Hospital Medicine

B-cell non-Hodgkin's lymphoma

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I. What every physician needs to know.

Non-Hodgkin's lymphomas (NHL) are a malignant proliferation of lymphoid cells. The subcategories of B-cell NHL can be traced to particular stages in the life cycle of the B-cell, which manifests itself as the pattern of cells on the biopsy of affected tissue. Molecular genetic testing (such as fluorescence in situ hybridization [FISH] and cytogenetics) and flow cytometry provide supportive information in diagnosis.

Indolent subtypes, such as chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma and the marginal-zone lymphomas are incurable and treatment may be delayed. Aggressive subtypes, such as diffuse large B-cell and mantle cell, and highly aggressive subtypes like Burkitt, lymphoblastic and acquired immune deficiency syndrome-related (AIDS-related) lymphomas, may be cured and are treated urgently due to their rapid growth.

II. Diagnostic Confirmation: Are you sure your patient has B-cell non-Hodgkin's lymphoma?

Diagnosis requires identifying the architecture of the diseased lymph node. Therefore, in order to avoid iatrogenic disruption of the node, excisional biopsy is required, generally of the largest palpable lymph node. If lymph nodes are deep-seated, core needle biopsy may be helpful, but it may not provide definitive diagnosis.

A. History Part I: Pattern Recognition:

Patients can be from any ethnic group or age and may be asymptomatic. Lymphadenopathy is typically firm, rubbery and not tender. Waxing and waning adenopathy can be confused with infectious etiology. Hepatomegaly and splenomegaly may be present. Approximately one third of patients with aggressive lymphomas describe fevers, night sweats and loss of more than 10% body weight within the prior 6 months (the "B" symptoms). B symptoms signify worse prognosis.

B. History Part 2: Prevalence:

Incidence is increasing, particularly with aggressive histologies, with an estimated new 65,540 cases diagnosed and 20,210 deaths from NHL in 2010. There are 19 new cases per 100,000 persons in the United States each year, with the incidence increasing to 68 per 100,000 in people over age 65.

The median age at diagnosis is 66 years. Risk is increased with immunodeficiency states such as human immunodeficiency virus (HIV)/AIDS, treatment for solid organ transplant and inherited diseases such as severe combined immunodeficiency and Wiskott-Aldrich. Particularly in immunodeficient patients, there is an association with Epstein-Barr virus (EBV). Other associations include hepatitis C (HCV), agricultural work and prior treatment for Hodgkin's lymphoma.

C. History Part 3: Competing diagnoses that can mimic B-cell non Hodgkin's lymphoma

Lymphadenopathy and B symptoms can be caused by a litany of infectious and malignant etiologies. Patients may describe a waxing and waning course of symptoms and enlarged nodes, further confounding diagnosis. Biopsy of a lymph node is needed.

D. Physical Examination Findings.

Patients are often asymptomatic. Enlarged, firm, non-tender, rubbery lymph nodes can be present in any chains and in node-bearing areas such as Waldeyer's ring. Splenomegaly and hepatomegaly may be present. Extranodal disease is often present, so sites such as bone, testes and salivary glands should be examined. Focal neurologic symptoms or headache may be present with central nervous system (CNS) disease. Performance status should be assessed. Patients may have resultant infections as well.

E. What diagnostic tests should be performed?

Excisional biopsy of the largest palpable lymph node should be pursued. If lymph nodes are deep-seated, core needle biopsy may be helpful but may not provide definitive diagnosis. Fine-needle aspiration has no role in the diagnosis of NHL.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

  • Lymph node biopsy should be sent for immunophenotypic analysis and often cytogenetics.

  • Complete blood and platelet count may show cytopenias related to enlarged spleen or to bone marrow involvement.

  • Chemistry and liver function panels may suggest visceral involvement and provide information regarding organ function prior to therapy. In addition, renal function and electrolytes, along with uric acid, may show tumor lysis syndrome even before treatment.

  • Lactate dehydrogenase (LDH) and beta-2 microglobulin are used for prognosis.

  • Bone marrow aspirate and biopsy should be performed for staging.

  • Cerebrospinal fluid (CSF) evaluation is needed in cases with higher incidence of involvement, including the highly aggressive subtypes, primary CNS lymphoma and in cases of diffuse large B-cells that have epidural, paraspinal, testicular, bone marrow, or paranasal involvement.

  • Acute hepatitis panel (particularly looking at B and C), and HIV testing provides important information, as these diseases may affect treatment modalities.

  • Esophagogastroduodenoscopy (EGD) and colonoscopy should be pursued in mantle cell and other select cases.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Computed tomography (CT) scans of the chest, abdomen and pelvis are needed for staging. Positron emission tomography (PET) scan may also be considered. If CNS involvement is suspected, magnetic resonance imaging (MRI) of the brain is useful.

