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NEURO-ONCOLOGY
NEURO-TRAUMA
NEURO-VASCULAR
SPINE SURGERY
PERIPHERAL CNS
 
 
 
Essentials in lymphoid hypophysitis:

It is an autoimmune disease.
Preoperative diagnosis is almost impossible.
High dose corticosteroids alleviate the course of the disease.
Other autoimmune diseases with panhypopituitarism hold the suspicion about the diagnosis.
Histological verification is mandatory.

 
 

Introduction

Autoimmune disease of the pituitary is rare and poorly understood as a pathologic entity. The first reported case was a young postpartum patient who had Hashimoto's thyroiditis and died of rapidly progressive hypopituitarism, which suggested that these two endocrinopathies have a common etiology. The fact that a lymphocytic inflammation was found in both the pituitary and the thyroid suggested that both glands were experiencing an autoimmune reaction. Since this first postmortem report, no other pituitary mass lesion has so consistently challenged a correct preoperative diagnosis as lymphocytic hypophysitis. The rarity of this disorder, as well as the lack of specific biological markers or radiologic features, has made it clinically difficult to diagnose without a tissue biopsy.

Histopathology and Current Concepts of Pathogenesis

There are now at least more than 100 published cases of documented lymphocytic hypophysitis. The pathophysiologic process apparently begins as an acute inflammatory response with enlargement of the gland, as noted in 95% tissue-documented cases. In cases of protracted disease, most of which have been diagnosed postmortem, the gland becomes atrophic and fibrotic. A survey of the cases studied indicates that the disease varies widely in the intensity of the inflammatory process.

Histologically, the anterior lobe of the affected pituitary gland shows an extensive cellular infiltration of lymphocytes and plasma cells. True lymphoid follicles with germinal centers are occasionally seen, and cellular destruction defaces the normal pituitary architecture. Diffuse interstitial fibrosis has been noted, and it is more common in cases with an atrophied gland. The neurohypophyseal tissue does not appear to be primarily involved in the lymphocytic infiltration or the fibrosis. Immunoperoxidase stains have consistently revealed the presence of immunoreactive cells positive for prolactin, growth hormone, adrenocorticotropic hormone, follicle-stimulating hormone, thyrotropin, and luteinizing hormone, although in diminished numbers.

Ultrastructural features studied by electron microscopy reveal degranulated, inactive secretory granules. There is an inflammatory cellular infiltrate in the periacinar basement membrane. In some cases, focal oncocytic changes have been noted in secretory cells. Activated cytotoxic lymphocytes are noted to be interdigitated with secretory cells. No immune complex deposits have been identified nor do the blood vessels show pathologic changes. These ultrastructural features resemble those of other auto immune endocrinopathies.

Immunocytochemical examination of the lymphocytic infiltrate demonstrates the presence of B lymphocytes, as confirmed by B4­positive (pan-B cell) monoclonal antibody stains, and the presence of kappa light chains. There is a preponderance of T cells over B cells, and this is characteristic of other autoimmune disease infiltrates. The T-cell subpopulation has been studied with two different observations. Originally, Parent et al. observed a preponderance of suppressor/cytotoxic T4 cells on formalin-fixed material that was embedded in paraffin. However, direct immunohistochemical studies on fresh-frozen tissue specimens have revealed that T 4 cells outnumber T8 cells in a ratio of 2 : 1. The precise T 4: T8 cell ratio seems to be related to the progression of the disease as well as to the specific disease process in a particular organ.

McCutcheon and Oldfield observed that class I major histocompitability (MHC) antigen was present mainly on the infiltrating cells and to a lesser degree on the pituitary parenchyma and vasculature. Class II MHC antigen as well as interleukin-2 receptors were distributed only on the infiltrating lymphocytes and macrophages. The presence of interleukin-2 receptors as well as other cytokines demonstrates that the neuroendocrine and immunologic systems are intimately involved in T-cell activation. The significance of the absence of class II MHC antigen on normal pituitary cells is unclear, since its inappropriate expression may occur only on altered pituitary cells. Some authorities believe that the aberrant expression of MHC II antigens leads to autoimmunity. On the other hand, the cytotoxic response of autoimmune disease acts through class I MHC.

