Potential Variant of Multiple Endocrine Neoplasia in a Dog

Introduction

Due to the diverse nature of endocrine organs and their vast range of physiologic functions, endocrine tumors origination from a wide range sites and are associated with various disease entities.¹ Multiple endocrine neoplasia (MEN) is a rare hereditary complex disorder characterized by the presence of two or more neoplasms of different endocrine tissues within a single patient. The tumors may be either functional or nonfunctional and can be observed as histologic progression from hyperplasia to adenoma, and occasionally, to adenocarcinoma. Development of tumors in MEN is likely a multicentric process with each tumor derived from a single clone.²

In humans, there are different forms of this syndrome characterized by involvement of different endocrine tissues: MEN 1, MEN 2A, and MEN 2B.³ Most cases of MEN reported in veterinary medicine have been in dogs and are consistent with human MEN 2A (i.e., bilateral and multicentric medullary thyroid carcinoma, unilateral or bilateral pheochromocytoma, and less commonly, parathyroid hyperplasia or adenomatosis).^4–7 In the canine medical literature, variants of MEN syndromes have also been described, but it is not clear if these variants represent a simple adaptation of the classification of human MEN.^8–11

In the veterinary literature, there has been only one case report of MEN in a dog with involvement of testicular tissue.⁸ In the case reported here, the authors described a dog with concomitant medullary thyroid carcinoma, adrenocortical carcinoma, and bilateral interstitial cell testicular adenomas as a possible expression of MEN. To the authors’ knowledge, this is the first report to describe the concomitant association of these forms of endocrine neoplasms in a single dog.

Case Report

A 14 yr old intact male mixed-breed dog weighing 22 kg was evaluated at the Dipartimento di Scienze Cliniche Veterinarie, Facoltà di Medicina Veterinaria, Università degli Studi di Milano, Italy with a 1 yr history of polyuria/polydipsia (water intake was 3–4 L/day), polyphagia, and abdominal enlargement. The dog was alert and responsive, well hydrated, and in good physical condition (body condition score was 5/9). Physical examination revealed a pendulous and pot-bellied abdomen, hepatomegaly, and a palpable mass on the left side of the ventral aspect of the neck in the area consistent with the location of the left lobe of the thyroid gland. Complete blood count abnormalities included a mild thrombocytosis (505×10³/μL; reference range, 143–400×10³/μL). Serum biochemical abnormalities included increased concentrations of: cholesterol (345 mg/dL; reference range, 135–270 mg/dL), triglycerides (78 mg/dL; reference range, <38 mg/dL), alanine aminotransferase (86 U/L; reference range, <60 U/L), and alkaline phosphatase (224 U/L; reference range, <170 U/L). Urine specific gravity was low (1.013). The history, clinical signs, and laboratory findings suggested hyperadrenocorticism (HAC) with concomitant left thyroid enlargement. The dog's thyroid gland function was evaluated and was normal (Table 1). Intramuscular administration of 0.25 mg synthetic adrenocorticotropic hormone^a (ACTH) caused an increase in serum cortisol concentration from a basal level of 102 nmol/L (reference range, 17–132 nmol/L) to 895 nmol/L (reference range, 165–480 nmol/L) 60 min postinjection. Ultrasonographic examination of the abdomen and neck were performed. Abdominal ultrasound revealed an enlarged left adrenal gland (13 mm in diameter) and a normal right adrenal gland. The liver was enlarged with a hyperechoic and homogenous parenchyma. A mass measuring 7 cm × 5 cm was identified cranially to the urinary bladder. The mass was characterized by a heterogeneous parenchyma. The presence of numerous vascular signals was identified by means of Doppler evaluation. The principal hypothesis for the nature of the mass was a metastatic lymph node of either a possible left adrenocortical carcinoma or metastasis of a possible thyroid gland carcinoma. The thyroid gland was asymmetrically enlarged due to the increased dimensions of the left lobe characterized by a heterogeneous parenchyma and by the presence of a hypoechoic lesion involving the peripheral parenchyma. Cytologic examination of a fine-needle aspirate of the abdominal mass and the thyroid cytology was inconclusive as the specimens showed poor cellularity.

