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non-Hodgkin's lymphoma

Classification: 1) B-cell lymphoma (85%), T-cell lymphoma (13%), NK-cell lymphoma (2%) 2) aggressive lymphomas a) rapidly progressive systemic disease b) diffuse large B-cell lymphoma c) high-grade Burkitt's lymphoma, Burkitt's-like lymphoma d) lymphoblastic lymphoma 3) indolent lymphomas a) slowly progressive lymphocytosis or lymphadenopathy, often asymptomatic b) follicular lymphoma c) chronic lymphocytic leukemia/small lymphocytic lymphoma Etiology: predisposing factors 1) majority of cases have no predisposing factors 2) immune suppression a) AIDS b) autoimmune disease c) inherited immunodeficiency states 3) viruses a) HIV-1 b) HTLV-1 c) Epstein-Barr virus d) hepatitis C virus [3] 4) Helicobacter pylori 5) toxins a) radiation b) herbicides, organochlorides used in farming c) prior chemotherapy - chemotherapy for Hodgkin's disease 6) pharmacologic agents - Dilantin Epidemiology: 1) approximately 40,000 cases/year 2) average age of presentation early 40's -> incidence of low-grade lymphomas increases with advanced age [5] {overall 35%} 3) majority of patients present with advanced disease 4) 10-20% present with disease outside of lymph nodes & spleen 5) more common in men [5] Pathology: 1) diverse group of lymphomas histologically & pathologically 2) tends to spread hematogenously 3) T- & B-cell dysfunction Immunohistochemistry: 1) CD5(+): a) small lymphocytic lymphoma b) chronic lymphocytic leukemia c) mantle cell lymphoma 2) CD10(+): follicular lymphoma 3) CD20(+): a) follicular lymphoma b) small lymphocytic lymphoma (+/-) c) chronic lymphocytic leukemia (+/-) d) mantle cell lymphoma e) MALT lymphoma 4) CD23(+): a) small lymphocytic lymphoma (+/-) b) chronic lymphocytic leukemia (+/-) Genetics: 1) t(14;18)(q32;q21) translocations a) 85% of follicular lymphomas b) 28% of higher-grade lymphomas c) BCL-2 juxtaposition with heavy-chain region of immunoglobulin region 2) t(1;1)(p36.3;q21.1-2) involving FCRL4 3) t(10;14)(q24;q32) involving NFKB2 with IGHA1 4) t(2;5)(p23;q35.1) involving ALK with NPM1 5) t(3;4)(q27;p11) involving RhoH with BCL6 6) t(11;14) bcl-1 with Ig heavy chain, mantle cell lymphoma 7) t(1;18) API2, MALT lymphoma 8) t(1;14) MALT1 with bcl-10, MALT lymphoma 6) trisomy 12 a) small lymphocytic lymphoma b) chronic lymphocytic leukemia 6) overexpression of RGS1 6) other implicated genes hemogen, LETMD1, CASP10, MCTS1, BRAF Clinical manifestations: 1) general a) fatigue b) localized pain c) pruritus may be a presenting symptom [9] d) does not produce ulcerations [10] 2) lymphadenopathy a) 75% of patients present with palpable lymphadenopathy b) any lymph node > 1 cm in diameter present for > 4 weeks not associated with infection should be biopsied 3) B-symptoms present in 20% of patients a) fever b) night sweats c) weight loss (> 10% of body weight) 4) mediastinal adenopathy (20%) a) persistent cough b) abnormal chest X-ray 5) retroperitoneal, mesenteric & pelvic adenopathy common a) generally asymptomatic b) obstruction may occur with massive disease 6) hepatosplenomegaly, hepatic infiltration (25-50%) 7) primary gastrointestinal lymphoma (<5%) a) pain b) obstruction c) hemorrhage d) abdominal fullness e) early satiety 8) primary bone lymphoma (<5%) a) pain b) lytic lesions on X-ray c) generally diffuse large B-cell lymphoma 9) primary CNS lymphoma a) especially prevalent in HIV+ patients b) headache c) lethargy d) seizures e) paralysis 10) primary cutaneous lymphoma 11) renal infiltration (rare) 12) prostate infiltration (rare) 13) testis infiltration (rare) 14) ovary infiltration (rare) Staging: - Clinical staging of non-Hodgkin's lymphoma (see lymphoma) Laboratory: 1) considered essential* - surgical excisional lymph node biopsy to examine lymph node architecture (most important test) - physical examination - documentation of B symptoms - laboratory evaluation - complete blood count (CBC) - lymphocytosis, thrombocytopenia [10] - liver function tests (including LDH) - LDH correlates with tumor bulk - renal function tests (BUN & creatinine) - uric acid - serum Ca+2 - serum protein electrophoresis - serum beta-2 microglobulin - associated with poor prognosis - bone marrow biopsy 2) tests which may be indicated* - lumbar puncture & CSF analysis - cytology of effusions - HIV1 serology 3) tests which may be useful - cell surface marker phenotype analysis - cytogenetic analysis - gene rearrangement analysis - polymerase chain reaction (PCR) - flow cytometry for DNA analysis - liver biopsy Special laboratory: - tests which may be indicated* 1) endoscopic examination 2) echocardiogram Radiology: 1) considered essential* - chest radiograph (hilar lymphadenopathy) - CT of abdomen & pelvis 2) tests which may be indicated* - CT of the thorax & head - gallium scan (planar or SPECT) - positive in almost all intermediate & high-grade lymphomas - barium studies of the GI tract 3) tests which may be useful - liver scan - bone scan - thallium scan - lymphangiography - ultrasonography - magnetic resonance imaging * essential for clinical staging Complications: 1) spinal cord compression 2) pericardial tamponade 3) hypercalcemia 4) superior vena cava syndrome, inferior vena cava syndrome 5) hyperuricemia, tumor