2.4.4 Lymphocytic hypophysitis and other inflammatory conditions of the pituitary

Inflammatory lesions of the pituitary are far less common than pituitary adenomas. Although the most common of these, lymphocytic hypophysitis, is limited to the pituitary and pituitary stalk, many of the other lesions are usually part of a systemic process. Nonetheless, even these lesions, such as Langerhans’ cell histiocytosis (LCH) and sarcoidosis, sometimes present as part of disease limited to the central nervous system (CNS) and, rarely, present as isolated lesions of the hypothalamic/pituitary area. When lesions are located in the base of the hypothalamus or in the stalk, they commonly present with a combination of diabetes insipidus and hypopituitarism. In some cases, hypothalamic infiltration may be more widespread, affecting a variety of additional hypothalamic functions, such as satiety, sleep, and temperature regulation. These inflammatory lesions tend to be progressively destructive, resulting ultimately in fibrosis but the rate of progression is highly variable. When hypopituitarism or diabetes insipidus occur, they rarely recover even if the underlying process is directly treated. Thus, these lesions present more with endocrine hypofunction than with mass effects, although in early stages lymphocytic hypophysitis may well present with mass effects to the point where it can be confused with a pituitary adenoma.

Lymphocytic hypophysitis is a rare but increasingly recognized disease associated with hypopituitarism and a sellar mass. It is most commonly seen in the peri- or postpartum period but it has also been reported after menopause (1). About 15% of reported cases occur in males. The diagnosis may be challenging, as the clinical and radiographic distinction from pituitary adenomas and other sellar masses is often not obvious. The disease is presumably autoimmune in aetiology, although there has never been a specific target antigen identified (1).

Pituitary lymphoplasmacytic infiltration and panhypopituitarism was first described by Rapp and Pashkis in 1953 (2), but the concept of endocrine autoimmunity had not yet been considered and was only introduced several years later for Hashimoto’s thyroiditis. In 1962, Goudie and Pinkerton reported a case of a young woman with hypothyroidism and amenorrhoea, who died at of adrenal insufficiency 14 months postpartum at the time of appendectomy; her autopsy showed lymphocytic thyroiditis, severely atrophic adrenals, and a small atrophic pituitary with extensive lymphocytic infiltration. As it is most commonly seen in young women after childbirth it can be confused with Sheehan’s syndrome and its true incidence is unknown. However, the number of reported cases has increased in the recent years, likely due to improved imaging criteria and techniques (3).

About 500 patients with primary lymphocytic hypophysitis have been described in the literature (4). It affects women more frequently than men, with a reported ratio of about 5:1; however, the female:male ratio has been decreasing in recent years as more male cases are reported. When lymphocytic hypophysitis affects women of the reproductive age, it shows a striking temporal association with pregnancy. The mean age at diagnosis is approximately 35 years for women and 45 years for men (4). Of the 57% of patients developing the disorder in association with pregnancy, most occur during the last month of pregnancy or during the first 2 months postpartum (1, 5).

Hypophysitis can be classified based on anatomical distribution and whether it is a primary disorder of the pituitary gland or a secondary manifestation of a systemic disease.

Anatomically, the most common form is lymphocytic adenohypophysitis, where anterior pituitary cells and hormones are affected but posterior pituitary involvement is absent or minimal. With the much less common lymphocytic infundibulo-neurohypophysitis, the posterior pituitary is primarily involved, causing diabetes insipidus, and anterior pituitary function is usually preserved (1, 6–8). Lymphocytic infundibulo-panhypophysitis is even more rare, with lymphocytic infiltration and destruction present in both the anterior and posterior pituitary. These patients present with a combination of diabetes insipidus and anterior pituitary deficiency (1, 6–8).

