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Background

This is a rare disorder that is an important consideration in the differential diagnoses of space-occupying lesions of the sella region in the brain. There may be an association with autoimmune diseases suchas Sjogren's syundrome, autoimmune gastritis, hepatitis, and Hashimoto's thyroiditis.

OUTLINE

Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/
Other Diagnostic Testing
 
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/
Immunohistochemistry/
Electron Microscopy
 
Differential Diagnosis  
Prognosis  
Treatment  
Commonly Used Terms  
Internet Links  

 

EPIDEMIOLOGY CHARACTERIZATION
SYNONYMS  
INCIDENCE/
PREVALENCE
 
AGE  
SEX  
GEOGRAPHY  
EPIDEMIOLOGIC ASSOCIATIONS  

 

DISEASE ASSOCIATIONS CHARACTERIZATION
DIABETES INSIPIDUS  
Two cases of lymphocytic hypophysitis presenting with diabetes insipidus: a variant of lymphocytic infundibulo-neurohypophysitis.

Nishioka H, Ito H, Sano T, Ito Y.

Department of Neurosurgery, Tokyo Medical College, Japan.

Surg Neurol. 1996 Sep;46(3):285-90; discussion 290-1. Abstract quote  

BACKGROUND: It has been thought that neurohypophysial involvement manifesting as central diabetes insipidus in lymphocytic hypophysitis is uncommon. Although cases with such an association have been reported recently with increasing frequency, the relationship with lymphocytic infundibular neurohypophysitis remains unclear.

METHODS AND RESULTS: Two postmenopausal women who presented with diabetes insipidus are reported. Adenohypophysial function was normal in both cases, apart from growth hormone secretion. Magnetic resonance imaging revealed a sellar mass lesion mimicking pituitary adenoma, with loss of the hyperintense signal of the neurohypophysis in both cases and thickening of the stalk in one case. The lesion was located behind the residual adenohypophysis during transsphenoidal biopsy; however, histologic examination showed chronic inflammation of the adenohypophysis, findings identical to those of lymphocytic adenohypophysitis. Although the principal site of the inflammation was considered to be the neurohypophysial system, adenohypophysis was also involved in the lesion. We suggest that these cases represent a variant of lymphocytic infundibular neurohypophysitis.

CONCLUSION: To avoid unnecessary surgical intervention, it is important to note that some variants of lymphocytic infundibulo-neurohypophysitis may form a mass lesion not localized in the neurohypophysial system but involving the adenohypophysis, thus resembling adenomas and other tumors.

Lymphocytic hypophysitis presenting with diabetes insipidus: case report and literature review.

Koshiyama H, Sato H, Yorita S, Koh T, Kanatsuna T, Nishimura K, Hayakawa K, Takahashi J, Hashimoto N.

Division of Endocrinology, Kyoto City Hospital, Japan.

Endocr J. 1994 Feb;41(1):93-7 Abstract quote.  

Lymphocytic adenohypophysitis is an autoimmune disorder of the anterior pituitary gland which usually occurs in a women in the postpartum period. It has been considered that lymphocytic hypophysitis is confined to the adenohypophysis sparing the neurohypophysis, and that diabetes insipidus is not a clinical feature of the disorder.

Here we report the case of a 50-year-old woman with lymphocytic hypophysitis which presented with diabetes insipidus. MRI indicated homogeneous swelling of the whole pituitary gland, loss of the normal high intensity of the posterior pituitary, and thickening of the pituitary stalk. A biopsied specimen of the pituitary revealed diffuse lymphocytic infiltration. The diabetes insipidus was controlled by the administration of DDAVP. The anterior pituitary function was not greatly damaged, and no hormonal replacement therapy was necessary.

We suggest that this case represents a variant of lymphocytic adenohypophysitis and/or lymphocytic infundibuloneurohypophysitis, in which the chronic inflammatory process involves the infundibulum, adenohypophysis and neurohypophysis.
PREGNANCY  
Lymphocytic hypophysitis of pregnancy resulting in hypopituitarism: a distinct clinicopathologic entity.

Asa SL, Bilbao JM, Kovacs K, Josse RG, Kreines K.

