A rare case of isolated IgG4-related hypophysitis with Rathke’s cleft cyst presenting as panhypopituitarism

Background

Hypophysitis is a rare inflammatory infiltrative condition involving the pituitary gland that may lead to transient or permanent glandular dysfunction. Immunoglobulin G4 (IgG4)-related hypophysitis is an increasingly recognized subtype of hypophysitis, with a prevalence of 5–41% in reported case series of hypophysitis (1). Imaging features of hypophysitis are sometimes difficult to distinguish from other pituitary sellar lesion-like adenomas with cysts and non-endocrine sellar tumors (2). Therefore, clinical diagnosis of IgG4 hypophysitis can be challenging, and a high degree of suspicion is needed while evaluating sellar lesions. We report a case of isolated IgG4-related hypophysitis associated with Rathke’s cleft cyst (RCC).

Case report

A 54-year-old Caucasian female presented to the emergency room with complaints of slurred speech, altered mental status, polyuria and polydipsia. She underwent brain MRI which incidentally revealed a pituitary mass. She also reported recurrent episodes of recent hypoglycemia on her usual dose of long-acting insulin. She denied any headache, vomiting or visual changes. Her medical history was remarkable for type 2 diabetes mellitus, hypertension and depression.

Endocrine assessment revealed panhypopituitarism (Table 1), characterized by central adrenal insufficiency, central hypothyroidism, central hypogonadism and decreased growth hormone and insulin-like growth factor-1 (IGF-1) levels. Prolactin was mildly elevated. Serum sodium was high (146 mmol/L), with low urine osmolality (106 mmol/kg) and elevated plasma osmolality (305 mmol/kg), consistent with diabetes insipidus. Visual field testing could not be completed due to the patient’s altered mental status. Her serum cortisol was undetectable with low adrenocorticotrophic hormone (ACTH). She underwent an ACTH stimulation test with inadequate cortisol response (30-min and 60-min cortisol levels after ACTH administration being 2.3 µg/dL and 1.5 µg/dL, respectively). A pituitary MRI (Fig. 1) revealed a 10 × 9 × 12 mm sellar mass that extended into the suprasellar region. There was an area of increased T1 signal in the anterior portion of the lesion of suspected intralesional hemorrhage along with a cystic component. The lesion was noted to abut the optic chiasm and distal left optic nerve. The lesion demonstrated predominantly peripheral enhancement with possible mild internal heterogeneous enhancement and internal fluid on post-contrast images (Fig. 1B and D). From a radiological perspective, the differential diagnosis included degeneration/necrosis within a craniopharyngioma (due to the peripheral enhancement) vs a pituitary adenoma, pituitary abscess, lymphocytic hypophysitis, sarcoidosis or less likely metastatic disease.

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MRI pituitary: T1 sagittal view, without contrast (A) and post-contrast (B). T1 coronal view, without contrast (C) and post-contrast (D).

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 2; 10.1530/EDM-22-0359

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The patient was started on hydrocortisone 20 mg every morning and 10 mg every afternoon along with 100 µg levothyroxine daily and desmopressin 50 µg per oral twice daily prior to the pituitary surgery. Based on her radiologic findings with concern for pituitary hemorrhage, a trans-sphenoidal resection of the sellar mass was performed. In the perioperative period, she was started on intravenous hydrocortisone 100 mg every 8 h, which was eventually tapered to a daily 30 mg oral replacement dose by the third day. Postoperative histopathology revealed an RCC lined by partially ciliated columnar epithelium (Fig. 2A). Eosinophilic colloidal material, consistent with cyst contents, was admixed with the specimen (Fig. 2B), most of which was composed of adjacent chronic inflammatory infiltrates containing dense collections of lymphocytes and plasma cells (Fig. 2C). The inflammatory changes involved the adenohypophysis as well as areas surrounding the cyst wall. The plasma cells were largely IgG4 immunoreactive with 40–50/400× microscopic field (Fig. 2D). Because of the colloidal material within the inflammatory specimen, it was thought that there was likely to have been leakage of the cyst contents prior to the resection.

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Pathology slides. (A) Cyst lining with ciliated columnar epithelium (arrow). (B) Surgical specimen with colloidal cyst contents (star). (C) Dense lymphoplasmacytic infiltrates with fibrosis with some normal adenohypophysial acinar cells. (D) Plasma cells with IgG4 immunoreactivity using diaminobenzedine–peroxidase detection. Scale bars for A, C, D = 50 μm, B = 100 μm.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 2; 10.1530/EDM-22-0359

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Based on the criteria proposed by Leporati et al. (3), the patient was diagnosed with IgG4 hypophysitis. With this diagnosis, we measured a serum IgG4 level which was within the normal range. Visual field testing post-surgery did not reveal any visual compromise. The patient was discharged home on hydrocortisone, levothyroxine and desmopressin. Repeat pituitary MRI in 3 months did not reveal any pituitary reoccurrence. ACTH stimulation test was normal when repeated 10 months later. Hydrocortisone was subsequently discontinued. Desmopressin was discontinued 1 year later, but she remains on levothyroxine. The patient did not have evidence of other IgG4-related systematic disease at diagnosis or over the 1 year follow-up.

