Case 3 -

Hodgkin's Lymphoma Paul E. Wakely, Jr.

Clinical History A 25 y/o female veterinary medicine student presented to clinic with a 4 cm. non-tender left neck mass. The mass has been present for 3 weeks according to her. She has no complaints of fever or weight loss. Cytopathology: Case 3 - Figure 1 - Case 3 - Figure 2 - Case 3 - Figure 3 - hypercellular smears dominated by small rounded lymphocytes. transformed lymphocytes present in large numbers, but FC fragments not seen. single forms or loose clusters of Reed-Sternberg cell: markedly enlarged cells with round bosselated nuclear outlines/enlarged nuclei contained two or more lobes/enlarged, often misshapen nucleoli. FNA diagnosis of Hodgkin lymphoma (HL) was made, and excision showed a mixed cellularity variant of classical HL. Diagnosis: Hodgkin's Lymphoma Discussion Table 19. Classical Hodgkin's Lymphoma, clinical: painless enlargement most commonly of cervical or mediastinal lymph nodes Bimodal age peak 2nd-4th decades of life; second smaller peak at 7th decade. Caucasians, HL comprises up to 35% of all lymphomas; only 5-10% in Orientals. either a single node or groups of nodes can be enlarged. "A" category without symptoms; "B" category with constitutional symptoms: include unexplained fever, drenching night sweats, and unexplained weight loss (>10%). no specific clinical laboratory abnormalities unique to HL modern chemo-/radiation therapy have led to a relatively high cure rate prognosis is not particularly dependent on histologic subtype, but on clinical stage, presence of absence of "B" symptoms, and patient age. The new WHO classification of HL has classified the tumor into two major subtypes: Table 20. WHO Classification: HODGKIN LYMPHOMA (Hodgkin's Disease) Nodular lymphocyte predominance HL Classical Hodgkin Lymphoma(HL) !HL, nodular sclerosis, grade I and II !HL, lymphocyte-rich !HL, mixed cellularity !HL, lymphocytic depleted The nodular LP form accounts for only 5-10% of cases while at least 50% are of the nodular sclerosis(N-S) subtype. Mediastinum often involved in N-S subtype. Major limitation of FNA biopsy in HL: inability to accurately subtype HL from smears alone. Therefore, a newly diagnosed patient requires node excision for accurate histologic subtyping. Granted, histologic subtyping has little prognostic significance with the therapies currently in use. Nonetheless, it is still required in most protocols and for some, subtype (lymphocyte depleted) is important. Patients with FNA-diagnosed recurrent HL do not require follow-up tissue confirmation. Identification of Reed-Sternberg(R-S) cells can, at times, be quite difficult from smears. Classic binucleated R-S cells can be hard to come by. It has been stated that R-S cells represent only 0.1%-1% of the entire cell population of classic HL[Kaplan H. Hodgkin's disease. Cambridge: Harvard University Press, 1980]. If one requires classic binucleated R-S cells before suggesting the diagnosis cytologically, one is going to overlook this entity. Note: The real clue to suggesting HL from aspirate smears is the presence of enlarged mononuclear R-S variants(rather than classic binucleated forms) in a lymphocytic background(milieu) that simulates reactive hyperplasia. Mononuclear R-S cells: enlarged (at least 20-30 μm) when compared to surrounding lymphocytes may have bosselated nuclear contours enlarged misshapen nucleoli; diameter = or > red cell often apparent at medium power (due to Ý size) R-S variants can "hide" in a sea of lymphocytes particularly when the smear is cellular Some cases only moderately enlarged bare R-S nuclei with no intact classic or mononuclear R-S cells. Stripped nuclei moderately enlarged with some lobulation of their nuclear contour. Because nucleoli in this form of R-S cell are smaller than classic R-S cells, and because the Romanowsky stain obscures rather than highlights nucleoli, this type of R-S cell can be overlooked. Hypocellular smears are a major reason for misdiagnosis. N-S Hodgkin often leads to hypocellular smears. Fibrosis can inhibit the extraction of sufficient numbers of diagnostic cells. Therefore a concentrated search for classic R-S cells/variants is required in a modestly cellular lymph node-particularly one that is firm to palpation and clinically suspicious. Other potential components include fibrous stroma, eosinophils, necrosis, plasma cells, neutrophils, and mini-granulomas. Table 21. Hodgkin's – Reasons for Diagnostic Failure [Cancer Cytopathol 2001;93:52.] Original FNA Dx Reason for Error 3 cases, benign misinterpretation 7 cases, benign rare R-S variants, hidden in a polymorphous bkgd. 3 cases, benign bx: partial node involvement (2) 10 cases, non-diagnostic bx: showed "considerable" fibrosis Table 22. FNA of HL – Diagnostic Accuracy reference # cases sensitivity (%) specificity (%) Acta Cytol 2001;45:300. 