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Editors

ErkkiElonen

Lymphomas

Essentials

  • Lymphomas form a heterogeneous group of diseases as regards aggressiveness, need of care and prognosis. In some disease types the treatment should be started without delay, whereas others may not need care at all.
  • Adults with generalized lymphadenopathy, hepatosplenomegaly or an enlarged lymph node (> 2 cm) that does not decrease in size during a follow-up of one month should be referred for biopsy to a specialist centre with good pathology services.
  • If a patient has prolonged symptoms after treatment of lymphoma, thorough investigations are indicated to rule out recurrence. Rapid access to investigations is important.
  • Consider the possibility of late adverse effects of treatment (early menopause, hypothyroidism, cardiac disease, certain infections and secondary malignancies).

Definition

  • Hodgkin lymphomas and non-Hodgkin lymphomas represent a heterogeneous group, as far as their clinical picture and prognosis are concerned, of diseases of the lymphoreticular system. Non-Hodgkin lymphomas are divided into B-cell and T-cell lymphomas and these further into numerous subgroups.
  • WHO classification contains several dozens of lymphoma types. The most common non-Hodgkin lymphomas include diffuse large cell B lymphomas, follicular lymphoma and lymphocytic lymphoma (lymphoma manifestation of chronic lymphatic leukaemia).
  • Hodgkin lymphomas are divided into classical Hogkin lymphoma and nodular lymphocyte-predominant Hogkin lymphoma.

Epidemiology

  • The annual incidence of Hodgkin lymphomas is about 2/100 000 in the Nordic countries. The disease occurs in all age groups but the majority of the patients consists of young adults.
  • The annual incidence of non-Hodgkin lymphomas is about 20/100 000 in the Nordic countries. The mean age at onset is about 60 years.
  • The incidence of non-Hodgkin lymphomas is increasing in all Western countries, particularly in the Nordic countries, but there has been a slight decline in mortality.
  • The incidence of Hodgkin lymphomas has slightly increased in recent decades but there has been a very significant decline in mortality.

Signs and symptoms

Hodgkin lymphoma

  • Most patients have no symptoms, or the symptoms are associated with the pressure caused by the tumour mass, such as a cough in hilar tumours and retrosternal feeling of heaviness, or superior vena cava syndrome, in mediastinal tumours.
  • Many patients themselves recognize an enlarged and painless lymph node in the neck, clavicular fossa or armpit.
  • A minority of patients have systemic symptoms: fever, night sweats and unexplained weight loss (known as the B symptoms), severe pruritus or pain in the affected glands after alcohol consumption.
  • The disease usually starts in the supraclavicular lymph nodes and spreads through the lymphatic system to the axillae or mediastinum and further to the retroperitoneal lymph nodes.
  • The disease may infiltrate from lymph nodes to other organs (for example from mediastinal lymph nodes to the pericardium, from hilar lymph nodes to the lung tissue or from para-aortic lymph nodes to the spinal cord).
  • A mediastinal tumour in a young adult is often Hodgkin lymphoma (picture 1).
  • Haematogenic spread to the bone marrow or liver is a late manifestation of the disease that follows the spread of the disease to the spleen from lower mediastinal or para-aortic lymph nodes.

Non-Hodgkin lymphoma

  • Symptoms are non-specific and dependent on the organs infiltrated by the tumour mass. Many patients are totally asymptomatic when lymphoma is diagnosed.
  • About 25% of patients with non-Hodgkin lymphoma have at least one of the aforementioned B symptoms. The prevalence of symptoms is influenced by histological characteristics, extent and growth rate of the disease.
  • In slightly less than 50% of the patients, lymphoma lesions are found only in the lymph nodes at the diagnosis. On the other hand, almost 20% of the patients have lymphoma tissue only in extranodal organs. The most commonly affected extranodal organs include the stomach, skin (picture 2), bone, central nervous system, thyroid gland and intestine.
  • Although diagnosis cannot be made on the basis of the clinical presentation alone, non-Hodgkin lymphoma should be suspected in the following cases:
    • Lymphadenopathy involving several lymph node areas in an elderly patient is often indicative of an indolent non-Hodgkin lymphoma, usually follicular lymphoma.
    • Lymphocytosis in an elderly patient is often indicative of an indolent non-Hodgkin lymphoma or chronic lymphocytic leukaemia.
    • Prolonged tonsillitis not responding to antimicrobials may indicate lymphoma.
    • A local lymphadenopathy that is growing aggressively or causes general symptoms is often caused by a fast-growing non-Hodgkin lymphoma.

