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Sato K, Suzuki T, Akaike K, Uchihara D, Ichii O, Tai M, Takagi T, Hakozaki H, Ejiri Y. A case of gallbladder neuroendocrine carcinoma complicated by ectopic adrenocorticotropic hormone syndrome and resulting in rapid fetal outcomes due to sepsis. Clin J Gastroenterol 2024; 17:724-730. [PMID: 38773001 DOI: 10.1007/s12328-024-01986-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 05/14/2024] [Indexed: 05/23/2024]
Abstract
A 52-year-old woman presented to our hospital with chief complaints of upper abdominal bloating and lower leg edema. Computed tomography (CT) revealed liver metastasis from a gallbladder tumor. This tumor was diagnosed as neuroendocrine carcinoma (NEC) on performing a biopsy. Physical examination revealed a moon face. Blood tests revealed hypokalemia and high levels of adrenocorticotropic hormone (ACTH) and cortisol. Dexamethasone suppression test revealed that cortisol secretion was not suppressed, and the patient was diagnosed with gallbladder NEC and ectopic ACTH syndrome (EAS). Metyrapone was administered to suppress cortisol production; however, she developed septic shock due to cellulitis in the lower leg and died on the 16th day of admission. A pathological autopsy was performed, which revealed disseminated intravascular coagulation and acute respiratory distress syndrome as the cause of death. Only a few cases of EAS due to NEC originating from the gallbladder have been reported. The patient reported here succumbed shortly after diagnosis, thereby highlighting the challenges in treating gallbladder NEC complicated by EAS.
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Affiliation(s)
- Kentaro Sato
- Gastroenterology, Fukushima Rosai Hospital, 3 Numajiri Tudura-machi Uchigo, Iwaki, Fukushima, 973-8403, Japan.
| | - Tomohiro Suzuki
- Gastroenterology, Fukushima Rosai Hospital, 3 Numajiri Tudura-machi Uchigo, Iwaki, Fukushima, 973-8403, Japan
| | - Kazuki Akaike
- Gastroenterology, Fukushima Rosai Hospital, 3 Numajiri Tudura-machi Uchigo, Iwaki, Fukushima, 973-8403, Japan
| | - Daiki Uchihara
- Gastroenterology, Sangyo Medical University School of Medicine, Kitakyushu, Fukuoka, 807-8556, Japan
| | - Osamu Ichii
- Gastroenterology, Fukushima Rosai Hospital, 3 Numajiri Tudura-machi Uchigo, Iwaki, Fukushima, 973-8403, Japan
| | - Mayumi Tai
- Gastroenterology, Fukushima Rosai Hospital, 3 Numajiri Tudura-machi Uchigo, Iwaki, Fukushima, 973-8403, Japan
| | - Tadayuki Takagi
- Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Fukushima, 960-1295, Japan
| | - Hando Hakozaki
- Pathology, Fukushima Rosai Hospital, Iwaki, Fukushima, 973-8403, Japan
| | - Yutaka Ejiri
- Gastroenterology, Fukushima Rosai Hospital, 3 Numajiri Tudura-machi Uchigo, Iwaki, Fukushima, 973-8403, Japan
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Agaimy A, Kasajima A, Stoehr R, Haller F, Schubart C, Tögel L, Pfarr N, von Werder A, Pavel ME, Sessa F, Uccella S, La Rosa S, Klöppel G. Gene fusions are frequent in ACTH-secreting neuroendocrine neoplasms of the pancreas, but not in their non-pancreatic counterparts. Virchows Arch 2023; 482:507-516. [PMID: 36690805 PMCID: PMC10033480 DOI: 10.1007/s00428-022-03484-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 12/01/2022] [Accepted: 12/18/2022] [Indexed: 01/25/2023]
Abstract
Ectopic Cushing syndrome is a rare clinical disorder resulting from excessive adrenocorticotrophic hormone (ACTH) produced by non-pituitary neoplasms, mainly neuroendocrine neoplasms (NENs) of the lung, pancreas, and gastrointestinal tract, and other less common sites. The genetic background of ACTH-producing NENs has not been well studied. Inspired by an index case of ACTH-producing pancreatic NEN carrying a gene fusion, we postulated that ACTH-producing NENs might be enriched for gene fusions. We herein examined 21 ACTH-secreting NENs of the pancreas (10), lung (9), thymus (1), and kidney (1) using targeted RNA sequencing. The tumors were classified according to the most recent WHO classification as NET-G1/typical carcinoid (n = 4), NETG-2/atypical carcinoid (n = 14), and NET-G3 (n = 3). Overall, targeted RNA sequencing was successful in 11 cases (4 of 10 pancreatic tumors, 5 of 9 pulmonary tumors, and in the one renal and one thymic tumor). All four successfully tested pancreatic tumors revealed a gene fusion: two had a EWSR1::BEND2 and one case each had a KMT2A::BCOR and a TFG::ADGRG7 fusion, respectively. EWSR1 rearrangements were confirmed in both tumors with a EWSR1::BEND2 by FISH. Gene fusions were mutually exclusive with ATRX, DAXX, and MEN1 mutations (the most frequently mutated genes in NETs) in all four cases. Using RNA-based variant assessment (n = 16) or via the TSO500 panel (n = 5), no pathogenic BCOR mutations were detected in any of the cases. Taken together, gene fusions were detected in 4/4 (100%) pancreatic versus 0/7 (0%) non-pancreatic tumors, respectively. These results suggest a potential role for gene fusions in triggering the ACTH production in pancreatic NENs presenting with ectopic Cushing syndrome. While the exact mechanisms responsible for the ectopic ACTH secretion are beyond the scope of this study, overexpressed fusion proteins might be involved in promoter-mediated overexpression of pre-ACTH precursors in analogy to the mechanisms postulated for EWSR1::CREB1-mediated paraneoplastic phenomena in certain mesenchymal neoplasms. The genetic background of the ACTH-producing non-pancreatic NENs remains to be further studied.
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Affiliation(s)
- Abbas Agaimy
- Institute of Pathology, University Hospital Erlangen, Friedrich Alexander University of Erlangen-Nuremberg & Comprehensive Cancer Center, European Metropolitan Area Erlangen-Nuremberg (CCC ER-EMN), Erlangen, Germany.
| | - Atsuko Kasajima
- Institute of Pathology, Technical University Munich, Munich, Germany
| | - Robert Stoehr
- Institute of Pathology, University Hospital Erlangen, Friedrich Alexander University of Erlangen-Nuremberg & Comprehensive Cancer Center, European Metropolitan Area Erlangen-Nuremberg (CCC ER-EMN), Erlangen, Germany
| | - Florian Haller
- Institute of Pathology, University Hospital Erlangen, Friedrich Alexander University of Erlangen-Nuremberg & Comprehensive Cancer Center, European Metropolitan Area Erlangen-Nuremberg (CCC ER-EMN), Erlangen, Germany
| | - Christoph Schubart
- Institute of Pathology, University Hospital Erlangen, Friedrich Alexander University of Erlangen-Nuremberg & Comprehensive Cancer Center, European Metropolitan Area Erlangen-Nuremberg (CCC ER-EMN), Erlangen, Germany
| | - Lars Tögel
- Institute of Pathology, University Hospital Erlangen, Friedrich Alexander University of Erlangen-Nuremberg & Comprehensive Cancer Center, European Metropolitan Area Erlangen-Nuremberg (CCC ER-EMN), Erlangen, Germany
| | - Nicole Pfarr
- Institute of Pathology, Technical University Munich, Munich, Germany
| | | | - Marianne E Pavel
- Department of Medicine 1, Division of Endocrinology, Comprehensive Cancer Center, Erlangen University Hospital, European Metropolitan Area Erlangen-Nuremberg (CCC ER-EMN), Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany
| | - Fausto Sessa
- Unit of Pathology, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Silvia Uccella
- Humanitas University, Pieve Emanuele, Milan, Italy
- Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Stefano La Rosa
- Unit of Pathology, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Günter Klöppel
- Institute of Pathology, Technical University Munich, Munich, Germany
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Corsello A, Ramunno V, Locantore P, Pacini G, Rossi ED, Torino F, Pontecorvi A, De Crea C, Paragliola RM, Raffaelli M, Corsello SM. Medullary Thyroid Cancer with Ectopic Cushing's Syndrome: A Case Report and Systematic Review of Detailed Cases from the Literature. Thyroid 2022; 32:1281-1298. [PMID: 35833793 DOI: 10.1089/thy.2021.0696] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Background: Medullary thyroid cancer (MTC) is a neuroendocrine tumor arising from parafollicular C-cells of the thyroid gland that, in rare cases, can cause a paraneoplastic ectopic Cushing's syndrome (ECS). The development of Cushing's syndrome (CS) in MTC patients is generally associated with advanced disease and poor prognosis. Summary: We described a case of severe CS due to MTC in a young male. We performed a systematic review to identify cases of ECS due to MTC. We searched PubMed, Scopus, and Web of Science for publications between database inception and February 2022 and we collected the patient characteristics, disease presentation, employed treatment strategies, and disease outcomes. In addition to our patient, we identified 96 cases of ECS due to MTC reported in literature. Mean age at diagnosis was 44.4 years (range 10-84), and there was a male predominance (male:female [M:F] = 1.8:1). Most patients (51%) presented with metastatic disease at diagnosis and showed severe hypercortisolism. Seventeen patients developed distant metastasis and hypercortisolism during follow-up. Interestingly, in 48% of patients, the diagnosis of CS followed the diagnosis of MTC with a median time of 48 months but, among patients in whom the diagnosis was concomitant (38%), symptoms due to hypercortisolism were frequently the reason for seeking medical advice. Pathology results showed evidence of adrenocorticotropic hormone (ACTH) or corticotropin releasing hormone (CRH) positive cells in 76% of patients in whom they were tested. The management of hypercortisolism was challenging in most patients with 48% requiring, eventually, definitive treatment with bilateral adrenalectomy (BLA). Recently, some limited evidence has emerged regarding tyrosine kinase inhibitors (TKIs) treatment for hypercortisolism in patients with ECS due to MTC. Despite limited information on survival, prognosis was generally poor and the main causes of death were either complications of CS or disease progression. Conclusions: Despite its rarity, MTC should be considered in the differential diagnosis of ECS. Management of hypercortisolism is a key factor to improve the patient's symptoms but it is often challenging and BLA is frequently required. Further studies are needed for investigating the role of TKIs in patients with MTC with ECS.
