Case 7 -

Anaplastic Large Cell Lymphoma Paul E. Wakely, Jr.

Clinical History A 29 y/o woman underwent CT guided FNA of a 4 cm. paratracheal mass. Cytopathology: Case 7 - Figure 1 - Case 7 - Figure 2 - Case 7 - Figure 3 - smears show an abundance of large cells most singly dispersed, but some in loose gatherings variety of nuclear shapes with single round nuclei, reniform nuclei, multilobed nuclei, and wreath-like or "donut" nuclei cytoplasm moderate – voluminous; variably vacuolated only small numbers of LGBs Diagnosis: Anaplastic Large Cell Lymphoma Discussion Table 42. Anaplastic large cell lymphoma(ALCL), Clinical: formerly alluded to as Ki-1 lymphoma 3% of adult NHL; 10-30% pediatric NHL; bimodal age distribution similar to HL M >> F extranodal sites common: skin, soft tissue, bone associated with a specific t(2;5)(p23;q35) translocation that fuses the ALK(anaplastic lymphoma kinase) gene with the NPM(nucleophosmin) gene. The protein product of this fusion is the chimeric NPM-ALK protein (also known as p80); commercially available as an immunohistochemical antibody ALK protein positive in 50-80% of cases. ALK-positive ("ALKoma") patients a relatively homogeneous group. Develop systemic advanced stage disease 1st 3 decades, no cutaneous disease, no association with EBV, and a much better prognosis (70% 5-yr. survival) than ALK-negative patients (30% survival). In tissue, classic ALCL is often recognized by the presence of so-called "hallmark" cells: large cells with eccentrically placed nuclei that have indented reniform shape, small nucleoli, prominent Golgi zone, and a large amount of amphophilic cytoplasm. The original "anaplastic" morphology of ALCL has given way to the recognition that a broad morphologic spectrum of ALCL exists - Table 43. Table 43. Morphologic Variants of ALCL [Blood 1998;91:2076] • Pleomorphic(common) • Lymphohistiocytic • Monomorphic • Signet-ring • Sarcomatoid • Neutrophil-rich • Small-cell • Mixed cell More than one morphologic variant may exist in a single node., and transformation from one variant to another has been reported [Am J Surg Pathol 1999;23:49]. The prominent sinusoidal pattern of infiltration that is notable in tissue sections is lost in smears. Aspirates of ALCL: moderate to high cellularity with large malignant cells multinucleated forms, pleomorphic shapes, intranuclear inclusions, concentric nuclear "donut" shapes, and nuclear notches, all possible large misshapen nucleoli common cytoplasm is abundant; may have coarse or fine vacuolation Difficulty exists in confusing ALCL with other lymphomas and with non-lymphoid tumors. Table 44. Differential Diagnosis of ALCL • Hodgkin lymphoma • Diffuse Large B-cell Lymphoma • Peripheral T-cell lymphoma • Pleomorphic Sarcoma • Non-Small Cell Carcinoma • Malignant Melanoma • Germ Cell Tumor   Since mirror image R-S like nuclei with large nucleoli are commonplace in ALCL, HL is first on the diff Dx list. Numerical superiority of pleomorphic cells and lack of an RLH background is the best evidence that one is not dealing with HL. However, some examples of grade II nodular sclerosis HL may strongly mimic ALCL. A panel of immunostains can make this distinction in most cases. CD30 positivity in HL has been described as weaker than that which occurs in ALCL, but this applies only to tissue sections. Table 45. Why Can Smears of ALCL Be Mistaken For A Non-Lymphoid Tumor? relative paucity of LGBs relative lack or absence of other lymphocytes on smear loose "clustering" of cells bizarre cell morphology binucleation Table 46. Classical Hodgkin's Lymphoma vs. ALCL Classical HL ALCL CD15 positive CD15 negative, 15-20% positive CD45 negative CD45 positive, up to 25% negative CD30 positive CD30 positive(100%) EMA negative EMA positive CD43 negative CD43 positive, few negative Diffuse Large B-cell Lymphoma [DLBL] Table 47. DLBL, Clinical: 30-40% of adult non-Hodgkin's lymphoma aggressive, but potentially curable wide age range, and is a major form of pediatric lymphoma about 40% present with extranodal disease primary mediastinal variant partial to young women, some have SVC syndrome variants: centroblastic, immunoblastic, anaplastic, T-cell rich In most instances one has little trouble recognizing the aspirates of DLBL as abnormal because of the large cell size and lack of lymphocyte heterogeneity. Cellularity of smears in DLBL is variable. Superficial aspirates seem to be more cellular in my experience than deep ones perhaps because there is greater difficulty in obtaining cells by CT guidance. Aspirates of mediastinal DLBL have the potential to be extremely hypocellular due to the extensive sclerosis that is common to these tumors, but occasionally extensive sclerosis can also occur in DLBL outside the mediastinum. This sclerosis can also induce an artifactual spindle cell configuration to these large lymphocytes. Aspirates of DLBL: lymphocytes are generally 3x or > small lymphocyte monomorphous large cells, or mixture with a minor percentage of small lymphocytes nuclei generally larger than those of tissue macrophages; round to irregular or multilobated; may be centroblastic, immunoblastic, or bizarrely shaped nucleoli usually conspicuous; may be multiple or single cytoplasm is moderate to abundant; may include small vacuoles tingible body macrophages and necrosis common Morphologic variants include Centroblastic, Anaplastic, Immunoblastic, And T-cell Rich. T-cell rich DLBL is associated with an overwhelming population of benign small T-lymphocytes that obscure the large B-lymphocytes on the smear. Because of the isolated large cells among an overwhelming small cell population, the aspirate