Ectopic ACTH syndrome associated with large-cell neuroendocrine carcinoma of the lung

Although ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a well-known paraneoplastic phenomenon, an association with large-cell neuroendocrine carcinoma of the lung (LCNEC) has not been reported. We describe a 63-year-old man with metastatic LCNEC to the left temporomandibular joint (TMJ) who presented with progressive muscle weakness and bilateral lower leg edema for 2 weeks. He did not have a typical Cushingoid appearance nor used diuretics. His newly noted hypertension, hypokalemia (plasma potassium (K) concentration 1.8 mEq/L) with renal K wasting, and metabolic alkalosis suggested a state of mineralocorticoid excess. His plasma renin activity and aldosterone concentrations were low, but cortisol and ACTH levels were extremely elevated, consistent with ACTH-dependent Cushing's syndrome. Nonsuppressible plasma cortisol level and normal sella turcica on magnetic resonance imaging pointed to EAS. A strongly positive stain for ACTH from the metastatic left TMJ mass supported LCNEC-related EAS. His hypokalemia and hypertension were controlled with spironolactone and K supplementation. This is the first reported case of EAS in LCNEC and should be kept in mind as a cause of hypokalemia in lung cancer patients.     

Ectopic ACTH syndrome associated with anorectal carcinoma

Summary A 25-year-old black homosexual was noted to be hypertensive, hypokalemic, and to have a rectal mass. Histopathology of the biopsied lesion revealed a mixture of poorly differentiated squamous cell and undifferentiated small cell carcinoma. Abdominopelvic CT showed multiple liver metastases, minimal local tumor extension, and normal adrenal glands. Despite aggressive treatment, he remained hypertensive and hypokalemic. Endocrine work-up revealed: normal 24-hr VMA and catecholamines, normal serum aldosterone and renin levels, elevated urinary free cortisol (3360 g/24 hr), elevated serum cortisol (60 g/dl), and elevated serum ACTH (1697 pg/dl). Liver biopsy confirmed metastatic anorectal carcinoma, and immunohistochemical stains of the rectal biopsy were positive for ACTH and neuron-specific enolase. Although many types of neoplasms have been associated with ectopic ACTH production, small cell carcinoma of the lung is the most common. While there are many reports of colorectal and anorectal neuroendocrine small cell carcinomas, few of these tumors have been associated with clinical ectopic hormone production. This case represents the first report of the ectopic ACTH syndrome associated with anorectal carcinoma.Presented in abstract form at the Virginia State American College of Physicians meeting, Charlottesville, Virginia, March 1991.     

胸腺类癌致异位ACTH综合征

目的 总结胸腺类癌引起的异位ACTH综合征临床表现，提高对此综合征的诊断率。方法 分析6例患者的临床表现，尤其是非典型胸腺类癌所致异位ACTH综合征的症状和体征、实验室相关测定值以及影像学表现。结果 6例患者均行胸腺肿瘤切除术并经病理证实为胸腺类癌导致异位ACTH综合征。结论 有明确库欣综合征临床表现，且伴有低血钾，浮肿，蛋白尿且出现不能解释的8mg地塞米松抑制试验不被抑制，均应考虑异位ACTH综合征，胸腺类癌是异位ACTH综合征的可能病因。     

Ectopic ACTH syndrome associated with ovarian steroid-cell tumor

Several cases of ovarian neoplasms resulting in Cushing's syndrome due to ectopic secretion of ACTH or ectopic secretion of F have been reported. Tumors producing ACTH include adenocarcinoma, androblastoma, Sertoli cell carcinoma, carcinoid tumor and teratoma. Cortisol secretion has been reported in ovarian steroid cell tumor (unclassified steroid cell tumor). We present a case of a 19-year-old woman with Cushing's syndrome in course of an ovarian steroid cell tumor with ectopic ACTH production. To our knowledge, it is the first reported case of ACTH secreting ovarian steroid cell tumor causing Cushing's syndrome.     

异位ACTH综合征伴全垂体功能减退症

一、病史摘要 患者男性,52岁,主因"多饮、多尿、体重减轻、浮肿和乏力2个月"于2002年2月21日入院.患者于2001年12月初无明显诱因出现烦渴、多饮、多尿、多食、体重减轻,每日饮水量达5 000 ml,尿量5 000～7 500 ml,夜尿增多,4～8次/晚.2个月内体重减轻约10 kg,以四肢消瘦为主.     

