Development of Delayed Paraneoplastic ACTH Syndrome in Small Cell Lung Carcinoma

Abstract

Background: Paraneoplastic/ectopic ACTH syndrome (EAS) is a rare but well-recognized syndrome in small cell lung carcinoma (SCLC), occurring in 1-5% of cases (1) and most often at diagnosis. We present a patient with SCLC who developed paraneoplastic ACTH syndrome 9 months after initiation of treatment. Case: A 73 year old female with long history of smoking and COPD (on home O ₂) and SCLC seen during hospitalization with severe muscle cramps, generalized weakness, hypertension and hypokalemia. Eleven months prior, she was diagnosed with SCLC after presenting with left superior mediastinum, supraclavicular and neck lymphadenopathy. She received 4 cycles of chemotherapy and immune checkpoint inhibitor (ICI) therapy (atezolizumab) was also initiated and continued throughout. Good response to therapy occurred until nine months post initiation, when relapse in same regions was identified on repeat PETCT. Physical examination revealed new onset resistant hypertension up to 240/120mmHg, and extensive bilateral lower extremity edema. Labs showed hypokalemia of 2.3 mmol/l and metabolic alkalosis with serum bicarbonate 43 mmol/l. Further investigations showed a random cortisol of 97.1 ug/dl with repeat of 175.9 ug/dl the following AM. ACTH was 374.1pg/ml. TSH was 0.25 uU/ml with low normal T4 and T3. Pituitary MRI showed no evidence of hypophysitis or enlargement. Repeat biopsy of cervical lymph node was unchanged from initial biopsy with two notable differences: morphology showed a “more organized, trabecular pattern” and MIB-1 staining had declined from 70-80% to 20%, and tumor cells stained positive for ACTH. She did not respond to octreotide, but did respond to ketoconazole (hypokalemia, edema improved and cortisol levels decreased to 24.2 ug/dl). However, hepatotoxicity occurred and thus it was discontinued with rapid rise of cortisol. As she was not a candidate for bilateral adrenalectomy, we started metyrapone with lowering of cortisol levels within 4 doses. However, new cavitary lesions on chest CT developed with concern for disseminated fungal infection. Patient elected for hospice and passed away the following day. Conclusion: We present an unusual case of paraneoplastic ACTH syndrome that developed after immunotherapy in SCLC. In summary, the relapse of SCLC while on immune therapy was associated pathologically by differentiation into a neuroendocrine tumor type and biochemically by a considerable ACTH production. We conclude that ACTH production with subsequent severe hypercortisolism causing immunosuppression may be a novel mechanism by which SCLC can evade immunotherapy.

Reference: (1) Nagy-Mignotte H, Shestaeva O, Moro-Sibilot D et al. Prognostic impact of paraneoplastic cushing’s syndrome in small-cell lung cancer. J Thorac Oncol. 2014 Apr,9.