Adrenal crisis due to pembrolizumab-induced hypophysitis in a patient with triple-negative breast cancer

Abstract

We report a case of a 43-year-old woman with stage IIB triple-negative breast cancer (TNBC) on neoadjuvant pembrolizumab presenting in adrenal crisis. Biochemical evaluation revealed isolated adrenocorticotropic hormone (ACTH) deficiency, and MRI demonstrated a partial empty sella; findings consistent with pembrolizumab-induced hypophysitis. Glucocorticoid replacement therapy led to symptom resolution. Pembrolizumab-induced hypophysitis is rare (incidence ∼0.98%), often associated with isolated ACTH deficiency, making diagnosis challenging due to nonspecific symptoms and frequently unremarkable pituitary imaging. As ICI use expands, clinician awareness of immune-related adverse effects (irAEs) is essential to prevent life-threatening complications and improve outcomes.

Background

Immune checkpoint inhibitors (ICIs) target programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), helping tumor cells evade immune surveillance. Pembrolizumab, an anti-PD-1 inhibitor, has become a key therapeutic option in stage II and III TNBC (Schmid et al. 2020), following the results of the KEYNOTE-522 trial and subsequent Food and Drug Administration (FDA) approval (Schmid et al. 2020). ICIs offer significant clinical benefits but carry the risk of irAEs, including hypophysitis with central adrenal insufficiency.

Although more common with CTLA-4 inhibitors, hypophysitis is rare with pembrolizumab, with an incidence of approximately 0.98% (Wang et al. 2024). This case is notable for presenting as adrenal crisis, highlighting the severity of this rare irAE. Pembrolizumab-induced hypophysitis typically presents with isolated ACTH deficiency (IAD), nonspecific symptoms, and subtle or normal imaging, making diagnosis challenging. With pembrolizumab’s expanding use across malignancies, heightened awareness is essential for timely recognition and management. In addition, we highlight the radiologic finding of partial empty sella, which, although often incidental, may represent a sequela of pituitary inflammation in this context.

Case presentation

A 43-year-old female with a history of type 2 diabetes mellitus and left-sided stage IIB TNBC enrolled in the S2212 SCARLET Trial (Shorter Anthracycline-Free Chemo Immunotherapy Adapted to Pathological Response in Early Triple Negative Breast Cancer), a phase III study comparing the efficacy of a shorter anthracycline-free chemo-immunotherapy regimen with the standard anthracycline-containing regimen in early-stage triple-negative breast cancer (TNBC). The primary aim is to determine if the anthracycline-free approach provides comparable outcomes while reducing toxicity. She experienced a grade 3 infusion reaction during cycle 3 of paclitaxel, leading to a switch to nab-paclitaxel, then successfully completed four cycles of pembrolizumab/nab-paclitaxel and carboplatin. The patient presented with a 4-day history of headaches and debilitating fatigue.

She was tachycardic (heart rate ranged 100–115 beats per minute) and hypotensive (blood pressure of 76/53 mmHg). Despite initial fluid resuscitation, hypotension persisted. Laboratory results showed mild hyponatremia (134 mmol/L; reference range 136–144 mmol/L), hypokalemia (3.2 mmol/L; reference range 3.5–5.1 mmol/L), hyperglycemia (193 mg/dL; 10.71 mmol/L, reference range 70–99 mg/dL; 3.89–5.49 mmol/L), and anemia (9.9 g/dL; reference range 12–16 g/dL). Renal and liver function tests were normal. Sepsis was ruled out with appropriate specimen cultures. She had received dexamethasone 6 days prior as part of her chemotherapy protocol. Random cortisol level was <0.40 μg/dL (<11.04 nmol/L; reference range 4.30–22.4 μg/dL; 119–617 nmol/L) with low-normal ACTH 6 pg/mL (1.32 pmol/L; reference range 6–50 pg/mL; 1.32–11 pmol/L), consistent with central adrenal insufficiency (AI). Thyroid function tests were normal (see Table 1). Brain MRI revealed partial empty sella (see Figs 1 and 2). These findings were consistent with adrenal crisis in the setting of central AI secondary to pembrolizumab-induced hypophysitis.

Table 1.

Laboratory results on presentation.

Parameter	Value	Reference range
Sodium	134	136–144 mmol/L; 136–144 mEq/L
Potassium	(L) 3.2	3.5–5.1 mmol/L; 3.5–5.1 mEq/L
Chloride	101	95–105 mmol/L; 95–105 mmol/L
Glucose	(H) 193 (10.71 mmol/L)	70–99 mg/dL; 3.89–5.49 mmol/L
BUN	6 (2.14 mmol/L)	8–20 mg/dL; 2.86–7.14 mmol/L
Creatinine	(L) 0.52 (39.65 mol/L)	0.9–1.3 mg/dL
eGFR	119	≥60 mL/min/1.73 m2
Bilirubin total	0.9 (15.39 μmol/L)	0.3–1.2 mg/dL; 5.13–20.52 μmol/L
Alkaline phosphatase	53	35–104 U/L
AST	(L) 13	15–41 U/L
ALT	(L) 7	14–54 U/L
WBC	6.30	4.5–11.0 × 103/μL
Hemoglobin	(L) 9.9	12–16 g/dL
Hematocrit	(L) 22.8	36–46%
Cortisol serum	(L) <0.40 (<11.04 nmol/L)	4.30–22.4 μg/dL; 119–617 nmol/L
ACTH	6 (1.32 pmol/L)	6–50 pg/mL; 1.32–11 pmol/L
T4 free	0.81 (10.43 pmol/L)	0.6–1.6 ng/dL; 7.72–20.59 pmol/L)
TSH	1.23	0.34–5.6 mIU/L
Procalcitonin	0.06	<0.5 ng/mL represents a low risk of severe sepsis and/or septic shock. >2 ng/mL represents a high risk of severe sepsis and/or septic shock

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; WBC, white blood cell count; eGFR, estimated glomerular filtration rate; BUN, blood urea nitrogen; ACTH, adrenocorticotropic hormone; TSH, thyroid-stimulating hormone.

Figure 1.

MRI of the brain with T2-weighted coronal images of partial empty sella.

Figure 2.

MRI of the brain with T1-weighted sagittal images showing empty sella.

Intravenous hydrocortisone 50 mg every 8 h was initiated and stabilized her blood pressure, and resolved her fatigue and headache. Hydrocortisone was then tapered to a physiologic dose of 20 mg on waking and 10 mg in the afternoon. One month later, attempts to taper hydrocortisone to 15 mg in the morning and 5 mg in the afternoon resulted in recurrent adrenal crisis and rehospitalization.

Ten months later, early morning ACTH level was <5 pg/mL (1.101 pmol/L; reference range: 6–50 pg/mL; 1.32–11 pmol/L) when assessed after withholding the afternoon dose of hydrocortisone the previous day. She continues to be maintained on oral hydrocortisone 20 mg in the morning and 10 mg in the afternoon for AI management (see Fig. 3 for summary of patient events). She completed neoadjuvant chemotherapy and is scheduled for nine more cycles of adjuvant pembrolizumab with capecitabine.

Figure 3.

Summary of patient events.

Discussion

Recognizing the rare but potentially life-threatening irAEs, such as hypophysitis and AI, is essential for optimizing patient care. AI often presents with symptoms such as fatigue, weight loss, and hypotension, which can progress to adrenal crisis if not promptly managed. Adrenal crisis has a reported mortality rate of 0.5/100 patient-years (Allolio 2015). Given the significant morbidity and mortality associated with acute adrenal crisis, physicians should be aware of this particular risk with pembrolizumab use.

A meta-analysis involving 7,551 patients found the occurrence of anti-PD-1/PD-L1 hypophysitis is rare (Barroso-Sousa et al. 2018), with a reported incidence of 0.5–0.98% (Faje et al. 2019, Schmid et al. 2020). The pathogenesis of anti-PD-1 hypophysitis is not fully understood. The Genotype-Tissue Expression RNA-seq (GTEx) data have shown that the pituitary gland ranks as the sixth highest expresser of PD-1, following organs such as the spleen and lung (Pouplard et al. 1976). Corticotropes are thought to be particularly vulnerable due to their expression of Fc receptors (Pouplard et al. 1976) and are theoretically more capable of binding the infused anti-PD-1 antibody as it flows through the hypophyseal portal circulation. This may explain why anti-PD-1 hypophysitis typically presents with IAD, while anti-CTLA-4 hypophysitis involves ACTH deficiency along with other pituitary hormone deficiencies, hypothyroidism in 85%, and secondary hypogonadism in 75% of cases (Di Dalmazi et al. 2019).

Our patient exhibited IAD with preserved thyroid function. The absence of hyperkalemia further supports central AI, as aldosterone secretion remains intact under renin-angiotensin-aldosterone system (RAAS) control. Conversely, the absence of hypoglycemia with the patient’s elevated serum glucose (193 mg/dL) may reflect poor baseline control of type 2 diabetes mellitus.

Diagnosing ICI-induced hypophysitis with AI presents a unique clinical challenge, particularly due to the frequent use of glucocorticoids in oncology patients. This overlap complicates the differentiation between ICI-induced central AI and steroid-induced suppression of the hypothalamic–pituitary–adrenal (HPA) axis. Nonspecific symptoms such as fatigue and headache further obscure the clinical picture. In this case, the administration of dexamethasone 6 days prior as part of the chemotherapy protocol may have temporarily masked early symptoms of AI. By day 6, as dexamethasone levels declined, AI may have become unmasked. In addition, ICI-induced hypophysitis can cause acute central AI, and early cases may evade detection on ACTH stimulation due to preserved adrenal reserve.

Normal MRI findings do not exclude the diagnosis, especially in anti-PD-1 hypophysitis, in which typical findings such as pituitary enlargement or stalk thickening are uncommon (Jessel et al. 2022). MRI abnormalities are reported in only 18% of patients on anti-PD-1/PD-L1, compared to 81% of patients treated with anti-CTLA-4 (Di Dalmazi et al. 2019). This disparity may reflect a delay in diagnosis, during which the window for detecting early radiological changes is missed. Interestingly, in a subset of patients (22%), secondary empty sella was seen on MRI, particularly among those receiving combination anti-CTLA-4/PD-1 therapy (Van Der Leij et al. 2024). This suggests that progressive pituitary atrophy may occur as a late sequela of hypophysitis (Van Der Leij et al. 2024).

Our case presents a unique diagnostic challenge, with MRI revealing partial empty sella, which may represent a baseline anatomical variant or a sequela of pituitary inflammation. Due to advances in radiologic technology, the incidence of empty sella has recently increased, and it is present in around 38% of patients undergoing neuroimaging (Carosi et al. 2022). Partial empty sella may indicate a predisposing anatomical susceptibility to pituitary dysfunction (Brismar & Efendič 1981). ACTH deficiencies in empty sella are reported in less than 7% of cases (Lundholm & Yogi-Morren 2024). The possibility that partial empty sella reflects either a predisposing factor or a sequela of hypophyseal inflammation further complicates interpretation.

Studies show that treated pituitary irAEs are associated with improved prognosis in non-small cell lung cancer and malignant melanoma (Kobayashi et al. 2020). Data on outcomes in TNBC remain limited. This case adds to the sparse literature on anti–PD-1–induced hypophysitis presentation and outcomes in breast cancer patients, showing that immunotherapy can often be continued with proper endocrine management and monitoring.

Conclusion

In this patient, clinical features, central AI, and partial empty sella on MRI support a diagnosis of pembrolizumab-induced hypophysitis, a rare but serious irAE. Diagnosis may be delayed due to nonspecific symptoms and confounding glucocorticoid use in cancer care. Early recognition and glucocorticoid treatment are vital to prevent adrenal crisis. Clinicians should maintain a high index of suspicion, even with normal imaging. Continued case reporting is crucial to improve recognition and management of this underrecognized toxicity in breast cancer patients receiving ICI therapy.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this work.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Author contribution statement

SSM: writing – original draft, obtaining patient consent, writing – review & editing manuscript, SA: writing – original draft. RA: supervision, writing – review & editing. We confirm that all listed authors have reviewed and approved the revised manuscript and are in agreement with the current version of the submission.

Patient consent

Written informed consent for publication of their clinical details and/or clinical images was obtained from the patient by Dr Sobrina Mohammed.