ABSTRACT

Hypophysitis is an inflammation of the pituitary gland and is a rare cause of hypopituitarism. It can be primary (idiopathic) or secondary to sella and parasellar lesions, systemic diseases, or drugs (mainly immune checkpoint inhibitors). Primary hypophysitis has five histologic variants: lymphocytic, granulomatous, xanthomatous, IgG4-related, and necrotizing. Lymphocytic hypophysitis is the most common form; it is likely an autoimmune disease and is more frequently observed in females during pregnancy or postpartum. Granulomatous hypophysitis is the second most common variant and possible secondary causes of granulomatous infiltration of the pituitary should be excluded before concluding that a case of granulomatous hypophysitis is idiopathic. Xanthomatous, necrotizing, and IgG4-related hypophysitis are very rare and the latter is often the manifestation of a systemic disease with multi-organ involvement (IgG4-related disease). Immune checkpoint inhibitors are monoclonal antibodies increasingly used for the treatment of solid and hematological malignancies. They cause a T-lymphocyte activation and proliferation that lead to the anti-tumor response, and may cause autoimmune manifestations known as part of what is called “immune-related adverse events”. A significant number of patients treated with immune checkpoint inhibitors develop immune-related hypophysitis and require prompt diagnosis and treatment. Regardless of the etiology, patients with hypophysitis present with various signs and symptoms caused by the pituitary inflammation that can lead to hypopituitarism and compression of sella and parasellar structures. Contrary to other causes of hypopituitarism, adrenocorticotropic hormone and thyroid-stimulating hormone deficiencies are very frequent in the early stages of hypophysitis and must be identified immediately. The diagnosis of hypophysitis is based on clinical, laboratory, and radiological data; while pituitary biopsy is the gold standard test for diagnosing primary hypophysitis, it should be reserved only for selected cases. Magnetic resonance imaging is the technique of choice for suspected hypophysitis, and the main differential diagnoses are pituitary adenomas in adults, germinomas, and Langerhans cell histiocytosis in adolescents, and metastases in those receiving immune checkpoint inhibitors. The mainstay of treatment of patients with hypophysitis is pituitary hormone replacement. Those with severe signs and symptoms of sella compression should be treated with high-dose glucocorticoids, which usually cause an excellent initial response, although relapse of the pituitary inflammation is common. Pituitary surgery should be considered in patients who do not respond to glucocorticoids and have progressive and debilitating symptoms. Pituitary fibrosis and atrophy often develop in the late stage of the disease, with persistent hypopituitarism. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Hypophysitis is a generic term that includes a variety of conditions that cause inflammation of the pituitary gland. It is an infiltrative cause of hypopituitarism and can cause symptoms related to sella compression and pituitary hormone deficiencies.

Hypophysitis can be classified according to the anatomic location of pituitary involvement (adenohypophysitis, infundibulo-neurohypophysitis, or panhypophysitis) and the cause (primary or secondary forms) (Table 1) (1-4). The primary forms are characterized by an idiopathic inflammatory process confined to the pituitary gland, while the secondary forms are triggered by a definite etiology (drugs and intracranial or systemic diseases). Five histologic variants of primary hypophysitis have been described: lymphocytic, granulomatous, xanthomatous, IgG4-related, and necrotizing (Table 1). Lymphocytic hypophysitis is the most common form of hypophysitis and occurs most commonly in women during late pregnancy and the postpartum period. However, thanks to the increasing use over the last two decades of monoclonal antibodies inhibiting immune checkpoints for the treatment of several solid and hematological malignancies, new immune-related adverse events have emerged, with hypophysitis being a relatively common occurrence.

PRIMARY HYPOPHYSITIS

Primary hypophysitis is a rare disease, with just over 1300 published cases so far (5). The incidence is estimated to be ~1 in 9 million/year (4,6), and hypophysitis accounts for ~0.4% of pituitary surgery cases (2). Five histologic variants of primary hypophysitis have been described, and there are mixed forms as well. Table 2 summarizes the epidemiological and histopathological features of these variants (2,5,7-9). Primary hypophysitis, apart from the rare IgG4-related and necrotizing variants, occurs more frequently in young females. The clinical manifestations of all forms of primary hypophysitis are similar and are linked to the degree of pituitary involvement and the associated hormonal deficiencies.

