Autoimmune hypophysitis associated with rheumatoid arthritis: Histopathological insights from a rare biopsy-proven case

Abstract

Background:

Autoimmune hypophysitis (AH), an uncommon inflammatory disorder of the pituitary gland, involves immune cell infiltration into pituitary tissue and often occurs concurrently with systemic autoimmune diseases. Although Hashimoto’s thyroiditis, systemic lupus erythematosus, and IgG4-related disease have been associated with AH, rheumatoid arthritis (RA)-associated AH remains exceedingly rare, particularly in seropositive cases. Clinical and imaging characteristics of AH mimic a wide range of infectious, neoplastic, and infiltrative pathologies. Biopsy remains the gold standard for definitive diagnosis, though it is rarely pursued.

Methods:

A retrospective chart review was performed to obtain the details regarding patient history, histopathological findings, and treatment course.

Results:

This rare case of biopsy-proven AH involved a 46-year-old female with seropositive RA. The patient presented with progressive headaches, small scotomas in both visual fields, and multiple endocrinopathies including central hypothyroidism and adrenal insufficiency. Magnetic resonance imaging revealed an infiltrative, contrast-enhancing suprasellar lesion. Surgical intervention was pursued for biopsy and debulking. Histopathology demonstrated pituitary tissue infiltrated by a heterogeneous population of inflammatory cells without evidence of well-formed granulomas. In the context of positive rheumatoid factor (RF) and anticyclic citrullinated peptide antibodies, the diagnosis of RA-associated AH was favored. The patient was treated with azathioprine with resolution of her headaches and scotomas and radiographic improvement. To our knowledge, this case represents the first biopsy-proven example of seropositive RA-associated AH.

Conclusion:

This case underscores the importance of maintaining a broad differential diagnosis when evaluating pituitary lesions, especially in patients with systemic autoimmune disorders, and highlights the role of tissue diagnosis and decompression in a symptomatic patient with a suprasellar lesion resulting in mass effect.

INTRODUCTION

Autoimmune hypophysitis (AH), an increasingly recognized but rare inflammatory condition, may involve autoimmune-mediated infiltration of lymphocytes, plasma cells, and histiocytes into pituitary tissue, leading to dysfunction of hormonal output and mass effect symptoms.[3,16] AH is traditionally classified by histological findings of lymphocytic, granulomatous, IgG4-related, xanthomatous, necrotizing, and immuno-therapy induced subtypes.[7,13] However, a growing body of literature points to overlapping and/or mixed histopathological presentations, complicating clinical and pathological diagnosis.[18]

AH often arises in association with systemic autoimmune diseases. Hashimoto’s thyroiditis, systemic lupus erythematosus (SLE), Sjögren’s syndrome, and IgG4-related disease are the most frequently reported comorbidities.[21,22] Rheumatoid arthritis (RA), another prevalent autoimmune disorder, is rarely linked to hypophysitis, with only a few biopsy-confirmed cases described in the literature. A recent review by Yan et al. failed to identify RA as a primary association in their nine-patient cohort of rheumatic disease-associated AH.[22] Kamran et al. reported one of the few documented cases, involving seronegative RA.[9] To our knowledge, the current case represents the first biopsy-proven example of seropositive RA-associated AH.

Central nervous system (CNS) involvement in RA has been reported in the form of rheumatoid meningoencephalitis and glial fibrillary acidic protein-associated astrocytopathy along with cases of mixed parenchymal–meningeal inflammation, indicating a potentially broader spectrum of CNS manifestations.[4,17] Here, we describe a case of AH with concurrent extensive inflammatory infiltration and seropositive RA requiring tissue diagnosis and decompression in a symptomatic patient with a suprasellar lesion, resulting in visual changes and endocrinopathies requiring hormone replacement therapy.

MATERIALS AND METHODS

A retrospective chart review was performed to obtain pertinent details regarding patient history, imaging, histopathological findings, and treatment course.

