Pediatric Lymphomas Resident Education Lecture Series

Cervical adenopathy

Concerns in enlarged LN Size >1-2 cm Increasing size over 2-4 weeks Matted or fixed Supraclavicular LN Fevers >38.5 for 2-4 weeks Constitutional symptoms HSM

When to biopsy Supraclavicular node Increasing size over 2-4 weeks Constitutional symptoms Asymptomatic enlarged node- not decreasing in size over 6 weeks or not normal after 8-12 weeks

Staging Evaluation Laboratory -CBC with smear -Chem profile LHD, uric acid Disease specific -ESR, IL2R for HD -LP if head/neck NHL -BMA/Bx for all NHL, only IIB or higher HD Radiology -CXR (PA & Lat) -CT scans neck, chest, abdomen -Gallium, bone scan -PET scan

Lymphoma Staging Murphy  Ann Arbor I: tumor at one site (nodal or extranodal -- “E”) II: two or more sites; same side of body (or resectable GI primary) III: both sides of body but not IV (& unresec. GI & mediastinal for NHL) IV: CNS or marrow involvement (Murphy); lung, liver, marrow, or bone for Ann Arbor (< 25% marrow) “B” sxs are defined for HD, as is “bulky disease” Head and neck (possibility of CNS involvement) is a further consideration for NHL PET or gallium

LYMPHOMA HODGKINSNON-HODGKINS LYMPHOBLASTIC LYMPHOMA BURKITT’S LYMPHOMA LARGE CELL LYMPHOMA IMMUNOBLASTICANAPLASTIC (40%)(60%) (<15%)(30-40%)(40-50%) (50%)

Non-Hodgkin’s Lymphoma u Malignant solid tumor of immune system u Undifferentiated lymphoid cells u Spread: aggressive, diffuse, unpredictable u Lymphoid tissue; BM and CNS infiltration u High growth fraction and doubling time u Dx and Rx ASAP u Rapid CTX response; tumor lysis concern

Incidence/Etiology - NHL u 6% childhood cancer 60% of childhood lymphomas u Peak age of 5-15; M:F ratio of 2.5:1 u Increased with u SCIDS, HIV, EBV u post t-cell depleted BMT u post solid organ transplant u Geographic, viral, genetic & immunologic factors

Types of NHL Lymphoblastic (30-35%)  90 % immature T cells (very similar to T-ALL) remainder pre-B phenotype (as in ALL)  50-70% anterior mediastinum  neck, supraclavicular, axillary adenopathy  Classic: older child with intussusception

Small non-cleaved cell (40-50%) --Mature B-cell phenotype --Burkitt's and non-Burkitt's --90% abdomen --Ascites and intusussception --Endemic in Africa (Burkitt's), with EBV 97%

Burkitt Facts 100 new cases/year in US, 2-3:1 male:female; mean age 11 years (in non-endemic form) small, noncleaved cell; mature B phenotype; intraabdominal (sporadic) or jaw (endemic) most common primary site 90% have t(8;14)  ( 8 ~ c-myc; 14 ~ heavy chains) others are 8;2 or 8;22  ( 2, 22 ~ light chains ) Extremely rapidly-growing; tumor lysis issues

Burkitt Prognosis Adult Data: Stage:EFSOS I-II91%78% IV25%25% but in patients < 40 yo 70%60% Pediatric Data: Localized > 90% Disseminated (but not B- ALL) 80-90% on newer protocols

Large-cell lymphoma (15-20%) - Anaplastic (Ki-1) lymphoma – ALK fusion protein - Diffuse Large B-cell lymphoma (DLBCL) - frequent Mediastinal involvement - More like Hodgkin lymphoma than other NHLs - “Peripheral T-cell” lymphoma - Often involves skin, CNS, lymph nodes, lung, testes, muscles, and GI tract

“low grade” lymphomas – rare in children  Follicular  marginal zone/MALT  primary CNS (often seen with HIV infection)  peripheral cutaneous (mycosis fungoides)

Clinical Presentations u Abdomen: (35%): pain, distention, jaundice, GI problems, mass u Head/neck (13%): lymphadenopathy, jaw swelling, single enlarged tonsil, nasal obstruction, rhinorrhea, cranial nerve palsies u Mediastinum (26%): SVC syndrome u CNS (rare): HA, V, irritability, papilledema +Fever, malaise, night sweats, wt. loss,