Imaging and Differential Diagnosis of Primary Hypophysitis

Magnetic resonance imaging (MRI) of the sella region typically shows an enlarged pituitary. In order to avoid unnecessary surgery, primary hypophysitis needs to be differentiated from other sella and parasellar masses (Table 5) (45), with pituitary adenomas being the most frequent differential diagnosis in adults.

Table 5.

Differential Diagnosis of Hypophysitis

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SELLA AND PARASELLAR MASSES

Pituitary adenomas (including pituitary apoplexy); Pituitary metastases: the differential diagnosis is particularly important in patients with suspected hypophysitis and malignant tumors receiving immune checkpoint inhibitors; Other sella and parasellar tumors (e.g., craniopharyngiomas, germinomas, gliomas, lymphomas, meningiomas, pituicytomas, chordomas, teratomas, dermoids and epidermoids); Rathke’s cleft cyst; Abscesses.

OTHER

Physiological hypertrophy of the pituitary in children and adolescents (especially pubertal females) and perimenopausal women; Pituitary hyperplasia associated with pregnancy; Sheehan’s syndrome at onset; Thyrotropic hyperplasia associated with severe, untreated primary hypothyroidism.

Primary hypophysitis typically presents as a homogeneous pituitary enlargement with intense and homogeneous enhancement post-gadolinium and no deviation of the stalk (Figure 1); these and other features can help differentiate between primary hypophysitis and pituitary adenomas at MRI (Table 6) (1,4,46,47). Gutenberg et al. developed a score using variables such as age, association with pregnancy, and MRI findings to distinguish hypophysitis from pituitary adenomas with high accuracy (47). Further differential diagnoses, especially for lymphocytic hypophysitis, are the physiologic pituitary enlargement associated with pregnancy and Sheehan’s syndrome, although these patients have no history of obstetric hemorrhage (48,49). A cautious balance between radiological, clinical, and laboratory findings is necessary to reach the correct diagnosis and avoid inappropriate treatment (50).

Table 6.

Differential Imaging Characteristics of Primary Hypophysitis and Pituitary Adenomas

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MRI	Primary hypophysitis	Pituitary adenoma
Pre-gadolinium	ACUTE / SUB-ACUTE PHASE: Homogeneous pituitary enlargement with symmetrical suprasellar expansion; Suprasellar extension with compression and displacement of chiasm; Stalk thickened but not deviated; * Loss of bright spot of the neurohypophysis in case of involvement of the posterior pituitary. ** CHRONIC PHASE: Pituitary atrophy; Empty sella.	Microadenoma (<1cm): unilateral, asymmetric endosellar mass; Macroadenoma (>1cm): expanding, not homogeneous pituitary mass with asymmetrical suprasellar expansion; Compression and displacement of chiasm (macroadenoma); Contralateral deviation of the stalk; The bright spot of the neurohypophysis can be usually seen. **
Post-gadolinium	Intense and homogeneous enhancement of the pituitary mass. Cystic areas have been described, especially in the xanthomatous variant; Dural tail sign can be present (thickening of the enhanced dura that resembles a tail extending from a mass). ***	Slight, delayed and not homogeneous enhancement. Cystic and necrotic areas are frequently observed in macroadenomas; Dural tail usually absent. ***

Abbreviations: MRI, magnetic resonance imaging.

*

An enlarged pituitary stalk can also be found in other intracranial pathologies (e.g., sarcoidosis, metastases, Langerhans cell histiocytosis, germinoma, craniopharyngioma, astrocytoma, pituitary adenoma, lymphoma, tuberculosis, Erdheim-Chester’s disease) (51).

**

The bright spot may be absent in up to 20% of healthy subjects (especially the elderly).