may resemble Hodgkin's lymphoma. FCM must gate on these large cells to identify the monoclonal population. Some aspirates of DLBL have a plasmacytoid appearance and may be mistaken for a plasmacytoma. Subtypes of DLBL: Intravascular (angiotropic) variant This variant cannot be recognized as such by FNA because the vascular luminal location cannot be appreciated in smears. Mediastinal (thymic) large B-cell lymphoma This variant requires knowledge of clinical/radiologic features. Morphologically there is no difference from nodal based DLBL. Primary Effusion Lymphoma This clinicopathologic entity has tumor localized to the body cavities(pleural, pericardial, peritoneal), and does not form a discrete mass. It is almost exclusive to AIDS patients and associated with human herpesvirus-8. Cytopathology shows markedly pleomorphic immunoblastic type B-cells. DLBL is positive for pan B-cell markers CD19/CD20, and for CD5, CD10, and CD30 in less than 50% of cases. Staining for CD15 is negative. Table 48. Differential Diagnosis of DLBL major large cell lymphomas   peripheral T-cell lymphoma   ALCL infectious mononucleosis non-lymphoid neoplasms   melanoma   non-small cell carcinoma   seminoma   epithelioid forms of sarcoma T-cell Lymphoma T-cell lymphomas are a heterogeneous category of both nodal and extranodal lymphomas. They comprise about 10% of all non-Hodgkin lymphomas in North America with a slightly higher percentage (»20% of cases) in Asian countries. With the exception of ALCL and precursor T-cell lymphoblastic lymphoma limited experience exists in the cytopathology of these lymphomas. Many neoplasms in this category have rarely been reported using FNA, or FNA has little role in their diagnosis, e.g. mycosis fungoides, the various T-cell leukemias, Sézary syndrome. Table 49. WHO Classification of Lymphoid Tissue, T-Cell Neoplasms Precursor T-cell neoplasms   Precursor T-cell lymphoblastic leukemia/lymphoma   Blastic NK cell lymphoma Mature T-cell and NK-cell neoplasms.   T-cell prolymphocytic leukemia   T-cell large granular lymphocytic leukemia   Aggressive NK-cell leukemia   Extranodal NK/T-cell lymphoma, nasal-type   Mycosis fungoides   Sézary syndrome   Angioimmunoblastic T-cell lymphoma   Peripheral T-cell lymphoma, unspecified   Adult T-cell leukemia/lymphoma   Anaplastic large cell lymphoma   Primary cutaneous anaplastic large cell lymphoma   Subcutaneous panniculitis-like T-cell lymphoma   Enteropathy-type T-cell lymphoma   Hepatosplenic T-cell lymphoma Table 50. Clinical features of Peripheral T-cell Lymphoma (PTCL), unspecified 40-50% of nodal T-cell NHL wide age spectrum accounts for about 6% of lymphomas nodal and extranodal[skin, subcutis, viscera] at the time of clinical presentation 5 yr. survival: 20-30% Aspirates of PTCL, Unspecified: variable morphology; most common picture is large cell lymphoma, but also may have a mixture of small/intermediate lymphocytes and a high percentage of large lymphocytes large cells may simulate R-S cells variable number of eosinophils, plasma cells, and epithelioid histiocytes Immunophenotyping: absence of B-cell markers; variable pan T-cell marker(CD1a, CD2, CD3, CD4, CD5, CD7, CD8) positivity usually with loss of 1 or more of these markers, typically CD7. Cellular heterogeneity of PTCL can be confused with RLH. FC fragments and TBMs are uncommon to rare in PTCL, and their absence could be a clue that one is not dealing with a normal population of lymphocytes. Genotype shows a re-arrangement of T-cell receptors. Angioimmunoblastic T-cell lymphoma closely mimics a reactive process (Ng). Large Cell Non-Lymphoid Neoplasms Morphologic Features Causing Potential Confusion between Large Cell Lymphomas and Large Cell Non-Lymphoid Tumors: the number of LGBs can be sparse in smears of large cell lymphoma other lymphoid appearing cells may be absent in the smear large cell lymphomas can show some loose "clustering" on the smear bizarre nuclear morphology of some large cell lymphomas mimics non-lymphoid malignancy Table 51. Nasopharyngeal carcinoma (lymphoepithelioma): affects adolescents/young adults a primary tumor of the roof /lateral walls of the nasopharynx 50% manifest as an enlarged cervical lymph node clinically imitating lymphoma M >> F; 2-3:1 Asia > North America strong association with EBV Cytopathology of N-P Carcinoma epithelial cells singly dispersed and/or tightly clustered epithelial cells display large nuclei, macronucleoli, moderate amounts of cytoplasm with indistinct cell borders/lack of cytoplasmic keratinization a range of lymphocytes exists in the background mimicking RLH; lymphoid cells can sometimes obscure the syncytia of malignant cells cytokeratin immunostaining diagnostically helpful –smears/cytospins/or cell blocks Granulocytic sarcoma (GS): rare tumor of myeloid precursors; occurs in extramedullary tissues-soft tissue and subcutis preferred sites majority of cases are associated with acute myeloid leukemia or other myeloproliferative disorder blastic/immature form of GS has features of lymphoma: single cell pattern, LGBs, high N/C ratio, lack of differentiating myeloid cytoplasmic features large series Suh YK et al. Cancer (Cancer Cytopathol) 2000;90:364-72 showed LGBs in 80% of lymph node aspirates/55% of extranodal aspirates more differentiated forms of GS shows a spectrum of later myeloid precursors(granular promyelocytes, metamyelocytes, and band forms) helpful when present but eosinophilic myelocytes/metamyelocytes not particularly sensitive markers of GS Immunophenotyping: positivity for CD13, CD33, CD43, and myeloperoxidase(often not positive in blastic forms of GS) References for All Cases