Echocardiogram or multigated acquisition (MUGA) assessment of baseline heart function is required prior to use of some chemotherapeutic agents.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

N/A

III. Default Management.

Management involves a multidisciplinary team. Staging work-up and treatment should be initiated after diagnosis. Whether to perform treatment as an inpatient or outpatient may depend on the subtype of lymphoma. For highly aggressive lymphomas, consider transfer to an experienced center. Treatment commonly consists of R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone) chemotherapy (or variations) for aggressive lymphomas.

A. Immediate management.

Treatment of NHL is usually delivered in an outpatient setting. Inpatient treatment may be preferred in patients with bulky tumors and aggressive pathologic subtypes. Indolent lymphomas are unlikely to be treated as an inpatient.

If treatment will be initiated immediately, staging and mitigating side effects are essential:

  • In addition to the labs and studies mentioned above, check baseline uric acid.

  • Pursue central access with peripherally inserted central catheter (PICC) or port-a-cath.

  • Intravenous (IV) normal saline and allopurinol (or rasburicase if uric acid is already high, or there is pre-existing renal failure, or highly-aggressive, advanced or bulky disease) should be initiated prior to treatment to help prevent tumor lysis syndrome.

  • Pregnancy test for women of childbearing potential.

B. Physical Examination Tips to Guide Management.

  • With treatment, monitoring for signs or symptoms of tumor lysis syndrome is advised. Arrhythmias and weakness may suggest hyperkalemia. Altered mental status, agitation or seizure may suggest hypocalcemia. Urine output goal should be over 100cc/hour.

  • If treated with doxorubicin, arrhythmias or pericarditis may be observed with acute toxicity. Dysuria or hematuria may be a sign of cyclophosphamide toxicity.

  • Abdominal tenderness and constipation may result from vincristine, as can paresthesias, orthostasis, cranial nerve palsy, or bone pain.

  • Skin rash or urticaria may present as a result of therapy. Acute fevers, rigors, arrhythmias, and pulmonary signs can occur with rituximab. Edema, rales or dyspnea may suggest development of cardiomyopathy due to treatment.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

  • Daily uric acid, potassium, phosphate, and calcium, as well as creatinine should be monitored during treatment. Rituximab use in patients with prior hepatitis B infection may cause reactivation and liver function tests (LFTs) should be monitored.

  • Bone marrow suppression usually nadirs 1-2 weeks from the start of treatment. Monitoring complete blood count (CBC) is useful during this time.

  • Neutropenic fever should be treated accordingly.

D. Long-term management.

Chemotherapy for aggressive and highly aggressive lymphomas is most commonly administered on a 3-week cycle.

E. Common Pitfalls and Side-Effects of Management

Regimens used will cause cytopenias, with nadirs in 1-2 weeks. Close follow-up with labs can be useful. Many chemotherapeutic agents commonly used in NHL are metabolized by the cytochrome p450 system, so medications such as phenytoin, cimetidine and erythromycin may affect half-life.

If tumor lysis syndrome develops, heralded by hypocalcemia, hyperkalemia, hyperphosphatemia, hyperuricemia, and acute renal failure, nephrology should be consulted immediately, as hemodialysis is the treatment.

Doxorubicin is a vesicant that can cause necrosis upon extravasation.

IV. Management with Co-Morbidities

N/A

A. Renal Insufficiency.

Dose adjustments of the chemotherapeutic regimen will be required. In addition, fluid balance compromise may make tumor lysis syndrome a prominent consideration. In such cases, rasburicase is typically preferred over allopurinol.

B. Liver Insufficiency.

Dose adjustments of the chemotherapeutic regimen will be required.

C. Systolic and Diastolic Heart Failure

Alternative chemotherapeutic regimens may be considered. Also, the patient may be at increased risk for development of other heart conditions during therapy. Digoxin interacts with some chemotherapeutic agents used in NHL.

D. Coronary Artery Disease or Peripheral Vascular Disease

Antiplatelet and anticoagulant therapies may increase morbidity with thrombocytopenias that result from therapy.

E. Diabetes or other Endocrine issues

Corticosteroids are often a part of regimens that may lead to uncontrolled diabetes.

F. Malignancy

Treatment may lead to secondary malignancies, including acute myelogenous leukemia and myelodysplastic syndrome.

G. Immunosuppression (HIV, chronic steroids, etc).

  • HIV positive patients should be on high active anti-retroviral therapy (HAART) therapy, which is an important component of the lymphoma treatment.

  • Neutropenia caused by chemotherapy can lead to life-threatening infections, even with mild symptomatology.

H. Primary Lung Disease (COPD, Asthma, ILD)

Patients with underlying lung disease might be more prone to infections caused by therapy. Steroids are often a part of chemotherapy regimens, so medicine reconciliation is important to avoid duplicate treatments.

I. Gastrointestinal or Nutrition Issues

Patients are likely to experience nausea and vomiting. Diarrhea is also common. As needed or scheduled antiemetics should be prescribed.

J. Hematologic or Coagulation Issues

Myelosuppression may lead to severe thrombocytopenia and anemia. Cyclophosphamide may also potentiate anticoagulant effects of warfarin.

