Background

Immune checkpoint inhibitors (ICIs) have been shown to contribute to the prolonged survival of patients with non-small cell lung cancer (NSCLC) and have enabled the option of performing complete resections of advanced lung cancers [1,2,3,4,5,6,7,8]. However, the administration of ICIs has been found to be associated with the development of immune-related adverse events (irAEs) [9,10,11]. Additionally, few reports have been published on the occurrence of irAEs in patients who had received immunochemotherapy followed by salvage surgery for NSCLC.

Here, we report a patient with lung cancer who underwent immunochemotherapy followed by surgery and subsequently presented with the irAEs of pituitary hypoadrenocorticism and hypothyroidism.

Case presentation

A 62-year-old man was admitted to our hospital because of fever, dyspnea, and anorexia. His medical history was insignificant except for a 44 pack-year history of smoking. His performance status (PS) was 1, and he had an elevated serum level of carcinoembryonic antigen (5.56 ng/mL). Chest computed tomography (CT) revealed a 73 mm tumor in the hilum of the right lung that compressed the left atrium. The tumor was also suspected of invading the esophagus and a vertebral body (Fig. 1).

Fig. 1
figure 1

Preoperative computed tomography images. The tumor was 73 mm in diameter and located in the right hilum of the lung (a). It compressed the left atrium of the heart. It appeared to invade the esophagus and a vertebral body (b)

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Examination of an endobronchial ultrasound-guided transbronchial needle aspirate from the subcarinal lymph node found squamous cell carcinoma of the lung. There were no distant metastases, and the patient was diagnosed with cT4N2M0-stage IIIB squamous cell carcinoma of the lung. Because the tumor was N2, and was suspected of invading the esophagus, a vertebral body, and left atrium of the heart, complete resection was thought to be impossible. In addition, he had marked emphysema due to smoking, which made radiotherapy difficult. Since the tumor cells were programmed cell death ligand 1 (PD-L1) positive (tumor proportion score = 1%), the patient underwent 4 courses of pembrolizumab plus carboplatin plus nab-paclitaxel chemotherapy in accordance with treatment guidelines for stage 4 NSCLC (Fig. 2).

Fig. 2
figure 2

Clinical course of the patient: four courses of pembrolizumab and carboplatin (CBDCA) plus nabPTX) chemotherapy were administered. After one course, because the patient developed pneumonia, the amounts of the CBDCA and nabPTX were reduced. After the treatment, CT showed that the tumor shrank (images of tumor are identified by red circles), which was considered to be a partial response. Radical surgery was performed on day 34 from the day of the last (fourth) administration of pembrolizumab. On postoperative day 39, the patient complained of anorexia, and on postoperative day 79, he went to the emergency room because of dizziness and worsening anorexia

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Posttreatment CT showed that the tumor had decreased to 44 mm in diameter, which was a partial response. The tumor was downstaged to ycT2bN0M0-stage 2A, which was considered to be resectable by radical surgery. The patient’s preoperative parameters were as follows: vital capacity, 1.92 L; forced expiratory volume in one second, 0.79 L; ratio of forced expiratory volume in one second/forced vital capacity, 43.2%; diffusing capacity for carbon monoxide, 6.40 mL/min/mm Hg; and % diffusing capacity for carbon monoxide, 51.2%. Although the patient’s respiratory function was reduced, he was young, and his PS had improved to 0, therefore, he underwent radical surgery 4 months after receiving immunochemotherapy.

A right lower lobectomy and systematic mediastinal lymph node dissection (ND2a-2) were performed (Additional file 1). The histopathological diagnosis was a keratinizing squamous cell carcinoma with a 4 × 4 mm residual tumor. The proportion of residual tumor cells was 5%, which was a major pathologic response (ypT1miN0M0-stage 1A1). The postoperative course was uneventful, and the patient was discharged on postoperative day 6.

On postoperative day 39, he complained of anorexia, and on postoperative day 79, he came to the emergency room because of dizziness and worsening anorexia. Blood testing showed hyponatremia, hypoglycemia, and eosinophilia (Table 1), which suggested endocrine disorders. He underwent further assessments of his endocrine system. His free triiodothyronine (T3), thyroxine (T4), and adrenocorticotropic hormone (ACTH) serum levels were low, and his serum thyroid-stimulating hormone (TSH) level was high (Table 1). Magnetic resonance imaging revealed swelling of the pituitary gland. A corticotropin-releasing hormone stimulation test showed that the levels of ACTH and cortisol were far below the normal ranges. We concluded that the patient had concomitant pituitary hypoadrenocorticism and hypothyroidism.

Table 1 Laboratory data on postoperative day 79. Blood testing showed hyponatremia, hypoglycemia, and eosinophilia. The free T3 and T4 levels were decreased, and the TSH level was elevated. The ACTH level was also decreased
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Oral and intravenous hydrocortisone were started, followed by oral levothyroxine. Specifically, the patient started taking oral hydrocortisone (15 mg/day) on the day of admission (postoperative day 79). Hydrocortisone was additionally administered either intravenously or orally from days 2 to 9 of hospitalization. Intravenous hydrocortisone (100 mg/day) was administered on days 2 to 4 of hospitalization followed by 75 mg/day on day 5 and 50 mg/day on day 6. The patient received oral hydrocortisone (15 mg/day) on hospitalization days 7 to 9.