Ann Intern Med. 1981 Aug;95(2):166-71. Abstract quote  

Two patients presented with abnormalities suggestive of pituitary adenoma; one during pregnancy and one in the postpartum period. However, pathologic examination of the pituitary showed extensive destruction by a lymphoplasmacytic infiltrate; no tumor was identified. Both patients developed hypopituitarism. We know of eight additional cases of lymphocytic hypophysitis, seven of which have been reported in the literature. In only three cases, including the two reported here, the diagnosis was established by biopsy. In each of those cases, the entity mimicked a pituitary tumor.

This is the first report of electron microscopy of this lesion and the ultrastructural features support the previously suggested autoimmune etiology. The lesion has been described only in women and seven of ten patients were pregnant or postpartum at the onset.

This fact and previously reported experimental evidence, including the identification of anti-prolactin cell antibodies, support our suggestion that lymphocytic hypophysitis associated with pregnancy represents a distinct clinicopathologic entity.

 

PATHOGENESIS CHARACTERIZATION
GENERAL  
Immunopathology of Primary Hypophysitis: Implications for Pathogenesis.

Gutenberg A, Buslei R, Fahlbusch R, Buchfelder M, Bruck W.

From the Departments of *Neuropathology and section signNeurosurgery, Georg August University, Gottingen, Germany; and Departments of daggerNeuropathology and double daggerNeurosurgery, Friedrich Alexander University, Erlangen, Germany.
Am J Surg Pathol. 2005 Mar;29(3):329-338. Abstract quote  

The etiology of primary hypophysitis is still not fully elucidated. Histologically, primary hypophysitis includes three different main subtypes: lymphocytic (LYH), granulomatous (GRH), and xanthomatous (XH) hypophysitis. Clinical and laboratory findings suggest an autoimmune basis in primary hypophysitis. Controversy still exists about the composition of the inflammatory infiltrate and the relevant immunopathogenic effector mechanisms.

Therefore, 21 cases of primary hypophysitis of different subtypes were analyzed with respect to the expression of lymphocyte and macrophage antigens as well as MHC class I and II molecules of the inflammatory infiltrate and the resident pituitary acinar cells. Lymphocyte infiltration in LYH (n = 15), but also in GRH (n = 4) and XH (n = 2), mainly consisted of T cells, while B cells were rare. Independent from the histopathologic subtype, T cell subsets showed equal ratios of CD4+ to CD8+ T cells. Highest numbers of activated CD8+ T cells were observed in LYH presenting during pregnancy, surrounding or even infiltrating preserved pituitary acinar cells. Moreover, an increased rate of activated CD8+ T cells correlated with a shorter duration of clinical symptoms. In LYH, aberrant expression of MHC class II antigens as well as overexpression of MHC class I molecules on pituitary cells were observed. Independent of the histologic subtype, macrophages mostly expressed markers of chronic activation and showed MHC class II positivity. LYH, GRH, and XH, although heterogeneous in their histologic appearance and in age distribution, exhibit a similar if not identical immunohistologic profile.

It is highly likely that direct T cell-mediated cytotoxicity through CD8+ T cells, with the initial help of CD4+ T cells, is pivotal in the pathogenesis of primary hypophysitis, implicating a target autoantigen expressed by pituitary cells.
Detection of autoantibodies against the pituitary-specific proteins in patients with lymphocytic hypophysitis.

Tanaka S, Tatsumi KI, Kimura M, Takano T, Murakami Y, Takao T, Hashimoto K, Kato Y, Amino N.

Department of Laboratory Medicine, Osaka University Graduate School of Medicine D2, Suita-shi Yamada-oka 2-2, Osaka 565-0871, Japan.
Eur J Endocrinol. 2002 Dec;147(6):767-75. Abstract quote  

OBJECTIVE: Several reports have described antipituitary antibodies by immunofluorescent or immunoblotting methods in patients with lymphocytic hypophysitis. However, with the exception of the pituitary hormones, individual antigens specific for the pituitary gland have not been studied. To understand the pathogenesis of lymphocytic hypophysitis and to diagnose this disease efficiently, we studied the presence of autoantibodies against three pituitary-specific proteins, GH and two novel pituitary-specific proteins, namely, pituitary gland specific factor 1a (PGSF1a) and PGSF2.