Table 1 Hormone Test Results in a 14 yr old Dog with Multiple Endocrine Neoplasia at Different Time Points After Being Diagnosed with Hyperadrenocorticism

Abnormal results are in bold. M0 refers to the time of diagnosis. Additional numbers refer to the number of months after the dog was diagnosed with hyperadrenocorticism. ACTH, adrenocorticotropic hormone; T4, thyroxine; TSH, thyroid stimulating hormone.

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Adrenal-dependent hyperadrenocorticism (ADH) was suspected, and a skull, neck, and abdominal computed tomography^b (CT) was performed to further characterize the thyroid, adrenal enlargement, and the mass and to evaluate the possibility of surgical excision. The CT scan did not detect any abnormalities at the level of the pituitary gland. The gland appeared normal in size (diameter was approximately 5 mm), and no pathologic enhancement was observed after IV administration of a water-soluble nonionic iodinate contrast medium^c. CT scans obtained at the level of the neck revealed a round mass (about 22 mm × 19 mm × 31 mm) arising from the left thyroid gland. In the precontrast examination, the mass appeared quite heterogeneous with a central hypoattenuated area mixed with multiple tiny calcified nodules. The postcontrast scan of the mass showed a typical ring-effect enhancement as a consequence of a large necrotic central area. No spread of the mass to nearby areas was detected, and the left carotid artery appeared normal without any signs of a filling defect. No abnormalities were detected in the right thyroid gland (Figure 1).

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Delayed enhanced transverse CT images of the abdominal region were obtained. A large rounded mass was detected cranially to the urinary bladder. CT confirmed the size and general characteristics observed on the ultrasonographic evaluation. The CT pattern showed an irregular outline with peripheral areas of low attenuation due to either necrosis or cystic changes. The nature of the mass was not assessed, but it had spread into the retroperitoneal space, involved regional lymph nodes, and caused severe compression of the caudal vena cava. Spreading of the mass in the wall of the caudal vena cava was suspected (Figure 2). The left adrenal gland appeared enlarged (14 mm in diameter) and had homogeneous enhancement. No abnormalities were observed in the right adrenal gland. The principal hypothesis for the nature of the abdominal mass was a metastatic lymph node of a possible left adrenocortical carcinoma.

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Unilateral adrenalectomy was proposed as a specific treatment of the ADH, but the owners declined due to the complexity of the case and possible complications. The owners also declined additional exams (i.e., cytology of a fine-needle aspirate and histopathology of a biopsy specimen of the abdominal mass) that would have facilitated obtaining a definitive diagnosis of the origin of the abdominal mass.

Treatment with trilostane^d, a competitive inhibitor of 3-β-hydroxysteroid dehydrogenase, was initiated at a dose of 60 mg per os (approximately 2.7 mg/kg) q 24 hr to control the HAC. At the follow-up examination 1 mo after starting the trilostane, the dog's daily water consumption had decreased to <2 L, and an ACTH stimulation test showed a nonoptimal reduction in adrenal glucocorticoid secretory capacity (Table 1).¹² Trilostane was increased to 45 mg in the morning and 45 mg in the evening (approximately 2.2 mg/kg q 12 hr). Clinical examination, ACTH stimulation test, and hematologic and biochemical evaluation were repeated 5 mo and 10 mo after the initial diagnosis of HAC and were compared with previous examinations (Table 1). At both of those examinations, the dog was in good physical condition, did not have any signs of HAC (i.e., thirst and appetite were normal), and showed an optimal reduction in adrenal glucocorticoid secretory capacity to the ACTH stimulation test.¹² Results of hematologic and biochemical exams were within the reference ranges, with the exception of a thrombocytosis (Table 2). Ultrasonography rechecks during the follow-up period showed unmodified aspects of the abdominal mass and adrenal glands and thyroid lobe enlargement.

