Case 5 -

Thymic Carcinoid Tumor in Association with Type-1 Multiple Endocrine Neoplasm Syndrome (MEN1) Laura H. Tang Memorial Sloan-Kettering Cancer Center New York, NY

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Clinical History 17 years old male with an anterior mediastinal mass, multiple liver lesions (biopsied), and Cushing's syndrome. Case 5 - Figure 1 Liver biopsy reveals several large and irregular tumor nests with prominent spindle cell morphology with noticeable whorl-formation. Case 5 - Figure 2 The epithelioid nature of the tumor is better appreciated at a higher magnification. Case 5 - Figure 3 The tumor cells reveal low nuclear to cytoplasmic (N/C) ratio with identifiable mitoses and single cell necrosis. Case 5 - Figure 4 Significant nuclear pleomorphism is depicted by enlarged and bizarre nuclei with intranuclear inclusions. Case 5 - Figure 5 The highest proliferative activity, assessed by Ki67 nuclear immunoreactivity, is 2%. Case 5 - Figure 6 The tumor cells are diffusely positive for chromogranin. Case 5 - Figure 7 The tumor cells are focally positive for ACTH. Case 5 - Figure 8 Surgical resection of the mediastinal tumor reveals an epithelial neoplasm with typical histologic pattern of a carcinoid tumor. Introduction: The case encapsulates the intricacy of pathology practice, in that, every time one believes that a pathologic puzzle is resolved, it is only one half of a clinical riddle. Clinical History The patient is a 17 years old male who presented with an anterior mediastinal mass, Cushing's syndrome, and multiple liver lesions. The latter was biopsied and submitted for pathologic evaluation. The mediastinal tumor was subsequently resected to ameliorate tracheal compression symptoms. Upon acquisition of the family history it emerged that the father had neck surgery for a parathyroid tumor; has and had been prescribed a proton pump inhibitor for peptic ulcer disease. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: A core liver biopsy reveals several large and irregular tumor nests (Figure 1). At low magnification, there is prominent spindle cell morphology with noticeable whorl- formation (Figure 1). However, at higher magnification, the tumor is better appreciated as epithelial/epithelioid in nature (Figure 2, 3), and a cytokeratin immunostain (AE1:AE3) is positive in tumor cells. The neoplasm exhibits significant nuclear pleomorphism although, in the presence of abundant cytoplasm, the nuclear to cytoplasmic (N/C) ratio is relatively low. While the severe cytologic atypia present in this tumor (Figure 4) creates the impression of a high grade carcinoma, the estimated mitotic activity is 2 mitoses per 10 high power fields and the proliferative index (MIB-1/Ki67) is 2% (Figure 5). Single tumor cell necrosis/apoptosis is also apparent in this biopsy (Figure 4). Immunohistochemical studies reveal that the tumor cells are positive for chromogranin, synaptophysion, and ACTH (Figure 6, 7); they are negative for TTF1, Napsin-A, CD30, PLAP, and hCGH. Surgical resection specimen of the thymic tumor reveals a 3.0 cm well-circumscribed fleshy tumor. Microscopically, the tumor demonstrates a nested pattern surrounded by abundant and delicate vasculature (Figure 8). Apparent vascular invasion by tumor is appreciated throughout the tumor. The morphological features are most consistent with a well differentiated neuroendocrine tumor (carcinoid) with intermediated cytologic grade. Differential Diagnoses: 1. Based upon anatomical location (anterior mediastinum): a. Primary thymic tumor: Thymoma/thymic carcinoma, thymic carcinoid tumor b. Lymphoma: Hodgkin's disease, large B-cell type, lymphoblastic type c. Primary or metastatic germ cell tumor: mature teratoma, seminoma, nonseminomatous germ cell tumor d. Thyroid - Substernal Goiter e. Parathyroid - Ectopic parathyroid adenoma 2. Based upon combined morphologic features and anatomic location: a. Epithelial neoplasm: thymic carcinoma, thymic carcinoid tumor, lung carcinoma b. Spindle cell features may suggest a mesenchymal neoplasm: solitary fibrous tumor, smooth muscle tumor, and synoviosarcoma 3. Based upon combined information (clinical, radiology, morphology, immunohistochemistry, and additionally acquired family history) A primary thymic epithelial neoplasm, possibly arising against a background of a hereditary condition Final Diagnosis: Thymic carcinoid tumor in association with type-1 Multiple Endocrine Neoplasm syndrome (MEN1) Discussion: Thymic carcinoid tumor (TCT) was historically classified as a foregut carcinoid tumor. This group also includes carcinoid tumors of the bronchus, stomach, and the pancreas. The entity of TCT was initially described by Rosai in 1972 with the recognition of its hisopathologic features, malignant clinical behavior, and its association other clinical syndromes [1] . The onset age for thymic carcinoid tumor is ~50 years with a male predominance (3:1). Approximately 40% patients with thymic carcinoid tumors present with ectopic Cushing's syndrome secondary to ACTH production by the tumor. The tumor is highly malignant with an estimated recurrence of 67% after surgical resection of the primary tumor [2] . The most significant clinical relationship in the diagnosis of a thymic carcinoid tumor is