Endocrine Abstracts

Background: Lynch syndrome (LS), an autosomal dominant genetic cancer predisposition syndrome, is caused by mutations in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 or PMS2. In autosomal dominant genetic cancer syndromes like LS, a germline mutation hits one MMR gene allele so that a somatic mutation in the wild-type allele of the same MMR gene will cause a complete loss of function. This results in hypermutability and microsatellite instability.1 LS gives rise to a broad spectrum of tumours, mainly colorectal and cervix carcinoma. We describe the first case of a neuro-endocrine lung tumour presenting as a Cushing syndrome in a LS patient.

Case presentation: A 49-year-old female LS patient (heterogenous for MLH1 mutation c.2103+3A>C) was diagnosed with Cushing syndrome after developing obesity WHO class 2, facial flushing, arterial hypertension and hypokalaemia. Serum, midnight salivary, and 24-hour urinary cortisol were markedly increased. ACTH was elevated at 148 pg/ml (normal range 7.2-63.3 pg/ml). A marked cortisol excess (urinary free cortisol 30 x ULN) and a normal pituitary MRI suggested an ectopic ACTH source. Chest/abdominal CT showed gross infracarinal lymph nodes (up to 51 mm) and a 15 mm-sized lung nodule, which was present and unaltered since 2016. The mediastinal lymph nodes exhibited increased somatostatin receptor (SSTR) expression on 68Gallium-DOTANOC-scan. The patient was started on spironolactone and octreotide in a dose elevation scheme till 1000 µg/24 h IV, quickly switched to ketoconazole 200 mg tid due to insufficient effect of octreotide on the cortisol levels. An endoscopic ultrasound-guided fine needle biopsy of the infracarinal lymph nodes confirmed the localization of a neuro-endocrine tumour with 10% cytoplasmatic ACTH expression. A robot-assisted thoracoscopic resection of the lymph nodes and a wedge resection of the lung nodule were performed. Ketoconazole could be ceased afterwards. Hydrocortisone was needed to counter postoperative adrenal insufficiency and was gradually tapered over a three-month period. Pathology of the lung nodule and lymph nodes proved an atypical carcinoid tumour, with tumour-free resection margins. On immunohistochemical analysis, a defect of MLH1/PMS2 was evident, consistent with the patient’s germline mutation, and the tumour showed a microsatellite-high phenotype. Three months after surgery, a new 68Gallium-DOTANOC-scan suggested local tumour relapse in the mediastinal lymph nodes. Octreotide was started and the patient received concomitant chemoradiotherapy (cisplatin 25 mg/m²-etoposide 100 mg/m² q3w); chemotherapy was ceased after 3 cycles due to intolerance (therapy-refractory vomiting) and severe grade 4 pancytopenia. Since then, she remains in sustained disease control, while continuing octreotide long-acting release 30 mg q4w.

Discussion: Cushing’s syndrome in this patient with LS was at first suggestive of adrenocortical carcinoma, a known tumour type in the Lynch spectrum. 2 Nevertheless, the cortisol excess proved to be ACTH-dependent and the source of ACTH was an atypical lung carcinoid with mediastinal lymph node extension. A total of 28 cases of neuro-endocrine tumours in LS have been described in the literature so far. Twenty of the 26 tumours with a known origin were located in the gastrointestinal and gynaeco-urological tract; the other reported tumour types were pheochromocytoma and pituitary tumours. In the case presented, the tumour is most probably driven by LS and not merely a coincidentally occurring neoplasm in a LS patient. This is supported by the fact that the tumour is MSI-high, as it was suggested that it takes a sufficient amount of cell cycles before MSI occurs, which is unlikely in a coincidental tumour. 3 Also, immunohistochemical analysis of the tumour showed loss of MLH1/PMS2, consistent with the germline mutation of our patient. In conclusion, our case expands the neuroendocrine tumour spectrum in LS. Clinicians treating LS patients should be aware of atypical or rare tumour presentations.

References: 1. Bengtsson, D. et al. Corticotroph pituitary carcinoma in a patient with Lynch Syndrome (LS) and pituitary tumors in a nationwide LS cohort. Journal of Clinical Endocrinology and Metabolism 102, 3928– 3932 (2017).

2. Kaur, R. J. et al. Adrenal cortical carcinoma associated with lynch syndrome: A case report and review of literature. Journal of the Endocrine Society 3, 784–790 (2019).

3. Karamurzin, Y. et al. Unusual DNA mismatch repair-deficient tumors in Lynch syndrome: A reportof new cases and review of the literature. Hum Pathol 43, 1677–1687 (2012).