Update on Hypophysitis and TTF‐1 Expressing Sellar Region Masses

Abstract

This article reviews recent literature on sellar region masses that most closely mimic nonsecretory pituitary adenomas: hypophysitis, pituicytoma, spindle cell oncocytoma, and granular cell tumor of neurohypophysis. Even today, these four entities often cannot be confidently distinguished from each other clinically or by preoperative neuroimaging features. Thus, they often come to biopsy/surgical resection and require tissue confirmation of diagnosis. Causes of secondary and primary hypophysitis will be discussed, including two newly described types, IgG4 plasma cell hypophysitis and hypophysitis caused by anti‐cytotoxic T‐lymphocyte antigen 4 antibody therapy for cancer. For the neoplastic conditions, emphasis will be placed on literature that has emerged since these entities were first codified in the 2007 World Health Organization fascicle. The finding that immunohistochemical staining for thyroid transcription factor‐1 is shared by pituicytoma, spindle cell oncocytoma, and granular cell tumor of neurohypophysis suggests common lineage and explains why histological overlap can be encountered. We incorporate our own experiences over the last 30 years from two referral institutions with specialty practices in pituitary region masses.

Hypophysitis

Hypophysitis is an uncommon disorder involving the pituitary gland, which by definition, shows inflammatory cells within the adenohypophysis, neurohypophysis, infundibulum or combined sites. It is not a singular disease, but rather several very different entities 94 and is rare when put in the context of all sellar region masses. Clinical reviews of hypophysitis cite an incidence of one case per 9 million person‐years and <1% occurrence among pituitary surgical cases 14, 42, with some 379 cases of the main subtype (lymphocytic hypophysitis) identified as of 2005 15.

Hypophysitis usually presents as a mass lesion of the pituitary gland that simulates a nonsecretory pituitary adenoma by clinical and neuroimaging studies 42. If hypophysitis occurs within the framework of a well‐understood set of predisposing clinical features, such as pregnancy or postpartum time period in women or certain medications (see later), the condition can be strongly suspected and requires no tissue confirmation of diagnosis. Empiric treatment may be started in an attempt to avert surgical decompression. However, in situations where the patient fails to respond to medical therapies and optic chiasmal compression persists with deterioration of vision, surgical decompression may be required and will result in a tissue specimen for the pathologist. Even today, however, in a percentage of cases, the diagnosis of hypophysitis is unsuspected clinically and comes only at the time of histological examination of the tissues by the pathologist 91.

The importance of recognizing this entity for pathologists is that if the diagnosis can be recognized at the time of intraoperative consultation, surgical treatment may be altered in cases of pure (primary) hypophysitis without a coexistent tumor or cyst. In cases of pure hypophysitis, neurosurgical treatment optimally would be a smaller decompressive procedure or even biopsy alone. Aggressive resection of the mass, as would be indicated for a pituitary adenoma, ideally is avoided in cases of primary hypophysitis, regardless of the underlying etiology 20. Thus, it is imperative then that pathologists be cognizant of the features of hypophysitis, as well as the conditions that can be mistaken histologically for the disorder.

Indeed, even on permanent sections the diagnosis may be challenging because the tissue samples may be quite small. The fibrosis that occurs in longer‐standing examples of hypophysitis can make it difficult for the neurosurgeon to obtain a reasonably sized piece of tissue for biopsy. Reticulin and trichrome stains, coupled with immunostaining for CD45 (leukocyte common antigen), CD3 (T‐cells), CD20 (B cells), CD68 (macrophages) and CD138 (plasma cells) or similar immunomarkers on permanent sections, usually clarify the inflammatory nature of the process and assists in assessing the background architecture of the pituitary gland. Immunostaining for a panel of anterior pituitary hormones can be undertaken in cases with sufficient tissue to assess whether there has been specific or nonspecific loss of pituicytes and to rule in/out coexistent pituitary adenoma. In some studies, selective loss of subtypes of hormonal cells has been detected in cases of primary hypophysitis 109, although in most examples, the destruction of the anterior gland is more nonspecific and may vary considerably, based on timing of the biopsy and/or severity of the process.

Hypophysitis has been classified both by etiology and by the cell type(s) that predominate histologically within the inflammatory cell infiltrates. Secondary hypophysitis cases are essentially those in which an underlying cause for the inflammation can be established. Primary hypophysitis, in contrast, are those examples in which coexistent sellar region tumors, systemic inflammatory diseases or infections have been excluded. Primary hypophysitis is today classified as an autoimmune disorder of the gland 14, 42.

When the pathologist first considers the diagnosis of hypophysitis, either primary or secondary, it is important to recognize that lymphocytes are not normally present in the anterior pituitary gland; even at autopsy, only very rare individual lymphocytes are usually detected by specific immunostaining (Figure 1A). Thus, the histological finding of significant numbers of inflammatory cells in pituitary gland should be considered abnormal.

Figure 1.

A. Even at autopsy the anterior pituitary gland is normally nearly devoid of lymphocytes, with only rare individual cells appreciated only on immunostaining (arrows). Immunostaining for CD45, with light hematoxylin counterstain, 200×. B. Both normal pituitary cells and adenoma cells are very subject to crush artifact especially on surgically resected specimens; note crushed cells in adenoma (top panel) vs. the non‐distorted, more voluminous cells elsewhere in the same tumor (bottom panel). Hematoxylin and eosin (H&E), both 600×. C. Treatment of a prolactinoma with dopamine agonist drugs (such as cabergoline) may lead to cytoplasmic shrinkage of adenoma cells either throughout the tumor, or only in subpopulations, as is illustrated here; when only a few cells display the look of “naked nuclei” (arrows) they are more readily mistaken for lymphocytes. H&E, 600×. D. Immunostaining for prolactin in the same treated prolactinoma illustrated in Figure 1c shows that some of the small cells (arrow) retain hormonal staining, negating consideration of lymphocytic infiltrates. Immunostaining for prolactin, with light hematoxylin counterstain, 600×. E. On low power initial inspection of tissues removed from patients with more remote pituitary apoplexy, significant fibrosis (*) can entrap islands of viable adenoma cells (arrow) that can also be mistaken for lymphocytes. H&E, 100×. F. Apoplexy infrequently generates a true lymphocytic response. In this case the organizing hemorrhage (*) is surrounded by a thick perimeter of small lymphocytes that obscure the underlying adenoma, a few cells of which can be seen at extreme upper right. H&E, 200×. G. Immunostaining for adrenocorticotroph hormone (ACTH) clarifies that the bleeding seen on F actually occurred within an ACTH‐secreting adenoma. Immunostaining for ACTH, with light hematoxylin counterstain, 200×. H. Rare cases of pituitary adenoma may bleed so profusely that the blood cannot be fully resorbed, leaving residual cholesterol clefts that may be surrounded by multinucleated giant cells and benign lymphocytes (arrows) as a nonspecific reaction to tissue injury. H&E, 200×. I. The same pituitary adenoma with remote bleeding as seen in H also shows brisk T‐cell reaction to the cholesterol debris. Immunostaining for CD3, with light hematoxylin counterstain, 200×.