the association with MEN-I in ~25% cases. Conversely, ~ 8% patients with MEN-I develop thymic carcinoid tumor. Thymic carcinoid tumor is a major cause of death in MEN-I, and the estimated 5-year survival is 30-40% [3] . In respect of the different neoplasms arising in MEN-1 syndrome (Table 1), the most malignant tumors are gastrinoma and thymic carcinoid tumor. Gastrinoma is commonly located in duodenum and presents as functional albeit often occult lesion before clinically evident metastasis are evident. Despite the presumption of "successful" surgical resection of thymic carcinoid tumors, the majority (67%) of patients will have recurrent disease and <50% survive in 5 years [3] . Table 1. MEN-1 Associated Neoplasia Parathyroid adenoma 75-95% Adrenal adenoma 20% Pancreatic endocrine tumor 70% Gastrinoma 45% Insulinoma 10% Non-functional 10% Foregut carcinoid Tumor 18% Thymus 8% Bronchial 8% Stomach 5% Pituitary adenoma 47% Prolactinoma 30% Non-functional 10% ACTH producing 1% GH producing 3-6% Skin lesions 80% Angiofibroma 75% Collagenomas 5% Mesenchymal Neoplasms Lipoma 30% Leiomyoma 5% MEN-1 associated tumors develop in a genetic background of germline MEN1 gene mutation on the first allele followed by somatic inactivation of the gene on the 2nd allele by LOH [4] . MEN1 constitutes a 9 kb genomic DNA with 10 exons, and 4-kb transcript is present in the pancreas, thymus and stomach. The mRAN of 1.83 kb encodes a 610 amino acid nuclear protein of menin, which regulates gene transcription and is involved in chromatin remolding [5] . MEN1 mutation/LOH has been recognized in many forget neuroendocrine tumors [4, 6, 7, 8, 9] , which include functional (up to 80%) and non-functional pancreatic neuroendocrine tumors (43%), thymic carcinoid (25%), gastric carcinoid (up to 75%), and pulmonary neuroendocrine tumors (20-60%). Given the potential for a number of predictable life threatening malignancies in MEN-1, MEN1 gene mutation analysis is recommend for individuals at risk (Table 2) [3] . In addition, patients with established or suspected MEN-1 syndrome should be clinically monitored with certain guidelines (Table 3) [3] . Table 2. Criteria for Mutation Analysis of MEN1 Diagnosis of three of five major MEN-1- associated lesions First degree family members of MEN-1 patients with a confirmed MEN1 germline mutation, family members of clinical MEN-1 patients without an identified germline mutation or who declined mutation analysis First degree family members of asymptomatic MEN1 germline mutation carriers Suspected MEN-1 patients: 2/5 major MEN-I tumors >2 MEN-1-associated tumors within one organ MEN-1-associated lesion at a young age (<35 years) Table 3. Recommended Periodical Clinical Monitoring of MEN-1 Inclusion of: MEN-1 patients MEN-1 gene germline mutation carriers Suspected MEN-1 patients without a confirmed mutation From the age of 5 - Biannual clinical examination Laboratory investigation (calcium, chloride, phosphate, parathyroid hormone, glucose, insulin, c-peptide, glucagon, gastrin, pancreatic polypeptide, prolactin, IGF-I, serotonin and chromogranin A) From the age of 15 - Once every two years MRI of the upper abdomen, pituitary, and mediastinum in males (prophylactic thymectomy?) In Summary: Thymic carcinoid is not benign (on the contrary) Atypical features provide diagnostic clues Additional work up is necessary to ensure an accurate clinical and pathologic diagnosis A personal or family history of endocrine/neuroendocrine tumors or multiple endocrine tumors in one organ should elevate the threshold for consideration of MEN-1 In conclusion, in current pathology practice, it is the responsibility of the pathologist to provide recommendations based upon specific pathologic findings. This is a matter of practical necessity to facilitate multi-disciplinary clinical management of the disease and optimize outcome. References: Rosai J, Higa E, Davie J. Mediastinal endocrine neoplasm in patients with multiple endocrine adenomatosis. A previously unrecognized association. Cancer. Apr 1972;29 (4):1075-1083. Gibril F, Chen YJ, Schrump DS, et al. Prospective study of thymic carcinoids in patients with multiple endocrine neoplasia type 1. J Clin Endocrinol Metab. Mar 2003;88(3):1066-1081. Dreijerink KM, Lips CJ. Diagnosis and Management of Multiple Endocrine Neoplasia Type 1 (MEN1). Hered Cancer Clin Pract. 2005;3(1):1-6. Larsson C, Skogseid B, Oberg K, Nakamura Y, Nordenskjold M. Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature. Mar 3 1988;332(6159):85-87. Guru SC, Olufemi SE, Manickam P, et al. A 2.8-Mb clone contig of the multiple endocrine neoplasia type 1 (MEN1) region at 11q13. Genomics. Jun 15 1997;42(3):436- 445. Corbo V, Dalai I, Scardoni M, et al. MEN1 in pancreatic endocrine tumors: analysis of gene and protein status in 169 sporadic neoplasms reveals alterations in the vast majority of cases. Endocr Relat Cancer. Sep 2010;17(3):771-783. Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine Tumors. Science. Jan 20 2011. Tang LH, Klimstra DS. Conundrums and Caveats in Neuroendocrine Tumors of the Pancreas Surgical Pathology Clinic. 2011;in press. Leotlela PD, Jauch A, Holtgreve-Grez H, Thakker RV. Genetics of neuroendocrine and carcinoid tumours. Endocr Relat Cancer. Dec 2003;10(4):437-450.