170 84 92 Cancer Cytopathol 2001;93:52 89 77 100 Mod Pathol 2000;14:472. 16 66 100 Cytopathology 1994;5:226. 62 97 100 TOTAL 337 81 98 Immunophenotyping of conventional smears or better yet, cytospin preparations or cell block specimens is valuable in differentiating HL from other lymphomas, and a host of other R-S mimics (Table 23). Table 23. Cytologic Mimickers of Reed-Sternberg Cells • Immunoblasts • Megakaryocytes • Dendritic Cells • Reactive Mesothelial Cells • Large Cell Lymphoma(B and T-cell) • Anaplastic Large Cell Lymphoma • Malignant Melanoma • Plasmablasts(Myeloma) • Pleomorphic Sarcoma • Large Cell Carcinoma The following comparison shows the immunophenotypic differences between the R-S cells of classic and lymphocyte predominant (LP) HL with the first result being the more common one. R-S cells Classic HL LPHL CD45 negative positive CD15 positive/negative negative CD30 positive(often weak) negative/positive EMA negative positive/negative CD20 negative/positive positive CD3 negative negative The differential diagnosis for HL can be extensive. Realistically however, the main entities are: forms of large cell non-Hodgkin lymphoma(NHL), both B- and T-cell including anaplastic large cell lymphoma(ALCL) immunoblasts that are part of a reactive or infectious condition Most examples of large cell NHL have a monotonous population of large cells, not the RLH-type background typical of HL. Some examples of grade II nodular sclerosis HL can have large numbers of R-S cells on the smear causing confusion with large cell lymphoma or even N-P carcinoma. The binucleation typical of R-S cells can occur frequently in both melanoma and ALCL. Typical for melanoma is the absence of LGBs in the smear, the presence of intra-nuclear inclusions, an eccentric position of the nucleus in the cell, and occasional cytoplasmic vacuolation; any one of these features would be extremely unusual in R-S cells or smears of HL. ALCL and HL may have multilobated "wreath" nuclei whereby nuclei are arranged in a concentric ring-like fashion within the cell. On a cell-for-cell basis one cannot distinguish between the two. Once again however in these non-HL conditions such as ALCL, the composition of the smear nearly always fails to show a background population of small lymphocytes and transformed cells. Table 24. Classic HL vs. Anaplastic Large Cell Lymphoma   Classic Hodgkin Lymphoma Anaplastic Large Cell Lymphoma CD15 positive, 80% negative, 90% CD30 positive positive CD45 negative, 90% positive, 70% CD43 negative, 93% positive, 90% EMA negative positive CD20 negative negative Immunoblasts (IB) may occasionally acquire mirror-image nuclei so that superficially they resemble R-S cells. Most have smaller nucleoli, and deep blue plasmacytic cytoplasm, and a paranuclear hof unlike R-S cells. IBs are found in smears of RLH, and in miscellaneous conditions; most common non-neoplastic lymphadenopathy harboring IBs is infectious mononucleosis. Table 25. Immunoblast vs. R-S Cell Immunoblast R-S Cell 3x small mature lymphocyte > 3x small mature lymphocyte rounded/irregular nuclei lobular or misshapen nuclear contour 1 or more nucleoli, usually spherical much larger misshapen nucleolus occasional perinuclear hof no perinuclear hof cytoplasm: deep blue (plasmacytoid) pale cytoplasm bi-/multi-nucleation rare binucleation, multi-lobation Megakaryocytes are rare in lymph node aspirates, but may be seen as a component of extramedullary hematopoiesis within a node. They simulate R-S cells due to their marked nucleomegaly, but unlike the former lack enlarged nucleoli, and typically have a lower N/C ratio. Nuclei of megakaryocytes are polylobated rather than having single nuclei or mirror image binucleation. Megakaryocytes are CD15/CD30 negative, and positive for Factor VIII, CD34, and CD31 antigens. Follicular and interdigitating dendritic cells may display nuclear enlargement as well as binucleation, and thus superficially resemble R-S cells. However, nuclei are rarely if ever as enlarged as R-S cells, and nucleoli are indistinct to absent in dendritic cells. Polykaryocytes (Warthin-Finkeldey cells) are large cells, and can stand out in a reactive background. They have small, but multiple nuclei that mimic those of an osteoclast-type giant cell. Although seen rarely in reactive hyperplasia, they are not disease specific and have been described in HIV-associated lymphadenopathy, Kimura's disease, and measles lymphadenitis. References for All Cases