Several things can mimic inflammatory cells, especially in surgical pituitary tissue specimens. Normal or especially adenomatous pituitary cells are prone to crush artifact. Artifactual compression and distortion of cytoplasmic volume can be mistaken for inflammatory cells at first glance (Figure 1B). Pituitary prolactinomas treated preoperatively with dopamine agonists such as bromocriptine or cabergoline may result in diffuse or focal cytoplasmic shrinkage of the adenoma cells, leading to the appearance of “naked nuclei” easily mistaken for lymphocytes (Figure 1C), although this histological effect is not invariably seen in all patients on this therapy. Shrunken adenoma cells usually still maintain at least focal immunoreactivity for prolactin, assisting in resolving diagnosis (Figure 1D).

Cases of subacute to chronic pituitary apoplexy that come to surgical resection can contain residual islands of viable adenoma cells, often in perivascular locations that, at least on low‐power inspection, can mimic inflammatory cells (Figure 1E). More recent bleeding into a pituitary adenoma, either clinical or subclinical apoplexy, is frequent. However, it can uncommonly be associated with true inflammatory cell collections, usually lymphocytes near the edge of the previous bleed (Figure 1F,G). These lymphocytes are predominantly CD3+ T‐cells, although scattered CD20+ B‐cells are usually present as well. Rarely, remote intra‐adenoma bleeding can lead to cholesterol cleft formation because of the inability of the blood to be resorbed. Cholesterol clefts may be surrounded by cytologically bland lymphocytes, numerous histiocytes and multinucleated foreign body giant cells (Figure 1H,I). Touch or smear preparations at the time of intraoperative consultation may allow detection of lymphocytes, histiocytes or plasma cells in a specimen.

An important point to note when considering the diagnosis of hypophysitis is that pituitary adenomas, like normal anterior gland, do not routinely contain significant lymphocytic infiltrates if they have not undergone remote bleeding/apoplexy or previous surgical resection. Heshmati et al retrospectively studied 1400 pituitary adenomas and noted lymphocytic infiltrates in only 2.9% of adenomas, always exclusively T‐cells, and usually perivascular (Figure 2A) rather than diffuse or nodular in distribution. They encountered no cases with germinal center formation 49.

Figure 2.

A. Pituitary adenomas only occasionally contain benign lymphocytes and then usually these are located in perivascular areas, as seen at upper left. Hematoxylin and eosin (H&E), 400×. B. Secondary hypophysitis associated with craniopharyngioma is rarely reported; this intrasellar adamantinomatous craniopharyngioma in an adult did not show inflammation within the tumor itself. H&E, 100×. C–F. The craniopharyngioma illustrated in Figure 2b showed overwhelming lymphocytic infiltrates in the adjacent anterior pituitary gland (C), partial destruction of pituitary acini with residual acini highlighted by synaptophysin immunostaining (D), and T‐cell lymphocytic predominance (E). Reactive B cells are, however, also present to a lesser degree in hypophysitis (F) and should not be mistaken for lymphoma. H&E, 400× (C), 600× (D), 200× (E), 600× (F).

Secondary hypophysitis

True examples of hypophysitis with follicle formation in association with pituitary adenomas are quite rare 52, 72, 76, as are rare reports of hypophysitis associated with craniopharyngioma 85 (Figure 2B–F). It is possible that the latter happens more frequently than recognized since only in the instances in which anterior pituitary gland is removed, such as in pure intrasellar craniopharyngiomas, is the anterior pituitary gland available for histological inspection. Cases in which there is a co‐associated pituitary adenoma or craniopharyngioma with the inflammation are, by definition, examples of “secondary” hypophysitis 94. In contrast to the rarity of hypophysitis associated with pituitary adenomas and craniopharyngiomas, hypophysitis associated with Rathke cleft cysts is becoming increasingly recognized 1, 25, 35, 46, 89.

Depending on the amount of inflammation present vs. xanthogranulomatous material, such cases are diagnosed variably as xanthomatous hypophysitis vs. sellar region xanthogranuloma. Some workers consider these two conditions as part of a spectrum 13.

Paulus et al in 1999 reported 37 cases of sellar region xanthogranuloma 82. These cases “were exclusively or predominantly composed of xanthogranulomatous tissue, consisting of cholesterol clefts (100%), lymphoplasmacellular infiltrates (100%), marked hemosiderin deposits (97%), fibrosis (89%), foreign‐body giant cells around cholesterol clefts (86%), eosinophilic, granular necrotic debris (78%) and accumulations of macrophages (59%)” 82. They found only 8% were associated with adamantinomatous craniopharyngioma while 13/37 (35%) had cyst‐like epithelium, which was squamous, cuboidal or mixed. At the time, they noted that “epithelium resembling a cyst wall (encountered in 35% of cases), occasional ciliated cells and the preferentially intrasellar localization of xanthogranulomatous lesions may suggest a relation to Rathke's cyst. However, blood breakdown products and cholesterol deposits are only exceptionally associated with Rathke's cyst” 82.

Today we recognize that bleeding into Rathke cleft cyst is not as rare as previously thought 17, and thus remote bleeding into a cyst as the cause of a xanthogranuloma is increasingly being accepted 74. Figure 3 illustrates a young girl pre‐ and postoperatively (Figure 3A,B) who had a sellar region xanthogranuloma associated with cholesterol debris (Figure 3C), grumous material (Figure 3D), lymphoplasmacytic infiltrates and foamy histiocytes (Figure 3E) and residual Rathke cleft epithelium (Figure 3F). Pituitary tissue was not resected with the xanthogranuloma so the presence, or absence, of adjacent hypophysitis could not be evaluated.

Figure 3.

A. Xanthogranuloma of the sellar region in a 14‐year‐old girl with a 2‐year history of amenorrhea and more recent onset of diabetes insipidus shows an enhancing partially cystic and solid sellar region mass. T1‐weighted MR with contrast, sagittal, preoperative scan. B. The same girl shown in A following gross total excision of the lesion showing no residual disease; she has not developed a craniopharyngioma or any further sellar abnormality in the 2‐year follow‐up since surgery. T1‐weighted MR with contrast, sagittal, postoperative scan. c‐f. Surgical resection specimen from the girl illustrated in A, B shows abundant cholesterol debris characteristic of xanthogranuloma of sella (C), grumous amorphous material (D), hemosiderin pigment (d, inset), and histiocytes and lymphoplasmacytic infiltrates (E). An underlying Rathke cleft cyst with characteristic pseudostratified epithelium within the resection material (F) suggests that cyst rupture/leakage may be causative of the lesion. Interestingly, prior to surgery she had mentioned an apoplectic‐like severe headache that had resolved after several days, occurring about one year previous. Hematoxylin and eosin, 200× (C), 400× (D), 600× (D inset, E, F).

A 2012 study by Müller et al confirms the results of Paulus et al 82, that xanthogranulomas of the sella are not usually due to craniopharyngiomas with rupture of cholesterol debris or previous bleeding. Müller et al point to the fact that xanthogranulomas predominantly affect adolescents and young adults, manifest smaller tumor size, longer preoperative history, lower frequency of calcifications and visual impairment, better resectability and more favorable clinical outcome than craniopharyngioma 77. Recent case studies note how closely xanthogranuloma can mimic pituitary adenoma on preoperative neuroimaging studies 4 or cause hydrocephalus 68. We would concur that depending on how much inflammation spills into the adjacent pituitary gland/infundibulum, these cases exist on a spectrum with xanthomatous hypophysitis (see later).