***

The dural tail sign is not specific to hypophysitis. It can be observed in meningioma (most frequently) and other intracranial pathologies (e.g. lymphoma, chloroma, metastasis, multiple myeloma, glioblastoma multiforme, aspergillosis, chordoma, schwannoma, pleomorphic xanthoastrocytoma, hemangiopericytoma, granulomatosis with polyangiitis, sarcoidosis, medulloblastoma, eosinophilic granuloma, pituitary adenoma, pituitary apoplexy, Erdheim-Chester’s disease) (52)

Figure 1.

Magnetic resonance imaging findings in a case of primary hypophysitis. Panel A) T1-weighted image, sagittal section. Panel B) T1-weighted image, coronal section. Panel C) T1-weighted image post-gadolinium, sagittal section. Panel D) T1-weighted image post-gadolinium, coronal section. A homogeneous enlargement of the pituitary with thickening of the stalk can be seen. The mass shows intense and homogeneous enhancement post-gadolinium.

Natural History of Primary Hypophysitis

Primary hypophysitis can be self-limiting and spontaneous remission may occur (Figure 2). Considering the low prevalence of the disease, however, robust data regarding the natural history of primary hypophysitis are lacking (54). Moreover, most of the literature regards lymphocytic hypophysitis, while data from other histology subtypes are less robust. A review of 76 cases of primary hypophysitis from Germany has shown that patients not receiving any active treatment had improvement, stability or progression of the pituitary involvement at MRI in 46%, 27% and 27% of cases, respectively; pituitary deficiencies improved, remained stable or worsened in 27%, 55% and 18% of patients, respectively (73). A previous study by Khare et al. showed that spontaneous resolution of sella compression symptoms occurred in all patients managed conservatively and that 33% had complete or partial recovery of pituitary function (74). Park et al. also reported similar findings (75).

Primary hypophysitis frequently evolves to fibrosis and pituitary atrophy in the chronic stages of the disease, which often impair pituitary function (Figure 2). The evolution to empty sella has also been shown in a mouse model of autoimmune hypophysitis (76). Caturegli et al. reported that only 4% of patients had spontaneous remission with recovery of pituitary function, while most patients will require long-term replacement of one or more pituitary axes (4,54). Whether medical treatment with glucocorticoids has a positive impact on the natural history of primary hypophysitis is still a matter of debate.

Figure 2.

Natural History of Primary Hypophysitis.

Most of the published case series mainly focus on the more frequent lymphocytic hypophysitis. Granulomatous hypophysitis can cause more severe signs and symptoms (headache, chiasmal compression and anterior/posterior hypopituitarism). Xanthomatous hypophysitis seems to cause sella compression and pituitary dysfunction less frequently. IgG4-related hypophysitis can cause various degree of involvement of the anterior pituitary, posterior pituitary and the stalk. Necrotizing hypophysitis is extremely rare and is associated with a high risk of panhypopituitarism and diabetes insipidus. The chronic stage of the disease is most likely related to the extent of damage of the pituitary. Some authors have suggested that some cases of lymphocytic hypophysitis may evolve to the granulomatous form, as mixed forms can rarely be observed. A death rate of 7% has been described in large case series of patients with primary hypophysitis and is probably related to unrecognized acute adrenal insufficiency.

Diagnosis and Treatment of Primary Hypophysitis

Pituitary biopsy is the gold standard to confirm the diagnosis of primary hypophysitis. This procedure, however, should be considered only in equivocal cases and when the outcome of the biopsy is expected to change the therapeutic management, and should be performed by a neurosurgeon with extensive expertise in pituitary surgery.

Due to the rarity of the disease, the management of hypophysitis is controversial. An algorithm in line with the more recent literature is reported in Figure 3. Initial evaluation of patients with suspected hypophysitis involves clinical and laboratory assessment. Patients with a suspicion of hypophysitis based on biochemical results should undergo a pituitary MRI, as well as visual assessment to check visual fields and acuity. Secondary causes of hypophysitis and other sella/parasellar masses should be considered in the differential diagnosis.

