Case 6 -

Follicular Lymphoma Paul E. Wakely, Jr.

Clinical History A 69 y/o man presents with a 2.0 cm. left posterior cervical lymph node of unknown duration. No prior medical history. Cytopathology: Case 6 - Figure 1 - Case 6 - Figure 2 - smears contain a dimorphic population of large cells and small cells with no range of lymphocytes cells distributed in a dissociated single pattern with LGBs easy to find larger cells have rounded nuclei without obvious nucleoli in the Diff-Quik stained smears smaller cells have round to slightly irregular nuclei with a smudged chromatin pattern tingible body macrophages and FC fragments absent. Diagnosis: Follicular Lymphoma Discussion Follicular lymphoma (FL), Clinical: vies with diffuse large B-cell lymphoma(DLBL) as the two most common forms of adult ML. From the NHL classification project, FL comprised 22% and DLBL 31% of non-Hodgkin lymphomas respectively[Blood 1997;89:3909-18] most patients older than 50 yrs. clinical presentation often asymptomatic, but vast majority(>80%) have disseminated disease[spleen, lymph node, & bone marrow involvement] at the time of diagnosis FL characterized by t(14:18) with rearrangement of the bcl-2 gene > 75% of cases antibody staining with bcl-2 extremely helpful in distinguishing FL from follicular hyperplasia in tissue, but ineffective in smears because spatial relationship of staining cannot be evaluated current therapy of FL not curable ML - subtypes, in order of incidence diffuse large B-cell follicular marginal zone, MALT type peripheral T-cell, NOS mantle cell small lymphocytic Aspirates of FL rather than strict cellular monotony, smears of FL are much more apt to show some variation in cell size and nuclear outline composed of a monotonous small lymphocytes, or more often, a mixture of transformed cells – centrocytes (small and large cleaved lymphocytes) and centroblasts (large non-cleaved lymphocytes) and small round lymphocytes nuclear notches/clefts and unevenness common; some appear to bisect or trisect a nucleus, while in others nuclear folds are more subtle FC fragments, TBMs rare, but dendritic cells present several variants. signet ring variant: conspicuous single cytoplasmic macrovacuole/stains with IgG/optically clear unlike the vacuoles of metastatic signet ring cell carcinoma that contain mucin. Signet ring morphology not unique to FL; has been described in SLL, DLBL, peripheral T-cell ML, and ALCL. Several other histologic variants of FL that have been described in tissue – table 39 – have rarely if ever been recognized in aspirates. Grading of FL (as recommended by WHO) is performed in tissue according to the Mann/Berard method. This method is based on the number of centroblasts in tissue sections: Grade I: 0-5 centroblasts/hpf. Grade II: 6-15 centroblasts/hpf. Grade III: >15 centroblasts/hpf. Grading of FL has only rarely been attempted in cytologic preparations by estimating the percentage of large cells (Young et al). The CD10+/CD5- immunoprofile of FL separates it from most small cell B-cell lymphomas. Differential diagnoses of FL: reactive hyperplasia small cell neuroendocrine carcinoma other small cell lymphomas [SLL, Mantle cell, MALT, peripheral T-cell] basaloid neoplasms The narrow range of small and large lymphocytes that exists in most cases of FL only superficially imitates RLH. Importantly, the expanded range of lymphocytes seen in reactive nodes[immunoblasts, plasmacytoid lymphocytes, plasma cells, and small round lymphocytes] does not exist in FL. Additional helpful features are the lack of FC fragments and TBMs. Many tissue variant of FL have rarely been described in smears: Table 39. Histologic Variants of FL • FL with monocytoid B cells • FL with rosettes • FL signet ring cell type • FL, cerebriform • FL with plasmacytic differentiation • FL, floral type Smears of FL differ from those of MtCL and SLL by the overwhelming uniformity of cell morphology in these latter two neoplasms that is not matched in FL. One can often find a "subpopulation" of