Hypophysitis Induced by Tislelizumab: A Case Report of Somnolence and Delirium with Elevated Eosinophils

Introduction

In recent years, immune checkpoint inhibitors (ICIs) have emerged as significant components of cancer therapy worldwide [1]. By targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and its ligand programmed cell death ligand 1 (PD-L1), ICIs enhance the activation and expansion of anti-tumor T cells, thereby strengthening the T-cell-mediated immune response to effectively destroy tumors [2]. Tislelizumab is a humanized IgG4 monoclonal antibody that binds to PD-1, thereby blocking its interaction with PD-L1 and PD-L2. This alleviates the inhibitory signals from tumors on immune cells and enhances antitumor immune responses, enabling immune cells to recognize and attack tumor cells more effectively for tumor elimination [3]. Tislelizumab received initial approval in December 2019 for the treatment of classical Hodgkin lymphoma. Since then, it has been approved for additional indications, including non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, and gynecological tumors [4–6]. The broad clinical application of tislelizumab has provided significant benefits to patients with various types of cancer. However, there has been a growing incidence of reported immune-related adverse events, including thyrotoxicosis [7], adrenal hypofunction and psoriasisby [8], ureteritis/cystitis [9], cytopenia [10], cytokine release syndrome [11], eyelid muscle weakness, and myocardial and skeletal muscle injury [12]. Although endocrine abnormalities represent the most frequent category of immune-related adverse events, there are relatively limited reports on hypophysitis induced by tislelizumab. Hypophysitis is a rare inflammatory disorder of the pituitary gland, with an estimated annual incidence in the general population of approximately 1 in 9 million [13]. It is broadly classified into primary and secondary forms. Secondary hypophysitis is predominantly associated with ICIs, among which CTLA-4 inhibitors (eg, ipilimumab) account for 70% of cases, PD-1 inhibitors for 23%, PD-L1 inhibitors for 2%, and combination therapy (concurrent use of CTLA-4 and PD-1 inhibitors) for 3.9% [14,15]. Herein, we present a case of a 69-year-old woman with advanced endometrial cancer who presented with somnolence, delirium, and eosinophilia after commencing treatment with tislelizumab and was subsequently diagnosed with hypophysitis. Moreover, after treatment with glucocorticoids, these symptoms vanished rapidly, and the eosinophil count returned to normal. This case report describes a unique clinical presentation of psychiatric symptoms associated with tislelizumab, which can contribute to a better understanding of the early diagnosis and management of hypophysitis induced by ICIs.

Case Report

A 69-year-old female patient was admitted to the hospital with a 1-week history of lethargy. In September 2022, the patient underwent radical surgery for endometrial cancer, and the postoperative pathology report indicated that it was endometrial low-differentiated carcinoma. After surgery, the patient received 6 cycles of chemotherapy with the TC regimen (paclitaxel + carboplatin). One year later, the axillary lymph nodes were found to be enlarged, and a lymph node biopsy was performed on November 27, 2023. The pathological results suggested that the low-differentiated adenocarcinoma (right axillary lymph node) was infiltrating or metastasizing, and the primary consideration was that it originated from endometrial carcinosarcoma. Furthermore, the immunohistochemistry of the lymphadenopathy demonstrated cytokeratin (CK) 7 (+), Vimentin (+), PAX-8 (−), Ki-67 (+, 70%), cyclin-dependent kinase inhibitor 2A (+), estrogen receptor (foci +), progesterone receptor (−), Wilms tumor protein 1 (nuclear −), CDX2 (−), SATB2 (−), GATA-3 (foci weak +), CK19 (+), glypican-3 (foci weakly +), hepatocyte (−), CK20 (foci partially +), thyroid transcription factor-1 (weakly +), and P53 (−) (Figure 1). The patient subsequently underwent second-line chemotherapy with doxorubicin liposomal injection combined with cisplatin for 4 cycles from December 1, 2023, to February 2, 2024. Unfortunately, the patient’s condition was reevaluated for progression, with an enlarged axillary lymph node metastatic lesion. Therefore, the patient received the first to fifth cycles of tislelizumab (200 mg) combined with the anlotinib regimen from February 27 to May 24, 2024. On June 18, 2024, twenty-five days after the last administration of tislelizumab, the patient was admitted to the hospital for persistent somnolence lasting 1 week (Figure 2). Physical examination revealed palpable enlarged lymph nodes in the axillae bilaterally, and the rest of the physical examination showed no obvious abnormalities. As the patient presented with symptoms of somnolence, a magnetic resonance imaging (MRI) plain scan of the head combined with diffusion-weighted imaging was initially performed to rule out somnolence caused by conditions such as brain metastases. The cranial MR examination revealed no significant abnormalities, including no evidence of brain metastases or acute cerebrovascular lesions. The signal intensity and size of the pituitary gland and pituitary stalk were normal, with no hypothalamic abnormalities observed (Figure 3). The imaging findings did not support the presence of brain metastases or acute central nervous system pathology, suggesting that the patient’s somnolence may be attributed to alternative etiological factors.