The mainstay of treatment of primary hypophysitis is pituitary hormone replacement (77,78). As outlined above, ACTH production is frequently impaired at presentation, and most patients will require glucocorticoid replacement. This should be started before thyroxine replacement (if TSH deficiency is present as well) to avoid precipitating acute adrenal insufficiency.

Conservative management is recommended for primary hypophysitis unless symptoms are severe and progressive. The only exception to this rule is IgG4-related hypophysitis that – like other manifestations of the disease – should be promptly treated to revert symptoms and prevent irreversible fibrosis (79,80). The mainstay of treatment are glucocorticoids, which often cause remission of symptoms within a few weeks. A typical starting dose is prednisone 30-40 mg/day (or equivalent), which should be continued for 2-4 weeks, and then tapered gradually over 2-6 months (19). However, some patients may benefit from long-term maintenance glucocorticoid therapy (with or without a steroid-sparing agent), especially in case of extensive multi-organ involvement. Relapse is possible and multiple courses of high-dose glucocorticoids are often necessary. Rituximab has also been used in patients with poor response to glucocorticoids (19,81,82). A case of IgG4-related hypophysitis successfully treated with azathioprine has also been reported (83).

High-dose glucocorticoids are the first-line treatment to improve the swelling of the pituitary and improve the symptoms related to significant sella compression. Anterior pituitary function can recover after pulse corticosteroid therapy, although >70% of patients will require long-term replacement with one or more hormones (4); central diabetes insipidus rarely recovers. Honegger et al. documented excellent initial responses to high-dose glucocorticoids, with radiological improvement, stability and progression in 65%, 31% and 4% of cases, respectively (73). However, these patients carried a higher risk of side effects (weight gain, psychiatric symptoms, peripheral edema, diabetes mellitus and glaucoma) and relapse of the pituitary inflammation was documented in 38% of cases. Relapses occurred 2-17 months after starting pulse steroids and the risk or relapse did not correlate with either initial glucocorticoid dose or treatment duration (73). Hormone deficiencies improved with glucocorticoids only in 15% of patients, while they remained stable or worsened in 70% and 15% of cases, respectively (73). Lupi et al. performed a review of the literature and found somewhat better outcomes with medical therapy, reporting pituitary mass reduction in 84% of cases, improving anterior pituitary function in 45%, and restored posterior pituitary function in 41% after high-dose glucocorticoids and/or azathioprine, with a relatively low risk of relapse (14%) (84). Recently, Chiloiro et al. found in a small prospective double-arm study that high-dose glucocorticoid treatment – compared with simple observation – was associated with higher rates of hypophysitis resolution and pituitary function recovery (85). The authors also showed that positive pituitary antibodies, a diagnosis of diabetes insipidus and secondary hypogonadism at the time of presentation, and specific MRI findings (a thicker pituitary stalk, a smaller pituitary volume, and the evidence of posterior pituitary involvement at MRI including absent bright spot) predicted better clinical outcomes following glucocorticoid therapy. These findings should be confirmed in a larger prospective cohort.

Whether central diabetes insipidus is an unfavorable prognostic factor for response to glucocorticoids is unclear. The abovementioned study by Chiloiro et al. suggests better outcomes in patients with central diabetes insipidus at the time of hypophysitis diagnosis (85); however, Lupi et al. found that patients with concomitant anterior and posterior pituitary dysfunction responded poorly to glucocorticoids, which were unable to revert the hypopituitarism (86). Glucocorticoid therapy was also found to be less effective in granulomatous or xanthomatous hypophysitis (35). In glucocorticoid-resistant cases and when high-dose glucocorticoids cause unacceptable side effects, immunosuppressive drugs such as azathioprine, methotrexate, and cyclosporin A have been used successfully. However, the long-term effects are unclear (1). Rituximab has also been employed to treat steroid-refractory hypophysitis (36,87-89).

