• This manual is not a substitute for consultation with an appropriate specialist.
• The contents of this manual have been developed through consensus of a Provincial Tumour Group. Please note the various update dates for each section as some of the content of the manual may not be up to date.

 Revised 14 March 2013

The diagnosis of malignant lymphoma requires the presence of malignant lymphocytes in a biopsy of lymph node or extra-lymphatic tissue. An excisional lymph node biopsy is essential for complete diagnostic assessment. If a whole lymph node is not obtainable, sufficient incised tissue from an extra-lymphatic site can be diagnostic but is less desirable. Fine needle aspiration biopsy (see Appendix I: Biopsy Procedures) is not sufficient for the initial diagnosis of malignant lymphoma.

The following histologic sub-classification of the malignant lymphomas is an adaptation of the WHO classification (Swerdlow, Tumours of Hematopoietic and Lymphoid Tissues, World Health Organization Classification of Tumours, IARC Press, 2008) and is based on the light microscopic interpretation complemented by special stains, immunophenotyping, cytogenetics and other information as available. The specific lymphomas are divided into three major groups for treatment planning.

Table 3.1

A clinically oriented classification of the lymphomas based on similar natural histories, modes of presentation and responses to treatment using the terminology of the REAL classification scheme:

* Small lymphocytic lymphoma is biologically similar to chronic lymphocytic leukemia and is treated the same as CLL
** Includes Waldenstrom’s Macroglobulinemia
*** Mucosa-associated lymphoid tissue
+ Includes T-cell rich B-cell, immunoblastic and intravascular variants of diffuse large B-cell lymphoma

Revised 1 June 2013

Treatment of malignant lymphoma is based on histologic subtype, extent of disease, and age of the patient as is shown in the following table. In the case of discordant (two separate sites of disease with differing types of lymphoma), composite (one site of disease with two discrete types of lymphoma at that site) or transformed (a second lymphoma developing out of a background of previously known lymphoma) lymphoma, treatment must be directed at the most aggressive phase of the disease.

See Table 3.1 for specific subtypes of lymphoma. Note that the approaches outlined in this table are generally applicable to both B-cell and T-cell lymphomas, however, special approaches to gastric low grade MALT, mycoses fungoides, HTLV-1 lymphoma and lymphomas presenting at special sites or in association with immunodeficiency are outlined in the Special Problems section. In addition, the use of rituximab is only appropriate for B cell lymphomas.

*Note: small lymphocytic lymphoma is managed similarly to chronic lymphocytic leukemia, not as an indolent lymphoma, and, follicular grade 3B lymphoma is managed similarly to diffuse large B cell lymphoma, not as an indolent lymphoma

**Central Nervous System Prophylaxis. Patients with initial involvement of paranasal sinuses with diffuse large B-cell or peripheral T-cell lymphoma (all subtypes) may require prophylactic intrathecal chemotherapy as outlined in the Special Problems section. The specific dose and schedule are shown in the Central Nervous System (CNS) Lymphoma section.

*** Rituximab should only be included if the lymphoma is documented to express CD20 (note: some B-cell lymphomas often do not express CD20 (for example, plasmablastic))

Involved Node Radiotherapy (INRT)

- Adopted mainly from Campbell’s papers on “INRT<5cm” = pre- and post-chemo involved lymph nodes (within post-chemo anatomical limits) + 1.5-5cm to field edge[1] or to PTV[2], [3]

• CTV = pre- and post-chemo involved lymph node(s), restricted by post-chemo anatomic limits, + 1cm axially and 1-4cm craniocaudally along lymphatic pathways
  • o craniocaudal margin adjusted based on level of uncertainty in localization of PET-avid abnormality (allows for positional and anatomical changes from pre-chemo PET to RT)[2], [3]
• PTV = CTV + ~1cm, depending on set-up variation and physiological intra-fraction and inter-fraction movement[4]
• Mediastinal Area[4], [5]
  • Length of CTV = length of mediastinal mass or LN(s) before chemo
  • Width of CTV = width of mediastinal mass or LN(s) after chemo
  • The normal mediastinum is contoured and the CTV should not exceed the lateral mediastinal boundaries, except where LN remnants persist

Residual Disease Radiotherapy (RDRT)