Diagnosis and determination of tumour spread

  • The diagnosis of Hodgkin lymphoma and non-Hodgkin lymphoma is always based on a thorough histopathological examination. A surgical biopsy is necessary.
  • If a patient has a palpable lymph node more than 2 cm in diameter that does not decrease in size during a follow-up of one month, or a similar lymphadenopathy is observed in imaging studies, he/she should be referred to a centre where appropriate samples can be obtained, processed and examined.
  • If lymphadenopathy is associated with general symptoms, rapid progress or haematological changes, the investigations should be performed without delay.
  • The World Health Organization classification of haematological malignancies should be used as a guideline of pathological diagnosis.
  • Chemical laboratory investigations are not particularly helpful in establishing the diagnosis, but significant lymphocytosis is seen in some lymphomas. Laboratory investigations are important in assessing the condition of the different organs and the feasibility of treatment. Carrier state for HIV and hepatitis viruses should be excluded.
  • Lymphoma staging helps in estimating the prognosis and in management choices.
    • The spread is determined by clinical examination, by computed tomography of neck and body, and by bone marrow biopsy. PET-CT or MRI scans are carried out if needed.
    • The extent of the disease is expressed using the Ann Arbor Staging System (I-IV A or B, see table T2).
    • In Hodgkin lymphoma, the prognosis is the better the more local the disease is. The presence of B symptoms indicates worse prognosis.
    • In non-Hodgkin lymphoma, prognosis can also be evaluated by the International Prognostic NHL Index (IPI) or its modifications. Points, which indicate poor prognosis, are allocated for the following factors:
      1. Age > 60 years
      2. Ann Arbor Stage III or IV (both sides of the diaphragm affected)
      3. WHO performance status > 1 (incapable of work because of symptoms)
      4. Plasma lactate dehydrogenase (LDH) concentration above the reference range
      5. Lymphoma has spread to more than one extranodal organ.
    • The higher the score the poorer the prognosis.
    • Important prognostic factors also include large tumour size (over 10 cm), PET-positivity after two treatment cycles and, in aggressive lymphomas, rearrangements in genes BCL2 and MYC or overexpression of their proteins (so-called double hit).

Ann Arbor staging system for lymphomas

StageDescription
IThe disease is located in a single lymph node region. If it has spread to the adjacent extranodal tissue, the stage is IE.
IIThe disease is located in two or more lymph node regions on the same side of diaphragm. If there is involvement of adjacent extranodal tissue, the stage is IIE.
IIIThe disease is located in lymph nodes on both sides of diaphragm. If there is involvement of adjacent extranodal tissue, the stage is IIIE.
IVDiffuse involvement of extralymphatic organs (e.g. bone marrow)
B symptoms of lymphomas
  • Weight loss of 10% within 6 months
  • Bouts of fever over 38°C
  • Night sweats
Also tonsillae, Waldeyer's ring and the spleen are regarded as lymphatic tissue.

Treatment and prognosis Granulopoiesis-Stimulating Factors to Prevent Adverse Effects in the Treatment of Malignant Lymphoma