Pathologically, primary hypophysitis has been described in three forms: lymphocytic, granulomatous, and xanthomatous. Lymphocytic hypophysitis is characterized by a dense lymphocytic infiltration of the anterior pituitary with destruction of the normal pituitary architecture and replacement with fibrosis (1, 6–9) as illustrated in the Fig. 2.4.4.1. The lymphocytes are predominantly cytotoxic T lymphocytes (CD8⁺), suggesting that T cell-mediated cytotoxicity is critical in the pathogenesis of the disorder (10).

Granulomas and multinucleated giant cells are not found in lymphocytic hypophysitis and, if observed, suggest an alternative diagnosis of granulomatous hypophysitis. This rare disorder has an incidence of 1/1 000 000. Granulomatous hypophysitis occurs in men and women with equal frequency and is not particularly associated with pregnancy. It may also present as a mass lesion with hypopituitarism and pathologically is characterized by giant cell granulomas (1, 6–10).

Xanthomatous hypophysitis, is exceedingly rare, with fewer than a dozen cases having been reported. The pathology of xanthomatous hypophysitis is characterized by a predominance of foamy macrophages, lymphocytes and single plasma cells (1, 10). Other more rare types of hypophysitis appear to be part of a more generalized inflammatory process and include Rosai–Dorfman disease and fibrosing inflammatory pseudotumor (also called Tolosa–Hunt syndrome and parasellar chronic inflammatory disease) (11).

Although hypophysitis is usually thought of as a primary process, it may occur secondarily in relation to infection (viral, bacterial, fungal, tuberculosis, syphilis) or other processes such as LCH, sarcoidosis, Wegener’s granulomatosis, Crohn–Takayasu disease and ruptured cysts (1, 6–8). It has also been documented to follow treatment with ipilimumab, a monoclonal antibody used in treatment of melanoma and renal cancer (12).

The aetiology of lymphocytic hypophysitis is unknown but it has been speculated to have an autoimmune basis (1, 6–8, 6–10). Nearly 30% of patients have a history of coexisting autoimmune diseases such as Hashimoto’s thyroiditis, Addison’s disease, type 1 diabetes, and pernicious anaemia (1, 6–9), and the condition is now considered a component of the type 1 polyglandular autoimmune syndrome (1, 6–8). Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade using the human anti-CTLA4 monoclonal antibody, ipilimumab, has antitumour activity in melanoma and renal cancer and has been found to be associated with lymphocytic hypophysitis (12), supporting an immune aetiology for the disorder.

Although antipituitary antibodies have been demonstrated in some patients with lymphocytic hypophysitis, their specificity for hypophysitis is poor, as they are also present in patients with nonautoimmune pituitary disease, other nonpituitary autoimmune disease (13, 14), and in normal postpartum women who do not develop hypophysitis. The pathogenic pituitary autoantigen(s) remain to be elucidated, although several candidates have been proposed (4).

When associated with pregnancy, lymphocytic hypophysitis typically presents in the third trimester of pregnancy or within 1 year postpartum, with symptoms usually related to a pituitary mass (headaches or visual symptoms) or hypopituitarism. The disorder often comes to attention due to failure of either lactation or menses following delivery (1, 3, 6–8). Neurohypophyseal involvement, manifesting as diabetes insipidus, occurs in 15% of cases (1, 3, 6–9). Other rare presentations of lymphocytic hypophysitis include meningeal irritation, diplopia due to cavernous sinus involvement, and occlusion of the internal carotid arteries.

Symptoms resulting from partial or panhypopituitarism occur in approximately 80% of cases, and multiple deficiencies are found in approximately 75% of cases (1, 3, 6–9) as illustrated in the Table 2.4.4.1.

There is an inexplicable unique predilection for the corticotrophs and thyrotrophs to be affected while the gonadotrophs may be spared. Prolactin levels range from unmeasurable to elevated; low levels are attributable to destruction of the lactotrophs, while hyperprolactinaemia is expected during pregnancy and the early postpartum period. However, elevated prolactin levels have been reported in cases of lymphocytic hypophysitis in men and nonpregnant women (9, 15), which is likely secondary to compression of the pituitary stalk.

