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Hypothalamic Vasopressin-Producing Tumors ORIGINAL ARTICLE Hypothalamic Vasopressin-Producing Tumors Often Inappropriate Diuresis But Occasionally Cushing Disease Sylvia L. Asa, MD, PhD,* Shereen Ezzat, MD,* Daniel F. Kelly, MD,† Pejman Cohan, MD,† 01/11/2019 on wQNKnv7CnbFJfsqMCBLY6Mv0gwMwzbd0t7buQgP7tOuYLvaPeYOQet1vMRfU5tCGYX+q0k9T6jI8ASCxm4qKm5OVKZR+I0JM4TZcmgfx7Dld9GipwRFmjaJDvfXvlSrC by http://journals.lww.com/ajsp from Downloaded Yuki Takasumi, MD,† Garni Barkhoudarian, MD,† Anthony P. Heaney, MD,‡ Downloaded Rowena Ridout, MD,* Constance L. Chik, MD, PhD,§ Lester D.R. Thompson, MD,∥ Fred Gentili, MD,* and Ozgur Mete, MD* from http://journals.lww.com/ajsp also can result in divergent clinical manifestations, one charac- Abstract: Tumors of hypothalamic neurons that produce vaso- by terized by reduced urine output and the other by the more insidious wQNKnv7CnbFJfsqMCBLY6Mv0gwMwzbd0t7buQgP7tOuYLvaPeYOQet1vMRfU5tCGYX+q0k9T6jI8ASCxm4qKm5OVKZR+I0JM4TZcmgfx7Dld9GipwRFmjaJDvfXvlSrC pressin are rare. We retrieved all cases of vasopressin-positive tu- features of glucocorticoid excess. mors in the sellar region from the database of the Department of Pathology. Five cases fulfilled the selection criteria, representing Key Words: vasopressin, hypothalamus, pituitary, tumor, syn- the first series of such tumors. Clinical, radiologic, and pathologic drome of inappropriate antidiuresis (SIAD), Cushing disease fi features were reviewed. Four tumors classi ed as neurocytomas (Am J Surg Pathol 2019;43:251–260) were identified in 3 females and 1 male patient; the ages at onset of symptoms ranged from 17 to 40 years. All were large sellar masses with suprasellar extension and/or invasion of the parasellar sinuses. umors of the sella turcica include a large number of Three patients had the syndrome of inappropriate antidiuresis; in entities.1 By far the most common are the epithelial ne- one of these, a 6-year history was initially considered to be idio- T oplasms of hormone-secreting adenohypophysial cells that pathic. One patient died of progressive disease; 3 had incomplete can be associated with hormone excess, such as prolactino- resections and are being followed. In contrast to these patients with mas or tumors giving rise to acromegaly or Cushing disease, neurocytoma, a 65-year-old woman had Cushing disease and a 0.8 or clinically nonfunctioning tumors that may produce hor- cm mass that was completely resected at transsphenoidal surgery; mones but do not give rise to clinical or biochemical features this tumor was a gangliocytoma producing vasopressin associated of pituitary hormone excess. The latter group can cause with corticotroph hyperplasia. We postulate that the small amount headache, visual symptoms, and hypopituitarism. of vasopressin secreted by this mature gangliocytic tumor was lo- Other lesions occur in the region of the pituitary. cally bound to corticotrophs, resulting in hyperplasia and Cushing These include cysts, inflammatory lesions and tumors of disease, without sufficient overproduction to cause systemic effects other cell types, including craniopharyngiomas, pituicyto- of vasopressin excess. Hypothalamic neurocytoma is a tumor that mas, gliomas, germ cell tumors, mesenchymal and hema- can mimic pituitary neuroendocrine tumors and olfactory neuro- topoietic proliferations, and metastatic malignancies.1 The blastoma but is distinguished by positivity for neurofilaments, manifestations of these various entities can overlap with NeuN, and TTF-1 and negative staining for adenohypophysial hormone-secreting tumors. Through interference with tonic biomarkers. Our cases illustrate that neurocytoma and gangliocy- inhibition of prolactin, they cause hyperprolactinemia. Some toma are 2 variants of tumors of hypothalamic neurons that can interfere with neurohypophysial function, giving rise to dia- produce vasopressin. The morphologic and proliferative features of betes insipidus. However, excess production of vasopressin these 2 tumor types represent 2 ends of a spectrum; their function (antidiuretic hormone, ADH) associated with sellar tumors on 01/11/2019 is exceedingly rare. From the *Endocrine Oncology Site Group, Princess Margaret Cancer The syndrome of inappropriate antidiuresis (SIAD), Centre, University Health Network, Toronto, ON, Canada; §De- partment of Medicine, Division of Endocrinology, University of Al- formerly known as syndrome of inappropriate ADH secretion berta, Edmonton, AB; †Pacific Brain Tumor Center & Pituitary (SIADH), is associated with excess vasopressin production by Disorders, John Wayne Cancer Institute at Providence Saint John’s tumors, usually small cell lung carcinomas2 but also other Health Center; ‡Department of Endocrinology, University of Cal- ectopic sources.3 It also may be due to medications; in