Table 2 Hematology and Biochemical Results of a 14 yr old Dog with Multiple Endocrine Neoplasia at Different Time Points After Originally Diagnosed with Hyperadrenocorticism

Abnormal results are in bold. M0 refers to the time of diagnosis. Additional numbers refer to the number of months after the dog was diagnosed with hyperadrenocorticism. ALP, alkaline phosphatase; ALT, alanine aminotransferase; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; PCV, packed cell volume; RBC, red blood cell(s).

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The dog presented with testicular enlargement 2 yr after being diagnosis with HAC. The left scrotum was distended and abnormally enlarged. A testicular ultrasound exam revealed an enlarged left scrotum due to retained fluid, a large dilatation of the epididymis, and a dishomogeneous testicular parenchyma of the left testis. The right testis had some cystic cavities and a dishomogeneous parenchyma with rare calcification lesions. The fluid was completely drained, and a cytologic exam was compatible with aspecific reactive effusion. Serologic evaluation indicated that testosterone was slightly increased and estradiol was low (Table 1; M24). The owners declined surgical excision of the possible neoplastic testis.

Abdominal ultrasound and blood exams were repeated at the same follow-up examination (24 months after initial diagnosis of HAC). Abdominal ultrasound revealed that the left adrenal gland could no longer be identified due to the increased size of the abdominal mass, which was now >8 cm in diameter. The thyroid gland had not changed. The principal hypothesis for the unidentified left adrenal gland was gland dislocation or gland inclusion by the mass. Ultrasound examination of the right adrenal gland confirmed its normal size. Hematologic exams revealed: thrombocytosis; a mild, normocytic, normochromic anemia; and a neutrophilic leukocytosis that worsened over time (Table 2; M24, M30, M35, M36). These hematologic alterations could be explained by a paraneoplastic syndrome as a normocytic, normochromic anemia, neutrophilic leukocytosis, and thrombocytosis, which are all described as hematologic manifestations of cancer.¹³ Results of repeated ACTH stimulation tests showed a good response to trilostane therapy (Table 1; M24, M36).

Approximately 3 yr after being diagnosed with HAC, the dog was examined for severe diarrhea and weight loss of 1 wk duration. An abdominal ultrasound indicated additional growth of the mass to approximately 12 cm in diameter and involvement of both adrenal glands. Development of profuse diarrhea at the terminal stages of the disease progression was likely caused by altered intestinal motility and decreased segmental contraction due to a mechanical effect of the abdominal mass on the abdominal organs (i.e., decreased segmental contractions result in transport of ingesta at a rate too fast for digestive and absorptive process to occur). Due to the poor clinical condition of the dog and the considerable extension of the abdominal mass, the owners requested the dog be euthanized. The owners gave their permission for necropsy, and four separate neoplasms were found. One was a 4 cm diameter dark reddish nodule involving the left thyroidal lobe (Figure 3). In the abdomen, a large yellowish mass, irregular in shape, and partially necrotic and hemorrhagic, was observed. The mass involved both adrenal glands and had extensive adhesions to the renal capsule, the external wall of the posterior vena cava, the great omentum, the external wall of the stomach, and the mesentery (Figure 4). The other two neoplasms were located in the testicles and were dark yellow nodules. The largest nodule (12 cm × 8 cm × 5 cm) completely effaced the testicular parenchyma of the left testicle whereas the other (measuring 1 cm in diameter) was located in the caudal part of the right testicle (Figure 5). A histologic examination identified the thyroidal tumor as follicular carcinoma. The abdominal mass completely obliterated the architecture of the adrenal glands and was composed of pleomorphic polygonal to spindloid cells organized in trabeculae, lobules, and nests, consistent with a malignant adrenal cortical carcinoma. Both testicular tumors had morphology typical of interstitial tumors, even though the growth pattern was different in the two tumors, with the larger tumor angyomatoid and the smaller tumor completely solid.