Repeatedly, this entity has been demonstrated to coexist with other autoimmune diseases. It was reasonably assumed, therefore, that this disease has an auto immune etiology. These associated autoimmune diseases have included Hashimoto's thyroiditis, silent thyroiditis, idiopathic adrenalitis, parathyroiditis, pancreatitis, and pernicious anaemia. During pregnancy, production of so-called fetal suppressor cells apparently allows the fetus to escape maternal immunologic rejection. The tendency of autoimmune disorders to remit during pregnancy and to exacerbate after parturition has been attributed to this phenomenon.

There seems to be a consensus that most auto immune diseases result from a combination of exogenous and indigenous factors. Some reports have demonstrated that auto immune diseases, such as an experimental allergic encephalitis, can be induced in rodents by the injection of an encephalogenic protein such as myelin basic protein. In a recent study, Yoon and colleagues investigated whether rubella virus structural protein could induce an organ­specific autoimmune disease in golden Syrian hamsters. Two weeks after the injection with rubella virus E-1 glycol protein, 50 percent of the hamsters had developed autoantibodies against pituitary cells. Without exception, the animals that were positive for antibodies showed diffuse histologic inflammatory cell infiltration throughout the pituitary gland comparable to lymphocytic hypophysitis in humans. Thymectomized animals produced neither antibodies nor the lymphocytic infiltration, suggesting that T cells play a crucial role in the development of auto immune lymphocytic hypophysitis syndromes. A variety of other rubella virus proteins was used, and only the E-1 and E-2 proteins of the recombinant rubella virus were able to induce this autoimmune lymphocytic hypophysitis. In was further observed that E-1 and E-2 shared a common sequence of three alanines located in the immunodominant helper T-cell antigenic site. This is the second animal model that has been developed for autoimmune lymphocytic hypophysitis. It is more consistent than the previous model in producing lymphocytic hypophysitis, and for the first time provides investigators with a model for elucidating both the molecular and the immunologic role of these viral-specific peptides in the initiation of auto immune diseases of endocrine glands.

Vanneste and Kamphorst have suggested the possibility that a prior or concurrent lymphocytic meningitis is an etiologic factor in inciting lymphocytic hypophysitis. Meningoencephalitis has been associated with pituitary insufficiency, and a contrast­enhancing sellar/suprasellar mass has been demonstrated in such cases. Jew and colleagues have reported a case in which the resolution of the meningoencephalitis was attended by endocrinologic and radiologic improvement. Although it is assumed that an immunologic process is involved, the precise initiation and pathogenesis of the disease are still unknown.

Clinical Presentation

Of the  reported patients with lymphocytic hypophysitis  90% were female; of these, 13% were nulligravidas, and of the 63% women who had been pregnant, (55 percent) were primigravidas. Of parous women, (73 percent) were within 1 year of parturition. 10% male cases have been reported, in whom the presentation was consistent with a destructive lesion of the pituitary.

Symptoms of a mass effect, including headaches, nausea, and vomiting as well as visual field defects, have been noted in approximately 60 percent of cases. Emotional disturbances are frequently noted in patients with this disorder, and there is one report of suicide. Amenorrhea has been noted in 30% of cases, and galactorrhea in 15%. Many patients presented with clinical findings consistent with adrenal insufficiency, such as postural hypotension, anorexia, fatigue, nausea, vomiting, and asthenia.

The hormonal abnormalities have varied from panhypopituitarism to single hormone abnormalities such as hyperprolactinemia, hypothyroidism, or hypoadrenalism. The amenorrhea and galactorrhea in these cases possibly resulted from primary hypogonadotropism or hypothalamic dysfunction rather than the elevated prolactin levels. The onset of diabetes insipidus with this disease entity is unusual, at least in the individual who has not undergone a pituitary operation. However, 15% of the cases have been reported presenting with documented diabetes insipidus with symptoms of polyuria, polydipsia implicating the involvement of the neurohypophysis without impairment of hypothalamic function. The endocrinopathy was transient in 10 of 64 biopsy-proven cases, suggesting that not all cases of lymphocytic hypophysitis inevitably lead to hypopituitarism. Presumably there are instances of transient reversible hypophysitis that are unrecognized. Nevertheless, most auto immune reactions are chronic and tend to be characterized by remissions and relapses.

Radiologic Features

Radiologically, this lesion is indistinguishable from a pituitary tumor. Plain x-ray skull films have usually been normal, but polytomography of the sella may demonstrate an enlarged, rounded sella without evidence of focal erosion. Although erosion of the dorsum sellae has been noted with this mass lesion, erosion of the floor of the sella has not. This observation is consistent with the presumed short course of the disease prior to initial diagnosis.

