Pathology in Practice
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History
An 8.5-year-old spayed female Siberian Husky weigh- ing 28.0 kg (61.6 lb) was evaluated because of a sudden onset of dyspnea. The dog was current with regard to rou- tine vaccinations and monthly heartworm prevention and had no prior underlying medical conditions.
Clinical and Gross Findings
On physical examination, the dog was quiet, alert, and responsive; dyspneic with clear lung sounds bilaterally; and tachycardie (160 beats/min) with muffled heart sounds and weak femoral pulses. No arrhythmias or murmurs were aus- cultated, and the other physical examination findings were considered normal. Pleural effusion was detected during a thoracic ultrasonographic examination; 1.75 L of blood-tinged lactescent fluid was removed via thoracocentesis and submit- ted for analysis. Assessment of a sample of the fluid revealed a nucleated cell concentration of 8,100 cells/uL, erythrocyte count of 30,000 erythrocytes/uL, and protein concentration of 4.2 g/dL; the fluid still appeared lactescent after centrifugation. On cytologic examination, the nucleated cells included non- degenerate neutrophils (53%), macrophages (27%), and small lymphocytes (20%) and no infectious agents or neoplastic cells were seen. These findings were considered consistent with a chylous lymphorrhagic effusion, with the high proportion of neutrophils likely reflecting a chronic process. Results of a CBC and serum biochemical analysis were unremarkable, with the
exception of mild thrombocytopenia (156 X 103 platelets/uL; reference interval, 220 X 103 platelets/uL to 600 X 103 platelets/ „L), which was considered most consistent with some degree of peripheral platelet consumption.
Thoracic radiography (3 views) was performed. On those images, the apex of the left cranial lung lobe appeared caudally displaced, and pleural effusion was evident. In addition, echocardiography revealed a small amount of pericardial effusion, although cardiac structure and function appeared normal. Abdominal ultrasonogra- phy revealed a 1.5-cm-diameter nodule in the right adrenal gland. The dog was hospitalized, received supportive care, and was managed with intermittent thoracocentesis prior to undergoing advanced diagnostic imaging. The dog was anesthetized, and thoracic CT was performed. During that CT examination, a cranial mediastinal mass with invasion into the cranial vena cava was identified and thrombi were detected within the left and right jugular veins and caudal lobar pulmonary arteries. Samples of the mass were ob- tained via CT-guided fine-needle aspiration and submitted for cytologic analysis. Given that the mass did not appear surgically resectable, the owners elected euthanasia.
At necropsy, the thoracic cavity and pericardium con- tained 100 and 150 mL of pink, cloudy fluid, respectively. A 5 X 5 X 5-cm dark red soft spherical mass was present in the craniodorsal mediastinum. On cut surface, the mass was mottled white to tan and vascular involvement was evident (Figure 1). The thyroid gland appeared normal on gross ex- amination. The right adrenal gland was moderately enlarged, measuring 1.5 X 2 X 2.5 cm; on cut surface, there was com- plete loss of corticomedullary distinction and the architecture of the normal adrenal gland was replaced by a solid tan mass.
Formulate differential diagnoses from the history, clinical findings, and Figure 1-then turn the page →
This report was submitted by Mary K. Leissinger, DVM, MS; Fabio Del Piero, DVM, PhD; Atsushi Kawabata, DVM, PhD; Andrea M. Dedeaux, DVM; and Stephen D. Gaunt, DVM, PhD; from the Depart- ments of Pathobiological Sciences (Leissinger, Del Piero, Kawabata, Gaunt) and Veterinary Clinical Sciences (Dedeaux), School of Veteri- nary Medicine, Louisiana State University, Baton Rouge, LA 70803. Address correspondence to Dr. Leissinger (mleiss1@lsu.edu).
Cytologic and Histopathologic Findings
Microscopic examination of the CT-guided fine- needle aspirate samples from the dog’s mediastinal mass contained moderate numbers of well-preserved nucle- ated cells and large amounts of blood. Nucleated cells formed clusters with indistinct cell borders (Figure 2). The cells had round to oval nuclei (approx 7 to 10 um in diameter) with clumped to smooth chromatin, no visi- ble nucleoli, and moderate amounts of lightly basophilic cytoplasm that occasionally contained low to moderate amounts of dark blue pigment granules interpreted as likely tyrosine granules. The cytologic interpretation was neuroendocrine neoplasm of thyroid origin.
