Multiple endocrine neoplasia in a sheep: insulinoma, adrenocortical carcinoma with myxoid differentiation, and thyroid C-cell carcinoma.

An ~10-y-old male sheep had anorexia and progressive weight loss for ~1 mo. The sheep was emaciated, and 20 d later, became recumbent and lethargic, and was hypoglycemic (0.33 mmol/L; RI: 2.6-4.4 mmol/L). The sheep was euthanized because of poor prognosis, and submitted for autopsy. We found no gross lesions in the pancreas; however, histologically, focal proliferations of round-to-polygonal cells were separated by connective tissue into small nests. These proliferating cells, which had abundant eosinophilic-to-amphophilic cytoplasm and hyperchromatic nuclei, were immunopositive for insulin and negative for glucagon and somatostatin; the lesion was diagnosed as an insulinoma. Insulinoma has not been reported previously in sheep, to our knowledge. In addition, autopsy and histologic examination revealed the presence of an adrenocortical carcinoma with myxoid differentiation and a thyroid C-cell carcinoma. Our case indicates that multiple endocrine neoplasms can occur in sheep, as in other animal species.

Concurrent endocrine neoplasias in dogs and cats: a retrospective study (2004-2014).

Multiple endocrine neoplasia (MEN) is a well-known syndrome in human medicine, whereas only a few cases of concurrent endocrine neoplasias have been reported in dogs and cats. The aim of this study was to evaluate the prevalence of concurrent endocrine neoplasias in dogs and cats at our clinic, identify possible breed and sex predispositions and investigate similarities with MEN syndromes in humans. Postmortem reports of 951 dogs and 1155 cats that died or were euthanased at the Clinic for Small Animal Internal Medicine, University of Zurich, between 2004 and 2014 were reviewed, and animals with at least two concurrent endocrine neoplasias and/or hyperplasias were included. Twenty dogs and 15 cats met the inclusion criteria. In dogs, the adrenal glands were most commonly affected. Multiple tumours affecting the adrenal glands and the association of these tumours with pituitary adenomas were the most common tumour combinations. Only one dog had a combination resembling human MEN type 1 syndrome (pituitary adenoma and insulinoma). In cats, the thyroid glands were most commonly affected and there were no similarities to human MEN syndromes. The prevalence of concurrent endocrine neoplasia was 2.1 per cent in dogs and 1.3 per cent in cats and MEN-like syndromes are very rare in these species.

Animal models of multiple endocrine neoplasia.

Multiple endocrine neoplasia (MEN) syndromes are autosomal dominant diseases with high penetrance characterized by proliferative lesions (usually hyperplasia or adenoma) arising in at least two endocrine tissues. Four different MEN syndromes have been so far identified: MEN type 1 (MEN1), MEN2A (also referred to as MEN2), MEN2B (or MEN3) and MEN4, which have slightly varying tumor spectra and are caused by mutations in different genes. MEN1 associates with loss-of-function mutations in the MEN1 gene encoding the tumor suppressor menin. The MEN2A and MEN2B syndromes are due to activating mutations in the proto-oncogene RET (Rearranged in Transfection) and are characterized by different phenotypic features of the affected patients. MEN4 was the most recent addition to the family of the MEN syndromes. It was discovered less than 10 years ago thanks to studies of a rat strain that spontaneously develops multiple endocrine tumors (named MENX). These studies identified an inactivating mutation in the Cdkn1b gene, encoding the putative tumor suppressor p27, as the causative mutation of the rat syndrome. Subsequently, germline mutations in the human ortholog CDKN1B were also found in a subset of patients with a MEN-like phenotype and this led to the identification of MEN4. Small animal models have been instrumental in understanding important biochemical, physiological and pathological processes of cancer onset and spread in intact living organisms. Moreover, they have provided us with insight into gene function(s) and molecular mechanisms of disease progression. We here review the currently available animal models of MEN syndromes and their impact on the elucidation of the pathophysiology of these diseases, with a special focus on the rat MENX syndrome that we have been characterizing.

Malignant paraganglioma in a cougar (Puma concolor).