On day 7 of hospitalization, he also started to receive oral levothyroxine (25 μg/day), followed by 50 μg/day on days 13 to 19, and thereafter starting on day 20, he received 75 μg/day.

The patient’s appetite improved on day 4 of hospitalization and his serum sodium level increased and normalized on day 11 of hospitalization. The patient was discharged on day 22 of hospitalization. The patient has been receiving ongoing supplementation with oral hydrocortisone and levothyroxine and is doing well 11 months after surgery.

Discussion

According to several global guidelines for patients with unresectable stage 3 NSCLC, cisplatin-based chemoradiotherapy followed by durvalumab is a standard practice [12, 13]. However, when neither radical surgery nor radiotherapy is possible, as in our patient, the guidelines recommend administering chemotherapy based on stage 4 NSCLC. Because the tumor cells were PD-L1 positive, the patient received pembrolizumab plus carboplatin plus nab-paclitaxel chemotherapy, which is the gold standard therapy as recommended by several global guidelines [12, 13].

At present, there are several ongoing clinical trials on preoperative ICIs. Published studies have already reported promising results for obtaining complete resections in patients with advanced lung cancer [1,2,3]. Phase 2 clinical trials such as the NADIM (NCT02716038) [4] and NEOSTAR (NCT03158129) [5] trials showed that preoperative immunochemotherapy obtained increased rates of major pathologic response or complete pathologic response. Other trials that have included patients with N2-IIIB lung cancer, such as the LCMC3 (NCT02927301) and KEYNOTE-671 (NCT03425643) trials, are in progress [6].

IrAEs associated with ICIs have become a concern [9,10,11]. These irAEs are completely different from the AEs associated with conventional anticancer agents. The most frequently reported AEs associated with ICIs involve the skin, gastrointestinal tract, liver, endocrine system, and lungs [14,15,16]. The KEYNOTE-407 study of pembrolizumab plus chemotherapy for advanced and relapsed squamous cell carcinoma of the lung found that 45 of 278 patients (16.2%) developed thyroid dysfunction, with 3 patients (1.1%) showing grade 3 or higher dysfunction. Pituitary dysfunction was observed in 3 patients (1.1%), with 2 patients (0.7%) showing grade 3 or higher dysfunction. Adrenal insufficiency was not observed in any patient [7].

The clinical trials that have investigated the preoperative ICIs for patients with NSCLC have not reported the rates of irAEs in their patients. Although irAEs could have developed during neoadjuvant therapy in the clinical trials setting, few reports have detailed documentation on the time of onset of irAEs. There are also few reports on the occurrence of irAEs after surgery for NSCLC.

The most common reported side effects associated with the administration of pembrolizumab to patients with NSCLC were hypo- and hyperthyroidism [17]. Although pembrolizumab plus a platinum-based regimen were reportedly less likely to lead to an endocrine disorder than other immunochemotherapies such as nivolumab, durvalumab, and atezolizumab [18], whether there are differences between the rates of irAEs associated with various ICIs has not been clarified. Anti-PD-L1 agents have produced a higher incidence of thyroid dysfunction compared to anticytotoxic T lymphocyte antigen-4 antibodies [19, 20].

Our patient had both hypothyroidism and secondary hypoadrenocorticism due to hypopituitarism. In addition to the AEs associated with immunochemotherapy, it cannot be ruled out that the stress of the surgery may have adversely affected the patient’s endocrine function.

Surgical stress can inhibit the peripheral conversion of T4 to T3, which can induce a hypothyroid-like state [21]. Furthermore, stressful events may also precipitate hypopituitarism [22]. We should keep in mind that endocrine abnormalities can occur during the perioperative period in patients who have received immunochemotherapy. Measurements of cortisol and free T3 and T4 levels during the perioperative and postoperative periods should be useful for the early detection of endocrine abnormalities.

Corticosteroids are used to treat hypoadrenocorticism resulting from the decreased secretion of ACTH due to hypopituitarism [23]. Levothyroxine, a thyroid hormone, is used to treat hypothyroidism. In patients with hypothyroidism concomitant with hypoadrenocorticism, corticosteroids should always be administered first, which can lead to acute adrenal crisis.

Perioperative irAEs associated with ICIs have problems. Firstly, the times to onset of irAEs remain unclear. Sun et al. reported that the median time from the start of the administration of ICIs to the onset of irAEs was 10 weeks, and the interquartile range of 6–19.5 weeks was relatively wide [24].

Secondly, patients with irAEs present with various signs/symptoms, including headache, visual abnormalities, tachycardia, fatigue, muscle pain, weight changes, dizziness, and dry mouth [23]. When patients present with such signs/symptoms after lung cancer surgery, irAEs must be differentiated from non-irAEs. Furthermore, based on our patient and another report, periodic endocrinological testing is also warranted when ICIs are administered perioperatively [23].

In conclusion, we reported a rare case of postoperative irAEs that developed after the administration of ICI followed by salvage surgery. As the number of patients treated with perioperative ICIs increases, the number of patients developing perioperative irAEs might also increase. Careful attention should be paid to the possible development of irAEs during the perioperative management of patients undergoing surgery for lung cancer.