MD2B - Non-Hodgkin's Lymphoma

Introduction

The non-Hodgkin’s lymphomas (NHL) comprise a diverse collection of lymphoreticular neoplasms, usually but not necessarily arising in nodal tissue. They account for about 4% of newly diagnosed adult cancers and rank 9^th in leading causes of cancer mortality [1, 2]. The various types have little similarity to each other and are categorized by the World Health Organization according to cell origin (B cell, T cell/NK cell). Most of these malignancies are of B-cell origin. The belief that T-cell lymphomas have a worse prognosis than B-cell lymphomas remains controversial.

Epidemiology and Etiology

• Incidence is estimated to be over 80,000 cases each year in the US [1]. The incidence of NHL increased 80% in the 20^th century but has since plateaued and begun to decrease in the 21^st century [1, 3, 4]. Known factors (aging population, HIV) accounted for less than half of the increase in incidence of NHL; the cause for the increase remains unknown [5].
• Broad age ranges from infancy to late adulthood, although the majority of cases occur in the fifth to eighth decades of life.
• Etiology: Many known risk factors include infection with certain viruses, such as HTLV- 1, EBV, HHV-8, and hepatitis C [6, 7]. There is a well-characterized association of gastric lymphoma with Helicobacter pylori and other bacterial infections.
• Family history does appear to increase risk for NHL, but most cases have no hereditary association that is known.
• Increased risk in multiple immunocompromised states, including HIV, collagen-vascular disease, celiac sprue, Hashimoto's, and post-organ transplant settings.
• Previous exposure to ionizing radiation or chemicals, including pesticides or alkylating agents, has been linked to NHL [8].

Pathogenesis

• The nature of the disease (indolent vs. aggressive) is correlated with the stage of lymphocytic differentiation of the malignant cells.
• Malignant blast cells (i.e., diffuse large B-cell lymphoma) are fast-growing and result in aggressive disease, whereas malignant mature lymphocytes (i.e., follicular lymphoma) behave indolently.
• Malignant transformation is usually the result of chromosomal translocations that activate proto-oncogenes or create a chimeric fusion protein. Translocations are thought to occur during normal gene rearrangements (Ig, T-cell receptor).
• The t(14;18) translocation (characteristic for follicular lymphoma but also common in other types) results in activation of the BCL-2 gene and suppression of apoptosis.

Diagnosis

• Histology of the affected tissue is the key
• Growth pattern of malignant cells
  • diffuse vs. nodular or follicular distribution of cells
• Fine-needle aspirate is sufficient for lymphoma diagnosis but rarely adequate for subtyping; thus, excisional or incisional biopsy is considered mandatory.
• Treatment depends on histologic subtype
• Histologic classification based on:
  • Working Formulation - 3 categories (low grade, intermediate grade, and high grade) with ten subtypes
  • REAL/WHO - classification includes leukemias and lymphomas, with three categories based on lineage and morphology (Hodgkin, B cell, and T/NK cell). Representative subtypes in the table below:

• For clinical relevance, classification based on natural history (indolent vs. aggressive) is often favored

Staging Evaluation

• Physical exam, particularly for adenopathy, hepatosplenomegaly, and constitutional (“B”) symptoms.
• Routine labs, particularly serum LDH.
• Radiologic studies, CXR, abdominal CT scan, and bone marrow biopsy.
• PET is widely accepted as more sensitive than CT and MRI, and the degree of uptake may help predict aggressive disease.
• Ann Arbor (Lugano) staging remains the mainstay of staging for NHL but often lacks clinical relevance. For this reason, stratification by risk is preferred.
• Most reliable predictors of outcome: histology, stage, age, serum LDH, performance status, bulk of tumor, and number of extranodal sites involved.

Indolent Lymphomas - long survival but often not curable (except in rare cases)

Important types include follicular lymphoma, MALT lymphoma, and small lymphocytic lymphoma.

• Clinical Manifestation
  • History: Usually asymptomatic but may present with advanced-stage disease.
  • Physical exam: Painless adenopathy
  • Common extranodal sites: Stomach, liver, spleen, marrow
•  Natural Course
  • Indolent clinical course, with a median survival of 7 to 8 years. Median survival for follicular lymphoma has not changed over the past 30 years
•  Treatment
  • Early stage (I or II): Rare, but potentially curable with radiation therapy to involved sites
  • Advanced stage: Majority of cases; treatment is withheld until symptoms develop, as intensive chemotherapy, total-body irradiation, or rituximab will not necessarily improve survival in comparison to watchful waiting.
  • When therapy is necessary, the standard of care is rituximab +/- chemotherapy. Chemotherapy includes R-CHOP (cyclophosphamide, Adriamycin, vincristine and prednisone)
  • Rituximab (monoclonal anti-CD20 antibody), when added to chemotherapy, has been shown to improve survival in follicular lymphoma, and early data indicate prolonged survival with maintenance therapy as well.
  • Clinical Pearl: Triple therapy (proton pump inhibitor, clarithromycin, and amoxicillin/metronidazole) for Helicobacter pylori-positive MALT lymphoma. This subtype can spontaneously resolve on its own with a resolution of the bacterial infection.

