Non-hodgkin's lymphomasC85.9

Non-Hodgkin's lymphoma" refers to a heterogeneous group of more than 50 different neoplasms of the lymphoid tissue. They are defined as malignant clonal neoplasms derived from B or T cells, as well as natural killer cells and their respective progenitor cells. The manifestations of non-Hodgkin's lymphoma are manifold. They differ from Hodgkin's lymphoma histologically and clinically. Non-Hodgkin's lymphoma can arise anywhere in the body. Lymph nodes are most commonly affected, but the lungs, liver, bone marrow, spleen, and skin can also be affected. In particular, NHL of the T-cell series have a high skin involvement. 30% of NHL also manifest leukaemically.

Classifications of non-Hodgkin's lymphomas

Different classification systems of non-Hodgkin lymphomas exist. In the past, the Kiel classification of non-Hodgkin lymphomas was used, in which B- and T-cell lymphomas are subdivided into high-malignant and low-malignant tumors according to their growth behavior. However, the Kiel classification has been largely superseded by the World Health Organization (WHO) classification, which subdivides NHL based on morphological, immunological, and genetic features. However, the terms high-malignant and low-malignant, or a corresponding classification of NHL from the Kiel classification, are still in common use, especially in the clinic.

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 manifest themselves predominantly in the gastrointestinal tract (mostly B-cell lymphomas of the MALT type), as well as on the skin. Lymphomas of the skin predominantly affect the T-cell series (cutaneous T-cell lymphomas, of which mycosis fungoides is the most prominent representative) and more rarely the B-cell series (see cutaneous B-cell lymphomas below). However, other organs such as the CNS or the lungs can also be affected.

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

• B-cell lymphomas
• and
• T-cell lymphomas

differentiated.

B-cell NHL (about 85% of NHLs are B-cell lymphomas). Within the B-cell series, further groups/entities are formed):

Progenitor cell lymphomas

Progenitor 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 (Approximately 15% of NHLs are T-cell lymphomas. Within the T-cell series, further groups/entities are distinguished):

Progenitor T-cell lymphomas

Progenitor T-cell lymphoblastic leukemia/lymphoma

Peripheral (mature) lymphoma

• 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, primary 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 lymphoma are determined using the Ann Arbor classification, which is also used for Hodgkin's lymphoma.

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

Supplement A: No B-symptomatology.

Addition B: Typical B-symptomatology: (fever > 38°C, night sweats, weight loss > 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 by the time of the survey. A total of 3,560 men and 2,949 women died of NHL in 2014.

The incidence is approximately 10-12/100,000 population/yr. For decades, an increase in the incidence of NHL has been observed, while the mortality rates have been decreasing.

The pathogenesis of the various non-Hodgkin lymphomas is based on the cloning of degenerate B or T cells as well as degenerate natural killer cells. Both mature cell and progenitor cells can become the origin of the clone and thus the neoplasia.

Hybrid genes formed by 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's lymphoma:translocation t(8;14) (q24;q32); gene: C-MYC

Due to the multiple manifestations of non-Hodgkin's lymphoma, a single cause is not likely. In fact, however, no singular causes are 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 an NHL:

Congenital or acquired immune deficiency

Weak radioactive radiation

Chemotherapy

Autoimmune diseases

Viral infections (e.g. HHV-4 in Burkitt's lymphoma, HIV- in HIV-associated NHLs; Helicobacter in low-malignant MALT lymphoma of the stomach)

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

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

Lifestyle factors

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

Symptoms of non-Hodgkin's lymphoma, with the exception of primarily cutaneous T-cell lymphomas, 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
• Extralymphoid masses (ENT, gastrointestinal, skin, eye, CNS)
• Extralymphatic infiltrates (e.g. ENT, gastrointestinal tract, skin, CNS)
• B symptoms: fever > 38°C, weight loss > 10% in six months, night sweats
• fatigue, tiredness
• Impairment of haematopoiesis with anaemia, fatigue, thrombocytopenia, granulocytopenia, hypogammaglobulinemia, susceptibility to infection
• Susceptibility to infection
• Inflammatory or non-inflammatory patches, plaques or nodules of the skin
• Edema
• Renal insufficiency

Examinations

The examinations include (depending on the symptoms):

• Anamnesis with special consideration of possibly existing B-symptomatics
• Physical examination, laboratory
• Blood count: cell count, differential blood count, reticulocytes, BSG
• ESR, electrophoresis, total protein
• GOT, GPT, AP, γ-GT, bilirubin, creatinine, uric acid, blood glucose.
• LDH, optional: β2-microglobulin
• Immunoglobulins quantitative
• 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, further hemolysis parameters if required
• FACS analysis (only in case of leukemic course)
• ENT examination (in case of high cervical lymph node involvement)
• Gastroscopy, colonoscopy, X-ray examination and/or scintigraphy of the skeleton if required.
• Diagnostic cerebrospinal fluid puncture
• ECG before anthracycline 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 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 basically systemic diseases, surgical tumor treatment is only effective in a few localized cases and early stages. The following therapies, often in combination, are used to treat NHL:

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

Newer therapeutic strategies

Radiotherapy: Targeted radiotherapy alone can lead to cure in certain cases (e.g. follicular lymphoma). In aggressive NHLs, radiotherapy after polychemotherapy or combined immuno-polychemotherapy can improve disease-free survival (DFS [disease-free survival]). Initial diagnosis by positron emission tomography (PET) in irradiation position is the 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 NHLs. 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 in use since the 1970s for the treatment of both B and T non-Hodgkin lymphomas. It still represents the basis of systemic therapy for many highly malignant NHL. Other examples of polychemotherapies include:

• ICE: ifosfamide, carboplatin, etoposide (relapses of T-cell lymphomas).
• DHAP: cisplatin, ARA-C, dexamethasone (relapses of T-cell lymphomas)
• Immunochemotherapy: Since the introduction of rituximab as a CD20 monoclonal 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 therapeutic regimens against the lymphocyte antigen CD20 (anti-CD20 therapies) are successful in the treatment of B-cell lymphomas. As a monotherapy, the anti-CD20 monoclonal antibody rituximab is used, for example, in the maintenance therapy of follicular lymphoma. Anti-CD20 therapies can be combined with radiotherapies or chemotherapies see above. Monoclonal antibodies against CD20 are for example Rituximab, Obinutuzumab, Ibritumomab-Tiuxetan (Tiuxetan is a chelator, the combination Ibritumomab-Tiuxetan is used in radioimmunotherapy).

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

High-dose chemotherapy with stem cell transplantation: The very stressful high-dose chemotherapy with subsequent stem cell transplantation is usually only performed in younger patients in a good general condition.

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

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

Criteria for a 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>12g/dl and platelets >100,000μl). Even with normalization of these values, residual lymphoma cells can still be detected by PCR in some patients (minimal residual disease - MRD).

In low-malignant, indolent NHL, adapted therapy strategies contribute to prolonging 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.