A 7½-yr-old male cougar (Puma concolor) was presented with a 2-wk history of progressive hindlimb abnormalities. An abdominal mass was palpated on physical examination. Computed tomography of the abdomen showed a mass surrounding the left ureter. A postmortem diagnosis of paraganglioma was established.

Potential variant of multiple endocrine neoplasia in a dog.

This report describes multiple endocrine neoplasia in a dog, which is a rare hereditary disorder characterized by the presence of two or more neoplasms of different endocrine tissues within a patient. A 14 yr old dog was evaluated for polyuria/polydipsia, polyphagia, and abdominal enlargement. Adrenal-dependent hyperadrenocorticism with concomitant left thyroid enlargement and a presumed abdominal metastatic lesion were diagnosed by an adrenocorticotropic hormone stimulation test, ultrasonography, and computed tomography. Trilostane therapy was initiated and resolved the clinical signs for 2 yr at which time the dog presented with left testicular enlargement. The dog was euthanized and was diagnosed with adrenocortical carcinoma, thyroid carcinoma, an abdominal mass compatible with a metastatic lymph node, and bilateral interstitial cell testicular adenomas. To the authors' knowledge, this is the first report to describe the concomitant association of these types of endocrine neoplasms in a dog. The concomitant presence of these neoplasms could represent a potential variant of multiple endocrine neoplasia; however, the presence of the interstitial cell testicular adenomas may have only been an incidental finding. If any of these tumors are diagnosed, veterinarians should perform a thorough clinical assessment to evaluate for the presence of additional endocrine neoplasms or hyperplasia.

A dog pedigree with familial medullary thyroid cancer.

Multiple endocrine neoplasia (MEN) is defined as concurrent neoplasia or hyperplasia in more than one endocrine gland. MEN is well known in humans and has also been reported in small animals. We report on a dog family of a mixed breed with Alaskan malamute as a major influence, where three members developed thyroid carcinomas and another dog had clinical signs mimicking the other three but without a confirmed diagnosis. The age of onset of the tumour was between 96-109 months. Clinical, biochemical and immunohistochemical examinations revealed that the affected individuals typically demonstrated symptoms including calcitonin positive thyroid cancer, hypothyroidism and chronic dermatitis. In addition, elevated serum calcium and multinodular adrenocortical hyperplasia were demonstrated in a single member. The diagnosis observed is similar to the familial form of medullary thyroid carcinoma (FMTC) in human. This is the first report of FMTC in dog. Up to 95% of FMTC and MEN2 is known to be caused by activating mutations in the RET gene. The dog Ret gene was analysed as a candidate in this pedigree. The complete dog Ret genomic sequence was predicted in silico. The lack of demonstratable Ret mutation suggests the involvement of alternative predisposing mutation in this pedigree. The unique occurrence of familial MTC makes this potentially an important model in further defining the genetic basis of MTC.

Multiple endocrine neoplasia type I in a cat.

A 13-year-old 4.6-kg (10.2-lb) neutered male domestic long hair cat was evaluated because of a history of lethargy, exercise intolerance, and ventroflexion of the cervical portion of the vertebral column. After extensive assessment at the Veterinary Teaching Hospital at Michigan State University, the clinical signs were attributed to an aldosterone-secreting tumor of the adrenal gland. Subsequently, an insulin-secreting tumor of the pancreas as well as a functional parathyroid gland adenoma were diagnosed. All 3 masses were surgically removed, and the cat made a full recovery with complete resolution of clinical signs. The syndrome of multiple endocrine neoplasia is well described in humans, and the heritability of the condition has been confirmed. In cats and other species with 1 or more endocrine neoplasms, it is important to perform thorough clinical assessments of patients to identify other endocrine organs that may also be affected concurrently with neoplastic disease.

Concurrent gastrinoma and somatostatinoma in a 10-year-old Portuguese water dog.