MRI in hypophysitis commonly shows an enlarged pituitary gland, often with suprasellar extension and stalk thickening (1, 6–9) as shown in the Fig. 2.4.4.2. With hypophysitis, the gland is generally symmetrically enlarged, and administration of gadolinium homogeneously enhances the gland. In contrast, in adenomas gadolinium enhances the gland more focally as described in Table 2.4.4.2. In lymphocytic hypophysitis, the pituitary displays a relative low signal on T₁- and a relatively high signal on T₂-weighted images. By comparison, in macroadenomas a low signal on T₁-weighted images is uncommon, but a high signal on T2 -weighted images is occasionally seen. Often, the dura mater adjacent to the mass in lymphocytic hypophysitis shows a unique, marked contrast enhancement referred to as a ‘dural tail’. In late stages, these MRI findings may be absent due to shrinkage of the mass with resolution of the inflammatory process, and fibrotic changes and an empty sella may be seen (15).

Lymphocytic hypophysitis should be considered in the differential diagnosis of pituitary masses and/or hypopituitarism in females who are pregnant or in the early postpartum period. This is especially true in cases associated with other autoimmune diseases or unusual patterns of hormone deficiencies. In the past many individuals with postpartum hypopituitarism who lacked a history of hypovolaemic shock were inadvertently labelled as having Sheehan’s syndrome when, in fact, they had hypophysitis.

A definitive diagnosis of lymphocytic hypophysitis requires tissue biopsy. However, it may be possible to make a presumptive clinical diagnosis in patients who meet the following criteria: (1) a history of gestational or postpartum hypopituitarism, especially after a delivery uncomplicated by hemorrhage or hypotension; (2) a contrast enhancing sellar mass with imaging features characteristic of lymphocytic hypophysitis; (3) a pattern of pituitary hormone deficiency with early loss of adrenocorticotropic hormone (ACTH) and thyroid-stimulating hormone (TSH)—unlike that typically found with macroadenomas (i.e. sequential loss of growth hormone, luteinizing hormone (LH)/follicle-stimulating hormone (FSH), ACTH, and TSH); (4) relatively rapid development of hypopituitarism in contrast to the expected slow development of hypopituitarism that would be expected with an adenoma; and (5) a degree of pituitary failure disproportionate to the size of the mass. Nevertheless, biopsy may be required in situations in which a distinction cannot be made between lymphocytic hypophysitis and a nonfunctioning macroadenoma or prolactinoma and when neurological signs develop.

Lymphocytic hypophysitis and infundibulo-neurohypophysitis likely represent distinctly separate pathological entities, as the latter tends to occur in older patients and is less likely to be associated with pregnancy (1, 6–9). Lymphocytic infundibulo-neurohypophysitis causes central diabetes insipidus and spares the anterior pituitary as a result of an inflammatory process confined to the stalk and posterior pituitary (17). The radiological features are generally more clearly delineated: thickening of the pituitary stalk or neurohypophysis and homogeneous enhancement of the pituitary stalk or neurohypophysis after the administration of contrast material (24).

The natural history of lymphocytic hypophysitis is variable and unpredictable. Typically, the pituitary initially becomes inflamed, oedematous, and enlarged, and the patient develops symptoms secondary to mass effects. Progressive fibrosis causing destruction of the parenchyma leads to hypopituitarism. In some cases, the course is aggressive and neurological deficits progress rapidly (1, 6–9). However, cases of spontaneous partial or full recovery of pituitary function, as well as resolution of pituitary masses in the absence of any intervention, have been well documented (25–27). Because the natural history of lymphocytic hypophysitis is so variable, appropriate management remains controversial.

