Case 7 -

Metastatic Carcinoma with Neuroendocrine Features Rana Hoda New York Presbyterian Hospital Weill Cornell Medical College New York, NY

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Clinical History Ultrasound-guided fine needle aspiration of left lobe of liver in a 54 year-old woman with multiple liver lesions. All images are from a Diff-Quik-stained touch imprint cytology of needle core biopsy. Case 7 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 7 - Figure 1 DiffQuik 10x Case 7 - Figure 2 DiffQuik 20x Case 7 - Figure 3 DiffQuik 40x Case 7 - Figure 4 DiffQuik 40x Case 7 - Figure 5 DiffQuik 40x Case 7 - Figure 6 DiffQuik 40x Case 7 - Figure 7 DiffQuik 60x Case 7 - Figure 8 DiffQuik 60x Case 7 - Figure 9 DiffQuik 60x Case 7 - Figure 10 DiffQuik 60x Cytological Diagnosis: Metastatic carcinoma with neuroendocrine features. Histological Diagnosis: Metastatic carcinoma with neuroendocrine features. Further history was elicited. Patient had a history of a recurrent pituitary carcinoma. The tumor was initially resected three years ago. A ventriculo-peritoneal shunt (VPS) was placed in early 2008 due to increased intracranial pressure. Patient presented at our institution in late 2008 with multiple liver, lung and bone lesions. Comparative review of prior material showed histological and immunohistochemical similarity to the tumor in the liver. Discussion: Adenomas originating from adenohypophysial cells are the most common neoplasms of pituitary. Other less common lesions include mesenchymal, neural, epithelial or metastatic tumors and other tumor-like growths, such as cystic and inflammatory lesions [1]. Pituitary tumors represent 10-15% of intracranial neoplasms and are most common in adults. Small incidental tumors frequently occur in autopsy material and in up to 20% in unselected MRI series. There are age and gender differences regarding incidence of various types of adenomas. Prolactin (PRL)-producing adenomas are most frequently seen in adults and gonodotroph adenomas in elderly. The cure rate for microadenomas is high (65-85%); however patients with large PRL-secreting adenomas associated with mass effects, such as sudden visual defects are treated with surgery. Majority of pituitary adenomas are single; multiple adenomas occur in <1% in surgical and autopsy series [1]. Most pituitary adenomas are slow growing tumors with few if any mitoses. Assessment of light microscopic, ultrastructural, immunohsitochemistry and DNA content may be indicative of aggressiveness and malignant potential. Ki-67 antigen is commonly used to classify pituitary tumors as it correlates with invasiveness and probably prognosis. Ki-67 is a proliferation marker that is expressed through all cell cycle phases except the early G1 phase and can be assessed by MIB-1 immunostain. Indices of MIB-1 are often increased in invasive adenomas and are high in carcinomas. The p53 tumor suppressor gene is thought to play a role in the development or evolution of adenophypophyseal neoplasms. Some invasive adenomas and carcinomas show extensive p53 immunohistochemical expression, although, mutations of p53 tumor suppressor gene have not been detected [1]. According to WHO classification, adenomas with increased (>3%) Ki-67 index and extensive p53 immunoreactivity should be termed "atypical adenomas" signifying the potential for aggressive behavior or malignant transformation [2]. Adenomas with Ki-67 index of >10%, regardless of p53 immunostaining and atypical adenomas should be closely followed. Pituitary carcinomas show a consistently high Ki-67 index and extensive p53 immunostaining in comparison to adenomas. Therefore, Ki-67 represents a predictive factor for these tumors. Pituitary Carcinoma, Important Features Rare, 0.1 - 0.2% of all pituitary tumors. To date 140 cases have been reported in English literature. Pituitary carcinoma is defined as primary neoplasms of adenohypophysis that undergo craniospinal (to any part of the brain) and/or systemic spread (to liver, lung, bones, lymph nodes). Liver is the most common site of extracranial metastasis. Pathobiology of systemic metastasis remains uncertain (please see below). Morphological separation of pituitary adenoma from carcinoma is not possible. Affects adults, age range 34 -71 years (mean 56 years), no gender predilection. Time interval between the diagnosis of pituitary adenoma and that of metastatic carcinoma is variable, ranging from 4 months to 18 years (mean 6.6 years). Longest interval is for ACTH-producing tumors. All tumors show tendency towards systemic spread; PRL cell > ACTH tumors: 71% vs. 57%. Metastases from the tumor include dissemination throughout the subarachnoid space and lymphatics. Hematogenous dissemination is rare and primarily seen in ACTH-producing carcinomas. Histologically, the tumor shows a monotonous proliferation of cells with uniform nuclei, inconspicuous nucleoli and low mitotic activity, with varying degrees of cellular pleomorphism. Generally, the cytologic atypia and mtitotic rate is higher in metastatic vs. primary tumors. Focal necrosis may be present. Immunoreactivity for pituitary hormones may vary. When present, the ACTH-producing carcinomas showed diffuse