Cushing's syndrome due to ectopic adrenocorticotropin secretion by a parotid carcinoma

SUMMARY We report a rare case of Cushing's syndrome in a 37-year-old female who initially presented with localized acinic cell carcinoma of the parotid gland. In January 2014, she underwent a right parotidectomy with facial nerve preservation and adjuvant radiotherapy. In August 2018, she presented a histologically-proven local regional relapse. The patient was considered for salvage surgery with facial nerve sacrifice and remained with no evidence of disease. One year later the patient developed pulmonary dissemination and started to gain weight and developed facial plethora and acne on the face and upper trunk. In a physical examination, the patient presented moon face, buffalo hump, acne and stage 2 hypertension. Biochemical evaluation confirmed ACTH-dependent Cushing's syndrome. IHC for ACTH in the lung biopsy revealed strong positive staining for ACTH confirming a diagnosis of ectopic ACTH secretion by a metastatic parotid acinic cell carcinoma. Ketoconazole (600 mg/d) was started to treat the CS. In addition, as chemotherapy was initiated to treat the metastatic disease. After the fifth cycle of chemotherapy, ketoconazole was suspended and the patient remained in remission of CS for four months, when CS recurred. A unique feature of this case is related to the clinical CS relapse associated with disease progression, which needed prompt treatment with ketoconazole, resulting in a significant improvement in the patient's condition. Although rare, should be attentive for possible CS features in patients with high-grade salivary gland carcinomas, since the diagnosis of ectopic secretion of ACTH may significantly impact their management and outcomes.

Ectopic Cushing's syndrome caused by a pulmonary ACTH-secreting tumor in a patient treated with octreotide / Síndrome de Cushing ectópico causado por um tumor pulmonar secretor de ACTH em tratamento com octreotide

Ectopic ACTH syndrome is a rare disease often associated with severe hypercortisolism. When feasible, optimal management is surgical excision of the tumor. A 33-year-old male patient was admitted to the hospital in 1993 with clinical manifestations suggestive of Cushing's syndrome. He presented high plasma ACTH and markedly elevated urinary free cortisol excretion that was not suppressed with high-dose dexamethasone administration. Pituitary MRI scan was normal. No central-to-peripheral ACTH gradient was present in bilateral inferior petrosal sinus sampling. Thoracic CT scan showed a 1.7 cm nodule at the left lung. Pulmonary fine needle cytology and immunocytochemical and ultrastructural studies, together with the presence of bone metastases, led to the diagnosis of an ACTH-producing neuroendocrine carcinoma. He was initially submitted to chemotherapy and has been on treatment with octreotide LAR since 1998, having shown a favorable clinical, biochemical and imaging response. We highlight the excellent long-term response to medical therapy with octreotide LAR, without tachyphylaxis, probably due to its antiproliferative effect.

A secreção ectópica de ACTH é uma síndrome rara associada habitualmente à hipercortisolemia grave. A remoção cirúrgica do tumor é o tratamento de primeira linha, sempre que seja exequível. Homem com 33 anos, internado em 1993 com manifestações clínicas sugestivas de síndrome de Cushing, apresentava valores elevados de ACTH plasmática e excreção urinária de cortisol livre muito aumentada, sem supressão na prova com dose alta de dexametasona; RM hipofisária sem alterações; cateterismo bilateral dos seios petrosos inferiores sem gradiente central-periférico de ACTH. A CT de tórax mostrou um nódulo de 1,7 cm no pulmão esquerdo. O diagnóstico de carcinoma neuroendócrino produtor de ACTH foi feito com base nos resultados citológico, imunocitoquímico e ultraestrutural, juntamente com a presença de metástases ósseas. Foi inicialmente submetido à quimioterapia e encontra-se em tratamento com octreotide LAR desde 1998, apresentando resposta clínica, bioquímica e imagiológica favorável. Destacamos a excelente resposta a longo prazo à terapêutica com octreotide LAR, sem taquifilaxia, provavelmente devido ao seu efeito antiproliferativo.