Controlled therapeutic trials are not feasible due to the rarity of hypophysitis, an inability to make definitive diagnoses without histological proof, and the considerable variability in the natural history of the disorder. Until recently, preoperative suspicion of the diagnosis was rare due to under-recognition, and the traditional diagnostic and therapeutic approach involved transsphenoidal biopsy, exploration, and/or pituitary resection. Consequently, cases illustrating only transient compressive effects and endocrine dysfunction support a case for conservative management. With a greater knowledge of the course of lymphocytic hypophysitis and the ability to make a presumptive diagnosis in highly suggestive cases, it is possible to avoid routine neurosurgical exploration in many cases.

Corticosteroid therapy has been advocated as a means of attenuating inflammation and, in some patients, has been associated with return of pituitary function and reduction of the mass (28, 29). Conversely, cases have also been reported in which lymphocytic hypophysitis failed to improve with glucocorticoid therapy (9, 30). There are also a few documented cases of improvement in symptoms with administration of corticosteroids followed by a relapse when therapy was discontinued (31). It is unclear, however, whether improvement in the clinical course is directly attributable to corticosteroid treatment or simply reflects the natural course of the disease (25–27). Given the uncertainty regarding the efficacy of corticosteroid treatment and its known adverse effects, such therapy does not seem justified for most patients.

Patients with a presumed diagnosis of lymphocytic hypophysitis should be observed closely and undergo serial visual field examinations or an MRI if they are managed medically. Surgical decompression of the pituitary mass may be required if the patient fails conservative therapy as demonstrated by progressive radiological or neurological deterioration or by signs of optic nerve compression. However, in this situation some would argue for a short course of steroids (1, 6–9). The optimal surgical strategy involves only partial resection of the mass to decompress the surrounding structures via a transsphenoidal approach rather than an attempt at complete resection, because surgery rarely improves endocrine dysfunction. All patients with lymphocytic hypophysitis require appropriate replacement therapy for deficient hormones. Long-term follow-up is mandatory to monitor for the development of other hormonal deficits. Because hypopituitarism is temporary in a subset of patients, a careful attempt should be made to withdraw hormone replacement after resolution of the inflammatory stage if progression to fibrosis does not result in irreversible hypopituitarism.

LCH is a rare disorder characterized by clonal proliferation of abnormal dendritic antigen-presenting histiocytes, known as Langerhans’ cells, with an accompanying infiltrate of lymphocytes, eosinophils, and neutrophils resulting in the destruction of a variety of tissues. LCH is also regarded as an inflammatory disease because an altered expression of cytokines and cellular adhesion molecules important for the migration and homing of Langerhans’ cells has been demonstrated (32, 33).

LCH is usually considered to be a disease of childhood, with a peak incidence at the ages of 1 to 3 years (34). Overall, the incidence is 3–5 cases per million per year, with a male to female ratio of 2:1 (34). In adults, the mean age at diagnosis is 33 years and it is seen even more rarely, the estimated prevalence being 1–2 cases per million (35).

LCH encompasses a group of diseases that have been referred to as Hand–Schüller–Christian disease, Letterer–Siwe disease, eosinophilic granuloma, histiocytosis X, Hashimoto–Pritzker syndrome, self-healing histiocytosis, pure cutaneous histiocytosis, Langerhans’ cell granulomatosis, type II histiocytosis, and nonlipid reticuloendotheliosis (36). Letterer–Siwe disease usually presents in the first 2 years of life and is an acute disseminated form of LCH with extensive cutaneous lesions classically resembling seborrhoeic dermatitis, and is associated with fever, anaemia, lymphadenopathy, osteolytic lesions, and hepatosplenomegaly. Hand–Schuller–Christian disease is a chronic, multisystem disease seen in older children, and the classic, although rare, triad consists of bone disease, diabetes insipidus, and exophthalmos. Eosinophilic granuloma presents in older children and adults, and the granulomatous lesions most often affect bone. Hashimoto–Pritzker disease, also known as congenital, self-healing reticulocytosis, is limited to the skin and resolves rapidly over a period of weeks. Two different phenotypes are usually seen in adults and children with LCH; involvement of bone, lung, skin and diabetes insipidus usually predominates in adults, whereas involvement of liver, spleen, lymph nodes and bone marrow is more common in children (37).

