Show Summary Details
Page of

Lymphoma 

Lymphoma
Chapter:
Lymphoma
Author(s):

Dale Bixby

DOI:
10.1093/med/9780190862800.003.0069
Page of

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford University Press, 2020. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy and Legal Notice).

date: 18 September 2020

  1. A. Introduction

    1. a. Definition. Lymphomas are a group of malignant neoplasms resulting from the transformation of normal lymphoid cells within preexisting lymphoid tissues.

    2. b. Classification. While numerous classification schemes have been developed over the years, the two most frequently used today are the Revised European-American Classification of Lymphoid Neoplasms (REAL) and the World Health Organization (WHO) classifications. Initial stratification of lymphomas consists of two groups: Non-Hodgkin’s lymphoma (NHL) and Hodgkin’s lymphoma (HL) (Table 69.1).

      1. i. HL. Reed-Sternberg cells are usually present.

      2. ii. NHL. Reed-Sternberg cells are absent.

        Table 69.1 Comparison of Hodgkin’s Lymphoma and Non-Hodgkin’s Lymphoma

        Disease

        Etiology

        Malignant Cell of Origin

        Site of Origin

        Spread

        Mediastinal Involvement

        Bone Marrow Involvement

        Systemic (B) Symptoms

        Prognostic Tools

        Hodgkin’s lymphoma

        Unknown

        Likely a B cell

        Nodal

        Contiguous

        Common

        Uncommon

        Very common

        Stage, ESR, B symptoms, age

        Non-Hodgkin’s lymphoma

        Unknown (some may be EBV associated)

        90% B cell

        10% T cell

        Extranodal in 40%

        Noncontiguous

        Rarer

        Low grade: common

        High grade:

        more common in higher stage

        Less than 50% of patients; more common in higher grade

        IPI

        ESR = erythrocyte sedimentation rate; IPI = International Prognostic Index.

        1. 1. B symptoms include weight loss of more than 10% of body weight during the 6 months before the diagnosis, recurrent temperatures above 38° C during the previous month, or recurrent drenching night sweats during the previous month.

        2. 2. Patients with an erythrocyte sedimentation rate (ESR) of >50 mm/hr (or >30 mm/hr in the presence of B symptoms) can be considered to have a poorer prognosis, stage for stage.

        3. 3. International Prognostic Index (IPI), including the traditional IPI, the age-adjusted IPI, or rituximab-adjusted IPI; or the Follicular Lymphoma International Prognostic Index (FLIPI).

  2. B. Hodgkin’s Lymphoma

    1. a. Epidemiology

      1. i. Incidence. Approximately 8000 cases are reported per year in the United States.

      2. ii. Patient profile

        1. 1. Age. HL has a bimodal age distribution. The incidence peaks in patients aged 20–25 years and again in patients older than 55.

        2. 2. Gender. Except for the nodular sclerosis subtype, HL is more common in men than women.

        3. 3. Race. HL is more common in Caucasians than African Americans.

        4. 4. Disease association. As is the case for many lymphomas, the prevalence of HL is increased in patients with HIV infection. However, it is unusual in that it is more frequent in those with a higher CD4+ T cell count rather than a lower one.

    2. b. Pathogenesis of HL. Based on available data, the cell of origin in most cases of HL is likely a germinal center or post–germinal center B cell. Disease progression is orderly. Initially, the malignancy spreads to anatomically adjacent lymph tissues. Hematogenous spread to the liver, bone marrow, and other viscera occurs only in advanced disease.

    3. c. Clinical manifestations of HL

      1. i. Painless, superficial adenopathy (usually involving the neck or supraclavicular areas).

      2. ii. Constitutional (B) symptoms occur in one-third of patients.

      3. iii. Severe pruritus is often encountered at some point during the disease.