Initial laboratory test results revealed no significant abnormalities in the complete blood count, liver and renal function tests, or coagulation parameters. Mild electrolyte disturbances were observed, characterized by hypokalemia (potassium 3.44 mmol/L) and hyponatremia (sodium 135 mmol/L). Furthermore, C-reactive protein (CRP) levels were slightly elevated at 50.20 mg/L. The patient experienced pain in the left axillary mass. Consequently, 1 sustained-release tablet of tramadol was administered orally twice a day. Three days after the use of tramadol, although the patient’s pain was relieved to some extent, the symptom of daytime somnolence worsened. Therefore, tramadol was discontinued, and the patient was prescribed 1 tablet of etoricoxib once daily for pain management. Nevertheless, the patient still displayed symptoms of somnolence during the day, accompanied by poor appetite, vomiting, and inability to sleep at night, during which she experienced delirium and urinary incontinence. On July 3, 2024, the patient developed symptoms of nocturnal delirium 40 days after the last administration of tislelizumab. The patient exhibited nocturnal delirium with incoherent and rambling speech. On occasion, she expressed fear of being harmed by an individual or a ghost, during which she prayed to the Chinese Buddha for protection. At other times, she referred to family-related matters; however, the exact content was difficult to ascertain due to her use of a local dialect. Laboratory test results revealed a complete blood count with white blood cell count of 6.36×109/L, lymphocytes of 16.2%, monocytes of 13.8%, and eosinophils of 4.1% (Figure 4). Liver and kidney function tests, along with electrolyte analysis, demonstrated total protein level of 51.3 g/L, albumin of 27.9 g/L, sodium of 129 mmol/L, chloride of 93 mmol/L, and magnesium of 0.61 mmol/L. Inflammatory markers included CRP level of 137.20 mg/L and quantitative procalcitonin level of 0.56 ng/mL. The patient’s blood inflammatory indexes were elevated, and we conjectured whether there was an intracranial infection causing psychiatric symptoms. Thus, piperacillin/tazobactam 4.5 g was given every 8 h for anti-infective treatment. Meanwhile, a computed tomography (CT) scan of the chest and abdomen was performed to identify the potential source of infection. Multiple enlarged lymph nodes were discerned in both axillae, which were larger than the left lymph nodes. Multiple slightly enlarged lymph nodes were recognized in the mediastinum. The plain and contrast-enhanced CT scans of the entire abdomen indicated that the endometrial cancer was comparable to the CT results of the previous year after surgery. The gastric wall at the cardia of the stomach was slightly thickened, and there were slightly enlarged lymph nodes around the lower segment of the esophagus. After anti-infective treatment, the patient’s blood inflammatory indexes decreased. Biologically, the complete blood count indicated a white blood cell count of 4.97×109/L, monocyte percentage of 14.5%, and eosinophil percentage of 7.20% (Figure 4). Liver and kidney function tests, along with electrolyte analysis, demonstrated total protein level of 64.2 g/L, sodium level of 134 mmol/L, chloride level of 92 mmol/L, and magnesium level of 0.64 mmol/L. Inflammatory marker testing revealed a CRP level of 28.00 mg/L, while quantitative procalcitonin testing showed no significant abnormalities. However, the patient still had delirium and incoherent speech at night. For the patient’s delirium symptoms, olanzapine was administered orally, along with concurrent intramuscular administration of haloperidol when symptoms were severe. After the administration of olanzapine, the patient’s daytime somnolence became more severe, and she continued to have delerium with difficulty in falling asleep after waking up at night.