DESIGN: Seventeen patients with lymphocytic hypophysitis, all of whom had pituitary enlargement (5 with lymphocytic adenohypophysitis and 12 with lymphocytic infundibuloneurohypophysitis, including 3 of the latter group proven by biopsy), and 14 patients with hypopituitarism without pituitary enlargement (10 with isolated ACTH deficiency and 4 with idiopathic TSH deficiency) were studied, and compared with 11 patients with non-functioning pituitary macroadenoma, 31 patients with other autoimmune diseases, and 36 healthy controls.

METHODS: The presence of each antibody was studied by radioligand assay using recombinant human (35)S-labeled protein. RESULTS: Three (18%) patients with lymphocytic hypophysitis having pituitary enlargement, five (36%) patients with hypopituitarism without pituitary enlargement and three (9.7%) patients with other autoimmune diseases were positive for one or more of the antibodies studied.

CONCLUSIONS: Anti-human GH, anti-PGSF1a, and anti-PGSF2 antibodies were detected in patients with lymphocytic hypophysitis and other hypopituitarism, but were not detected in patients with non-functioning pituitary macroadenoma. Detection of these antibodies may be useful for the diagnosis of lymphocytic hypophysitis.

 

LABORATORY/
RADIOLOGIC/
OTHER TESTS

CHARACTERIZATION
RADIOLOGIC  
LABORATORY MARKERS  

 

GROSS APPEARANCE/
CLINICAL VARIANTS
CHARACTERIZATION
GENERAL  
Spectrum of different types of hypophysitis: a clinicopathologic study of hypophysitis in 31 cases.

Tashiro T, Sano T, Xu B, Wakatsuki S, Kagawa N, Nishioka H, Yamada S, Kovacs K.

Department of Pathology, University of Tokushima School of Medicine, Tokushima, Japan.
Endocr Pathol. 2002 Fall;13(3):183-95. Abstract quote  

Hypophysitis has been histologically classified into five types: lymphocytic hypophysitis (LYH), granulomatous hypophysitis (GRH), xanthogranulomatous hypophysitis (XGH), xanthomatous hypophysitis (XH), and necrotizing hypophysitis.

The present study evaluated 31 cases of hypophysitis to clarify their characteristic clinicopathologic features. The lesions were histologically classified into four groups: LYH (22 cases) including lymphocytic adenohypophysitis (LAH) (19 cases) and lymphocytic infundibuloneurohypophysitis (LINH) (3 cases), GRH (5 cases), XGH (2 cases), and XH (2 cases). In each group, the pituitary gland showed lymphocytic infiltration associated with focal or diffuse hypophysial destruction of variable severity and fibrosis.

Histologic and clinical overlap among different types of hypophysitis, especially between LAH and LINH, suggest that these entities may have similar etiologic background and/or represent different stages of the same lesion. Considering the sampling sites and clinical manifestations, LAH may not usually involve the neurohypophysis, but LINH may often extend to the adenohypophysitis. A selective loss of adrenocorticotropic hormone-positive cells was seen in two patients with LAH despite only very slight lymphoplasmacytic infiltration.

This suggests that there may be at least two causative mechanisms for hypopituitarism in hypophysitis: nonspecific destruction of all types of adenohypophysial cells by severe inflammation and selective destruction of specific adenohypophysial cells.
The spectrum and significance of primary hypophysitis.

Cheung CC, Ezzat S, Smyth HS, Asa SL.

The Freeman Center for Endocrine Oncology, Mount Sinai Hospital, Department of Pathology, University of Toronto, Toronto, Ontario M5G 1X5, Canada.
J Clin Endocrinol Metab. 2001 Mar;86(3):1048-53. Abstract quote  

Hypophysitis can present clinically as a mass lesion of the sella turcica. Secondary hypophysitis occurs in cases where a definite etiologic agent or process inciting the inflammatory reaction can be identified. In contrast, primary hypophysitis refers to inflammation confined to the pituitary gland with no identifiable etiologic associations.