cytoplasmic staining for ACTH, whereas, the PRL-producing carcinomas showed a juxtanuclear, globular or Golgi-pattern of PRL immunoreactivity. Staining for MIB-1 can be detected in almost all primary and metastatic tumors. Immunostaining for p53 is also present. Treatment consists of pituitary surgery and radiation. For metastatic disease surgical decompression, radiation, dopamine antagonists and combination chemotherapy are used. Pituitary carcinomas are associated with a poor prognosis. They have a poor response to treatment and die within one year of the disease. Further studies are needed to identify pathologic parameters that are reliable for prognosis, and to develop more effective treatment modalities Pathophysiology of Systemic Metastasis of Pituitary Carcinoma The mechanism remains uncertain due to rarity of the tumor. Like other neoplasms, pituitary carcinoma must have the ability to adhere to and degrade a variety of extracellular matrix materials, thereby permitting access to vascular spaces and subsequent embolization. Environment in which foci of metastatic tumors come to rest probably determines whether they grow as viable metastases or fail to survive. This chain of event may need to be repeated in order to ensure establishment of viable tumor deposits. Tumor cells shed by invasive carcinomas of the cavernous sinus could readily access the petrosal sinus and jugular vein and then metastasize to lung and other organs. Lymphatic invasion within the sphenoid sinus could underlie cervical lymph node metastases. In analogy to the systemic spread of gliomas, surgical intervention may play a role in promoting metastasis. It is not known if the hormonal subtype, tumor size and frequency of invasiveness affect prognosis [3]. Adenoma-to-Carcinoma Transformation A proportion of pituitary carcinomas may develop from adenomas. Mean interval is 6.5years between the diagnosis of adenoma and occurrence of metastasis. Possible evidence of adenoma-to-carcinoma sequence is most compelling in cases of Nelson's syndrome in which the interval between adenoma-to-carcinoma is 15 years. Although, it is recognized that majority of corticotrophic adenomas associated with Nelson's syndrome are aggressive, 2/3rd being invasive macroadenomas, only a small subset appear to undergo malignant transformation by the acquisition of metastatic potential. Increased proliferation indices are also seen in metastasis compared to adenomas. The increase in percentage of nuclear staining for p53 oncoprotein in metastatsis as compared to pituitary tumors further supports the stepwise evolution to carcinoma, from an invasive intrasellar lesion to a tumor capable of metastasis [3]. VPS-related Systemic Metastasis Internal drainage of cerebrospinal fluid to the abdominal or pleural cavities via a ventriculoperitoneal or ventriculopleural shunt (VPS) is a common procedure for therapy of obstructive hydrocephalus. Because this condition is often caused by brain tumors blocking the natural cerebrospinal fluid pathways, the VPS, as an artificial anastomosis, can provide the means for the spreading of tumor cells via the cerebrospinal fluid. The most common brain tumors to metastasize via VPS include germinomas, medulloblastomas, endodermal sinus tumors and rarely glioblastomas. Most cases with VPS-related metastasis involve omentum and/or peritoneum, sometimes in direct proximity to the tip of the catheter [4]. Pituitary carcinoma shows distant cerebrospinal and/or systemic metastases. Liver is the most common site of systemic spread. Our patient had a clinical history of long-standing PRL-producing pituitary adenoma which was resected. The tumor subsequently recurred with increasingly aggressive histology and underwent four transnasal and transsphenoidal resections. Subsequently the tumor progressed to pituitary carcinoma with development of liver, lung, bone and lymph nodes metastases. The patient had a VPS placement, however, no involvement of either perioteneum or omentum was noted. Please see pathophysiology of systemic metastasis of pituitary carcinoma (above). In Our Case: Initially presented with clinical features of PRL-secreting tumor which was histologically diagnosed as pituitary adenoma with neuroendocrine features. Patient had four recurrences and underwent repeated resections by a skull-based approach over a 3-year-period. After an interval of 3 years the patient developed systemic metastases. References: Kontogeorgos G. Classification and pathology of pituitary tumors. Endocrine. 2005 Oct;28(1):27-35. Review. Lloyd, R. V., Kovacs, K., Young, W. F. Jr., et al. (2004). In: WHO classification of tumors of the endocrine organs: Pathology and genetics of endocrine organs. DeLellis, R. A., Heitz, P., Lloyd R. V., and Eng, C. (eds.). IARC Press: Lyon, France. Pernicone PJ, Scheithauer BW, Sebo TJ, Kovacs KT, Horvath E, Young WF Jr, Lloyd RV, Davis DH, Guthrie BL, Schoene WC. Pituitary carcinoma: a clinicopathologic study of 15 cases. Cancer. 1997 Feb 15;79(4):804-12. Bilic M, Welsh CT, Rumboldt Z, Hoda RS. Disseminated primary diffuse leptomeningeal gliomatosis: a case report with liquid based and conventional smear cytology. Cytojournal. 2005 Sep 20;2:16.