After eliminating coexistent pituitary adenoma, craniopharyngioma and Rathke cleft cyst in association with infundibular stalk/pituitary gland inflammation, several other tumor types should be considered, especially in pediatric patients. Suprasellar germinomas are well known to be associated with sometimes overwhelming numbers of lymphocytic, histiocytic and/or plasma cells that obscure the rare tumor cells. Such cases can be mistaken for primary hypophysitis until immunohistochemistry reveals the rare tumor cells 32.

Lymphoma can also be a consideration in some cases of inflammatory sellar region masses and needs to be excluded based on cytological and immunohistochemical criteria. While most lymphomas are B‐cell tumors by immunophenotyping, it should be emphasized that hypophysitis may also manifest collections of B‐cell lymphocytes, albeit cytologically benign.

The infundibulum/pituitary gland are sites of predilection for involvement by systemic inflammatory disorders that normally manifest inflammation wherever in the body they occur, such as Langerhans cell and non‐Langerhans cell histiocytoses, including Erdheim‐Chester disease 101 (Figure 4A,B) and xanthoma disseminatum 124 (Figure 4C–I). Correct diagnosis of the systemic disorder is best made from the constellation of clinical features and the systemic sites of involvement because the pituitary biopsies, if taken, are often small (Figure 4D).

Figure 4.

A. Langerhans and non‐Langerhans histiocytoses both have a predilection for involvement of pituitary gland, infundibular stalk, or hypothalamus. This 44‐year‐old man presented with progressive ataxia (note enhancement surrounding cerebellar lesion near dentate nucleus on this magnetic resonance imaging scan) and erectile dysfunction (note enlargement of the pituitary gland). He was eventually diagnosed as having Erdheim‐Chester disease. T1‐weighted magnetic resonance (MR) with contrast, sagittal to right of midline. B. When the patient seen in A succumbed approximately 3 years later, anterior pituitary gland contained the typical large histiocytes seen in Erdheim‐Chester disease; these were negative for CD1a by immunohistochemistry. Hematoxylin and eosin (H&E), 600×. C. This male adult showed an enlarged pituitary gland on magnetic resonance imaging (MRI) and clinically manifested diabetes insipidus (note the minimally enhancing stalk and pituitary gland). T1‐weighted MR with contrast, sagittal. D. Biopsy of the pituitary gland showed the anterior gland overrun by CD68‐ immunopositive, CD1a‐negative histiocytes. No germ cell tumor or adenoma was present. Although Langerhans cell histiocytosis is excluded by this, further classification of his histiocytic disorder is impossible from the pituitary biopsy alone. Immunostaining for CD68, with light hematoxylin counterstain, 600×. E. Clinically, the patient seen in C, D had systemic findings, most notably, extensive cutaneous papules suggestive of xanthoma disseminatum, although he was also found to have a coexistent phytosterolemia. F–I. Skin biopsy from the patient illustrated in C–E verified that this is a systemic histiocytosis, with histiocytes in dermis (F), Touton giant cells (G), an admixture of extremely foamy histiocytes possibly because of his coexistent phytosterolemia (H), and CD68‐immunopositivity (I). H&E, 400× (F, G, H) 400× (I).

Sarcoidosis 48, 70, Wegener granulomatosis, and Sjögren syndrome 65 can affect the pituitary gland or stalk. Correlation with laboratory and systemic organ findings is usually necessary to render a correct diagnosis in these instances of secondary hypophysitis.

Infections are infrequent as the cause of secondary hypophysitis, but have been reported due to bacterial, fungal, and viral organisms, such as in patients with human immunodeficiency virus infection 93. Tuberculosis is always mentioned in the differential diagnosis for infectious lesions of the pituitary gland, but this is largely now of historical interest. Special stains for organisms are rarely indicated, but should be considered in cases with necrotizing foci or true granulomas; it may be difficult to perform all the desired stains on the limited tissue or to confidently exclude infectious causes of secondary hypophysitis on tiny samples.

Primary hypophysitis

Primary hypophysitis, by definition, has had the underlying conditions described earlier excluded. Patients with primary hypophysitis usually present with nonspecific symptoms of a sellar region mass that mimics nonsecretory pituitary adenoma (Figure 5A), namely headache, hypopituitarism and visual compromise 64, 112. In a few cases, diabetes insipidus, thickening of the pituitary stalk or enlargement of the posterior gland provides preoperative clues to the correct diagnosis and excludes consideration of nonsecretory pituitary adenoma 15, 23, 29. This is true, however, only for the minor subset of hypophysitis, which involves infundibular stalk and/or posterior gland.

Figure 5.

A. Primary lymphocytic hypophysitis in a woman with recent pregnancy has neuroimaging features that completely simulate nonsecretory pituitary adenoma. T1‐weighted MR with contrast, sagittal. B. In primary lymphocytic hypophysitis, the majority of cells are lymphocytes, although a few plasma cells and even occasionally lymphoid follicles can be present; note obscuration of anterior pituitary gland features. Hematoxylin and eosin, 400×. C. Reticulin stain in specimens with primary lymphocytic hypophysitis may variably show completely intact architecture, partially disrupted architecture (as in this case), or dense fibrosis and loss of pituicytes, depending on the stage and severity of the process. Modified Gordon Sweet reticulum stain, 400×. D–F. T‐cells predominate in this example of primary lymphocytic hypophysitis in a young woman, associated with recent pregnancy (D), although limited B‐cells are present (E); both CD4 (F) and CD8 T‐cell subsets were present, negating clonality. All 400×.

Thus, even at experienced medical centers, the initial presumptive diagnosis in cases subsequently proven on tissue biopsy to be hypophysitis was pituitary adenoma in at least 1/3 of patients 64.

Unfortunately, laboratory testing has not proven fruitful as a method to confidently diagnose primary hypophysitis and 79 not one serum or cerebrospinal fluid test is definitive.

Glezer and Bronstein recently reviewed clinical and research data on antipituitary antibodies in hypophysitis and concluded that the “specificity and sensitivity are not high enough to permit an accurate diagnosis” 42. In their review, they noted that antipituitary antibodies have been reported in patients with Sheehan's syndrome, idiopathic growth hormone deficiency, idiopathic hyperprolactinemia, idiopathic isolated hypopituitarism and autoimmune polyendocrine syndromes, but also traumatic brain injury in male boxers and a small percentage of primary empty sella syndrome 42. DeBellis has suggested that only when antibodies show high titers do they have the potential to be helpful 27. In either case, these antibody tests are not widely available. However, on a research basis, the findings of antibodies directed against pituitary tissues 105, 108, including most recently T‐box transcription factor 103, remain interesting and may eventually assist in subcategorizing autoimmune hypophysitis even further.