In adults, LCH has a predilection for the hypothalamus and pituitary. When only patients with multisystem disease are included, the prevalence of diabetes insipidus can be as high as 40% and diabetes insipidus is considered to be the most common disease-related permanent consequence (38). Diabetes insipidus can also be the presenting feature, pre-dating the diagnosis of LCH. Established diabetes insipidus is generally permanent and does not respond to any disease-modifying treatment; hence the only treatment is desmopressin (39). Diabetes insipidus associated with structural abnormalities of the hypothalamus and pituitary often heralds the development of anterior pituitary hormone deficiencies and CNS involvement (18). Anterior pituitary dysfunction is found in up to 20% of patients with LCH, and is almost always associated with diabetes insipidus (39, 40). Once established, anterior pituitary deficiencies seem to be permanent and are not affected by any form of LCH disease-modifying treatment (18).

The most frequent anterior pituitary hormone deficiency is that of growth hormone, which is found in up to 42% of patients and generally diagnosed with a latency of 1 year from the diagnosis of diabetes insipidus. Deficiencies of luteinizing hormone/FSH are next most common, with a latency of 7 years from the diagnosis of diabetes insipidus (40). Therefore if a partial pituitary hormone deficiency is identified in a patient with LCH, regular monitoring for the remaining hormones is advised. In addition to pituitary involvement, up to 40% of patients with diabetes insipidus have hypothalamic infiltration which results in nonendocrine hypothalamic manifestations, including abnormal eating patterns, morbid obesity, and disturbances in social behaviour, temperature, sleep pattern, and thirst. Diabetes insipidus may be particularly difficult to manage in patients with impaired memory.

Patients with LCH and diabetes insipidus commonly demonstrate a loss of the hyperintense signal of the posterior pituitary on T₁-weighted images (‘bright spot’) on MRI (39). Infundibular enlargement is present in up to 71% of patients at the time of diagnosis of diabetes insipidus (41) as illustrated in the Fig. 2.4.4.3. Hypothalamic mass lesions have been described in 8–18% of patients exhibiting one or more pituitary hormone deficiencies (41). The LCH lesions typically are isointense on T₁ images, hyperintense on T₂ images and enhance with gadolinium (41).

In order to make the diagnosis of LCH, one must search for extracranial manifestations of LCH with a radiographic skeletal survey, skull series, chest X-ray, and bone scan so that these lesions can be biopsied. Osteolytic lesions due to LCH may be present in the jaw or mastoid, so radiographs of the jaw are a worthwhile part of the diagnostic evaluation. When biopsies of other tissues show LCH and the MRI and clinical picture are compatible, biopsy of the hypothalamic/stalk lesion is rarely necessary.

To establish a diagnosis according to the published criteria of the Histiocytosis Society, a tissue biopsy must either show presence of pathognomonic Birbeck granules on electron microscopy or stain positive for CD1a (43). Birbeck granules are pentalaminar cell inclusions that sometimes have a ‘tennis racquet’ dilated terminal appearance (44). Their exact function is unknown, but some studies implicate them in antigen processing.

The course of LCH is often unpredictable, varying from spontaneous regression and resolution to rapid progression and death or repeated recurrence with a considerable risk of permanent sequelae. Patients with disease that is localized to one organ system—single system disease—usually in the bone, skin, or lymph nodes, have a good prognosis and seem to need minimal or even no treatment. In contrast, multiple organ involvement—multisystem disease—carries a risk of a poor outcome, including 10–20% mortality and a 50% risk of life-impairing morbidity. Therefore an early diagnosis and close follow-up is critical. The mainstays of treatment of LCH have been surgery and radiation over the years. However, vinblastine in combination with steroids is now the most frequently used initial therapy for multisystem disease (40). Reports have shown that the purine analogue cladribine (2-chlorodeoxyadenosine) can be effective for adults with recurrent and/or disseminated disease (45).

