Non-hodgkin's lymphomasC85.9

Non-Hodgkin's lymphoma" refers to a heterogeneous group of over 50 different neoplasms of the lymphatic tissue. These are defined as malignant clonal neoplasms that originate from B or T cells as well as natural killer cells and the respective precursor cells. The manifestations of non-Hodgkin's lymphoma are manifold. They differ from Hodgkin's lymphoma histologically and clinically. Non-Hodgkin's lymphomas can develop anywhere in the body. Lymph nodes are most frequently affected, but the lungs, liver, bone marrow, spleen and skin can also be affected. NHL of the T-cell series in particular is highly skin-related. 30% of NHLs also manifest as leukemia.

Classification of lymphatic non-Hodgkin's lymphomas

There are different classification systems for non-Hodgkin's lymphomas. In the past, the Kiel classification was used, which divides B- and T-cell lymphomas into high- and low-grade tumors according to their growth behavior. However, the Kiel classification has largely been replaced by the classification of the World Health Organization (WHO), which divides NHL on the basis of morphological, immunological and genetic characteristics. However, the terms "high-grade" and "low-grade" or a corresponding classification of NHL from the Kiel classification are still in use, particularly in clinical practice.

The 4-stage classification of NHL is similar to that of Hodgkin's lymphoma according to the Ann Arbor classification, whereby a distinction is made between a

• primary nodal
• and a
• primary extranodal involvement.

The rarer extranodal NHL mainly manifests itself in the gastrointestinal tract (mostly B-cell lymphomas of the MALT type) and on the skin. Lymphomas of the skin predominantly affect the T-cell series (cutaneous T-cell lymphomas, of which mycosis fungoides is an outstanding representative), less frequently the B-cell series (see below Cutaneous B-cell lymphomas). However, other organs such as the CNS or the lungs can also be affected.

Classification: In the WHO classification , non-Hodgkin's lymphomas are divided into

• B-cell lymphomas

and

• T-cell lymphomas

are distinguished.

NHL of the B-cell series (Around 85% of NHLs are B-cell lymphomas. Further groups/entities are formed within the B-cell series):

Progenitor cell lymphomas

Precursor cell B-lymphoblastic leukemia/lymphoma

Peripheral (mature) lymphomas

B-cell type of chronic lymphocytic leukemia, small cell lymphocytic lymphoma (B-CLL)

B-CLL variant with monoclonal gammopathy/plasma cell differentiation

B-cell prolymphocytic leukemia

Lymphoplasmocytic lymphoma

Mantle cell lymphoma

• Variant: Blastic mantle cell lymphoma

Follicular lymphoma

• Variants: Grade 1, 2, 3
• Cutaneous follicular germinal center lymphoma

Marginal zone B-cell lymphoma (MZL)

• MALT type
• Nodal marginal zone B-cell lymphoma
• Marginal zone B-cell lymphoma of the spleen
• Hairy cell leukemia

Plasma cell myeloma/plasmacytoma

Diffuse large B-cell lymphoma

• Variants: centroblastic, immunoblastic, T-cell-rich, histiocyte-rich, anaplastic large cell
• Primary mediastinal large B-cell lymphoma
• Intravascular large B-cell lymphoma
• Primary effusion lymphoma

Burkitt's lymphoma

• Atypical (pleomorphic) Burkitt's lymphoma

Gray zone lymphoma (with features of diffuse large cell and Hodgkin's lymphoma or with features of diffuse large cell and Burkitt's lymphoma)

Non-Hodgkin's lymphoma of the T-cell series (around 15 % of NHLs are T-cell lymphomas. Further groups/entities are distinguished within the T-cell series):

Progenitor cell lymphomas

Precursor T-cell lymphoblastic leukemia/lymphoma

Peripheral (mature) lymphomas

• T-cell prolymphocytic leukemia
• T-cell large granular lymphocytic lymphoma
• Aggressive NK-cell leukemia

Mycosis fungoides

• Variant: Sézary syndrome
• Peripheral T-cell lymphoma, unspecified
• Subcutaneous panniculitis-like T-cell lymphoma
• Hepatosplenic gamma-delta T-cell lymphoma
• Angioimmunoblastic T-cell lymphoma

Extranodal NK/T-cell lymphoma, nasal and nasal type

• Enteropathy-type T-cell lymphoma
• Adult T-cell leukemia/lymphoma (^HTLV1+)

Anaplastic large cell lymphoma, primarily systemic

• Primary cutaneous CD30-positive T-cell proliferative disease
• Cutaneous gamma-delta T-cell lymphoma

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Ann Arbor Classification

The stages of non-Hodgkin's lymphomas are determined using the Ann Arbor classification, which is also used for Hodgkin's lymphoma.