Severe hypergastrinaemia in the dog is considered a strong indicator for a gastrin-producing pancreatic islet cell tumour. In human medicine, gastrinomas are described as enteropancreatic neuroendocrine tumours that cause the Zollinger-Ellison syndrome. However, in contrast to the supposed origin of canine gastrinomas in pancreatic islets, gastrinomas in human beings arise predominantly in the duodenum and gastric antrum, and are often a component of the syndrome of multiple endocrine neoplasia type I. This report is of a canine case of multiple endocrine neoplasms, consisting of a pancreatic islet cell somatostatinoma, and a gastrinoma in the mesenteric lymph nodes and liver. From the literature and the authors' findings, it is concluded that the clinical diagnosis of hypergastrinaemia is not pathognomonic for a gastrin-producing islet cell tumour. Furthermore, the presence of an islet cell tumour in the face of hypergastrinaemia does not warrant a diagnosis of an islet cell gastrinoma. Immunohistochemistry is necessary to confirm the diagnosis of a pancreatic islet cell gastrinoma.

Mapping of a novel MEN-like syndrome locus to rat chromosome 4.

Multiple endocrine neoplasia-like syndrome (MENX) is a hereditary cancer syndrome in the rat characterized by inborn cataract and multiple tumors affecting the neuroendocrine system developed within the first year of life. The spectrum of affected organs is intermediate between MEN type 1 (MEN1) and MEN type 2 (MEN2) syndromes in human, but, in contrast to them, MENX is inherited in a recessive fashion. Here we report the mapping of the MENX locus to rat Chromosome (Chr) 4 by a genome-wide linkage analysis. This analysis was done in 41 animals obtained from a (Wistar/Nhg x SDwe) x SDwe interstrain backcross, where SDwe (Sprague-Dawley white eye) indicates the affected animals. The MENX disease locus was ultimately mapped to a approximately 22-cM interval on Chr 4 that includes the rat homolog of the human RET proto-oncogene. As activating point mutations of RET are known to be responsible for MEN2 in human, we analyzed several markers located in the proximity of Ret for linkage to the disease phenotype. Our data exclude Ret involvement in MENX and establish that a second gene, playing a role in endocrine tumor formation, lies within the distal part of rat Chr 4. Although heritable human endocrine tumors are quite rare, sporadic tumors of MEN-affected tissues occur at a much higher frequency, and their pathogenesis is poorly understood. The identification of the MENX gene should contribute to our understanding of the genetic mechanisms of neuroendocrine tissue tumorigenesis and may assist in developing new and more appropriate therapeutic strategies for these diseases.

Endocrine tumors.

Because of the diverse nature of endocrine organs, and their vast range of physiologic functions, endocrine tumors encompass a wide range of origination sites and disease entities. The clinical picture of affected individuals is highly dependent on the tissue of origin, and the presence or absence of functional hormone secretions. Identification, localization, and therapeutic strategies, as well as prognosis can vary greatly. Many endocrine tumors have been described in human as well as veterinary patients. This article focuses on endocrine tumors of dogs and cats. Various tumors affecting the pancreas, thyroid, parathyroid, adrenal and pituitary glands are described, including insulinoma, gastrinoma, glucagonoma, and thyroid carcinoma, as well as parathyroid hormone- and growth hormone-secreting tumors. The syndrome of multiple endocrine neoplasia is also described.

C-cell carcinoma (medullary thyroid carcinoma) associated with multiple endocrine neoplasms in a ferret (Mustela putorius).

A firm, infiltrative mass was found in the thyroid region of an adult castrated male ferret (Mustela putorius) presenting with vague signs of weight loss, minor inappetence, and decreased activity. Efforts to surgically excise the tissue were unsuccessful, and the animal was euthanatized. Gross and histopathologic evaluation revealed multiple endocrine neoplasms, including C-cell carcinoma, adrenocortical adenoma, pheochromocytoma, and endocrine tumor of the pancreas. This is the first descriptive account of a C-cell carcinoma, also known as medullary thyroid carcinoma, in a ferret, although other endocrine neoplasms in this species have been reported with some frequency. These findings mimic features observed in human multiple endocrine neoplasia syndromes.

Simultaneous occurrence of multiple neoplasms and hyperplasias in the adrenal and thyroid gland of the horse resembling multiple endocrine neoplasia syndrome: case report and retrospective identification of additional cases.