胰头部神经内分泌肿瘤所致的异位ACTH综合征

异位ACTH综合征是非垂体的ACTH肿瘤分泌ACTH样物质,刺激肾上腺而引起皮质醇增多征,约占全部库欣综合征的10%～15%[1].导致该综合征的肿瘤多位于肺部或胸腺,而胰腺肿瘤所致异位ACTH综合征较罕见.     

Ectopic ACTH syndrome

Ectopic adrenocorticotropic secretion (EAS) is responsible for 12-17% of cases of Cushing's syndrome (CS) and covers a range of tumours, from undetectable benign lesions to widespread metastases. The syndrome is often associated with severe hypercortisolaemia, which aggravates the underlying condition. EAS requires a complete workup that includes the establishment of endogenous CS, diagnosis of adrenocorticotropic hormone (ACTH) dependency, localization of the source of ACTH secretion and rapid biochemical control of hypercortisolaemia. Dynamic endocrine tests should include inferior petrosal sinus sampling with CRH stimulation. Localization studies depend on the availability of reliable high-resolution cross-sectional imaging. This systematic review of the largest published series of patients with EAS (over 380 patients) reveals the common trends in the prevalence and management of this syndrome. The concept of 'occult' EAS has been revisited and the terms 'overt' and 'covert' EAS introduced. In addition to small cell lung carcinoma, the most common causes of ectopic EAS are bronchial carcinoids, thymic tumours, islet cell tumour of the pancreas, medullary thyroid carcinomas, and phaeochromocytomas. Their prevalence and the best localization modalities are presented. Medical and surgical management is discussed on the basis of the extensive experience of major referral centres.     

异位ACTH综合征的研究进展

能引起异位促肾上腺皮质激素(ACTH)综合征的肿瘤种类较多,β连环蛋白相关的Wnt信号通路、Nouch信号通路、P21活化的蛋白激酶3在异位分泌ACTH肿瘤的发生、发展中起重要作用,促阿片黑素细胞皮质素原基凶启动子区去甲基化与肿瘤异位分泌激素密切相关.在诊疗方面,血清嗜铬粒蛋白A的测定大大提高了异位ACTH综合征的阳性预测率.除手术治疗外,联合用药较单独使用生长抑素或选择性多巴胺受体激动剂更为有效.     

Subcentimeter large cell neuroendocrine carcinoma of the lung

To our knowledge, no report exists of a subcentimeter size large cell neuroendocrine carcinoma (LCNEC) of the lung. A 75-year-old man participating in a low-dose CT screening program for lung cancer was found incidentally to have a partly-solid nodule in the right upper lung. After treatment with antibiotics, a repeat CT showed resolution of the nodule, but a new solid nodule measuring 9 x 9 mm was detected in the left lower lobe. The lesion showed marked enhancement on dynamic contrast-enhanced MRI. Video-assisted thoracic surgery and frozen section biopsy was suggestive of malignant lesion, resulting in extension of surgery to lobectomy with nodal dissection. The final diagnosis was stage IA-LCNEC. The estimated volume doubling time of the tumor was 30.1 days. These aggressive tumors may rarely have doubling times that overlap with benign processes.     

Ectopic ACTH syndrome due to salivary gland adenoid cystic carcinoma.

A 68-year-old woman developed Cushing syndrome associated with a submaxillary salivary gland adenoid cystic carcinoma. High levels of immunoreactive adrenocorticotrophic hormone (ACTH) were found in the tumor and peripheral blood. Urinary 17-hydroxycorticosteroid levels decreased following administration of dexamethasone, suggesting possible suppression of ectopic ACTH production. however, there was no specific in vitro binding of dexamethasone by tumor cytosol. A trial of metyrapone therapy resulted in control of hypokalemia and hyperglycemia. Both plasma cortisol and 11-deoxycortisol levels decreased with metyrapone administration, suggesting that this agent may inhibit not only 11-beta-hydroxylation, but also possibly earlier steps in glucocorticoid synthesis.     

