrow failure (anemia, thrombocytopenia, neutropenia), fever, weight loss, night sweats, and bone pain.

Characteristic are Hepatosplenomegaly, Lymphadenopathy and in about 5–8 % of patients a CNS involvement.

In T-ALL of the T-cell type, Mediastinal masses in the thorax, which clinically become relevant as pressure symptoms (e.g., dyspnea, cough) or as an indication for radiation therapy.

Clinical-morphological features

• Cytomorphology
  Lymphoblasts show a high cell count, large nuclei with fine chromatin, and 1-3 nucleoli. The cytoplasm volume is small.
• Immunophenotyping (central to diagnosis)
  Blasts express T-cell-specific surface antigens such as CD2, CD3, CD5, CD7 (mostly very positive), CD1a (in thymic subtypes), TdT Terminal deoxynucleotidyl transferase and CD4/CD8 (depending on the differentiation stage: early immature, thymic, or mature T-ALL)
  CD7 is positive in over 90 % of cases. A CD4+/CD8– immunophenotype is typical of early immature T-ALL
• Cytogenetics and molecular genetic markers
  Common genetic aberrations include t(14;14)(q11;q32), inv(14)(q11q32), t(X;14)(q11;q32) and del(11q)
  Additional risk markers are ATM Mutations (in 60 %), TP53 mutations (at 20–30 %) and IKZF1 Deletions
  The Next-Generation Sequencing (NGS)Analysis is increasingly used for the identification of complex genetic changes and for risk assessment.

Differential diagnostics

The differential diagnosis includes other lymphoproliferative disorders:

• B-cell ALL/LBL
  Distinction by absence of T-cell antigens (CD3, CD7, CD2), positive B-cell markers (CD19, CD20, CD79a)
• T-cell prolymphocytic leukemia (T-PLL)
  Distinction by slower progression, typical cell morphology (large, cerebriform nuclei), CD4+/CD8- phenotype with CD26+, CD52+, TCL1A+, as well as complex karyotype and inv(14)
• Chronic lymphocytic leukemia (CLL)
  In T-CLL (rare), typical CLL markers (CD5+, CD23+, CD79b–) are absent
• Sézary syndrome
  A cutaneous T-cell lymphoma subtype with erythroderma, pruritus, alopecia, and CD4+/CD8– phenotype with CD7–, CD26–
• Adult T-cell leukemia/lymphoma (ATLL)
  Caused by HTLV-I, occurs in endemic areas (Japan, Caribbean)
  shows CD25++, CD4+/CD8–, CD7–, TP53 mutations and HTLV-I DNA in the blood
• T-lymphoblastic lymphoma (T-LBL)
  Distinguishing T-ALL by primary extramedullary involvement (e.g., mediastinum), with little or no bone marrow involvement (<20 % blasts)

Diagnostics

• Blood smear and bone marrow biopsy
  Detection of lymphoblasts (>20 % in bone marrow for ALL)
• Immunophenotyping (Flow Cytometry)
  Mandatory for T-cell phenotype identification
• Chromosome analysis (karyotype)
  Identification of translocations such as t(14;14), inv(14)
• FISH (fluorescence in situ hybridization)
  Rapid detection of cryptic aberrations (e.g. t(14;14))
• Molecular Genetics (PCR, NGS)
  Detection of fusion transcripts (e.g. TAL1, LYL1, HOXA-gene), mutations (TP53, ATM, IKZF1).

Therapy

• Induction therapy
  Intensive chemotherapy with steroids (e.g., dexamethasone), vincristine, cyclophosphamide, daunorubicin, and methotrexate (e.g.,. UKALL2003 Protocol)
• Consolidation and conservation
  Phase of intensive therapy with central nervous system prophylaxis (e.g., intrathecal methotrexate)
• Allogeneic stem cell transplantation (SCT)
  Indexed at high risk (e.g.,. TP53 mutation, KMT2A Rearrangement, no remission after induction)
• Targeted therapy
  For certain subtypes (e.g. JAK-STAT activating mutations) will JAK inhibitors (e.g., Ruxolitinib) examined
  Blinatumomab (BiTE antibodies) are used in individual cases

Forecast

Unfavorable prognostic factors:
Over 50 years old, high white blood cell count, Bone marrow infiltration, CNS involvement, TP53 mutation, ATM Mutation, KMT2A Rearrangement, T-ALL with mature phenotype

In children, the recovery rate 85 %

In adults, the prognosis is worse: 50–60 % achieve long-term remission

NK-cell lymphomas

Extranodal NK cell lymphoma

The Extranodal NK/T-cell lymphoma, nasal type (ENKTL-NT) is a also associated with EBV, rare, aggressive form of non-Hodgkin lymphoma, predominantly composed of natural killer cells (NK cells) or is derived from T cells and is closely related to the Epstein-Barr Virus (EBV) Infection associated, as if through CD56 positivity, EBV detection, and angiotropic growth is characterized.

It occurs primarily in Asia, Central, and South America and mainly affects adults, with men being affected more frequently.

 Therapy is combined (Radiation therapy + chemotherapy), prognosis remains relatively bad, however, the situation is improving with novel immunotherapies. 

Clinical picture and morphological features

• Clinical
  Typical symptoms begin with chronic nasal congestion, nosebleeds, and painful, ulcerating lesions in the nasal cavity.
  Advanced stages show centrofacial destructions, destruction of the cranial base, necroses of the alae nasi and septum, as well as B symptoms such as fever, night sweats, and weight loss.
• Morphological
  Histologically, the lymphoma is characterized by angiocentric and angiodestructive growth with extensive coagulation necrosis
  The tumor cells are medium to large in size, with irregular nuclei and granular chromatin. They are often surrounded by a dense infiltrate of reactive cells (lymphocytes, macrophages, eosinophils).
• Immunophenotype
  CD56 positive (identical to N-CAM), CD4 positive, CD8 negative, CD20 negative, CD30 in about 20% positive.
  The EBV RNA Detection by means of EBER in situ hybridization is groundbreaking

Differential diagnostics

The differential diagnosis includes:

• Granuloma gangrenescens nasi (older designation)
  Inflammatory disease that can appear clinically and histologically similar but does not show malignancy
• Infectious or granulomatous diseases (e.g., tuberculosis, leishmaniasis, sarcoidosis) – to be differentiated by clinical, microbiological, and histological examinations
• Other T-cell lymphomas, especially Cutaneous T-cell lymphomas, angioimmunoblastic T-cell lymphoma or Enteropathy-associated T-cell lymphoma, via immunophenotyping and molecular analysis (e.g., T-cell receptor genes) differentiation
• EBV-associated neoplasms in HIV infection, special consideration in immunosuppressed patients

The differential diagnosis requires careful histological and molecular biological clarification.

Diagnostic Methodology

• Biopsy affected tissue (e.g., nasal septum, skin, gastrointestinal tract), central diagnostic basis
• Immunohistochemistry
  Detection of CD56, CD4, CD3, CD30, CD20 (negative), and EBV (EBER hybridization)
• Molecular biology methods
  Detection of clonal T-cell receptor genes (of T-cell origin), FISH for detection of gene alterations
• Imaging
  CT or MRI for assessment of extent (e.g., skull base involvement, extranodal lesions)

Therapy

• Localized disease
  Radiotherapy as standard treatment. 
• Systemic disease or high recurrence rate
  Combination therapy from Chemotherapy (e.g., asparaginase-containing regimens such as SMILE or DA-EPOCH-R) and Irradiation
• New approaches
  In advanced cases, immunotherapeutic strategies (e.g., PD-1 inhibitors) and Cell therapies (e.g., CAR T-cells) evaluated in clinical trials

Forecast

• The forecast is unfavorable, especially in advanced stages
• Median survival time is about 15–36 months, depending on the stage and response to therapy. 
• CD30 positivity correlates with a better prognosis (median survival >35 months vs. approx. 9.6 months in CD30-negative cases)
• EBV DNA quantity in serum can serve as a prognostic marker, high values associated with poorer prognosis

Aggressive NK-cell leukemia (ANKL)

Aggressive NK-cell leukemia (ANKL) is a rare, highly malignant disorder caused by the proliferation of natural killer (NK) cells, which follows a rapid, aggressive clinical course. It is strongly associated with Epstein-Barr Virus (EBV) associated, though EBV-negative cases are also known.

The disease is more common in Asia, particularly in Japan and Southeast Asia, than in Europe or North America.

Clinical and Morphological Picture

• Clinical picture
  – Rapid, aggressive course with B-symptoms Fever, night sweats, weight loss
  – Common Hepatosplenomegaly and Lymphadenopathy
  - Pancytopenia in blood count (anemia, neutropenia, thrombocytopenia)
  In some patients
  Insect sting hypersensitivity with pronounced swelling and necrosis
  – Frequent complications
  Disseminated intravascular coagulation (DIC), Hemophagocytic Syndrome (HPS), Multiorgan failure
  
• Morphological features (bone marrow biopsy)
  – Interstitial or sinusoidal infiltration by medium-sized neoplastic cells
  - Marked nuclear atypia, prominent nucleoli, focal necrosis and apoptotic cells
  - Complete Blood Count Atypical leukemic cells with azurophilic granules and core-typical changes

Differential diagnosis and methodology

The diagnosis of ANKL requires a combination of clinical, morphological, immunohistochemical, and molecular biological investigations to differentiate it from other lymphatic malignancies:

Differential diagnoses

• Diffuse large B-cell lymphoma (DLBCL)
  – Unlike ANKL, DLBCL are typically CD20-positive, CD56-negative and EBV-negative
  – Unlike ANKL, DLBCL show More favorable forecast during therapy with R-CHOP
• Extranodal Natural Killer/T-Cell Lymphoma (ENKTL)
  – Similar to ANKL, ENKTL are associated with EBV and show CD56-positive, CD2-positive, CD3-negative
  Differentiation: ENKTL mostly affects Nose and sinuses, while ANKL proceeds systemically
  - EBER in situ hybridization is positive for both, but mostly in ANKL systemic provable
• Peripheral T-cell lymphomas, NOS (PTCL, NOS)
  – PTCL, NOS are mostly CD56-negative, CD2-positive, T-cell receptor genes are clonally rearranged
  – ANKL shows non-clonal T-cell receptor genes, which NK cell lineage points to
• Hemophagocytic Syndrome (HPS)
  ANCL can be underlying disease for HPS occurrences
  differentiation
  HPS is a Syndrome, not a neoplasm, ANKL is the predisposing tumor disease 
• Other EBV-associated lymphomas (e.g., Hodgkin lymphoma, EBV-positive DLBCL, NOS)
  Distinction by Immunohistochemistry, EBER-ISH, Gene expression analysis and Clonality tests

Your differential diagnosis requires a comprehensive diagnostics, especially Immunohistochemistry, EBER-ISH, PCR for T-cell receptor genes and molecular biology analyses.

Diagnostic Methodology

• Immunohistochemistry
  - PositiveCD2, CD16, CD56, CD45, CD43, TIA-1, Granzyme B
  - NegativeCD3, CD4, CD5, CD7, CD8, CD57, CD20, CD30
  - CD56-positive is characteristic, but not specific (also in ENKTL, DLBCL)
• Molecular biological investigations
  - EBER in situ hybridization (obligatorily positive in most cases)
  - PCR of clonal T-cell receptor genes: Negative – speaks for NK cell lineage
  - Next-generation sequencing (NGS)
  – – Mutations in JAK/STAT signaling pathway (JAK3, STAT3), TP53, Deletions on chromosome 6q
  – – Distinction from other lymphomas by molecular subtyping
• Imaging
  - CT/MRI for the assessment of hepatosplenomegaly, lymph node involvement, and extranodal lesions
  - FDG-PET/CT for staging and therapy monitoring (not standard, but helpful in case of complications)

Therapy

• First-line therapy
  - CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or R-CHOP (with Rituximab), however low efficacy at ANKL
  - Etoposide-based regimens (e.g. Hyper-CVAD) are used more frequently because they respond better to more aggressive tumors
  - Allogeneic stem cell transplantation (allo-SCT)
  – – Gold standard in appropriate patients, especially in remission
  – – Offers the Best chance for long-term remission or cure
• Second-line therapy
  - CAR T-cell therapy (e.g., against CD19 or CD22), in clinical trials, limited data in ANKL
  - Immunotherapy with anti-EBV-CTL (T-cell therapy), experimental, but promising
  - BCL2 inhibitors (Venetoclax), in combination with other regimens, if BCL2 expression is present

Forecast

• Very unfavorable - Median survival time is less than 12 months
• 5-year survival rate under 20%
• Unfavorable prognostic factors
  – High LDH, B symptoms, bone marrow infiltration, DIC, hemophagocytosis
  Not responding to standard chemotherapy (e.g. R-CHOP)
• Allogeneic stem cell transplantation is the only approach with potentially curative effect

Chronic NK cell leukemia

Chronic NK-cell leukemia, also referred to as aggressive NK-cell leukemia or aggressive NK-cell lymphoma, is a rare, highly aggressive malignant disorder of natural killer cells (NK cells).

It shows a characteristic clinical-morphological and immunophenotypic profile that requires differential diagnostics. 

Clinical picture and clinical-morphological features

• Age group
  Affected are primarily Teenagers and young adults, older patients are rarer
• Clinical presentation
  Typically, a systemic infestation with Hepato- and splenomegaly, Lymphadenopathy, Bone marrow infiltration and Peripheral blood involvement
• Morphology
  In peripheral blood and bone marrow are found Large, atypical lymphoid cells with granular cytoplasmic changes that can show a high proliferation rate and necrotizing cell destruction.
  The cells show a pleomorphic cell morphology open, with frequent nuclear deformation and a hyperchromatic nucleus
• Immunophenotype
  The tumor cells express CD56, CD2, CD3ε Cytotype, Granzyme B, TIA-1, Perforin and other cytotoxic molecules. They are CD3-, CD4-, CD8-, and CD5-negative, which deviates from T-cells
  The expression of CD56 alone is not specific, but must be interpreted in the context of other NK markers.
• Molecular Pathology
  In the In the vast majority of cases, the Epstein-Barr virus (EBV) is clonally present, demonstrable by means of EBER in situ hybridization
  Are found no clonal TCR gene rearrangements, which proves the NK cell lineage

Differential diagnosis and methodology

The diagnosis requires a multimodal analysis:

• Clinical examination
  Differentiation of systemic inflammation, infections, and other hematological diseases
• Blood count and bone marrow biopsy
  Detection of atypical lymphoid cells in peripheral blood and bone marrow
• Immunophenotyping (Flow Cytometry)
  Confirmation of CD56+, CD2+, CD3ε+, cytotoxic molecules+, and T-cell antigen-negative phenotype
• Molecular pathology: EBER in situ hybridization for the detection of EBV
  PCR on clonal TCR rearrangements (usually negative)
• Differential diagnoses
  - Nasal NK/T-cell lymphoma
  Similar phenotype, but local localization (nose, nasopharynx)
  strong angio-centric growth
  also EBV+
  - Aggressive B-cell lymphomas (e.g., DLBCL)
  CD20+, CD5-, CD10+
  no CD56+; No EBV+
  - T-cell lymphomas
  CD3+, CD4+, or CD8+
  Clonal TCR rearrangement; CD56- or weakly
  - Reactive lymphadenopathies (e.g., Kikuchi's disease):
  Focal infiltrates, mass apoptosis, young Asian women
  No EBV+
  no systemic infestation
  - Myeloid Leukemias
  CD3-, CD13/CD33+, no CD56+

Therapy

• Standard therapy
  Intensive Chemotherapy (e.g., CHOP, Hyper-CVAD) in combination with anti-CD52 antibodies (Alemtuzumab) or anti-CD25 antibodies (Denileukin diftitox)
• Targeted therapies
  BTK inhibitors (e.g., Ibrutinib) and PI3K inhibitors (e.g., Idelalisib) are effective in individual cases, especially in EBV-positive tumors
• Allogeneic stem cell transplantation (SCT)
  The only potentially curative therapy, especially in patients with good general condition and a suitable donor.
  Indexed at First-line therapy failure or relapse
• Immunotherapy
  NK cell-based cell therapies and CAR-NK cells evaluated in clinical trials

Forecast

• Very unfavorable
  The 5-year survival rate is less than 20 %, especially in advanced stages. 
• Factors with an unfavorable prognosis
  - Systemic infestation
  - Bone marrow involvement
  - large tumor mass
  - EBV positivity
  - high proliferation rate
• Favorable prognostic factors
  - Early diagnosis
  - Good general condition
  . Reaction to chemotherapy
  - Success of allogeneic SCT

The diagnosis and therapy require a interdisciplinary collaboration between hematologists, oncologists, pathologists, and molecular biology laboratories.