Neoplastic and hyperplastic disorders that affect multiple endocrine tissues in a single individual are well described in humans but less so in domestic animals. Multiple endocrine neoplasia (MEN) in humans is a genetically determined syndrome characterized by the appearance of benign or malignant proliferations within two or more endocrine glands. The primary endocrine tumors that are characteristic of MEN arise from cells that share the capacity for amine precursor uptake and decarboxylation. Here we describe the case of a 22-year-old Thoroughbred mare that died during an unattended parturition and subsequently was presented for necropsy at the University of California, Davis, Veterinary Medical Teaching Hospital. A C-cell (medullary) thyroid adenoma, pheochromocytoma, and multicentric bilateral nodular hyperplasia of the adrenal medulla were present, findings that are remarkably similar to those of human MEN syndrome. Mortality during pregnancy in women with undiagnosed pheochromocytoma is high (approximately 50%), typically because of hypertension and/or hemorrhage associated with catecholamine release from the tumor. Similarly, the mare in this report died of hemorrhage subsequent to parturition. A retrospective evaluation of endocrine tumors in horses that underwent necropsy at the Veterinary Medical Teaching Hospital from 1987 to 1997 was undertaken to identify additional possible cases of MEN in horses. Data from this retrospective evaluation suggest that coexistence of hyperplasias and neoplasias of the thyroid and adrenal glands, similar to MEN syndrome of humans, also occurs with some frequency in the horse.

Multiple endocrine neoplasias in a dog: corticotrophic tumour, bilateral adrenocortical tumours, and pheochromocytoma.

In a 10-year-old ovariohysterectomized standard Schnauzer, the finding of dexamethasone-resistant hypersecretion of cortisol, the results of computed tomography, and elevated plasma concentrations of ACTH suggested the presence of both adrenocortical tumour and pituitary-dependent hyperadrenocorticism. The dog made an uneventful recovery after bilateral adrenalectomy and remained in good health for 31/2 years with substitution for the induced hypoadrenocorticism. Then the enlarged pituitary caused neurological signs and eventually euthanasia was performed. The surgically excised right adrenal contained a well-circumscribed tumour of differentiated adrenocortical tissue and in the left adrenal there were two adrenocortical tumours and a pheochromocytoma. The unaffected parts of the adrenal cortices were well developed and without regressive transformation. At necropsy there were no metastatic lesions. The cells of the pituitary tumour were immunopositive for ACTH and had characteristics of malignancy. The present combination of corticotrophic tumour, adrenocortical tumours, and pheochromocytoma may be called 'multiple endocrine neoplasia' (MEN), but does not correspond to the inherited combinations of diseases known in humans as the MEN-1 and the MEN-2 syndromes. It is suggested that the co-existence of hyperadrenocorticism and pheochromocytoma may be related to the vascular supply of the adrenals. Some chromaffin cells of the adrenal medulla are directly exposed to cortical venous blood, and intra-adrenal cortisol is known to stimulate catecholamine synthesis and may promote adrenal medullary hyperplasia or neoplasia.

Diagnostic and therapeutic considerations in a hypercalcemic dog with multiple endocrine neoplasia.

Hypercalcemia was found in a dog examined for episodic weakness and disorientation. A right adrenal mass identified on abdominal ultrasonographic examination was diagnosed as a pheochromocytoma based on increased 1231-metaiodobenzylguanidine uptake and characteristic histopathological features. Serum intact parathyroid hormone (iPTH), total serum calcium, and ionized serum calcium were increased prior to surgery. Although both total and ionized serum calcium concentrations decreased to within normal reference ranges following surgery through postoperative day 17, subsequent high concentrations with increased serum iPTH concentrations confirmed concurrent primary hyperparathyroidism. A right parathyroid tumor was suspected based on a technetium-99m-sestamibi (99mTc-sestamibi) scan.

Effects of treatment with prolactin or progesterone on the coincidence of mammary tumors and uterine adenomyosis in young SHN mice.

The relative incidence of mammary tumors with uterine adenomyosis was examined in SHN mice subjected to hormonal manipulation between 30 and 90 days of age. The incidence of mammary tumors paralleled that of adenomyosis in controls. A single pituitary grafted under the kidney capsule or progesterone pellet implanted at a young age increased the incidence of both mammary and uterine lesions. However, the pattern of long-term response to hormones was different between mammary gland and uterus. The results indicate the possible relevance of this animal model for study of the cause and management of multiple endocrine syndrome in women.