A rare case of Cushing syndrome by cyclic ectopic-ACTH / Um caso raro de síndrome de Cushing associada a ACTH-ectópico cíclico

ACTH-dependent Cushing syndrome (CS) due to ectopic ACTH production is most times difficult to manage. The identification of the source of ACTH may take many years. Surgery or chemotherapy for the primary tumor is not always possible. Control of Cushing symptoms is many times achieved using medication, or bilateral adrenalectomy in refractory cases. This case presents a Brazilian male who showed severe hypertension, mood changes, muscle weakness, darkening of skin, and increased abdominal fat. An investigation for Cushing syndrome was carried out and, after a four-year follow-up, a carotid glomus tumor (chemodectoma) was confirmed, a rare ectopic ACTH-producing tumor. Besides, the patient presented cyclic Cushing syndrome that was exacerbated by diverticulitis episodes. This case presents interesting pitfalls on diagnosis and management of ACTH-dependent CS. This is the only report of a chemodectoma that produced ACTH in the literature.

A síndrome de Cushing ACTH-dependente causada por produção ectópica de ACTH é, muitas vezes, difícil de diagnosticar e conduzir. A identificação da fonte produtora de ACTH pode demorar muitos anos. A cirurgia ou quimioterapia para o tumor primário nem sempre é possível, sendo o controle do hipercortisolismo alcançado com uso de fármacos ou adrenalectomia bilateral, nos casos refratários. Este caso apresenta um homem com hipertensão grave, mudança de humor, fraqueza proximal, escurecimento da pele e aumento de gordura abdominal. A investigação para síndrome de Cushing foi feita e, após quatro anos de acompanhamento, confirmou-se um tumor de glomus carotídeo (quemodectoma), causa rara de tumor secretor de ACTH. Nesse período, o paciente apresentou síndrome de Cushing cíclica, exacerbada por crises de diverticulite. O caso ilustra pontos importantes no diagnóstico, no acompanhamento e na condução da síndrome de Cushing ACTH-dependente, sendo este o único caso de tumor de glomus de carótida produzindo ACTH descrito na literatura médica.

Ectopic Cushing's syndrome: experience from a tertiary care centre.

BACKGROUND & OBJECTIVE: Ectopic secretion of adrenocorticotropic hormone (ACTH) is rare, contributing to 10 per cent cases of endogenous Cushing's syndrome. We describe our experience of about two decades of patients with ectopic Cushing's syndrome (ECS) seen at a tertiary care centre from north India. METHODS: Records of patients with ECS from 1985 to 2006 were retrospectively reviewed that included the presenting manifestations, clinical symptoms and signs, biochemical investigations including plasma cortisol, ACTH and high dose dexamethasone suppression test (HDDST), imaging modalities to localize the non pituitary source of ACTH production, management and follow up of these patients. RESULTS: The study group included 12 patients (7 men) with mean (+/-SD) age at presentation 27.6 +/- 9.5 yr (range 13 to 48 yr) and the mean lag period between onset of symptoms and the diagnosis was 18.3 +/- 12.9 months with a range of 3 to 48 months. The weight loss (41.7%) followed by hyperpigmentation (25%) and infections (16.7%) were the common presenting manifestations. Cuticular atrophy (100%), hypertension (100%), bruise (92%) and proximal myopathy (83%) were the commonest signs. Plasma cortisol at 0800 h was 1267.3 +/- 483.3 nmol/l and at 2200 h was 1214.9 +/- 442.6 nmol/l indicating loss of circadian rhythm. The mean plasma ACTH was 221.1 +/- 55.9 (range 21.7 to 950 pg/ml). All but 2 patients had non-suppressibility of 0800 h plasma cortisol with HDDST. Five patients had thymic carcinoid, 3 had bronchial and one each had islet, hepatic and gut carcinoid and one had medullary thyroid carcinoma as a cause of ectopic ACTH secretion. The mean duration of follow up of these patients was 42.6 months and only two could sustain cure while remaining had either residual or recurrence. INTERPRETATION & CONCLUSION: Ectopic Cushing's syndrome is a rare disease with varied manifestations and associated with increased morbidity and mortality. It presents with clinical features quite similar to classical Cushing's. Surgery with removal of primary tumour was found to be treatment of choice.