If the diagnosis of primary hypophysitis is suspected preoperatively, and if vision is not being compromised by severe chiasmal compression, attempts may be made to manage the patient medically. The most commonly utilized anti‐inflammatory drugs have been high‐dose methylprednisolone 122 or dexamethasone (with or without successful outcome) 86. Azathioprine 14 and rituximab 99 have also been utilized. Lupi et al, in their review of the treatment of autoimmune (primary) hypophysitis, found that medical therapy was effective in reducing the pituitary mass in 84%, in improving anterior pituitary function in 45% and in restoring posterior pituitary function in 41% 69. Hormonal replacement is usually necessary and should be “periodically reassessed as spontaneous recovery of pituitary function, albeit rare, may occur” 42. Partial hypophysectomy may still be required for decompression of the mass effects 14. Stereotactic radiation is an additional treatment modality 14.

Early descriptions suggested that an overwhelming majority of patients with primary hypophysitis were women, with an approximately 8:1 female: male ratio 20. Indeed, the disease was thought to be almost exclusively one of females since it was classically described in young women during late pregnancy or in the early postpartum period 33. The third trimester is the time of peak occurrence 15, 45. However, in the last 20 years, many examples of primary hypophysitis have been reported in non‐pregnant women as well as in men 29, 51, 62, 64.

Reports by Cheung et al in 2001 20, Tashiro et al in 2002 109, Leung et al in 2004 64, and Gutenberg et al in 2006 45 served to further our understanding of the fact that primary hypophysitis is not confined to pregnant women. Indeed, in the three larger series of 16, 31 and 31 primary hypophysitis cases, reported respectively by Leung et al 64, Tashiro et al 109, and Gutenberg et al 45, only 18.8% 64 to 26% 109 to 30% 45 were associated with pregnancy or the postpartum period. In addition, 24% 45, to 29% 109 to 32% 64 were co‐associated with other autoimmune clinical conditions. In the series by Tashiro et al, the overwhelming majority had thyroid diseases 109, while Leung et al noted coexistent autoimmune thyroid disorders, orbital pseudotumor, temporal arteritis and myopathy 64. In several of these reports, men and women were found to be nearly equally affected 45, 64.

When classified by inflammatory cell type, hypophysitis is most commonly divided into lymphocytic, granulomatous and xanthomatous types 20, 45 with some workers additionally recognizing mixed xanthogranulomatous 109 and necrotizing forms 3, 64. Cheung et al defined those subtypes as lymphocytic in which lymphocytes predominated, but cases could also show plasma cells and lymphoid follicles 20. Lymphocytes often overrun the pituitary gland, obscuring architectural features (Figure 5B) and may disrupt the acinar pattern to some extent, as assessed by reticulin stain (Figure 5C). CD3+ T‐cells (Figure 5D) over CD20+ B‐cells (Figure 5E) and both CD4 and CD8 T‐cell subsets may be seen (Figure 5F).

Cheung et al defined granulomatous hypophysitis as containing granulomas, histiocytes and giant cells, while xanthomatous hypophysitis had the signature feature of foamy histiocytes 20. Tashiro et al further recognized that lymphocytic adenohypophysitis showed histological and clinical overlap with cases in which the lymphocytic inflammation spilled into the adjacent infundibulum and/or neurohypophysis 109. In actuality, most types of hypophysitis manifest some lymphocytic infiltrates and small biopsy size may preclude appreciation of the full histological features of the process. Thus, everything from follicle formation 33, 61 to admixtures of B‐ and T‐cells, histiocytes, and plasma cells, with or without fibrosis, can be seen in cases of primary hypophysitis and categorization may be subjective.

All larger series agree, however, that lymphocytic hypophysitis is the most frequent subtype of primary hypophysitis, followed by granulomatous. These subtypes constituted respectively 76.9% and 23.1% in the series by Leung et al 64, 64.6% and 19.3% in the series of Gutenberg et al 45 and 61.2% and 16.1% in the series by Tashiro et al 109.

Xanthomatous hypophysitis is said to be the rarest of the three types of primary hypophysitis, although if a spectrum from xanthomatous hypophysitis to xanthogranuloma is acknowledged, as noted earlier, the disease is more common, particularly in adolescents and young adults (Figure 3A–F). Folkerth and coworkers first coined the term “xanthomatous hypophysitis” in 1998 for the process they found in three of their patients who had undergone transsphenoidal hypophysectomy for presumed adenoma 36. No adenoma or epithelial cyst lining was discernible in the resected tissue. Instead, residual anterior pituitary cells were admixed with histiocytes (CD68+, CD1a‐, S100‐), lymphocytes, and acellular eosinophilic debris. The authors suspected, but could not identify, an infectious or other etiology. Thus, xanthomatous hypophysitis may well be multifactorial.

The exact number of published reports with granulomatous hypophysitis is difficult to discern because many cases are not published under that name. One group recently reviewed the literature, “searching in PubMed via the key words of “hypophysitis,” and “primary” or “idiopathic,” and identified only 37 examples 104, but the true number must be at least several‐fold more than that number. Most cases are non‐necrotic and, as noted earlier, particularly in this form of hypophysitis, infectious or systemic inflammatory disorders must be excluded (Figure 6A,B). Sarcoidosis especially should be a consideration in cases of granulomatous inflammation. In a recent multicenter review of 24 patients with hypothalamic–pituitary gland (H‐P) sarcoidosis, the patients had previously diagnosed sarcoidosis in only 11 of 24 cases (46%), that is, H‐P sarcoidosis preceded the diagnosis of systemic involvement in 13 of 24 patients (54%) 59. Magnetic resonance imaging (MRI) showed infundibular involvement in 8/24, pituitary stalk thickness in 12/24, and involvement of the pituitary gland in 14/24 59. While H‐P sarcoidosis is uncommon, H‐P involvement can be the first manifestation of sarcoidosis in over half of these cases. In patients with granulomatous hypophysitis, strong consideration of sarcoidosis should be raised prior to rendering a firm diagnosis of primary granulomatous hypophysitis.

Figure 6.

A, B. Granulomatous hypophysitis usually shows small discrete, non‐necrotic granulomas surrounded by abundant lymphocytes and plasma cells (A) and multinucleated giant cells (B); this 60‐year‐old woman had a 2‐month history of severe headache and signs and symptoms of hypocortisolism. Extensive testing failed to reveal additional endocrine or infectious disease and cerebrospinal fluid polymerase chain reaction testing was negative for mycobacteria. Hematoxylin and eosin, 400×, 600×. C, D. Coronal (C) and sagittal (D) magnetic resonance (MR) scans, with contrast, taken pre‐study from a patient about to be placed on anti‐cytotoxic T‐lymphocyte antigen 4 therapy for melanoma. T1‐weighted MR with contrast. E, F. The same patient shown pre‐study in C, D developed a headache after the third dose of the drug and the headache became excruciating by the fourth dose, prompting this MR study; now the patient has pituitary gland enlargement and enhancement (C, coronal, D, sagittal) corresponding to his hypophysitis. This patient, as is the case with almost all of patients on this drug, did not have severe visual compromise, was able to be managed medically and surgical resection was not required. T1‐weighted MR.

