The Diagnosis and Management of Lymphocytic Hypophysitis

Sherry L Iuliano; Edward R Laws

Disclosures

Expert Rev Endocrinol Metab. 2011;6(6):777-783. 

In This Article

Abstract and Introduction

Abstract

Although a relatively rare phenomenon, lymphocytic hypophysitis can represent a difficult diagnostic and therapeutic challenge. This condition was initially thought to be an autoimmune phenomenon occurring primarily in women in the postpartum state. It is now recognized as a disorder that can affect both men and women over a rather large age range, from young adults to the elderly, and may be linked to a number of autoimmune phenomena. We have reviewed the literature on lymphocytic hypophysitis, and added the detailed analysis of seven cases of presumed lymphocytic hypophysitis from our own experience. The case studies demonstrate the wide spectrum of manifestations of this disorder, the differential diagnosis and the rationale and the nuances of treatment. Diagnostic studies, including laboratory evaluation and the characteristic MRIs, are reviewed. The histopathology and results of special stains are also presented, emphasizing the characteristic pathologic findings in this spectrum of pituitary disease. Our experience and that of others demonstrates that this condition has a characteristic presentation – that is, headache, hypopituitarism and diabetes insipidus. When significant mass effect is present, suprasellar and parasellar extension may produce visual loss and/or diplopia. Treatment strategies and outcomes are given for each of the seven patients. Corticosteroids are recommended as first-line management, and are usually successful. Relapses requiring additional therapy, however, are not uncommon. In such cases, trans-sphenoidal surgery, other more aggressive forms of medical therapy and rarely, radiosurgery can also be employed. Lymphocytic hypophysitis is a challenging entity. With accurate diagnosis and sequential, expertly managed therapeutic measures, it can be controlled. Continued surveillance of the patients is essential, as relapses may occur.

Introduction

Lymphocytic hypophysitis is a rare disease, and represents an inflammatory/autoimmune disorder that primarily involves the pituitary gland and, in many cases, the pituitary stalk.[1] This condition remains rather poorly defined and includes a spectrum of several types of disease processes that need to be differentiated.

The classification of hypophysitis in general is presented in Box 1. The different varieties of hypophysitis and differing subclassifications are described in Box 2.[2] Diagnosing and differentiating them can be a major challenge.

The clinical presentation of this inflammatory condition may mimic that of a pituitary adenoma.[3] It includes headache, nausea and vomiting, fatigue, hypopituitarism and diabetes insipidus. If there is mass effect on the optic chiasm, vision may be impaired, usually with a typical bitemporal hemianopsia, and if the cavernous sinus is involved, patients may have diplopia and orbital pain.[4]

Lymphocytic hypophysitis is most commonly diagnosed in women during pregnancy or in the postpartum period, and can be associated with other types of autoimmune disease, as listed in Box 3.[1,3,5–10]

Although most commonly occurring in women during the child-bearing years, lymphocytic hypophysitis is now recognized to affect both men and women of any age.[11]

Clinical Presentation

The most common presenting symptom of lymphocytic hypophysitis is headache, which may become severe, intractable, and is usually generalized, but can be focally retro-orbital or bitemporal. Major accompanying symptoms and signs are those of hypopituitarism, as the inflammatory process damages both the anterior and posterior pituitary gland, along with the pituitary stalk (infundibulum). The symptoms of hypopituitarism include fatigue, lethargy, loss of libido, amenorrhea, dizziness, nausea and vomiting, and diabetes insipidus. The enlargement of the pituitary may be significant enough to cause compression of the optic nerves and optic chiasm. Encroachment on, or involvement of, the cavernous sinus may produce diplopia and pupillary abnormalities from involvement of the third, fourth and sixth cranial nerves.[4] Pressure on branches of the trigeminal nerve may result in orbital pain or facial paraesthesias. The details of the differential diagnosis between lymphocytic hypophysitis and pituitary adenoma are systematically described by Gutenberg et al.[3]

Laboratory Evaluation

Because patients with lymphocytic hypophysitis present with symptoms and signs of hypopituitarism, they should have a complete evaluation, preferably by an endocrinologist, for pituitary hormone function. Laboratory tests include assessment of serum adrenocorticotropin, thyroid stimulating hormone, testosterone, follicle stimulating hormone, luteinizing hormone, prolactin, growth hormone and IGF-1, also known as somatomedin C. Patients presenting with diabetes insipidus should be evaluated with serum and urine osmolality and electrolyte determinations, and possibly with a formal water deprivation test.[1]