• CTV = pre- and post-chemo involved lymph node(s), restricted by post-chemo anatomic limits, + 1cm axially and 1-4cm craniocaudally along lymphatic pathways
  • craniocaudal margin adjusted based on level of uncertainty in localization of PET-avid abnormality (allows for positional and anatomical changes from pre-chemo PET to RT)[2], [3]
  • Do not include any pre-chemo involved LN region that is far away from the residual disease
• PTV = CTV + ~1cm, depending on set-up variation and physiological intra-fraction and inter-fraction movement[4]
• Mediastinal Area[4], [5]
  • Length of CTV = length of mediastinal mass or LN(s) before chemo
  • Width of CTV = width of mediastinal mass or LN(s) after chemo
  • The normal mediastinum is contoured and the CTV should not exceed the lateral mediastinal boundaries, except where LN remnants persist

References

[1] B. A. Campbell et al., “Involved-Nodal Radiation Therapy As a Component of Combination Therapy for Limited-Stage Hodgkin's Lymphoma: A Question of Field Size, ”Journal of Clinical Oncology, vol. 26, no. 32, pp. 5170–5174, Oct. 2008.

[2] B. A. Campbell et al., “Long-term outcomes for patients with limited stage follicular lymphoma,”Cancer, vol. 116, no. 16, pp. 3797–3806, May. 2010.

[3] B. A. Campbell, J. M. Connors, R. D. Gascoyne, W. J. Morris, T. Pickles, and L. H. Sehn, “Limited-stage diffuse large B-cell lymphoma treated with abbreviated systemic therapy and consolidation radiotherapy,” Cancer, vol. 118, no. 17, pp. 4156–4165, Jan. 2012.

[4] T. Girinsky, “Radiotherapy Recommendations for Patients with Early Stage Hodgkin's Lymphoma: Involved Node Radiation Therapy (INRT),” pp. 1–9, Mar. 2008.

[5] T. Girinsky et al., “The conundrum of hodgkin lymphoma nodes: To be or not to be included in the involved node radiation fields. The EORTC-GELA lymphoma group guidelines,” Radiotherapy and Oncology, vol. 88, no. 2, pp. 202–210, Aug. 2008.

[6] P. J. Hoskin, P. Díez, M. Williams, H. Lucraft, and M. Bayne, “Recommendations for the Use of Radiotherapy in Nodal Lymphoma,” Clinical Oncology, vol. 25, no. 1, pp. 49–58, Jan. 2013.

[7] Rummel MJ, et al.  Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial.  Lancet 2013:381:1184 

​​Revised 22 October 2002

Poor Prognosis Hodgkin's Lymphoma

Detailed analyses of prognostic factors have identified several simply measurable aspects of Hodgkin's lympho​ma which allow recognition of patients with a poor prognosis. Since limited stage confers a good prognosis, such results apply only to those with advanced stage.

Patients with advanced stage Hodgkin's lymphoma of age 65 years or less should be considered for intensified treatment to attempt to improve their poor prognosis.

Hodgkin's lymphoma - high risk (see Hodgkin lymphoma)

These patients should be treated with four cycles of standard chemotherapy followed by high dose intensified chemotherapy. The intensified consolidation must be given in a setting with specialized supportive care and such plans should be discussed with a VCC medical oncology member of the Lymphoma Tumour Group

​Revised 29 October 2012

The gastrointestinal (GI) tract is a frequent site of involvement with lymphoma which usually involves the stomach, less frequently the small intestine and rarely the colon or esophagus. As with other sites, management is dependent on type, stage and age but with several additional special requirements as outlined below. Previously the Lymphoma Tumour Group recommended resection of GI lymphoma to prevent hemorrhage or perforation, however, earlier diagnosis and current management techniques seem to have reduced this risk. Thus, resection of GI lymphoma is no longer recommended, unless necessary to establish a definite diagnosis or to control the complications of hemorrhage or perforation. 

Special Requirements

1. All patients with GI lymphoma should have a careful ENT examination because of the 20% risk of associated involvement at that site.
2. Helicobacter pylori and gastric lymphoma
   There is a strong association between H. pylori and gastric lymphoma of the MALT (mucosa associated lymphoid tissue) type. This, combined with the general frequency of H. pylori infection, makes it prudent to give a course of antibiotics to eradicate H. pylori to all patients with gastric lymphoma, either as the primary treatment (see section on MALT lymphoma below) or after completion of planned chemotherapy and/or irradiation whether or not H. pylori has been actually proven to be present.