We report three cases of primary hypophysitis to illustrate the spectrum of three clinicopathological entities that encompass this disease: lymphocytic hypophysitis, granulomatous hypophysitis, and xanthomatous hypophysitis. Our three patients underwent surgery, with variable response. However, conservative, supportive treatment with or without surgical decompression is generally favored over aggressive and extensive surgical resection that results in hypopituitarism.

We conclude that the optimal management of patients with hyophysitis requires a high index of suspicion before extensive surgical resection. Histological confirmation of the diagnosis of hypophysitis can be obtained by performing a biopsy or by requesting an intraoperative frozen section consultation.
Lymphocytic hypophysitis. Report of 3 new cases and review of the literature.

Cosman F, Post KD, Holub DA, Wardlaw SL.

Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032.
Medicine (Baltimore). 1989 Jul;68(4):240-56. Abstract quote  

Lymphocytic hypophysitis is an uncommon but increasingly recognized disorder characterized by chronic inflammation and destruction of the anterior pituitary. Three new cases are presented here with a review of the 27 previously reported cases. The disease affects primarily young women in late pregnancy or in the postpartum period but also has been described in postmenopausal women and in one man. It presents as an expanding intrasellar mass or as partial or panhypopituitarism. The etiology may be autoimmune.

The natural history of this entity begins with enlargement of the pituitary secondary to inflammatory infiltration and progresses to atrophy of the gland with destruction of pituitary tissue and replacement with fibrosis. At least 1 patient had documented recovery of pituitary function, and the overall potential incidence of recoverable function is unknown.

Our improved understanding of this disease has led us to conclude that surgical intervention is not always necessary.
VARIANTS  
NECROTIZING  
Necrotizing infundibulo-hypophysitis: a unique syndrome of diabetes insipidus and hypopituitarism.

Ahmed SR, Aiello DP, Page R, Hopper K, Towfighi J, Santen RJ.

Department of Neurosurgery, University Hospital, Pennsylvania State University, Hershey 17033.

J Clin Endocrinol Metab. 1993 Jun;76(6):1499-504. Abstract quote  

Clinical, radiological, histological, and anatomical features in 2 patients with necrotizing infundibulo-hypophysitis are reported. The patients presented with a combination of diabetes insipidus and hypopituitarism. Each was found to have a sellar mass lesion with an abnormally thickened enlarged pituitary stalk that intensively enhanced on contrast magnetic resonance imaging. They were suspected to have pituitary tumors with suprasellar extension. However, tissue obtained at transphenoidal surgery revealed necrosis, fibrosis, and chronic inflammation; there was no evidence of infiltrative, infective, or neoplastic disease processes. Postoperatively, they continued to have diabetes insipidus and hypopituitarism despite radiological improvement and steroid therapy.

Several clinical and anatomical features distinguish these 2 cases from classical lymphocytic hypophysitis, the most common entity in the differential diagnosis. Specifically, diabetes insipidus has not been observed preoperatively in 30 cases of lymphocytic hypophysitis, but was present in the 2 cases reported.

Histological evidence of tissue necrosis present in these 2 cases is not a feature of lymphocytic hypophysitis. Pituitary stalk involvement on magnetic resonance imaging or computed tomographic scan present in these 2 cases is highly unusual in lymphocytic hypophysitis. Finally, 29 of 30 cases of lymphocytic hypophysitis were females, whereas the 2 cases reported are men.

On the basis of these disparate findings, we suggest that these 2 cases represent a unique syndrome, which may be recognized clinically and radiologically.

 

HISTOLOGICAL TYPES CHARACTERIZATION
GENERAL  
Hypophysitis in surgical and autoptical specimens.

Sautner D, Saeger W, Ludecke DK, Jansen V, Puchner MJ.

Department of Pathology, Marienkrankenhaus Hamburg, Germany.

Acta Neuropathol (Berl). 1995;90(6):637-44. Abstract quote  

We present the clinical and histological findings of 11 cases of inflammatory anterior pituitary lesions, 8 of which were obtained during surgery and 3 of which were obtained from autopsies. Additionally, we extended the conventional classification of pituitary inflammatory disease by the new entity " secondary hypophysitis".