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Affiliation(s)
- Andrea Corsello
- Division of Endocrinology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Vittoria Ramunno
- Division of Endocrinology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Pietro Locantore
- Division of Endocrinology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giovanni Pacini
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Division of Endocrine and Metabolic Surgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Esther Diana Rossi
- Division of Anatomic Pathology and Histology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Francesco Torino
- Medical Oncology, Department of Systems Medicine, Tor Vergata University of Rome, Rome, Italy
| | - Alfredo Pontecorvi
- Division of Endocrinology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Carmela De Crea
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Division of Endocrine and Metabolic Surgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Rosa Maria Paragliola
- Division of Endocrinology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Marco Raffaelli
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Division of Endocrine and Metabolic Surgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Salvatore Maria Corsello
- Division of Endocrinology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Medicine, UniCamillus-Saint Camillus International University of Health Sciences, Rome, Italy
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Rodrigues de Sousa M, Martins S, Soares N, Coelho L, Neto T, Balhau R. Acinic cell carcinoma emerging as a paraneoplastic Cushing's syndrome: A systematic review. ADVANCES IN ORAL AND MAXILLOFACIAL SURGERY 2022. [DOI: 10.1016/j.adoms.2021.100236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
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Varghese J, Ayyagari M, Reddy SS, Mandapati NS, Subrahmanyam K. Rapidly Fatal Ectopic Adrenocorticotropic Hormone Syndrome in a 9-Year-Old Girl With Ewing Sarcoma. AACE Clin Case Rep 2021; 8:69-72. [PMID: 35415231 PMCID: PMC8984523 DOI: 10.1016/j.aace.2021.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 09/15/2021] [Accepted: 09/24/2021] [Indexed: 11/02/2022] Open
Abstract
Background Case Report Discussion Conclusion
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Jin M, Zhou B, Jiang XL, Zhang QY, Zheng X, Jiang YC, Yan S. Flushing as atypical initial presentation of functional gallbladder neuroendocrine carcinoma: A case report. World J Gastroenterol 2020; 26:686-695. [PMID: 32103876 PMCID: PMC7029351 DOI: 10.3748/wjg.v26.i6.686] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 12/31/2019] [Accepted: 01/11/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Neuroendocrine neoplasms are rarely located in the gallbladder (GB), and carcinoid syndrome is exceedingly rare in patients with GB neuroendocrine neoplasms.
CASE SUMMARY We report a case of GB neuroendocrine carcinoma (GB-NEC) in a 65-year-old man, who presented with flushing for 2 mo. Pathological specimens of the flushed skin revealed that mucin was deposited between the collagen bundles in the dermis. Computed tomography and magnetic resonance imaging indicated neoplasm in the GB with liver invasion and enlarged lymph nodes in the portacaval space. High fluorodeoxyglucose uptake was detected in lymph nodes in the portacaval space, but distant metastasis was not seen by positron emission tomography. Ultrasound-guided needle biopsy of the GB neoplasm was suggestive of high-grade NEC. Because of the functional characteristics of poorly differentiated NEC, en bloc cholecystectomy, resection of hepatic segments IVb and V, pancreaticoduodenectomy, and regional lymphadenectomy were performed. A diagnosis of poorly differentiated NEC was made by pathological findings and immunohistochemical staining data. Ki-67 index was > 80%. The patient refused adjuvant therapy and passed away in the 7th month.
CONCLUSION Distinctive manifestation combined with imaging helps make correct preoperative diagnosis. Radical surgery and adjuvant chemotherapy might improve prognosis.
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Affiliation(s)
- Ming Jin
- Department of General Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Bo Zhou
- Department of General Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Xiong-Ling Jiang
- Department of Pathology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Qi-Yi Zhang
- Department of General Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Xiang Zheng
- Department of General Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Yuan-Cong Jiang
- Department of General Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Sheng Yan
- Department of General Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
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7
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Ectopic Cushing's Syndrome Unveiling a Metastatic Parotid Carcinoma. Case Rep Endocrinol 2019; 2019:3196283. [PMID: 31737376 PMCID: PMC6815534 DOI: 10.1155/2019/3196283] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 08/23/2019] [Indexed: 12/05/2022] Open
Abstract
Introduction Adrenocorticotropic hormone (ACTH) ectopic production is a rare cause of Cushing syndrome (CS). The most commonly associated tumours are small-cell lung carcinoma along with bronchial and thymic carcinoids. To date, only 5 cases have been published in the literature featuring ectopic ACTH secretion from metastatic acinic cell carcinoma (ACC) of the parotid gland. We hereby describe a very uncommon case of ectopic CS (ECS) unveiling a metastatic parotid ACC. Case Presentation A 46-year-old man with hypertension and dyslipidemia diagnosed 4-months before, as well as new-onset diabetes mellitus unveiled 1-month earlier, was referred to emergency department for hypokalemia. Hormonal study and dynamic biochemical tests performed indicated ECS. Imaging and cytological findings pointed toward a likely primary right parotid malignancy with liver metastases. Somatostatin receptor scintigraphy has shown an increased uptake in the parotid gland and mild expression in liver metastasis. The patient underwent right parotidectomy, and histopathologic examination confirmed ACC. Meanwhile, hypercortisolism was managed with metyrapone, ketoconazole, and lanreotide. Despite chemotherapy onset, a rapid disease progression and clinical course deterioration was observed. Conclusion The present report highlights a rare ECS, exposing a metastatic parotid ACC, with an aggressive and challenging clinical course, representing the first case whose diagnosis of ECS came prior to ACC.
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8
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Nakhjavani M, Amirbaigloo A, Rabizadeh S, Rotondo F, Kovacs K, Ghazi AA. Ectopic cushing's syndrome due to corticotropin releasing hormone. Pituitary 2019; 22:561-568. [PMID: 31041631 DOI: 10.1007/s11102-019-00965-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Cushing's syndrome (CS) secondary to corticotropin releasing hormone (CRH) producing tumors is rare. In this paper we present an Iranian patient who was admitted to our hospital with classic signs and symptoms of CS. Laboratory evaluation revealed high serum and urine cortisol which could not be suppressed with dexamethasone. Abdominal CT scan revealed a mass in abdominal cavity. A percutaneous needle biopsy was performed and histopathologic evaluation revealed that the mass was a neuroendocrine tumor. A multi-disciplinary approach including resection of the mass, bilateral adrenalectomy somatostatin analogue and chemotherapy was applied for management of the disease. Extensive review of English literature focusing on the topic from 1971 to 2018 revealed that there have been only 75 similar cases. Clinical, laboratory, imaging, histopathologic characteristics and managements of these patients will also be discussed in this paper.
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Affiliation(s)
- Manouchehr Nakhjavani
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Soghra Rabizadeh
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Fabio Rotondo
- Department of Laboratory Medicine, Division of Pathology, Toronto, Canada
- The Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada
| | - Kalman Kovacs
- Department of Laboratory Medicine, Division of Pathology, Toronto, Canada
- The Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada
| | - Ali A Ghazi
- Endocrine Research Center, Research Institute for Endocrine Sciences (RIES), Shahid Beheshti University of Medical Sciences, P.O. Box: 19395-4763, Tehran, Iran.
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9
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Takeuchi M, Sato J, Manaka K, Tanaka M, Matsui H, Sato Y, Kume H, Fukayama M, Iiri T, Nangaku M, Makita N. Molecular analysis and literature-based hypothesis of an immunonegative prostate small cell carcinoma causing ectopic ACTH syndrome. Endocr J 2019; 66:547-554. [PMID: 30918166 DOI: 10.1507/endocrj.ej18-0563] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Ectopic ACTH syndrome (EAS) due to a prostate small cell carcinoma (SCC) is very rare with only 26 cases reported to date and has a poor prognosis. We here describe another case of this disorder that was clinically typical based on prior reports as it showed hypercortisolemia and severe hypokalemia with multiple metastasis. However, our current case of prostate SCC causing EAS is the first to display negative immunostaining for ACTH despite detectable POMC mRNA expression in the primary lesion. ACTH immunonegativity is thought to be associated with a more aggressive disease course and a poorer prognosis although there are few studies of the underlying mechanisms. We explored two possibilities for this finding in our current patient: aberrant POMC processing prevented immunodetection with an anti-ACTH antibody; and the ACTH content per cell was below the threshold for immunodetection due to its rapid secretion or low synthesis. The aberrant processing theory was thought to be less likely because of immunonegative findings even using anti-POMC/ACTH antibodies. As the plasma ACTH levels in our patient were comparable with those reported for previous immunopositive prostate EAS cases, we speculated that the depletion of ACTH may be caused not only by rapid secretion but also by low production levels as a sign of de-differentiation. De-differentiation may therefore explain the mechanism underlying the negative correlation between immunoreactivity for ACTH in EAS and disease aggressiveness. We believe that our present findings will be of use in future prospective studies aimed at confirming the mechanism of immunonegativity.