Surgery should be considered only in cases with serious and progressive deficits of the visual field, visual acuity, or nerve paralysis not responsive to medical treatment. Surgery generally improves sella compression in the short term; however, Honegger et al. observed progression/relapse of the disease in 25% of patients after a mean follow-up of 3 years (73). Pituitary function improved only in 8% of patients after surgery, and the rates of resolution of chiasmal compression were also low (73). Further supporting the limited role of surgery in the management of hypophysitis, two small observational studies found that surgery did not impact significantly on the resolution of neurological symptoms or hormonal deficits during follow-up (90,91).

Stereotactic radiotherapy (radiosurgery) has been effectively employed in selected patients who have failed medical treatment or suffer from repeated recurrence of lymphocytic hypophysitis (92,93).

Figure 3.

Diagnosis and management of primary hypophysitis. ¹ Check random ACTH and cortisol if acute adrenal insufficiency is suspected. Consider confirmatory testing (e.g., Synacthen) if equivocal or borderline results. The Synacthen test can give false-positive results in the early stages of central adrenal insufficiency. During pregnancy and in patients receiving oral estrogens, the rise of corticosteroid-binding globulin (CBG) leads to falsely elevated cortisol levels and the normal reference ranges and stimulated cortisol cut-offs do not apply. ² Pituitary surgery can also provide histology for definitive diagnosis.

DRUG-INDUCED HYPOPHYSITIS: IMMUNE CHECKPOINT INHIBITORS

Immune checkpoint inhibitors are monoclonal antibodies increasingly used for solid and hematological malignancies (94). They block several regulators of the immune activation (immune checkpoints), enhancing the host’s immune response to tumor cells (Figure 4). These drugs have shown a favorable toxicity profile and significant anti-tumor activity but, because of their mechanism of action, new typical side-effects have emerged (immune-related adverse events, irAEs) (Figure 4) (95,96).

Figure 4.

Mechanism of Action of Immune Checkpoint Inhibitors. Tumor antigens are presented to T-cells by antigen-presenting-cells (APCs) via the interaction of the major histocompatibility complex (MHC) and the T-cell receptors, representing the primary signal for activating T-cells. Another costimulatory signal involving interaction between B7 on APCs and CD28 on T-cells is needed to complete T-cell activation and expansion (Panel A). Several co-receptors act as negative modulators of immune response at different molecular checkpoints. The CTLA-4 is induced in T-cells at the time of their initial response to antigen. CTLA-4 is transported to the cell surface proportionally to the antigen stimulation; it binds to B7 with greater affinity than CD28, resulting in specific T-cell inactivation (Panel B). The PD-1/PD1-L1 pathway is not involved in initial T-cell activation: it regulates inflammatory responses in peripheral tissues sustained by already activated effector T-cells. Activated T-cells up-regulate PD-1 and inflammatory signals in the tissue induce the expression of PD1-L1s, which downregulate the activity of T-cells, protecting normal tissues from collateral destruction; this mechanism is also exploited by tumor cells to evade the immune system response (Panel B). Monoclonal antibodies that block either CTLA-4 or PD1/PD1-L1 increase cytotoxic T-cell activity by expanding T-cell activation and proliferation (Panel C). The eventual T-cell reactivation is responsible for the both anti-tumor response and the immune-related adverse events associated with these drugs.

irAES mirror the immune response reactivation induced by immune checkpoint inhibitors and may predict better survival and response to the treatment of the underlying malignancy (97-100). irAEs can affect multiple organs and systems, including the pituitary and other endocrine glands (Table 7) (101).

Pathogenesis

The pathogenesis of anti-CTLA-4 antibody-induced hypophysitis involves type II and IV hypersensitivity, as well as the humoral immune response (Figure 5). This has been suggested by histopathological findings of patients with hypophysitis following treatment with Ipilimumab (alone or in combination with Nivolumab or Pembrolizumab), evidence of pituitary antibodies in the serum of these patients, association with specific human leucocyte antigens, and animal models of anti-CTLA-4-induced hypophysitis (8,15,115-118).