addi- ∥ ifornia, Los Angeles; and Department of Pathology, Southern Cal- tion to anticancer therapies, many classes of medications can ifornia Permanente Medical Group, Woodland Hills, CA. fl Conflicts of Interest and Source of Funding: The authors have disclosed also lead to SIAD such as nonsteroidal anti-in ammatory 2 that they have no significant relationships with, or financial interest drugs, antiseizure medications and some psychotropic agents. in, any commercial companies pertaining to this article. Itcanbeattributedtoheadtrauma,4 and occurs in hospi- Correspondence: Sylvia L. Asa, MD, PhD, Department of Pathology, talized patients due to poorly understood mechanisms.5 Here, University Health Network, Laboratory Medicine & Pathobiology, University of Toronto, 200 Elizabeth Street, 11th floor, Toronto, ON, we report a series of 5 patients with sellar lesions producing Canada M5G 2S3 (e-mail: [email protected]). vasopressin that resulted in 2 distinct manifestations, usually Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. SIAD, but in one case, with Cushing disease. These tumors Am J Surg Pathol Volume 43, Number 2, February 2019 www.ajsp.com | 251 Copyright r 2018 Wolters Kluwer Health, Inc. All rights reserved. Asa et al Am J Surg Pathol Volume 43, Number 2, February 2019 TABLE 1. Clinical and Radiologic Features of Sellar Tumors Producing Vasopressin Age at Onset (y) Sex Presentation Recurrence Location Tumor Pathology 39 F 6 y history of idiopathic Unknown Focally calcified 3 cm sellar mass with suprasellar Neurocytoma SIADH extension and cavernous sinus invasion 34 F Galactorrhea, amenorrhea, Multiple Sellar mass with erosion of the sellar floor by a Neurocytoma hyponatremia recurrences contrast-enhancing tumor that also extended (superiorly into the suprasellar cistern 17 M Nausea, vomiting, dysarthria, Stable residual Focally calcified sellar mass with cavernous Neurocytoma hyponatremia sinus invasion 40 F Sellar mass with visual Recurrence Sellar mass invading right cavernous sinus and Neurocytoma disturbance and headache requiring encasing ICA; suprasellar nodule abutting the reoperation floor of the third ventricle 65 F Cushing disease Unknown Intrasellar 0.8 cm microtumor Gangliocytoma with corticotroph hyperplasia F indicates female; M, male. were all neoplasms of hypothalamic neuronal lineage but Laboratories), vasopressin (ADH; T-4563, Peninsula), and showing different degrees of differentiation, distinct pro- Ki-67 (MIB-1, Dako). The Ki-67 labeling index (LI) was liferative capacities and levels of hormone production and calculated as the percentage of positive cells over total nuclei secretionthatresultedinmarkedly distinct clinical manifes- based on manual counts of printed images that included at tations. least 500 cells. Not all stains were performed on all cases, as in 2 instances (cases 4 and 5), the material was insufficient for MATERIALS AND METHODS complete analysis. Cases were retrieved from the archives of the Depart- ment of Pathology of a tertiary referral center between 2001 RESULTS and 2017 with the approval of the University Health Network The 5 tumors occurred in 4 females and 1 male (Table 1). Research Ethics Board. The selection criteria included all cases The age range was 17 to 65 years. of vasopressin-positive tumors in the region of the hypothal- Four tumors classified on pathology as neurocytomas amus and sella turcica. Five cases were identified as fulfilling were identified in 3 females and 1 male patient whose age at the selection criteria. Clinical, radiologic, and pathologic fea- onset of symptoms ranged from 17 to 40 years. Three had tures were reviewed. Consent to publish their case was ob- clinical features of vasopressin excess with SIAD; the history tained from 4 patients after full explanation of the purpose and of the fourth patient is incomplete. The tumors were large and nature of this publication; the details of the fifth patient who focally calcified sellar masses; all had suprasellar extension could not be reached are abbreviated to ensure confidentiality. and/or invasion of the cavernous and sphenoid sinuses. Three The following immunostains were performed: synapto- patients have persistent disease and are being followed; one physin (27G12; Novocastra), chromogranin A (polyclonal; died of progressive disease. Dako), neurofilaments (M076229-2, Dako), neuronal nuclear In contrast, 1 patient, a 65-year-old woman, had antigen (NeuN; MAB 377(CH), Millipore), S100 protein Cushing disease and a 0.8 cm sellar gangliocytoma producing (polyclonal, Dako), glial fibrillary acidic protein (GFAP; 6F2, vasopressin associated with corticotroph hyperplasia; she had Dako), epithelial membrane antigen (EMA; E29, Roche), no clinical evidence of vasopressin excess. She has had an calretinin
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