lysis syndrome 6) autoimmune hemolytic anemia 7) immune thrombocytopenic purpura -> infection with Pneumocystis carinii [4] a) steroid chemotherapy b) T- & B-cell dysfunction Management: 1) rituximab (monoclonal antibody against CD20) for routine treatment of B-cell lymphoma a) used for induction & maintenance b) rituximab alone c) rituximab combination chemotherapy for stage 3 & 4 regardless of age - cyclophosphamide, vincristine & prednisone (R-CVP) - cyclophosphamide, doxorubicine, vincristine & prednisone (R-CHOP) - rituximab + bendamustine 4) pixantrone may be appropriate in patients who fail rituximab 2) also see more specific lymphomas 3) recommendations prior to the introduction of rituximab a) based on histopathology, extent of disease, performance status - aggressive lymphomas are curable - indolent lymphomas are not b) stage IA or IIA: - radiation, 3500-5000 cGy adjuvant to combination chemotherapy c) low-grade lymphoma: - small lymphocytic lymphomas & follicular small cleaved cell lymphomas are not treated until they produce symptoms - long term remissions are not usual - overall survival is not favorably influenced - transformation to a higher-grade lymphoma is common - median survival is about 7 years - radiation therapy, local or extended field [3] - chemotherapy: single alkylating agent - cyclophosphamide - chlorambucil - combination chemotherapy - chlorambucil & prednisone - CVP (cyclophosphamide, vincristine & prednisone) - CHOP (CVP + doxorubicin) - three purine analogs have shown activity in low-grade non-Hodgkin's lymphoma - fludarabine - 2-Chlorodeoxyadenosine (2-CDA) - 2-deoxyformycin (adenosine deaminase inhibitor) d) intermediate-grade-lymphoma: - intermediate-grade-lymphomas are treated similarly - diffuse large-cell lymphoma - follicular mixed cell lymphoma - follicular large-cell lymphoma - diffuse small cleaved lymphoma - treatment of large-cell lymphomas is one of the major success stories of chemotherapy - combination chemotherapy - C-MOPP (cyclophosphamide, vincristine, prednisone, & procarbazine) first regimen, 40% remissions - CHOP (cyclophosphamide, vincristine, prednisone, & doxorubicin), 35% long-term disease-free survival - BACOD (CHOP plus one or more of *) - M-BACOD (CHOP plus one or more of *) - m-BACOD (CHOP plus one or more of *) - Pro-MACE-MOPP (CHOP plus one or more of *) - COP-BLAM (CHOP plus one or more of *) - COMLA (CHOP plus one or more of *) - MACOP-B (CHOP plus one or more of *) - ProMACE/CytaBOM (CHOP plus one or more of *) - MACOB-B (CHOP plus one or more of *) * bleomycin, methotrexate, procarbazine, nitrogen mustard, cytosine arabinoside, etoposide. - duration of treatments may be as long as 12 months - complete remission rates 80% - however, toxicities have increased: - infections - pulmonary & cardiac complications e) high-grade lymphoma: - extremely poor prognosis - aggressive treatment indicated - 56% disease-free survival at 3 years has been reported in patients treated with CHOP & high-dose methotrexate, L-asparaginase & intrathecal methotrexate 4) AIDS-related lymphomas: a) most a high-grade immunoblastic or non-cleaved cell types b) some intermediate-grade large cell lymphomas are observed c) combination chemotherapy, intrathecal methotrexate, & GM-CSF produce remissions in 1/3 of patients with high incidence of CNS-relapse & fatal opportunistic infections 5) cutaneous T-cell lymphoma: a) topical chemotherapeutic agents such as nitrogen mustard can produce remissions in up to 90% of patients b) local radiation also produces high rates; however, most patients relapse within 3 years c) 8-methoxypsoralen followed by UV light (PUVA) also produces similar remissions d) systemic therapy in combination with topical therapy results in few long-term remissions 6) prognosis: a) histology is most important factor b) markers associated with poor prognosis - CD71 (transferrin receptor) present on proliferating cells - CD44 (homing receptor) - serum beta-2 microglobulin c) extranodal involvement (multiple lymph nodes involved) is associated with poor prognosis d) serum LDH correlates with tumor bulk e) increased age is associated with a poorer prognosis f) better physical condition or performance status is associated with better prognosis g) sex is not a factor h) 89% 5 year survival if no poor prognostic factors; 56% 5 year survival with 5 poor prognostic factors 7) salvage chemotherapy for patients who fail to achieve remission on conventional chemotherapy: - cytosine arabinoside, cisplatin, etoposide, ifosamide may produce remission in 20-30% of patients; however long term survival is minimal. 8) stem cell transplantation: a) very high dose chemotherapy can induce complete remission in patients with relapses after conventional therapy b) however, prolonged myelosuppression occurs c) bone marrow transplantation, usually autologous from harvested circulating hematopoietic stem cells benefits a subset of patients who have previously responded favorably to conventional therapy. [3,8] d) non-myeloablative allogeneic hematopoietic stem-cell transplantation may be useful for relapses, refractory, & transformed indolent non-Hodgkin's lymphoma [7] 9) GM-CSF & G-CSF appear to be useful adjuncts for hastening recovery from chemotherapy