Evidence regarding the pathophysiology of anti-PD1/PD1-L1 antibody-induced hypophysitis is scant, but immune response reactivation most likely targets ACTH-secreting cells because of the very frequent isolated ACTH deficiency (5). Kanie et al. recently postulated that ectopic expression of ACTH in the tumor may contribute to some cases of anti-PD1/PD1-L1 antibody-induced hypophysitis, as a form of paraneoplastic syndrome (119). Furthermore, Bellastella et al. identified a higher prevalence of anti-pituitary and anti-hypothalamus antibodies in patients with cancer treated with anti-PD1/PD1-L1 agents (120). In a small longitudinal study, the same group also found that more than half of patients who start anti-PD1/PD1-L1 treatment developed anti-pituitary or anti-hypothalamus antibodies after 9 weeks of treatment, with a concomitant increase prolactin and a reduction in ACTH and IGF-1 levels compared to baseline (120). These preliminary results need to be validated in a larger cohort, but the presence of anti-hypothalamus antibodies would suggest that – at least in some patients – hypothalamic autoimmunity might contribute to the development of anti-PD1/PD1-L1 antibody-induced pituitary dysfunction.

Figure 5.

Proposed pathogenesis of anti-CTLA-4 antibody-induced hypophysitis. Anti-CTLA-4 antibody-induced hypophysitis accounts for ~70% of immune-checkpoint induced hypophysitis cases. The CTLA-4 antibody binds to pituitary CTLA-4 antigen, inducing complement activation and infiltration with macrophages and other inflammatory cells, leading to phagocytosis and enhanced antigen presentation. Subsequently, autoimmune type IV hypersensitivity reactions start, with infiltration of the anterior pituitary by autoreactive T lymphocytes that eventually leads to pituitary cytotoxicity and inflammation. Moreover, patients with anti-CTLA-4 antibody-induced hypophysitis develop pituitary antibodies that predominantly recognize TSH- FSH- and ACTH-secreting cells. Pituitary cytotoxicity in anti-PD1/PD1-L1 antibody-induced hypophysitis presumably affects mostly ACTH-secreting cells, as isolated ACTH deficiency is the most common occurrence in these patients.

Diagnosis and Management

An algorithm for diagnosis and management of immune checkpoint-induced hypophysitis in line with the more recent literature is shown in Figure 6. Patients should be regularly monitored with clinical assessment and hormonal tests during treatment with immune checkpoint inhibitors. Almost invariably, patients who develop hypophysitis have ACTH deficiency and cases of fatal acute adrenal insufficiency have been reported (139); this highlights the importance of pituitary function assessment at baseline and during treatment, also in asymptomatic patients (140). If there is a strong suspicion of adrenal insufficiency on clinical grounds (e.g. G3-G4 symptoms), glucocorticoid replacement should be started without delay (141). TSH deficiency is also very common (>60% of patients). Indeed, a fall in serum TSH and free T4 have been suggested to be early signs of immune checkpoint inhibitor-induced hypophysitis and can be a clue to the diagnosis (141-144). A recent paper has identified antibodies against two autoantigens (anti-GNAL and anti-ITM2B) that may aid in the diagnosis of and predict the risk of developing immune checkpoint-induced hypophysitis (145). Moreover, Kobayashi et al. evaluated the usefulness of pituitary antibodies and human leukocyte antigen alleles in predicting immune checkpoint-induced pituitary dysfunction. The authors showed distinct and overlapped patterns of pituitary antibodies and human leukocyte antigen alleles between patients who developed hypophysitis (n=5) or isolated ACTH deficiency (n=17) (117). The usefulness of anti-GNAL and anti-ITM2B antibodies, pituitary antibodies, and human leukocyte antigen alleles as biomarkers in the clinical setting needs to be validated in larger cohorts of patients.

Patients with suspected drug-induce hypophysitis should undergo a pituitary MRI and visual assessment (141,146). The importance of obtaining pituitary imaging was recently highlighted in a retrospective study by Nguyen et al., where 33% of hypophysitis cases would have been missed if no MRI were carried out (143). Also, pituitary MRI is important for the differential diagnosis of other pituitary lesions, in particular metastases (Table 12). Faje et al. reported that ~50% of patients with immune checkpoint-induced hypophysitis presented with diffuse pituitary enlargement at MRI before the onset of clinical symptoms (98). ¹⁸F-FDG PET performed as part of the staging of the underlying malignancy can show intense radiotracer uptake and may precede clinical symptoms and biochemical abnormalities (147,148); however, its routine use for the diagnosis of hypophysitis is not recommended.