      4. iv. Alcohol-induced pain can occur at the site of enlarged lymph nodes, usually within minutes of ingestion of even small amounts of alcohol. This symptom occurs in approximately 10% of patients

      5. v. Characteristic laboratory findings include:

        1. 1. Anemia

        2. 2. Leukocytosis (initially) and thrombocytosis

        3. 3. Eosinophilia

        4. 4. Elevated erythrocyte sedimentation rate (ESR)

        5. 5. Elevated alkaline phosphatase level

    4. d. Approach to the patient

      1. i. Diagnosis. Obtaining a core biopsy or excisional biopsy is essential because fine-needle aspiration (FNA) will not allow for evaluation of architectural findings and a proper diagnosis. The finding of Reed-Sternberg cells on lymph tissue biopsy is characteristic of HL.

        1. 1. Differential diagnosis. Reed-Sternberg cells can also be seen in phenytoin-induced lymphoid hyperplasia, NHL, solid tumors, and mononucleosis. These should therefore be considered when Reed-sternberg cells are encountered.

        2. 2. Subtypes. Initial stratification involves classifying the disease as either classic HL or nodular lymphocyte predominant Hodgkin’s lymphoma (NLPHL). Within the classic HL category, there are four main histologic subtypes, which are distinguished by the morphology of the Reed-Sternberg cells and the architecture of the surrounding cells (Table 69.2).

          Table 69.2 Histopathologic Subtypes of Hodgkin’s Lymphoma

          Histologic Subtype

          Comments

          Nodular lymphocyte predominant Hodgkin’s lymphoma

          Represents 5% of all cases; characterized by the presence of Reed-Sternberg cell variants (called “popcorn” cells); often treated similarly to B-cell non-Hodgkin's lymphoma; often responds to chemotherapy but higher recurrence rate

          Classic Hodgkin’s lymphoma

          Mixed cellularity

          Represents 15% to 30% of all cases; intermediate prognosis; patients are older

          Lymphocyte depleted

          Usually presents in an earlier stage; better prognosis; rare relapses after remission

          Lymphocyte rich

          Usually presents in an earlier stage; better prognosis; rare relapses after remission

          Nodular sclerosis

          Represents 65% to 80% of all cases; female predominance; patients are younger; usually involves lower cervical, supraclavicular, and mediastinal nodes

      2. ii. Staging. Survival is affected by multiple factors, including the clinical stage, presence of B symptoms, elevated ESR, and bulk of disease.

        1. 1. Staging evaluation. Most patients are staged clinically; pathologic staging (i.e., exploratory laparotomy, including splenectomy, liver biopsy, and lymph node sampling) is rarely required given current imaging technologies.

          • a. Radiographic imaging. A chest radiograph is the initial evaluation for mediastinal involvement, but almost all patients will need a computed tomography (CT) scan of the chest, abdomen, and pelvis to document size and location of all involved lymph nodes.

          • b. Other studies. Many patients will undergo positron-emission tomography (PET) scanning before the initiation of therapy and at predetermined intervals during and after the completion of chemotherapy to assess “responsiveness.” The clinical utility of assessing responses with CT versus PET scans (or combined PET-CT scans) is currently being evaluated. Patients should also undergo bilateral bone marrow biopsies before therapy to assess stage. Pulmonary function tests (PFTs) are performed if patients will receive bleomycin given that it can cause pulmonary fibrosis. An echocardiogram or multiple gated acquisition (MUGA) is required if the patient will receive an anthracycline. Hepatitis B and HIV testing is encouraged.

        2. 2. Staging classification. The staging system for HL is based on the Ann Arbor classification system. Like most oncologic staging systems, prognosis is best for stage I patients and worst for stage IV patients. Table 69.3 presents a simplified staging scheme based on extent of lymph node and extranodal involvement. Within these stages are factors that may affect treatment and prognosis.

