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HEMATOLOGY-ONCOLOGY

LYMPHOMA

Definition

•  Malignant disorder of lymphoid cells that reside predominantly in lymphoid tissues

•  Hodgkin lymphoma (HL) is distinguished from non-Hodgkin lymphoma (NHL) by

the presence of Reed-Sternberg (RS) cells

Clinical manifestations

•  Lymphadenopathy (nontender)

HL: superficial (usually cervical/supraclavicular) ± mediastinal lymphadenopathy; nodal disease with orderlyanatomic spread to adjacent nodes

NHL: diffuse; nodal and extranodal disease with noncontiguous spread; symptoms reflect involved sites (abdominal fullness, bone pain)

•  Constitutional (“B”) symptoms: fever (>38°), drenching sweats, ↓ weight (>10% in 6 mo)

HL: periodic, recurrent “Pel-Ebstein” fever; 10–15% have pruritus; ~35% “B” symptoms

NHL: “B” symptoms vary between types, ~15–50%

Diagnostic and staging evaluation

•  Physical exam: lymph nodes, liver/spleen size, Waldeyer’s ring, testes (~1% of NHL), skin

•  Pathology: excisional lymph node bx (not FNA b/c need surrounding architecture) with immunophenotyping and cytogenetics; BM bx (except in HL clinical stage IA/IIA with favorable features or CLL clone by flow); LP if CNS involvement clinically suspected

•  Lab tests: CBC, BUN/Cr, LFTs, ESR, LDH, UA, Ca, alb; ✓ HBV & HCV (and must ✓ HBsAg & anti-HBc if planning rituximab Rx as can lead to HBV reactivation); consider HIV, HTLV, & EBV serologies and connective tissue diseases autoAbs

•  Imaging: chest/abd/pelvic CT, but doesn’t reliably detect spleen/liver involvement

consider PET-CT scans (esp. in HL, DLBCL). PET response to Rx can be prognostic (Blood 2006;107:52; JCO 2007;25:3746); has role to assess PR/CR after treatment.

Head CT/MRI only if neurologic symptoms.

HODGKIN LYMPHOMA (HL) (NEJM 2010;363:653)

Epidemiology and risk factors

•  ~9,000 cases/y; bimodal distribution (15–35 & >50 y); ↑ ; role of EBV in subsets of HL, esp. immunocompromised patients

Pathology

•  Affected nodes show RS cells (<1%) in background of non-neoplastic inflammatory cells

•  Classic RS cells: bilobed nucleus & prominent nucleoli with surrounding clear space (“owl’s eyes”). RS cells are clonal B-cells: CD15+, CD30+, CD20– (rarely +).

• Nonclassical (5%): nodular lymphocyte predominant (NLP); involves peripheral LN

80% present in stages I–II and Rx can be RT alone or combination chemo + RT w/ 80% 10-y progression-free survival, 93% overall survival ( JCO 1997;15:3060)

Consider rituximab as most NLP RS cells are CD20+

Stages III–IV treated with combination chemo (see below)

Treatment (Lancet 2012;380:836)

•  Stages I–IIABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) ± RT

Lower intensity regimens comparable efficacy if favorable prognosis (NEJM 2010;363:640)

•  Stages III–IVABVD × 6 cycles or escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone)

•  Refractory/relapsed disease: salvage chemo + auto HSCT, ± RT

•  Late effects include ↑ risk for:

second cancersbreast (if RT), ∴ annual screening at age 40 or 8–10 y post RT; lung, ? role of screening CXR or CT (controversial); acute leukemia/MDSNHL

cardiac disease (if RT or anthracycline), ? role of echo/stress at 10 y (controversial)

pulmonary toxicity (if bleomycin)

hypothyroidism (if RT), ∴ annual TSH (if neck RT)

NON-HODGKIN LYMPHOMA (NHL)

