Section 3 -

FNA Cytopathology Of Tumours Of The Mediastinum Paul E. Wakely, Jr. The Ohio State University Columbus, OH, USA

Introduction: The mediastinum is a site for the development of epithelial, mesenchymal, lymphoproliferative, neurogenic, & germ cell neoplasms. Utilization of fine needle aspiration biopsy (FNAB) for the diagnosis of mediastinal tumours is much less than for other body sites. A study comparing the efficacy of mediastinal FNAB & core needle biopsy showed both methods performed with an overall diagnostic accuracy of 100%, however the ability of FNAB to subtype lesions was less than tissue biopsy. FNA is increasingly being used to sample mediastinal masses by combining it with endoscopy and ultrasound. Some centers using endoscopic ultrasound-guided FNA also combine it with core needle biopsy so that both conventional cytologic smears & tissue sections can be simultaneously examined. Because of the broad spectrum of tissue types in this region, and the variety of cell morphology even within the same neoplasm, adequate sampling cannot be overemphasized; close communication with the interventional radiologist or endoscopist is mandatory. I. EPITHELIAL TUMORS A. Thymoma Thymoma arises in the antero-superior mediastinum, is a neoplasm of older adults, and occurs in up to 40% with a paraneoplastic syndrome. The cytologic diagnosis is demanding. Smears vary depending on the area sampled, what cell type (epithelial or lymphoid) is most common, whether spindle cell foci are present, and whether fluid has been aspirated. Cytopathology moderately cellular smears with a mixture of lymphocytes and epithelial cells. epithelial cells in tightly clustered microfragments, some as loose clusters, and some as single cells. Cells are isomorphic, polygonal or spindle shaped with round to oval smooth nuclear borders, indistinct nucleoli, and finely dispersed chromatin. lymphocytes are primarily small mature forms thymomas with spindle morphology have a fusiform configuration Many of the histologic features of thymoma, e.g. perivascular spaces, cystic transformation, organotypical architecture, and lobule formation cannot be recognized in smears. Certainly any attempt to distinguish an invasive from a non-invasive thymoma is impossible using FNAB since the cell morphology is identical to both, and smears cannot evaluate capsular invasion in any neoplasm. Immunophenotyping on smears or cell block is helpful to recognize the epithelial cells. Prudence dictates that cytokeratin (CK) staining of a smear should be performed whenever possible if thymoma is suspected. These CK+ cells are randomly scattered as single cells or small cell groups within the lymphoid population whereas entrapped thymic epithelium in a lymphoma consists of an irregular branching network. B. Thymic Carcinoma Primary carcinomas of the thymus are rare lesions. The vast majority are actually derived from the lung. Histologic variants of thymic carcinoma include keratinizing squamous cell carcinoma, sarcomatoid carcinoma, neuroendocrine carcinoma, mucoepidermoid carcinoma, and undifferentiated (lymphoepithelioma-like) carcinoma. No substantial series exists. The cytopathology is similar to that seen in lung aspirates. II. LYMPHOPROLIFERATIVE DISORDERS A. Hodgkin Lymphoma Hodgkin lymphoma (HL) is the most common mediastinal lymphoma. There is a predilection for women with a peak in the 2nd - 4th decade. In Caucasians, HL comprises up to 35% of all lymphomas in contrast to only 5-10% in Orientals. Cytopathology heterogeneous lymphocyte background key feature is identification and recognition of randomly dispersed Reed-Sternberg (R-S) cells. These are large cells with mirror-image binucleation, or mononuclear variants greater than 20 μm. diameter, with smooth, bosselated, or distinctly multilobated nuclei. nucleoli as large as a red cell in most cases, and often misshapen cytoplasm is moderate to sometimes abundant, and pale staining. Sclerotic bands, and lacunar cells per se cannot be appreciated. Cytologic Mimics of Reed-Sternberg Cells Immunoblasts Dendritic Cells Pleomorphic Sarcoma Large Cell Lymphoma Melanoma Large Cell Carcinoma Flow cytometry plays no role in the immunophenotyping of HL due to its non-diagnostic results. R-S cells are CD15/CD30 positive, and CD45/CD20/epithelial membrane antigen (EMA) negative in classic HL, while the Lymphocyte Predominant form shows CD15/CD30 negative, and CD45/CD20/EMA positive R-S cells. B. Large Cell Lymphoma Large cell non-Hodgkin lymphoma (NHL) of the mediastinum can be a primary tumor arising in the thymus, or a lymphoma secondarily involving lymph nodes in this region. B1. Primary mediastinal (thymic) Large B-cell Lymphoma: Accounts for 2-3% of all NHL with a putative origin from thymic B-cells. Demographics include young adults (avg. 37 y.), and a female predominance (2:1). Patients present with superior mediastinal syndrome (dyspnea, tracheal compression, SVC obstruction). Cytopathology smears may be hypocellular. Large lymphocytes are in a predominantly non-cohesive