Of the surgically obtained specimens 5 consisted of inflammatory extension into the pituitary gland out of the surrounding tissue. In all of these patients the inflammation originated from an additional tumor in the sellar region (4 craniopharyngiomas, 1 prolactinoma). These will be referred to as "secondary hypophysitis", an entity which has not yet been mentioned in the literature. Of the remaining 6 cases, 2 were granulomatous hypophysitis, 2 pituitary abscesses, 1 lymphocytic hypophysitis, and 1 showed extensive scarring of the anterior pituitary lobe due to preceeding lymphocytic hypophysitis. At histological examination the basic structure of the anterior pituitary was maintained in all cases. Relative counts of hormone-producing cells were normal. In secondary hypophysitis, the affected area was composed of fibrous tissue and granulation tissue. B and T lymphocytes were present in equal amounts. Granulomas were not found. Inflammatory infiltrates, granulation tissue and fibroses were seen in different proportions.

Based on our results and three other cases reported in the literature so far, we think that the presently used classification of pituitary inflammatory diseases lacks an entity which describes a non-abscess-forming inflammation of the pituitary gland originating from an associated pathological process.

Therefore, we introduced the term secondary hypophysitis to describe this fourth entity of pituitary inflammatory disease.
A case of lymphocytic infundibuloneurohypophysitis: histophathological studies.

Waki K, Yamada S, Ozawa Y, Seki K, Endo Y.

Department of Endocrinology, Toranomon Hospital, Tokyo, Japan.
Pituitary. 1999 May;1(3-4):285-90. Abstract quote

A 57-year-old woman presented with 2-year history of polyuria and polydipsia. Hormonal studies revealed almost normal anterior pituitary function and central diabetes insipidus. Magnetic resonance imaging showed thickening of the pituitary stalk and enlargement of the neurohypophysis without high intensity of the posterior lobe on T1-weighted images, which were compatible with lymphocytic infundibuloneurohypophysitis.

Transsphenoidal biopsy was done and histological examination disclosed moderate fibrosis and lymphocytic infiltration not only in the posterior pituitary, but also in the adjacent anterior pituitary part of the gland. The lymphocytes both in the anterior and posterior pituitary were mainly T cells that were positive for UCHL 1, CD 3, and CD 8. Immunofluorescence of frozen tissue detected immunecomplex deposition in small vessels and the interstitium.

These findings suggested that allergic reactions may play an important role in the pathogenesis of lymphocytic infundibuloneurohypophysitis.

 

SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHER
CHARACTERIZATION
SPECIAL STAINS  
IMMUNOPEROXIDASE  
ELECTRON MICROSCOPY  

 

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

 

PROGNOSIS CHARACTERIZATION

 

TREATMENT CHARACTERIZATION
GENERAL  
Lymphocytic and granulomatous hypophysitis: experience with nine cases.

Honegger J, Fahlbusch R, Bornemann A, Hensen J, Buchfelder M, Muller M, Nomikos P.

Department of Neurosurgery, University of Erlangen-Nurnberg, Germany.
Neurosurgery. 1997 Apr;40(4):713-22; discussion 722-3. Abstract quote  

OBJECTIVE: Lymphocytic hypophysitis and granulomatous hypophysitis are rarely encountered. The aim of this study was to demonstrate their clinical peculiarities among pituitary disorders and to provide an approach for their clinical management.

METHODS: In a retrospective study, we reviewed our surgical experience with nine patients harboring hypophysitis. The series included six cases of lymphocytic hypophysitis, two cases of granulomatous hypophysitis, and one case with evidence of coexisting lymphocytic and granulomatous hypophysitis.

RESULTS: A striking similarity of clinical signs was found for our nine patients. Headache or aseptic meningitis, thickening of the sphenoid sinus mucosa, pituitary stalk enlargement, and tongue-shaped extension of the lesion along the basal hypothalamus were characteristic signs. Lymphocytic hypophysitis was not associated with pregnancy in any of the seven cases. No recurrence has been observed in six cases with total removal of the inflammatory tissue.

CONCLUSION: Lymphocytic hypophysitis and granulomatous hypophysitis represent related inflammatory disorders. Their conspicuous clinical features frequently allow preoperative diagnosis of hypophysitis. In view of their sometimes insidious clinical course, early surgical exploration is justified.

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Last Updated March 11, 2005

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