Evaluation

• Physical exam, particularly for adenopathy and hepatosplenomegaly.
• Routine labs, particularly serum LDH
• Radiologic studies, CXR, abdominal CT scan and bone marrow biopsy
• 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 and stage, age, serum LDH, performance status, number of extranodal sites involved

Low Grade Lymphomas
Small lymphocytic, small cleaved cell (follicular) and mixed cell (follicular)

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

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 or total-body irradiation will not necessarily improve survival in comparison to watchful waiting [4].
• When chemotherapy is felt to be necessary, treatment involves single oral agents (cyclophosphamide, chlorambucil) or more aggressive combo regimens (CVP, CHOP)

Intermediate Grade Lymphomas
Large cell (follicular), small cleaved cell (diffuse), mixed cell (diffuse) and large cell (diffuse)

Clinical Presentation

• History: Most are asymptomatic, but present with advanced-stage disease
• Physical exam: Painless adenopathy
• Common extranodal sites: Liver, spleen, Waldeyer's ring or GI tract, lung/pleura, skin, marrow

Natural Course

• Indolent; rapid clinical remission possible in 50-80% of patients receiving chemotherapy, with 30-40% of these apparently cured

Treatment

• Limited stage: excellent curability with aggressive combination chemotherapy and radiation to involved sites
• Advanced stage: require chemotherapy for cure
• Optimum regimen not determined, but the standard remains the CHOP regimen, first developed in 1972 [5].

High Grade Lymphomas
Immunoblastic, lymphoblastic, small noncleaved cell (all diffuse)

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, and 35-45% of patients will enter complete remission, with cure rates of up to 50% in the young

Treatment

• Chemotherapy is mandatory for cure, with aggressive induction phase of intense combination chemotherapy regimen, followed by lengthy maintenance phases [6]
• Prophylactic CNS treatment with direct instillation of chemotherapy into subarachnoid space is highly recommended.

Special Situations

Relapsed disease

• Bone marrow transplantation, with 20-40% "cure" in intermediate-grade patients [7].
• Unknown efficacy in low-grade lymphomas
• HIV-Associated Lymphoma
  • Overall incidence of presentation is 3%
  • HIV patients have 60-fold increased risk of lymphoma [8].
  • May account for up to 10% of newly-diagnosed lymphomas
  • Most are of diffuse histology, high-grade, B-cell neoplasms
  • Risk factors include: younger, more advanced HIV disease
  • Involve extranodal sites in over 60% of cases
  • Less responsive to chemotherapy than non-HIV-associated lymphomas
  • PCP prophylaxis and CNS treatment are vital
• Mycosis Fungoides
  • Most common clinical form of cutaneous T-cell lymphomas (CTCL) [9].
  • Variable natural history, from benign-looking skin eruptions to visceral and nodal involvement
  • Sezary syndrome is particular manifestation of CTCL in which the malignant cell is of the helper-T-cell type and is found in abundance in the blood
  • Best controlled in early stages with topical nitrogen mustard, skin electron beam therapy or PUVA
  • Advanced stage disease treatments are unsatisfactory with short survival

References

1. Purtilo DT, Stevenson M: Lymphotropic viruses as etiologic agents of lymphoma. Hematol Oncol Clin North Am 5:901-923, 1991

2. Wright DH: Pathogenesis of non-Hodgkin's lymphoma: clues from geography. The Non-Hodgkin's Lymphomas. Baltimore, Williams and Wilkins, 1990, pp.122-134

3. Yang E, Korsmeyer SJ: Molecular thanatopsis: a discourse on the BCL2 family and cell death. Blood 88:386-401, 1996

4. Young RC, Longo DL, Glatstein E, et al: The treatment of indolent lymphomas: watchful waiting versus aggressive combined modality treatment. Semin Hematol 25:11-16, 1988 (suppl)

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

6. Vose JM: Current approaches in the management of non-Hodgkin's lymphoma. Semin Oncol 25:483-491, 1998

7. Philip T, Guglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy sensitive non-Hodgkin's lymphoma. N Engl J Med 333:1540-1555, 1995

8. DeMario MD, Liebowitz DN: Lymphomas in the immunocompromised patient. Semin Oncol 25:492-502, 1998

9. McFadden ME: Cutaneous T-cell lymphoma. Semin Oncol Nurs 7:36-44, 1991