Characterization of Outcomes by Surgical Management of Lung Neuroendocrine Tumors Associated With Cushing Syndrome

Key Points Question What is the optimal surgical management of ectopic adrenocorticotropic hormone secreting pulmonary carcinoid tumors associated with Cushing syndrome (CS)? Findings In this case series study of 68 patients with Cushing syndrome, ectopic adrenocorticotropic hormone–secreting carcinoid tumors with CS were associated with increased metastasis to lymph nodes, higher recurrence, and lower overall disease-free survival at 5 and 10years compared with quiescent bronchial carcinoid tumors, irrespective of histologic subtype, with no difference in outcome based on surgical approach. Meaning Results of this study suggest that underlying carcinoid biologic factors may not be as important as the symptomatic hormonal physiology, and a lung-sparing surgical approach coupled with routine lymphadenectomy may be an optimal intervention when CS resolves.


eMethods
Specific protocol approvals were from the National Institute Child Health and Human Development (NICHD) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Institutional Review Boards. Ectopic adrenocorticotropic hormone secretion (EAS) was likely if inferior petrosal sinus sampling (IPSS), 8 mg dexamethasone suppression and/or Corticotropin Releasing Hormone (CRH) stimulation tests were consistent with the diagnosis. 1 Such patients underwent additional testing for tumor markers at the endocrinologist's discretion, including urine 5hydroxyindoleacetic acid (5-HIAA), serum gastrin, plasma and urine catecholamines and metabolites and/ or serum calcitonin. Imaging studies identifying the source of EAS included computed tomography (CT) and/or magnetic resonance imaging (MRI) scans of the neck, chest, abdomen, and pelvis. Some patients also underwent scintigraphy with 6 mCi octreotide, 18 mCi octreotide, 18 F-DOPA positron emission tomography (PET)/CT, and/or Gallium-68 Dotatate PET/CT. Surgical techniques included posterolateral thoracotomy, anterior thoracotomy, and video-assisted thoracoscopic surgery (VATS). The goal of operation was to resect all gross disease for negative margins whenever practicable. Post-operatively, morning serum cortisol, Adrenocorticotropic Hormone (ACTH) and 24-hour urinary cortisol levels were measured. Patients were considered disease-free if the post-operative serum cortisol level was below 5 g/dL in those who were hypercortisolemic at the time of surgery. Adrenalectomized patients were deemed cured if ACTH decreased to normal adrenalectomized levels and suppressed after 8 mg dexamethasone. Eucortisolemic patients receiving preoperative steroidogenesis inhibitors were considered cured if they had normal 1 mg dexamethasone suppression and a normal cortisol diurnal rhythm. After surgery, patients with persistent endocrinopathy continued follow-up and laboratory/imaging testing to identify EAS.
Tumors were reviewed by pathologists, with most specimens evaluated for ACTH by immunohistochemistry (IHC). Histologic classification as Atypical Carcinoid (AC) was based on World Health Organization (WHO) criteria, 2 with any of these features: increased mitotic rate, pleomorphism, irregular nuclei, or areas of necrosis. Otherwise, tumors were classified as Typical Carcinoid (TC) if none of those features were present. Staging was updated according to the 8 th edition of the American Joint Committee on Cancer (AJCC) system for lung cancer. 3 Tumors without nodal evaluation were categorized as NX. Follow-up information including recurrence, adjuvant treatments, and survival status was identified from the medical record at the last clinical visit or contact and the Social Security Death Index.
For the Kaplan-Meier analysis, patients who completed lung surgery but had ongoing hypercortisolism/ excessive ACTH are defined as persistent and treated as being failures at time zero in the Disease-Free Survival (DFS) curves (i.e., zero duration of being disease-free), while patients who completed lung surgery with no residual hypercortisolism/ excessive ACTH but later redeveloped Cushing's Syndrome (CS) are defined as recurrent and treated as a failure for DFS at the time of recurrence.

Imaging Studies
Chest CT and MRI localized the target pulmonary lesion(s) in 62/68 (91.2%) and 49/61 (80.3%) of patients, respectively. Of the patients with CS and known pulmonary lesions on imaging, 12/65 (18.5%) of patients also had an abnormal pituitary MRI. Since 2002, PET-based modalities have been used routinely to identify a pulmonary source of CS. Dotatate and 18 F-DOPA PET/CT imaging detected lung lesions in 13/20 (65.0%) and 23/37 (62.2%) of patients respectively. Adrenal gland nodules were also noted in 6/60 (10.0%) of patients by abdominal CT imaging. The adrenal lesions were present in the background of bilateral adrenal hyperplasia, and none proved to be ACTH-secreting.

Persistent/Recurrent Disease Patterns and Treatments
Four of seven patients with recurrent tumor underwent adrenalectomy. Six of seven had additional surgical therapy for lung resection with repeated lymph node dissection when indicated, with sub-lobar resection employed in 1/7 of patients. Complete lymph node assessment was performed in 5/7, with 2/7 having a partial nodal assessment (N1 only). Pathologic nodal disease was found in 4/7, including the lone patient with an AC tumor.
Regarding the location of the recurrent tumors, disease occurred locoregionally in 5/7, the contralateral chest in 1/7, or locoregional and distant in 1/7.
Of patients with persistent disease, sub-lobar resection was used in 2/4, with complete nodal dissection performed in 3/4 that yielded negative findings. Persistence of disease after surgery was definitively treated with bilateral adrenalectomy in 1/4, redo-sub-lobar/nodal resection in 1/4, bilateral adrenalectomy plus redo-chest/nodal dissection in 1/4, or medical management in 1/4 until further work up and definitive redo therapy is planned.
Adjuvant therapy was used on a case-by-case basis, including radiation therapy (in a total of 6 patients from our first report 4 ), medical therapy to reduce cortisol production (ketoconazole, aminoglutethimide, cabergoline, metyrapone, and/or mitotane), and repeat surgical resections in the chest or bilateral adrenalectomy per the treating physicians.