Hodgkin's lymphoma - Related diseases

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)

The Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare subtype of Hodgkin's lymphoma, accounting for about 5–10 % of all Hodgkin lymphoma cases makes the difference.

He is characterized by a cheap forecast, a Typical age of onset before age 40 and a male prevalence of 3:1 Australia.

Clinical and Morphological Picture

• Clinical features
  Often limited disease to peripheral lymph nodes (Neck, Armpit, Groin)
  - Rare B-symptoms Fever, night sweats, weight loss
  - Mediastinal involvement is rare, no spatially continuous spread
  - More than 80 % of cases in Stage I or II
  – Extranodal involvement (spleen, liver, bone marrow, lung) occurs only in 10–15 % (spleen), <5 % (liver, bone marrow, lung) on
• Morphological characteristics
  - No typical Hodgkin and Reed-Sternberg (HRS) cells
  - Malignant Lymphocyte Predominant (LP) cells – monoclonal B cells from the germinal center
  - CD20-positive, CD15-negative, CD30-negative (differentiated from classical HL)
  - Typical Growth Forms
  – – Knotty (nodular) shape (Pattern A) – Lower forecast
  - – Diffuse (atypical) form (patterns C, E) – More frequent advanced stage, higher recurrence rate
  - Angiogenesis – Low vascular density (MVD), diffuse vascular distribution
  differs from classic HL and AITL

Differential diagnosis and methodology

The differential diagnosis is crucial, as NLPHL morphologically and immunophenotypically overlaps with other lymphomas:

Differential diagnosis	Key features	Distinguishing features
Classic lymphocyte-rich HL (cHL)	HRS cells, CD30+/CD15+, CD20–	LP cells in NLPHL are CD20+ and CD30–
Progressive Transformation of Germinal Centers (PTGC)	Germinal center proliferation, CD20+ B cells	No structural destruction, no LP cells; NLPHL shows characteristic nodular structures
T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL)	Aggressive growth, high T-cell/histiocyte surplus	Similar morphology to diffuse NLPHL; Differentiation solely by immunophenotype (CD20+ B cells) and molecular investigation (clonal B cell rearrangement)
Follicular lymphoma (FL)	CD10+, BCL2+, BCL6+	No LP cells; No CD20+ LP cells, but rather uniform B-cell proliferation
Angioimmunoblastic T-cell lymphoma (AITL)	CD4+ T cells, HEV changes, CD10+ T cells	CD20– in T cells, Clonal T-cell rearrangement; in contrast to NLPHL, which shows clonal B cells
Follicular T-cell lymphoma (FTCL)	T-cell-based, CD4+	Clonal T-cell rearrangement, no B-cell lineage

Diagnostics

• Lymph node biopsy
• Immunohistochemistry
  CD20+, CD15–, CD30–, CD45+, BCL2+ (in LP cells)
• Molecular biology
  Detection of clonal B-cell rearrangements (Ig genes)
• Biopsy for recurrence
  Mandatory, yes bis zu 10 % der Patienten eine Transformation in ein aggressives B-Zell-Lymphom (z. B.  DLBCL) experience

Therapy

• Early stage (IA without risk factors)
  - Irradiation of the affected area (IFRT) with 30–36 Gy
  - Rituximab alone (Anti-CD20) as an alternative, radiation-free option in studies
• Early stage (not IA or with risk factors)
  - Therapy analogous to classic HLChemotherapy (e.g. ABVDProtocol
  - B-cell NHL protocols (e.g. R-CHOP) can also be effective
• Recurrence
  - Rituximab (Anti-CD20) is effective in relapsed NLPHL
  - High-dose chemotherapy + autologous stem cell transplantation only for few patients required
  - Salvage therapies like ICE or according to cHL protocols

Forecast

• Very cheap
  - 10-year survival rate >90 % (limited stadium)
  - First-line treatment leads to remission in 90–100 %
  - Recurrence in 10–15 %, mostly 3–6 years after diagnosis
• Long-term consequences
  - Secondary malignancies e.g., diffuse large B-cell lymphoma – 25 % Risk after 20 years)
  – Carcinomas (lung, breast, gastrointestinal tract) – often in irradiated regions
• Long-term monitoring required
  – Proof of secondary malignancies
  Screening for cardiopulmonary diseases (caused by radiation therapy)

EBV-positive Diffuse Large B-cell Lymphoma (PTLD)

Epstein-Barr virus-positive diffuse large B-cell lymphoma (EBV+ DLBCL) in the context of post-transplant lymphoproliferative disorder (PTLD) is a rare but potentially life-threatening complication after organ or stem cell transplantation.

It typically arises in patients with an immunosuppressed immune response who are unable to control Epstein-Barr virus (EBV)-infected B cells.

The incidence is higher in the first few years after transplantation, with a second peak in frequency occurring five to ten years later. 

Clinical and Morphological Picture

• Clinical picture
  The illness often manifests extranodal (e.g., in the gastrointestinal tract, lungs, skin, CNS), but can also occur nodularly
  Symptoms are non-specific and include fever, night sweats, weight loss (B symptoms), as well as organ dysfunction depending on the location.
  Systemic involvement is possible, especially in the primary cutaneous form.
• Morphological characteristics
  - Diffuses, polymorphous lymphatic infiltrate with large, atypical B-cell blasts
  – Common Hodgkin and Reed-Sternberg-like cells (HRS-like), necrosis and ulcerations
  - CD30 positivity in about 10–20 % of cases, CD138-negative (distinguishes from plasma cell neoplasms)
  - EBV latency type III with expression of EBNA-2, LMP1, and LMP2 – typical for PTLD
  - Immunohistochemistry
  Positive for CD20, CD79a, PAX5, MUM1
  negative for CD5, CD10 (unlike GCB-DLBCL)
  - Ki67 Index
  High (>90 %), indicating rapid proliferation

Differential diagnostics

The differential diagnosis includes:

• EBV-negative DLBCL
  mostly in older adulthood, without immunosuppression
• Primary cutaneous DLBCL
  localized to the skin, rarely systemic
• EBV-positive mucocutaneous ulcer
  Self-limiting course, good response to conservative measures, no systemic growth
• Primary cutaneous intravascular large B-cell lymphoma (PCIVLBL)
  Intra- and perivascular infiltrates, high morbidity due to thrombosis
• Other forms of PTLD
  - Monomorphic PTLD (EBV-negative)
  More frequent, monoclonal, less responsive to immunosuppression reduction
  - Polyclonal PTLD
  Self-limiting, often responsive to reduction of immunosuppression

Diagnostics

• Histology
  Lymph node or organ biopsy
• Immunohistochemistry
  CD20, CD79a, MUM1, CD30, CD138
• EBV Detection
  In situ hybridization (ISH) for EBV-miRNA (EBER-ISH) – imperatively necessary for confirmation. 
• FISH
  Exclusion of MYC/BCL2/BCL6 rearrangements (e.g., for DLBCL/HGBL-MYC/BCL2)
• Molecular genetics
  PCR for EBV DNA in serum or tissue (quantification for monitoring)
• Imaging
  PET-CT for staging and therapy planning
• Bone marrow biopsy
  In case of suspected systemic involvement

Therapy

• First line
  - Reduction of immunosuppression (with stable organ function)
  - Rituximab (anti-CD20 antibody) - effective for EBV+ PTLD, often alone or in combination
  – In advanced stages: R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone)
• Second line
  - CAR T-cell therapy (e.g., Tisagenlecleucel, Axicabtagen-ciloleucel) in relapsed or refractory disease
  - EBV-specific T-cell preparations (in specialized centers)
  - Bispecific antibodies (e.g., Epcoritamab, Glofitamab)
• High-dose chemotherapy with autologous stem cell transplant
  In selected patients with early recurrences

Forecast

• Inexpensive with early diagnosis and therapy
• Unfavorable factors
  Altered >60 years old, advanced stage (III/IV), multiple extranodal locations
  Elevated LDH, No response rate to immunosuppression reduction
• Median survival
  After rituximab therapy, the median survival time is approximately 8.7 months, with significant improvement through modern therapies
• Prognosis for EBV+ PTLD
  in general better than in EBV-negative PTLD, especially regarding response to immunosuppression reduction and rituximab

Detection and early therapy are crucial. Interdisciplinary tumor conference is recommended, especially in complex cases.

Immunoproliferative diseases & borderline cases

MALT lymphomas

The MALT lymphoma (mucosa-associated lymphoid tissue lymphoma) is a rare form of malignant non-Hodgkin lymphoma that arises from B-cells and typically develops in mucous membranes, especially in the stomach, lungs, lacrimal glands, thyroid, or salivary glands.

It is a indolent (slowly progressing) Lymphoma, which in about 5 % of annually diagnosed non-Hodgkin lymphomas appearance. A crucial etiology is the Chronic immune stimulation through infections (e.g. Helicobacter pylori in the stomach) or autoimmune diseases (e.g., Sjögren's syndrome, Hashimoto's thyroiditis).

In contrast, the Post-transplant lymphoproliferative disorder (PTLD) after a solid organ or allogeneic stem cell transplant and is closely related to a Epstein-Barr Virus (EBV) Infection connected.

PTLD occurs 0.5–12 % of transplant patients and shows a spectrum from early lesions to aggressive monomorphic lymphomas. 

Clinical picture and morphological features

MALT lymphoma

• Clinical picture
  Symptoms are often non-specific: Fatigue, fever, weight loss, nausea, anemia
  Localized infestation causes organ symptoms Upper abdominal pain, reflux, stomach bleeding, Visual disturbances with lacrimal gland involvement, Respiratory tract infections with lung involvement
  B-symptoms (fever, night sweats, weight loss) are rare
  No lymphadenopathy is typical
• Morphology
  Histologically, MALT lymphoma shows a polymorphous small cell infiltrate with reactive follicles populating the mantle zone and interfollicular region
  Neoplastic B cells are CD20+, CD19+, CD22+, but CD5–, CD10–, CD23–
  Common translocations such as t(11;18)(q21;q21) BIRC3-MALT1 fusion is prognostically relevant

Post-transplant lymphoproliferative disorder (PTLD)

• Clinical picture
  PTLD can early (after 3–6 months) or late occur after several years
  Symptoms depend on the infestation: Enlarged lymph nodes, hepatosplenomegaly, organ failure (e.g., kidney failure after kidney transplant)
  EBV-positive in over 90 % of early lesions, but often EBV-negative in monomorphic lymphomas
• Morphology
  PTLD shows a spectrum: early lesions (polyclonal, EBV+), Polymorphic PTLD (oligoclonal, EBV±), monomorphic PTLD (monoclonal, often EBV–)
  Histologically, it often resembles a Diffuse large B-cell lymphoma (DLBCL)
  CD20+ and CD79a+; often CD30+, CD5-

Differential diagnosis and diagnostics

Differential diagnoses for MALT lymphoma

• Reactive lymphoproliferations (e.g., in H. pyloriGastritis
• Other non-Hodgkin lymphomas (DLBCL, follicular lymphoma)
• Infections (e.g. H. pylori, Chlamydia psittaci)
• Autoimmune diseases (e.g., Sjögren's syndrome, lupus) 

Differential diagnoses for PTLD

• Reactive lymphadenopathy
• Chronic infections (e.g., EBV infection)
• Other lymphomas (e.g., DLBCL, Hodgkin lymphoma)
• Organ rejection

Diagnostic Methodology

• Biopsy the affected localization (gold standard)
• Histology, Immunophenotyping
  CD20, CD79a, CD5, CD10, CD23
• PCR analysis of IgH rearrangement
  for clonal analysis
• FISH/Genetics
  on the proof obligation for translocations (t(11;18), t(14;18))
• Imaging
  (CT, MRI, PET-CT) for staging
• Bone marrow aspiration
  to exclude bone marrow involvement
• EBV DNA PCR in serum
  for PTLD diagnosis and monitoring 

Therapy

MALT lymphoma

• H. pylori-positive gastric lymphoma: Antibiotic therapy Eradication Regression of lymphoma
• H. pylori-negative gastric lymphoma or Non-gastric MALT lymphoma
  - Radiotherapy (e.g., in conjunctival lymphoma)
  - ChemotherapyChlorambucil, Cyclophosphamide, Fludarabine
  - Rituximab CD20 antibodies in advanced cases
• Indolent course → Treatment often not necessary, if asymptomatic („Observe“) 

Post-transplant lymphoproliferative disorder (PTLD)

• First line
  Reduction of immunosuppression (Core therapy)
• Monoclonal antibody
  Rituximab (CD20) – alone or in combination
• Chemotherapy
  in advanced or aggressive courses (e.g., CHOP)
• Cytokines
  (e.g., Interferon-α) for specific forms
• Surgical removal
  for localized lesions 

Forecast

MALT lymphoma

• Good prognosis
  The 10-year survival rate in treated isolated lymphomas is approximately 75 %
  Median survival >10 years
  The risk of transformation into aggressive DLBCL is low (approx. 5-10 %)

Post-transplant lymphoproliferative disorder

• 1-year survival rate is up to 90 % with early detected and treated PTLD, depending on the stage and therapy
• Monomorphic PTLD have a poorer prognosis
• Long-term survival is threatened by immunosuppression and the risk of infection.

Summary

Feature	MALT lymphoma	Post-transplant lymphoproliferative disorder
Etiology	Chronic infection (e.g.  H. pylori), autoimmune	EBV infection, immunosuppression
Typical localization	Stomach, lungs, eye adnexa, thyroid gland	Lymph nodes, liver, small intestine, lungs
Clonality	Monoclonal	Oligo-/polyclonal (early), monoclonal (late)
EBV status	Rarely positive	Mostly positive (early), often negative (late)

Lymphomatoid granulomatosis

The Lymphomatoid granulomatosis is a rare, angiocentric and destructive lymphoproliferative disease that belongs to the B-cell proliferative diseases with varying malignant potential.

It is called granulomatous systemic disease with a Epstein-Barr virus (EBV) association (detectable by LMP1 expression) and shows a CD20 and CD30 expression of the tumor cells. 