Epidemiology and risk factors

•  ~70,000 new cases/y; median age at dx ~65 y;  predominance; 85% B-cell origin

•  Associated conditions: immunodeficiency (eg, HIV, posttransplant); autoimmune disorders (eg, Sjögren’s, RA, SLE); infection (eg, EBV, HTLV-I, H. pylori)

•  Burkitt’s lymphoma: (1) endemic or African (jaw mass, 80–90% EBV-related); (2) sporadic or American (20% EBV-related); (3) HIV-related

Treatment (Lancet 2012;380:848)

•  Treatment and prognosis determined by histopathologic classification rather than stage

•  Rituximab (antibody to CD20; NEJM 2012;366:2008) if CD20+; no role if tumor is CD20–

•  Indolent: goal is sx management (bulky dis., cytopenias, “B” sx); not curable w/o allo HSCT

Options include radiation for localized disease, rituximab ± chemo (bendamustine, CVP, fludarabine)

For MALT → treat H pylori if 

Rituximab maintenance ↑ survival in relapsed disease (JNCI 2009:101:248); growing role for rituximab maintenance in indolent and aggressive disease (Lancet 2011;377:42)

•  Aggressive (DLBCL, 30–40% of NHL): goal is cure (JCO 2005;23:6387)

R-CHOP (rituximab, cyclophosphamide, doxorubicin = hydroxydaunorubicin, vincristine = Oncovin, prednisone) (NEJM 2002;346:235 & 2008;359:613) 10-y progression-free survival = 45%; overall survival = 55% (Blood 2010;116:2040)

? R-ACVBP (ritux, doxorubicin = Adriamycin, cyclophosph, vindesine, bleo, prednisone) ↑ 3-y OS vs. R-CHOP, but ↑ adverse events (Lancet 2011;378:1858)

Radiation for localized or bulky disease

Consider CNS prophylaxis w/ intrathecal or systemic high-dose methotrexate if paranasal sinus, testicular, breast, periorbital, paravertebral or bone marrow involved; ≥2 extranodal site + ↑ LDH may also warrant

Refractory/relapsed disease: salvage chemo; high-dose chemo + auto-HSCT (NEJM 1995;333:1540); allo-HSCT if beyond 2nd relapse

•  Highly aggressive

Burkitt’s: intensive short-course chemotherapy (Blood 2004;104:3009)

Low risk defined as nl LDH & single focus of disease <10 cm; all others high risk

Low risk Rx = CODOX-M (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate ± rituximab) (Leuk Lymph 2004;45:761)

High risk Rx = CODOX-M/IVAC (above w/ ifosfamide, etoposide, high-dose cytarabine), hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone)

All Pts receive CNS prophylaxis & tumor lysis syndrome prophylaxis

Lymphoblastic lymphoma (B or T cell): treated like ALL (see “Acute Leukemia”)

Prognosis

• Indolent: typically incurable, but long median survival

• Aggressive: ↑ chance of cure, but overall worse prognosis

HIV-associated NHL (Blood 2006;107:13)

•  HIV  imparts 60–100× relative risk

•  NHL is an AIDS-defining malignancy along with Kaposi’s, cervical CA, anal CA

•  Concurrent HAART & chemotherapy likely provide survival benefit

•  DLBCL & immunoblastic lymphoma (67%): CD4 <100, EBV-associated Treat as immunocompetent (CHOP-R), but avoid rituximab if CD4 <100 Alternative regimens include R-EPOCH (etop, pred, vincristine, cyclophos, doxorubicin)

•  Burkitt’s (20%): can occur with CD4 >200 Treat as immunocompetent; prognosis is not significantly worse

•  Primary CNS lymphoma (16%): CD4 <50, EBV-associated (also seen in Pts w/o HIV) Treat with high-dose methotrexate + steroids ± RT

•  Primary effusion lymphoma (<5%): HHV8 driven; also can be seen in other immuno- supp. Pts such as s/p solid organ transplant or w/ chronic HBV.  Treat with standard CHOP (often CD20–), but poor prognosis.