Hodgkin lymphoma

  • Local Hodgkin lymphoma with no B symptoms (Ann Arbor I-IIA) and with no risk factors is treated, depending on the treatment response, by two cycles of combination chemotherapy, i.e. the ABVD regime (doxorubicin, bleomycin, vinblastine and dacarbazine), followed by radiotherapy to the involved area, or by three cycles of ABVD therapy without radiotherapy if PET CT result is negative.
  • Local (Ann Arbor I-IIA) Hodgkin lymphoma associated with risk factors is treated, depending on the treatment response (PET CT examination), by four cycles of ABVD therapy and radiotherapy, or by two cycles of ABVD therapy, two cycles of BEACOPP therapy (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) and radiotherapy.
  • The treatment of widespread disease, or disease with B symptoms, consists usually of six cycles of ABVD therapy or, especially in disease with poor prognosis, of six cycles of BEACOPP therapy, after which any residual tumours may then be treated, as necessary, with radiotherapy.
  • Nodular lymphocyte predominant Hodgkin's lymphoma is treated by local radiotherapy or by the combination of ABVD and antibody, rituximab.
  • Residual tumour activity (lymphoma or scar tissue?) after the treatment period is assessed by PET CT or CT scan. A positive result should be confirmed by histology.
  • More than 95% of patients with local Hogkin lymphoma are permanently cured. Conservative treatment is used in order to reduce toxicity and late adverse effects of the treatment as well as mortality.
  • The average 5-year survival rate is 90% among patients with widespread Hodgkin lymphoma (67-98% depending on the risk group).
  • In recurring Hodgkin lymphoma, a new remission is sought by cytostatic therapy, after which an autologous stem cell transplantation is sometimes performed.
  • New medications for the treatment of Hodgkin's lymphoma include brentuximab vedotin, a combination of a cytostatic drug and an anti-CD30 antibody, as well as the immune checkpoint inhibitors nivolumab and pembrolizumab.

Non-Hodgkin lymphomas

Follicular lymphoma Chemotherapy Plus Rituximab Versus Chemotherapy Alone for B-Cell Non-Hodgkin's Lymphoma, Rituximab as Maintenance Therapy for Patients with Follicular Lymphoma, High-Dose Therapy with Autologous Stem Cell Transplantation Versus Chemotherapy or Immuno-Chemotherapy for Follicular Lymphoma in Adults

  • The objective of the treatment is in most cases a remission for as long as possible.
  • Follicular lymphoma remains local in 10-20% of patients (Ann Arbor stage I or II). A proportion of these can be cured by radiotherapy.
  • Asymptomatic patients with a more widespread disease can often be monitored without treatment for rather long times.
  • If the individual disease burden is high, the patient has symptoms or the lymphoma progresses, treatment is indicated. Patients with mild symptoms may be treated with the antibody rituximab only. Patients requiring stronger treatment are in most cases treated with a combination of rituximab and bendamustine or with R-CHOP regimen (cyclophoshamide, doxorubicin, vincristine and prednisone plus antibody rituximab). Rituximab is often used as maintenance therapy. Instead of rituximab, the antibody obinutuzumab may be used. Patients who only tolerate lighter therapy may be treated with oral chlorambucil and glucocorticoid or with only low-dose radiotherapy.
  • Follicular lymphoma has a high risk of recurrence, but a new treatment episode often produces new response. Autologous stem cell transplantation may be considered in some patients with a relapse and in patients whose lymphoma has been transformed to a more aggressive one, when cytotoxic chemotherapy has provided a good response. Ibritumomab tiuxetan, an antibody labelled with a radioactive isotope, may also be considered in the treatment of relapsed lymphoma.
  • Life expectancy is very variable; on average, it is about 10 years.

Mantle cell lymphoma

  • Patients with mantle cell lymphoma are treated with high-dose CHOP regimen plus cytarabine in combination with the antibody rituximab. Depending on the age and condition of the patient, autologous stem cell transplantation may be included. Life expectancy depends on the prognostic factors and treatability of the patient. Of the patients who can be treated with an intensive multidrug chemotherapy regime, more than 50% are in remission for more than 5 years. Relapses, however, occur during long-term follow-up. Newer drugs for mantle cell lymphoma include bortezomib, lenalidomide and ibrutinib.

Diffuse large B-cell lymphomas High-Dose Chemotherapy Followed by Autologous Stem Cell Transplantation (Hdt) as First-Line Therapy in Aggressive Non-Hodgkin's Lymphoma (NHL)