Surgical results of large cell neuroendocrine carcinoma of the lung

Large cell neuroendocrine carcinoma is rare in the group of primary lung cancers and its appropriate treatment and prognosis are controversial. In this report, patients diagnosed as large cell neuroendocrine carcinoma of the lung were presented and discussed in the light of pertaining literature. Between February 1997 and March 2005, eight patients, who were diagnosed as large cell neuroendocrine carcinoma postoperatively among the patients with a preoperative diagnosis of nonsmall cell lung cancer, were analyzed retrospectively, by means of treatment method, disease free survival and overall survival. All eight patients were male and their mean age and age range were 64 +/- 7.6 and 50-72, respectively. Four patients had lobectomy, two had pneumonectomy and two had limited resections. One patient received neoadjuvant chemotherapy and seven patients received adjuvant chemotherapy, radiotherapy, or chemoradiotherapy. Follow-up period was 19.7 +/- 12.5 (3-39) months and disease-free interval was 19 +/- 12.9 (3-39) months. Two patients died of recurrence 14 and 16 months postoperatively, whereas six of the cases are alive with disease-free. Large cell neuroendocrine carcinomas are aggressive tumors with poor prognosis but better prognosis is also revealed after surgery at early stages. Most of the series in the literature are small in number of patients, as in our report, and treatment strategies are tried to be formed according to these data.     

Prostatic metastasis of large cell neuroendocrine carcinoma of the lung

Large cell neuroendocrine carcinoma (LCNEC) of the lung is a rare and aggressive tumour with a poor prognosis. Lung cancer metastases to the prostate are also uncommon, and are usually found incidentally during autopsy. Most reported primary lung cancers with prostatic metastases are small cell carcinomas, and prostatic metastases from LCNEC of the lung have not been reported previously. This case report describes a 70-year-old man with LCNEC of the lung and metastases in the prostate, brain, bone, liver and lymph nodes.     

Complexity in the treatment of pulmonary large cell neuroendocrine carcinoma

Purpose According to the World Health Organization (WHO) classification of pulmonary large cell neuroendocrine carcinoma (LCNEC), one of the neuroendocrine tumors of the lung, is considered as a variant of non-small cell lung carcinoma. The objective of this study was to investigate the treatment strategy for LCNEC.Methods We retrospectively reviewed the clinical information of 12 patients with LCNEC.Results Three patients with stage I disease underwent curative resection but all relapsed within 20 months. One with stage IIA disease underwent non-curative resection received adjuvant chemoradiotherapy (cisplatin plus etoposide) and is well with no evidence of recurrence. Two with stage IIIB disease received concurrent chemoradiotherapy. Both achieved partial response (PR) but relapsed within 2 months. One elderly patient with stage IIIA disease received vinorelbine alone and did not respond. Of five patients with stage IV disease, three received platinum-based chemotherapy but no patient achieved PR. Of five patients with gefitinib as salvage therapy, one achieved PR.Conclusions The prognosis of LCNEC is poor. To improve the outcome, we must evaluate the effectiveness of adjuvant or neoadjuvant therapy in patients with resectable disease. In addition, the evaluation of systemic and multimodality treatment strategies similar as in small cell lung cancer is worthy of consideration.     

Simultaneous large cell neuroendocrine carcinoma and adenocarcinoma of the stomach

A large cell neuroendocrine carcinoma (LCNEC) of the stomach is very rare. A 76-year-old Japanese man was admitted to our hospital because of epigastralgia and nausea. Endoscopy revealed 2 large tumors in the stomach. He did not have multiple endocrine neoplasia type I or Zollinger-Ellison syndrome. Imaging modalities, including computed tomography and magnetic resonance imaging, revealed no other tumors. Gastrectomy, cholecystectomy, and lymph node dissection were performed. The resected stomach had 2 tumors: one was an antral ulcerated type 3 tumor measuring 5 cm x 5 cm, and the other was a polypoid type 1 tumor measuring 6 cm x 6 cm x 3 cm in the fundus. Microscopically, the antral ulcerated tumor was a well differentiated adenocarcinoma with deep invasion. The fundus polypoid tumor was a LCNEC, being composed of malignant large cells arranged in trabecular and nested patterns. The tumor cells were large and the nuclei were vesicular. Nucleoli were frequently present, and there were many mitotic figures, apoptotic bodies, and necrotic areas. Much lymphovascular permeation was seen. Seven out of 29 dissected lymph nodes showed metastatic foci; 6 were from the LCNEC and 1 from the adenocarcinoma. Many intravascular tumor emboli of LCNEC were seen in the peritoneum around the lymph nodes. Mucins were present in the adenocarcinoma but not in the LCNEC. Immunohistochemically, the LCNEC tumor cells were positive for pancytokeratins, synaptophysin (50% positive), chromogranin A (10% positive), Ki-67 (90% labeled), and platelet-derived growth factor-α (80% positive). They were negative for KIT, p53, CD56, and neuron-specific enolase. The non-cancerous stomach showed a normal number of endocrine cells. The patient is now treated with adjuvant chemotherapy.