Standard Treatment of GI Lymphoma

MALT Lymphoma of Stomach
 
Gastric mucosa associated lymphoid tissue (MALT) lymphoma almost always arises in association with Helicobacter pylori. When the MALT lymphoma is low grade and confined to the stomach eradication of the H. pylori may induce prolonged remission of the lymphoma. Low grade MALT lymphoma of the stomach should be treated as follows:  

1. Standard staging for lymphoma. If diagnosis is made via gastroscopy, multiple large, deep biopsies should be taken and processed for lymphoma and stained for H. pylori.        
2. Stage II AE or greater should be managed as advanced low grade lymphoma (see table 3.3.2) plus eradication of H. pylori with antibiotics.
3. Stage I AE should be treated with oral omeprazole 20 mg bid, clarithromycin 500 mg bid and either metronidazole 500 mg bid or amoxicillin 1000 mg bid for one week (Soll, JAMA, 1996; 275:622) or an equivalently effective regimen.        
4. After treatment with antibiotics patients should undergo repeat gastroscopy every six months for two years then annually for three years. Each time biopsies should be taken to examine for lymphoma and H. pylori. If H. pylori persists one re-treatment should be tried. If lymphoma persists or recurs more than six months after eradication of H. pylori the patient should be treated with upper abdominal irradiation or oral chlorambucil.

Updated 21 February 2006

Testicular lymphoma is almost always of an aggressive histologic subtype, usually diffuse large B cell type. In contrast to other patients with localized large cell lymphoma, patients with stage 1AE or 2AE testicular lymphoma are only cured about 50% of the time using brief chemotherapy and irradiation. Thus, the recommended treatment for all stages of testicular lymphoma is a full course of chemotherapy as for advanced disease. An additional problem often seen in patients with testicular lymphoma is relapse in the opposite testicle. This can be prevented by irradiation. Finally, patients with testicular lymphoma in association with stage 3 or 4 disease are at increased risk of CNS involvement and require prophylactic intrathecal chemotherapy. The following table summarizes these recommendations by stage:

*Chemotherapy protocols:  CHOP + rituximab

Revised 29 October 2012

Revised 14 June 2013

Lymphoma may involve the eye or surrounding structures in 4 distinct patterns. Each requires a specific approach to treatment. 

1. Bony Orbit and Sinus Lymphoma

Lymphoma of the bony orbit or paranasal sinuses is usually diffuse large B cell lymphoma and should be managed as appropriate for the presenting stage (see 3 Central Nervous System (CNS) Lymphoma and 5 Paranasal sinus lymphoma)

2. Ocular Adnexal Lymphoma

Lymphoma involving the conjunctiva, lacrimal gland, extraocular muscles and other soft tissues within the orbit but outside the globe but not the structures within the globe or the optic nerve is usually of indolent type and such lymphoma is highly responsive to radiation. Approximately 30% of such patients have advanced disease. Radio-immunotherapy offers the advantage of delivering potentially curative radiation while minimizing eye toxicity (reference Ann Oncology 2009;20:709-14). Patients should be offered radioimmunotherapy (I¹³¹ tositumomab or Y⁹⁰ ibritumomab tiuxetan). If this is declined or there is a contraindication, unilateral external beam radiation (disease localized to one eye) or systemic chemotherapy (advanced stage including bilateral involvement, symptomatic) using the currently recommended combination for advanced stage indolent lymphoma should be offered.

3. Intra-ocular and Optic Nerve Lymphoma

Lymphoma involving the vitreous, retina or other structures within the optic globe or the optic nerve.

Lymphoma of the vitreous or retina or the optic nerve itself is usually of large cell type and is equivalent to CNS lymphoma, although it may pursue a more indolent course. Bilateral involvement is common. Evaluation and management should be the same as for primary CNS lymphoma with the following exceptions/additions:

• All patients should also be followed by an ophthalmologist experienced in the evaluation of lymphoma of the eye.
• Patients suspected of having intra-ocular lymphoma should be referred to an ophthalmologist with specific expertise in the assessment and management of intra-ocular lymphoma for diagnostic confirmation and for treatment planning that may include intra-ocular methotrexate and rituximab. The exact number of intra-ocular injections required will be tailored to the patient’s disease status and rate of response, but will typically include a minimum of 4 injections. Patients eligible to receive systemic high dose methotrexate should also be treated with 4 cycles of IV high dose methotrexate prophylactically to minimize the risk of recurrence within the brain. Systemic therapy with IV high dose methotrexate can be integrated between intra-ocular injections, although timing should be discussed with the ophthalmologist with specific expertise in the assessment and management of intra-ocular lymphoma. If concomitant brain involvement is present high dose methotrexate should be used, followed by radiation to the involved globe if response is less than complete. For recurrence after primary radiation, intra-ocular injection of methotrexate plus rituximab should be considered, in consultation with an ophthalmologist familiar with this technique.