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Discussion

In this case report, a dog diagnosed with multiple synchronous endocrine neoplasms initially affecting the thyroid and adrenal gland and, subsequently, testicular tissue, was described. In humans, several combinations of endocrine tumors are known to occur (referred to as MEN), which is related to a common gene defect that inactivates both alleles of a tumor suppressor gene. In humans, MEN has been classified into three types. MEN 1 is characterized by hyperplasia or neoplasia of the endocrine pancreas, parathyroid glands, and anterior pituitary gland. The classic MEN 2 syndrome involves neoplasms of the thyroid gland and the medulla of the adrenal glands as well as variable hyperplasia of the parathyroid glands and ganglioneuromas. In MEN 2A, medullary thyroid carcinomas, pheochromocytomas, and parathyroid hyperplasia occur simultaneously. In MEN 2B, medullary thyroid carcinomas, pheochromocytomas, and ganglioneuromas are found. A simple adaptation of the human MEN classification for dogs seems questionable.³ Combinations of the neoplastic lesions in the dog described in this case report did not fulfill the requirements for diagnosis of either MEN 1 or MEN 2 in human medicine. Presently, there are few complete descriptions of MEN syndromes in veterinary patients.^2,4–10 Some authors suggest that the incidence of MEN syndromes among cats, dogs, and horses may be considerably higher than realized and that MEN syndromes are under diagnosed by veterinarians because of a failure to recognize the syndrome.² Nevertheless, a recent paper described 53 dogs diagnosed with multiple distinct malignancies of different origins, but only one dog presented with MEN. No dog in that report presented with both an endocrine neoplasia and male reproductive tract neoplasia.¹⁴

The dog in this case report was examined initially because of clinical signs associated with HAC, which is one of the most common endocrine diseases in dogs. Classifying abnormal adrenal tissue as ADH on the basis of histologic examination can be a diagnostic challenge because it can be difficult to distinguish macronodular hyperplasia from adenoma and to distinguish adenoma or hyperplasia from carcinoma.¹⁵ Nevertheless, in the present case, the adrenal neoplasm was very large, invaded surrounding tissue (i.e., the wall of the posterior vena cava). In addition, the histologic examination revealed cellular pleomorphism and numerous mitoses. These histologic characteristics, together with the size and invasiveness, are distinctive in distinguishing between adrenal cortex adenomas and carcinomas in both veterinary and human medicine.^16,17

Unilateral adrenalectomy is the treatment of choice for ADH. When surgery is not a suitable therapy option due to its complication or, as in this case report, because the owner declined the surgical approach, medical therapy is the only therapeutic option to control signs of HAC. Trilostane obstructs hormone synthesis by inhibiting 3-β-hydroxysteroid dehydrogenase thereby reducing the synthesis of cortisol, aldosterone, and adrenal androgens. Inhibition is reversible and apparently dose-dependent.^12,15 In this case, cortisol reduction was required and trilostane was prescribed, which resulted in clinical recovery and a 3 yr period of freedom of clinical signs associated with HAC. The owners reported that the dog had no noticeable treatment-related side effects and his activity and quality of life were considered good.

In this case report the dog had a concomitant nonsecreting medullary thyroid neoplasia. Tumors of the thyroid gland are relatively common in dogs and account for up to 4% of canine tumors.¹⁸ Thyroid tumors may present as an isolated neoplastic “event,” or they may occur in conjunction with the development of other tumors.^14,18 In veterinary medicine, unlike human medicine, it is difficult to identify thyroid tumors and distinguish between benign and malignant types on the basis of thyroid cytology. Therefore, as was seen in this case report, thyroid gland cytology may often be nondiagnostic.¹⁸

The dog in this case report also presented with hematologic abnormalities. The most noteworthy was a thrombocytosis that worsened over time. Thrombocytosis, defined as a platelet count >500×10³/μL, is an extremely common paraneoplastic syndrome in humans with lymphomas and leukemias; however, it is rarely noted in veterinary oncology. Myeloproliferative disorders (paraneoplastic production of thrombopoietin) appear to be the most common cause of paraneoplastic thrombocytosis in dogs and cats. Some important causes of primary thrombocytosis include inflammatory processes, some hemolytic anemias, posthemorrhagic anemia, iron deficiency, and postsplenectomy syndrome.¹³ A paraneoplastic syndrome could explain the hematologic abnormalities observed in the dog described herein, including the following: normocytic, normochromic anemia; neutrophilic leukocytosis; and thrombocytosis.