Samples of the mediastinal mass, thyroid glands, and adrenal gland mass were collected at the time of
necropsy, routinely processed, and stained with H&E stain for histologic examination. Microscopically, the mediastinal mass was a nonencapsulated multilobulat- ed infiltrative moderately cellular neoplasm (Figure 3). Neoplastic cells were cuboidal to low columnar epithe- lial cells arranged in papillary projections and in acini that variably contained eosinophilic fluid, separated by fibrous connective tissue with mineralization. Neoplas- tic cells had round to oval nuclei, 1 to 2 small basophilic nucleoli, and abundant eosinophilic cytoplasm with distinct cell borders. Anisocytosis and anisokaryosis were moderate, and mitotic index was 2 to 3 mitotic fig- ures/10 hpf. Multifocally, aggregates of neoplastic cells were found within blood vessels. The stroma also con- tained multifocal aggregates of lymphocytes and plasma cells as well as hemorrhage and necrotic foci. On sec- tions stained with indirect immunohis- tochemical stains for thyroglobulin and hematoxylin, cells had intracytoplasmic immunoreactivity for thyroglobulin. His- tologic lesions were not found within the thyroid gland tissues.
The adrenal mass was a nonencap- sulated well-demarcated moderately cel- lular neoplasm. Neoplastic cells were polygonal, arranged in packets, and sup- ported by a scant fibrovascular stroma. The cells had round to oval nuclei with stippled chromatin, small eosinophil- ic nucleoli, and abundant amounts of eosinophilic granular cytoplasm with distinct cell borders. Anisocytosis and anisokaryosis were moderate, and the mitotic index was 1 to 2 mitotic fig- ures/10 hpf. The stroma also contained moderate numbers of lymphocytes and macrophages, few megakaryocytes, and occasional areas of hemorrhage.
Morphologic Diagnosis and Case Summary
Morphologic diagnosis and case sum- mary: mediastinal thyroid follicular carci-
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noma with vascular invasion, moderate pleural and peri- cardial effusion (presumptive chylous effusions), and ad- renal cortical carcinoma of the right adrenal gland in a dog.
Comments
Development of ectopic thyroid tissue is not uncom- mon among mammalian species. The tissue develops as a result of aberrant migration of the medial primordium during embryogenesis, which may result in ectopic tis- sue development along midline anywhere from the base of the tongue to the mediastinum and even within the heart.1 The physiologic and pathological behavior of ec- topic tissue is believed to be identical to that of normal thyroid glands, and normal ectopic tissue in dogs as well as ectopic thyroid adenomas and carcinomas have all been described.2-4 Regardless of the malignant potential of the ectopic tissue, its location may cause obstruction of nearby normal structures, as occurred with lymphatic vessels in the case described in this report, contributing to the dog’s pericardial and pleural effusion.
The pleural effusion in the dog of this report was classified as lymphorrhagic and chylous because it had a high proportion of small lymphocytes and lactescent appearance, although triglyceride concentration was not measured. Long-standing lymphorrhagic or chy- lous effusion may incite inflammation, and as such, the high numbers of neutrophils were thought to most likely reflect chronicity5; however, neutrophilic inflam- mation secondary to neoplasia could not be ruled out.
Although well described in the veterinary medical lit- erature, ectopic thyroid carcinomas remain a rare cause of mediastinal disease, with lymphoma and thymoma being the most common mediastinal masses in dogs.2 In a small retrospective case series2 of 9 dogs with histologically con- firmed mediastinal carcinomas, thyroid carcinomas repre- sented the majority (5/9); among those 5 tumors, there were 4 follicular carcinomas and 1 medullary carcinoma.