Recent attempts to correlate the clinical with the histological features of hypophysitis suggest that of the three subtypes of primary hypophysitis the most distinct is xanthomatous hypophysitis. Gutenberg et al found that lymphocytic hypophysitis—but not granulomatous or xanthomatous types of hypophysitis—occurred in association with pregnancy or autoimmune diseases 45. In contrast, Tashiro et al identified 5/19 cases of lymphocytic adenohypophysitis with pregnancy but also 3/5 granulomatous cases 109. Neither group found xanthomatous nor xanthogranulomatous cases associated with pregnancy. Thus, there seems to be overlap between the etiologies of lymphocytic and granulomatous, but not xanthomatous, forms. Gutenberg et al further noted that visual field and acuity abnormalities were not seen in their cases of xanthomatous hypophysitis and that lymphocytic and granulomatous hypophysitis more often resulted in severe dysfunction of the endocrine axes (particularly adrenal, gonadal, and thyroid), than did cases of xanthomatous hypophysitis 45.

Emerging types of hypophysitis

The latest updates on hypophysitis are: 1.) identification of a novel clinical entity, IgG4‐related disease, and its hypophysitis component 63, 116 and 2.) emergence of hypophysitis related to treatment of metastatic melanoma or other cancers with the monoclonal immunomodulatory antibody directed against cytotoxic T‐lymphocyte antigen 4 (CTLA4) such as ipilimumab 113.

IgG4‐related disease shows elevated serum IgG4 concentrations and tissue infiltrates by IgG4‐positive plasma cells. The condition was originally described in patients with sclerosing pancreatitis and has also been seen in patients with sclerosing cholangitis, sialadenitis, pseudotumor of the orbit, thyroiditis, retroperitoneal fibrosis, mediastinal fibrosis, aortitis, prostatitis, Castleman's disease, hypertrophic pachymeningitis and hypophysitis 116. First reported in Japan, the condition can be seen in other populations, with a case of IgG4‐related hypophysitis in a Caucasian first reported in 2011 63. The condition is mainly associated with increased numbers of plasma cells, many of which are IgG4‐positive 63. This plasma cell hypophysitis represents yet another histological subtype of hypophysitis in addition to lymphocytic, granulomatous, xanthogranulomatous, and mixed xanthogranulomatous and necrotizing forms.

Hypophysitis related to administration of immunomodulatory drugs has been reported after use of interferon alpha and ribavirin 110 and CTLA‐4 blocking antibodies 54. In the case of interferon alpha and ribavirin treatment, one of two cases came to biopsy and showed noncaseating granulomatous hypophysitis 110. In the case of ipilimumab treatment, the condition was recognized during clinical trials and is now carefully monitored by clinicians.

Juszczak et al in a 2012 review of ipilimumab‐induced hypophysitis identified a reported incidence of 4.9%–17.0% of patients using the drug 54. Hypopituitarism develops at a median time of 11 weeks after starting the drug and occurrence is unrelated to the underlying type of cancer for which the drug is given 54. Patients present with headache, fatigue, lethargy, nausea and loss of libido, but only very rarely with visual field defects because the enlargement of the pituitary gland is usually modest 54 (Figure 6C–F). This contrasts the condition with primary hypophysitis, where visual disturbance and optic chiasmal compression uncontrolled by steroids is the main indication for surgical debulking.

Use of anti‐CTLA4 antibodies is associated with several other types of grades 3 and 4 immune‐related adverse effects and the recommended treatment for all of these adverse conditions is high‐dose glucocorticoids. Some workers have even suggested that physiological doses of corticosteroids might be sufficient. Juszczak et al note that “in all reported cases of ipilimumab‐induced hypophysitis, symptoms resolved with glucocorticoids, T4 and testosterone replacement” 54. Hence, the condition should rarely come to surgical debulking in the future and is unlikely to present itself as a surgical specimen for the pathologist. Not surprisingly, limited information exists about the histological range of features possible in CTLA4‐related hypophysitis.

Pituicytoma

Pituicytoma was first codified in the 2007 edition of the World Health Organization (WHO) 120 as a primary glial neoplasm from the posterior pituitary and infundibulum. In 1930, Bucy coined the term “pituicyte” for the glial cell comprising the stroma of the posterior pituitary gland 11. In the 1950s, Liss 66 and Liss and Kahn 67 had utilized the term “pituicytoma” for tumors of the sellar region, but this included what today would be called granular cell tumor of the neurohypophysis 66, 67. It took until the landmark 2000 American Journal of Surgical Pathology article by Brat et al 10 of nine cases culled from several different major institutions for modern classification of the tumor we today call “pituicytoma.” Reports adding to our understanding of pituicytoma soon followed upon those of Brat et al 6, 19, 34, 55, 78, 114, 115, 121.

Pituicytoma is an uncommon mimic of nonsecretory pituitary adenoma, with approximately 55 reported cases 18, 30. Preoperative confident diagnosis of pituicytoma vs. other sellar region masses such as nonsecretory pituitary adenoma, spindle cell oncocytoma, granular cell tumor or even some meningiomas is difficult to impossible, based on overlapping clinical presentation, endocrine features or neuroimaging characteristics (Figure 7A,B).

Figure 7.

A, B. Pituicytomas are homogenously enhancing tumors that simulate nonsecretory pituitary adenomas preoperatively and may be either predominantly sellar (A) or show suprasellar extension (B). T1‐weighted magnetic resonance (MR), with contrast, coronal. C–F. Pituicytomas are composed of compact fascicles of elongate, bipolar spindle cells (C); although these tumors can somewhat resemble schwannomas, reticulin fibers are confined to vessels and abundant intercellular reticulin is not present, as would be expected for compact Antoni A areas of a schwannoma (D). Diffuse immunoreactivity for S100 (E) and focal immunostaining for glial fibrillary acidic protein (GFAP) (f) are characteristic. Hematoxylin and eosin 400× (C) modified Gordon Sweet reticulum histochemical stain 200× (d), 400× (E, F). G–I. Normal posterior pituitary gland included in biopsy specimens (G) can prompt diagnostic consideration of pituicytoma, but is less hypercellular and lacks a storiform pattern (G); compare directly with the pituicytoma in C at the same magnification. Most helpful however in distinguishing posterior gland is the strong diffuse immunoreactivity for synaptophysin (H) and neurofilament (I), neither of which would be seen in pituicytoma, spindle cell oncocytoma, or granular cell tumor of neurohypophysis. 400× (G–I).

Patients with pituicytoma present clinically with symptoms referable to mass effect, with compression of the optic chiasm and pituitary gland resulting in headache, visual disturbance and hypopituitarism. Compression of the infundibulum results in “stalk effect” with mild hyperprolactinemia 120. A recent review by Chakraborti et al identified visual disturbances (50.9%), headache (35.2%), decreased libido (23.5%), fatigue (13.7%), and amenorrhea (7.8%) 18. Hyperprolactinemia (25.4%) and hypopituitarism (19.6%) were the major endocrinological disturbances, with only 3.9% of cases manifesting diabetes insipidus.