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Affiliation(s)
- Maki Takeuchi
- Department of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
| | - Junichiro Sato
- Department of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
| | - Katsunori Manaka
- Department of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
| | - Mariko Tanaka
- Department of Pathology, The University of Tokyo, Tokyo, Japan
| | - Hotaka Matsui
- Department of Urology, The University of Tokyo, Tokyo, Japan
| | - Yusuke Sato
- Department of Urology, The University of Tokyo, Tokyo, Japan
| | - Haruki Kume
- Department of Urology, The University of Tokyo, Tokyo, Japan
| | | | - Taroh Iiri
- Department of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
- Department of Pharmacology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Masaomi Nangaku
- Department of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
| | - Noriko Makita
- Department of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
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10
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Mitchell E, Ciccone M, Zhang B, Tsai A, Brunette LL. Paraneoplastic Cushing's syndrome and hypercalcemia arising from metastatic endometrioid endometrial adenocarcinoma: A case report. Gynecol Oncol Rep 2019; 29:58-60. [PMID: 31334321 PMCID: PMC6620411 DOI: 10.1016/j.gore.2019.06.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 06/12/2019] [Indexed: 01/22/2023] Open
Abstract
Paraneoplastic Cushing's syndrome is rarely seen in gynecologic cancers, appearing only in case reports It almost universally results in acute decompensation and portends a poor prognosis We describe a patient with metastatic endometrial carcinoma with both paraneoplastic Cushing's syndrome and hypercalcemia High clinical suspicion for malignancy is essential, as these syndromes improve with treatment of the underlying malignancy
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Affiliation(s)
- Evelyn Mitchell
- Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, USA
| | - Marcia Ciccone
- Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, USA
| | - Bing Zhang
- Department of Medicine, Keck School of Medicine, University of Southern California, USA
| | - Arnold Tsai
- Department of Medicine, Keck School of Medicine, University of Southern California, USA
| | - Laurie L Brunette
- Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, USA
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11
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Barghouthi N, Perini J, Cheng J. Ectopic Adrenocorticotropic Hormone Production: A Case of Neuroendocrine Cervical Small Cell Carcinoma Presenting as Cushing Syndrome. AACE Clin Case Rep 2018. [DOI: 10.4158/accr-2018-0080] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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12
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Mokhtar A, Arnason T, Gaston D, Huang WY, MacKenzie H, Al-Hazmi R, Vaninetti N, Tugwell B, Rayson D. ACTH-Secreting Neuroendocrine Carcinoma of the Cecum: Case Report and Review of the Literature. Clin Colorectal Cancer 2018; 18:e163-e170. [PMID: 30314823 DOI: 10.1016/j.clcc.2018.07.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 07/26/2018] [Accepted: 07/30/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Approximately 30% of neuroendocrine tumors (NETs) present with secretory syndromes or develop one during the course of the disease. Cushing syndrome caused by a gastrointestinal tract NET is rare, with limited published information. We describe a patient with florid Cushing syndrome due to ectopic adrenocorticotropic hormone (ACTH) from a NET of colonic origin. A literature review was conducted to describe the spectrum of this clinical and pathologic entity as reported in the scientific literature. PATIENT AND METHODS Next-generation sequencing and microsatellite instability testing was carried out on the tumor from our case. A preliminary PubMed search was conducted using the following terms under the publication type "Case Reports": "Cushing" AND "colon," "neuroendocrine" AND "colon" and "neuroendocrine AND Cushing AND "colon." A manual search was performed to review all references for inclusion and relevant clinical, biochemical and pathologic data was abstracted. RESULTS Mutations in BRAF V600E and TP53 were detected in our case. We retrieved 18 previously reported cases of Cushing syndrome associated with a NET of colonic origin, none of which had next-generation sequencing performed. Median age at diagnosis was 54.5 years (range, 24-74 years), with equal gender distribution. ACTH was detected by immunohistochemistry in the primary tumor and/or metastatic lesion in 61.5%. Review of the reports suggested that ectopic ACTH secretion from a colonic tumor might be more common in mixed glandular and NETs, including mixed adenocarcinoma-neuroendocrine carcinoma. Among studies reporting outcomes, the unadjusted mortality rate was 77.7%, with median overall survival from presentation of 63 days (range, 17-380 days). CONCLUSION Cushing syndrome associated with ectopic ACTH from tumors of colonic origin is a rare phenomenon with poor outcomes and can be associated with pure NETs, adenocarcinomas, and mixed-phenotype tumors, including mixed adenocarcinoma-neuroendocrine carcinoma.
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Affiliation(s)
- Ahmed Mokhtar
- Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Thomas Arnason
- Division of Anatomical Pathology, Department of Pathology and Laboratory Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Daniel Gaston
- Department of Pathology and Laboratory Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Weei-Yuarn Huang
- Division of Anatomical Pathology, Department of Pathology and Laboratory Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Heather MacKenzie
- Division of Endocrinology and Metabolism, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Rayan Al-Hazmi
- Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Nadine Vaninetti
- Division of Endocrinology and Metabolism, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Barna Tugwell
- Division of Endocrinology and Metabolism, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Daniel Rayson
- Division of Medical Oncology, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
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Perez-Rivas LG, Oßwald A, Knösel T, Lucia K, Schaaf C, Hristov M, Fazel J, Kirchner T, Beuschlein F, Reincke M, Theodoropoulou M. Expression and mutational status of USP8 in tumors causing ectopic ACTH secretion syndrome. Endocr Relat Cancer 2017; 24:L73-L77. [PMID: 28710116 DOI: 10.1530/erc-17-0054] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2017] [Accepted: 07/13/2017] [Indexed: 02/03/2023]
Affiliation(s)
- Luis G Perez-Rivas
- Medizinische Klinik und Poliklinik IVLudwig-Maximilians-Universität München, Munich, Germany
| | - Andrea Oßwald
- Medizinische Klinik und Poliklinik IVLudwig-Maximilians-Universität München, Munich, Germany
| | - Thomas Knösel
- Institute of PathologyLudwig-Maximilians-Universität München, Munich, Germany
| | - Kristin Lucia
- Medizinische Klinik und Poliklinik IVLudwig-Maximilians-Universität München, Munich, Germany
- Department of EndocrinologyMax Planck Institute of Psychiatry, Munich, Germany
| | - Christian Schaaf
- Institute of PathologyLudwig-Maximilians-Universität München, Munich, Germany
| | - Michael Hristov
- Institute for Cardiovascular PreventionLudwig-Maximilians-Universität München, Munich, Germany
| | - Julia Fazel
- Medizinische Klinik und Poliklinik IVLudwig-Maximilians-Universität München, Munich, Germany
| | - Thomas Kirchner
- Institute of PathologyLudwig-Maximilians-Universität München, Munich, Germany
| | - Felix Beuschlein
- Medizinische Klinik und Poliklinik IVLudwig-Maximilians-Universität München, Munich, Germany
| | - Martin Reincke
- Medizinische Klinik und Poliklinik IVLudwig-Maximilians-Universität München, Munich, Germany
| | - Marily Theodoropoulou
- Medizinische Klinik und Poliklinik IVLudwig-Maximilians-Universität München, Munich, Germany
- Department of EndocrinologyMax Planck Institute of Psychiatry, Munich, Germany
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An Ectopic ACTH Secreting Metastatic Parotid Tumour. Case Rep Endocrinol 2016; 2016:4852907. [PMID: 26904316 PMCID: PMC4745306 DOI: 10.1155/2016/4852907] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Revised: 12/21/2015] [Accepted: 12/22/2015] [Indexed: 11/17/2022] Open
Abstract
A 60-year old woman presented with features of Cushing's syndrome (CS) secondary to an ectopic adrenocorticotropic hormone (ACTH) secreting metastatic parotid tumour 3 years after excision of the original tumour. She subsequently developed fatal intestinal perforation and unfortunately died despite best possible medical measures. Ectopic ACTH secretion accounts for 5–10% of all patients presenting with ACTH dependent hypercortisolism; small cell carcinoma of lung (SCLC) and neuroendocrine tumours (NET) account for the majority of such cases. Although there are 4 previous case reports of ectopic ACTH secreting salivary tumours in literature, to our knowledge this is the first published case report in which the CS developed after 3 years of what was deemed as a successful surgical excision of primary salivary tumour. Our patient initially had nonspecific symptoms which may have contributed to a delay in diagnosis. Perforation of sigmoid colon is a recognised though underdiagnosed complication associated with steroid therapy and hypercortisolism. This case demonstrates the challenges faced in diagnosis as well as management of patients with CS apart from the practical difficulties faced while trying to identify source of ectopic ACTH.
