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
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.
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
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
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.
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.
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
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.
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.
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
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.
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
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.