distribution (so-called single cell pattern); lymphoglandular bodies present. round to oval nuclei with smooth or irregular borders, visible nucleoli, intensely basophilic cytoplasm. connective tissue microfragments may distort lymphocytes making them spindled shaped and thus confused for a sarcoma. Flow cytometry shows CD45, CD19, CD20 positive. B2. Anaplastic Large Cell Lymphoma (ALCL) is a T-cell lymphoma that may occur in the mediastinum. Children and young adults are principally affected. Cytopathology moderate to high cellularity with large malignant cells having multinucleated forms, pleomorphic shapes, intranuclear inclusions, concentric nuclear "donut" shapes, and nuclear notches are all possible. Large misshapen nucleoli are common cytoplasm is abundant; may have coarse or fine vacuolation. Flow cytometry shows CD2, CD30, CD4 + while CD5, CD7 are frequently negative. C. Lymphoblastic Lymphoma (LL) One of the three most common NHL of children. Experience has shown that FNAB is an excellent method for the diagnosis of LL. This aggressive neoplasm comprises 1/3rd to ½ of pediatric lymphomas. The peak incidence is in adolescent and young adult males. An anterior mediastinal mass occurs in up to 80% of patients is often massive, and may induce a superior vena cava syndrome. Cytopathology hypercellular single cell pattern of monotonous lymphoblasts 1.5-2 x > small lymphocytes. finely dispersed chromatin, small or imperceptible nucleoli, smooth or irregular (convoluted) nuclear rims, and an extremely meager amount of cytoplasm. mitotic figures, tingible body macrophages, and lymphoglandular bodies are variable About 80% are T-cell and stain for these markers, while the remaining are B-cell. Nearly all are positive with terminal deoxynucleotidyl transferase (Tdt). It should be remembered that thymic lymphocytes are normally also Tdt positive, and immunophenotypically identical to T-lymphoblasts. III. GERM CELL TUMORS A. Germinoma/Seminoma Mature teratoma is the most common form of mediastinal germ cell tumor (GCT). Germinoma/seminoma is the 2nd most frequent type. Men in the 2nd - 4th decade are affected. These may be discovered as incidental lesions on chest X-ray, but large masses are symptomatic. The possibility of a metastasis always needs to be excluded. Cytopathology cells in small loose clusters or singly. Large cells have rounded to polygonal shape, round or oval nuclei with coarse chromatin, and a single large nucleolus. Many bare nuclei. moderate amount of cytoplasm; often contains coarse sharply demarcated glycogen-filled vacuoles in a "bleb or blister-like" fashion. detached cytoplasmic contents distributed in a lacy linear configuration producing a so-called "tigroid" pattern. Smears may contain lymphoglandular bodies. Germinomas: CK negative, and PLAP+, and focal staining with CD30. B. Non-Seminomatous Germ Cell Tumors The major subtypes in this category include yolk-sac tumor, embryonal carcinoma, and choriocarcinoma. Clinical features are similar to those for seminomatous GCT. Cytopathology large cytologically malignant cells with nucleo- and nucleolomegaly. variable vacuolated cytoplasm, & background necrosis cells loosely or tightly aggregated into 3-dimensional groups; may display papillary or glandular features. Hyaline globules are unusual. Immunophenotypically, express AFP & focal staining for b-HCG, CD30. IV. NEURAL TUMORS The vast majority of posterior mediastinal neoplasms are neurogenic. A. Schwannoma Neurogenic tumors account for ≈ 20-30% of mediastinal neoplasms. Schwannoma is the most common mediastinal neural tumor. Patients are usually 20-40 yrs. Cytopathology spindle cells in loose clusters and single forms often but not invariable distinctive irregular nuclear outline described as "buckled", "wavy", or "fish-hook". homogeneous bland chromatin; cytoplasm pale, in thin strands; cell borders typically indistinct. Metachromatic stroma is variable. B. Ganglioneuroma Older female children and young adults are affected. Most are paraspinal. Cytopathology hypocellular smears; microfragments on occasion. Isomorphic spindle cells mixed with ganglion cells which have voluminous cytoplasm; 1 or more nuclei & a centrally placed nucleolus. C. Neuroblastoma/Ganglioneuroblastoma The most common childhood tumor in that site. Cytopathology highly cellular smears of uniform, round to polygonal small cells in clusters, acinar structures (Homer-Wright rosettes) with fibrillary matrix (neuropil). nuclei: single, hyperchromatic, diffuse even chromatin, small nucleoli; binucleation cytoplasm: scanty in solitary cells; wispy cell processes; more apparent in aggregates; increased volume in maturing neuroblasts and ganglion cells References Wakely PE Jr. Cytopathology-histopathology of the mediastinum. I. Epithelial, germ cell, and lymphoproliferative neoplasms. Ann Diagn Pathol 2002;6: 30-43. Wakely PE Jr. Cytopathology-histopathology of the mediastinum. II. Mesenchymal, neural, and neuroendocrine neoplasms. 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