Assessment of markers of autoimmune/inflammatory disease may be appropriate.[5] This includes a complete blood count with differential, erythrocyte sedimentation rate, C-reactive protein, serum angiotensin-converting enzyme levels, lupus antibodies, and antinuclear antibody. Cultures for tuberculosis and fungal disease may also be indicated.[1,6] The measurement of pituitary antibodies, although not yet generally available, may be helpful.[3,5]

If germinoma is part of the differential diagnosis, serum and cerebrospinal fluid levels of β human chorionic gonadotrophin, placental alkaline phosphatase (PLAP) and α-fetoprotein may be useful.[3,6]

Imaging Studies

When this condition is suspected, definitive imaging is performed by MRI, with and without the infusion of contrast. Imaging studies of patients with lymphocytic hypophysitis usually demonstrate a diffuse homogeneous sellar mass with both an enlarged pituitary gland and enlargement of the pituitary stalk with a characteristic 'pear-shaped' appearance (Figures 1–4).[1,3,7,11] Cystic components and contrast enhancement may occur. Lymphocytic hypophysitis is often mistaken for pituitary adenoma or other pituitary tumors on imaging.[3] The diffuse enlargement of the pituitary can also mimic pituitary hyperplasia (e.g., thyroid-stimulating hormone hyperplasia in hypothyroidism and pituitary hyperplasia in pregnancy).

Figure 1.

Pre- and post-operative MRI from case four. (A) Preoperative MRI, coronal. (B) Postoperative MRI, coronal.

Figure 2.

Post-contrast sagittal and coronal MRI images demonstrate a homogenous avidly enhancing enlarged pituitary with thickening of the pituitary stalk (case seven). The sella is mildly expanded and there is compression/impingement of the optic chiasm. There is invasion of the right cavernous sinus.

Figure 3.

Post-contrast sagittal and coronal MRI. A 59-year-old woman initially thought to have a pituitary adenoma. Biopsy-proven lymphocytic hypophysitis. Reproduced with permission from [101].

Figure 4.

Post-contrast coronal MRI. A 27-year-old woman several months postpartum with headache and hypopituitarism. Biopsy-proven lymphocytic hypophysitis.
Reproduced with permission from [102].

Patients presenting with lesions abutting the optic chiasm should be referred for a complete neuro-ophthalmological evaluation with funduscopic examination, visual acuity and precise plotting of the visual fields.

Differential Diagnosis

The definitive diagnosis of lymphocytic hypophysitis cannot be made without a tissue biopsy and confirmed pathology.

Without a biopsy, in the presence of a pituitary mass, typical clinical presentation and hypopituitarism, there are numerous potential differential diagnoses (Box 4). These include: pituitary adenoma, Rathke cleft cyst, craniopharyngioma, chordoma, glioma, lymphoma, leukemia, metastasis and germinoma. A thorough medical history and physical examination helps in the differential, but is rarely fully diagnostic.

Several other types of inflammatory and infectious conditions may be part of the differential diagnosis. These include sarcoidosis, tuberculosis, fungal infection, abscess, Langerhans cell granulomatosis, Tolosa–Hunt syndrome, IgG4-related hypophysitis (plasma cell rich),[5] CTL4 blockade-related hypophysitis[3] and Wegener's granulomatosis. If these are suspected, the appropriate laboratory testing should be performed, but surgical biopsy may still be necessary to achieve a secure diagnosis.

Histopathology

The primary diagnostic features on histological evaluation include the finding of normal pituitary gland with infiltration by lymphocytes, plasma cells, epithelioid histiocytes, macrophages, eosinophils and other aspects of immune responses (e.g., inflammation and fibrosis).[7] The spectrum ranges from modest to complete inflammatory change with destruction of the pituitary gland. Special stains may be helpful, including those for CD4 and CD8, characterizing the nature of the lymphocytic infiltrate.[8,11]

If germinoma is part of the histologic differential diagnosis, markers for germinomas such as Oct3/4, PLAP and NANOG may be useful.[3,6]

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