Current guidelines on the management of immune-checkpoint induced hypophysitis suggest clinicians to consider with holding treatment in G1-G2 hypophysitis until the patient is stabilized on hormone replacement (101). We believe that patients with immune checkpoint inhibitor-induced hypophysitis should not stop treatment unless they develop severe and progressive symptoms (G3-G4 hypophysitis). In fact, this type of hypophysitis if often self-limiting and most of patients do not show progression of sella compression. Therefore, the decision whether to withhold a treatment that can have a significant impact on the progression-free survival of the underlying malignancy should be balanced carefully. When G3-G4 hypophysitis is suspected, a course of high-dose corticosteroids given during the acute phase may result in inflammation reversal and ameliorate the compression of sella and parasellar structures. Whether high-dose glucocorticoids have an impact on the anti-tumor effect of immune checkpoint inhibitors is uncertain. Earlier evidence suggested a neutral effect on survival (99,149,150); however, a study from Faje et al. questioned this, showing reduced survival among patients with melanoma treated with high-doses glucocorticoids for Ipilimumab-induced hypophysitis (100,126). Nonetheless, treatment should not be delayed in patients with severe symptoms of sella compression.

The resolution of the neuroradiological abnormalities is usually observed within 2 months (128,130). Treatment with high-dose glucocorticoids, however, does not restore ACTH deficiency and most patients will require long-term replacement (Table 10) (5,123). On the other hand, thyroid and gonadal deficiencies often recover and the need for hormone replacement needs to be reassessed in the long term (123,124,143,151,152). In addition, patients developing irAEs can be severely ill and can present with a “euthyroid sick syndrome” and/or a “sick eugonadal syndrome” that can affect the interpretation of the laboratory results (130).

Figure 6.

Diagnosis and Management of Immune Checkpoint Inhibitor-Induced Hypophysitis. ¹ Some authors suggest laboratory evaluation before the first infusion, then at 8 weeks for patients receiving Ipilimumab (i.e., prior to cycle 3) and then at week 16 if there are no interim signs/symptoms suggestive of hypophysitis. Other authors recommend laboratory evaluation for hypophysitis prior to each infusion of immune checkpoint inhibitors in the first 12-16 weeks of treatment, in order to pick up early or late onset of the disease. ² Check random ACTH and cortisol if acute adrenal insufficiency is suspected. Exclude recent glucocorticoid use and concomitant treatment that may alter serum cortisol measurement (e.g., oral estrogens). As a guide, in patients that are unwell serum cortisol >450 nmol/L makes the diagnosis of adrenal insufficiency unlikely. Adrenal insufficiency is possible if morning cortisol 200-450 nmol/L or random cortisol 100-450 nmol/L; consider confirmatory testing with Synacthen, although this can give false-positive results in the early stages of central adrenal insufficiency. Adrenal insufficiency is likely if morning cortisol <200 nmol/L or random cortisol <100 nmol/L and patients should be started on hormone replacement. These cut-offs should be seen only as a guide and need to be adapted to local laboratory assays and reference ranges. Patients receiving immune checkpoint inhibitors can also develop adrenalitis and primary adrenal insufficiency. These patients have high ACTH and renin/aldosterone should be measured to investigate mineralocorticoid deficiency. ³ IGF-1 is valuable to confirm changes from baseline that may suggest new-onset hypophysitis. However, further tests to prove GH deficiency are not required because these patients would not be treated (active malignancy). ⁴ Pituitary MRI is normal in ~20% and ~80% of hypophysitis cases associated with anti-CTLA-4 and anti-PD1/PD1-L1 antibodies, respectively. Therefore, normal imaging does not exclude hypophysitis. MRI changes can be very subtle (Table 11). ⁵ We believe that patients with immune checkpoint inhibitor-induced hypophysitis should not stop treatment unless they develop severe and progressive symptoms (G3-G4 hypophysitis). Once the acute symptoms of hypophysitis have resolved, restarting treatment with immune checkpoint inhibitors is not contraindicated. Adequately treated, long-term hypopituitarism is not a contraindication to restarting immune checkpoint inhibitors.

