Hypophysitis induced by immune checkpoint inhibitors: a 10-year assessment

ABSTRACT

Introduction: Hypophysitis caused by immune checkpoint inhibitors (ICIs) has risen to the medical attention during the past decade. ICIs are monoclonal antibodies that block the interaction between molecules that normally inhibit the function of effector T cells, ultimately increasing their ability to destroy cancer cells but also causing immune-related adverse events, such as hypophysitis. Ipilimumab, a CTLA-4 blocker, was the first ICI approved from the Food and Drug Administration for advanced melanoma patients in 2011. Several additional ICIs targeting CTLA-4, PD-1, or PD-L1 are now used in many clinical trials, making it important for physicians to recognize and treat hypophysitis adequately.

Areas covered: This review will provide insights into the mechanisms of pituitary toxicity, highlight the complexity of clinical phenotypes of ICI hypophysitis, and offer practical recommendations.

Expert opinion: ICI hypophysitis differs in many respects from primary hypophysitis, and also according to the type of ICI that caused it. Its pathogenesis remains unknown, although the expression of CTLA-4 and PD-1 on pituitary cells could play a role. The diagnosis is mainly clinical since there are no specific serological markers and MRI findings are subtle. The treatment is based on long-term hormone replacement and does not typically require discontinuation of immunotherapy

KEYWORDS:

• Hypophysitis
• immune checkpoint inhibitors
• CTLA-4
• PD-1
• PD-L1

Article highlights

• Hypophysitis secondary to immune checkpoint inhibitors (ICIs) is an emerging and important condition in cancer patients treated with this kind of immunotherapy.

• The mechanisms of pituitary toxicity following ICI administration remain to be elucidated. For the CTLA-4, an ‘ectopic’ expression of this immune molecule on adenohypophyseal cells has been demonstrated and proposed as a disease pathway. For the PD-1, experimental articles have yet to be published, although its ‘ectopic’ expression on corticotrophs cells could be a mechanism considering the exquisite predilection for ACTH-deficiency these patients exhibit.

• ICI hypophysitis has some distinctive features from primary hypophysitis, such as male predominance, older age at diagnosis, shorter time of onset, severe hypocortisolism, rarity of posterior pituitary and optic chiasm involvement, and often persistent hypopituitarism.

• Hypophysitis caused by CTLA-4 blockade is also distinct from that caused by PD-1/PD-L1 blockade, likely reflecting different mechanisms of toxicity. Hypophysitis from CTLA-4 blockade often leads to pan-hypopituitarism and is associated with mild pituitary enlargement. The one from PD-1 blockade, instead, is characterized by isolated and severe ACTH deficiency, no mass effect symptoms, and no imaging abnormalities.

• The diagnosis of ICI hypophysitis diagnosis requires a high degree of suspicion and is based mainly on clinical and imaging grounds. It remains a challenge, also considering that specific serological markers are lacking.

• The mainstay of treatment is hormonal replacement. The use of high dose of glucocorticoids should be reserved to cases with severe headache and visual disturbances. ICI can be suspended or delayed until the acute symptomatology is resolved.

Acknowledgments

We thank Dr. Elena Sabini, Department of Pathology, Johns Hopkins University, Baltimore, Maryland, for providing the picture shown in Figure 2(b).

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

The study was supported by NIH grant [RO1 CA-194042] to Patrizio Caturegli.