Abstract
We report a rare case of Cushing’s syndrome in a 59-year-old man who initially presented with concurrent acinic cell carcinoma of the parotid with high-grade transformation and co-existing papillary and medullary thyroid carcinomas, without noticeable cushinoid symptoms. Six-months later, he developed clinical features of Cushing’s syndrome which coincided with disease progression in the form of lung metastasis and mediastinal lymphadenopathy. Ectopic adrenocorticotropic hormone (ACTH) production and protein expression was limited to the high-grade transformed component of acinic cell carcinoma and in the lymph node metastasis, and was absent in the conventional acinic cell carcinoma as well as in the papillary and medullary thyroid carcinoma. He received adjuvant chemotherapy and supportive management with interval improvement for 8 months followed by disease progression with increasing serum cortisol levels and bone metastasis. He was offered palliative chemotherapy, however, declined further therapy and was lost to follow up. We discussed clinical and pathologic implications of ectopic ACTH production associated with acinic carcinoma and also reviewed the literature of this rare paraneoplastic syndrome.
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References
DeLellis RA, Xia L. Paraneoplastic endocrine syndromes: a review. Endocr Pathol. 2003;14(4):303–17.
Alexandraki KI, Grossman AB. The ectopic ACTH syndrome. Rev Endocr Metab Disord. 2010;11(2):117–26.
Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK. Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the National Institutes of Health. J Clin Endocrinol Metab. 2005;90(8):4955–62.
Kamp K, Alwani RA, Korpershoek E, Franssen GJ, de Herder WW, Feelders RA. Prevalence and clinical features of the ectopic ACTH syndrome in patients with gastroenteropancreatic and thoracic neuroendocrine tumors. EurJ Endocrinol. 2016;174(3):271–80.
Ballav C, Naziat A, Mihai R, Karavitaki N, Ansorge O, Grossman AB. Mini-review: pheochromocytomas causing the ectopic ACTH syndrome. Endocrine. 2012;42(1):69–73.
Thomas T, Zender S, Terkamp C, Jaeckel E, Manns MP. Hypercortisolaemia due to ectopic adrenocorticotropic hormone secretion by a nasal paraganglioma: a case report and review of the literature. BMC Res Notes. 2013;6:331.
Marques P, Vieira Mda S, Bugalho MJ. Ectopic cushing in a patient with medullary thyroid carcinoma: hypercortisolism control and tumor reduction with Sunitinib. Endocrine. 2015;49(1):290–2.
Singer K, Heiniger N, Thomas I, Worden FP, Menon RK, Chen M. Ectopic Cushing syndrome secondary to metastatic medullary thyroid cancer in a child with multiple endocrine neoplasia syndrome type 2B: clues to early diagnosis of the paraneoplastic syndromes. J Pediatr Endocrinol Metab. 2014;27(9–10):993–6.
Dacruz T, Kalhan A, Rashid M, Obuobie K. An Ectopic ACTH Secreting Metastatic Parotid Tumour. Case Rep Endocrinol. 2016;2016:4852907.
Jamieson L, Taylor SM, Smith A, Bullock MJ, Davis M. Metastatic acinic cell carcinoma of the parotid gland with ectopic ACTH syndrome. Otolaryngol Head Neck Surg. 2007;136(1):149–50.
Cox ML, Gourley RD, Kitabchi AE. Acinic cell adenocarcinoma of the parotid with ectopic production of adrenocorticotropic hormone. Am J Med. 1970;49(4):529–33.
Butt MI, Rose SC, Robinson AM. Cushing syndrome secondary to ectopic ACTH secretion by dedifferentiated acinic cell carcinoma of the parotid gland. Endocrinologist. 2008;18:161–2.
Shenoy VV, Lwin Z, Morton A, Hardy J. Ectopic adrenocorticotrophic hormone syndrome associated with poor prognosis in metastatic parotid acinic cell carcinoma. Otolaryngol Head Neck Surg. 2011;145(5):878–9.
Alcantara V, Urgell E, Sancho JF, Chico A. Severe ectopic cushing syndrome caused by adenoid cystic carcinoma of a salivary gland. Endoc Pract. 2013;19(5):e118–21.