Clinical picture and clinical-morphological features

• Skin manifestations occur at about 45 % of the patients and are uncharacteristic:
  - Painless reddish-brown spots, papules, plaques or nodules
  - Rare: Erythema nodosum-like nodules with a tendency to Ulceration
  - No epidermotropism
• Extracutaneous organ involvement
  - lungCough, shortness of breath, chest pain, fever, weight loss
  - Central nervous system (CNS): At approx. 26 % of the patients - Headaches, ataxia, hemiplegia, cramps
  - Liver and kidneyPathological laboratory values (e.g. elevated liver values, renal insufficiency)
• General symptomsFever, non-specific inflammatory phenomena, B-symptoms (weight loss, night sweats)

Differential diagnosis and methodology

The differential diagnosis is crucial, as the clinical picture is non-specific.
Main candidates:

• Sarcoidosis
  Granulomatous processes, but No angiocentric destruction, no EBV association, No atypical lymphocytes
• B-cell lymphomas (especially diffuse large B-cell lymphoma)
  Monoclonal B-cell proliferation, Lack of granulomatous structures, higher blast rate (Grade III)
• Wegener's granulomatosis (GPA)
  Small vessel vasculitis, positive ANCA, non-EBV-associated, no CD20 expression of the cells
• Cutaneous lymphomas
  Distinction by Epidermotropism (absent in lymphomatoid granulomatosis)
• Eosinophilic myalgia syndrome
  No granulomatous infiltration, usually with eosinophilia and myalgia
• Infectious granulomatoses
  (e.g. tuberculosis, histoplasmosis)
  Detection of pathogens in the tissue. 

Diagnostic methods:

• Skin and organ biopsy (lung, kidney) with histological analysis
• Immunohistochemistry
  CD20+, CD30+, LMP1+ (EBV)
• Molecular biological analysis
  EBV DNA detection in tissue
• Imaging
  CT/MRI (lung, CNS), PET-CT for staging and therapy monitoring (e.g. increased FDG uptake)
• Laboratory
  Elevated inflammatory parameters (CRP, SED), positive EBV serology, elevated LDH

Therapy

It exists No established therapy standard.

The therapy is based on the Histology stage:

• Grade I (Low-Grade)
  - Watchful Waiting with immunomodulation (e.g. improvement of the immune status), as spontaneous remissions are possible.
• Grade II and III (high-grade) or multiple affected organs
  - Combination therapy: CHOP scheme (cyclophosphamide, doxorubicin, vincristine, prednisone) or R-CHOP (with Rituximab)
  - Immunosuppressive therapy to Fauci scheme (prednisone + cyclophosphamide)
  - Aggressive therapy for recurrence or grade III
  – – High-dose chemotherapy (e.g. BEAM) + Autologous stem cell transplantation (ASCT)
  – – Radioimmunotherapy with Y-90-Ibritumomab-Tiuxetan in combination with ASCT (proven for recurrences)
  – – Interferon-α2b as an additional option (demonstrably effective in individual cases)

Forecast

• Variable course
  Possible Spontaneous remissionsbut also rapid progression
• Frequent complication
  Development of a aggressive B-cell lymphoma (e.g. diffuse large B-cell lymphoma)
• Cause of death
  Most respiratory insufficiency or septic complications
• Long-term survival rate
  Approx. 25 % (depending on severity and response to therapy)
• Prognostic factors
  Stage, organ involvement (especially CNS), EBV load, LDH values.

One Early histological confirmation and multimodal therapy are decisive for the prognosis.

Skin biopsies can provide the decisive clue, but Systemic participation must always be clarified.

Granulomatosis with organ-preserving vasculitis (GANZL)

Granulomatosis with polyangiitis (GPA), formerly known as Wegener's disease, is a rare, systemic, necrotizing small vessel vasculitis characterized by a Extravascular granulomatous inflammation in the respiratory tract and a Vasculitis of small and medium-sized vessels is marked.

It belongs to the ANCA-associated vasculitides (AAV) and is typically associated with PR3-ANCA associated. 

Clinical picture and clinical-morphological features

The clinical picture varies depending on the involvement of the organs, with the pulmonary-renal syndrome (alveolar hemorrhage, rapidly progressive glomerulonephritis) and the Involvement of the upper respiratory tract are typical. 

• Upper respiratory tract
  Recurrent bloody rhinitis, nosebleeds, nasal crusts, mucous membrane appears granulated, Saddle nose (nasal bridge collapse), sinusitis, subglottic stenosis
• Lower respiratory tract
  Cough, hemoptysis, pulmonary nodules with cavitation, interstitial lung changes, alveolar hemorrhage (acute dyspnea, blood in sputum)
• Kidneys
  Glomerulonephritis with focal necrotizing glomerulonephritis, often with crescent formation, hypertension, edema, elevated serum creatinine
• skin
  Palpable purpura, subcutaneous nodules, pyoderma gangraenosum
• Nervous system
  Mononeuritis multiplex, cranial nerve palsies
• Eyes
  Conjunctivitis, scleritis, uveitis, retro-orbital infiltrates (exophthalmos, visual disturbances)
• Other organs
  Heart (rarely coronary involvement), joints (non-erosive arthritis), liver, spleen

Histologically, the biopsy shows a Necrotizing vasculitis of small and medium-sized vessels, granulomatous inflammation with epithelioid cells, giant cells and geographic necrosis.

However, the classic triad (granulomatous inflammation, necrotizing vasculitis, geographic necrosis) is not present in the localized GPA rarely detectable. 

Differential diagnosis and methodology

The diagnosis requires a differentiated clarification, as many diseases have similar symptoms. 

• Clinical symptoms
  (e.g. nosebleeds, pulmonary nodules, glomerulonephritis) must be differentiated from other causes
• Serological tests: Proof of PR3-ANCA (specific for GPA) or MPO-ANCA (for MPA/EGPA)
  ANCA positivity is not 100 % certain, as ANCA-negative cases also occur
• Biopsy
  Tissue samples from affected organs (e.g. nose, lung, kidney) are the gold standard for confirming the diagnosis.
  Histologically detectable: necrotizing vasculitis, granulomatous inflammation
• Imaging procedures
  CT of the thorax (lung nodules, cavitation), MRI (e.g. brain, nerves), ultrasound (kidneys)
• Cerebrospinal fluid examination
  In case of neurological symptoms: increased cell count and protein (inflammatory CSF), but no oligoclonal bands

Differential diagnoses

• Infections
  Tuberculosis, fungal infections (e.g. aspergillosis), bacterial endocarditis
• Other vasculitides
  Giant cell arteritis, Takayasu's arteritis, polyarteritis nodosa
• Autoimmune diseases
  Systemic lupus erythematosus (SLE), Sjögren's syndrome
• Tumors
  Lymphoma, carcinoma (especially pulmonary)
• Infectious granulomas
  Tuberculosis, sarcoidosis

Therapy

The therapy depends on the severity and organ involvement and is divided into Remission induction and Maintenance of remission.

• Remission induction (in case of serious illness)
  - Rituximab (anti-CD20 antibody) or Cyclophosphamide (in combination with Glucocorticoids, e.g. prednisone)
  - In severe alveolar hemorrhage or rapid progressive glomerulonephritis: Plasma exchange
• Maintenance of remission
  - Azathioprine or Methotrexate (effective)
  - Mycophenolate mofetil (less effective)
  - Rituximab also for maintenance therapy (for PR3-ANCA-positive patients)

Forecast

• With modern therapies, the following can be achieved more than 80 % of patients achieve remission
• Recurrences are frequent, especially with PR3-ANCA positivity, pulmonary involvement or involvement of the upper respiratory tract
• Prognostic factors for poor outcome
  - Poor kidney function at the time of diagnosis (e.g. need for dialysis)
  - High disease activity (Birmingham Vasculitis Activity Score)
  - Cardiac or gastrointestinal manifestations
  - Age >65 years
  - Sclerosing glomerulonephritis in the biopsy
• Mortality
  is increased, especially with severe kidney involvement or infections (therapy-associated)

GPA is a complex, multi-organ disease whose diagnosis is based on a combination of clinical presentation, ANCA serology and biopsy-confirmed histological change is based on.

Early, centralized therapy with immunosuppressants is crucial for a favorable prognosis.

EBV-associated B-cell lymphoproliferations

Epstein-Barr virus (EBV)-associated B-cell lymphoproliferations comprise a spectrum of diseases that differ in their biology, clinical manifestation and prognosis.

A differentiated differentiation is crucial for the treatment decision. 

Clinical picture and morphological features

• Post-transplant lymphoproliferative diseases (PTLD)
  Occurs after solid organ or hematopoietic stem cell transplantation. The clinical picture depends on the stage of the disease:
  - Early lesions (approx. 5%)
  Oligo- or polyclonal, almost always EBV-positive, often with monoclonal B-cell expansion. Morphologically, they show diffuse infiltrative lymphocyte proliferation with cellular atypia
  - Poly- and monomorphic PTLD
  – – Polyclonal PTLD: EBV-positive or -negative, often with polyclonal B-cell proliferation
  – – Monomorphic PTLD: often EBV-negative (up to 50%), monoclonal, morphologically similar to a diffuse large B-cell lymphoma (DLBCL), often with immunoblastic or anaplastic morphology
• Epstein-Barr virus-positive DLBCL in older people
  - Mainly meets older adults (mostly >60 years), often not immunosuppressed
  - Clinical
  – – Extranodal manifestations (e.g. skin, gastrointestinal tract, CNS)
  – – B symptoms Fever, night sweats, weight loss
  – – Rapid progression
  - Morphology
  – – Diffuse large cell population with centroblastic or immunoblastic atypia
  – – high proliferation rate (Ki67 >90%)
• Aggressive primary cutaneous B-cell lymphoma (primary cutaneous DLBCL, lower extremity)
  - Extralymphatic infestation (skin, especially legs), mostly non-systemic, often only a single stove
  - EBV-positive in elderly patients, EBV-negative for younger
  - Morphology
  – – diffuse large B-cell proliferation with expression of cell types (e.g. immunoblastic)

Differential Diagnosis and Methodology

• Cytomorphology
  - DLBCL, NOS vs. EBV+ DLBCL
  Morphology alone is not enough to differentiate
  - PTLD vs. DLBCL
  Clinic (transplant history), clonality (PCR), EBV status (EBER-ISH) are decisive
• Immunophenotyping
  - All EBV-associated lymphomas
  – – CD20+, CD79a+, PAX5+, CD45+, CD10+ (for GCB subtype)
  – – BCL6+, CD30+ (for 10-20% of cases)
  - EBV+ DLBCL in the elderly
  – – CD30+ in up to 70% of cases
  – – CD5-, CD138-, MYC- (not double-expresser)
• Genetic and molecular biological methods
  - EBER-ISH (Epstein-Barr virus-encoded RNA in situ hybridization), EBV detection in cells
  - FISH
  Exclusion of MYC/BCL2 translocations (then: Double-hit lymphoma)
  - PCR for EBV DNA
  Quantification in serum/plasma (not for diagnosis alone, but for monitoring)
  - Gene expression analysis (COO subtype)
  – – GCB subtype (germinal center B-cell) - more common with EBV+ DLBCL in the elderly
  – – ABC subtype (activated B-cell) - more common in Post-transplant lymphoproliferative disorder
• Differential diagnosis
  - DLBCL, NOSWithout EBV association, often with MYC/BCL2 translocations
  - Burkitt's lymphoma
  – – Extremely high proliferation rate (Ki67 >95%), MYC translocation, „starry sky“ pattern, CD10+, BCL6+, CD5-
  - Anaplastic large cell lymphoma (ALCL)
  – – CD30+, ALK+ (for ALK-positive ALCL), CD15+, T-cell phenotype
  - Hodgkin's lymphoma
  – – CD15+, CD30+, CD20-, CD45-, Reed-Sternberg cells

Therapy

• Post-transplant lymphoproliferative disorder
  - First line
  – – Reduction of immunosuppression (if possible)
  – – Rituximab (monoclonal), First choice for EBV+ PTLD
  – – Advanced stage
  – – – R-CHOP or R-CHOP-like regimes
  – – For non-responsive cases
  – – – Chemotherapy, Cell therapy (e.g. CAR-T cells).
• EBV+ DLBCL in the elderly
  - R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone)
  - For patients with high risk (e.g. IPI high) Intensified therapy (e.g. DA-EPOCH-R)
  - CAR-T cells in case of recurrence/refractory disease
• Primary cutaneous DLBCL, lower extremity
  - Local therapy (radiation) With limited infestation
  - Systemic therapy (R-CHOP) for multiple or systemic lesions

Forecast

Post-transplant lymphoproliferative disorder

• Inexpensive with early diagnosis and reduction of immunosuppression
• 5-year survival rate: approx. 60–70%, depending on the stage and response to therapy

EBV+ DLBCL in the elderly

• Worse forecast compared to EBV-negative DLBCL (especially in older patients). 
• 5-year survival rate: approx. 40-50%.

Primary cutaneous DLBCL, lower extremity

• More favorable forecast, if locally limited
• 5-year survival rate>80% with local therapy

The differential diagnosis of EBV-associated B-cell lymphoma requires multimodal diagnostics (histology, immunophenotype, EBER-ISH, FISH, gene expression analysis).

Therapy is based on the clinic, stage classification and risk profile, with rituximab and R-CHOP being central therapy components.

The prognosis varies greatly depending on the subtype and is generally less favorable compared to EBV-negative DLBCL, especially in older patients.

Hodgkin's lymphoma

Classical Hodgkin's lymphoma, nodular sclerosis (cHL, NS)

Classical Hodgkin's lymphoma (cHL) with nodular sclerosis is the most common subtype of cHL, with a prevalence of about 70 % in western countries.

It shows a bimodal age distribution with a peak occurrence between the ages of 20 and 30 and a second peak after the age of 65.

Clinical picture

• Symptomatology
  Painless enlargement of lymph nodes, often in the neck and cervical region, supraclavicular and in the mediastinum.
  One B-symptomatics (fever, night sweats, weight loss >10 %) is present in about 50 % of patients.
• Localization
  Preferential infestation of mediastinal lymph nodes, which leads to a typical mediastinal tumor mass (in about 80 % of cases).
• Laboratory findings
  Anemia and/or pruritus occur in about a quarter of patients. 

Clinical-morphological features

• Histology
  Characterized by a nodular growth pattern, pronounced sclerosis (collagenous connective tissue strands) and Lacunar cells (a special form of Hodgkin-Reed-Sternberg cells that show an optically empty cytoplasm during formalin fixation)
• Cell population
  Only about 1 % of the cells are malignant tumor cells (Hodgkin-Reed-Sternberg cells). The remainder consists of a mixed infiltrate reactive cells: Lymphocytes, plasma cells, eosinophil granulocytes and histiocytes
• Immunophenotype of the tumor cells
  - CD30+, CD15+, PD-L1+, MUM1+
  - CD20-/+ (positive in approx. 20 %), CD45-
  - EBV- or EBV+ (in variable numbers)
  - J-chain

Differential diagnostics

The differential diagnosis is crucial because of the clinical and histological similarity with other diseases:

• Infectious mononucleosis (EBV-associated)
  Differentiation by clinical picture, serological findings (heterophilic antibodies), and lack of clonal cell population
• Follicular lymphoma
  Differentiation by lack of Reed-Sternberg cells, typical follicular growth pattern and CD10+/CD20+/BCL2+ immunophenotype
• Lymphocyte-predominant Hodgkin's lymphoma (NLPHL)
  Differentiation by lack of CD30/CD15 expression, positive CD20/CD45/J-chain expression and typical L&H cells (lymphocyte- and histiocyte-rich cells)
• Aggressive T-cell histiocyte-rich large B-cell lymphoma (TCHRBCL)
  Differentiation due to lack of CD30/CD15 expression in tumor cells and other immunophenotypes (e.g. CD5+, CD10-)
• Reactive germinal center progression (PTKZ)
  Differentiation by lack of clonal cell population and lack of typical HRS cells
• EBV-associated diseases (e.g. EBV-positive mucocutaneous ulcer)
  Differentiation by clinical picture, localization and EBV DNA detection
• Anaplastic large cell lymphoma (ALK-negative)
  In lymphocyte-poor cHL, especially in HIV-positive patients, differentiation is necessary

Diagnostics

• Biopsy
  Primary diagnosis by lymph node biopsy (usually mediastinal or cervical)
• Immunohistochemistry
  Crucial for confirmation of the immunophenotype (CD30, CD15, CD20, CD45, PD-L1).
• Imaging
  Computed tomography (CT) of the thorax, neck, abdomen and pelvis; positron emission tomography (PET) for staging and therapy monitoring
• Bone marrow biopsy
  Only indicated for B symptoms or abnormal laboratory values

Therapy

Stage-adapted therapy

• Stage I/II without risk factors
  Combined radio- and chemotherapy (e.g. ABVD + Involved Field Radiotherapy)
• Stage I/II with risk factors or stage III/IV
  Chemotherapy (e.g. ABVD) with or without radiotherapy
• New therapies
  Anti-CD30 antibody-cytostatic conjugates (e.g. brentuximab vedotin) in salvage therapy
• Goal
  Long-term survival of 80-90 % with adequate therapy

Forecast

• Without treatment moderately aggressive
• With treatment extremely favorable, about 80 % of the patients are cured in the long term
• The Histological subclassification (e.g. nodular sclerosis) has No therapeutic relevance today's therapy is adapted to the stage and risk of the disease. 