RESULTS

Case presentation

A 46-year-old female with a medical history of RA and hypothyroidism initially presented with severe headaches. She was also noted to have multiple endocrinopathies requiring hormone replacement therapy with vasopressin, hydrocortisone, and levothyroxine. Visual field testing was performed by ophthalmology, revealing some small scotomas of bilateral temporal fields. Magnetic resonance imaging brain with and without contrast demonstrated a contrast-enhancing lesion involving the hypothalamus, pituitary stalk, and pituitary gland with infiltrative expansion of these structures [Figures 1a-b]. Given the need for tissue diagnosis and decompression of crucial structures, including the optic chiasm, neurosurgical intervention was pursued.

Figure 1:

Delayed postoperative magnetic resonance brain images. (a) T1-weighted postcontrast images: sagittal, (b) coronal demonstrate decreased enhancement and volume of the lesion (denoted by white arrows in (a)) following endoscopic endonasal biopsy and partial decompression. Partial regression of the stalk and hypothalamic involvement is noted (denoted by red arrows in (b)), consistent with therapeutic response and inflammatory etiology. The lesion measures 17mm on cranial-caudal dimension.

The patient underwent an endoscopic endonasal transsphenoidal approach to the sella. An abnormal mass was encountered that was very infiltrative, hemorrhagic, and necrotic. A partial debulking was performed to ensure that resected diagnostic material and decompression of the optic chiasm were achieved. Intraoperative frozen section revealed lesional tissue favoring an inflammatory process with macrophages and plasma cells identified.

Histopathological sections showed small fragments of pituitary tissue overrun by a mixed inflammatory infiltrate composed predominantly of small lymphocytes and plasma cells intermixed with foamy macrophages, neutrophils, and occasional eosinophils. Focal necrosis and rare mitotic figures were additionally noted [Figure 2a]. Granulomas and sclerosis were absent. The differential diagnosis for inflammatory cell-rich lesions of the adenohypophysis was broad and included histiocytoses such as Rosai–Dorfman disease and anaplastic lymphoma kinase-positive histiocytosis, germ cell neoplasms, infectious processes, and AH. A panel of immunostains was performed to distinguish between these possibilities. The majority of lymphocytes were CD3-positive T-cells [Figure 2b]; however, scattered aggregates of small, mature CD20-positive B-cells were also present [Figure 2c]. CD68 highlighted scattered macrophages both in viable and necrotic areas [Figure 2d], which were negative for S100, CD1a, and cyclin D1. CD138 labeled numerous plasma cells [Figure 2e], which were polytypic on kappa/lambda in situ hybridization (not shown). A small subset (~1%) of plasma cells expressed IgG4 [Figure 2f]. CD117 labeled scattered mast cells, and placental-like alkaline phosphatase was absent (not shown). Special stains, including periodic acid-Schiff (for fungi), gram, and acid-fast bacillus, were negative for organisms. Overall, the morphology and immunoprofile were most consistent with a RA-associated AH, especially in the context of the patient’s anticyclic citrullinated peptide (anti-CCP) antibodies.

Figure 2:

Histopathologic evaluation. Hematoxylin and eosin-stained sections (a) show anterior pituitary tissue with dense lymphoplasmacytic inflammation, focal necrosis, and scattered histiocytes and neutrophils. (200x magnification) CD3 (b) labels the majority of lymphocytes (100x magnification), while CD20 (c) labels scattered aggregates of small, mature lymphocytes (100x magnification). CD68 (d) highlights scattered histiocytes (100x magnification). CD138 (e) labels numerous plasma cells, which are polytypic by kappa/lambda ISH (not shown) (100x magnification). IgG4 (f) labels a small subset (~10%) of plasma cells. (100x magnification)

The patient was treated with azathioprine and noted to have resolution of her presenting headaches and visual field improvement back to normal. She was maintained on her preoperative hormone replacement medication, and repeat imaging at 3 months showed a significant decrease in the size of the infiltrative mass [Figures 3a and b]. Her multidisciplinary treatment plan was to continue with her immunosuppressive therapy and perform surveillance imaging to ensure continued radiographic resolution.