Sugawara M, Hagen GA. Ectopic ACTH syndrome due to salivary gland adenoid cystic carcinoma. Arch Intern Med. 1977;137(1):102–5.
Marks AD, Kim YN, Kroop HS. Letter: ectopic production of ACTH by a minor salivary gland tumor. Ann Intern Med. 1975;83(4):521–2.
Southgate HJ, Archbold GP, el-Sayed ME, Wright J, Marks V. Ectopic release of GHRH and ACTH from an adenoid cystic carcinoma resulting in acromegaly and complicated by pituitary infarction. Postgrad Med J. 1988;64(748):145–8.
Davi MV, Cosaro E, Piacentini S, et al. Prognostic factors in ectopic Cushing’s syndrome due to neuroendocrine tumors: a multicenter study. Eur J Endocrinol. 2017;176(4):453–9.
Isidori AM, Kaltsas GA, Pozza C, et al. The ectopic adrenocorticotropin syndrome: clinical features, diagnosis, management, and long-term follow-up. J Clin Endocrinol Metab. 2006;91(2):371–7.
Ejaz S, Vassilopoulou-Sellin R, Busaidy NL, et al. Cushing syndrome secondary to ectopic adrenocorticotropic hormone secretion: the University of Texas MD Anderson Cancer Center Experience. Cancer. 2011;117(19):4381–9.
Nagao T. “Dedifferentiation” and high-grade transformation in salivary gland carcinomas. Head Neck Pathol. 2013;7:S37–47.
Stanley RJ, Weiland LH, Olsen KD, Pearson BW. Dedifferentiated acinic cell (acinous) carcinoma of the parotid gland. Otolaryngol Head Neck Surg. 1988;98:155–61.
Perzin KH, LiVolsi VA. Acinic cell carcinomas arising in salivary glands: a clinicopathologic study. Cancer. 1979;44(4):1434–57.
Simpson RHW, Chiosea S, Katabi N, Leivo I, Vielh P, Williams MD. Acinic cell carcinoma. In: El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ, editors. WHO classification of head and neck tumours. 4th ed. Lyon: IARC/WHO Press; 2017. p. 166–7.
Thompson LD, Aslam MN, Stall JN, Udager AM, Chiosea S, McHugh JB. Clinicopathologic and immunophenotypic characterization of 25 cases of acinic cell carcinoma with high-grade transformation. Head Neck Pathol. 2016;10(2):152–60.
Chiosea SI, Griffith C, Assaad A, Seethala RR. The profile of acinic cell carcinoma after recognition of mammary analog secretory carcinoma. Am J Surg Pathol. 2012;36:343–50.
Haller F, Bieg M, Will R, et al. Enhancer hijacking activates onocogenic transcription factor NR4A3 in acinic cell carcinomas of the salivary glands. Nat Commun. 2019;10:368.
Haller F, Skalova A, Ihrler S, et al. Nulcear NR4A3 immunostainig is a specific and sensitive novel marker for acinic cell carcinoma of the salivary glands. Am J Surg Pathol. 2019. https://doi.org/10.1097/PAS.0000000000001279.
Fernandez PM, Brunel F, Jiminez MA, et al. Nuclear receptors NOR1 and NGF1-B/Nur77 play similar, albeit distinct, roles in the hypothalmo-pituitary-adrenal axis. Endocrinology. 2000;141:2392–400.
Oliveira JH, Vieira JG, Abucham J, Lengyel AM. GHRP-6 is able to stimulate cortisol and ACTH release in patients with Cushing’s disease: comparison with DDAVP. J Endocrinol Invest. 2003;26(3):230–5.
Landon J, Ratcliffe JG, Rees LH, Scott AP. Tumour-associated hormonal products. J Clin Pathol Suppl (R Coll Pathol). 1974;7:127–34.
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Saluja, K., Ravishankar, S., Ferrarotto, R. et al. Ectopic ACTH Production and Cushing’s Syndrome in a Patient with Parotid Acinic Cell Carcinoma with High-Grade Transformation: Tumor Context and Clinical Implications. Head and Neck Pathol 14, 562–569 (2020). https://doi.org/10.1007/s12105-019-01054-w
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DOI: https://doi.org/10.1007/s12105-019-01054-w