Notice: The differential diagnosis requires a Multidisciplinary clarification by pathology, hematology and oncology. The Early and correct diagnosis is crucial for successful therapy.

Classical Hodgkin's lymphoma (cHL) - mixed cellularity (MC)

The classical Hodgkin's lymphoma (cHL), mixed cellularity (MC), is a histologic subtype of cHL, which is approximately 25 % of cases and is particularly common in patients over the age of 50 and in HIV-positive people. Men are more frequently affected than women.

Clinical picture and morphological features

• Clinical
  Infestation preferred Cervical and abdominal lymph node regions
  Compared to other cHL subtypes, the mixed type is diagnosed more frequently in a advanced stage discovered and shows frequent B-symptomatics (fever, night sweats, weight loss >10 % within 6 months)
• Morphological
  - Characteristic is a Mixed cell infiltrate from Hodgkin and Reed-Sternberg cells (H-RS cells), lymphocytes, histiocytes, granulocytes (especially eosinophils) and fine fibrillar fibrosis
  - H-RS cells are multinucleated (Reed-Sternberg cells) or mononuclear, with prominent nucleoli („owl's eye cells“) and basophilic cytoplasm
  - The tumor cells only make up about 0.1-10 % of the total cell mass; the rest consists of reactive inflammatory infiltrate

Differential diagnosis and methodology

Differential diagnosis is crucial, as cHL must be differentiated by its characteristic biphasic pattern (few tumor cells, strong reactive infiltrate) and specific immunophenotypes. 

• Important differential diagnoses
  - Follicular lymphoma (FL)
  Neoplastic proliferation of centrocytes/centroblasts with typical germinal center architecture, CD10+, bcl-2+, t(14;18)
  - Diffuse large B-cell lymphoma (DLBCL)Diffuse infiltration of large, transformed B cells, CD20+, BCL6+, MUM1+, more frequently with B symptoms and rapid growth
  - Chronic lymphocytic leukemia (CLL)Peripheral lymphadenopathy, bone marrow involvement, CD5+, CD23+, CD20 (weak), CD10-
  - Mantle cell lymphoma (MCL)CD5+, CD23-, CD10-, t(11;14), mostly advanced at diagnosis, poor prognosis
  - Multiple myelomaBone pain, pathological fractures, plasma cell infiltration in the bone marrow, anemia, hypercalcemia
  - Reactive lymphadenopathyNo clonal proliferation, typically after infections, with normal architecture and lack of H-RS cells
• Diagnostic Methodology
  - Histology
  Microscopic examination of the lymph node preparation with detection of H-RS cells and reactive infiltrate
  - Immunohistochemistry
  H-RS cells are positive for CD30, CD15, MUM1, PD-L1 and mostly negative for CD45, CD20 (positive in approx. 20 %), J-chain, and BOB.1/Oct2 (negative in classic HL)
  - Molecular pathology
  Detection of clonal B-cell neoplasia (e.g. by immunoglobulin gene PCR, mutations)
  - Imaging
  CT/MRI for staging (Ann Arbor classification), PET-CT for therapy planning and monitoring
  - Bone marrow biopsy
  For B symptoms or advanced stage to rule out bone marrow involvement

Therapy and prognosis

• Therapy principle
  Stage-adapted polychemotherapy (e.g. ABVD: doxorubicin, bleomycin, vinblastine, dacarbazine) combined with Radiotherapy For localized infestation (stages I-II)
• Forecast
  Achieve with modern therapies over 80 % of patients achieve a long-term cure
  The 5-year survival rate is between 75 % and 99 %, depending on the stage and risk factors
• Prognostic factors
  B symptoms, high LDH, age >50 years, extent of the disease (stage IV), number of affected lymph node regions

The classic Hodgkin's lymphoma, mixed cellularity, is a Well treatable but complex disease, whose diagnosis and therapy are based on a multimodal, individualized approach based.

Classical Hodgkin's lymphoma - lymphocyte-rich type (cHL, LR)

The Lymphocyte-rich classical Hodgkin's lymphoma (cHL, LR) is a rare histologic variant of classic Hodgkin's lymphoma, which occurs in about 4 % of all cases.

Through a Dominant lymphocyte-rich environment characterized by only a few Hodgkin and Reed-Sternberg cells (H-RS cells), which are typically CD30- and CD15-positive are.

The tumor cells often also carry CD20 and CD23, but are CD30-negative.

The disease occurs more frequently in male patients around the age of 30 and has a Very good forecast on.

Clinical picture and morphological features

• Clinical picture
  The LR type usually manifests itself as Infestation of peripheral lymph nodes, often in the Cervical or axillary region
  Patients often show painless swelling of the lymph nodes, that persist for weeks to months.
  B symptoms (fever, night sweats, weight loss) are less common than in other subtypes. 
• Morphological
  The histologic image shows a lymphocyte-rich infiltrate (predominantly T lymphocytes) in the marginal and mantle zones of the lymph follicles
  It is characterized by a diffuse fibrosis and a small number of H-RS cells
  The environment consists of a mixture of lymphocytes, histiocytes and granulocytes

Differential diagnosis and methodology

Differential diagnosis is crucial, as the LR type can be confused morphologically and immunophenotypically with other lymphomas:

• Aggressive T-cell histiocyte-rich large B-cell lymphoma (TCHRBCL)
  This aggressive non-Hodgkin's lymphoma may have similar morphologic features, in particular a rich lymphocytic environment
  In terms of differential diagnosis, it is crucial that TCHRBCL CD20-positive is, but CD30-negative and CD15-negative
  The tumor cells are MUM1-positive and show a high proliferation rate
• Reactive proliferation of germinal centers (PTKZ)
  These can be irritated by a lymphocyte-rich environment and occasional H-RS-like cells
  The criteria for differentiation are Absence of CD30- and CD15-positive H-RS cells and the positive B-cell marker (CD20, CD79a, CD45) in the reactive cells
  The EBV negativity is also typical
• Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)
  Although NLPHL also shows a lymphocyte-rich environment, the tumor cells are CD20-positive, CD30-negative and CD15-negative
  The cells are EBV-negative and show a characteristic Lymphocyte predominance with small lymphocytes and epithelioid cells

The differential diagnosis requires a Careful histological and immunophenotypic analysis, to differentiate with aggressive lymphomas such as TCHRBCL or reactive proliferations.

Therapy

As the LR type is a Very good forecast a Risk-adapted therapy applied.
Patients with early stages (I-II) often receive short chemotherapies (e.g. ABVD) in combination with certain irradiation
For advanced stages (III-IV), a more intensive chemotherapy (e.g. BEACOPP), but with lower irradiation requirements

Forecast

The 5-year survival rate is over 90 %.
The favorable forecast is due to the High sensitivity to chemotherapy and radiation attributable.
However, late complications (e.g. secondary tumors, cardiovascular diseases) are possible in younger patients and require careful follow-up care. 

Classical lymphocyte-poor Hodgkin's lymphoma (cHL)

The Classical lymphocyte-poor Hodgkin's lymphoma (cHL) is a rare form of Hodgkin's lymphoma that affects about 1 % of cases and especially with older patients performance.

It is characterized by a Diffuse, blastic infiltrate with few lymphocytes and atypical Hodgkin and Reed-Sternberg cells (H-RS cells) which are often accompanied by mitoses and necrosis.

Histologically there is a diffuse HRS cell infiltration with only a sparse accompanying non-neoplastic reaction, resulting in a sarcomatous image can lead to. 

Clinical picture and morphological features

• Primary localization
  Frequently abdominal lymph node involvement, especially in the area of the mesentery or retroperitoneally
• Symptoms
  Typically B symptoms (fever, night sweats, unintentional weight loss >10 % in 6 months), which occur more frequently in this subtype
• Sleeve
  Prefers patients in the older age (mostly >60 years), with a Male preference
• Morphology
  H-RS cells are pleomorphic, with large, granular nuclei and prominent nucleoli; lymphocytes are minimally present

Differential diagnosis and methodology

The lymphocyte-poor classical Hodgkin's lymphoma (cHL) must be distinguished from the following diseases in particular:

• Anaplastic large cell lymphoma (ALK-negative)
  This differential diagnosis is particularly important as both diseases have similar morphological and immunophenotypic characteristics (e.g. CD30+, CD15+)
  Immunohistochemistry (CD20-, CD30+, CD15+, ALK-) and molecular biology analyses (e.g.  ALK-genre arrangements) are crucial for differentiating
• Reactive lymph node changes (e.g. in the case of infections or autoimmune diseases)
  Due to missing clonal cell population and missing H-RS cells
• Aggressive B-cell lymphoma (e.g. T-cell histiocyte-rich large B-cell lymphoma, TCHRBCL)
  Differentiation through CD20 positivity (at TCHRBCL), CD30 positivity and CD15 negativity at TCHRBCL
  In contrast to cHL, the H-RS cell structure is not typical for TCHRBCL
• EBV-associated diseases, especially EBV-positive mucocutaneous ulcer, as CD30+ and CD15+ cells can also occur here

Diagnostics

• Histological diagnosis
  Only through Lymph node biopsy with whole lymph node possible
  Fine needle aspiration (cytology) is insufficient!
• Immunohistochemistry
  CD30+, CD15+, CD20-/±, CD45-, PD-L1+, MUM1+
  EBV positivity can be variable
• Imaging
  PET-CT for staging and treatment planning
  CT thorax/abdomen with contrast medium
• Staging
  After modified Ann Arbor classification (Stage I-IV)

Therapy

• Therapy principle
  Polychemotherapy (e.g.  BEACOPP-protocol) with or without Irradiation. 
• Risk-adapted therapy
  Due to the poor prognosis, this subtype is often treated with a intensive chemotherapy recommended
• New therapies
  In case of recurrence or treatment failure: Antibody therapies (e.g.  Brentuximab vedotin, an anti-CD30 antibody), Checkpoint inhibitors (e.g. Pembrolizumab, Anti-PD-1)

Forecast

• Worst forecast of all Hodgkin's lymphoma subtypes
• 5-year survival rate
  Significantly lower compared to other subtypes (below 75 %, depending on staging and therapy)
• Risk of recurrence
  is high, therefore Intensive aftercare with regular PET-CT and clinical checks required

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)

The Nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL) is a rare subtype of Hodgkin's lymphoma, accounting for about 5–10 % of all Hodgkin lymphoma cases makes the difference.

It is characterized by a cheap forecast, a Tendency towards limited lymph node involvement (especially the neck, axilla and groin region) and a Low frequency of B-symptoms (fever, night sweats, weight loss). 

Clinical picture and morphological features

• Sleeve
  Typically begins before the age of 40, with a male proportion of about 3:1
• Clinical picture
  Most limited stage I or II disease (>80 % of cases).
  Mediastinal involvement is rare
  Extranodal manifestations only occur in 10-15 % of cases in the spleen, less frequently in the liver, bone marrow or lungs
• Morphology
  Histologically characterized by lymphocyte-predominant (LP) cellswhich CD20-positive, CD15-negative and CD30-negative are.
  These cells are monoclonal B cells originating from the germinal center.
  In contrast to classic Hodgkin's lymphoma, typical Hodgkin's and Reed-Sternberg cells are absent.
  The tumor cells are located in nodular structures, often surrounded by a dense lymphocyte envelope, before

Differential diagnoses and differential methodology

The differential diagnosis is crucial, as NLPHL overlaps morphologically and immunophenotypically with other lymphomas.

The most important differential diagnoses are

• Classical lymphocyte-rich Hodgkin's lymphoma (cHL, lymphocyte-rich type)
  - DifferenceAlthough both have a lymphocyte-rich environment, the tumor cells in cHL CD20-negative, CD15-positive and CD30-positive, in contrast to NLPHL
  - Differentiation: Immunophenotype is decisive
• Progressive Transformation of Germinal Centers (PTGC)
  - DifferencePTC is a premalignant, non-clonal Change that appears very similar histologically
  - DifferentiationClonality (e.g. through PCR for immunoglobulin genes) shows monoclonal B-cell proliferation in NLPHL, but polyclonal B-cell proliferation in PTC.
• T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL)
  - DifferenceTHRLBCL shows Aggressive clinical behavior, advanced stage and poor prognosis
  - DifferentiationHistologically similar patterns (diffuse, atypical), but T cells dominate, CD20-positive with B cells, no LP cells
  - MolecularTHRLBCL shows Clonal T-cell receptor rearrangement - in contrast to NLPHL, which B-cell clonal rearrangement has
• Follicular lymphoma (FL)
  - DifferenceFL is a Non-Hodgkin lymphoma, with follicular proliferation and B cellswhich CD20-positive, CD10-positive are
  - DifferentiationNo LP cells, no T cell-histiocyte overlap. CD21-positive in follicles (in contrast to NLPHL)
• Angioimmunoblastic T-cell lymphoma (AITL)
  - Difference: Shows T-cell clonal rearrangement, CD4-positive, CD10-negative, CD21-negative
  - Differentiation: Vessel density and T-cell infiltrate (high for AITL, low for NLPHL) and CD20-positive with T cells in the AITL
• Follicular T-cell lymphoma (FTCL)
  - Difference: T-cell clonal rearrangement, CD4-positive, CD8-negative, CD20-negative
  - Differentiation: Molecular detection of a T-cell receptor rearrangement

Diagnostics

• Lymph node biopsy with histological and immunophenotypic analysis
• Central marker
  CD20+, CD15-, CD30-, PAX5+, BCL6+, CD45+. 
• Molecular biology
  PCR for immunoglobulin genes to ensure B-cell clonality
• Staging
  Cotswold staging system to determine the degree of severity and spread
• Biopsy for recurrence
  Mandatory, yes Transformation into diffuse large B-cell lymphoma (DLBCL) approximately 10 % of cases within 10 years appearance

Therapy

• Stage IA without risk factors
  - Irradiation of the affected area (IFRT) with 30–36 Gy 
• Stage IA with risk factors or higher stage (II-IV)
  - Similar to classic HL: Chemotherapy (e.g. ABVD) or Combined therapy
  - Protocols from B-cell non-Hodgkin's lymphoma therapy (B-NHL) are also effective
• Recurrence
  - Rituximab (anti-CD20 antibody) is Very effective
  - High-dose chemotherapy with autologous stem cell transplantation only for few cases required
• New approaches
  Check clinical studies Rituximab + chemotherapy in the first line, especially in higher stages

Forecast

• Very good
  - 10-year survival rate >90 % for limited illness
  - First-line therapy leads to remission in 90-100 %
• Recurrence rate
  10-15 %, mostly 3–6 years after diagnosis
• Long-term consequences
  - Secondary malignancies
  – – Diffuse large B-cell lymphoma (DLBCL): 25 % Risk after 20 years
  – – Carcinomas (lung, breast, gastrointestinal tract) often in irradiated regions
  – – Cardiopulmonary diseases as a result of radiotherapy

The Differential diagnosis is critical, especially with THRLBCL, PTC, FL and AITL.