According to the latest World Health Organization classification of tumors of domestic animals, the most common types of testicular tumors reported in dogs are seminomas, Sertoli cell tumors, and interstitial cell tumors (ICTs). ICTs seem to be the most common testicular tumors identified in some dog studies.^19,20 ICTs arise from the endocrine cells of the testis, are usually small, nonpalpable, hormonally silent, are most commonly identified as an incidental finding at necropsy, and are considered to be of low malignancy.²⁰ In this case report, one of the two ICTs was large, easily palpable, and was not an incidental finding at necropsy. It is not known if the ICTs in this case report were functional or if testosterone levels were increased or not because testosterone levels were not measured at the time of initial diagnosis of HAC. In addition to secreting cortisol, most functional adrenocortical tumors concurrently secrete one or more sex hormones, including testosterone.²¹ Therefore, the adrenal tumors may have also caused an elevation in serum testosterone levels.

In 2004, Feldman and Nelson listed histologic evidence of MEN syndrome in 63 dogs with thyroid tumors. In four of those cases there were associations between thyroid follicular carcinoma and adrenocortical carcinoma as described in this case report. Feldman and Nelson suspected that many of those dogs simply had coincidental multiple problems, and the answer as to whether those dogs had familial disorders analogous to the well-defined MEN syndromes in humans awaits genetic study.¹⁸ It is not clear if the occurrence of bilateral testicular ICT and multiple endocrine neoplasms in the dog of the current case report represented an incidental finding or part of a syndrome. However, in the opinion of the authors of this report, the simultaneous occurrence of multiple neoplasms in different endocrine organs is suggestive of an association between the tumors and a potential variant of MEN. To the authors’ knowledge, this is the first report that describes this specific association of endocrine neoplasms in a single dog and is only the second report with testicular ICT as a component of MEN syndrome in dogs. In 1982, Peterson et al. described a dog with bilateral ITC that was castrated 5 yr earlier and subsequently developed medullary carcinoma of the thyroid gland and pheochromocytoma.⁸ The case reported herein, and others in the past, emphasize the value of a complete diagnostic evaluation of animals with endocrine neoplasms. In particular, when there is a suspicion of MEN, attention should be paid to the secreting activity of the endocrine neoplasms using hormonal tests to verify if medical therapy can be an option. Because endocrine tumors, in particular thyroid and adrenal gland carcinomas, have moderate to high metastatic rates, advanced imaging techniques such as CT and MRI should be used to identify the stage of the tumors and provide a more accurate prognosis. Finally, biopsies or even entire tumor histopathology examination is recommended because distinguishing between benign and malignant endocrine tumors can be challenging and cytology evaluation of these tumors is often nondiagnostic.¹⁶

Conclusion

In the case described herein, the concomitant presence of bilateral testicular adenomas, the adrenocortical carcinoma, and medullary thyroid carcinoma (all endocrine neoplasms) could represent a potential variant of MEN, although the presence of the ICT may have only been an incidental finding. The prognosis for dogs with MEN depends on the endocrine glands involved, their biologic behavior, and the stage of the tumors. For the dog in this case report, the principal clinical symptoms arising from HAC could be pharmacologically controlled even in the presence of a suspected thyroidal or adrenal abdominal metastasis. If any of these endocrine tumors are diagnosed, veterinarians should perform a thorough clinical assessment, including additional diagnostics for other endocrinopathies, in an effort to test for the presence of additional neoplasms or hyperplasia. Follow-up evaluations should be completed as endocrine neoplasms could develop subsequent to the first tumor diagnosis.