          Table 69.3 Staging System for Patients with Lymphoma

          Stage

          Definition

          I

          Limited to one lymph node region or one extranodal site (stage IE)

          II

          Two or more lymph node regions on one side of the diaphragm or with involvement of a limited, contiguous extralymphatic site (IIE)

          III

          Lymph node involvement on both sides of the diaphragm, which may include the spleen (IIIS) or a limited, contiguous extralymphatic site (IIIE), or both (IIIES)

          IV

          Disseminated involvement of more than one extranodal site with or without lymph node involvement

          • a. If patients have no B symptoms, the letter “A” is added to the stage.

          • b. If B symptoms are present, the letter “B” is added. In general, those with B symptoms have a poorer prognosis.

          • c. Involvement of the spleen is designated by the letter “S.”

          • d. Contiguous lymph node masses >10 cm in size may be designated by the letter “X,” indicating bulky disease.

    5. e. Treatment. In general, HL should be thought of as a curable cancer.

      1. i. Treatment depends on the stage. General approaches follow; an oncology reference can provide detailed information regarding regimens.

        1. 1. Low-stage disease (e.g., stages I and IIa) is divided into diseases with favorable versus unfavorable characteristics (bulky disease, increased number of sites of disease, extralymphatic disease, or an elevated ESR). Patients with favorable disease may be treated with two or three cycles of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) chemotherapy followed by a restaging PET scan. If the PET is negative, then the patient will receive consolidative radiation therapy to the involved site. Patients with unfavorable or bulky disease are typically treated with an increased number of ABVD chemotherapy cycles followed by radiation therapy.

        2. 2. High-stage disease (i.e., stages III and IV) is usually treated with multiple cycles of chemotherapy (ABVD) followed by involved-site radiation therapy, especially for patients with bulky disease or those with persistent PET positivity at selected sites.

        3. 3. Patients with aggressive disease that relapses after treatment may be candidates for high-dose therapy followed by autologous bone marrow transplantation. Those with chemotherapy-refractory disease have only a small chance for long-term survival even with allogeneic bone marrow transplantation.

      2. ii. Long-term complications of treatment

        1. 1. Chemotherapy increases the risk for acute leukemia; this risk peaks 5 years after initiation of therapy and decreases after 10 years. The development of acute leukemia as a result of chemotherapy for HL is much more common in older patients.

        2. 2. Radiation therapy leads to an increased incidence of solid tumors (e.g., breast, stomach, or thyroid tumors); this risk, unlike that of leukemia, continues to increase with time. Additionally, the risk for breast cancer in women is higher for those receiving greater doses of radiation or those receiving radiation at a younger age.

        3. 3. Cardiovascular disease. There appears to be an increased risk for heart failure as well as coronary artery disease in patients receiving chemo- and radiation therapy.

        4. 4. Fertility. Fertility can be affected by many anticancer therapies, and the issue should be discussed before initiating chemotherapy to allow for possible gamete preservation.

  3. C. Non-Hodgkin’s Lymphoma. NHL is the name given to a heterogeneous group of malignancies involving either B or T cells.

    1. a. Epidemiology

      1. i. Incidence. The incidence of NHL is much higher than for HL. There were approximately 72,580 new cases in 2016 and almost 20,000 deaths from NHL annually in the United States.

      2. ii. Patient profile

        1. 1. Age. The median age at the time of diagnosis is 50 years.

        2. 2. Gender. NHL is 50% more common in men than women.

        3. 3. Race. NHL is more common in Caucasians than African Americans or Asian Americans.

        4. 4. Other factors

          • a. NHL is more common in patients with altered immunity (e.g., HIV-positive patients, those receiving immunosuppressive therapy, or those with congenital immunodeficiencies or autoimmune disease).

          • b. Some subtypes are associated with specific balanced chromosomal translocations.

    2. b. Pathogenesis of NHL. NHL involves the malignant transformation of either a B or T cell. The spread of the disease is often not contiguous, skipping over lymph node sites.

    3. c. Clinical manifestations of NHL. Presentations depend on the site and subtype of tumor.