The therapy is stage-adapted, with Radiation for early stages and Chemotherapy for advanced cases. Rituximab is the therapy of choice.

Standard therapeutics (chemo)

Chemotherapy for lymphomas depends on the type (Hodgkin's vs. non-Hodgkin's lymphoma), the stage and the risk profile.

Common undesirable side effects are (see below for specific side effects):

• Myelosuppression (anemia, neutropenia, thrombocytopenia)
• Nausea, vomiting, tiredness (fatigue)
• Hair loss
• Immunosuppression
• Fertility impairment (in men and women)
• Secondary tumors (long-term, especially with alkylants and topoisomerase II inhibitors such as etoposide)

Hodgkin's lymphoma

ABVD

Standard in early and advanced stages:

• Bleomycin
  Pulmonary fibrosis (dose-dependent), pneumonitis (rare but serious)
• Doxorubicin
  Cardiotoxicity (dose-dependent), hair loss, nausea
• Vinblastine
  Neuropathy (sensory disturbances), constipation
• Dacarbazine
  Nausea, fatigue, myelo-suppressive.
  → Lower hematotoxicity than BEACOPP, but lung and heart risk

BEACOPP

For medium to high risk:

• Bleomycin
  Pulmonary fibrosis (dose-dependent), pneumonitis (rare but serious)
• Adriamycin
• vincristine (Oncovin)
  Neuropathy (tingling, furred skin), constipation
  → Higher acute toxicity, especially hematological; increased risk of secondary tumors in the long term
• Prednisolone
  FrequentlyWeight gain, increased appetite, water retention (edema), redistribution of fatty tissue (truncal obesity, moon face, bull neck), increased blood sugar (risk of diabetes), immunosuppression (increased susceptibility to infections), osteoporosis, muscle loss, sleep disorders.
  OccasionallySkin changes (thin skin, stretch marks, acne), eye problems (cataracts, glaucoma), high blood pressure, gastrointestinal complaints (ulcers). 
  RarerMood swings, depression, euphoria, psychotic states, headaches, menstrual disorders, impotence. 
  Long-term useRisk of kidney damage, premature arteriosclerosis, adrenal dysfunction.
• Etoposide
  Myelosuppression (neutropenia, thrombocytopenia), increased risk of infection
• Cyclophosphamide
  Bladder damage (hemorrhagic cystitis), myelosuppressive
• Procarbazine
  Myelosuppression, gastrointestinal toxicity, interaction with MAO inhibitors
• vincristine
  Neuropathy (tingling, furred skin), constipation
  → Higher acute toxicity, especially hematological; increased risk of secondary tumors in the long term

BrECADD

New standard in advanced stages (18-60 years)

• Brentuximab vedotin
  Peripheral neuropathy (sensory/motor), most common specific side effect, in up to 50 % of patients, leads to discontinuation of therapy in 23 %
  Demyelinating polyneuropathy, rare but serious (e.g. Guillain-Barré-like). 
  Infusion reactions and anaphylactic reactions due to the antibody component. 
  !- Pulmonary toxicity, absolute contraindication with Bleomycin – Life-threatening pulmonary fibrosis possible - !
  Rare but severe skin reactions - Stevens-Johnson syndrome and toxic epidermal necrolysis
  Progressive multifocal leukoencephalopathy (PML) due to JC virus reactivation, potentially fatal
  Tumor lysis syndrome for high tumor burden
  Fertility restriction, Possible impairment of male fertility - freezing of sperm recommended before starting therapy
• Etoposide
  Myelosuppression (neutropenia, thrombocytopenia), increased risk of infection
• Cyclophosphamide
  Bladder damage (hemorrhagic cystitis), myelosuppressive
• Doxorubicin
  Cardiotoxicity (dose-dependent), hair loss, nausea
• Dacarbazine
  Nausea, fatigue, myelo-suppressive.
  → Lower hematotoxicity than BEACOPP, but lung and heart risk

Non-Hodgkin's lymphoma (NHL)

CHOP

Basic regime, often combined with Rituximab (R-CHOP)

• Cyclophosphamide
  Bladder damage (hemorrhagic cystitis), myelosuppressive
• vincristine (Oncovin)
  Neuropathy (tingling, furred skin), constipation
  → Higher acute toxicity, especially hematological; increased risk of secondary tumors in the long term
• Doxorubicin
  Cardiotoxicity (dose-dependent), hair loss, nausea
• Prednisone - Prednisone is a Prodrug and must be activated via the liver → prednisolone is preferable in the case of liver dysfunction.
  FrequentlyWeight gain, increased appetite, water retention (edema), redistribution of fatty tissue (truncal obesity, moon face, bull neck), increased blood sugar (risk of diabetes), immunosuppression (increased susceptibility to infections), osteoporosis, muscle loss, sleep disorders.
  OccasionallySkin changes (thin skin, stretch marks, acne), eye problems (cataracts, glaucoma), high blood pressure, gastrointestinal complaints (ulcers). 
  RarerMood swings, depression, euphoria, psychotic states, headaches, menstrual disorders, impotence. 
  Long-term useRisk of kidney damage, premature arteriosclerosis, adrenal dysfunction.
  

R-Bendamustine

Alternative to R-CHOP, especially for older patients

• Rituximab
  Infusion reactions.
  → Severe kidney and nerve damage possible
• Bendamustine
  Myelosuppression, susceptibility to infections, skin reactions
  Lower risk of hair loss and neuropathy

R-DHAP / R-ICE

Intensive therapies for relapse, before stem cell transplantation

• Rituximab
  Infusion reactions.
  → Severe kidney and nerve damage possible
• Dexamethasone
  Higher risk of osteoporosis compared to other glucocorticoids, especially due to calcium loss. 
  Pheochromocytoma crisis Rare, but life-threatening, with symptoms such as high blood pressure, headaches, sweating and palpitations in unknown adrenal gland tumors
  Severe anaphylactic reactionsRare, but possible, up to circulatory failure, cardiac arrest or bronchospasm
  Central side effects Mental disorders (euphoria, intoxication, depression), insomnia, headaches, rarely epileptic seizures or pseudotumor cerebri (increase in intracranial pressure)
  Intravenous administration too fast can lead to short-term paraesthesia (tingling, burning), flushing or vein irritation, therefore run in slowly (2-3 minutes)
  Contraindication for certain infections due to the risk of activation of latent infections (e.g. chickenpox, measles, dwarf threadworm)
  Eyes Risk of glaucoma and cataract, especially with ocular or prolonged use. 
  Joint injection Rarely tendon rupture or vertebral body fracture
• High-dose cytarabine (Cytarabine)
  Ataxia, conjunctivitis, myelosuppressive
• Platinum (Cisplatin)
  

R-ICE

Intensive therapies for relapse, before stem cell transplantation

• Rituximab
  Infusion reactions.
  → Severe kidney and nerve damage possible
• Ifosfamide
  Neurotoxicity (encephalopathy), urinary bladder damage (mesna protection required)
• Carboplatin
  Myelosuppression (sharp drop in blood values)
• Etoposide
  Myelosuppression, secondary leukemia risk.
  → Less nephro- and ototoxicity than cisplatin, but higher neuro- and bladder toxicity

CVP

For indolent forms such as follicular lymphoma

• Cyclophosphamide
  Bladder damage (hemorrhagic cystitis), myelosuppressive
• vincristine (Oncovin)
  Neuropathy (tingling, furred skin), constipation
  → Higher acute toxicity, especially hematological; increased risk of secondary tumors in the long term
• Prednisone - Prednisone is a Prodrug and must be activated via the liver → prednisolone is preferable in the case of liver dysfunction.
  FrequentlyWeight gain, increased appetite, water retention (edema), redistribution of fatty tissue (truncal obesity, moon face, bull neck), increased blood sugar (risk of diabetes), immunosuppression (increased susceptibility to infections), osteoporosis, muscle loss, sleep disorders.
  OccasionallySkin changes (thin skin, stretch marks, acne), eye problems (cataracts, glaucoma), high blood pressure, gastrointestinal complaints (ulcers). 
  RarerMood swings, depression, euphoria, psychotic states, headaches, menstrual disorders, impotence. 
  Long-term useRisk of kidney damage, premature arteriosclerosis, adrenal dysfunction.

Special shapes

• Mantle cell lymphoma
  Often intensive with R-DHAP or R-CHOP, followed by high-dose chemotherapy + stem cell transplantation
• T-cell lymphomas
  CHOP-based regimens, possibly with etoposide (CHOEP)

Standard therapeutics - signaling pathways

Bendamustine

• Alkylation of the DNABendamustine is a bifunctional alkylane (nitrogen oxide derivative), which forms electrophilic alkyl groups. These bind covalently to the N7 position of guanine in the DNA → leads to intra- and interstrand DNA cross-links
• The cross-links interfere DNA replication, Transcription and Repair → DNA strand breaks (especially double strand breaks)
• Activation of p53 and DNA damage response → Cell cycle arrest and Apoptosis
• Inhibits the Alkyltransferase repair pathway and instead favors the Nucleotide excision repair pathway, which makes the repair more difficult

Additional effect: Purine analog structure → inhibits purine synthesis (antimetabolite properties). 

Effective Cycle non-specific, also against dormant cells. 

Shows activity in alkylansiene-resistant tumors, as the repair of DNA damage is slower and less efficient.

Bleomycin

• Binds to Iron(II) (Fe²⁺) and forms a Bleomycin-Fe(II) complex
• This complex reacts with oxygen and forms reactive oxygen species (ROS) such as superoxide and hydroxyl radicals
• The ROS cause DNA strand breaks (single and double-strand breaks), especially on G-C-rich sequences
• Specific damage caused by Abstraction of the 4′-H atom at the deoxyribose → break in the DNA backbone
• Resulting free base propenals (e.g. of thymine) contribute to cytotoxicity
• DNA damage leads to Cell cycle arrest in the G₂ phase → Inhibition of mitosis → Apoptosis
• Bleomycin acts as Pseudoenzyme, which can catalyze DNA damage multiple times. 
• Additional inhibition of the DNA-dependent DNA polymerase.

Cisplatin / carboplatin

Both act as Platinum-based alkylans, form after intracellular activation electrophilic aquo-complexes. These bind preferentially to N7 position of guanine and adenine in the DNA.
Emergence DNA cross-links:

• Intrastrand cross-linking (within a strand)
• Interstrand cross-linking (between both strands)

DNA deformation blocked Replication and transcription. 
Activation of DNA damage responses:

• p53 activation → Cell cycle arrest (usually in G2/M phase)
• Induction of Apoptosis via mitochondrial and caspase-dependent pathways

Additional effects:

• Inhibition of the DNA repair
• Inhibition of the Telomerase activity
• Induction of Point mutations
• At high concentrations: PARP hyperactivation → NAD+/ATP degradation → Necrosis

Carboplatin acts more slowly, but has the same mechanism of action as cisplatin → Cross-resistance possible.

Cyclophosphamide

Cyclophosphamide is a Prodrug, which is produced in the liver by CYP2B6 to 4-hydroxycyclophosphamide is converted. 

• This decomposes into Aldophosphamide and on to Phosphoramide Mustard (active) and Acrolein
• Phosphoramide Mustard acts as bifunctional alkylaneIt transfers alkyl groups to the N7 position of guanine in the DNA
• This results in DNA-DNA cross-links (cross-links) and DNA-protein cross-links, which fix the DNA strands
• Blocking the cross-links DNA replication and Transcription, lead to Strand breaks and activate p53-dependent Apoptosis

Effect is Cycle non-specific, but particularly effective in proliferating cells.

Acrolein causes the Bladder damage (hemorrhagic cystitis).

Cytarabine (Ara-C)

• Cytarabine is converted intracellularly to Ara-CTP phosphorylated, the active metabolite
• Ara-CTP inhibits DNA polymerase and is incorrectly incorporated into the DNA → Termination of the DNA chain
• Blockade of the DNA replication and repair → Cell cycle arrest in the S phase
• Induction of Apoptosis via DNA damage response (e.g. p53 activation)

Effect is Cycle phase specific (only in proliferating cells)

Dacarbacin

Dacarbazine is a Prodrug, which is produced in the liver by Cytochrome P450 to Monomethyltriazenylimidazole carboxamide (MTIC) is metabolized. MTIC spontaneously decomposes to a reactive Methyl cation, which is known as Alkylans works. 

• Alkylation of the DNA: The methyl cation binds primarily to the O-6 and N-7 position of guanine in the DNA
• This leads to DNA strand breaks, Mismatches during replication and Blockade of DNA synthesis
• Activate the damage DNA repair systems, but overloading or inefficient repair (e.g. low MGMT activity) results in Apoptosis

Effect is Cycle-independent, but particularly effective in proliferating cells

Dexamethasone

Binds to intracellular Glucocorticoid receptors → Complex migrates into the cell nucleus. 

• TransrepressionInhibits the transcription factors NF-κB and AP-1 → reduces expression of pro-inflammatory genes (cytokines such as IL-1, IL-6, TNF-α; enzymes such as phospholipase A2, COX-2)
• TransactivationActivates anti-inflammatory genes (e.g. for IκB, which inhibits NF-κB)
• In lymphatic cells
  activates the intrinsic apoptosis pathway → Mitochondrial permeabilization, cytochrome c release, caspase-9 activation
• In fibroblasts
  shows anti-apoptotic effect about:
  - Induction of the Sphingosine kinase 1 → increased production of Sphingosine-1-phosphate (S1P)
  - Activation of the PI3K/Akt signal path
  - Up-regulation of the anti-apoptotic protein Bcl-xL
  - Preservation of the mitochondrial membrane potential
• Inhibits Phospholipase A2 → Reduced release of pro-inflammatory mediators

Doxorubicin

• DNA intercalationThe planar molecule intercalates between DNA base pairs in a sequence-specific manner → interferes with helicases, blocks DNA replication and Transcription
• Topoisomerase II inhibition: Doxorubicin stabilizes the Topoisomerase II DNA cleavage complex → prevents DNA strands from reuniting → leads to Double-strand breaks
• ROS formationThe quinone structure is reduced to a semiquinone radical → generated reactive oxygen species (ROS) → Oxidative damage to DNA, lipids and proteins → DNA strand breaks
• Chromatin dynamics: Increases the Torsional stress in the DNA and promotes Nucleosome switching → Exposes DNA to further damage
• Cell cycle arrest and apoptosisActivate DNA damage p53 and DNA repair systems → in case of overload: cell cycle arrest (G2/M) and Apoptosis

Effect is Cycle non-specific, but particularly effective in proliferating cells.

Etoposide

• Inhibits Topoisomerase II, an enzyme that uncoils DNA during replication and transcription
• Binds to the Topoisomerase II DNA complex and stabilizes it → prevents the Re-ligation (reconnection) of the DNA strands after cleavage
• Leads to persistent double-strand breaks in the DNA
• Activate DNA damage p53 and other repair mechanisms → in the event of overload: Cell cycle arrest in the G2 phase
• Induction of the Apoptosis via mitochondrial and caspase-dependent signaling pathways

Effect is Cycle phase specific, especially in the late S and G2 phase.