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Shusterman M, Bloomgarden NA, Sotardi ST, Shastri A. Tumor Lysis Syndrome in an Unusual Metastatic Pancreatic Neuroendocrine Tumor with Ectopic ACTH Secretion. J Gastrointest Cancer 2015; 47:423-428. [PMID: 26271662 DOI: 10.1007/s12029-015-9755-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Affiliation(s)
- Michael Shusterman
- Department of Medicine, Montefiore Medical Center, Bronx, NY, 10467, USA
| | - Noah A Bloomgarden
- Department of Medicine, Division of Endocrinology, Montefiore Medical Center, Bronx, NY, 10467, USA
| | - Susan T Sotardi
- Department of Radiology, Montefiore Medical Center, Bronx, NY, 10467, USA
| | - Aditi Shastri
- Department of Oncology, Montefiore Medical Center, 111 East 210th Street, Hofheimer Main, Room 111, Bronx, NY, 10467, USA.
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Wahlberg J, Ekman B. Atypical or typical adrenocorticotropic hormone-producing pulmonary carcinoids and the usefulness of 11C-5-hydroxytryptophan positron emission tomography: two case reports. J Med Case Rep 2013; 7:80. [PMID: 23509950 PMCID: PMC3608321 DOI: 10.1186/1752-1947-7-80] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2012] [Accepted: 02/10/2013] [Indexed: 11/10/2022] Open
Abstract
Introduction Pulmonary carcinoids associated with ectopic adrenocorticotropic hormone secretion have a good prognosis if histological examination shows typical pulmonary carcinoid and low proliferation, whereas a poor outcome is linked to atypical pulmonary carcinoid and high proliferation. Here we describe the diagnostic challenges to find the tumor in Cushing’s syndrome secondary to ectopic adrenocorticotropic hormone secretion in two cases with an atypical and a typical pulmonary carcinoid, respectively. Case presentation A 63-year-old Caucasian woman presented with aggressive clinical features related to Cushing’s syndrome, having very high levels of urinary cortisol and circulating adrenocorticotropic hormone and cortisol. Magnetic resonance imaging showed no pituitary tumor, and bilateral inferior petrosal sinus sampling revealed no central peripheral ratio of adrenocorticotropic hormone. Computed tomography and 111Indium-pentetreoide somatostatin receptor scintigraphy could not visualize any ectopic tumor. The patient was referred for an 11C-5-hydroxytryptophan positron emission tomography, and a small 8mm nodule in her left lung was found. The tumor was removed via a lateral thoracic incision and wedge excision. The histological examination showed an atypical carcinoid with Ki-67 index of 9 to 10%, and an additional lobectomy was performed. The second patient, a 22-year-old Caucasian man, also presented with aggressive Cushing’s syndrome, with very high urinary cortisol levels and increased circulating cortisol as well as adrenocorticotropic hormone levels. A magnetic resonance imaging scan of the pituitary showed no tumor, whereas a 12×9×14mm tumor was detected in the right lung on the primary computed tomography scan and no further investigation was performed. The tumor was removed via a lateral thoracic incision and wedge excision. A typical carcinoid with Ki-67 index of 1 to 2% was found and no further surgery was performed. After surgical removal, the biochemical disturbances resolved and significant clinical improvement were achieved in both patients after 24 months of follow up. Conclusions Diagnostic evaluation time is limited due to the aggressive course in ectopic adrenocorticotropic hormone-dependent Cushing’s syndrome. We suggest that 11C-5-hydroxytryptophan positron emission tomography could be considered early as a secondary diagnostic tool when primary computed tomography and/or magnetic resonance imaging scans fail to show any tumor.
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Affiliation(s)
- Jeanette Wahlberg
- Section of Endocrinology, Department of Medicine and Health Sciences, Faculty of Health, Sciences, Linköping University, Linköping, Sweden.
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Cassarino MF, Ambrogio AG, Pagliardini L, De Martin M, Barresi V, Cavagnini F, Pecori Giraldi F. ACTH-secreting pheochromocytoma with false-negative ACTH immunohistochemistry. Endocr Pathol 2012; 23:191-5. [PMID: 22644873 DOI: 10.1007/s12022-012-9212-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Sharma ST, Nieman LK. Prolonged remission after long-term treatment with steroidogenesis inhibitors in Cushing's syndrome caused by ectopic ACTH secretion. Eur J Endocrinol 2012; 166:531-6. [PMID: 22190002 PMCID: PMC3744890 DOI: 10.1530/eje-11-0949] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Spontaneous remission is rare in ectopic ACTH syndrome (EAS). We describe four patients with presumed EAS in whom long-term treatment with steroidogenesis inhibitors was followed by prolonged remission of hypercortisolemia. Biochemical testing was consistent with EAS, but imaging failed to identify a tumor. Patients were treated with ketoconazole alone or with mitotane and/or metyrapone to control hypercortisolemia. Dexamethasone was added when a block and replace strategy was used. Treatment with steroidogenesis inhibitors for 3-10 years in these patients was followed by a prolonged period of remission (15-60 months). During remission, the first patient had an elevated ACTH, low cortisol and 24-h urinary free cortisol (UFC), and adrenal atrophy on computerized tomography scan during remission, suggesting a direct toxic effect on the adrenal glands. Cases 2 and 3 had normal to low ACTH levels and low-normal UFC, consistent with an effect at the level of the ectopic tumor. They did not have a history of cyclicity and case 3 has been in remission for ~5 years, making cyclic Cushing's syndrome less likely. Case 4, with a history of cyclic hypercortisolism, had normal to slightly elevated ACTH levels and low-normal UFC during remission. The most likely etiology of remission is cyclic production of ACTH by the ectopic tumor. Spontaneous and sustained remission of hypercortisolemia is possible in EAS after long-term treatment with steroidogenesis inhibitors; a drug holiday may be warranted during chronic therapy to evaluate this. The pathophysiology remains unclear but may involve several different mechanisms.
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Affiliation(s)
- S T Sharma
- Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Building 10, CRC, 1 East, Rm 3140, Bethesda, Maryland 20892-1109, USA.
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Filippella M, Davì MV, Doveri G, Lillaz E, Ciccarelli A, Massimetti E, Toaiari M, Falconi M, Colao A, Faggiano A. Hyperinsulinemic hypoglycemia associated with ectopic Cushing's syndrome due to a pancreatic endocrine tumor in a Type 2 diabetes mellitus patient: clinical implications of a rare association. J Endocrinol Invest 2011; 34:175-9. [PMID: 20386090 DOI: 10.1007/bf03347062] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
BACKGROUND The coexistence of insulin and ACTH hypersecretion in the same patient is extremely rare. A diabetic patient with a pancreatic endocrine tumor (PET) co-secreting insulin and ACTH is even rarer and has never been described. The combination of these two endocrine syndromes results in a peculiar clinical picture. AIM To determine the cause of glycemic variations in a patient with previously stable diabetes mellitus. SUBJECTS AND METHODS This is a clinical case report from the Endocrinology Unit of Aosta Hospital and Internal Medicine and Surgical Unit of Verona University. A 69-yr-old diabetic patient was hospitalized for recurrent severe hypoglycemic events persistent after withdrawal of anti-diabetic drugs. The causes of hypoglycemia and subsequent resumption of hyperglycemia were investigated. RESULTS An insulin-secreting PET was diagnosed. Diazoxide and octreotide therapy initially was able to control hypoglycemic symptoms, then, a Cushing's syndrome occurred resulting in worsening of diabetes control. ACTH was found to be released by the PET previously diagnosed as an insulin-secreting tumor. The tumor was removed and the histology was consistent with a well differentiated endocrine carcinoma. After surgery, adrenal function was normal and insulin therapy was again necessary to control diabetes. CONCLUSIONS A single PET may be responsible for both a hyperinsulinemic and a Cushing's syndrome. When this rare association occurs, each of the two syndromes may affect the other resulting in a peculiar clinical course. Finally, an insulin-secreting PET has to be kept in mind as a rare cause of hypoglycemia in diabetic patients.
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Affiliation(s)
- M Filippella
- SC Internal Medicine Unit of Diabetology and Endocrinology, Parini Hospital, Aosta, Italy
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Lin D, Suwantarat N, Kwee S, Miyashiro M. Cushing’s syndrome caused by an ACTH-producing large cell neuroendocrine carcinoma of the gallbladder. World J Gastrointest Oncol 2010; 2:56-8. [PMID: 21160818 PMCID: PMC2999155 DOI: 10.4251/wjgo.v2.i1.56] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2009] [Revised: 09/02/2009] [Accepted: 09/09/2009] [Indexed: 02/05/2023] Open
Abstract
Malignancies of the gallbladder, including neuroendocrine tumors, are uncommon, mostly found incidentally after cholecystectomy and are frequently asymptomatic in the early stages, but highly fatal. Limited data is available on adrenocorticotropic hormone (ACTH)-producing neuroendocrine tumors specifically originating from the gallbladder. We report the clinical and radiographic findings, which included positron emission tomography and computed tomography, of a patient with a gallbladder mass who presented with Cushing’s syndrome. Subsequently, a diagnosis of ACTH-producing large cell neuroendocrine carcinoma of the gallbladder was made. Despite being rare and having a poor prognosis, hormone-producing neuroendocrine tumors should be part of the differential diagnosis in the approach of patients with Cushing’s syndrome.