Figure 3:

Preoperative magnetic resonance brain images. T1-weighted postcontrast images: (a) sagittal, (b) coronal demonstrate a heterogeneously enhancing lesion involving the hypothalamus, pituitary stalk, and anterior pituitary gland (denoted by white arrows in (a)), with suprasellar extension and mild mass effect on the optic chiasm (denoted by red arrows in (b)). The lesion measures 23mm on cranial-caudal dimension.

DISCUSSION

This case highlights the diagnostic complexity and evolving spectrum of AH, particularly in the context of systemic autoimmune conditions such as RA. The histopathological examination revealed a polymorphic inflammatory infiltrate with plasma cells, small lymphocytes, histiocytes, neutrophils, and focal necrosis, features that strongly support AH, yet defy strict categorization into one histological subtype.[13,18] RA has been reported to affect the CNS in rare instances, most commonly through meningoencephalitis and vasculitis processes.[2,4,6] However, pituitary involvement remains largely undocumented. Our patient’s positive RF and anti-CCP antibodies, in combination with exclusion of other autoimmune and infectious etiologies, strengthen the case for RA-associated AH. In contrast to granulomatous hypophysitis, where epithelioid histiocytes and multinucleated giant cells are hallmarks, our case lacked granulomas but showed mixed inflammation and necrosis without IgG4 predominance.[1,11]

In rare instances, AH can coexist with other pituitary or CNS pathologies, which further complicates the diagnostic process. Patra and Trivedi described a unique case of a plurihormonal pituitary adenoma coexisting with granulomatous hypophysitis, highlighting the need to account for dual pathology in imaging and histology.[15,19] Similarly, Huang et al. reported granulomatous hypophysitis preceding the diagnosis of CNS vasculitis, a reminder of how early pituitary inflammation may be a harbinger of broader CNS involvement.[8]

The treatment of AH remains variable depending on the underlying immune etiology and extent of pituitary involvement. Recurrent and refractory cases have been managed with steroid-sparing agents and biologics. Kruse et al. detailed the successful use of rituximab in a patient with CD20-positive AH after relapse on corticosteroids and azathioprine, suggesting B-cell targeting therapy as a viable option in select cases.[12] Furthermore, xanthomatous variants such as those presented by Kini et al. and Wong et al. demonstrate a distinct clinical course and often require tailored surgical or immunosuppressive strategies.[10,14,20]

Systemic autoimmune manifestations must also be closely monitored in patients with AH. Guarda et al. documented the development of retroperitoneal fibrosis and SLE years after the diagnosis of IgG4-related hypophysitis, supporting a role for long-term multidisciplinary follow-up.[5] Similarly, Yum et al. reported a patient with Sjögren’s syndrome who developed both AH and hypoparathyroidism, emphasizing that autoimmune polyendocrine syndromes may evolve dynamically over time.[23] Our case stands out as the only biopsy-proven seropositive RA-associated AH diagnosis with clear exclusion of other etiologies, supporting the notion that RA may directly mediate primary pituitary autoimmunity in rare instances [Table 1].

Table 1:

Summary of selected published cases of rheumatoid arthritis (RA)-associated hypophysitis and meningoencephalitis

CONCLUSION

AH, often associated with systemic autoimmune diseases, is a rare autoimmune-mediated infiltration of the pituitary gland and may result in hormonal disruption and/or symptoms related to mass effect. Here, we present the first biopsy-proven example of seropositive RA-associated AH. Our case highlights the need for surgeons to consider a broad differential when evaluating patients with RA or other autoimmune diseases with sellar and suprasellar masses and the importance of a tissue diagnosis in select instances.

Ethical approval:

Institutional review board approval was exempt given all data was de-identified prior to its use in this retrospective study.

Declaration of patient consent:

The authors certify that they have obtained all appropriate patient consent.

Financial support and sponsorship:

Nil.

Conflicts of interest:

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation:

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

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