      1. i. Common complaints include:

        1. 1. Asymptomatic superficial lymphadenopathy

        2. 2. B symptoms are much less common in low-grade than in high-grade NHL

        3. 3. Abdominal complaints because of bulky lymph nodes pressing on vital structures

        4. 4. Bone pain

        5. 5. Symptoms related to pancytopenia

        6. 6. Skin changes due to cutaneous involvement

        7. 7. Acute emergencies (e.g., superior vena cava syndrome, spinal cord compression, airway compression) may occur and be the presenting symptom of NHL.

      2. ii. Characteristic laboratory findings include:

        1. 1. Complete blood count (CBC) may be normal or reveal pancytopenia, due to marrow involvement.

        2. 2. Elevated uric acid and lactate dehydrogenase (LDH) levels

        3. 3. Elevated alkaline phosphatase levels

          Table 69.4 Common Chromosomal Translocations in Non-Hodgkin’s Lymphoma

          Translocation

          Genes Involved

          t(14;18)

          The bcl-2 antiapoptotic gene on chromosome 18 is fused to the immunoglobulin heavy-chain gene on chromosome 14. Found in 85% of follicular lymphomas.

          t(11;14)

          The cell cycle regulatory protein bcl-1 (cyclin D1) on chromosome 11 is fused to the immunoglobulin heavy-chain gene on chromosome 14. This finding is nearly diagnostic for mantle cell lymphoma.

          Chromosome 8q24

          c-Myc gene. Several translocations involving this locus [t(8;14); t(2;8); or t(8;22)] are associated with highly aggressive B cell lymphomas (e.g., Burkitt’s lymphoma).

          t(2;5)

          The nucleophosmin (NPM) gene on chromosome 5 is fused to the anaplastic lymphoma kinase (ALK1) on chromosome 2. Occurs in anaplastic large cell lymphomas.

    4. d. Approach to the patient

      1. i. Diagnosis. Just as in HL, a core biopsy or excisional biopsy is essential because FNA will not allow for architectural findings and a proper diagnosis. The initial classification of the lymphoma will determine whether it is of a B cell, T cell, or NK cell origin (WHO/REAL classification). Subtypes can then be grouped into three categories based on the histologic grade of the tumor: indolent, aggressive, or highly aggressive.

      2. ii. Staging

        1. 1. Staging evaluation. Chest radiographs, and abdominal and pelvic CT scans are often performed, and some patients require lumbar puncture or a bone scan. Bilateral bone marrow biopsies are routinely performed. PET scanning is increasingly employed in the staging and management of NHL. As with HL, staging laparotomy and lymphangiography are not usually indicated.

        2. 2. Staging classification. The Ann Arbor staging system is used for both HL and NHL (Table 69.4).

    5. e. Treatment depends primarily on histology, the extent of disease, and patient characteristics. Treatment options are diagrammed in Figure 69.1. Most patients with B cell NHL receive chemotherapy/immunotherapy involving rituximab (a monoclonal antibody against the protein CD20).

Figure 69.1 General therapeutic measures for patients with non-Hodgkin’s lymphoma (NHL).

Figure 69.1 General therapeutic measures for patients with non-Hodgkin’s lymphoma (NHL).

Hot Key

There exists a curious irony to NHL: tumors that confer a favorable prognosis are the least likely to be cured because low-grade tumors are less responsive to chemotherapy. Patients with high-grade lymphomas generally have a poorer overall prognosis, but the chance of cure is increased.

Suggested Further Readings

Bartlett NL. Fine-tuning the treatment of Hodgkin’s lymphoma. N Engl J Med 2016;374:2490–2.Find this resource:

Bobrove AM. Alcohol-related pain and Hodgkin’s disease. West J Med 1983;138:874–5. (Classic Article.)Find this resource:

Coiffier B, Lepage E, Brière J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-b-cell lymphoma. N Engl J Med 2002;346:235–42. (Classic Article.)Find this resource:

Kwee TC, Kwee RM, Nievelstein RAJ. Imaging in staging of malignant lymphoma: a systematic review. Blood 2008;111:504.Find this resource: