Case 8 -

Lymphoblastic Lymphoma Paul E. Wakely, Jr.

Clinical History A 15 y/o male presented to the emergency room with wheezing and difficulty breathing. Physical examination revealed a 4 cm. midline neck mass. Cytopathology: Case 8 - Figure 1 - Case 8 - Figure 2 - extremely hypercellular smears monomorphic population of intermediate-large lymphocytes in a single cell pattern N/C ratios very high/finely granular nuclear chromatin/nucleoli are generally inapparent, but one-two nucleoli possible LGBs present, but variable in amount Diagnosis: Lymphoblastic Lymphoma Discussion Chest X-ray showed a large anterior mediastinal mass in this teenager with some tracheal compression–most likely cause of his wheezing. Cells collected in balanced salt solution and submitted for immunophenotyping showed a T-cell lymphoma with positive nuclear staining for terminal deoxynucleotidyl transferase[TdT], and other T-cell markers, CD3, CD5, CD7. Chemotherapy was instituted, and the mediastinal mass eventually disappeared. Table 52. Comparing NHL in Adults and Children Children Adults often extranodal predominantly nodal rarely follicular often follicular usually high grade usually low-intermediate grade often leukemic rarely leukemic Lymphoblastic Lymphoma(LL), Clinical: an aggressive lymphoma comprising 30%-50% of pediatric lymphoma; M>F lymphadenopathy above the diaphragm; anterior mediastinal mass in up to 80% of patients may have clinical symptoms of: Superior Mediastinal Syndrome SVC obstruction/compression tracheal compression/ respiratory symptoms signs & symptoms: cough, hoarseness, dyspnea, wheezing, cyanosis, syncope FNA is an excellent initial step to establish diagnosis of LL. Several series report near perfect accuracy for the FNA diagnosis of LL. Since these patients often have a palpable neck mass and are critically ill [many with some degree of respiratory compromise], the expediency of FNA with minimal invasiveness, reliable accuracy, ability to procure cells for ancillary studies, and no requirement for sedation or general anesthesia demands that it be one of the first (if not the 1st) procedure used to secure a diagnosis. Aspirates of LL: monotonous lymphoblasts cover the slide in a dissociated cell pattern little cell variation exists although a dimorphic pattern may occur due of the presence of smaller more hyperchromatic blasts lymphoblasts about 2x diameter of mature lymphocytes; conform to L 1-L 2 morphology of FAB classification nuclei typically rounded but may display some nuclear irregularity(convolutions) 1-2 indistinct nucleoli or no visible nucleoli cytoplasm extremely meager with/without tiny vacuoles variable number of TBMs Mitotic counts on smears[regardless of the tumor type or anatomic site] always underestimate those performed on tissue since one is evaluating what should be a monolayer of cells in the former, as opposed to a 4-5 m thick tissue section with multiple layers of cells in the latter. LGBs vary in amount in smears of LL, but can be found in almost every case. Nearly all cases are positive for Tdt - a nuclear marker in tissue sections and cytologic smears- that can be stained from cytospin preparations or by FCM. About 90% of cases of LL are T-cell phenotype with the remainder of pre-B cell lineage.Differential diagnosis primarily involves other malignant small round cell tumors metastatic to lymph node and Burkitt lymphoma. In children, these small cell malignancies include neuroblastoma, Ewing sarcoma/PNET, and rhabdomyosarcoma (RMS), while in adults consideration needs to be given to small cell types of non-Hodgkin lymphoma(discussed above), and metastatic small cell neuroendocrine carcinoma. The complete lack of a range of lymphocyte cell types omits RLH from consideration. Pitfall: FNA of the anterior mediastinum may capture thymocytes which are also TdT positive. However, thymocytes are small mature forms unlike the larger blastic morphology of LL. Burkitt Lymphoma Burkitt lymphoma (BL), along with LL and large cell lymphoma, is the third component of the triad of pediatric lymphomas that comprise over 95% of lymphomas in this age group. Akin to LL, a definitive diagnosis by FNA biopsy is possible when morphology is combined with immunophenotyping. Clinical: endemic in equatorial Africa; arises in the head and neck of young children; associated with EBV infection sporadic form predominates in North America; occurs in older children/teenagers; M:F, 3:1. BL can occur in adults, but at a much lower incidence most patients with sporadic BL present with intra-abdominal tumors[cecum, ileum] reported FNA sensitivity and specificity near 100% Aspirates of BL: highly cellular; cells dispersed in a single cell pattern monotonously uniform cells 2-3 times diameter of mature lymphocytes nuclei rounded, coarse chromatin and 1-4 discrete nucleoli cell cytoplasm deeply basophilic, many coarse vacuoles (lipid filled) background LGBs also commonly vacuolated TBMs may be randomly dispersed throughout the smear mimicking the "starry sky" pattern because individual cell necrosis is common, a "dirty" background is typical. BL express pan-B cell markers(CD20,CD19, CD79a), CD10, and CD43, and are negative for CD5, CD23. TdT is negative with very rare exception. The genotype shows t(8;14), t(2;8), or t(8;22) translocations with rearrangement of the c-myc gene. Table 53. Lymphoblastic Lymphoma vs. Burkitt Lymphoma   Lymphoblastic Lymphoma Burkitt Lymphoma Nucleoli Inapparent, 1-2 Obvious, 1-5 Nuclear chromatin Fine Coarse, granular Cytoplasmic vacuoles Few, if any Often numerous, obvious Immunophenotype Primarily T-cell, TdT+ B-cell, TdT negative Metastatic Malignant Small Round Cell Tumors (SRCT) Metastatic lymph node deposits are uncommon events in childhood malignancy in contrast to adults. Rhabdomyosarcoma(RMS) and neuroblastoma(NBL) are 2 most likely to metastasize to lymph nodes. Table 54. Lymph Node Metastazing Sarcomas • rhabdomyosarcoma • epithelioid sarcoma • clear cell sarcoma of tendon sheath • angiosarcoma • synovial sarcoma • Ewing sarcoma • Kaposi sarcoma   Features of non-lymphoid SRCTs: absence of numerous LGBs in the smear background cells scattered singly and in clusters cells about same diameter as LL and BL multinucleated cells seen in differentiating RMS nuclear molding and clustering common in Nbl. background neuropil - delicate fibrillary tangle of cell processes - helpful feature of Nbl. Occasional Homer-Wright rosettes in aspirates. Table 55. Differential Diagnosis of Lymphoblastic Lymphoma Feature LL Burkitt Nbl Ewing/PNET RMS single cell pattern present present absent absent to focally present absent to focally present LGBs present present absent absent absent neuropil absent absent present absent absent rosettes absent absent present present absent cell molding absent absent present focally present present bi-/multinucleation absent absent absent to focally present absent present in differentiating blasts nucleoli absent to small conspicuous inapparent inapparent inapparent to present immunophenotype T-cell, CD99 B-cell NSE VIM, CD99, Myogenic markers Nbl = neuroblastoma NSE = neuron specific enolase VIM = vimentin RMS = rhabdomyosarcoma References for All Cases