Prior to the era of computed tomography (CT), no case of this disease was diagnosed before death. The lesion usually enhances densely on CT scans, and a generalized enlargement of the sella may be visible. Other than the gothic-arch stretching of the anterior cerebral arteries over the suprasellar mass lesion, angiography shows no specific vascular abnormalities. On T1­weighted magnetic resonance imaging (MRI), these lesions show a homogeneous signal intensity and are hypointense or isointense to brain parenchyma. On T2-weighted spin echo sequences, they are hyperintense to brain. They may enhance uniformly with gadolinium administration. Intense enhancement of the dura adjacent to the pituitary mass as well as thickening and enhancement of the pituitary stalk may be important characteristics of lymphocytic hypophysitis.

Differential Diagnosis

Pituitary insufficiency with a sellar or suprasellar mass lesion certainly is suggestive of a nonsecreting pituitary tumor, which cannot be differentiated clinically from lymphocytic adenohypophysitis. Hypersecretory adenomas will readily be identified by their unique hormonal excess, except in cases of the hyperprolactinemia due to pituitary stalk compromise. Other neoplastic lesions, such as craniopharyngioma, germinoma, or a metastasis, could radiographically or hormonally mimic this destructive lesion. The enlargement of the pituitary due to hyperplasia of thyrotropes in primary hypothyroidism may present with a sellar mass lesion, but the serum thyroid-stimulating hormone (TSH) level should be elevated and other pituitary hormonal deficits absent with this entity.

Sheehan's syndrome. or postpartum pituitary necrosis, is usually associated with hemorrhage and hypotension. Pituitary apoplexy is classically attended by the triad of altered consciousness, extraocular motor palsy. and sudden-onset visual loss. Other sellar/suprasellar lesions, such as arachnoid cysts, meningiomas, chordomas, choristomas, and gliomas, have characteristic radiologic features and usually are not associated with hypopituitarism.

Histologically, the granulomatous inflammation of the pituitary seen in syphilis, tuberculosis, sarcoidosis, and giant cell granuloma is similar to that of lymphocytic hypophysitis. Syphilis may affect the entire pituitary, causing hypopituitarism, but tuberculosis rarely does so. These entities can be readily distinguished clinically by blood examination and skin tests, respectively. Sarcoidosis usually causes diabetes insipidus, whereas lymphocytic hypophysitis rarely involves the neurohypophysis.

Plasmocytoma and lymphoma can imitate lymphocytic adenohypophysitis histologically. but these tumors usually have immunocytochemically distinct cell populations as well as neoplastic cellular features. The usual enlargement of the pituitary during pregnancy by lactotropes. as well as the occasional finding of lymphoid tissue in the pars intermedia, should not be confused with the diffuse inflammatory response of lymphocytic adenohypophysitis.

In any woman presenting with a sellar mass lesion during pregnancy or in the first year after parturition, lymphocytic adenohypophysitis should be suspected. However, some patients have presented up to 40 years postpartum or even without pregnancy. Until a specific pituitary antibody for this disease or a characteristic radiographic feature, as by MR spectroscopy, has been identified, the clinical diagnosis of this entity must rely on the histologic study of the pituitary

Therapy and Prognosis

The present approach to lymphocytic adenohypophysitis, both for pathologic diagnosis and for chiasmal decompression, involves prompt surgical intervention. A transsphenoidal approach is best, as it not only allows a limited biopsy to be performed but also preserves the great bulk of viable pituitary tissue. Unfortunately, the pituitary gland may be uniformly involved in the inflammatory reaction, and thus surgical manipulation may lead to vascular compromise of the remaining gland. To diminish this risk, decompression should be performed laterally along the cavernous sinus margins of the pituitary, with preservation of the midline infundibulum, neurohypophysis, and portal hypophyseal system. Early diagnosis is important because the concomitant pituitary insufficiency is often rapidly progressive, and prompt hormonal replacement, especially for hypoadrenalism, is essential.

Several authors have suggesting using steroid therapy to decrease the pituitary size and possibly alter the autoimmune response. Several patients treated in this fashion had marked short-term improvement in visual fields, while at least one failed to respond. No shrinkage of the mass was reported. Two immunotherapeutic agents that might be considered include azathioprine (Imuran) and cyclosporine.

 

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