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Affiliation(s)
- Dagmar Lin
- Dagmar Lin, Nuntra Suwantarat, Department of Internal Medicine and John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, United States
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21
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Alwani RA, Neggers SJCMM, van der Klift M, Baggen MGA, van Leenders GJLH, van Aken MO, van der Lely AJ, de Herder WW, Feelders RA. Cushing's syndrome due to ectopic ACTH production by (neuroendocrine) prostate carcinoma. Pituitary 2009; 12:280-3. [PMID: 18322802 DOI: 10.1007/s11102-008-0100-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Ectopic adrenocorticotropin (ACTH) secretion accounts for less than 10% of all causes of endogenous Cushing's syndrome (CS) and is usually associated with neuroendocrine tumors and small cell carcinoma of the lung. We report the case of a 62-year-old man with CS due to ectopic ACTH production by small cell carcinoma of the prostate. He presented with severe hypercortisolism and associated symptoms. Plasma neuron specific enolase (NSE) was grossly elevated. Despite performing a laparoscopic bilateral adrenalectomy, the patient died as a result of sepsis with multi-organ failure. Post-mortem immunohistochemical staining of prostate tumor tissue showed ACTH expression. ACTH staining was also performed in four additional patients with small cell carcinoma of the urinary tract without CS. None of these additional cases showed a positive staining for ACTH. Although a rare cause of ectopic ACTH production, neuroendocrine prostate carcinoma should be considered in male patients with Cushing's syndrome, in particular in those with an occult source of ACTH overproduction.
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Affiliation(s)
- R A Alwani
- Department of Internal Medicine, Endocrine Section, Rotterdam, The Netherlands.
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Davì MV, Bodei L, Ferdeghini M, Falconi M, Testoni M, Paganelli G, Oliani C, Lo Cascio V, Francia G. Multidisciplinary approach including receptor radionuclide therapy with 90Y-DOTATOC ([90Y-DOTA0, Tyr3]-octreotide) and 177Lu-DOTATATE ([177Lu-DOTA0, Tyr3]-octreotate) in ectopic cushing syndrome from a metastatic gastrinoma: a promising proposal. Endocr Pract 2008; 14:213-8. [PMID: 18308661 DOI: 10.4158/ep.14.2.213] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE To present a case of a young woman with Cushing syndrome caused by ectopic production of adrenocorticotropic hormone from a metastatic pancreatic gastrin-secreting endocrine carcinoma, who had a good response to combination peptide receptor radionuclide therapy. METHODS We review the history, physical examination, laboratory investigations, and radiographic findings in this unusual patient. Moreover, the multimodal interventions are described and discussed. RESULTS In a 38-year-old woman with typical signs of cortisol excess, laboratory studies revealed diabetes mellitus, hypokalemia, and high levels of adrenocorticotropic hormone, plasma cortisol, and urinary cortisol. Abdominal computed tomography showed a 4-cm pancreatic mass and multiple metastatic lesions in the liver, and ectopic Cushing syndrome was diagnosed. Treatment consisted of surgical debulking of the tumor, ketoconazole, somatostatin analogues, chemoembolization of the liver metastatic lesions, and peptide receptor radionuclide therapy with the radiolabeled somatostatin analogues 90Y-DOTATOC ([90Y-DOTA0, Tyr3]-octreotide) and 177Lu-DOTATATE ([177Lu-DOTA0, Tyr3]-octreotate). The 5 1/2-year follow-up showed positive results, which included complete regression of all clinical and hormonal evidence of the tumor and substantial decrease in the size and number of hepatic metastatic lesions. The patient achieved and still maintains an optimal quality of life. CONCLUSION To the best of our knowledge, this is the first report of a multidisciplinary approach including peptide receptor radionuclide therapy with 90Y-DOTATOC and 177Lu-DOTATATE, which proved to be effective in improving clinical outcome in a case of metastatic endocrine carcinoma of the pancreas in conjunction with ectopic Cushing syndrome. In this unusual case, the patient has one of the longest durations of survival in this setting described in the literature.
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A Rare Case of Ectopic Adrenocorticotropic Hormone Syndrome in Small Cell Carcinoma of the Vagina. J Low Genit Tract Dis 2008; 12:140-5. [DOI: 10.1097/lgt.0b013e31815cda1e] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Galac S, Kooistra HS, Voorhout G, van den Ingh TSGAM, Mol JA, van den Berg G, Meij BP. Hyperadrenocorticism in a dog due to ectopic secretion of adrenocorticotropic hormone. Domest Anim Endocrinol 2005; 28:338-48. [PMID: 15760674 DOI: 10.1016/j.domaniend.2004.11.001] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2004] [Accepted: 11/14/2004] [Indexed: 11/21/2022]
Abstract
Spontaneous hyperadrenocorticism in dogs is known to be the result of excessive secretion of adrenocorticotropic hormone (ACTH) by the pituitary gland or excessive autonomous glucocorticoid secretion by an adrenocortical tumor. Here, we report on an 8-year-old German shepherd dog in which ACTH-dependent hyperadrenocorticism was a result of ectopic ACTH secretion and could be related to an abdominal neuroendocrine tumor. Hyperadrenocorticism was diagnosed on the basis of the history, clinical signs, and elevated urinary corticoid/creatinine ratios (UCCRs; 236 and 350 x 10(-6); reference range < 10 x 10(-6)). The UCCR remained elevated (226 x 10(-6)) after three oral doses of dexamethasone (0.1 mg/kg body weight) at 8-h intervals. Ultrasonography revealed two equivalently enlarged adrenal glands, consistent with adrenocortical hyperplasia. Plasma ACTH concentration was clearly elevated (159 and 188 ng/l; reference range 5-85 ng/l). Computed tomography (CT) revealed that the pituitary was not enlarged. These findings were interpreted as indicating dexamethasone-resistant pituitary-dependent hyperadrenocorticism. Transsphenoidal hypophysectomy was performed but within 2 weeks after surgery, there was exacerbation of the clinical signs of hyperadrenocorticism. Plasma ACTH concentration (281 ng/l) and UCCRs (1518 and 2176 x 10(-6)) were even higher than before surgery. Histological examination of the pituitary gland revealed no neoplasia. Stimulation of the pituitary with corticotropin-releasing hormone did not affect plasma ACTH and cortisol concentrations. Treatment with trilostane was started and restored normocorticism. CT of the pituitary fossa, 10 months after hypophysectomy, revealed an empty sella. Hence, it was presumed that there was ectopic secretion of ACTH. CT of the abdomen revealed a mass in the region of the pancreas and a few nodules in the liver. Partial pancreatectomy with adjacent lymph node extirpation was performed and the liver nodules were biopsied. Histological examination revealed a metastasized neuroendocrine tumor. Abdominal surgery was not curative and medical treatment with trilostane was continued. At 18 months after the abdominal surgery, the dog is still in good condition. In conclusion, the combination of (1) severe dexamethasone-resistant hyperadrenocorticism with elevated circulating ACTH levels, (2) definitive demonstration of the absence of pituitary neoplasia, and (3) an abdominal neuroendocrine tumor allowed the diagnosis of ectopic ACTH secretion.
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Affiliation(s)
- S Galac
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 8, P.O. Box 80.154, 3508 TD Utrecht, The Netherlands.
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Miehle K, Tannapfel A, Lamesch P, Borte G, Schenker E, Kluge R, Ott RA, Wiechmann V, Koch M, Kassahun W, Paschke R, Koch CA. Pancreatic neuroendocrine tumor with ectopic adrenocorticotropin production upon second recurrence. J Clin Endocrinol Metab 2004; 89:3731-6. [PMID: 15292297 DOI: 10.1210/jc.2003-032164] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
We present a 54-yr-old woman with ectopic corticotropin syndrome caused by a neuroendocrine tumor of the pancreas. At initial presentation, the patient suffered from diarrhea, heartburn, and nonspecific abdominal pain. There was no evidence of Cushing's syndrome. A neuroendocrine tumor in the head of the pancreas with metastases into peripancreatic lymph nodes was diagnosed and completely resected. Fourteen months later, abdominal computed tomography and scintigraphy with (111)In-labeled octreotide suggested relapse of the tumor. The patient again had no evidence of Cushing's syndrome. A second in toto tumor resection was performed. Another 8 months later, the patient developed forgetfulness, depressive episodes, muscle weakness, new-onset hypertension, hypokalemia, plethora, diabetes mellitus, polyuria, and weight loss. Endocrine testing suggested a source of ectopic ACTH production. An octreotide scan showed an intense uptake ventromedial of the left kidney, an area that showed a mass lateral of the superior mesenteric artery on abdominal magnetic resonance imaging. A complete pancreatectomy with splenectomy and left-sided adrenalectomy were performed. At this second relapse, this neuroendocrine tumor clinically had changed its hormonal profile. Immunohistochemically, in contrast to primary tumor and first relapse, we found strong immunostaining for ACTH in tumor cells of the second relapse and a MIB-1 index greater than 20%. To our knowledge, this is the first report describing a pancreatic neuroendocrine tumor that started to secrete ACTH de novo at the time of the second relapse after two former complete tumor resections. This case underscores the pluripotency of neuroendocrine tumor cells and the importance of keeping in mind a possible shift in hormone production during tumor evolution and progression.