4. Uveal lymphoma

Lymphoma involving the uveal structures (iris, ciliary body, lens, and choroid (vascular layer between the sclera and the retina)) is almost always marginal zone lymphoma and is typically unilateral. Radio-immunotherapy (see section 2 above) or external beam radiation is appropriate.

Lymphoma involving the ethmoid, frontal, sphenoid or maxillary sinuses is usually one of the aggressive histologic subtypes. Treatment should be given as appropriate for the histology and stage of the tumour and age of the patient. While previously it was recommended that patients with paranasal sinus lymphoma receive prophylactic intrathecal therapy, since the introduction of rituximab the risk of central nervous system involvement has significantly diminished. Therefore, the use of intrathecal prophylaxis is no longer necessary

Revised 23 October 2002

Patients with epidural lymphoma should have a CSF cytology examined to determine if leptomeningeal spread of disease has occurred.

Updated 15 February 2006 

Updated 20 June 2007 

The lymphomas which arise in association with the human immunodeficiency virus are usually of large cell or Burkitt or Burkitt-like histologic subtype or, less often Hodgkin lymphoma. In general treatment should be the same as for non-AIDS related lymphoma if the patient's performance status is not otherwise compromised by the AIDS and he or she is free of coincident serious opportunistic infection. Rapid, effective control of the HIV and vigorous supportive care are essential to maximize the likelihood of cure of the lymphoma.

Treatment of HIV associated lymphoma should include (1) initiation of highly active anti-retroviral therapy (HAART) before or coincident with the planned chemotherapy; (2) lymphoma specific chemotherapy with or without rituximab and with or without radiation as determined by stage, histology and presence of CD20; (3) supportive care including anti-fungal, anti-Herpes virus and anti-Pneumocytis antibiotics and granulocyte stimulating growth factors as needed. To prevent rapid emergence of lamivudine-resistant HIV, patients with prior hepatitis B infection should not initiate lamivudine prophylaxis until HAART has also been started.

The malignant lymphomas seen in patients who are receiving immunosuppressant therapy after an organ transplant are in many ways similar to those seen in AIDS patients. They are usually large cell or small non-cleaved cell lymphomas but polymorphous B-cell hyperplasias and plasma cell dyscrasias also occur. These lymphomas occur with greater than expected frequency in the CNS. Transplant patients receiving immunosuppressant medications tolerate chemotherapy poorly often developing profound and prolonged pancytopenia. Their lymphoma should be treated in a stepwise fashion. 

1. The immunosuppression should be reduced to the absolute minimum possible. Some lymphomas will spontaneously regress if the immunosuppression can be sufficiently reduced.        
2. If reduction of immunosuppression fails to control the lymphoma, the chair of the Lymphoma Tumour Group should be consulted to determine if novel experimental treatment would be of use. Rituximab is effective for such patients and may be recommended (Cook, Lancet, 1998; 354:1698).

 Only a small number of cases of lymphoma due to human T-cell lymphotropic virus (HTLV) type 1 have occurred in British Columbia patients. This type of lymphoma should be suspected in patients who develop a syndrome of widespread lymphoma involving skin and bone or bone marrow, often associated with hypercalcemia. Origin from, or previous residence in Southern Japan or the Caribbean Basin, where this virus is endemic, should also suggest possible HTLV disease.

Treatment of HTLV associated lymphoma requires intensive multi-agent chemotherapy. Because of the rarity of this disease and its aggressive nature, management should be discussed with a Core Member of the Lymphoma Tumour Group. Special attention should be directed at the tendency of this type of lymphoma to involve the CNS and the need for family screening and counselling for presence of HTLV which can be spread by sexual contact or from body fluids. A screening test for presence of antibody to HTLV-1 is available. Information about this test should be obtained from one of the pathologist Core Members.

Approximately 5% of patients present with two different histologic subtypes of lymphoma at the time of diagnosis, usually with low grade lymphoma in the bone marrow or a lymph node and large cell lymphoma at another lymph node or extra-nodal site. Initial management should be as appropriate for the most aggressive subtype present, the apparent extent (stage) of the aggressive subtype and the age of the patient. Subsequent relapse is common, but may occur after a long interval and may be from either of the presenting types of lymphoma. Treatment of the relapse depends on the histologic type and clinical behaviour of the disease.

