The differential diagnosis and treatment of Cushing's syndrome

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Ectopic adrenocorticotropic hormone secretion from lung tumors causing Cushing syndrome is associated with high rates of morbidity. Optimal management remains obscure because knowledge is based on rare reports with few patients. An observational case series review from 1982 to 2020 was conducted. Participants underwent curative-intent surgery for a lung neuroendocrine tumor causing Cushing syndrome. Of the 68 patients, the median age was 41 years (range, 17-80 years), 42.6% (29 of 68) were male, 81.8% (54 of 66) were White, with a mean follow-up after surgery was 16 months (range, 0.1-341 months). Lobectomy was the most common procedure (48 of 68 70.6%), followed by wedge resection (16 of 68 23.5%) and segmentectomy (3 of 68 4.4%). Video-assisted thoracoscopic surgery was performed in 19 of 68 (27.9%) of patients. Surgical morbidity was 19.1% (13 of 68), and perioperative mortality was 1.5% (1 of 68). Lymph node positivity was 37% (22 of 59) when evaluable. The overall incidence of persistence/recurrence was 16.2% (11 of 68) with a median time to recurrence of 55 months (range, 18-152 months). The median disease-free survival was reached in 12.7 years (0.1-334 months). There were no statistical differences in disease-free survival based on tumor size, stage (8th edition TNM), whether full systematic lymphadenectomy was performed or not, nodal status, or surgical approach. In this case series study, neuroendocrine pulmonary tumors associated with Cushing syndrome had increased nodal metastasis, higher recurrence, and lower DFS than quiescent bronchopulmonary carcinoid tumors, but many patients experienced favorable outcomes. This observation is underscored by the discordance of TNM-stage classifications vs prognosis. Observing no difference in surgical techniques, the implication may be that a lung-sparing approach could suffice. These results may reflect the intrinsic importance of the hormone physiology instead of the carcinoid biologic factors. Confirming a diagnosis of Cushing disease (CD) remains challenging, yet is critically important before recommending transsphenoidal surgery for adenoma resection. We retrospectively reviewed the preoperative biochemical and imaging data in 105 patients with presumed CD to evaluate whether they could predict post-operative remission. Patients were classified into 3 groups: group A (n = 84) pathology-proven ACTH adenoma; group B (n = 6) pathology-unproven but with postoperative hypocortisolemia consistent with CD; and group C (n = 15) pathology-unproven, without postoperative hypocortisolemia. Group A + B were combined as confirmed CD and group C as unconfirmed CD. All groups had a similar clinical phenotype. Compared with group C, group A + B had higher mean UFC (P < 0.001), LNSC (P = 0.003), DST (P = 0.06), and ACTH (P = 0.03) and larger MRI-defined lesions (P < 0.001). Early (3-month) biochemical remission was achieved in 76/105 (72%) patients: 76/90(84%) and 0/15(0%) of group A + B vs group C, respectively, P < 0.0001. In group A + B, nonremission was strongly associated with adenoma cavernous sinus invasion. Use of strict biochemical thresholds may help avoid offering transsphenoidal surgery to presumed CD patients with equivocal data and improve surgical remission rates. Patients with Cushingoid phenotype but equivocal biochemical data warrant additional rigorous testing.