Ectopic adrenocorticotropic hormone‐secreting carcinoid with solitary cryptococcosis in the lungs

Abstract Background Carcinoid tumors can on rare occasions ectopically produce adrenocorticotropic hormone (ACTH), causing Cushing's syndrome, and patients could become immunocompromised. Care must therefore be taken regarding infectious complications. In particular, ACTH‐producing pulmonary carcinoid is not easy to diagnose by itself, and when combined with pulmonary nodules as infectious foci, each is very difficult to diagnose. Case The patient was a 71‐year‐old woman with refractory diabetes. She showed clinical symptoms of Cushing's syndrome during treatment for diabetes and ectopic ACTH production was suspected based on biochemical and imaging tests. Nodules were identified in the left lung apex and lingual segment. Examination of resected nodules revealed that the nodule in the apex was pulmonary cryptococcosis, while the nodule in the lingual segment represented typical carcinoid. After surgery, clinical symptoms, laboratory findings, and diabetes all improved. Conclusion We present this very instructive case in terms of the difficulty of diagnosing ACTH‐producing tumors, the possibility of infection complicating the immunodeficiency caused by ACTH‐producing tumors, and the surgical strategy.


| INTRODUCTION
Ectopic adrenocorticotropic hormone (ACTH)-producing tumors produce ACTH from sources other than the pituitary gland. Small cell lung carcinoma is the most common ectopic ACTH-producing tumor, accounting for 45%-50%, followed by thymic carcinoid (15%-42%) and bronchopulmonary carcinoid (10%-40%). 1,2 Less than 1% of all pulmonary tumors are carcinoid tumors. 3 Only 1%-5% of bronchopulmonary carcinoids produce ACTH. 4 Another study specifically reporting on resected pulmonary carcinoids, 24.8% of tumors produced ACTH, and 17.4% of those tumors were associated with Cushing's syndrome. 5 Carcinoid tumors are highly sensitive to detection by somatostatin receptor scintigraphy (SRS) because of the high expression of somatostatin receptors, but some cases may go undetected. 6 In such cases, the utility of 68 Ga-DOTATATE imaging has been reported in recent years. 7,8 Cryptococcal infections usually occur in immunocompromised patients, and excessive secretion of ACTH and cortisol could theoretically cause immunodeficiency. 9 In a previous report, disseminated cryptococcosis developed in a patient with pituitary Cushing's disease. 10 We present a case of isolated pulmonary cryptococcosis due to immunodeficiency caused by an ectopic ACTH-producing tumor and associated elevations in cortisol, in which preoperative diagnosis proved difficult and diagnosis from a surgical specimen was required. This case provides a valuable lesson in that when ACTH-producing tumors are suspected and multiple nodules are present in the lungs, infectious lesions may be present along with carcinoid tumors.

| Case
The patient was a 71-year-old woman. She did not keep any birds or animals, and had been treated for diabetes for over 30 years. She was on diet therapy and insulin therapy, but her diet appeared inadequate and her hemoglobin (Hb)A1c levels were within the range of 7.9%-  0.288 μg/dL), confirming improvement of Cushing's syndrome. Furthermore, basal plasma concentration of ACTH was 20.05 pg/mL and cortisol was 10.32 μg/dL, so secretions were considered to be adequately maintained and hydrocortisone dose was further tapered and terminated 2 years postoperatively. Preoperatively, we did not test for cryptococcal antigen in the serum because we did not strongly suspect infection. Results for cryptococcal antigen in the serum examined 2 days postoperatively were negative. Cerebrospinal fluid was also examined after discharge, but no cryptococcus was found. The patient did not request additional lobectomy. As of July 2022, 18 months postoperatively, the patient was alive with no tumor recurrence and no clinical or laboratory evidence of elevated ACTH or Cushing's syndrome. She remains on insulin therapy for diabetes, but HbA1c is hovering around 7%. She patient is living independently and we will continue careful observation with laboratory data and CT.

| DISCUSSION
In this case, the patient showed elevated levels of ACTH and cortisol and poorly controlled diabetes mellitus that was affected by ectopic ACTH-producing typical carcinoid in the lingual region of the left lung.
This was thought to have caused the patient to become immunocompromised and to have developed isolated pulmonary cryptococcosis in the left lung apex. Past reports have described cases of systemic infection due to the immunocompromised state caused by ectopic ACTH-producing tumors, 10 but cases of infection with isolated nodule only in the lungs, as in this case, are rare. 11,12 No elevated inflammatory response was seen preoperatively and sputum culture yielded negative results. On CT, nodules in the apex and lingual region appeared difficult to diagnose by bronchoscopic lung biopsy. Based on the elevated ACTH and cortisol levels and CT results, either or all of the nodules were suspected to be ACTH-producing tumors. In recent years, the usefulness of 68 Ga-DOTATATE imaging as a test for diagnosing and localizing neuroendocrine tumors, including carcinoid, has been reported. 7,8 However, since our hospital lacks the equipment for 68 Ga-DOTATATE and the test is not covered by insurance in Japan, we performed the 111 In-octreotide scan. Unfortunately, the octreotide scan did not yield useful findings, but ACTH-producing carcinoid tumor was still suspected, and surgery was performed to allow diagnosis from the resected specimens. Where available, 68 Ga-DOTATATE scans could be useful in determining treatment strategies, particularly in cases of suspected carcinoid tumors, including multiple pulmonary nodules, such as in the present case.
Intraoperative pathological evaluation of the tumor at the lung apex led to the suspicion of mycobacterial infection. The operation was therefore terminated with partial resection of two nodules from the lung. Since lobectomy would have been performed if pulmonary carcinoid had been diagnosed, the patient was carefully followed-up postoperatively with endocrine and imaging tests. If a nodule is suspected to represent pulmonary carcinoid with ectopic ACTH production, a nodule of pulmonary infection may be present at the same F I G U R E 3 Tumor in the lingular area: Spindle cells proliferated in ribbon-and spore-like patterns with hematoxylin and eosin stain. Magnification, Â200.

ACKNOWLEDGMENTS
We wish to thank M. Morgan from FORTE Science Communications (www.forte-science.co.jp) for editing a draft of this article.

CONFLICT OF INTEREST
This report did not receive any other specific grant from funding agencies in the public, commercial, or not-for-profit sectors. None of the authors have any commercial or financial involvements in connection with this study that represent or appear to represent any conflicts of interest.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.

ETHICAL STATEMENT
Institutional approval was not required for this case report. All patient information was deidentified for the purposes of this case report.