In addition to collecting the patient’s history of previous tislelizumab treatment, we monitored the patient’s cortisol and adrenocorticotropic hormone (ACTH) levels. The results indicated a cortisol level of less than 1.00 ug/dL (reference range: 5.00–25.00 ug/dL), with an ACTH level of less than 5.00 pg/mL at 8 AM (reference: 0.00–46.00 pg/mL). Similarly, the patient’s cortisol level at 4 PM remained less than 1.00 ug/dL (reference: 5.00–25.00 ug/dL), and the ACTH level was again less than 5.00 pg/mL (reference: 0.00–46.00 pg/mL). The hormonal findings were consistent with secondary adrenal insufficiency, suggestive of anterior hypopituitarism, likely related to ICI-induced hypophysitis. Additionally, the laboratory results of thyroid function, reproductive hormones, growth hormone, insulin-like growth factor-1, and insulin-like growth factor binding protein-3 showed no significant abnormalities. Due to the patient’s evident daytime somnolence and nocturnal delirium, pituitary MRI and lumbar puncture examinations were challenging to complete. We conducted a plain and contrast-enhanced CT of the head, which revealed no significant signs of abnormality. On July 28, 2024, given that the patient’s hypophysitis was likely induced by tislelizumab therapy, we initiated hormone replacement with hydrocortisone at a dose of 100 mg every 12 h. After the treatment, the patient’s daytime somnolence vanished and her consciousness became clear, but her nighttime delirium was exacerbated with screaming and clamor. Considering that the dose of hydrocortisone might have been too high, we reduced the hydrocortisone to 100 mg once daily. Surprisingly, the patient regained consciousness during the daytime, showed resolution of nocturnal delirium, exhibited an improved appetite, and demonstrated normalization of blood eosinophils (Figure 4). Subsequently, the dose of hydrocortisone was gradually reduced until it was switched to oral medication for maintenance. On August 5, 2024, the patient’s symptoms, including somnolence and delirium, had fully resolved, and she was discharged home in stable condition.

Twenty-one days later, on August 26, 2024, the patient presented to our Emergency Department again due to rupture and hemorrhage of a left axillary lymph node metastasis. We executed vascular embolization of the left subclavian artery to control the hemorrhage caused by the rupture of the axillary tumor. After the surgery, the patient’s level of consciousness gradually declined, and the somnolence symptoms gradually recurred, but there were no delirium symptoms at night. Subsequently, the symptoms progressively deteriorated, and a deep coma emerged, making it difficult to arouse the patient. Cranial CT scanning indicated ischemic changes in the paraventricular and hemiovascular centers on both sides of the lateral ventricles, with no evident signs of acute cerebrovascular disease. Considering the patient’s history of hypophysitis, we administered 100 mg of hydrocortisone intravenously and re-tested for hormones related to adrenocortical function. After just 1 dose of hydrocortisone, the patient’s consciousness returned to a state of wakefulness. Laboratory test results showed the patient’s cortisol level was 10.20 ug/dL (reference: 5.00–25.00 ug/dL), and ACTH level was less than 5.00 pg/mL at 8 AM (reference: 0.00–46.00 pg/mL). Meanwhile, the patient’s cortisol level at 4 PM was 122.00 ug/dL (reference: 5.00–25.00 ug/dL), and the ACTH level was less than 5.00 pg/mL (reference: 0.00–46.00 pg/mL). Subsequently, we gradually decreased the dosage of hydrocortisone until it was switched to oral administration. Thyroid function tests revealed that tetraiodothyronine (T4) was 62.24 nmol/L (reference: 62.68–150.84), triiodothyronine (T3) was 0.93 nmol/L (reference: 0.98–2.33), thyrotropin was 12.534 mIU/L (reference: 0.350–4.940), free thyroxine was 10.36 pmol/L (reference: 9.01–19.05), and free triiodothyronine was 2.93 pmol/L (reference: 2.43–6.01). The test of thyroid function indicated hypothyroidism; therefore, we prescribed levothyroxine sodium 25 mg once daily orally. On September 6, 2024, following a series of comprehensive treatments, the patient was discharged from the hospital once again.

