Case 2 -

Metastatic Papillary Thyroid Carcinoma to Pancreas Jennifer A. Brainard

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Clinical History: An 82 year old man with history of recurrent bouts of pancreatitis and a large duodenal polyp underwent upper GI endoscopy. An endoscopic ultrasound showed diffuse changes of chronic pancreatitis as well as a mass in the neck of the pancreas. The mass obstructed the main pancreatic duct and encased splenic vessels. The duodenal polyp appeared stable. This patient had a history of papillary thyroid carcinoma in 2002 that penetrated the thyroid capsule to involve adjacent fat and muscle and was metastatic to regional lymph nodes. He is status post total thyroidectomy and radioactive iodine treatment in 2002. A jugular lymph node was positive for metastatic papillary thyroid carcinoma in 2005. Case 2 - Figure 1 The pancreatic aspirate sample is highly cellular with large fragments and numerous single cells. The large cohesive aggregates have a papillary architecture with central fibrovascular cores. Small groups and single cells appear to be falling off the large papillary structures. Case 2 - Figure 2 The pancreatic aspirate sample is highly cellular with large fragments and numerous single cells. The large cohesive aggregates have a papillary architecture with central fibrovascular cores. Small groups and single cells appear to be falling off the large papillary structures. Case 2 - Figure 3 The cell population is monotonous. Cohesive papillary fragments and syncytial aggregates are seen. Occasional tumor cells have a plasmacytoid appearance. Blood and occasional stripped nuclei are present in the background. Case 2 - Figure 4 The individual cells comprising the syncytial groups have high N/C ratios, fine chromatin and inconspicuous nucleoli. Histiocytes are seen here, suggestive of a cystic component. Case 2 - Figure 5 Overlapping nuclei with nuclear grooves and membrane irregularities are prominent in this aggregate. Still, many of the nuclear changes are subtle and not typical of pancreatic ductal adenocarcinoma. Case 2 - Figure 6 There is minimal variability in tumor cell morphology from field to field. Occasional tumor cells with intranuclear cytoplasmic inclusions are seen. Case 2 - Figure 7 The cell block highlights the uniformity and relative blandness of the cell population. The cells are arranged in strips. The major contribution of the cell block is to provide material for immunohistochemical staining. Cytologic Diagnosis: Papillary carcinoma, consistent with metastatic papillary thyroid carcinoma. Histology Diagnosis: There is no corresponding histologic diagnosis for the pancreas tumor. The duodenal mass is a tubulovillous adenoma. Cytologic Findings: The pancreatic mass yielded a highly cellular sample of tumor cells with a conspicuous papillary architecture at low magnification. In addition to papilla, tumor cells are arranged in syncytial aggregates and scattered singly in the background. Occasional histiocytes are present, consistent with cystic change. The tumor cell population is monotonous with high N/C ratios, fine powdery chromatin and small nucleoli. Nuclear changes characteristic of papillary thyroid carcinoma are identified. Nuclear folds and grooves are prominent. Occasional cells show intranuclear cytoplasmic inclusions. The tumor cells in the cell block are positive for thyroglobulin and TTF-1. Discussion: Metastatic tumors involving the pancreas are infrequent, accounting for 3%-16% of pancreatic tumors. Pancreatic involvement is usually a consequence of disseminated metastatic disease. Metastatic lesions in the pancreas may be single, multiple or diffuse and there is no site predilection. Occasionally, as in this case, a metastasis may mimic a pancreatic primary. The most common tumors to secondarily involve the pancreas include melanoma, lymphoma and carcinomas of the lung, kidney, gastrointestinal tract and ovary. Fine needle aspiration is an important tool in the setting of metastatic and hematologic malignancies involving the pancreas, as it may obviate the need for open biopsy or resection. Papillary thyroid carcinoma is the most common malignancy of the thyroid gland. Though many of these tumors metastasize to regional lymph nodes, distant metastasis is infrequent. Fewer than 10% of patients with papillary thyroid carcinoma have distant metastatic disease at some point in their course. Lung and bone are the two most common sites. Some histologic variants of papillary thyroid carcinoma, such as the tall cell variant, are known to follow a more aggressive course. Pancreatic involvement by metastatic papillary thyroid carcinoma is distinctly uncommon as evidenced by only a rare case report in the literature. While this case of metastatic papillary thyroid carcinoma to the pancreas is quite rare, it serves to highlight a number of useful points. First, it is important to consider the possibility of a metastatic lesion involving the pancreas whenever a neoplasm on pancreatic fine needle aspiration is not typical of ductal adenocarcinoma. Clinical information as well as review of prior pathology case material may prove invaluable. Immunohistochemistry is still often necessary in this setting, which argues for routine preparation of cell block material of pancreatic FNA specimens. Second, the possibility of more than one primary tumor in a given patient should remain a consideration. Third, this case illustrates a differential diagnosis that includes important non-ductal neoplasms of the pancreas, such as solid-pseudopapillary neoplasm, pancreatic acinar cell carcinoma and neuroendocrine carcinoma. These are pancreatic primary neoplasms that