Revised 28 November 2002

When marginal zone lymphoma, splenic type occurs in association with hepatitis C (serologic positivity for hepatitis C antibody is sufficient proof) the lymphoma may regress completely when the hepatitis is effectively treated with interferon or interferon plus ribavirin (Hermine, N Engl J Med,2002;347:89-94). All lymphoma patients, regardless of type, should have hepatitis C serology performed at diagnosis. Any patient found to have positive serology for Hepatitis C and a small B-cell lymphoma, especially marginal zone lymphoma, splenic type, should be considered for treatment with interferon and if that fails to suppress the hepatitis C, with the addition of ribavirin.​

Updated 20 June 2007 ​

Patients found to have a positive test for either hepatitis B surface antigen (HBsAg) or antibody to hepatitis B core antigen (HBcoreAb) are at risk for fulminant hepatitis if treated with immunosuppressive chemotherapy, especially agents such as corticosteroids or purine analogues, and including monoclonal antibodies such as rituximab. All patients with lymphoid cancer should be tested for both HBsAg and HBcoreAb. If either test is positive when such patients require systemic treatment they should also be treated with lamivudine 100 mg/day orally, for the entire duration of the systemic treatment and for six months afterwards. Systemic treatments include chemotherapy, rituximab (including maintenance rituximab) and radio-immunotherapy. Such patients should also be monitored with frequent liver function tests and hepatitis B virus DNA at least every two months during the systemic treatment. If the hepatitis B virus DNA level rises during this monitoring, management should be reviewed with an appropriate specialist with experience managing hepatitis and consideration given to halting chemotherapy. Special note for patients with coincident human immunodeficiency virus (HIV) infection and prior hepatitis B: To prevent rapid emergence of lamivudine-resistant HIV, patients with prior hepatitis B infection should not initiate lamivudine prophylaxis until HAART has also been started.

Updated 20 June 2007

Five percent to 10% of patients with lymphoma and an associated IgM monoclonal protein (usually lymphoplasmacytic lymphoma, also known as Waldenstrom’s macroglobulinemia) also develop anti-MAG (myelin-associated glycoprotein) antibodies and polyneuropathy. Such patients should be treated with standard chemotherapy for advanced stage indolent lymphoma (see Table 3.1) and approximately 50% will experience improvement in the neuropathy. However, some patients with IgM monoclonal protein and anti-MAG antibodies develop polyneuropathy without histologic evidence of underlying lymphoma despite the fact that the presence of the monoclonal IgM implies the existence of an underlying monoclone of malignant B-cells. Evidence concerning the usefulness of anti-lymphoma treatment in such patients is not definitive, with anecdotal series documenting improvement and the only randomized trial under-powered and not focused on the most relevant endpoints.

The BCCA Lymphoid Cancer Tumor Group recommends that patients with IgM-associated polyneuropathy be co-managed by an oncologist/hematologist and a neurologist experienced in the diagnosis and treatment of polyneuropathy as shown below. Such patients should undergo a careful search for underlying lymphoma, including a bone marrow biopsy, and all other conditions such as nutritional deficiency or spinal stenosis should be eliminated as possible causes before employing these treatment recommendations.

Clinical setting: IgM-associated polyneuropathy and histologically proven coincident indolent lymphoma

Recommended treatment: As for advanced stage indolent lymphoma, see Treatment section above

Clinical setting: IgM-associated polyneuropathy in the absence of histologically proven coincident indolent lymphoma

Recommended treatment: Single agent rituximab 375 mg/m2 IV weekly for 4 weeks (LYRITUX, requires Compassionate Access Program (CAP) approval)

Updated: 13 May 2005

Many patients with malignant lymphoma, especially those below the age of 65-70 years at diagnosis, can be cured. Most cured patients experience minimal long-term toxicity from the treatments, however, certain predictable and occasional rare and unpredictable late effects may occur and require preventive measures and/or recognition and treatment. 

The following late effects of malignant lymphoma or its treatment should be considered when patients are reviewed in follow-up:

 The following minimum follow-up tests and examinations should be performed on all patients after treatment for malignant lymphoma. Visits should be every 3 months for 2 years, then every 6 months for 3 years, then annual. Patients should be encouraged to perform careful breast and skin examination on a regular basis and to keep their immunizations up to date (see Appendix III).