An abnormal chest x-ray finding in a 79-year-old man during a health checkup program in X-6 led him to consult a nearby physician. Suspected of having lung cancer, the patient presented to our department on October 28, X-6. He was confirmed to have a history of pulmonary tuberculosis, disc herniation, and chronic obstructive pulmonary disease (COPD) but no particular family history. He reported having smoked 20 cigarettes a day between the ages of 20 and 72 years and having had 1 cup of distilled spirits a day. A bronchoscopic examination performed on November 2 led to the diagnosis of EGFR mutation-negative SCC cT2aN0M1b stage IV (M1, bone metastasis) in this patient. Thus, he underwent 4 courses of first-line chemotherapy with CBDCA and S-1 from January 17, X-5 onwards, followed by an additional course of treatment with S-1, after which he was diagnosed with progressive disease (PD) with enlargement of the primary lesion. All bone metastases were shown to have disappeared on PET, which led to the patient being down-staged as cT2N0M0 stage IIA. Preferring not to be operated on for his cancer, the patient chose to undergo radical radiotherapy with 50-Gy (five fractions at 10-Gy) between January 22 and February 4, X-4 but was diagnosed with PD on CT in September the same year with enlargement of the primary lesion. Subsequently, he underwent 5 courses of chemotherapy with docetaxel from October 1 onwards, 4 courses of chemotherapy with carboplatin plus paclitaxel from February 18 onwards, and 19 courses of chemotherapy with gemcitabine from January 13, X-2 onwards. Finally, diagnosed with PD again, he was started on nivolumab as a fifth-line treatment from August 23, X-1 onwards, which elicited PR in this patient thus leading to the regimen being continued up to 20 courses (final administration, May 2, X). A blood sample was drawn from him on May 9, X, which revealed his serum sodium level to be 134 mmol/L. The patient began to complain of nausea, appetite loss, and difficulty walking from around May 13, X and further complained of worsening nausea on May 15, X and was symptomatically treated with drip infusions and oral agents. However, he had persistent nausea, difficulty eating, and abdominal bloating until he was found to have difficulty walking, dyspnea, and oliguria on May 18 and was immediately admitted on the same day.
At admission, he had clear consciousness with clear breath sounds (body temperature, 34.9  C; blood pressure, 114/58 mmHg; pulse rate, 83/minute; breathing rate, 20 times/minute; and SpO2 at room temperature, 98%), with no signs of jaundice or anemia in bulbar conjunctiva, cardiac murmur, or abdominal bloating or tenderness, and with no neurological findings suggestive of paralysis.
Hematological findings at admission are summarized in Table 1. Chest roentgenogram findings at admission (Fig. 1a) included a tumor mass shadow in the upper lung field, left costophrenic (CP) angle blunting, and a central venous access port device planted in the left subclavian vein. Plain chest-abdominal CT findings (Fig. 1b) included a 50-mm tumor mass shadow in the left superior lobe, left pleural effusion, and absence of gut distention or niveau formation.
After admission, the patient was being observed while being treated with drip infusions, with no clues available as to the cause of nausea and appetite loss in this patient. However, on the third day of admission, he was found to have a decline in blood pressure, when adrenal failure was suspected and hydrocortisone was administered at a daily dose of 500 mg, which led to an increase in blood pressure as well as improvements in activities of daily living (ADL) and appetite in this patient. On the fifth day of admission, ACTH and cortisone levels were confirmed to have decreased based on a blood sample drawn before hydrocortisone administration, which led to the diagnosis of adrenal failure in this patient. With attention given to monitoring his symptoms and serum sodium levels, hydrocortisone was gradually down-titrated to be maintained at 15 mg/day. Subsequently, an array of endocrinological investigations were conducted to identify the organ responsible for adrenal failure as well as to assess hormone secretory status in this patient (Table 2). The insulin hypoglycemia test, GH-releasing peptide 2 (GHRP-2) test, and corticotrophin-releasing hormone (CRH) test elicited a poor ACTH/cortisol response, while the thyrotropin-releasing hormone (TRH) test and luteinizing hormone-releasing hormone (LHRH) test elicited an intact TRH/LHRH response, in this patient, which led to the diagnosis of isolated ACTH deficiency, with the pituitary determined as the responsible organ. Again, based on the pituitary MRI (Fig. 2) finding suggestive of no pituitary enlargement and the fact that this ACTH deficiency developed during nivolumab therapy, the condition was finally diagnosed as nivolumab-induced isolated ACTH deficiency.
Hydrocortisone administration led to an improvement in PS and the patient was discharged on the 22nd day of admission. Subsequently, the patient was restarted on nivolumab therapy from September, X, and is currently receiving the 44th course of nivolumab therapy, which continued to elicit PR from the patient, with no evidence of recurrent adrenal failure.