Glucocorticoids (prednisone / prednisolone)

• Genomic effect
  Prednisone is converted in the liver to Prednisolone (active). Both bind to cytoplasmic Glucocorticoid receptors (GKR). The complex translocates into the cell nucleus and modulates gene expression via:
  - TransactivationBinding to Glucocorticoid response elements (GRE) → increased expression of anti-inflammatory genes (e.g.  Lipocortin, which inhibits phospholipase A2)
  - TransrepressionInhibition of transcription factors NF-κB and AP-1 → reduced production of pro-inflammatory cytokines (IL-1, IL-2, IL-6, TNF-α, IFN-γ), enzymes (COX-2, phospholipase A2) and leukotrienes
• Non-genomic effect
  - At high doses (e.g. i.v.) rapid effect via membrane receptors → improved microcirculation in shock, increased effect of catecholamines
• Further effects
  - Inhibition of fibroblast proliferation and collagen synthesis (antiproliferative)
  - Immunosuppression through inhibition of proliferation of T lymphocytes
  - Metabolic effects: Gluconeogenesis, lipolysis, proteolysis → increased blood sugar

Ifosfamide

ProdrugIs produced in the liver by CYP450 enzymes (e.g. CYP3A4) to 4-Hydroxy-Ifosfamide activated.

• Spontaneous conversion to Isoaldophosphamide, which in Isophosphamide-Lost (alkylating) and Acrolein disintegrates
• Isophosphamide-Lost transfers alkyl groups to the N7 position of guanine in the DNA → causes DNA strand breaks and Inter- and intrastrong cross-linking
• This DNA damage blocks Replication and Transcription → lead to Cell cycle arrest in the G2 phase
• If the repair mechanisms are overloaded (e.g. by MGMT) → Apoptosis
• Acrolein causes the urotoxic effects (e.g. hemorrhagic cystitis)

Effect is Cycle non-specific, but particularly effective in proliferating cells.

Cross-resistance with cyclophosphamide possiblebut also Activity in cyclophosphamide-resistant tumors.

Procarbazine

Is oxidized in the liver (via CYP450) and spontaneously to Azo-procarbazine, then continue to Methylazoxy- and Benzylazoxy compounds. 

• Alkylation of the DNAactive metabolites (e.g. Methyl diazonium ion) alkylate the N7 position of guanine → leads to DNA single-strand breaks, Cross-linking and Mismatches
• Inhibition of protein synthesis inhibits the Transmethylation of methionine in t-RNA → Defective t-RNA → Termination of protein synthesis → Secondary inhibition of DNA and RNA synthesis
• ROS formation - is formed during autooxidation Hydrogen peroxide → Oxidative damage to proteins (e.g. sulfhydryl groups)
• Cell cycle arrest - Damage activates DNA repair mechanisms → Cell cycle arrest → in case of overload Apoptosis
• Further effect is a weak MAO inhibition (central nervous system)

Rituximab

The name results from

• RI - Variable (defined by the manufacturer)
• you - for „tumor“
• xi - for „chimeric“ (the variable region is murine, the constant region is human)
• mab - for „monoclonal antibody“ 

Rituximab binds to the CD20 antigen on B cells and activates several mechanisms of action:

• Antibody-dependent cell-mediated cytotoxicity (ADCC)Fc region of the antibody activates natural killer cells that destroy the target cell
• Complement-dependent cytotoxicity (CDC)Activation of the complement system (via C1q) → Formation of the membrane attack complex → Cell lysis
• Direct apoptosis inductionCD20-mediated signaling pathway → Activation of p38 MAP kinase → programmed cell death (apoptosis), especially after cross-linking of the antibody
• Phagocytosis: Macrophages recognize and phagocytose labeled B cells

These mechanisms lead to selective elimination of CD20-positive B cells without affecting stem cells in the bone marrow.

Rituximab is a cHimeric monoclonal antibody, which comes from murine (mouse) variable domains and human (human) constant domains, interacts optimally with Fc receptors (crystallizable fragment / crystallizable fragment) on effector cells (NK cells, monocytes, macrophages) and the complement system.

• Fc receptors are Membrane proteins on the surface of immune cells, that recognize and bind to the constant Fc portion of antibodies. 
  They combine humoral immunity (antibodies) with cell-mediated immunity by activating immune cells as soon as they bind to target cells (e.g., bacteria, tumor cells, viruses) marked with antibodies.

• NK cells are a Lymphocyte type of the innate immune system, recognize and destroy infected and tumor cells without having to recognize specific antigens.
  As soon as one cell has less MHC-I molecules (Surface proteins for the presentation of peptides from the cell interior, e.g., in viral infections or tumor formation) are presented as usual, it is recognized as foreign and killed.

• Monocytes arise, such as B cells (B lymphocytes), in the bone marrow and circulate in the blood as Part of the non-specific immune defense. Once they have migrated into tissue, they differentiate into macrophages.

• Macrophages are derived from monocytes as mature phagocytes All macrophages together manage around one million cells per second! They dispose of dead, destroyed cells and cell debris. A macrophage can phagocytose several hundred to a thousand cells a day.

• Complement system is Essential component of the innate immune system, consisting of 30 proteins that are produced in the liver and circulate in the plasma to supplement the effect of antibodies.

This means:

The rituximab structure:

├─ Variable domains (Fab part): MURINE (mouse sequence)
│ └─ This part recognizes CD20
├─ Constant domains (Fc part): HUMAN (human sequence)
│ └─ This part activates ADCC, CDC

Finding out how and why it came about is a very exciting development that here is described in more detail below ...!

Vincristine / vinblastine

• Binding to β-tubulin and inhibit the Polymerization of microtubules. 
• Disturb the structure of the mitotic spindle during the metaphase → Mitosearrest. 
• Lead to Cell cycle arrest in the M phase and ultimately to Apoptosis. 
• Effect Cycle phase specific against rapidly dividing cells (e.g. tumor cells).
• Vinblastine can also Crystallize tubulin leave. 
• Both substances impair axonal transport → contribute to the neurotoxic side effect with. 
• Additional inhibition of DNA and RNA synthesis (secondary effect).

Phyto-therapy options

All references are from the NIH National Library of Medicine of the National Center of Biotechnology Information, 8600 Rockville Pike, Bethesda, MD 20894, or recognized publishers. Care was taken to ensure that there were no conflicts of interest in order to guarantee a largely objective, scientifically sound level.
The articles may only contain abstracts. However, full texts are usually linked at the top right, either as free or fee-based publications.

Commonly known radioprotective agents include

Huaier's mushroom (Trametes robiniophila Murr.)

The Huaier mushroom has been used in traditional Chinese medicine (TCM) for centuries and is gaining increasing attention in complementary cancer therapy. Studies indicate that huaier extracts can Support immune function, Reducing the side effects of radiotherapy and that Reducing the risk of recurrence can.
Particularly relevant is its effect on the Protective function of the bone marrow and the Stimulation of immune cells, which is of great importance in radiotherapy, as radiation can damage the bone marrow and impair blood formation.
The mushroom contains bioactive polysaccharides and peptidoglycans, which have an immunomodulating and anti-tumor effect.

It should be noted that the percentage of Polysaccharides 32% the content of β-glucan fractions should also be determined using Laboratory analysis is proven to be around 47%, as both are the main active ingredients for which the effects proven by studies are also present!

Sources

- Hong Tang, Yujuan Yi, Yuru Yang, Qi Dai, Ziyan Zhao, Ning Jiang, Han Wang, Kangzi Li, Jianing Liu, Jia Li, 
Zheng - Sun June 3, 2024 - The potential therapeutic benefits of Huaier in digestive system cancer: Its chemical components, pharmacological applications and future direction
- Hongrong Long, Zhngcai Wu - Front Immunol. 2023 Jun 28 - Immunoregulatory effects of Huaier (Trametes robiniophila Murr) and relevant clinical applications
- Qu P, Han J, Qiu Y, Yu H, Hao J, Jin R, Zhou F. - Biomed Pharmacother. 2019 Sep - Huaier extract enhances the treatment efficacy of imatinib in Ik6(+) Ph(+) acute lymphoblastic leukemia.

Reishi (Ganoderma lucidum)

Known as the „mushroom of immortality“, Reishi has the following effectsimmunomodulating, anti-inflammatory and protects the liver.
It can increase stress resistance and support regeneration after radiation damage.
Triterpenes and beta-glucans promote the activity of macrophages and NK cells.

Sources

- Jiao C, Chen W, Tan X, Liang H, Li J, Yun H, He C, Chen J, Ma X, Xie Y, Yang BB. - J Ethnopharmacol. 2020 Jan 30 - Ganoderma lucidum spore oil induces apoptosis of breast cancer cells in vitro and in vivo by activating caspase-3 and caspase-9
- Lihua Chen, Abudumijiti Abulizi, Min Li - November 28, 2019 - Protective Effect of Ganoderma (Lingzhi) on Radiation and Chemotherapy
- Xirui He, Xiaoxiao Wang, Jiacheng Fang, Yu Chang, Ning Ning, Hao Guo, Linhong Huang, Xiaoqiang Huang,
Zefeng Zhao - April 06, 2017 - Ganoderma lucidum (Reishi mushroom) for cancer treatment
- Calviño E, Pajuelo L, Casas JA, Manjón JL, Tejedor MC, Herráez A, Alonso MD, Diez JC. - Phytother Res. 2011 Jan - Cytotoxic action of Ganoderma lucidum on interleukin-3 dependent lymphoma DA-1 cells: involvement of apoptosis proteins
- Müller CI, Kumagai T, O'Kelly J, Seeram NP, Heber D, Koeffler HP. - Leuk Res. 2006 Jul - Ganoderma lucidum causes apoptosis in leukemia, lymphoma and multiple myeloma cells.
- Dr. med. Silke Fischer - December 11, 2025 - The medicinal mushroom Ganoderma lucidum (Reishi) in modern medicine: An evidence-based review article for the professional audience

Shiitake (Lentinula edodes)

Contains lentinan and beta-glucans, which Immune cell activity such as NK cells and macrophages.
Studies show a antimicrobial and antiviral effect, which is helpful for infectious risks after radiotherapy.

Sources

- Egilius L.H. Spierings, Hajime Fujii, Buxiang Sun, Thomas Walshe - March 14, 2007 - A Phase I study of the safety of the nutritional supplement, active hexose correlated compound, AHCC, in healthy volunteers
- Joichi Matsui, Juna Uhara, Sohei Satoi, Masaki Kaibori, Hitoshi Yamada, Hiroaki Kitade, Atsusi Imamura, Soichiro Takai, Yusai Kawaguchi, A-Hon Kwon, Yasuo Kamiyama - March 18, 2002 - Improved prognosis of postoperative hepatocellular carcinoma patients when treated with functional foods: a prospective cohort study
- Kyoku Shimizu, Shinya Watanabe, Seiji Watanabe, Kenji Matsuda, Tetsuya Suga, Sabburo Nakazawa, Keiko Shiratori - Hepatogastroenterology 2009 Jan-Feb - Efficacy of orally administered superfine dispersed lentinan for advanced pancreatic cancer Source 4
- Clinical application of a combination therapy of lentinan, multi-electrode RFA and TACE in HCC Source 5

Maitake (Grifola frondosa)

Rich in beta-glucans, which Strengthen immune defenses and the Promote cell regeneration.
Studies indicate a role in the Blood sugar regulation and Weight management important aspects of nutrition during and after radiotherapy.

Sources

- Yanli He, Lijuan Zhang, Hua Wang - 2019 Mar 25 - The biological activities of the antitumor drug Grifola frondosa polysaccharide
- Xirui He, Xiaoxiao Wang, Jiacheng Fang, Yu Chang, Ning Ning, Hao Guo, Linhong Huang, Xiaoqiang Huang, 
Zefeng Zhao - April 6, 2017 - International Journal of Biological Macromolecules - Polysaccharides in Grifola frondosa mushroom and their health promoting properties: A review.

Coriolus (Trametes versicolor / Polyporus umbellatus)

Often used as Accompanying therapy for chemotherapy and radiotherapy used.
He improves the quality of life, strengthens the immune system and increases the Radiosensitivity of cancer cells (the response to radiation, - However, radiosensitivity varies greatly between different tumor types and even within a tumor.
The ingredient PSK (polysaccharide crestin) has been well studied clinically.

Sources

- Habtemariam S. Biomedicines. - 2020 May 25 - Trametes versicolor (Synn. Coriolus versicolor) Polysaccharides in Cancer Therapy: Targets and Efficacy
- Yang CL, Chik SC, Lau AS, Chan GC.J Ethnopharmacol. - 2023 Jan 30 - Coriolus versicolor and its bioactive molecule are potential immunomodulators against cancer cell metastasis via inactivation of MAPK pathway
- Pilkington K, Wieland LS, Teng L, Jin XY, Storey D, Liu JP. - Cochrane Database Syst Rev - 2022 Nov 29 -Coriolus (Trametes) versicolor mushroom to reduce adverse effects from chemotherapy or radiotherapy in people with colorectal cancer
- Lau CB, Ho CY, Kim CF, Leung KN, Fung KP, Tse TF, Chan HH, Chow MS. - Life Sci. 2004 Jul 2 - Cytotoxic activities of Coriolus versicolor (Yunzhi) extract on human leukemia and lymphoma cells by induction of apoptosis

Barbary (Berberis vulgaris)

• Radiotherapy damagePreclinical and initial clinical studies indicate that berberine has radioprotective properties, particularly through antioxidant and anti-inflammatory effects. A pilot study showed a reduction in radiation-related side effects in cancer patients. 

• LymphomasIn vitro and animal studies show that berberine can inhibit the growth of lymphoma cells, e.g. by suppressing the CD47 immune escape mechanism in diffuse large B-cell lymphoma. Synergistic effects with chemotherapeutic agents have also been observed.

Sources

- Mohammadian Haftcheshmeh S, Musavi M, Lotfi S, Soleimani A, Dodangeh M, Mohammadi A, Momtazi-Borojeni AA. - Inflammopharmacology. 2025 Aug - Berberine as a natural immunomodulator of B lymphocytes
- Cao YQ, Sun C, Li JY, Zhou X. - Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2024 Apr - Research Progress on the Role of Berberine in Hematologic Malignancies and Its Related Mechanisms -Review
- Chang S, Li B, Xie Y, Wang Y, Xu Z, Jin S, Yu D, Wang H, Lu Y, Zhang Y, Ma R, Huang C, Lai W, Wu X, Zhu W, Shi J. - Neoplasia. 2022 Jan - DCZ0014, a novel compound in the therapy of diffuse large B-cell lymphoma via the B cell receptor signaling pathway
- Ren S, Cai Y, Hu S, Liu J, Zhao Y, Ding M, Chen X, Zhan L, Zhou X, Wang X. - Biochem Pharmacol. 2021 Jun - Berberine exerts anti-tumor activity in diffuse large B-cell lymphoma by modulating c-myc/CD47 axis

Echinacea (coneflower)

Strengthens the Innate immunity by stimulating phagocytes and NK cells.
Often used for colds and as part of therapies for Defense against infections used.

Sources

- Salama AAA, Elgohary R, Elwahab SA, Mostafa RE. - Sci Rep. 2025 Sep 2 - Echinacea purpurea ameliorates bleomycin-induced pulmonary fibrosis in rats through modulating NADPH oxidase-4 and endothelin-1/connective tissue growth factor/matrix metalloproteinases signaling axis.
- Mishima S, Saito K, Maruyama H, Inoue M, Yamashita T, Ishida T, Gu Y. - Biol Pharm Bull. 2004 Jul - Antioxidant and immuno-enhancing effects of Echinacea purpurea
- Hussien SM, Rashed ER - Dose Response 2023 Jun 21 - Immuno-Biochemical Impacts of Gamma Irradiation in Male Rats: A Dose-Response Study
- Joksić G, Petrović S, Joksić I, Leskovac A. - Arh Hig Rada Toksikol. 2009 Jun - Biological effects of Echinacea purpurea on human blood cells

Turmeric (curcumin)

Effective anti-inflammatory, antioxidant and protects cells from oxidative stress, which is caused by radiation.
Curcumin can improve the Support cell regeneration and the Enhancing the effect of radiotherapy, without damaging healthy cells.