Unusual causes of Cushing's syndrome: [review]

Although in the majority of the patients with Cushing's syndrome (CS), hypercortisolism is due to ACTH hypersecretion by a pituitary tumour or to ectopic ACTH secretion from an extrapituitary neoplastic lesion or to autonomous cortisol secretion by an adrenal tumour, in occasional patients a much rarer entity may be the cause of the syndrome. Herein, we attempted to summarise and categorise these unusual causes according to their presumed aetiology. To this end, we performed a comprehensive computer-based search for unusual or rare causes of CS. The following unusual forms of CS were identified: (i) ACTH hyperesecretion due to ectopic corticotroph adenomas in the parasellar region or the neurohypophysis, or as part of double adenomas, or gangliocytomas; (ii) ACTH hypersecretion due to ectopic CRH or CRH-like peptide secretion by various neoplasms; (iii) ACTH-independent cortisol hypersecretion from ectopic or bilateral adrenal adenomas; (iv) glucocorticoid hypersensitivity; (v) iatrogenic, due to megestrol administration or to ritonavir and fluticasone co-administration. Such unusual presentations of CS illustrate why Cushing's syndrome represents one of the most puzzling endocrine syndromes.

Embora na maioria dos pacientes com síndrome de Cushing (SC), o hipercortisolismo se deva à hipersecreção de ACTH resultante de um tumor hipofisário ou de uma fonte ectópica de ACTH por uma lesão neoplásica extra-hipofisária, ou ainda pela secreção autônoma de cortisol por um tumor adrenal, ocasionalmente uma entidade muito mais rara pode ser a causa da síndrome. Nesta revisão, tentaremos sumarizar e categorizar essas causas incomuns de acordo com sua pressuposta etiologia. Para isso, fizemos uma ampla pesquisa por computador em busca dessas causas raras ou não usuais de SC. As seguintes formas não usuais de SC foram identificadas: (i) hipersecreção de ACTH devida a adenomas corticotróficos ectópicos na região parasselar ou na neuro-hipófise, ou como parte de adenomas duplos, ou gangliocitomas; (ii) hipersecreção de ACTH devida à secreção ectópica de CRH ou peptídeo CRH-símile por várias neoplasias; (iii) hipersecreção de cortisol ACTH-independente por adenomas adrenais ectópicos ou bilaterais; (iv) hipersensibilidade aos glicocorticóides; (v) iatrogênica, devida à administração de megestrol ou à co-administração de ritonavir e fluticasona. Essas apresentações incomuns da SC ilustram por que essa síndrome é considerada uma das mais desafiadoras da endocrinologia.

Síndrome de Cushing por secreçäo ectópica de corticotrofina (ACTH) / Cushing's syndrome due to ectopic ACTH secretion

Avaliamos oito pacientes (4F e 4M) com quadro clínico de síndrome de Cushing por secreçäo ectópica de ACTH. A idade cronológica variou de 15 a 45 anos e o tempo de duraçäo da doença de 3 a 48 meses. Todos os pacientes apresentavam aspecto cushingóide e hipertensäo arterial e quatro revelavam hiperpigmentaçäo. Cinco pacientes portavam glicemia de jejum elevada e todos, exceto um caso, apresentavam hipopotassemia; K sérico = 2,2 a 3,9 m Eq/l. O ritmo circadiano do cortisol estava ausente em todos os pacientes e os níveis basais de cortisol estavam elevados em todos os pacientes, exceto em um caso; os níveis de ACTH, em sete pacientes avaliados elevados em seis (29 a 1.050pg/ml MRC). Em seis casos avaliados, näo houve depressäo dos níveis de cortisol sérico e de 17-OH urinário após dois dias de 2 mg de dexametasona; após dois dias de 8 mg de dexametasona, um paciente apresentou depressäo normal e um paciente, depressäo parcial dos níveis de 17-OH urinários. O teste da metopirona (750 mg VO 4/4 horas x 6 doses), realizado em realizado em sete pacientes, mostrou resposta normal de composto S e 17-OH urinário no caso que apresentava depressäo normal após 8 mg de dexametasona. Quatro pacientes eram portadores de carcinóides (três de timo e um de brônquio), dois de tumor de ilhotas do pâncreas, um de feocromocitoma bilateral e carcinoma medual e um carcinoma oat cell do pulmäo e carcinoma medular da tiróide. Seis pacientes faleceram num período de três anos após o diagnóstico. RX simples de tórax identificou lesäo primária em quatro casos, confirmada pela tomografia computadorizada (CT). A CT de abdome identificou feocromocitoma bilateral e revelou aumento difuso das adrenais em todos os casos. Sugerimos que RX de tórax e tomografia computadorizado de crânio, tórax e abdome sejam realizados rotineiramente em todos os casos de síndrome de Cushing, já que os achados clínicos e hormonais podem ser semelhantes na secreçäo ectópica de ACTH e doença de Cushing