Several uncommon additional co‐occurring endocrinopathies have been noted, however. Katsuta et al reported a patient who had diabetes insipidus that persisted for 1 1/2 years 55. In addition, at least four patients with pituicytomas in whom there were abnormalities in adrenocorticotroph hormone (ACTH) levels have been reported. These have included one with selective ACTH deficiency 81, one with very mildly elevated preoperative ACTH serum level with postoperative level unrecorded 114, and two with cushingoid features, elevated preoperative ACTH serum levels, and postoperative drop in levels 18, 98. One of these two cases was presumed to have an ACTH‐secreting pituitary microadenoma, although this could not be documented microscopically in the surgically resected material 98. Although not syndromic or seen as part of multiple endocrine neoplasia conditions, several patients with pituicytomas have harbored additional endocrine tumors including a micropapillary carcinoma of the thyroid confined to the gland 106, a single man with both parathyroid adenomas and follicular carcinoma of the thyroid 100, and a thyroid goiter 57.

Several uncommon additional clinical features have been reported in the literature since the 2007 WHO report 120. Although all pituicytomas had occurred in adults at the time of the WHO publication, two reports in children have now appeared, ages 7 18 and 11 years 123, although in one case, no pathological description of the tumor is provided 123 and neither report includes histopathological images. Pituicytomas occur sporadically and have no known germline causation. Although most have been symptom‐producing, incidental examples have also been identified [44, 47 (case 10), 58, 106].

By neuroimaging, tumors may be purely intrasellar, purely suprasellar, or mixed sellar/suprasellar (Figure 7A,B) 23. In a large literature review of neuroimaging features of rare sellar region masses, including pituicytomas, granular cell tumors of neurohypophysis, and spindle cell oncocytomas, only pituicytomas were recorded as occurring as purely intrasellar lesions (7/33 informative cases) 23. In comparison, 13/33 spindle cell oncocytomas were purely suprasellar and the same number were mixed suprasellar/sellar 23. Thus, no uniform sellar appearance occurs for pituicytomas, and in most cases, neuroanatomical location does not allow preoperative neuroimaging distinction from spindle cell oncocytoma and granular cell tumor. Covington et al noted that 25% of pituicytomas were separate from the pituitary gland, but the remainder appeared infiltrative of the underlying pituitary gland by neuroimaging 23.

MRI studies with contrast‐enhanced T1‐weighted image indicate that 74% pituicytomas show homogenous enhancement (14/19) while the remainder (5/19) have heterogenous enhancement 23. However, this enhancement pattern also fails to distinguish pituicytoma in individual cases preoperatively from spindle cell oncocytoma or granular cell tumor, because both could also show either homogeneous or heterogenous enhancement.

Pituicytomas are almost all solid masses, with stereotypic features from one case to the next and infrequent cystic change (1/10 cases) 47. In this recent MRI study of 10 cases, all were isointense on T1‐weighted sequences and slightly hyperintense or isointense on T2‐weighted studies 47.

One of the features that may be rather distinctive is that a significant subset of pituicytomas appears to be extremely vascular. Angiogram has usually not been performed, but in the report by Gibbs et al, there were features indicating hypervascularity and the pituicytoma intraoperatively was noted to be highly vascular 41. In the patient reported by Katsuta et al, there was marked early‐phase homogeneous gadolinium enhancement and the tumor was also noted intraoperatively to bleed easily, such that an inordinate amount of blood was lost during surgery 55. The pituicytoma reported by Wolfe et al had shown flow voids on T2‐weighted imaging that suggested increased vascularity and during the first surgical approach such vigorous bleeding was encountered that several units of blood transfusion were required and only a small biopsy could be achieved 121. Despite embolization before the second surgical approach, there was still significant bleeding that required transfusion, but this time a larger resection was feasible 121. Both cases of Ulm et al manifested considerable bleeding intraoperatively 115 and the case of Benveniste et al actually first presented with spontaneous hemorrhage 6.

Pituicytomas are slowly growing, usually treated by surgical resection alone, and were assigned a WHO grade of I in 2007 WHO 120. Subtotal resection was noted to be potentially associated with slow recurrence, but no metastases or malignant transformation have been reported 120. Chakraborti et al were able to identify no recurrence in patients with gross total resection, whereas subtotal resection in 20 cases resulted in recurrence in seven, of which two were treated with stereotactic or fractionated radiotherapy 18.

Pituicytomas are histologically composed of solid sheets of elongate bipolar spindle cells arranged in fascicles or with storiform pattern 10 (Figure 7C). Unlike pilocytic astrocytomas, biphasic pattern, coarsely fibrillar cytoplasm, Rosenthal fibers, calcifications, and eosinophilic granular bodies are all lacking. Cytoplasm shows neither granularity nor periodic acid‐Schiff (PAS) positivity, as might be seen with granular cell tumor of infundibulum, and lacks vacuolization. Cell borders are distinct and tumors lack the hyalinized blood vessels or pericellular reticulin seen with schwannomas (Figure 7D). Whorls, psammoma bodies or nuclear features of meningiomas are lacking and if immunostaining is found for epithelial membrane antigen (EMA), it is usually patchy and focal 120. Mitotic figures are rare and MIB‐1 is <2% in the vast majority of pituicytomas 120, but examples with increased mitotic activity (up to 5/10 HPFs) 125 and MIB‐1 rates of 5% 125, 5.3% 97, 8% 30, 10% 60 and 12% 60 have now been reported. Two of the “atypical pituicytomas” also manifested chronic inflammatory cell infiltrates 60.

The immunophenotype for pituicytomas is fairly consistent for vimentin (27/28 cases reviewed by Ellis et al; 30) and S100 protein (45/46 cases; 30) (Figure 7E), but variable for glial fibrillary acidic protein (GFAP; 38/45 cases; 30), which is often in a focal and patchy pattern (Figure 7F). In a 2011 review of 38 cases, Ogiwara et al identified 23.7% of cases that were entirely GFAP‐negative 80.

There is consistent agreement that pituicytomas are negative for markers expected in pituitary adenomas such as synaptophysin, chromogranin or any of the anterior pituitary hormones. Small fragments of posterior gland may be included in biopsies of sellar region masses and prompt consideration of pituicytoma. However, in direct comparison, small fragments of posterior gland are less hypercellular than pituicytoma (Figure 7G compare with Figure 7C at same magnification). Negative immunostaining for synaptophysin (Figure 7H) and neurofilament (for axons, Figure 7I) allows pituicytoma to be immunohistochemically distinguished from normal posterior pituitary gland, which could be a diagnostic consideration on small biopsies.

Immunoreactivity for EMA is also highly variable [9/35 cases reviewed by Ellis et al 30], but when present is usually focal and cytoplasmic rather than membranous, usually allowing distinction from meningioma. Whether those cases with EMA immunoreactivity are somehow more recapitulative of the ependymal type (cell type 3, see later) of Takei et al is unknown 107.

Seldom utilized markers have included CD56 106 and neuron‐specific enolase 30, 34. Galectin‐3 has been shown to be too ubiquitously expressed in several types of sellar regions masses to be useful as a discriminator of pituicytoma 87.

Since the original report, several additional histopathological features have been reported. Cases with scattered pleomorphic cells 58, 106, 125, occasional multinucleated cells 106 or large numbers of epithelioid cells 30 have appeared in literature examples. The original report commented on the absence of eosinophilic Herring bodies, as are seen normally in neurohypophysis 10, but several others have noted them within pituicytomas since that time 58, 106, 115. The most unusual histological features recorded, however, are two cases of sellar masses diagnosed as pituicytomas that have shown ependymal features 58, 97. The case of Scheithauer et al showed ependymal differentiation by electron microscopy alone (microvilli, occasional cilia and desmosomal junctions, basal lamina formation), and they identified four other human examples of pituitary region ependymomas, all of which had perivascular and true rosettes, contrasting with their case 97. The more recent report by Kwon and Suh also showed perivascular pseudorosettes, but on electron microscopy failed to show cilia or intracytoplasmic lumens with microvilli, and so was diagnosed as an “unusual pituicytoma” 58.

