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 are among the leading causes of cancer mortality. 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 63,000 cases each year in the US [1], with a dramatic increase in Western countries in the last 40 years.
• Broad age range from infancy to late adult, although majority of cases occur in the fifth to eighth decades of life.
• Etiology: Generally unknown, but well-described association with certain viruses, such as HTLV- 1 [2] and EBV, [3] and certain geographic locations [3]. There is a well-characterized association of gastric lymphoma with Helicobacter pylori infection.
• No hereditary association is known, and data regarding occupational, environmental, and dietary factors are inconclusive.
• Increased risk in multiple immunocompromised states, including HIV, collagen-vascular disease, celiac sprue, Hashimoto's, and post-organ transplant settings.
• Known factors (aging population, HIV) account for less than half of the increasing incidence of NHL; the cause for the increase remains unknown. [4]

Pathogenesis [4]

• The nature of disease (indolent vs. aggressive) is correlated to 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[5].
• 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 [6] – classification includes leukemias and lymphomas, with 3 categories based on lineage and morphology (Hodgkin, B cell, and T/NK cell). Representative subtypes in table below:

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

Staging Evaluation

• Physical exam, particularly for adenopathy and hepatosplenomegaly.
• 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 degree of uptake may help predict aggressive disease
• Ann Arbor staging remains the mainstay of staging for NHL, but often lacks clinical relevance
• Modifications of Ann Arbor are being developed
• Most reliable predictors of outcome:histology,stage, age, serum LDH, performance status, number of extranodal sites involved

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

Important types include follicular lymphoma and small lymphocytic lymphoma.

• Clinical Manifestations
• • History: Usually asymptomatic, but often present with advanced-stage disease.
  • Physical exam: Painless adenopathy
  • Common extranodal sites: Liver, spleen, marrow
• Natural Course
• • Indolent clinical course , with 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 [7,8].
  • When therapy is necessary, standard of care is rituximab +/- chemotherapy [8]. Chemotherapy includes single oral agents (cyclophosphamide, chlorambucil, fludarabine) or more aggressive combo regimens (CVP, CHOP).
  • 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 [9].

Aggressive Lymphomas – short survival if untreated but 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
  • 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% [10].
• Treatment
• • Limited stage: combination chemotherapy +/- radiation with excellent curability. Recent trials question the benefit of adding radiation:
  • • A French study showed no benefit to CHOP + RT in elderly patients in terms of event-free and overall survival [11].
    • The addition of RT after a complete response from CHOP was found to have improved disease free survival but not overall survival [12].
  • Advanced stage: requires chemotherapy for cure. The addition of rituximab to CHOP in diffuse large B cell lymphoma has shown to increase overall survival [13].
  • Optimum regimen not determined, but the standard is CHOP + rituximab; other combination therapies are still under investigation

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 [14]
• 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 to rituximab to chemotherapy may have a benefit in Burkitt’s and lymphoblastic leukemia [14]
  • Prophylactic CNS treatment with direct instillation of chemotherapy into subarachnoid space is highly recommended.

Relapsed disease [15]

• 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 20-40% chance of "cure"

HIV-Associated Lymphoma [16]

• 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 60% complete response to chemotherapy and 51% 5-year survival
• Treatment is systemic chemotherapy (CHOP) +/- CNS coverage. Prophylaxis against opportunistic infections is vital.
• Adding rituximab has shown benefit, however up to 14% die of treatment-related infection (highest risk with CD4 <50)

Mycosis Fungoides [17]

• Most common clinical form of cutaneous T-cell lymphomas (CTCL)
• Variable natural history, from benign-looking 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 treated withtopical modalities - nitrogen mustard, retinoids, skin electron beam therapy or PUVA; good control but with high relapse rates
• Advanced stage disease treatments are unsatisfactory with short survival; therapies under investigation include monoclonal antibodies to CD52 and human T cells