Staging of NHL ISingle tumor /node NOT in mediastinum or abdomen II1-2 nodes same side of diaphragm or resectable GI primary III2+ nodes both sides of diaphragm; intrathoracic or extensive intra-abd IVAny of above with CNS and/or BM

Prognosis affected by… u Incomplete remission in first 2 mos. Rx u Large tumor burden (LDH >1000) u Stages III and IV: CNS or BM involvement u Delay in treatment u Relapse **More favorable: Stage I or II, head/neck, peripheral nodes, GI tract

NHL Treatment u Surgery for diagnostic bx or second look u Radiation Therapy: emergency airway obstruction or CNS complication – may be used for local control of residual mass u Chemotherapy: Combination chemo is usual, with overall cure rates %; high risk of tumor lysis and hyperuricemia u Relapse: Re-induction, followed by BMT

NHL chemotherapy overview Low-stage NHL’s are treated with CHOP (+/- rituximab – anti-CD20) Higher-stage lymphoblastic lymphomas are treated on leukemia protocols Higher-stage non-lymphoblastic NHLs require extremely aggressive chemotherapy with significant infectious risks, but still have generally good remission rates High-dose chemotherapy with stem cell rescue is considered an option for relapse, though without the success rates of HD; T cell disease probably requires an allogeneic response

Hodgkin’s Disease u Immune system malignancy, involving B or T lymphocytes u Reed-Sternberg cells u Spread: slow, predictable, with extension to contiguous lymph nodes u Infiltration to non-lymphoid organs is rare

Hodgkin’s disease with Reed Sternberg cell often CD20+

Incidence and Etiology u Hodgkin’s 5% of childhood cancers u Bimodal peaks, at and >50; rare < 5 u M:F ratio of 3:1; variation r/t geography and SES, and type u Increased in immunologic disorders, HIV, EBV

Types of Hodgkin’s Lymphoma u Nodular sclerosing (NS), 40-60%, lower cervical, supraclavicular, mediastinal nodes u Mixed cellularity (MC), 15-30%; advanced disease with extranodal involvement u Lymphocyte predominance (LP), 5-15%, presents as localized disease u Lymphocyte depletion (LD) (<5%); widespread disease

Clinical Presentation u Painless lymph node swelling (90%) that persists despite antibiotic therapy u Palpable non-tender, firm, mobile, rubbery nodes; Mediastinal adenopathy (60%); SVC u Bulky: when mass is > 1/3 thorax diameter u B symptoms: Fever of >38C for 3 days, drenching night sweats, 10% weight loss

Mediastinal masses Risk for anesthesia (esp. if tracheal compression > 50% by CT) Least invasive diagnostic procedure therefore indicated (incl. thoracentesis) Emergent steroids or RT generally acceptable prior to biopsy HD and DLBCL tend to have areas of necrosis and therefore look more “bumpy” than T-ALL

Hodgkin’s Ann Arbor Staging ISingle lymph node region IITwo+ node regions on same side of diaphragm IIINodes on both sides of diaphragm, or localized extralymphatic spread IVDiffuse or disseminated involvement of one+ extralymphatic organs or tissues

Prognosis FAVORABLE: <10, F, favorable subtypes (LP and NS) and Stage I non-bulky disease UNFAVORABLE: Persistently elevated ESR; LD histopathology; bulky disease--largest dimension >10cm; B symptoms;

Treatment and Prognosis u Dependent on age, stage, and tumor burden u RT alone, CTX alone u RT: varies from involved field for localized disease to extended field to total nodal irradiation, inverted Y plus mantle u most often multimodal therapy, with low- dose involved field RT and multi-agent CTX u Combined modality 70-90% LT cure

Hodgkin Px and Rx Splenectomy generally no longer used Exact type and ratio of combined modality therapy changes… due to differences in success rates for salvage therapy and concerns for late effects of therapy  Second malignancy risks  Sterility risks

From ABP Certifying Exam Content Outline Know how to evaluate a child with an acute cervical lymphadenopathy Know the differential diagnosis of neck masses:  lymphoma,  cystic hygroma,  thyroglossal duct cyst  branchial cleft abnormalities

From ABP Certifying Exam Content Outline, continued Recognize the need for evaluation of supraclavicular lymph node enlargement Identify the chest x-ray as an important part of the initial evaluation of the patient with an unexplained lymphadenopathy Know that overwhelming sepsis is a serious complication in patients with Hodgkin disease who have undergone splenectomy, and know that such patients should be evaluated thoroughly if fever develops

Credits Meghen Browning MD Anne Warwick MD MPH