Discussion

The clinical presentation of ICI-induced hypophysitis is frequently atypical, particularly among patients with advanced malignancies. For individuals who are receiving or have completed ICI therapy, the onset of symptoms, such as somnolence and delirium, warrants careful evaluation for hypophysitis, particularly when accompanied by elevated peripheral blood eosinophil counts. In this case report, we describe a patient who developed hypophysitis following treatment with tislelizumab, presenting with daytime somnolence and nocturnal delirium. During the treatment, the patient exhibited eosinophilia (Figure 4). Following hydrocortisone therapy, the patient’s somnolence and delirium resolved, and all laboratory parameters returned to normal levels. The symptoms of ICI-mediated hypophysitis are heterogeneous, encompassing headache, fatigue, nausea, loss of appetite, gastrointestinal symptoms, weight loss, hypotension, dizziness, decreased libido, burning sensation, and visual impairment [16]. In a case report, a 72-year-old male patient with concurrent bladder and prostate cancer developed hypophysitis following treatment with tislelizumab. The initial clinical presentation included nausea, vomiting, and loss of appetite [17]. In the present case, the patient exhibited prominent clinical features of somnolence and delirium. Following the exclusion of potential confounding factors, including analgesic adverse effects, intracranial infection, brain metastasis of tumors, and acute cerebrovascular diseases, a diagnosis of immune therapy-related hypophysitis was established based on the significant reduction in cortisol and ACTH, along with the clinical manifestations. The patient’s neurological symptoms, including somnolence and delirium, directed our attention to potential neurological lesions. However, normal imaging with cranial MRI or CT does not exclude the possibility of hypophysitis. This is because hypophysitis induced by anti-CTLA-4 monoclonal antibodies typically results in panhypopituitarism and is often associated with mild pituitary enlargement. In contrast, hypophysitis caused by anti-PD-1 or anti-PD-L1 monoclonal antibodies can manifest as isolated and severe ACTH deficiency without evident pituitary enlargement [18]. Therefore, it is rather difficult to diagnose PD-1 monoclonal antibody-induced hypophysitis based solely on head MRI or enhanced CT images. An accurate diagnosis requires the integration of hormone levels and clinical manifestations. Laboratory test results related to adrenal cortex function indicated that cortisol levels were extremely low (<1.00 ug/dL) at 8 AM, suggesting that the patient had adrenal insufficiency. Adrenocortical insufficiency is classified as peripheral, central, and other [19]. This patient had extremely low levels of ACTH (<5.00 pg/mL) at 8 AM, indicating the presence of central adrenocortical insufficiency. Therefore, even if the patient did not present the typical manifestations of pituitary enlargement, the combination of clinical manifestations and biochemical results could lead to the diagnosis of immunotherapy-associated hypophysitis. Furthermore, given that the secretion of other pituitary hormones apart from ACTH in this patient was largely within normal limits, this case of hypophysitis is more likely to represent isolated ACTH deficiency induced by tislelizumab. In the existing literature, isolated ACTH deficiency has been reported to cause mental symptoms, such as delirium and depression, but the underlying mechanism of it remains unclear [20,21]. From the treatment process of this patient, we conclude that hypophysitis should be considered in patients treated with ICIs who present with mental symptoms, such as somnolence and delirium.

In addition, the observation of eosinophilia in the peripheral blood of the patient in the present case can serve as supportive evidence for using eosinophil counts as a diagnostic marker for pituitary inflammation induced by tislelizumab or PD-1 monoclonal antibodies. Eosinophilia is defined as an elevated count of eosinophils in the peripheral blood, surpassing the normal upper limit (3% to 6% of total peripheral blood leukocytes), with specific thresholds potentially differing slightly across laboratories. Eosinophilia is frequently associated with parasitic infections, atopic diseases, drug reactions, and hematological disorders [22]. The administration of ICIs has been associated with an increase in peripheral blood eosinophil counts [23]. Diamantopoulos et al reported in a study involving 308 patients with advanced or metastatic melanoma treated with ICIs that eosinophilia most frequently occurred asymptotically and was typically identified during routine laboratory monitoring [24]. However, other studies have indicated that the incidence of eosinophilia is higher among patients with recurrent or metastatic squamous cell carcinoma of the head and neck who received nivolumab treatment and experienced immune-related adverse events [25]. Takayasu et al reported that the eosinophil count can serve as a potential predictive biomarker for secondary autoimmune diseases induced by ICIs [26]. Additionally, Yamada et al found that patients with renal cell carcinoma receiving combination ICI therapy exhibited elevated eosinophil counts [27]. Although these studies indicate that eosinophilia can serve as a potential biomarker for predicting ICI-induced hypophysitis, the diagnostic value of eosinophilia for specific types or categories of ICI-induced hypophysitis requires confirmation through further large-scale, multi-center research. Additionally, the underlying mechanism of eosinophilia induced by ICIs remains unclear and warrants further investigation.