Sources

- Zhang X, Cui Q, Yin L, Zhu J, Mao Y, Yin R, Shao H, Wang W, Sun X, Zhang Z, Gu C, Zhang M, Zhang R, Lu H, Cai Z, Li H, Yang Z. - Gut Microbes. 2025 Dec - Ginger-derived vesicle-like nanoparticles loaded with curcumin to alleviate ionizing radiation-induced intestinal damage via gut microbiota regulation
- Xiu Z, Sun T, Yang Y, He Y, Yang S, Xue X, Yang W. - Oxid Med Cell Longev. 2022 Oct 4 - Curcumin Enhanced Ionizing Radiation-Induced Immunogenic Cell Death in Glioma Cells through Endoplasmic Reticulum Stress Signaling Pathways
- Jagetia GC. - int J Radiat Biol. 2021 - Antioxidant activity of curcumin protects against the radiation-induced micronuclei formation in cultured human peripheral blood lymphocytes exposed to various doses of gamma-radiation

Ginger (gingerols)

Has antimicrobial and anti-inflammatory properties.
Supports digestion and can improve Mitigating the side effects of therapies.

Sources

- Zhang L, Hu R, Zhang J, Zhang H. - Colloids Surf B Biointerfaces. 2026 Feb - Dual-targeted exosome nanoplatform co-delivering doxorubicin and Fuzi Lizhong Tang bioactives for synergistic DLBCL therapy and chemotherapy-induced diarrhea management.
- Nafees S, Zafaryab M, Mehdi SH, Zia B, Rizvi MA, Khan MA. - Anticancer Agents Med Chem. 2021 - Anti-Cancer Effect of Gingerol in Cancer Prevention and Treatment

Citrus fruits & quercetin

Quercetin from onions and citrus fruits shows Antiviral and immunomodulating effect.
Studies investigate its role in the Strengthening the immune system (also in the context of COVID-19).

Sources

- Han P, Chu S, Shen J, Li L, Zhang Y, Wang S, Chen Y, Ma Y, Tang X, Gao C, Zheng X, Xu B, Wang Q, Yuan D, Li S. - Cell Metab. 2025 Dec 2 - Quercetin-derived microbial metabolite DOPAC potentiates CD8(+) T cell anti-tumor immunity via NRF2-mediated mitophagy
- Soofiyani SR, Hosseini K, Forouhandeh H, Ghasemnejad T, Tarhriz V, Asgharian P, Reiner Ž, Sharifi-Rad J, Cho WC. - Oxide Med Cell Longev. 2021 Aug 2 - Quercetin as a Novel Therapeutic Approach for Lymphoma
- Granato M, Rizzello C, Gilardini Montani MS, Cuomo L, Vitillo M, Santarelli R, Gonnella R, D'Orazi G, Faggioni A, Cirone M. - J Nutr Biochem. 2017 Mar - Quercetin induces apoptosis and autophagy in primary effusion lymphoma cells by inhibiting PI3K/AKT/mTOR and STAT3 signaling pathways
- Li X, Wang X, Zhang M, Li A, Sun Z, Yu Q. - Cell Biochem Biophys. 2014 Nov - Quercetin potentiates the antitumor activity of rituximab in diffuse large B-cell lymphoma by inhibiting STAT3 pathway

Black cumin seed oil (Nigella sativa)

Has been used as an immune booster since time immemorial.
The contained Thymoquinones work Antioxidant, anti-inflammatory and immunomodulating.
Shows positive effects on blood sugar, blood lipid levels and the immune system.

Sources

- Arslan BA, Isik FB, Gur H, Ozen F, Catal T. - Pharmacogn Mag. 2017 Oct - Apoptotic Effect of Nigella sativa on Human Lymphoma U937 Cells
- Salomi NJ, Nair SC, Jayawardhanan KK, Varghese CD, Panikkar KR. - Cancer Lett. 1992 Mar 31 - Antitumor principles from Nigella sativa seeds

Ginseng (Panax ginseng)

Acts as Adaptogen, improves the Stress resistance and supports the Energy generation after therapies.
Can the Stabilize immune function and the Promote regeneration.

Sources

- Li Q, Chen Y, Zhao X, Lu B, Qu T, Tang L, Zheng Q. - PLoS One. 2023 May 19 - Ginsenoside 24-OH-PD from red ginseng inhibits acute T-lymphocytic leukaemia by activating the mitochondrial pathway
- Pradhan P, Wen W, Cai H, Gao YT, Shu XO, Zheng W. - J Nutr. 2023 Apr - Prospective Cohort Study of Ginseng Consumption in Association with Cancer Risk: Shanghai Women's Health Study
- Lee SY, Shin YW, Hahm KB. - J Dig Dis. 2008 Aug - Phytoceuticals: mighty but ignored weapons against Helicobacter pylori infection

Phyto-therapeutics - signaling pathways

Huaier (Trametes robiniophila Murr.)

The active ingredients of the Huaier mushroom - in particular polysaccharides, proteoglycans and flavonoids - intervene in several central signaling pathways:

• PI3K/Akt/mTOR
  Inhibition of this growth and survival pathway → reduces proliferation and induction of apoptosis in cancer cells
• MAPK/ERK and p38
  Modulation of these pathways → influences cell proliferation, differentiation and stress response
• TLR4/NF-κB
  Activation via polysaccharides → stimulates immune cells (e.g. dendritic cells, macrophages) → improves immune response
• AMPK
  Activation → promotes cellular energy balance and inhibits anabolic processes
• YAP1 and Wnt/β-catenin
  Inhibition of oncogenic signaling pathways → reduces tumor growth and tumor stem cell properties
• TGF-β/Smad
  Modulation → inhibits fibrotic processes in organs
• Apoptosis-
  Induction via Caspase-3/9, ROS increase and mTOR inhibition
• Autophagy
  Promotion via mTOR inhibition and ROS → contributes to detoxification (e.g. of spike proteins)
• EMT (Epithelial-Mesenchymal Transition)
  Escapement via Snail and MMP-9 downregulation → Reduces metastasis

Reishi (Ganoderma lucidum)

• Immunomodulation
  Polysaccharides (e.g. β-glucans) bind to Dectin-1, TLRs and Complement receptor 3 → activate NF-κB and MAPK → promote differentiation and activation of macrophages, dendritic cells and NK cells
• Inflammation inhibition
  Triterpenes inhibit NF-κB and that NLRP3-Inflammasome → reduce production of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6)
• Neuroprotection
  Inhibition of neuroinflammation, modulation of microglia, upregulation of BDNF → promotes neuroplasticity; activation of the FGFR1 signaling pathway → Increases neurogenesis in the hippocampus
• Gut-brain axis
  Reishi modulates the microbiome → increases Bifidobacterium → improves tryptophan metabolism → increases Serotonin (5-HT) in the hypothalamus → sleep-promoting and mood-regulating
• AMPK activation
  Regulates energy metabolism, promotes glucose uptake, improves insulin sensitivity (analogous to metformin)
• Antihypertensive
  Inhibit peptides ACE and activate the eNOS/NO/cGMP signaling pathway → leads to vasodilation
• Antidiabetic
  Activated AMPK, improves phosphorylation of IR, IRS1 and Act → Increases insulin sensitivity; inhibits SREBP1c, FAS, SCD1 → suppresses lipogenesis
• Antioxidant
  Reduces ROS via activation of endogenous antioxidant systems

Shiitake (Lentinula edodes)

• Immunomodulation
  The polysaccharide Lentinan binds to Dectin-1, TLRs and Complement receptor 3 → activated NF-κB and MAPK → Stimulates macrophages, dendritic cells and NK cells
• Cytokine production
  Lentinan induced Interleukin-1 (IL-1), Interleukin-2 (IL-2), Interferon-γ and TNF-α → enhances cellular immune response and apoptosis of tumor cells
• Antitumor effect
  Lentinan has No direct cytotoxicity, but indirectly strengthens the fight against tumors via immune activation → increases Antibody production and endogenous interferon
• Apoptosis induction
  Promotes apoptosis of cancer cells via Caspase-3/8/9-Activation and mitochondrial signaling pathways
• Antiviral
  Increases resistance to viruses (e.g. influenza) via interferon induction
• Lipid metabolism
  The ingredient Eritadenin activated Lipoprotein receptors in the liver → increases LDL uptake → lowers LDL and VLDL cholesterol
• Anti-inflammatory
  Inhibits NF-κB and NLRP3-Inflammasome → Reduces inflammation
• Microbiome regulation
  Promotes the growth of Bifidobacteria and Lactobacteria → Improves intestinal barrier and immunological regulation

Maitake (Grifola frondosa)

• Immunomodulation
  Polysaccharides (e.g. D-fraction, Grifolan) bind to TLR4, Dectin-1 and Complement receptor 3 → activate TLR4-MyD88-IKKβ-NF-κB p65-Signalweg → stimulate macrophages, dendritic cells, NK cells and cytotoxic T cells
• TH1/TH2 balance
  Shift from TH2 to TH1 response → increased production of Interferon-γ, IL-12, IL-18 → Strengthens cellular immune defense
• Antitumor effect
  Induction of Apoptosis about the mitochondrial signaling pathway (Caspase-3/9 activation) → Tumor cell death
• MAPK signaling pathway
  Activate maitake polysaccharides p38 MAPK and JNK → Promote immune response and protect against immunosuppression
• Blood sugar regulation
  Inhibition of the Alpha-glucosidase → Slows down glucose release; increases the Insulin sensitivity via F2/F3 polysaccharides and SX glycoprotein. 
• Metabolism
  Activation of PPARδ and insulin-independent signaling pathways → improve glucose tolerance, lower triglycerides and cholesterol
• Blood pressure regulation
  Influence on the Renin-angiotensin system → Lowering of the systolic blood pressure
• Intestinal health
  Modulation of the Intestinal microbiota → Increase from Bifidobacteria and short-chain fatty acids → Anti-inflammatory and metabolically stabilizing
• Antioxidant
  Activation of endogenous enzymes (SOD, glutathione peroxidase) → reduces oxidative stress

Coriolus (Trametes versicolor / Polyporus umbellatus)

• Immunomodulation
  Polysaccharide peptides (PSP, PSK) bind to TLRs (e.g. TLR2, TLR4), Dectin-1 and Complement receptor 3 → activate NF-κB and p38 MAPK → Stimulate macrophages, dendritic cells, NK cells and T cells 
• Cytokine production
  Induction of IL-2, IFN-γ, TNF-α and IL-6 → strengthens cellular immune response
• Antitumor effect
  Indirectly via immune activation; directly through Cell cycle arrest and Apoptosis induction in tumor cells (e.g. via caspase activation)
• Anti-inflammatory
  Modulation of the TLR4-MyD88-NF-κB signaling pathway → Regulates inflammatory response
• Inhibition of metastases
  PSK inhibits Metalloproteinases (MMPs) → Reduces tumor invasion
• Liver protection
  PSP increased GSH/GSSG ratio → Antioxidant protection of hepatotoxic damage

Barbary (Berberis vulgaris)

• Apoptosis induction
  Activated p53, Caspase-3/9, Cytochrome c; inhibits anti-apoptotic proteins such as Bcl-2 and Mcl-1
• Cell cycle arrest
  Blocks G1 and G2/M phase through upregulation of p21 and GADD153
• Inhibition of growth pathways
  Inhibited PI3K/Akt/mTOR, MAPK, NF-κB, STAT3 and Wnt/β-catenin
• Mitochondrial effect
  Disturbs membrane potential → ROS increase → Energy crisis in tumor cells
• DNA interaction
  Binds directly to DNA and inhibits Topoisomerase I
• Inflammation inhibition
  Inhibits NF-κB and pro-inflammatory cytokines (TNF-α, IL-6)
• Antioxidant
  Activated Nrf2/HO-1- and AMPK-signaling pathways → protects healthy cells
• Immunomodulation
  Suppressed CD47 („Don't-eat-me“ signal) → promotes phagocytosis of tumor cells

Echinacea (coneflower)

• CB2 receptor activation
  Alkylamides bind to cannabinoid receptor 2 (CB2) on immune cells → modulate immune response without psychoactive effects
• cAMP-PKA signaling pathway
  CB2 activation increases cAMP → activates PKA → regulates NF-κB and cytokine production
• MAPK signaling pathways
  Activation of p38/MAPK, JNK and ERK1 → Influences cell proliferation, differentiation and inflammatory response
• NF-κB inhibition
  Through CB2 and TLR4 modulation → reduces pro-inflammatory cytokines (TNF-α, IL-1β, IL-6)
• TLR4 antagonism
  Suppresses MyD88/TRIF-dependent signaling pathways → reduces inflammation
• JAK1/STAT1 signaling pathway
  Induction of interferon-dependent genes → strengthens antiviral defense
• Cytokine modulation
  Increase of IL-10 (anti-inflammatory), inhibition of IL-12 (pro-inflammatory) → promotes TH1/TH2 balance
• T-cell regulation
  Promoted Foxp3 expression in regulatory T cells → immunomodulatory effect

Turmeric (curcumin)

• Inhibition of NF-κB
  Suppresses this central transcription factor → reduces inflammation, cell proliferation and apoptosis inhibition → lowers expression of COX-2, TNF-α, IL-6, IL-8, MMP-9
• Activation of p53
  Increases the tumor suppressor p53 → promotes DNA repair and apoptosis
• Regulation of the Bax/Bcl-2 ratio
  Increases pro-apoptotic Bax, lowers anti-apoptotic Bcl-2 → promotes mitochondria-mediated apoptosis
• Inhibition of mTOR
  Inhibits growth and proliferation → anticarcinogenic effect
• Antiangiogenesis
  Inhibits VEGF → prevents the formation of new tumor vessels
• Inhibition of MMP-9
  Reduces tissue degradation → inhibits invasion and metastasis
• Inhibition of adhesion molecules (e.g. CD44)
  Impairs tumor cell adhesion and invasion
• Activation of the Nrf2 signaling pathway
  Increases the body's own antioxidants → protects against oxidative stress
• Modulation of cell cycle proteins
  Inhibits cyclin D1, p16, CDK inhibitors → arrest in the cell cycle

Ginger (gingerols)

• TRPV1 receptor activation
  Gingerols bind to the TRPV1 ion channel on immune cells → put neutrophil granulocytes on high alert → increased ROS production and CXCL8 secretion during bacterial stimulation
• Inflammation inhibition
  Inhibition of NF-κB, p38 MAPK and JNK → reduces expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8), COX-2 and PGE2
• Antioxidant
  Increase in antioxidant enzymes (e.g. SOD), protection against mitochondrial damage
• Antiemetic
  Effect via serotonergic and cholinergic signaling pathways in the vomiting center → relieves nausea
• Metabolic effect
  Improves insulin sensitivity, promotes GLUT4-mediated glucose uptake → helpful for diabetes
• Cartilage protection
  Inhibition of the p38/JNK signaling pathway → reduces cartilage degradation in osteoarthritis
• Apoptosis induction
  6-Shogaol induces apoptosis in inflamed synovial cells → anti-inflammatory effect

Citrus fruits & quercetin

• NF-κB inhibition
  Blocks this central inflammatory switch → reduces TNF-α, IL-6, IL-1β, COX-2 and iNOS
• Nrf2 activation
  Binds to antioxidant response elements (ARE) → increases expression of HO-1, NQO1, GCLC → strengthens endogenous antioxidant defense
• MAPK modulation
  Inhibits p38, JNK and ERK → regulates inflammation, proliferation and apoptosis
• JAK/STAT inhibition
  Suppresses pro-inflammatory signal transmission
• COX-1/2 and LOX inhibition
  Reduces prostaglandin and leukotriene formation → anti-inflammatory
• AMPK/SIRT1 activation
  Improves mitochondrial metabolism, promotes autophagy, protects against oxidative stress
• Mast cell stabilization
  Inhibits histamine and cytokine release (e.g. IL-8, TNF) → anti-allergic
• NLRP3 inflammasome attenuation
  Suppresses IL-1β production
• Senolytic effect
  Promotes elimination of old, dysfunctional cells (senescence)