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Isidori AM, Kaltsas GA, Mohammed S, Morris DG, Jenkins P, Chew SL, Monson JP, Besser GM, Grossman AB. Discriminatory value of the low-dose dexamethasone suppression test in establishing the diagnosis and differential diagnosis of Cushing's syndrome. J Clin Endocrinol Metab 2003; 88:5299-306. [PMID: 14602765 DOI: 10.1210/jc.2003-030510] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Cushing's syndrome requires a screening test of high sensitivity, followed by biochemical evaluation of the source of the tumor when the cause is ACTH dependent. The high-dose dexamethasone suppression test is still in common use as an aid in differential diagnosis, although its value has been queried. We have routinely used the low-dose dexamethasone suppression test for many years in the diagnosis of Cushing's syndrome but noticed that patients with pituitary-dependent Cushing's syndrome or Cushing's disease, usually showed some degree of suppression of their serum cortisol, compared to those with the ectopic ACTH syndrome. We therefore analyzed retrospectively the serum cortisol responses during the low-dose dexamethasone suppression test and the high-dose dexamethasone suppression test in 245 patients with ACTH-dependent Cushing's syndrome and compared the diagnostic utility of each test either alone or in combination with a standard test using CRH. Evaluation of the serum cortisol response at 24 and 48 h during the low-dose dexamethasone suppression test correctly identified 98% of patients with ACTH-dependent Cushing's syndrome and distinguished between pituitary and ectopic causes with a sensitivity of 82% and a specificity of 79%. In the same patients, the serum cortisol response to the high-dose dexamethasone suppression test had a slightly higher sensitivity (91%) and specificity (80%). However, the combined criteria of a more than 30% suppression of serum cortisol during the low-dose dexamethasone suppression test and/or a more than 20% increase in the CRH test had a significantly higher sensitivity (97%) and specificity (94%) than either the high-dose dexamethasone or the CRH tests alone in the differential diagnosis of ACTH-dependent Cushing's syndrome. It produced equivalent information to that when high-dose and CRH test results were combined. We therefore conclude that in our patient series, the serum cortisol response during the low-dose dexamethasone suppression test is highly sensitive in diagnosing Cushing's syndrome and, combined with the results of the serum cortisol response to the CRH test, offered a safe and cost-effective test in the differential diagnosis of ACTH-dependent Cushing's syndrome. There does not appear to be any necessity for retaining the high-dose dexamethasone suppression test in this diagnostic work-up.
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Affiliation(s)
- Andrea M Isidori
- Department of Endocrinology, St. Bartholomew's Hospital, London ECIA 7BE, United Kingdom
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Aniszewski JP, Young WF, Thompson GB, Grant CS, van Heerden JA. Cushing syndrome due to ectopic adrenocorticotropic hormone secretion. World J Surg 2001; 25:934-40. [PMID: 11572035 DOI: 10.1007/s00268-001-0032-5] [Citation(s) in RCA: 175] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cushing syndrome (CS) caused by ectopic adrenocorticotropic hormone (ACTH) production (EA) poses major challenges diagnostically by mimicking the pituitary-dependent form of CS and therapeutically by producing severe, life-threatening hypercortisolemia. This retrospective follow-up study describes the clinical characteristics and course of EA in a large referral center. Computer-based cross-index codes for EA, CS, and bilateral adrenalectomy were used to identify patients treated at the Mayo Clinic between 1956 and 1998. EA was confirmed in 106 patients. Gender distribution showed a slight female predominance (61:45). Bronchial carcinoid was the most frequent cause of EA (25%), followed by islet cell cancer (16%), small-cell lung carcinoma (11%), medullary thyroid cancer (8%), disseminated neuroendocrine tumor of unknown primary source (7%), thymic carcinoid (5%), pheochromocytoma (3%), disseminated gastrointestinal carcinoid (1%), and other tumors (8%). No tumor was found in 16% of patients. Altogether, 28 patients were managed medically, and the others underwent curative tumor resection (13 patients) or bilateral adrenalectomy (65 patients). Surgically treated patients had longer survival, but this was most likely affected by treatment bias. The diagnoses of CS and ACTH-secreting neoplasm were usually concurrent, although, there were remarkable cases in which the two conditions were diagnosed several years apart. Curative resection of the tumor producing EA was possible in a small proportion of patients (12%). When curative resection is not possible, patients who are reasonable surgical candidates are likely to benefit from adrenalectomy. Additional experience with bilateral laparoscopic adrenalectomy should increase the number of patients who benefit from adrenal-directed surgery.
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Affiliation(s)
- J P Aniszewski
- Division of Endocrinology, Metabolism, Nutrition, and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA
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Rickman T, Garmany R, Doherty T, Benson D, Okusa MD. Hypokalemia, metabolic alkalosis, and hypertension: Cushing's syndrome in a patient with metastatic prostate adenocarcinoma. Am J Kidney Dis 2001; 37:838-46. [PMID: 11273885 DOI: 10.1016/s0272-6386(01)80134-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Ectopic adrenocorticotropic hormone (ACTH) and/or corticotropin-releasing hormone (CRH) are associated with a growing list of tumors. We report a 69-year-old white man with a history of high-grade prostate carcinoma and widely metastatic adenocarcinoma who presented with metabolic alkalosis, hypokalemia, and hypertension secondary to ectopic ACTH and CRH secretion. Laboratory values were consistent with hypokalemia and metabolic alkalosis. Markedly elevated serum cortisol (135 microg/dL), ACTH (1,387 pg/dL), CRH (69 pg/dL), and urine free cortisol (16,276 microg/24 h) levels were found. Chest computed tomographic (CT) scan showed small noncalcified parenchymal densities; however, bronchoscopy and bronchoalveolar lavage washings were unremarkable for a neoplastic process. Abdominal CT scan and magnetic resonance imaging showed multiple small liver lesions and multiple thoracic and lumbar intensities consistent with diffuse metastatic disease. Histological analysis of a biopsy specimen from the thoracic spine showed an undifferentiated adenocarcinoma consistent with a prostate primary tumor. The severe metabolic alkalosis secondary to glucocorticoid-induced excessive mineralocorticoid activity was treated with potassium supplements, spironolactone, and ketoconazole. In this case report, we describe an unusual tumor associated with ectopic ACTH and CRH production and the pharmacodynamic relationship of plasma cortisol levels and urinary cortisol excretion with ketoconazole treatment.
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Affiliation(s)
- T Rickman
- Department of Medicine, University of Virginia Health Systems, Charlottesville, VA 22901, USA
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Grobholz R, Back W, Pörner T, Ertl G, Bleyl U. FatalAspergillus fumigatus septicemia in a patient with an ectopic ACTH-producing neuroendocrine pancreatic tumor. Endocr Pathol 1999; 10:181-5. [PMID: 27519222 DOI: 10.1007/bf02739830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
The case of a 71-yr-old Caucasian patient who suffered from an adrenocorticotropic hormone (ACTH)-producing tumor and developed a fulminantAspergillus fumigatus septicemia is reported. The patient presented initially with a recent onset of hyperglycemia and had excessive plasma levels of cortisol and ACTH. A computer-assisted tomography scan showed a tumor associated within the head of the pancreas. During his hospital course, he developed a rapid progressive fatalAspergillus fumigatus pneumonia and an upper gastrointestinal bleeding. At necropsy multiple abscesses in the brain, lungs, heart, kidneys, small bowel and mesentery were present as a result of Aspergillus septicemia. A neuroendocrine pancreatic tumor, 8 cm in diameter, was found in the head of the pancreas without any signs of malignancy. The tumor showed immunohistochemical and electron microscopic evidence of ACTH expression, but of no other pituitary or pancreatic hormones. This case demonstrates the fulminant progress of a septicemia based on an immunologically compromised patient because of ectopic Cushing's syndrome. Early diagnosis of ectopic ACTH syndromes is essential for adequate therapy in order to prevent complications and fatal infections.
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Affiliation(s)
- R Grobholz
- Department of Pathology, Heidelberg, Germany.