Cytologically, thyroid tissue has a neuroendocrine appearance, containing epithelial cells with indistinct cell borders. To differentiate thyroid tissue from other neuroendocrine tissues, distinguishing features such as blue-black cytoplasmic granules considered to represent tyrosine or amorphous eosinophilic extracellular colloid material must be identified.6 In the absence of such find- ings, a cytologic diagnosis of neuroendocrine neoplasm is most appropriate, considering that nonthyroidal neuroen- docrine carcinomas in the mediastinum of dogs have also been reported.2 As for other neuroendocrine tissues, cy- tologic criteria of malignancy are often lacking in thyroid carcinomas and concern for the malignant potential of the cell population must be based on clinical judgment, which combines cytologic appearance with the known biological behavior of the aspirated tissue in a given species.6
Histologically, thyroid-related neoplasms can be fur- ther divided on the basis of cell of origin. Follicular tu- mors are derived from follicular epithelium and may con- tain cells with a follicular, compact, or mixed phenotype. Medullary or C-cell tumors are derived from parafollicu- lar cells and have a compact cellular appearance.7 If cellu- lar morphology is not helpful in distinguishing between the 2 entities, immunohistochemical stains can be used. Follicular neoplasms are expected to be immunoreactive for thyroglobulin, whereas medullary tumors are immu- noreactive for calcitonin and the neuroendocrine marker
chromogranin.2,7 Nonthyroidal neuroendocrine tumors may also develop in the mediastinum, and although these tumors are also immunoreactive for chromogranin, they should not be immunoreactive for calcitonin.2
Although thyroid tumors account for only 1% to 2% of neoplasms in dogs, they remain the most common endo- crine neoplasm in this species.7 It is well-known that Gold- en Retrievers and Beagles have an increased risk for thyroid neoplasms; however, a recent 10-year multi-institutional retrospective study8 also identified Siberian Huskies as having an increased odds of thyroid tumor development. Most thyroid tumors are malignant (approx 90%), and the majority (75%) are follicular carcinomas.2,7,8 Metastasis rates vary from 18% to 34% at the time of initial diagnosis to as high as 60% to 80% at the time of necropsy.2,7,8 In the dog of this report, vascular invasion with thrombosis was evident prior to death, as detected by CT, and on gross and histologic postmortem examination, thereby providing evidence for the malignant potential of this tumor and a plausible explanation for the dog’s mild thrombocytopenia.
An additional interesting finding in the dog of the present report was the presence of a concurrent adrenal gland cortical carcinoma. In a recent prospective study9 of 1,772 dogs with a diagnosed neoplasm, 53 (3%) had at least 1 distinct concurrent primary tumor. Dogs with thyroid tumors were significantly overrepresented, with 12 of 37 (32%) dogs with thyroid tumors having at least 1 additional distinct primary tumor.9 In that case series, 1 dog had a thyroid carcinoma and adrenocortical car- cinoma, a combination of distinct endocrine neoplasms in dogs that has also been reported elsewhere in the veterinary medical literature.9,10
In human medicine, multiple endocrine neoplasia is a rare hereditary complex disorder characterized by the de- velopment of > 1 distinct endocrine neoplasm within an in- dividual, and many variations of the disease are described, depending on the endocrine tissues affected.9,10 Although development of multiple discrete endocrine neoplasms in veterinary species is well described, no conserved genetic basis for tumor formation has yet been identified.9,10
References
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2. Liptak JM, Kamstock DA, Dernell WS, et al. Cranial mediastinal carcinomas in nine dogs. Vet Comp Oncol 2008;6:19-30.
3. Kang MH, Kim DY, Park HM. Ectopic thyroid carcinoma in- filtrating the right atrium of the heart in a dog. Can Vet J 2012;53:177-181.
4. Di Palma S, Lombard C, Kappeler A, et al. Intracardiac ectopic thyroid adenoma in a dog. Vet Rec 2010;167:709-710.
5. Rebar AH, Thompson CA. Body cavity fluids. In: Raskin R, Meyer DJ, eds. Canine and feline cytology: a color atlas and interpretation guide. 2nd ed. St Louis: Saunders Elsevier, 2010;171-191.
6. Alleman AR, Choi US. Endocrine system. In: Raskin R, Meyer DJ, eds. Canine and feline cytology: a color atlas and interpretation guide. 2nd ed. St Louis: Saunders Elsevier, 2010;383-394.
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9. Rebhun RB, Thamm DH. Multiple distinct malignancies in dogs: 53 cases. J Am Anim Hosp Assoc 2010;46:20-30.
10. . Proverbio D, Spada A, Perego R, et al. Potential variant of multiple endocrine neoplasia in a dog. J Am Anim Hosp Assoc 2012;48:132-138.