Black cumin seed oil (Nigella sativa)

• Nrf2/ARE activation
  Increases antioxidant enzymes (HO-1, SOD, CAT) → protects against oxidative stress
• NF-κB inhibition
  Suppresses inflammation → reduces TNF-α, IL-6, IL-1β, COX-2, iNOS
• PI3K/Akt/mTOR inhibition
  Inhibits growth and proliferation → anticarcinogenic effect
• MAPK modulation
  Inhibits p38, JNK and ERK → regulates inflammation and apoptosis
• AMPK/SIRT1 activation
  Improves mitochondrial metabolism, promotes autophagy
• Apoptosis induction
  Activates p53, Bax/Bcl-2 ratio, caspases → cellular tumor death
• COX-2 inhibition
  Reduces inflammatory mediators
• JAK/STAT inhibition
  Suppresses pro-inflammatory signal transmission
• GABA increase
  Increases cerebral GABA levels → anticonvulsant, neuroprotective

Ginseng (Panax ginseng)

• HPA axis modulation
  Ginsenosides (e.g. Rd) dampen the stress-induced Cortisol production → adaptogenic effect for exhaustion and stress
• Neurotransmitter systems
  Activate cholinergic and dopaminergic signaling pathways → improve cognitive performance, concentration and mood (e.g. through ginsenoside Rg1)
• Inflammation inhibition
  Inhibit NF-κB and proinflammatory cytokines → reduce neuroinflammatory processes
• Antioxidant effect
  Activate Nrf2-signaling pathway → increase endogenous antioxidants (HO-1, SOD) → protect against oxidative stress
• Neuroprotection
  Convey BDNF (brain-derived neurotrophic factor) → support neuronal regeneration and synaptic plasticity
• Amyloid β-inhibition
  Suppress the formation of Amyloid-β plaques → Potentially neuroprotective in Alzheimer's disease
• Promoting blood circulation
  Increase the production of Nitric oxide (NO) → Vasodilation, improved cerebral and peripheral perfusion
• Immunomodulation
  Regulate macrophage and NK cell activity via TLR4 and MAPK → strengthen immune defense

Rituximab - the history of development

1975 - Development of the Hybridoma technology

Before 1975, researchers were unable to find large quantities of identical antibody produce antibodies. When they immunized a mouse with an antigen, the mouse produced a limited number of different antibodies against different parts of the antigen (polyclonal).

Georges Köhler and César Milstein developed the Hybridoma technology by

• B lymphocytes from the spleen of an immunized mouse took
• these with immortal myeloma cells (cancer cells that can divide indefinitely) immunized with

That was revolutionary, which is why both were awarded the Nobel Prize for Physiology or Medicine received.

How can cells be immortal?

Tumor cells are always immortal because they use a trick to stimulate the cell to divide again and again and maintain this ability to divide. Normal cells, on the other hand, die automatically, as explained below.

Plasmacytoma in mice - the original source

The immortal myeloma cells originate from natural plasmacytomas (lymphoma tumors) in inbred mice, especially from BALB/c mouse strains. These tumors developed spontaneously or were induced by oil injections.

The first common cell line - SP2/0

The first common cell line was SP2/0 and was established in 1979. These cells were used by Köhler and Milstein to develop the first hybridoma technology.

Other important cell lines are:

• NSO (NSO/U mouse myeloma)
• Ag8 (a mouse myeloma)
• P3/NS1/1-Ag4-1 (also mouse myeloma)

Why are myeloma cells immortal?

Normal cells - The Hayflick limit

Normal cells can only divide 50-70 times (Hayflick limit, discovered in 1961). Then division stops and the cell dies. The reason for this is that the telomeres (ends of the chromosomes) become shorter with each division and after a certain shortness the cell dies (senescence), or apoptoses.

Visual:

Normal cell (young)
├─ Telomeres long
├─ Cell divides 1x → telomeres shorter
├─ Cell divides 2x → even shorter
├─ ...
├─ cell divides 50x → telomeres CRITICALLY short
└─ STOP: cell dies (senescence)

Cancer cells are inventive - activate telomerase

Cancer cells (such as myeloma cells) break free from this system:

1. Activation of telomerase, which rebuilds telomeres
2. TP53 mutations (p53 inactivation) that switch off the tumor suppressor
3. other survival signals.

Myeloma cell (tumor)
├─ Telomerase activated ← (this is the key!)
├─ Cell divides 1x → Telomeres are REPAIRED
├─ Cell divides 2x → Telomeres are repaired again
├─ Cell divides 50x → Telomeres are still long
├─ Cell divides 1000x → still alive
└─ UNLIMITED divisions possible

Why telomerase?

Telomerase is a ribonucleoprotein enzyme (consisting of TERT = Telomerase Reverse Transcriptase and TERC = Telomerase RNA Component). It repeatedly adds the sequence TTAGGG to the telomere ends and thus repairs the shortening caused by the division process, which leads to the immortality of the cell.

Normal:

• Telomerase is present in normal cells OFF
• Only weakly present in germ cells (sperm, egg cells) and stem cells
• Therefore: Normal cells age and die

For cancer:

• Telomerase is ON (85-95% of all cancer cells)
• Constant repair of telomeres
• Cell becomes „immortal“

TP53 mutation - the other piece of the puzzle

But telomerase alone is not enough, the cell would still trigger a senescence checkpoint:

When telomeres become critically short, TP53 (the „guardian of the genome“) is normally activated, which says: „Stop, the cell is damaged, let's die“. In cancer cells, TP53 mutated or inactivated, so the cell ignores this command.

This means:

• Short telomeres → normally: p53 activated → cell death
• Myeloma cell: short telomeres → p53 is INACTIVE → cell says: „Never mind“ → continue

How myeloma cells became immortal

The myeloma cells in mice developed in several steps over decades:

1. A normal plasma cell suffered a t(12;15) translocation or other genetic errors
2. The MYC gene was overexpressed (cancer driver)
3. p53 mutated
4. Telomerase was activated,
5. After many cycles of selective printing, true immortal cells were created.

The first SP2/0 hybridoma cell

SP2/0 originates from a mouse myeloma. The myeloma was isolated from a BALB/c mouse (probably after oil injection). The cells were then cultured and established. They have TELOMERASE active and defective p53.

The name is explained by:

• SP stands for Spleen (spleen), as the cells originate from spleen cells. 
• 2 refers to the second generation of the cell line. 
• 0 symbolizes the Loss of the HGPRT function („zero“ activity), which causes HAT sensitivity*.
  * Sensitivity of cells to a HAT medium (hypoxanthine-aminopterin-thymidine), which is used for the selection of hybridomas

The criticism at the time:

• These cells are cancer cells themselves!
• In other words, „tumor cells“ are fused with normal B cells
• That was ethically/practically worth considering

The solution:

• The cells were deliberately eradicated for antibody production
• They do produce immunoglobulins (because part of the B cell is inside), but no other „harmful“ genes

Why no normal B cells?

B cells from the spleen (or blood) can only divide to a limited extent (Hayflick limit). After they have been fused with myeloma cells, the new „hybridomas“ must also be able to divide indefinitely, otherwise they are useless.

This means:

Experiment 1: Only B cells from spleen
├─ Produce antibodies (+)
└─ Divide only 50x, then dead (-)

Experiment 2: Myeloma cells only
├─ Divide indefinitely (+)
└─ Do not produce specific antibodies (-)

Experiment 3: HYBRIDOMA (fusion)
├─ Divide indefinitely (+) (from myeloma)
├─ Produce antibodies (+) (from the B cell)
└─ Perfect!  (+)

The fusion - the hybridoma process

Fusion takes place using polyethylene glycol (PEG) or electrical pulses (electrofusion). PEG reinforces membrane adhesion: two cells fuse to form one cell with two nuclei. After cytokinesis (cytokinesis ensures that each daughter cell receives organelles and cytoplasm and can function as an independent cell): One cell with genetic material from both parent cells.

Visual:

B cell (antibody producer)
    +
Myeloma cell (immortal)
    ↓ (PEG or electrofusion)
Hybridoma (both!)
    ├─ Immortal (from myeloma)
    └─ Produces antibodies (from B cell)

Why myeloma cells and not other tumors?

Myeloma cells (plasma cell lymphomas) were chosen because they:

• divide quickly (high proliferation rate)
• are genetically stable (not too many other mutations)
• can reject non-productive antibodies (selection pressure)
• are already specialized in protein secretion (produce antibodies)

Other types of cancer would not have worked, for example:

• Prostate cancer - Not specialized in protein secretion
• Melanoma - too many other mutations
• Hepatocellular carcinoma - no antibody production

The paradox - cancer cells as a remedy for cancer

The beauty and paradox of hybridoma technology: Cancer cells (myeloma) are used to produce drugs against cancer (lymphoma)!

Myeloma cells are themselves a type of cancer, but by fusing with B cells they become a therapeutic production site for monoclonal antibodies.

Newer alternatives

Today, myeloma cells are used less frequently, but

• Humanized cell lines (e.g. CHO = Chinese Hamster Ovary cells)
• Display technologies (Phage Display, Yeast Display)
• In vitro mutagenesis instead of animal immunization.

Why the change?

• (+) No myeloma cell contamination
• (+) More direct than chimeric antibodies
• (+) Ethically cleaner
• (+) Faster

In 1990, the hybridoma technology with myeloma cells for rituximab was the only practical solution available.

Summary

Question	Answer
Where did myeloma cells come from?	Spontaneous or oil-induced lymphomas in mice
Which line?	SP2/0, NSO, Ag8 (all mouse myeloma cell lines)
Why immortal?	Telomerase active + p53 mutated = Hayflick limit overcome
How does telomerase work?	TERT + TERC enzymes endlessly repair telomeres
Why not just B cells?	Would die after 50 divisions (Hayflick limit)
Why not just myeloma?	Would not produce antibodies
Why fusion?	Best of both worlds: immortality + antibody production

1980 - Discovery of the surface protein CD20

Lee Nadler from the Dana Farber Cancer Institute in Boston discovered the surface protein CD20 as a surface marker on B lymphocytes.
He used the new hybridoma technology to make antibodies against B cell markers. He identified CD20 as:

• A protein on the surface of all B cells
• Also present on B-cell lymphoma cells
• A potential therapeutic target

First experiment

He tested a murine (mouse) anti-CD20 antibody on lymphoma patients. The result was weak, but it was the first proof-of-concept that CD20 targeting is possible.

The chimeric antibody problem

Nadler's antibody and other research teams had murine (mouse) antibodies against CD20, but there were two critical problems:

Problem 1: HAMA (Human Anti-Mouse Antibodies)

• The human body recognized the mouse antibody as „foreign“
• The patient formed antibodies against the antibody
• After a few infusions, the mouse antibody was neutralized

Problem 2: Poor effectiveness

• The mouse Fc part (constant region) insufficiently activated the human immune system
• Mouse IgG does not bind optimally to human Fc receptors
• Mouse IgG does not optimally activate human complement

The solution

Geneticists came up with the idea to combine the mouse part (variable region) with the human region (constant region):

• Variable region (Fab part) - Mouse
  This is the part that recognizes CD20
  Mouse antibodies have special gene segments that can recognize CD20 very specifically
• Constant region (Fc part) - Human
  This is the part that activates the immune system
  Human Fc regions bind perfectly to human Fc receptors

Result: the chimeric monoclonal antibody

• Specific enough (due to mouse recognition part)
• Effective enough (due to human effector function)
• Fewer HAMA problems (because more human)

1990-1992 - Rituximab development

The IDEC team

A biotech company called IDEC Pharmaceuticals (founded in 1990) began working on CD20 antibodies. They wanted to

• Find murine antibodies against CD20
• convert into chimeric antibodies
• test whether they work better than Nadler's previous attempts

Development

1. immunization of mice

• Mice were immunized with human B cell lines
• The mouse immune system recognized: „These are foreign cells, make antibodies against them!‘
• Hybridomas were obtained from the mouse splice cells by fusion with the myeloma cells

2. screening

• The best was selected from thousands of hybridomas
• Which one recognizes CD20 very selectively?
• It should be a strong IgG1 antibody (the best isotype for ADCC and CDC)

3. chimerization

• The best murine antibody gene was taken
• The variable region (antigen-recognizing) remained murine
• The constant region (IgG1-Fc) was replaced by human
• Result: C2B8 (chimeric antibody #2, B-cell antigen #8)

4. production

• The rituximab gene was found in CHO cells (Chinese Hamster Ovary) inserted
• These cells produced Rituximab in bioreactors
• Batches could be cleaned for medical quality

1993-1997 - Clinical tests

1994 - Phase I study

The first paper on the clinical testing of Rituximab:

• Reff, M. E., et al. (1994). „Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20„

This study showed:

• 15 patients with refractory B-cell lymphoma (not responding to standard chemotherapy)
• Rituximab was infused in doses of 10 to 500 mg/m²
• Result: 6 out of 15 patients (40%) had objective remissions
• Side effects: Surprisingly mild for such an effective therapy

That was sensational - an antibody ALONE (without chemotherapy!) was effective against lymphoma!

1997 - Phase II study

A larger study of 166 patients with refractory lymphoma:

• McLaughlin, P., et al. (1998). „Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphomas: half of patients respond to a four-dose treatment program„

Result:

• 48% of the patients had objective remission
• Some had complete remissions that lasted a long time
• The response rate was higher than in historical data with chemotherapy alone

1997 - FDA approval (November)

Based on the Phase I and Phase II data, IDEC submitted a Biologics License Application (BLA) with the FDA. On November 26, 1997 Rituximab (under the name Rituxan) approved by the FDA.

That was a milestone:

• First monoclonal antibody for oncology
• Others came later (trastuzumab for breast cancer in 1998, etc.)

Why exactly this mouse antibody?

CD20 is a surface protein with a 3D structure recognized by the IDEC hybridoma antibody. Mouse immune systems have different V genes (variable region genes) than humans. This means that mouse antibodies can sometimes recognize structures that human antibodies do not.

Why wasn't a humanized antibody developed directly?

That was technically very difficult in 1990:

• Humanization requires transplanting murine CDRs (Complementarity-Determining Regions) into human framework regions
• This was possible, but complex
• Chimeric antibodies were faster and more practical

Fusion combines the best:

• From the B cell: ability to produce specific antibodies
• From myeloma: unlimited ability to divide

Since 1997

• Rituximab became standard treatment for non-Hodgkin's lymphoma
• Later approved for rheumatoid arthritis and other indications
• Biologists called it „The first antibody miracle of modern medicine„

Dosage recommendations

All recommendations are to be considered exclusively as a basis for discussion with the treating physicians, in particular oncologists, and do not represent a generally valid dosage indication.

For ABC-DLBCL

Dosages of Huaier are NOT generally dependent on body weight and therefore usually do not require adjustment, as the effect is not dependent on blood concentration (like antibiotics, for example), but rather addresses signaling pathways, thereby inducing the intended effects.

• FL with t(14;18)
  PI3K/AKT-dominant → Huaier ideal
• DLBCL-ABC
  NF-κB-dominant → Huaier + curcumin ideal
• DLBCL-GCB
  BCL2-dominant → similar to FL
• Burkitt
  MYC-driven → mTOR inhibitors (sulforaphane, berberine)

... will be continued ...