- Pathologisches Institut, Universitätsklinikum Mannheim, Theodor-Kutzer-Ufer 1-3, D-68167, Mannheim, Germany.
| | - W Back
- Department of Pathology, Heidelberg, Germany
- Pathologisches Institut, Universitätsklinikum Mannheim, Theodor-Kutzer-Ufer 1-3, D-68167, Mannheim, Germany
| | - T Pörner
- Department of Medicine, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany
| | - G Ertl
- Department of Medicine, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany
| | - U Bleyl
- Department of Pathology, Heidelberg, Germany
- Pathologisches Institut, Universitätsklinikum Mannheim, Theodor-Kutzer-Ufer 1-3, D-68167, Mannheim, Germany
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Ohtake H, Katabuchi H, Tashiro H, Khan S, Fukumatsu Y, Okamura H. Establishment of a new cell line, OKT1, from small cell carcinoma secreting ectopic ACTH of the uterine cervix. Gynecol Oncol 1998; 71:177-84. [PMID: 9826457 DOI: 10.1006/gyno.1998.5170] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
OBJECTIVE Small cell carcinoma of the uterine cervix is rare and represents a unique entity among gynecological tumors. It sometimes demonstrates neuroendocrine differentiation, including adrenocorticotropin (ACTH) secretion. In this study, we established a new cell line, OKT1, from a case of carcinoma secreting ectopic ACTH without Cushing's syndrome and determined the character of the cell line. METHODS OKT1 was established from OKT tumor cells, derived from a biopsy specimen of small cell cervical carcinoma, and serially heterotransplanted into nude mice. To characterize OKT1, the cell morphology, growth properties, immunohistochemical properties, hormone- and tumor-associated antigen secretion, tumorigenic potential, DNA profile, and chromosomal alteration were studied. RESULTS The population doubling time of OKT1 was approximately 27 h. The cytological properties of OKT1, including DNA ploidy pattern, were similar to those of the primary tumor. Neuroendocrine differentiation was shown in the OKT1 cells by the positive immunocytochemical staining of neuron-specific enolase (NSE) and the presence of NSE and ACTH in the culture media. The xenograft of 1 x 10(8) OKT1 cells into nude mice yielded tumor mass. Furthermore, OKT1 demonstrated HPV type 18 and absence of a p53 gene mutation from exons 5 through 8. CONCLUSION To our knowledge, OKT1 is the first cell line established from small cell cervical carcinoma with ACTH secretion.
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Affiliation(s)
- H Ohtake
- Department of Obstetrics and Gynecology, Kumamoto University School of Medicine, Kumamoto City, 860-8556, Japan
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Colleran KM, Burge MR, Crooks LA, Dorin RI. Small cell carcinoma of the vagina causing Cushing's syndrome by ectopic production and secretion of ACTH: a case report. Gynecol Oncol 1997; 65:526-9. [PMID: 9190988 DOI: 10.1006/gyno.1997.4701] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Small cell carcinomas of pulmonary or extrapulmonary origin are neuroendocrine tumors classically associated with ectopic hormone production, particularly ACTH secretion resulting in Cushing's syndrome. However, ectopic Cushing's syndrome has not previously been reported in the setting of small cell carcinoma of the vagina. METHODS A primary vaginal tumor with hepatic metastases was evaluated with light microscopy. Serum cortisol and plasma ACTH levels were evaluated by radioimmunoassay and immunoradiometric assay, respectively, during a standard high-dose (8 mg) overnight dexamethasone suppression test. RESULTS Vaginal small cell carcinoma with hepatic metastases was demonstrated. Electrolyte abnormalities, elevated cortisol and ACTH levels, and failure to suppress ACTH secretion during high-dose dexamethasone administration confirmed the diagnosis of ectopic ACTH syndrome. CONCLUSIONS This case report establishes a clinical association between vaginal small cell carcinoma and ectopic Cushing's syndrome, confirming the neuroendocrine potential of this malignancy and features common to small cell neoplasms originating in other sites.
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Affiliation(s)
- K M Colleran
- Department of Medicine, Albuquerque VA Medical Center and University of New Mexico School of Medicine, 87108, USA
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Abstract
BACKGROUND When hormones are detected in the serum of patients with bronchial carcinoma they are generally considered to originate from the tumour, but this may be not the only explanation. Pulmonary endocrine cells proliferate in lungs affected by non-neoplastic disease and their products are often demonstrable in the serum. The aim of this study was to examine the pulmonary endocrine systems of a series of tumour-bearing lungs to see whether any changes in them could possibly account for raised levels of pulmonary peptides in the blood. METHODS The morphology, number, distribution, and content of pulmonary endocrine cells in 30 pairs of tumour-bearing lungs from patients coming to necropsy with bronchial carcinoma were examined. These features were related to the pathology of the tumour and to other pathological changes present in the lungs, and compared with pulmonary endocrine cells in 10 pairs of control lungs from patients without pulmonary disease. RESULTS Increased numbers of endocrine cells, often in the form of large abnormal aggregates, were present in 17 pairs of tumour-bearing lungs where they were associated not with the tumour but with non-tumoral pathology, especially inflammation and changes associated with cardiac failure. Appropriate and inappropriate peptides were identified within them. CONCLUSION The possibility is raised that, in some subjects with bronchial carcinoma who have raised serum hormone levels, the source of these substances might be the endocrine cells in the diseased lung around the tumour.
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Affiliation(s)
- J D Sheard
- Department of Pathology, University of Liverpool, UK
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Onishi R, Sano T, Nakamura Y, Namiuchi S, Sawada S, Ihara C, Shimatsu A. Ectopic adrenocorticotropin syndrome associated with undifferentiated carcinoma of the colon showing multidirectional neuroendocrine, exocrine, and squamous differentiation. Virchows Arch 1996; 427:537-41. [PMID: 8624584 DOI: 10.1007/bf00199515] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
We report a rare case of ectopic ACTH syndrome associated with undifferentiated carcinoma of the ascending colon. A 62-year-old woman developed hypokalaemia and metabolic alkalosis associated with markedly elevated serum cortisol and plasma ACTH levels. High-dose dexamethasone (8 mg/day) did not suppress increased urinary 17-hydroxycorticosteroid and 17-keto-steroid excretion. Barium enema and abdominal computerised tomography showed a Borrmann II type tumour in the ascending colon, multiple metastatic nodules in the liver and bilateral enlargement of the adrenal glands. Histological examination of the resected primary colon cancer and metastatic liver tumour showed undifferentiated carcinoma with areas of distinct neuroendocrine, exocrine, and squamous differentiation. ACTH production by the tumour was confirmed by radioimmunoassay and immunohistochemistry. This is a unique case report of carcinoma of the colon with distinct multidirectional differentiation causing ectopic ACTH syndrome.
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Affiliation(s)
- R Onishi
- Department of Haematology and Immunology, Kitano Hospital, Tazuke-Kofukai Medical Research Institute, Osaka, Japan
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Abstract
Ectopic ACTH syndrome represents a cancer-induced amplification of a property [proopiomelanocortin (POMC) peptides production] normally present in the cells from which the cancer originated but with aberrant posttranslational processing of POMC resulting in a greatly elevated secretion of ACTH precursors. The classic ectopic ACTH-producing tumors described in the 1960s were highly malignant but more recently slowly growing tumors such as carcinoids are reported with increasing frequency. Clinical features of patients with ectopic ACTH were analyzed, including biochemical abnormalities, plasma ACTH, cortisol and urinary steroids. Dynamic tests such as high-dose dexamethasone suppression, metyrapone and ovine-CRH (oCRH) stimulation were explored, as well as inferior petrosal sinus ACTH sampling before and after oCRH. Among the tumor markers examined, elevation of ACTH precursors was uniformly present followed by increased output of calcitonin, gut hormones, oncofetal and placental hormones in decreasing order. Since more than 90% of ectopic ACTH tumors are neuroendocrine in nature exhibiting APUD characteristics, their 2 markers, neuron-specific enolase and chromogranins are very useful. The imaging procedures for localization of the tumor ranged from chest X-rays to computed tomography and magnetic resonance of the chest and abdomen. Abdominal ultrasonography was also useful. Finally somatostatin receptor scintigraphy permitted demonstration of unrecognized tumors and/or metastases, even when the tumors were occult. The ACTH content, immunostaining for APUD markers and altered POMC processing were evaluated in ectopic tumors and/or metastases. Occult ectopic ACTH syndrome of more than 4-6 months of symptoms without the emergence of an obvious source was reviewed. Since the tumors are often clinically and biochemically undistinguishable from pituitary-dependent Cushing's disease, inferior petrosal sinus sampling for ACTH after oCRH stimulation established the diagnosis in over 90% of the cases. 60% of the occult tumors were thoracic carcinoids (3/4 bronchial carcinoids), followed by small cell lung cancer and pancreatic neuroendocrine tumors. In 12% the primary etiology was not detected. The rare syndrome of ectopic CRH syndrome (6 published cases) leading to excessive stimulation of the pituitary which became hyperplastic and secreted excessive amounts of ACTH is discussed. Finally, the 12 published cases and 1 unreported patient with ectopic CRH-ACTH tumors were reviewed, the majority being metastatic small cell lung carcinomas, bronchial and thymic carcinoids.
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Affiliation(s)
- B L Wajchenberg
- Endocrine Service, Hospital das Clínicas, University of São Paulo School of Medicine, Brazil
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Tsigos C, Papanicolaou DA, Chrousos GP. Advances in the diagnosis and treatment of Cushing's syndrome. BAILLIERE'S CLINICAL ENDOCRINOLOGY AND METABOLISM 1995; 9:315-36. [PMID: 7625987 DOI: 10.1016/s0950-351x(95)80354-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Excess endogenous glucocorticoid production, whether ACTH-dependent or ACTH-independent, results in the classic clinical and biochemical picture of Cushing's syndrome. The diagnosis requires demonstration of an increased cortisol secretion rate, best achieved using determination of urinary free cortisol as an index. In mild cases, distinction from the hypercortisolism of pseudo-Cushing states may prove difficult. If the physician is in doubt, a dexamethasone/CRH test should be performed. Primary adrenal Cushing's syndrome can be diagnosed on the basis of undetectable plasma ACTH and the results of adrenal imaging procedures. ACTH-dependent Cushing's syndrome can be differentiated using an oCRH test and imaging procedures. In the presence of a discrete pituitary lesion on imaging, a standard oCRH test with results consistent with such a lesion is sufficient to proceed to transsphenoidal surgery. In the absence of such a lesion or if the oCRH test is equivocal, simultaneous BIPSS with oCRH administration should be performed to distinguish between a pituitary or ectopic source. Surgical ablation is the treatment of choice for all types of Cushing's syndrome. In the 5% of cases with Cushing's disease in whom transsphenoidal surgery fails and in the 5% of cases in whom the disease recurs, repeat transsphenoidal surgery or radiation therapy in association with mitotane treatment are reasonable alternatives. Bilateral adrenalectomy effectively cures hypercortisolism if resection of the ACTH-secreting tumour is unsuccessful and radiation/medical therapy fails.