Anterior and posterior pituitary hormonal deficits are replaced as necessary. With disease limited to the stalk, panhypopituitarism and diabetes insipidus may be present early and need immediate treatment. As with other infiltrative diseases of the hypothalamus, the anterior pituitary hormone deficits may gradually appear. Therefore, periodic testing for many years and then treatment of new deficits may be necessary.

The prevalence of CNS involvement in sarcoidosis is 5–15% and most of these patients are found to have non-caseating granulomas in the hypothalamo-pituitary region in addition to the leptomeninges and cranial nerves (46). The most commonly found hormonal abnormality is diabetes insipidus (17–90% of patients), followed by hyperprolactinemia (3–32%) (19). Hypothalamic involvement may also cause obesity, somnolence with disruption of sleep cycle, alteration in the thirst centre, and loss of short-term memory (47).

MRI usually shows pituitary stalk thickening and enhancement as well as pituitary enlargement. Periventricular lesions and leptomeningeal enhancement can be seen in sarcoidosis and this can help distinguish it from lymphocytic hypophysitis. Significant laboratory findings that may aid in diagnosis are elevated levels of serum and cerebrospinal fluid angiotensin-converting enzyme (ACE). As with LCH, a search for other systemic tissue involvement is important, so that a biopsy can be obtained.

Management of sarcoidosis frequently involves the use of steroids, but recovery of anterior and posterior pituitary function usually does not occur (19). Recently, cladribine was also found to reverse diabetes insipidus caused by sarcoidosis (48). The hypothalamic/pituitary involvement may be gradual and progressive, so that periodic testing is necessary and hormonal deficits treated as they develop.

Wegener’s granulomatosis is a systemic vasculitis affecting small- and medium-sized vessels, most commonly in the respiratory tract and kidneys; the pituitary is involved in less than 1% of cases (20). Involvement of the pituitary can occur via direct extension from nasal, paranasal, or orbital disease, from remote granulomatous involvement, or from vasculitis of the hypothalamus. Patients most frequently present with diabetes insipidus, but hyperprolactinaemia and panhypopituitarism have also been reported (7).

The finding of high titres of antineutrophil cytoplasmic antibody (c-ANCA) can be diagnostic but in some cases biopsy of affected tissue is required. When there is hypothalamic/pituitary involvement, MRI reveals an enlarged pituitary with homogeneous enhancement, thickening,and enhancement of the pituitary stalk, and enhancement of the optic chiasm (7, 21).

Wegener’s granulomatosis is usually treated with glucocorticoids and/or cyclophosphamide. However, such treatment does not usually lead to reversal of the hypopituitarism. Similar to other infiltrative disease, the destruction may be gradual, necessitating repeated testing and treatment of hormonal deficits as they develop.

Since the introduction of antibiotics sellar tuberculomas have become rare, now constituting only 0.15–4.0% of all intracranial mass lesions (49). However, CNS tuberculosis is still relatively common in developing countries. Interestingly, pituitary tuberculomas are found more commonly in women.

Patients may have both anterior and posterior pituitary hormone deficiencies as well as manifestations of other hypothalamic dysfunction. In some cases, these disorders may manifest very gradually over many years, as depicted in Fig. 2.4.4.4. In one series of patients followed up after having had tuberculous meningitis, 20% were found to have anterior pituitary hormone deficiencies (22).

Imaging can reveal involvement of the paranasal sinuses or pituitary fossa, enhancing lesions in the hypothalamus, thickening of the pituitary stalk, pituitary atrophy, and adjacent meningeal enhancement. Pituitary abscesses may also have peripheral contrast enhancement. Tuberculomas are isointense to hypointense on T₁-weighted images and hyperintense on T₂-weighted images. However, these signal characteristics are not unique to tuberculomas and can be seen in pituitary adenomas as well.

Therapy with antituberculous drugs along with surgery when indicated has been used; improvement in pituitary function has been reported in rare cases (23). Pituitary hormonal deficits should be treated when they develop.