  • As a rule, the objective of the primary treatment is to be curative. Combination chemotherapy including anthracyclines and given in combination with the antibody rituximab is the therapy of choice. The intensity and duration of chemotherapy is planned according to the stage and the IPI score of the lymphoma.
  • Local stage I lymphoma is treated with 6 cycles of R-CHOP or with 3 cycles of R-CHOP plus radiotherapy directed to the tumour area.
  • A disseminated disease with IPI score 0-1 is treated with 6 cycles of R-CHOP combination chemotherapy at 3-week intervals. At discretion, radiotherapy may be administered after chemotherapy to areas with large tumours, to extranodal foci and to tumours remaining after chemotherapy.
  • Disseminated lymphoma with IPI score 2-5 is treated with R-CHOP or R-CHOEP chemotherapy (E=etoposide) administered every 2-3 weeks, and, as a prophylaxis for central nervous system lymphoma, high-dose methotrexate and cytarabine therapy. Radiotherapy is administered to the areas with large tumours and with possible residual tumours.
  • Advanced age usually does not prohibit seeking curative therapy.
  • In relapsed diffuse large B-cell lymphoma, combination therapies containing platinum, ifosfamide or gemcitabine are used, and an autologous stem cell transplant is possibly performed. Other possibilities include combination therapy with bendamustine, rituximab and polatuzumab vedotin, as well as treatment with genetically engineered T-cells (chimeric antigen receptor T-cells or CART).
  • With the modern treatments about 60-70% of patients who are suitable for active treatment will be permanently cured.

The most aggressive lymphomas

  • Lymphoplastic lymphoma and Burkitt's lymphoma are are the most rapidly progressing lymphomas. Similar regimens are used in the treatment of lymphoplastic lymphoma as in acute lymphocytic leukaemia. The treatment of Burkitt's lymphoma is intensive, but if the disease remains in remission for more than one year it probably is completely cured.

Follow-up

  • The risk of recurrence of Hodgkin lymphoma is greatest during the first 2 years from the diagnosis, but recurrence is possible even after 10 years.
  • Aggressive lymphomas usually do not recur if 3 years has elapsed from the initial treatment.
  • Indolent lymphomas may recur at any time during the remainder of the patient's life.
  • At the initial stage the primary aim of follow-up is to detect recurrence as early as possible. While the risk of recurrence remains high follow-up visits should be carried out every 3 months. A thorough history should be taken during the visits, and palpation of lymph nodes is essential. Any symptom that has continued for several weeks, and/or has become worse, warrants thorough investigation to rule out the possibility of a recurrence. Imaging the focus of the symptoms (computed tomography or magnetic resonance imaging) is the primary examination.
  • An increased ESR may indicate the recurrence of Hodgkin lymphoma and an increased plasma LDH the recurrence in cases of non-Hodgkin lymphoma. Other laboratory tests are of little value in the detection of recurrence.
  • After the highest risk of recurrence has subsided, follow-up is aimed at detection of late sequelae of treatment and the disease.

Radiotherapy

  • Follow-up of potential adverse effects is dependent on the area irradiated.
    • Thyroid gland - risk of hypothyroidism
    • Ovaries - risk of early menopause, infertility
    • Heart - risk of pericarditis, insufficiency, valvular disorders, early coronary heart disease
    • All areas - increased risk of secondary malignancies > 10 years after initial treatment; particularly breast and lung cancer, melanoma and soft tissue sarcoma
    • If the breast has been irradiated, regular screening for breast cancer has to be started 8 years after the treatment ended and no later than at the age of 40.
    • Other important measures
      • Cessation of smoking
      • Removal of naevi from irradiated skin areas

Chemotherapy

  • Follow-up is dependent of the combination of chemotherapy used:
    • Alkylating drugs - risk of secondary leukaemia after 3-6 years
    • Alkylating drugs - risk of early menopause, infertility
    • Anthracyclines - risk of heart failure

Splenectomy or hyposplenism

References

  • Swerdlow SH, Campo E, Pileri SA ym. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016;127(20):2375-90. [PubMed]
  • Johnson PW. Response-adapted frontline therapy for Hodgkin lymphoma: are we there yet? Hematology Am Soc Hematol Educ Program 2016(1):316-322. [PubMed]
  • Beaven AW, Diehl LF. Peripheral T-cell lymphoma, NOS, and anaplastic large cell lymphoma. Hematology Am Soc Hematol Educ Program 2015:550-8. [PubMed]
  • Friedberg JW. Using the pathology report in initial treatment decisions for diffuse large B-cell lymphoma: time for a precision medicine approach. Hematology Am Soc Hematol Educ Program 2015;2015():618-24. [PubMed]

Evidence Summaries ⬆