Interactions

disease interactions

Related

bcl-2 proto-oncogene chromosomal translocation t8q24.1:14q32 (B-cell leukemia, Burkitt's lymphoma) classification of non-Hodgkin's lymphoma

Specific

B-cell lymphoid neoplasm (B-cell lymphoma) body cavity-based lymphoma cutaneous lymphoma lymphoblastic lymphoma lymphoma by size & distribution lymphomatous meningitis primary central nervous system (CNS) lymphoma (PCNSL) primary thyroid lymphoma stem cell leukemia lymphoma syndrome (SCLL) T-cell lymphoid neoplasm (T-cell leukemia, T-cell lymphoma)

General

lymphoma (lymphosarcoma)

References

  1. Harrison's Principles of Internal Medicine, 13th ed. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1994, pg 1782, 1786
  2. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 426-28
  3. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012
  4. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 539
  5. Schiller G, in: UCLA Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
  6. Ferri's Clinical Advisor, Instant Diagnosis and Treatment, Ferri FF (ed), Mosby, Philadelphia, 2003
  7. Resvani AR et al, Nonmyeloablative allogeneic hematopoietic cell transplantation in relapses, refractory, and transformed indolent non-Hodgkin's lymphoma. J Clin Oncol 2008, 26:211 PMID: 18056679
  8. 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. 1995 Dec 7;333(23):1540-5. PMID: 7477169
  9. Deng J et al. Risk of hematologic cancer in patient with undifferentiated pruritis. JAMA Dermatol 2022 Jul; 158:791. PMID: 35612839 PMCID: PMC9134041 (available on 2023-05-25) https://jamanetwork.com/journals/jamadermatology/fullarticle/2792454
  10. NEJM Knowledge+ Otolaryngology

Databases & Figures

OMIM 605027 Figures/diagrams/slides/tables related to non-Hodgkin's lymphoma