Rapid disease progression in a patient with mismatch repair-deficient and cortisol secreting adrenocortical carcinoma treated with pembrolizumab

Abstract

Context: Metastatic adrenocortical carcinoma (ACC) is an aggressive malignancy with a poor prognosis and limited therapeutic options. A subset of ACC is due to Lynch syndrome, an inherited tumor syndrome resulting from germline mutations in mismatch repair (MMR) genes. It has been demonstrated that several cancers characterized by MMR deficiency are sensitive to immune checkpoint inhibitors that target PD-1. Here, we provide the first report of PD-1 blockade with pembrolizumab in a patient with Lynch syndrome and progressive cortisol-secreting metastatic ACC.

Case report: A 58-year-old female with known Lynch syndrome presented with severe Cushing's syndrome and was diagnosed with a cortisol-secreting ACC. Three months following surgical resection and adjuvant mitotane therapy the patient developed metastatic disease and persistent hypercortisolemia. She commenced pembrolizumab, but her second cycle was delayed due to a transient transaminitis. Computed tomography performed after 12 weeks and 2 cycles of pembrolizumab administration revealed significant disease progression and treatment was discontinued. After 7 weeks, the patient became jaundiced and soon died due to fulminant liver failure.

Conclusion: Treatment of MMR-deficient cortisol-secreting ACC with pembrolizumab may be ineffective due to supraphysiological levels of circulating corticosteroids, which may in turn mask severe drug-induced organ damage.

Keywords: Adrenocortical carcinoma; Cortisol; Hepatitis; Lynch syndrome; Pembrolizumab.

Fig. 1

Time course of laboratory and radiological results. (A) The 24-hour urinary cortisol and ALT concentrations plotted against time (days). Solid line indicates urinary free cortisol levels. Dashed line indicates ALT levels. (B) Representative cross-sectional CT images at diagnosis (day 0), postadrenalectomy (day 91), and following initiation of pembrolizumab therapy (day 180). White arrowheads indicate the primary tumor at diagnosis and, following treatment, sites of local and metastatic recurrence.

Fig. 2

(A) Representative hematoxylin and eosin-stained photomicrograph of ACC. (B–G) Immunohistochemical analyses of protein expression in resected ACC. (B) PD-L1 expression in tumor cells was <1%. The tumor did not express (C) MSH2 or (E) MSH6 but expression of (D) MLH1, (F) PMS2, and (G) β2-microglobulin was preserved (scale bar = 200 µm).