share overlapping cytomorphologic including relatively monotonous and often low grade nuclei. They vary clinically and have distinct immunohistochemical staining patterns. Solid-pseudopapillary neoplasms of the pancreas are uncommon tumors accounting for 1-2% of exocrine pancreatic tumors. The overwhelming majority of patients are women. These tumors occur over a wide age range, but are most common in young women with an average age of 25 years. Fewer than 10% of cases occur in men. On imaging, solid-pseudopapillary neoplasms are large, well circumscribed, partially cystic and most commonly located in the body and tail. Clinically they behave as benign tumors or low grade malignancies. Metastases, usually to the liver or peritoneum, are present in 10-15%. Lymph node metastases are rare. Even patients with metastases tend to follow a long indolent course. The overall mortality of this tumor is estimated at approximately 2%. Older patients and males may follow a more aggressive clinical course. Surgical resection with a negative margin is the treatment of choice and is often curative. Fine needle aspiration of solid-pseudopapillary neoplasms is useful for preoperative diagnosis. False negative results may occur due to cystic degeneration, hemorrhage or necrosis. These tumors often yield highly cellular aspirate samples with papillary architecture with tumor cells lining fibrovascular cores with prominent capillaries. Small groups and single tumor cells commonly appear to be falling off the adjacent papilla. Histiocytes consistent with cyst contents, blood and debris are often present in the background. Psammoma bodies may be seen. Intracytoplasmic eosinophilic hyaline globules are also frequently reported. Individual tumor cells are characteristically small, bland and uniform with round nuclei and moderate amounts of granular cytoplasm. Nuclear grooves are commonly seen. Nucleoli are inconspicuous. Intranuclear inclusions are not described. Mitoses are not identified in most cases, but may point to the rare biologically aggressive neoplasm. By immunohistochemistry, solid-pseudopapillary neoplasms are positive for vimentin, alpha-1-antitrypsin and neuron-specific enolase. Focal cytokeratin positivity may be seen. These tumors show diffuse cytoplasmic and nuclear reactivity for beta-catenin. Progesterone receptor positivity is common in tumors in women but not men. Acinar cell carcinoma of the pancreas is rare, accounting for 1-2% of non-endocrine pancreatic tumors. As the name implies, these tumors show acinar differentiation. The majority of acinar cell carcinomas occur in adult men, with an average age of 55-65 years. There is no site predilection within the pancreas. On imaging, these tumors are large with an average size of 10cm, solitary and well circumscribed. Hemorrhage, necrosis and cystic change may be evident. Acinar cell carcinoma is an aggressive disease, with an average survival of 18 months, and 5 year survival less than10%. About 50% of patients have metastases at the time of diagnosis. Aspirate samples from acinar cell carcinomas are generally highly cellular with prominent loss of cellular cohesion resulting in numerous small loose clusters of cells and single tumor cells. Acinar structures with central lumens are commonly seen. The individual tumor cells have moderate amounts of granular or finely vacuolated cytoplasm, round to oval uniform eccentric nuclei with only slight nuclear membrane irregularities and prominent nucleoli. The nuclear chromatin of tumor cells is described as irregularly clumped. This is to help distinguish acinar cell carcinoma from neuroendocrine tumors with finely granular, "salt and pepper" chromatin. Acinar cell carcinomas stain diffusely, strongly positive for pancytokeratin and at least one of the pancreatic enzyme markers: trypsin, lipase, and chymotrypsin. Trypsin positivity is most common. Neuroendocrine markers and vimentin are negative. Pancreatic endocrine neoplasms are also uncommon and account for less than 2% of pancreatic neoplasms. Though these tumors may occur at any age, they are most common in adults and >90% occur in patients over 30 years old. Most are functional tumors that cause symptoms related to the hormone that is produced, most commonly insulin or gastrin. Between 20%-40% of these tumors are nonfunctional, and may be more difficult to diagnose. Most pancreatic endocrine tumors are located in the body and tail of the pancreas. A cystic component may be seen. Surgical resection is the mainstay of treatment. Aspirate samples from endocrine tumors are generally highly cellular and homogeneous. Single cells often predominate. Small loose clusters of tumor cells as well as syncytial groups with indistinct cell borders are common. Cells may also be arranged in pseudorosettes. Histiocytes indicative of cystic degeneration may ve seen. Moderate amounts of cytoplasm and an eccentrically placed nucleus imparts the characteristic "plasmacytoid" appearance of tumor cells. Red cytoplasmic granules may be seen in Diff Quik stains. Nuclei are round and uniform with finely stippled chromatin. Nucleoli are inconspicuous, but small nucleoli may be seen. Tumor cells may be binucleate. Pancreatic neuroendocrine neoplasms are characteristically positive for the neuroendocrine markers chromogranin, synaptophysin, neuron-specific enolase and CD56. They are also positive for CAM 5.2. These tumors do not express pancreatic enzyme markers. Solid-pseudopapillary neoplasms, acinar cell carcinoma and pancreatic endocrine tumors have overlapping cytologic features and usually consist of cellular samples of low grade tumor cells. 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