An important differential diagnosis in patients with suspected drug-induced hypophysitis and a sella mass are pituitary metastases (Table 12) (95,141,153-155). The early studies on immune checkpoint inhibitors mainly assessed their efficacy in patients with advanced melanoma. Pituitary metastases are rare in melanoma (~2.5% of pituitary metastasis cases reported in the literature); however, these drugs are increasingly used for other malignancies including lung cancer, which accounts for ~25% of pituitary metastases (153). Central diabetes insipidus in immune checkpoint inhibitor-induced hypophysitis is extremely rare; therefore, a sella mass associated with diabetes insipidus is strongly suggestive of a metastasis.

Table 12.

Differential Diagnosis of Immune Checkpoint Inhibitor-Induced Hypophysitis and Pituitary Metastases

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Characteristics	Immune checkpoint inhibitor-induced hypophysitis	Pituitary Metastases
Clinical presentation	Central diabetes insipidus is extremely rare; Anterior pituitary insufficiency is very common (chiefly ACTH, FSH/LH and TSH deficiency). Headache is a frequent presenting symptom.	Central diabetes insipidus is the most common hormonal abnormality (~45%); Cranial nerve deficits due to involvement of the chiasm and the cavernous sinus are common (22-28%); Anterior pituitary insufficiency has been described in ~24% of patients; Headache and retro-orbital pain have been reported in ~16% of patients;
Imaging	MRI: Mild-to-moderate diffuse enlargement of the pituitary (up to 60-100% of the baseline size). Pituitary height typically does not exceed 2 cm. Pituitary enlargement resolves in most cases over the course of weeks/months. Empty sella can develop in the long term. Extension into the cavernous sinus or above the sellar diaphragm is uncommon. Homogeneous (more frequent) or heterogeneous enhancement (less frequent) post-gadolinium; Suprasellar extension with compression and displacement of chiasm is uncommon; The pituitary stalk may be thickened but not deviated; The posterior pituitary is preserved in most of cases.	MRI: Sella or suprasellar mass; Isointense or hypointense mass on T1WI, with a usually high-intensity sign on T2WI; Homogeneous enhancement post-gadolinium, although hemorrhage, necrosis and areas of cystic degeneration can be observed; Thickened and enhancing pituitary stalk is possible, but it is typically less common than immune checkpoint inhibitor-induced hypophysitis; Presence of other brain metastases (~15%); Invasion of the cavernous sinus, chiasm, or hypothalamus (~14%) Loss of bright spot of the neurohypophysis (~13%); Dumbbell-shaped mass (~11%); Sphenoid sinus invasion (~9%); CT: may show bony destruction.

Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; T1WI, T1 weighted images; T2WI, T2 weighted images.

DRUG-INDUCED HYPOPHYSITIS: OTHER DRUGS

Reversible or irreversible hypopituitarism may be a rare side effect following treatment with interferon-α, and interferon-α/ribavirin combination therapy has been associated with cases of granulomatous hypophysitis with anterior pituitary dysfunction (156-160). The anti-interleukin-12 and -23 monoclonal antibody ustekinumab (used in the treatment of psoriasis) has been associated with a case of hypophysitis with panhypopituitarism (161).

HYPOPHYSITIS SECONDARY TO SELLA AND PARASELLAR DISEASE

Pituitary inflammation can be triggered by sella and parasellar disease. The infiltrate is mainly lymphocytic or xanthogranulomatous and focuses around the lesion rather than diffusing to the entire gland (4).

HYPOPHYSITIS SECONDARY TO SYSTEMIC DISEASE

OTHER CAUSES OF SECONDARY HYPOPHYSITIS

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