Repeat MRI at 1-year follow-up revealed minimal thickening of the pituitary stalk and a 5 mm mid-sellar complex cystic signal focus likely representing recurrence of RCC. Repeat imaging was stable at 4-year follow up.

Discussion

Systemic IgG4-related disease is characterized by infiltration of IgG4, plasma cells and lymphocytes into almost any organ of the body (most commonly involving pancreas, salivary glands, orbital tissues, lymph nodes, lungs and kidneys). Isolated IgG4-related hypophysitis is a rare inflammatory disorder which solely affects the pituitary gland. It typically presents with diffuse pituitary enlargement with loss of at least one element of the pituitary hormonal axis (4).

Leporati et al. have refined the diagnostic criteria for IgG4-related hypophysitis, based on (i) pituitary histopathology alone or (ii) combination of pituitary MRI findings and biopsy-proven IgG4 involvement in another organ or (iii) combination of pituitary MRI findings, serum IgG4 levels and treatment response to steroids (3). In a previous review of IgG4 hypophysitis by Shikuma et al., 84 cases were identified which fulfilled the diagnostic criteria, of which 21 cases (25%) had isolated IgG4 hypophysitis without any systemic involvement (5). The overall mean age of presentation was 64 years, with women presenting at an earlier age (mean age in females was 56 years). Systemic disease had a predilection for males with a male–female ratio of 2.4:1. In contrast, the incidence of isolated IgG4 hypophysitis is higher in women (52%) as compared to men (13.6%) (6).

Leaked RCC contents may cause inflammatory reactions including hypophysitis and are typically described as granulomatous or lymphocytic (7). IgG4 histopathological accompaniment is a rare occurrence which has only recently been recognized. The first case of a co-occurrence of IgG4-related hypophysitis and RCC was reported by Yuen et al. in 2018 (6) and followed by the description of three more cases by Vasaitis et al. in 2021 (8). The reported cases have a female preponderance with a mean age of 50 years, which is similar to our patient. The common MRI finding at presentation was a combined, heterogenous, peripherally enhancing, cystic and solid sellar mass with suprasellar extension. Impingement of the optic chiasm was noted in three out of the four cases, with patients reporting visual symptoms which resolved postoperatively. The MRI findings usually resulted in misdiagnosis as craniopharyngioma or pituitary adenoma, while one case was mistaken for neurosarcoidosis. The most common hormonal deficiency at presentation in these four cases was follicular stimulating hormone/luteinizing hormone (3/4), followed by antidiuretic hormone (2/4) and thyroid-stimulating hormone (2/4). IGF-1 and ACTH levels were low in 1/4 cases each. Our patient presented with panhypopituitarism, with low serum levels of all the aforementioned hormones. Interestingly, one of the reported cases (6) of a young 24-year-old patient presented without any noted prior hormonal deficiencies despite having the largest tumor dimensions on MRI, double that of our reported case, suggesting that lesion size may not be a predictor of the extent of hormonal insufficiency.

One case initially mistaken for neurosarcoidosis proved a litmus test for the failure of high-dose steroid therapy and methotrexate as a tool for managing IgG4 hypophysitis and RCC (8). Surgical intervention was eventually required. Our reported case was histopathologically diagnosed as IgG4-related hypophysitis concomitant with leakage of RCC contents (Fig. 2). Plasma cells with IgG4 reactivity were detected in the absence of a foreign body reaction. This is a rare phenomenon, with only 4 other cases, to our knowledge, having been described in the literature thus far (Table 2).

The association of isolated IgG4 hypophysitis and RCC is nebulous. One postulated mechanism of association is that mucinous cystic, fluid rich in proteins and cholesterol, triggers hyperimmune reactions in the surrounding tissues (9). Per this mechanism, pathology findings consistent with a granulomatous reaction would be expected, which were conspicuously absent in our case. Furthermore, there have been several reported cases of RCC with ensuing inflammatory changes who have not developed IgG4-related pathology (8); therefore, a cause-and-effect relationship is unlikely. An alternate explanation such as a genetic or autoimmune antibody-mediated predisposition to developing isolated IgG4-related hypophysitis can be considered (8).

In our case, there was recurrence of a small mid-sellar cystic lesion, considered to most likely be an RCC. It has remained stable in size thus far, obviating the need for surgical intervention; therefore, its true histopathology is unknown. Only one of the other reported cases described long-term follow up of 5 years during which a centrally calcified sellar lesion developed. Postresection histopathology revealed fibrosis, with a less cellular infiltrate than prior and no epithelial components.

It remains to be seen whether the co-occurrence of IgG4 and RCC results in a blunted steroid response, the need for direct surgical intervention or higher rates of recurrence of either lesion. It is worth reporting secondary pathological changes, particularly RCC, in future studies reviewing cases of isolated IgG4 to better inform conclusions about prognosis.

Declaration of interest

There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

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

Patient consent

Written informed consent for publication of their clinical details and clinical images was obtained from the patient.

Author contribution statement

H Hashmi: literature review, writing manuscript, formatting; D Rupakula: literature review, writing manuscript, formatting; R Magar: editing manuscript, formatting; H B Clark: Review and editing; A Moheet: Review and editing.