Aggressive Lymphomas – short survival if untreated, but can be curable

Important subtypes include diffuse large B-cell (30% of NHL, most common) and peripheral T cell lymphomas

• Clinical Presentation
  • History: Most present symptomatically and thus at earlier stages
  • Physical exam: Painless adenopathy, hepatosplenomegaly
  • Common extranodal sites: GI tract, lung/pleura, marrow, liver, spleen, skin, Waldeyer's ring
•  Natural Course
  • Prognosis dependent on risk factors: clinical remission in 40 – 80%, and 5-year overall survival of 30 – 70%
•  Treatment
  • Limited stage: combination chemotherapy +/- radiation with excellent cure rates. Trial results studying the efficacy of combination therapy have varied. Therefore, treatment decisions for patients with limited-stage NHL are typically made based on performance status and the relative toxicity profiles of the therapies being considered [9, 10, 11, 12]. Advanced stage: requires chemotherapy for cure. The addition of rituximab to CHOP in diffuse large B-cell lymphoma has been shown to increase overall survival.
  • Optimal regimen not determined, but the standard is CHOP + rituximab; other combination therapies include Pola-R-CHP. Other therapies considered for specific subtypes or relapsed/refractory disease include autologous stem cell transplants, CNS prophylaxis, CART and R-EPOCH (which adds etoposide to the standard R-CHOP regimen)

Highly Aggressive Lymphomas – very short survival if untreated (weeks), but curable

Rare (1-5% of NHL), important subtypes include (all adult) include Burkitt’s lymphoma, lymphoblastic leukemia, and T cell lymphoma.

•  Clinical Presentation
  • History: Most present symptomatically and thus at earlier stages
  • Physical exam: Painless adenopathy
  • Common extranodal sites: GI tract, lung/pleura, marrow, liver, spleen, skin, Waldeyer's ring
• Natural Course
  • Highly aggressive and lethal in weeks without treatment, but ALL are potentially curable. With improved outcomes from hyperintensive therapy, 60-80% of patients will enter complete remission, with cure rates of up to 60% in the young
•  Treatment
  • Dose-intensive chemotherapy is mandatory for cure, with regimens such as hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) patterned after treatment of childhood ALL
  • Adding rituximab to chemotherapy may have a benefit in Burkitt’s and lymphoblastic leukemia
  • Prophylactic CNS treatment with direct instillation of chemotherapy into the subarachnoid space is highly recommended.

Relapsed disease

• Indolent lymphoma (follicular): no proven standard therapy; variety of palliative options include "watch and wait", chemotherapy, rituximab, radioimmunotherapy, and bone marrow transplantation
• Aggressive lymphoma (diffuse large B cell): standard is high-dose chemotherapy followed by autologous stem cell transplantation with a 20-40% chance of "cure"

HIV-Associated Lymphoma

• 70-90% are aggressive lymphomas; diffuse large B cell is most common (80%)
• Risk of NHL is inversely proportional to CD4 count.
• Highly active antiretroviral therapy (HAART) has resulted in decreased incidence of HIV associated-NHL and improved outcomes.
• Involve extranodal sites in over 60% of cases.
• Former dismal prognosis (2-year survival <10%); now, patients with good risk factors have a 60% complete response to chemotherapy and a 51% 5-year survival [13].
• Treatment is systemic chemotherapy (CHOP) +/- CNS coverage. Prophylaxis against opportunistic infections is vital.
• Adding rituximab has shown benefit, particularly since the widespread use of HAART therapy. In one trial, the addition of rituximab did not increase the risk of life-threatening infections in HIV positive patients, in contrast to historical trials before the widespread use of HAART therapy [14, 15, 16].

Mycosis Fungoides

• Most common clinical form of cutaneous T-cell lymphomas (CTCL)
• Variable natural history, from benign-appearing skin eruptions to visceral and nodal involvement
• Sezary syndrome is a systemic form of CTCL manifesting with diffuse erythroderma, lymphadenopathy, and circulating malignant CD4+ lymphoid cells
• Early-stage treatment with Psoralen + UV-A radiation (PUVA) therapy +/- systemic therapy with excellent remission rates. Topical treatments, including nitrogen mustard, can also be used [17].
• Advanced-stage disease treatments are unsatisfactory, with short survival. Similar regimens for the early stage can be used for advanced-stage mycosis fungoides, but the goal is palliation of symptoms [18].