K. Dementia or Psychiatric Illness/Treatment

Dementia or psychiatric disease can potentially present a severe challenge. Chemotherapy and radiation require frequent scheduled follow-up, as well as close surveillance for symptoms to manage potentially dangerous side-effects in a timely manner. The physician must evaluate the patient's ability to comply, often in conjunction with caregivers, prior to embarking on such a treatment plan.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

  • With rituximab therapy, alert the provider that infusion reactions such as fever, chills, headache, bronchospasm, dyspnea, and hypotension may improve with slowing or interrupting infusion.

  • Repeated labs should be done with all patients, particularly those with large tumor burden, arrhythmia or altered mental status to check for tumor lysis syndrome, which requires an emergent nephrology consult for hemodialysis.

  • Doxorubicin may cause orange discoloration of urine.

  • If central line doesn't return, consider a patency study prior to infusion of doxorubicin, a vesicant.

B. Anticipated Length of Stay.

Patients can usually be discharged after completion of the chemotherapeutic regimen, which typically lasts around 5 days. Otherwise, NHL treatment is usually initiated on an outpatient basis.

C. When is the Patient Ready for Discharge.

Typically, the patient can be discharged upon diagnosis of the indolent lymphoma or after completion of the first round of therapy for highly aggressive lymphoma if there is no evidence of tumor lysis syndrome.

D. Arranging for Clinic Follow-up

N/A

1. When should clinic follow up be arranged and with whom.

Patients with indolent lymphoma should be seen by an oncologist shortly after staging work-up. Patients with aggressive lymphoma that is not yet treated should be seen by oncology within a matter of days. Similarly, patients who have received initiation of treatment should have labs monitored, beginning before the expected nadir of counts and should be seen by their oncologist prior to the next scheduled cycle of therapy (within 2 weeks).

Patients with HIV should have close follow-up with infectious disease physicians as well.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

If oncology evaluation will be done as an outpatient prior to initiation of chemotherapy, a staging work-up, including CT scan of chest, abdomen and pelvis, as well as CBC and complete metabolic profile (CMP) is a good baseline.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

CBC, basic metabolic panel (BMP) and LFTs should be done on the day of the clinic visit. Also, CBCs 1-2 times a week at the time of expected nadir if the patient has received chemotherapy.

Patients receiving chemotherapy should be advised to check their temperature regularly and to seek medical attention for fever.

E. Placement Considerations.

Patients with indwelling lines will require line care depending on the type of line and institution protocols.

F. Prognosis and Patient Counseling.

Indolent lymphomas are usually not curable, but have a median survival of 10 years. Because they are recurrent processes, treatment goals include prolongation of disease-free survival, maintenance of quality of life and provision of long-term support.

In contrast, the aggressive NHL, while having a short natural history, can be cured in 30-60% of patients with intensive chemotherapy. Overall survival at 5 years is 50-60%, with most relapses occurring within the first 2 years after therapy. The treatment goal in aggressive histologies is therefore cure, along with management of side effects and long-term toxicities.

Prognosis depends on a number of factors, including, prominently, histologic subtype. Generally, prognosis is worse in patients older than 60 or with poor performance status, with bulky disease and with the presence of B symptoms.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

N/A

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

  • While deep vein thrombosis (DVT) prophylaxis with low-molecular weight heparin is preferred, decisions regarding DVT prophylaxis may be affected by cytopenias.

  • Tumor lysis prophylaxis should be instituted as mentioned.

  • Many regimens involve infectious prophylaxis with antiviral, antifungal and sometimes antibiotic agents.

VII. What's the evidence?

Advani, R, Rosenberg, SA, Horning, SJ. "Stage I and II follicular non-Hodgkin lymphoma: long-term follow-up of no initial therapy". J Clin Oncol. vol. 22. 2004. pp. 1454-1459.

Alizadeh, AA, Eisen, MB, Davis, RE. "Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling". Nature. vol. 403. 2000. pp. 503-511.

Coiffier, B, Lepage, E, Briere, J. "CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large B-cell lymphoma". N Engl J Med. vol. 346. 2002. pp. 235-242.

Fisher, RI, Gaynor, ER, Dahlberg, S. "Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma". N Engl J Med. vol. 328. 1993. pp. 1002-1006.

Juweid, ME, Stroobants, S, Hoekstra, OS. "Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma". J Clin Oncol. vol. 25. 2007. pp. 571-578.

Milpied, N, Deconinck, E, Gaillard, F. "Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support". N Engl J Med. vol. 350. 2004. pp. 1287-1295.

Romaguera, JE, Khouri, IF, Kantarjian, HM. "Untreated aggressive mantle cell lymphoma: results with intensive chemotherapy without stem cell transplant in elderly patients". LeukLymphoma. vol. 39. 2000. pp. 77-85.

Sehn, LH, Berry, B, Chhanabhai, M. "The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP.". Blood. vol. 109. 2007. pp. 1857-1861.

Swerdlow, SH, Campo, E, Harris, NL. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues,. IARC Press. 2008.

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