• Stage 1: Infestation of a lymph node region (LK region) of an extralymphatic region (localized infestation outside the lymphatic system)
• Stage 2: involvement on the same side of the diaphragm of two or more LK regions or localized extralymphatic regions
• Stage 3: Involvement of two or more lymph node regions or extralymphatic organs on both sides of the diaphragm
• Stage 4: Diffuse or disseminated involvement of one or more extralymphatic organs with or without involvement of lymphatic tissue

Addition A: no B symptoms

Addition B: typical B symptoms with fever > 38°C, night sweats, weight loss of > 10 % of body weight in six months

In Germany, around 17,000 people were newly diagnosed with non-Hodgkin's lymphoma in 2014. The prevalence in Germany is around 100,000 patients who had been living with the disease for up to 10 years at the time of the survey. A total of 3,560 men and 2,949 women died of NHL in 2014.

The incidence is around 10-12/100,000 inhabitants/year. An increase in the incidence of NHL has been observed for decades, although mortality rates are falling.

The pathogenesis of the various non-Hodgkin's lymphomas is based on the cloning of degenerated B or T cells and degenerated natural killer cells. Both mature cells and precursor cells can become the origin of the clone and thus of the neoplasia.

Hybrid genes resulting from translocation play a pathogenetic role.

Follicular lymphoma: translocation t(14;18)(q32;q21); gene: Bcl2

Mantle cell lymphoma: Translocation t(14;18) (q13;q32); Gene: Cyclin D1

Anaplastic large cell lymphoma: translocation t(2;5) (p23;q35); gene: NPM-ALK

Extranodular marginal zone lymphoma: translocation t(11;18) (q24;q32); gene: MIT-1

Burkitt lymphoma: translocation t(8;14) (q24;q32); gene: C-MYC

Due to the diverse manifestations of non-Hodgkin's lymphoma, a single cause is unlikely. In fact, no single cause is known for the individual manifestations either. It is likely that many different factors are involved in the development of NHL. The following are discussed as risk factors for the development of NHL:

congenital or acquired immunodeficiency

low-level radioactive radiation

chemotherapy

autoimmune diseases

viral infections (e.g. HHV-4 in Burkitt's lymphoma, HIV in HIV-associated NHL; Helicobacter in low-malignant gastric MALT lymphoma)

Bacterial infections (e.g. Helicobacter pylori in MALT lymphoma)

Environmental toxins (e.g. benzene, toluene, xylene, phytanic acid)

Lifestyle factors

NHL mainly occurs in older people: on average, men were 70 years old and women 73 years old at the time of diagnosis, but children can also develop NHL.

With the exception of primary cutaneous T-cell lymphomas, the symptoms of non-Hodgkin's lymphoma are usually characterized by peripheral lymphadenopathy. In some NHL, peripheral circulation of abnormal lymphocytes without lymphadenopathy is predominant. The following symptoms may indicate NHL:

• painless, rubbery lymph node swelling, persistent or progressive
• splenomegaly or, more rarely, hepatomegaly
• extralymphatic masses (ENT area, gastrointestinal area, skin, eyes, CNS)
• extralymphatic infiltrates (e.g. ENT area, gastrointestinal tract, skin, CNS)
• B symptoms: fever > 38°C, weight loss > 10 % of body weight in six months, night sweats
• Fatigue, tiredness
• Impairment of hematopoiesis with anemia, fatigue, thrombocytopenia, granulocytopenia, hypogammaglobulinemia, susceptibility to infection
• susceptibility to infection
• Inflammatory or non-inflammatory spots, plaques or nodules on the skin
• oedema
• renal insufficiency

Examinations

The examinations include (depending on the symptoms):

• Medical history with special consideration of any existing B symptoms
• Physical examination, laboratory
• Blood count: cell count, differential blood count, reticulocytes
• ESR, electrophoresis, total protein
• GOT, GPT, AP, γ-GT, bilirubin, creatinine, uric acid, blood sugar
• LDH, optional: β2-microglobulin
• Quantitative immunoglobulins
• Immunofixation electrophoresis
• Quick value, PTT
• Bone marrow cytology, bone marrow histology
• Molecular diagnostics
• Lymph node extirpation, no biopsy (essential for diagnostic and therapeutic reasons)
• Supplementary diagnostics
• Coombs test, other hemolysis parameters if required
• FACS analysis (only for leukemic progression)
• ENT examination (for highly cervical lymph node involvement)
• Gastroscopy, colonoscopy, X-ray examination and/or scintigraphy of the skeleton (if necessary)
• Diagnostic cerebrospinal fluid puncture
• ECG before anthracycline-containing therapy
• Audiogram before platinum-containing therapy
• Patients > 75 years with poor general condition: determination of the comorbidity index (CIRS [Cumulative Rating Illness Scale])

• CT neck/thorax/abdomen
• PET in combination with a high-dose (contrast medium) CT
• Sonography for follow-up

The diagnosis of non-Hodgkin's lymphoma is made on the basis of the histological findings and/or the blood count. In principle, any painless enlargement of the lymph nodes that persists for more than four weeks or is associated with B-symptomatology should be clarified histologically.

