A 69-year-old man underwent right nephrectomy surgery in May 2019 for a renal carcinoma with sarcomatoid (Ki67 40%, p53 <1%) and poorly differentiated clear renal cell components, pT3a pNx, stage III according to AJCC 2017. The postsurgery total-body contrast-enhanced computed tomography (CT) showed suspected pulmonary and mediastinal lymph node metastasis, confirmed by transbronchial needle aspiration (TBNA). According to the prognostic criteria of Motzer and Coll and Heng, for the presence of hypercalcemia and the time to start systemic treatment less than 1 year after diagnosis, the patient belonged to the intermediate prognosis group. In August 2019, he began immunotherapy with nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks. In view of the combination of an anti-CTLA4 and an anti-PD1, a periodic monitoring of thyroid function (TSH, FT3, FT4), for each of the first four doses, and hypophyseal function (basal ACTH and cortisol) was performed. At the third administration, we observed a grade 1 (G1) hyperthyroidism according to Common Terminology Criteria for Adverse Events 5.0 (CTCAE) [ TSH 0.03 microIU/ml (normal range 0.27-4.2),  FT4 2.29 ng/dl (normal range 0.7-1.48), FT3 2.5 pg/ml (normal range 1.71-3.71)], without related symptoms, and as recommended by guidelines, immunotherapy was continued with laboratory monitoring. At the fourth cycle, the G1 hyperthyroidism was stable. The revaluation CT showed a partial response and nivolumab was continued. At the first maintenance cycle, the patient was asthenic, with muscle weakness, constipation, and limitation of daily activities. Laboratory tests showed normal pituitary function and confirmed G2 hypothyroidism [TSH 130.0 microIU/ml (0.27-4),   FT4 0.10 ng/dl (0.7-1.48), FT3 2.0 pg/ml (1.71-3.71)   thyroglobulin 187 ng/ml (normal range 3-40)]. Treatment was discontinued until control of symptoms, from December 2019 to February 2020, and a different thyroid hormone supplementation with levothyroxine was prescribed ( Figure 1 ). In February 2020, the patient started therapy with nivolumab, reaching in August 2020 an optimal response with a resolution of hypothyroidism at the end of October 2020.
In December 2020, the patient had G2 asthenia, restriction of activities of daily living but not of personal care, dizziness, headache, non-alterations of vision, and G1 diarrhea. Laboratory tests showed hypoglycemia (72 mg/dl), hyponatremia, reduced levels of ACTH (5.4 pg/ml; normal range 7.2-63.3 pg/ml), and cortisol (3.5 microg/l; normal range 23-194 microg/l) at 8:00 a.m., TSH (0.18 microUI/ml), and FT4 (0.6 ng/dl). The ACTH stimulation test (1 microg) showed an insufficient adrenal response (basal cortisol: 3.3 microg/dl; cortisol 60 min: 6.8 ug/dl). Due to the headache and dizziness, a magnetic resonance imaging (MRI) of the brain was performed and highlighted the radiological signs of a meningeal irritation attributable to an hypophysitis ( Figure 2 ).
Then, in the presence of secondary adrenal insufficiency and secondary hypothyroidism, a diagnosis of immuno-related hypophysitis was placed, also supported by radiological imaging. The ICI was stopped, and an adrenal and thyroid replacement therapy (levothyroxine, 125 microg in the morning and cortisone acetate 25 mg upon awakening and 12.5 mg in the early afternoon) was administered. The immunotherapy was suspended for a month and resumed after normalization of pituitary function. The patient still maintains a complete radiological response with an OS of 29 months.