Signalment:  

A mixed breed (miniature schnauzer) dog, 12 years, spayed femaleThe dog was presented in 2003 with a growth in the ventral neck region (approximately 3cm diameter). The mass was excised at that time and in 2005 the mass had re-grown. Again the tumor was excised and a diagnosis similar to the 2003 evaluation was made.


Gross Description:  

A round mass, 2-2.5cm in diameter was attached to the left thyroid gland.


Histopathologic Description:

A soft tissue mass from the ventral neck consists of a very cellular mass, a neuroendocrine neoplasm (Fig. 4-1). The cells are in packets separated by a thin vascularized stroma. Peripheral to the mass are numerous satellite nodules with tumor invasion of the lymphatics. The lesion was immunohistochemically positive for thryocalcitonin and negative for thyroglobulin and parathormone.


Morphologic Diagnosis:  

Mass: Thyroid carcinoma parafollicular


Lab Results:  

CBC and chemistries were all unremarkable except for slight elevation of ALP and ALT, both in the 300s. The animal had slightly elevated ionized calcium at 1.5. Total calcium was normal. Urinalysis was unremarkable. Thoracic and abdominal radiographs and abdominal ultrasound were unremarkable. No evidence of metastatic disease was found. Sections of the neoplasm were immunostained to confirm the biologic activity of the tumor


Condition:  

C-cell carcinoma


Contributor Comment:  

Incidence: The C-cell thyroid parafollicular cells are seen most frequently in adult cattle2,11, aged horses9 and infrequently in other domestic species.12,22 As bulls age there is an increased incidence of neoplastic C-cells, especially where bulls are fed high calcium diets.13 Multiple endocrine tumors have been associated with pheochromocytoma in bulls with C-cell tumors.19 In the dog, a pheochromocytoma has been also associated with parathyroid chief cell hyperplasia.15 In a histochemical study of 33 thyroid carcinomas in the dog, 36% were of C-cell original and 64% were from thyroid follicle cells.4 The affect on the elevated calcium is uncertain. In adult bulls, various skeletal lesions have been associated with C-cell neoplasia.20 In man, prominent bone lesions have not been reported as the result of excessive calcitonin.14


JPC Diagnosis:  

Fibrovascular tissue, ventral neck (per contributor): C-cell (parafollicular) carcinoma, mixed breed dog (Canis familiaris), canine.


Conference Comment:  

In domestic animals, most thyroid neoplasms are thyroid follicular cell tumors or C-cell (also called parafollicular or medullary) tumors. These tumors can have similar (endocrine/neuroendocrine) histologic features, ie. packets and trabeculae of epithelioid cells supported by a fine fibrovascular stroma. While C-cell carcinomas may have pallisading of columnar cells along the periphery of the lobules, dense bands of connective tissue, and/or amyloid deposits, and thyroid follicular cell tumors usually have some follicular differentiation, immunohistochemistry may be needed to differentiate between thyroid follicular cell tumors and C-cell tumors. One study4 suggested that C-cell tumors have been underdiagnosed when the diagnosis was based on histologic evaluation of H&E stained sections alone.

C-cell neoplasms exhibit positive cytoplasmic immunoreactivity for calcitonin and are negative for thyroglobulin. The sensitivity for thyroglobulin for thyroid carcinomas is 90.5% alone, but if it is combined with TTF-1, that sensitivity increases to 95.2%.16 TTF-1, thryoid transcription factor, is expressed in the thyroid, brain, and lung during early embryogenesis, and the thyroid cells and bronchioloalveolar epithelial cells following birth. In the lung, it activates surfactant proteins and Clara cell secretory protein gene promoters.1 In the thyroid gland, it activates many factors including thyroglobulin, thyroperoxidase, thyrotropin receptor, and thyroid peroxidase.5,6,8,10,18 When positive, TTF-1 is diffusely located within the nucleus and never in the cytoplasm. In one study, approximately 50% of the C-cell neoplasms also stained positive for TTF-1, therefore it is not suitable to use as a single marker.16

C-cell tumors in bulls, often occur concurrently with bilateral pheochromocytomas and pituitary adenomas.4 Multiple endocrine tumors are thought to arise due to a simultaneous neoplastic mutation of multiple endocrine cell populations of neural crest origin in the same individual.3,23 In humans, multiple endocrinen neoplasia type 2 (MEN-2) occurs in an autosomal dominant pattern, and is classified into three clinical manifestations.17 MEN-2A is characterized by the presence of a medullary thyroid carcinoma in addition to a pheochromocytoma and multiple tumors of the parathyroid gland.7 MEN-2B consists of a medullary thyroid carcinoma, a pheochromocytoma, ganglioneuromatosis, and marfanoid habitus.21 FMTC syndrome, is the third form of MEN-2 and is defined as the development of a medullary thyroid carcinoma and a low incidence of other clinical manifestations of either MEN-2A or MEN-2B.7


References:

1. Bohinski RJ, Di Lauro R, Whitsett JA: The lung-specific surfactant protein B gene promoter is a target for thyroid transcription factor 1 and hepatocyte nuclear factor 3, indicating common factors for organ-specific gene expression along the foregut axis. Mol Cell Biol 14:5671-5681, 1994
2. Capen CC and Block H E; Calcitonin secreting ultimobranchial neoplasms of the thyroid gland in bulls: An animal model for medullary thyroid carcinoma in man. Am J Pathol. 1974; 74:371-380
3. Capen CC: Tumors of the endocrine glands. In: Tumors in Domestic Animals, ed. Meuten DJ, 4th ed., pp. 657-664. Blackwell Publishing, Ames, IA, 2002
4. Carver JR, Kapatkin A, Patnaik AK: A comparison of medullary thyroid carcinoma and thyroid adenocarcinoma in dogs: A retrospective study of 38 cases. Vet Surg 24:315-319, 1995
5. Civitareale D, Castelli MP, Falasca P, Saiardi A: thyroid transcription factor 1 activates the promoter of the thyrotropin receptor gene. Mol Endocrinol 7:1589-1595, 1993
6. Civitareale D, Lonigro R, Sinclair AJ, Di Lauro R: A thyroid-specific nuclear protein essential for tissue-specific expression of the thyroglobulin promoter. EMBO J 8:2537-2542, 1989
7. Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P, Wells SA: Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 2:851-856, 1993
8. Endo T, Kaneshige M, Nakazato M, Ohmori M, Harii N, Onaya T: Thyroid transcription factor-1 activates the promoter activity of rat thyroid Na+/I- symporter. Mol Endocrinol 11:1747-1755, 1997
9. Hillage CJ, Sanecki RK, Theodorakis MC: Thyroid carcinoma in a horse. J Amer Vet Med Assoc 181:711-714, 1982
10. Kikkawa F, Gonz+�-�lez FJ, Kimura S: Characterization of a thyroid-specific enhancer located 5.5 kilobase pairs up-stream of the human thyroid peroxidase gene. Mol Cell Biol 10:6216-6224, 1990
11. Krook L., Lutwak L, McEntee K: Dietary calcium and osteopetrosis in the bull: Syndrome of calcitonin excess? Am J Clin Nutr 22:115-118, 1969
12. Leav I, Schiller AL, Rijiiberk A, Kegg MB, der Kinderen PJ: Adenomas and carcinomas of the canine and feline thyroid. Am J Pathol 83:61-64, 1976
13. McEntee K, Hall CE, Dunn HO: The relationship of calcium intake to the development of vertebral osteophytosis and ultimobranchial tumors in bulls. In: Proceedings of the Eight Technical Conference on Artifical Insemination Reproduction, pp. 45-47, 1980
14. Melvin KW, Miller HH, Tashjean AH Jr: Early diagnosis of medullary carcinoma of the thyroid gland by means of calcitonin assay. N Engl J Med 285:1115-1120, 1971
15. Peterson ME, Randolph JF, Zaki FA, Heath H: Multiple endocrine neoplasia in a dog. J Amer Vet Med Assoc 180:1476-1478, 1982
16. Ramos-Vara JA, Miller MA, Johnson GC, Pace LW: Immunohistochemical detection of thyroid transcription factor-1, thyroglobulin, and calcitonin in canine normal, hyperplastic, and neoplastic thyroid gland. Vet Pathol 39:480-487, 2002
17. Raue F, Frank-Raue K: Multiple endocrine neoplasia type 2: 2007 update. Horm Res 68:101-104, 2007
18. Saji M, Shong M, Napolitano G, Palmer LA, Taniguchi S-I, Ohmori M, Ohta M, Suzuki K, Kirshner SL, Giuliani C, Singer DS, Kohn LD: Regulation of major histocompatibility complex class I gene expression in thyroid cells. J Biol Chem 272:20096-20107, 1997
19. Spoonenberg DP, VcEntee K: Phoechromocytoma and ultimobranchial (C Cell) neoplasms in the bull: Evidence of autosomal dominant inheritance in the Guernsey breed. Vet Pathol 20:369-400, 1983
20. Thomas RG: Vertebral body osteophytes in bulls. Pathol Vet 6:1-46, 1969
21. Vasen HF, van der Feltz M, Raue F, Nieuwenhuyzen Kruseman A, Koppeschaar HPF, Pieters G, Seif FJ, Blum WF, Lips CJM: the natural course of multiple endocrine neoplasia type 2b. Arch Intern Med 152:1250-1252, 1992
22. Wadsworth PF, Lewis DJ, Jones DM: Medullary carcinoma of the thyroid in a Mouflon (Ovis musimon). J Comp Pathol 91:313-316, 1981
23. Weichert RF III: The neural ectodermal origin of the peptide-secreting endocrine gland: a unifying concept for the etiology of multiple endocrine adenomatosis and the inappropriate secretion of peptide hormones by nonendocrine tumors. Amer J Med 49:232-241, 1970

A virtual slide is not available for this case.


(Fig 4-1) Thyroid gland


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