Due to the insidious course of low-malignant, indolent NHL, the initial diagnosis is often only made at an advanced stage. In early stages, low-malignant, indolent NHL may be detected as an incidental finding (e.g. lymphadenopathy on chest x-ray or blood count changes).

Since non-Hodgkin's lymphomas are essentially systemic diseases, surgical tumor treatment is only effective in a few localized cases and early stages. The following therapies are used to treat NHL, often in combination:

• Radiotherapy and radioimmunotherapy
• Chemotherapy, usually as polychemotherapy
• Immunotherapies, usually in combination with polychemotherapy but also as monotherapy (e.g. in maintenance therapy)

Newer therapy strategies

Radiotherapy: In certain cases (e.g. follicular lymphoma), targeted radiotherapy alone can lead to a cure. In aggressive NHL, radiotherapy after polychemotherapy or combined immuno-polychemotherapy can improve disease-free survival (DFS). Initial diagnostics using positron emission tomography (PET) in the radiation position is a prerequisite for modern targeted radiotherapy.

Radioimmunotherapy: A special form of radiotherapy is radioimmunotherapy with yttrium-90-[90Y-]labeled ibritumomab tiuxetan. The chelator tiuxetan couples the radioactive 90Y to the antibody ibritumomab, which selectively binds to the CD20 antigen of NHL. In this way, the beta emitter 90Y is delivered directly to its radiation target.

Chemotherapy and immunochemotherapy: Polychemotherapy according to the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisolone) has been used since the 1970s for the treatment of both B and T non-Hodgkin's lymphomas. It continues to form the basis of systemic therapy for many highly malignant NHL. Other examples of polychemotherapies are:

• ICE: ifosfamide, carboplatin, etoposide (relapses of T-cell lymphomas)
• DHAP: cisplatin, ARA-C, dexamethasone (recurrences of T-cell lymphomas)
• Immunochemotherapy: Since the introduction of Rituximab as a monoclonal CD20 antibody , it has been successfully combined with CHOP (R-CHOP). Other immunochemotherapeutic regimens include:
• R-CVP: cyclophosphamide, vincristine, prednisolone
• R-FC: fludarabine, cyclophosphamide
• BR: rituximab, bendamustine

Immunotherapies: Antibody-based therapy regimens against the lymphocyte antigen CD20 (anti-CD20 therapies) are successful in the treatment of B-cell lymphomas. The monoclonal anti-CD20 antibody rituximab, for example, is used as a monotherapy in the maintenance treatment of follicular lymphoma. Anti-CD20 therapies can be combined with radiotherapy or chemotherapy (see above). Monoclonal antibodies against CD20 are, for example, rituximab, obinutuzumab or ibritumomab tiuxetan.

The antibody conjugate brentuximab vedotin, which binds to the CD30 antigen, is used for cutaneous T-cell lymphomas.

High-dose chemotherapy with stem cell transplantation: The very stressful high-dose chemotherapy with subsequent stem cell transplantation is usually only carried out in younger patients in good general health.

Other therapeutic strategies: New therapeutic approaches based on tyrosine kinase inhibitors of the B-cell receptor signaling pathway and immunomodulatory substances are currently being developed and tested.

With relative 5-year survival rates of 67% for men and 71% for women, the prognosis for non-Hodgkin's lymphoma is good overall. Even highly malignant diseases can now be permanently cured.

Criteria for complete remission are: Complete regression of all objective disease findings with complete regression of pre-existing lymph node enlargement and pre-existing lymph node enlargement/hepatomegaly/splenomegaly. Normalization of the blood count (granulocytes > 1,500/μl, Hb > 12 g/dl and platelets > 100,000/μl). Even when these values are normalized, residual lymphoma cells can still be detected in some patients using PCR (minimal residual disease - MRD).

In the case of low-grade malignant, indolent NHL, adapted treatment strategies help to extend the disease-free (DFS) or progression-free periods (PFS).

There is no known targeted prophylaxis for non-Hodgkin's lymphoma.

It is foreseeable that new findings through gene expression analyses will enable a new classification of non-Hodgkin's lymphomas. This will open up targeted, personalised therapy options.