large cells in grade I FL that would be absent in MtCL, and more of a 50/50 split of small and large cells in grade II FL. Nonetheless, morphologic overlap exists, and immunotyping is mandatory. Rarely, aspirates of FL can be populated by numerous follicular center fragments. Table 40. Summary of Cytomorphologic Features of Small Cell B-cell Lymphomas Lymphoma type Small Cell Morphology Transformed Cells SLL/CLL rounded prolymphocytes/paraimmunoblasts LpL rounded, plasmacytoid, plasma cell centroblasts, immunoblasts Mantle Cell rounded, cleaved, slightly irregular none Follicular cleaved, angulated, rounded centroblasts, centrocytes Marginal Zone polymorphous: rounded, cleaved, monocytoid, plasmacytoid, plasma cell centroblasts, centrocytes, immunoblasts Extranodal Marginal Zone Lymphoma of mucosa associated lymphoid tissue(MALT) is also in the differential diagnosis of FL as well as that of other small cell lymphomas. MALT lymphoma: May have a history of autoimmune disease: Sjogren's syndrome/Hashimoto's thyroiditis Patients usually have stage I or stage II disease Potentially curable by surgery or regional radiotherapy. MALT Lymphoma – Potential Anatomic Sites of Involvement • gastrointestinal • head and neck: salivary gland, thyroid, sinonasal • gynecologic sites • mediastinum/lung • retroperitoneum • ocular/intracranial Aspirates from MALT lymphoma are easily confused with reactive hyperplasia because of their polymorphous nature including small lymphocytes, centrocytes, and monocytoid B-cells. A conspicuous number of monotonous cells with pale cytoplasm [monocytoid B-cells] is helpful in differentiating MALT lymphoma from other small cell lymphomas. Since reactive germinal centers are often present in extranodal sites, this mixing of a reactive cell population with a neoplastic one adds to the confusion. Small cells with distinct plasmacytoid features, plasma cells, and a minor population of large cells may be found. Histologic Components of MALT Lymphoma • lymphoepithelial lesion • monocytoid B-cell hyperplasia • plasma cells • minor T-cell population • follicular center cells   Matsushima et.al. stress that a mixed population of small and intermediate lymphocytes with pale staining cytoplasm(monocytoid cells), large transformed cells, plasmacytoid cells, and plasma cells in tissue where lymphoid tissue is normally sparse should raise the suspicion of MALT lymphoma. The characteristic "lymphoepithelial lesion" observed in tissue sections of MALT lymphoma – absent on smears. Non-lymphoid small cell tumors The most common non-lymphoid malignancy confused with all forms of small cell lymphoma in adults is small cell neuroendocrine carcinoma (SCNEC). Head and neck lymphadenopathy may be the initial clinical presentation of SCNEC prior to recognition of a pulmonary mass. Aspirates of SCNEC: highly cellular smears renowned for their abundant "tumor diathesis" with a result that the smear is laden with nuclear and cytoplasmic debris. 2 cell population – that of intact viable malignant cells and of apoptotic/individually necrobiotic cells typical cells about 3x that of a small lymphocyte with an extremely high N/C ratio, coarse nuclear chromatin [best with Papanicolaou stain], inapparent nucleoli, and the presence of "nuclear molding" focally a single cell pattern cellular debris can be mistaken for LGBs Basaloid squamous cell carcinoma and Merkel cell carcinoma(neuroendocrine carcinoma of the skin) are two other non-lymphoid cancers that may produce lymphadenopathy with their metastatic deposits, and mimic SCNEC. Both have a predominant aggregate cell architecture and nuclear molding. Table 41. Basaloid Squamous Cell Carcinoma. age range: 60 –80 years male predominance sites: supraglottic, pyriform sinus, floor of mouth, nasopharynx, tonsillar region biphasic histologic pattern of basaloid cells with small foci of squamous differentiation surface carcinoma in situ EMA +, weak cytokeratin, negative neuroendocrine markers References for All Cases