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Affiliation(s)
- C Tsigos
- Developmental Endocrinology Branch, National Institutes of Health, Bethesda, MD 20892, USA
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Crawford SM, Pyrah RD, Ismail SM. Cushing's syndrome associated with recurrent endometrioid adenocarcinoma of the ovary. J Clin Pathol 1994; 47:766-8. [PMID: 7962637 PMCID: PMC502157 DOI: 10.1136/jcp.47.8.766] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Ectopic production of adrenocorticotrophic hormone (ACTH) by malignant neoplasms is a well recognised cause of Cushing's syndrome but is extremely rare in ovarian carcinoma. A patient who underwent surgery for ovarian carcinoma followed by a course of chemotherapy is reported. The tumour was a bilateral moderately differentiated endometrioid adenocarcinoma and contained numerous chromogranin immunoreactive endocrine cells as well as small foci of ACTH immunoreactivity. She subsequently presented with Cushing's syndrome in association with extensive pelvic recurrence of the tumour.
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Affiliation(s)
- S M Crawford
- Cancer Medicine Research Unit, University of Bradford, West Yorkshire
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Black M, Carey FA, Farquharson MA, Murray GD, McNicol AM. Expression of the pro-opiomelanocortin gene in lung neuroendocrine tumours: in situ hybridization and immunohistochemical studies. J Pathol 1993; 169:329-34. [PMID: 8388056 DOI: 10.1002/path.1711690309] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Neuroendocrine tumours of the lung may be associated with the ectopic adrenocorticotrophin (ACTH) syndrome and may synthesize and secrete ACTH-related peptides in the absence of the syndrome. However, immunocytochemical analysis may not confirm these biochemical findings, particularly in small cell carcinoma, which is poorly granulated. To investigate further the morphological evidence for expression of the pro-opiomelanocortin (POMC) gene in neuroendocrine lung tumours, we have examined a series of 46 small cell carcinomas and 13 carcinoid tumours of the lung by in situ hybridization for POMC mRNA using a digoxigenin-labelled oligoprobe. We have compared the findings with the immunocytochemical detection of ACTH and beta-endorphin. In situ hybridization was positive in 15 of 46 small cell carcinomas (33 per cent) and in 8 of 13 carcinoid tumours (62 per cent). Immunocytochemical staining was positive in only one carcinoid tumour. These in situ hybridization studies have corroborated biochemical data indicating POMC gene expression in a high proportion of lung neuroendocrine tumours. This suggests that the low levels of expression detected by immunocytochemistry may be due to low levels of hormone storage. Multivariate analysis showed a weak negative association between POMC expression and survival in small cell carcinomas, although this did not reach statistical significance.
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Affiliation(s)
- M Black
- University Department of Pathology, Royal Infirmary, Glasgow, U.K
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Schteingart DE. Ectopic Secretion of Peptides of the Proopiomelanocortin Family. Endocrinol Metab Clin North Am 1991. [DOI: 10.1016/s0889-8529(18)30253-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Abstract
Endocrine tumors of the pancreas may produce characteristic syndromes attributable to the increased secretion of one or more hormones. These tumors provide valuable opportunities for the analysis of hormone biosynthesis and secretion in the neoplastic human endocrine cell. The authors studied a pancreatic endocrine tumor obtained from a patient with classical glucagonoma syndrome. Characterization of plasma and tumor glucagon-like immunoreactivity (GLI) by high-performance liquid chromatography and radioimmunoassay for GLI showed different chromatographic profiles, with glucagon the major molecular form in the tumor, and glicentin and oxyntomodulin predominating in plasma. Although immunocytochemical staining of the tumor showed only focal weak positivity for glucagon, tumor extracts contained large amounts of immunoreactive GLI peptide. Northern blot analysis of tumor RNA demonstrated that abundant glucagon mRNA transcripts were present, just slightly larger in size than those detected in normal pancreas and intestine. Electron microscopic analysis of the tumor cellular ultrastructure revealed only occasional small electron dense secretory granules. A large number of complex lysosome-like structures of variable size and electron density were detected throughout the cytoplasm and ringing the nucleus of most cells, a feature atypical of endocrine tumors of the pancreas. Primary cultures of dispersed tumor cells were established and, in contrast to previous results, were obtained using normal or neoplastic islet cell models, GLI secretion was found to be stimulated eightfold by incubation with 5 mM dibutyryl cyclic adenosine monophosphate. Phorbol myristate acetate, the calcium ionophore A23187, and sodium butyrate had no effect on GLI secretion in vitro. These observations indicate that neoplastic human A cells may have abnormalities at different points in the biosynthesis and secretion of glucagon.
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Affiliation(s)
- D J Drucker
- Department of Medicine, Toronto General Hospital, Ontario, Canada
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White A, Clark AJ, Stewart MF. The synthesis of ACTH and related peptides by tumours. BAILLIERE'S CLINICAL ENDOCRINOLOGY AND METABOLISM 1990; 4:1-27. [PMID: 2167656 DOI: 10.1016/s0950-351x(05)80313-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Despite all we have learned, the reason why certain tumours and particularly non-pituitary tumours synthesize ACTH remains an enigma. There is no clear theory which links the neoplastic process with the expression of peptide hormones but it is interesting to speculate that the amplification of certain oncogenes may be linked to de-repression of hormone genes. Once the gene has been switched on, there should be some mechanism for preventing continuous expression and in the pituitary the POMC gene is normally inhibited by glucocorticoids. Therefore it is crucial to investigate the role of glucocorticoids in non-pituitary tumours and this requires an understanding of the molecular mechanisms involved in glucocorticoid inhibition of the normal POMC gene in the pituitary. The evidence presented in this chapter describing the glucocorticoid receptor binding site in the promoter region of the POMC gene in rat pituitary gives an exciting insight into the regulatory mechanisms and their potential for aberrant control. Taken with the presence of pituitary-specific regions regulating the POMC gene promoter there appear to be multiple approaches to dissecting out the differences in non-pituitary tumours. Thus in a relatively short period of time there has been a marked increase in our understanding of the molecular mechanisms underlying POMC gene expression. At the level of the peptides, progress has been slower. We are now aware that secretion of ACTH implies that a number of other peptides will be found in the circulation, even though there is limited evidence for a specific role for any of the co-secreted peptides. However, it is hard to understand the conflicting reports that N-POC is synthesized by non-small cell and small cell carcinoma of the lung when ACTH, which we assume to be co-secreted, is thought to be synthesized only by small cell carcinoma. The most likely explanation for this is the difficult nature of the radio-immunoassays for these hormones and the problems associated with studying large groups of clearly defined patients. Development of very simple methods for measuring the ACTH precursors has demonstrated that they are released into the circulation in normal subjects and that the levels are markedly elevated in non-pituitary tumours, suggesting that they are the major circulating forms in the ectopic ACTH syndrome. This implies that these tumours cannot process the precursor molecules suggesting that the processing enzymes are lacking.(ABSTRACT TRUNCATED AT 400 WORDS)
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Warren WH, Gould VE. Long-term follow-up of classical bronchial carcinoid tumors. Clinicopathologic observations. SCANDINAVIAN JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY 1990; 24:125-30. [PMID: 2166332 DOI: 10.3109/14017439009098055] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Twenty-seven cases of classical bronchial carcinoid were followed up for at least 10 years after curative resection. Surgery was conservative in 15 cases. True lymph-node metastases were identified at operation in two cases. Distant metastases were confirmed in two patients after 5 and 10 years, respectively. One died of unrelated cause 10 years, and the other is alive 19 years, postoperatively. Radiotherapy relieved bone pain in both cases, and chemotherapy halted disease progression in one of them. In immunostaining the original histologic material, all carcinoids expressed neuron-specific enolase, and most expressed chromogranin A, synaptophysin and serotonin. Demonstration of ACTH and related opiopeptides did not portend a more aggressive course or identify cases with nodal metastases. Despite their low malignant potential, long-term follow-up of bronchial carcinoids is warranted. Even in the rare cases of distant metastases, long-term survival seems to be the rule. The occasional presence of nodal metastases and/or demonstration of ACTH and other opiopeptides, while more frequent in neuroendocrine carcinomas, are not inconsistent with bronchial carcinoids and seemingly do not alter their overall favorable prognosis.
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Affiliation(s)
- W H Warren
- Department of Cardiovascular-Thoracic Surgery, Rush Medical College, Chicago
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