Upon the occurrence of ICI-mediated hypophysitis, it is essential to evaluate the alterations in hormone levels across multiple endocrine axes influenced by this condition. When pituitary dysfunction occurs, multiple endocrine axes can be affected by pituitary inflammation, leading to conditions such as secondary adrenal insufficiency, central hypothyroidism, and hypogonadotropic hypogonadism [28]. In the present case, tislelizumab-induced hypophysitis resulted in secondary adrenal insufficiency. During the initial hospitalization, assessments of thyroid function, sex hormones, insulin, and other relevant parameters indicated no significant effects on other endocrine axes. However, during the subsequent hospitalization, the patient developed hypothyroidism with elevated thyroid-stimulating hormone (TSH) levels. This presentation differs from the typical characteristics of central hypothyroidism, which is usually marked by low free T4 levels and low or low-normal TSH levels. Spagnolo et al reported a case of hypophysitis induced by anti-PD-1 pembrolizumab therapy in a patient with metastatic melanoma. The patient exhibited reduced levels of TSH and ACTH, indicative of central hypothyroidism [29]. However, despite the presence of both adrenal insufficiency and hypothyroidism in the present patient, the hypothyroidism was attributable to direct thyroid gland damage induced by tislelizumab, rather than secondary hypothyroidism resulting from tislelizumab-associated pituitary dysfunction. This mechanism differs from that described in the case reported by Spagnolo et al. Therefore, the clinical manifestations and symptoms of ICI-mediated hypophysitis may be non-specific, necessitating systematic evaluations, including blood hormone level assessments and cranial MRI examinations, for accurate diagnosis. Additionally, it is crucial to differentiate ICI-mediated hypophysitis from other immune checkpoint-related endocrine adverse events. It is notable that at the second thyroid function test, the patient developed hypothyroidism, while thyroid function was normal at the time of the diagnosis of ICI-induced hypophysitis 1 month earlier. Therefore, endocrine disorders caused by ICIs do not occur simultaneously. For hypophysitis caused by ICIs, it is essential to regularly monitor changes in relevant hormone levels and administer medications in a timely manner.

In the management of ICI-induced hypophysitis, hormone replacement therapy with physiological doses of hydrocortisone is essential to correct adrenal insufficiency [30]. High-dose glucocorticoids should be reserved exclusively for patients with severe pituitary mass effect, visual impairment, or acute adrenal crisis [31]. Given that immunotherapy-related hypophysitis often results in prolonged hormonal deficiency, many affected individuals experience permanent pituitary dysfunction [16]. Patients with this type of hypophysitis require long-term exogenous supplementation of their hormone levels and cannot discontinue it at will [32]. Accordingly, doctors need to educate patients to take hydrocortisone on time and not to forget or discontinue medication casually. Of note, adrenal crisis can occur during stressful events, such as surgery and bleeding, demanding rapid administration of high-dose hormone therapy [14]. When there is a sudden change in the patient’s condition, the patient is at a high risk of adrenal crisis. Hydrocortisone needs to be administered along with vasoactive drugs to rapidly replenish hormone levels and restore adrenocortical function. As the testing of cortisol and ACTH requires blood sampling at the time points of 8: 00 AM and 4: 00 PM, it is necessary for the patients and their families to cooperate with the testing of the relevant hormone levels. In addition, the pituitary gland is related to the secretion of several endocrine hormones. Apart from adrenocortical function, levels of growth hormone, thyroid hormone, sex hormones, and insulin need to be monitored when there is clinical suspicion of ICI-induced hypophysitis. If necessary, pituitary MRI can be conducted to assist in the diagnosis of hypophysitis.

Conclusions

This case demonstrates that neurological manifestations such as somnolence and delirium can represent a clinical feature of tislelizumab-induced hypophysitis. Elevated eosinophil counts should raise clinical suspicion for hypophysitis, prompting evaluation of hormone levels, including cortisol and ACTH. When indicated, pituitary MRI should be performed to support the diagnosis. In terms of treatment, secondary adrenal insufficiency resulting from ICI-induced hypophysitis is typically prolonged and necessitates long-term hormone replacement therapy. Therefore, clinicians must provide thorough patient education to ensure adherence to hydrocortisone therapy and prevent unintentional omission or discontinuation of medication.