The explanation for such cases was discussed by Scheithauer et al 97 in context with their own previous EM experience 96, who noted the studies of Takei et al identifying five types of pituicytes by electron microscopy in the normal human neurohypophysis 107. Takei et al subdivided normal pituicytes into: (1) “The most common type, referred to as ‘major pituicytes,’ is reminiscent of astrocytes. (2) ‘Dark pituicytes’ are thought to represent different functional stages of the ‘major pituicytes.’ (3) ‘Ependymal pituicytes’ are believed to provide ultrastructural evidence that human pituicytes are phylogenetically derived from ependymal cells. (4) ‘Oncocytic pituicytes’ were observed in all cases and are of unknown significance. (5) The ultrastructural features of ‘granular pituicytes’ suggest the existence of an active uptake and catabolism of extracellular material by pituicytes, probably through ‘ultraphagocytosis’ or ‘endocytosis’ ” 107. This classification system would explain the possible origin for ependymoma‐like pituicytomas and even true ependymomas of the pituitary gland from cell type 3, granular cell tumors of the infundibulum from cell type 5, and possibly even spindle cell oncocytomas (discussed later) from cell type 4, leaving types 1 and/or 2 to possibly give rise to ordinary pituicytomas.

An alternate cell of origin for pituicytomas, however, is folliculostellate cells, normal residents of the anterior gland; these cells are immunoreactive for both S100 (Figure 8A) and GFAP (Figure 8B). Based on the shared bcl‐2 immunoreactivity seen in normal folliculostellate cells and some pituicytoma cells in their cases, Ulm et al felt that this was the most likely cell of origin 115. Immunoreactivity in pituicytomas for bcl‐2 ranges from diffuse and strong 83 to focal and strong 115 and was identified in 10/11 cases reviewed by Ellis et al 30. Ulm et al felt that the bcl‐2 immunoreactivity pattern suggested an origin of pituicytoma from folliculostellate cells 115, and the shared immunostaining for S100 and GFAP (Figure 8A,B) would be concordant with this interpretation also. Although most reports of pituicytomas with electron microscopic studies have failed to find neurosecretory granules 8, 83, in one case, each reported by Cenacchi et al 16 and Figarella‐Branger et al 34, occasional granules were identified 8, 16, 34, 83.

Figure 8.

A–D. Normal anterior pituitary gland contains S100‐immunoreactive (A) and glial fibrillary acidic protein (GFAP)‐immunoreactive (B) folliculostellate cells, as illustrated here; these cells are, however, immunonegative for thyroid transcription factor‐1 (TTF‐1), even in early fetal time periods, while pituicytes in the normal posterior gland (C, D) are positive for this marker, both in adults (C) and in this 12‐week fetus (D). Note negative immunostaining for TTF‐1 in adjacent anterior fetal gland (D). Because TTF‐1 is positive in nuclei of both normal pituicytes in posterior gland and in tumors derived from pituicytes, that is, pituicytomas, spindle cell oncocytomas, and granular cell tumors of neurohypophysis, this marker cannot be used to distinguish small fragments of normal pituitary gland from these tumors on biopsies. 400× (A), 600× (B–D). E–F. Recently, the common origin of pituicytoma, as well as spindle cell oncocytoma and granular cell tumor of the neurohypophysis was clarified by their shared nuclear immunoreactivity for TTF‐1; this 55‐year‐old man was found to have an incidental pituitary region mass after a syncopal episode that completely simulates a nonsecretory pituitary adenoma (E); resection specimen showed typical histological but atypical immunohistochemical results (negative S100 using two separate antibodies); immunoreactivity for TTF‐1 clarified the diagnosis (F). T1‐weighted magnetic resonance with contrast, sagittal (E), 400× (F).

The newest insight into pituicytoma histogenesis, as well as histogenesis of spindle cell oncocytoma and granular cell tumor of neurohypophysis, is that all share immunoreactivity for thyroid transcription factor‐1 (TTF‐1) similar to normal pituicytes. Pituicytes are embryologically derivated from the floor of the diencephalon, an area under the influence of TTF‐1 expression during normal development 60. TTF‐1 was first touted as a promising marker for sellar region masses by Lee et al, who noted strong nuclear expression in fetal and adult human pituicytes/posterior pituitary gland, pituicytomas (n = 3), atypical pituicytomas (n = 2), spindle cell oncocytomas (n = 8) and granular cell tumors (n = 4), indicating a common pituicyte lineage 60. This work has now been verified by Mete et al 73 (Figure 8C–F). Indeed, one of the greatest contributions of this second study is that it verified the diagnostic utility of TTF‐1 for identifying these sellar region masses vs. TTF‐1 negative potential look‐alikes, including meningiomas, pilocytic astrocytomas and schwannomas (see Figure 8E,F). It should be noted, however, that because TTF‐1 is positive in nuclei of both normal pituicytes in posterior gland and in tumors derived from pituicytes, ie, pituicytomas, spindle cell oncocytomas, and granular cell tumors of neurohypophysis, this marker cannot be used to distinguish fragments of normal pituitary gland from these tumors on small biopsies. Mete et al further contributed to our understanding of pituicytomas, spindle cell oncocytomas, and granular cell tumors of the neurohypophysis by showing absence of IDH1/2 or BRAF mutations in these tumors 73.

Array comparative genomic hybridization analysis has been limited, but it appears that pituicytoma is distinct from at least pituitary adenomas 83. Specifically, these authors noted that “Array comparative genomic hybridization demonstrated genomic copy number imbalances, including losses on chromosome arms 1p, 14q and 22q and gains on 5p. This pattern of genetic changes only partially overlaps with the genomic alterations reported in pituitary adenomas.” 83

Spindle cell oncocytoma

Spindle cell oncocytoma was also first codified in 2007 WHO 38. It had first been reported as a distinct entity by Roncaroli in 2002, in five patients culled from four different institutions, reflecting the rarity of the entity 90. Even with these five initial examples, only approximately 20 total cases have been published 2, 8, 26, 37, 56, 75, 88, 102, 117, 118. All have occurred in adults thus far, with a mean of 56 years 38.

Clinical presentation and neuroimaging usually fail to definitively distinguish between nonsecretory pituitary adenoma and spindle cell oncocytoma, or even between pituicytoma and spindle cell oncocytoma, although some features seem more frequent in one tumor type than the other.

A meta‐analysis of the literature on spindle cell oncocytomas, pituicytomas, and granular cell tumors of neurohypophysis by Covington et al, published in 2011, compared presenting symptoms and neuroimaging features for these tumors 23. Of 35 pituicytomas and 13 spindle cell oncocytomas, visual disturbance was found to be the presenting symptom in approximately one‐half of each tumor type (18/35, 8/13, respectively), although panhypopituitarism was felt to be more typical of spindle cell oncocytoma than pituicytoma and a possible distinguishing clinical feature 23. This was likened to the fact that spindle cell oncocytoma is thought to be a derivative of a cell type within adenohypophysis (folliculostellate cell), not neurohypophysis (pituicyte), and hence, anterior gland destruction was perhaps more to be expected. Headache was identified in 16/18 pituicytomas and 4/13 spindle cell oncocytomas as a presenting symptom; diabetes insipidus was reported in 1/35 pituicytomas published at that time, but in none of the 13 reviewed spindle cell oncocytoma cases 23.

Similarly, neuroimaging was slightly different between pituicytoma and spindle cell oncocytoma, although in many cases, preoperative distinction by neuroimaging was not possible. All spindle cell oncocytomas were found to be “infiltrating” and none could be clearly separated from the pituitary gland, unlike the case with 25% of pituicytomas that appeared distinct from the pituitary gland 23. All were both suprasellar and intrasellar, unlike the occasional pure sellar location of pituicytoma, although about one‐third of pituicytomas were also mixed sellar/suprasellar 23. Like pituicytomas, most were hyperintense on T1‐weighted MRI imaging and either heterogeneous or homogenous enhancement could be found, similar to pituicytoma. They concluded that spindle cell oncocytoma should be favored in patients with panhypopituitarism and only be considered “for infiltrating pituitary masses with a mixed intra‐ and suprasellar location” that did not arise from the neurohypophysis 23.

Several of the uncommon clinical and biological features mentioned earlier for pituicytoma are, however, shared with spindle cell oncocytoma, including occasional association with other endocrine abnormalities in the same patient 8 and tendency for bleeding or high vascularity 8, 28, 37. One of the original five patients reported by Roncaroli et al had an oncocytic thyroid adenoma 90, and the case reported by Borges et al had thyroid disease 8. In addition, several reports have commented on the presence of hemosiderin or microfoci of hemorrhage within spindle cell oncocytomas, as reviewed by Borges et al 8.

Spindle cell oncocytomas histologically are characterized by interlacing fascicles of spindled to epithelioid cells with variably oncocytic cytoplasm (Figure 9A–C), features that can often be detected at the time of intraoperative touch/smear preparation (Figure 9A). Some examples show significant pleomorphism or small infiltrates of non‐neoplastic inflammatory cells 31, 38. Mitotic counts are usually less than 1/10 HPFs and MIB‐1 rates usually less than 8% 38. The histological overlap with pituicytoma may be significant in some instances and the finding that these tumors share TTF‐1 nuclear immunoreactivity 60, 73 may explain why this is so.

Figure 9.

A–E. Spindle cell oncocytoma is composed of interlacing fascicles of spindle cells with variably plump and oncocytic cytoplasm (intraoperative touch preparation (A), permanent sections (B,C), galectin immunoreactivity (D), initially thought to be useful, was subsequently found to be too ubiquitous in nervous system tumors to provide diagnostic assistance. Abundant mitochondria on electron microscopy are characteristic (E). 600× (A, C, D), 400× (B). F. Microscopic‐sized granular cell lesions of the neurohypophysis are frequently incidental findings in the posterior gland at autopsy. Hematoxylin and eosin, 400×. G–I. Symptomatic granular cell tumors of neurohypophysis are quite rare and seldom come to biopsy; this one shows the characteristic plump granular cytoplasmic contents of these tumors retain periodic acid‐Schiff staining (PAS) after diastase treatment (G), immunoreactivity for alpha‐1‐antitrypsin (H) and nuclear immunoreactivity for thyroid transcription factor‐1 (TTF‐1) (I). Case courtesy of Dr. Richard A. Prayson. All 600×. PASD, periodic acid Schiff diastase.

Spindle cell oncocytoma and pituicytoma share immunoreactivity for vimentin, S‐100 protein, and galectin‐3 87 (Figure 9D), but lack GFAP, cytokeratins, CD34, synaptophysin, chromogranin, bcl‐2, CD68 and pituitary hormones 38. EMA is often positive. The key distinguishing feature between spindle cell oncocytoma and pituicytoma has been described in the WHO fascicle 38 as the finding of abundant cytoplasmic mitochondria by electron microscopy (Figure 9E) or significant immunoreactivity for antimitochondrial antibody MU213‐UC clone 131‐1 2, 88. A single report with more extensive immunostaining has appeared that suggested additional expression of p‐mTOR, nestin, and CD44 2, but this requires validation by others.

Like pituicytomas, these tumors were assigned a WHO grade of I in WHO 2007 38. In some instances, long‐term follow‐up has shown excellent prognosis 118. However, case reports emerging since WHO 2007 indicate that recurrences may be even more frequent than with subtotally resected pituicytomas, although the tendency to report adverse or unusual outcomes obviously can skew the literature. Cases reported by Demssie et al 28, Coiré et al 21, Borota et al 9, Kloub et al 56, Matyja et al 71, Fujisawa et al 37 and Borges et al 8 have all had recurrences, some within 5 21, 9 28 or 18 37 months' time, but most over several years 56, 71, or even as long as after a 16‐year interval 8. Whether this suggests that spindle cell oncocytoma might deserve a higher WHO grade than I is conjectural at this point.

The cell of origin for spindle cell oncocytoma has not been as debated as it has been for pituicytoma. The original report by Roncaroli et al advocated folliculostellate cell origin based on the electron microscopic features 90. As noted earlier, the shared TTF‐1 immunoreactivity of pituicytomas and spindle cell oncocytomas 60, 73 may suggest more similarity in origin than was originally suspected.

Granular cell tumor of neurohypophysis

Granular cell tumors are unique neoplasms of the pituitary gland that may arise in infundibulum and/or posterior pituitary gland 39. The overwhelming majority of the granular cell tumors in the neurohypophysis are microscopic‐sized lesions found incidentally at autopsy (Figure 9F). Symptomatic examples are considerably rarer. Sellar granular cell tumors have similar histopathological features as granular cell tumors that arise in the tongue, gastrointestinal tract and skin, although the latter are thought to be of Schwann cell origin. Other names for which these tumors have been previously described include choristoma, granular cell myoblastoma, granular cell pituicytoma and granular cell schwannoma.

Granular cell tumors are believed to originate from pituicytes, the modified glia of the neurohypophysis 50, 92. As previously discussed, one of the five types of pituicytes described by Takei et al 107 at the ultrastructural level is the “granular pituicytes” that contain electron‐dense granules similar to those seen in granular cell tumors. Granular cell tumors are believed to originate therefore from this type of pituicytes.

Granular cell tumors only rarely present clinically as tumor masses, corresponding to less than 0.5% of tumors involving this region in a large referral center 111. Symptomatic granular cell tumors are rare with less than 100 reported cases 23. However, not uncommonly, these tumors are encountered in postmortem studies wherein tumorlets have been described in as high as 17% of adult autopsy cases 7. The majority of these lesions found at autopsy are small, asymptomatic masses.

Granular cell tumors arise in a wide range of age distribution. Most symptomatic tumors are diagnosed in the fourth or fifth decade of life, with a 2:1 predominance of women 23, 95. Only rarely do these tumors arise in the pediatric population 5, 40. The symptoms are related to tumor size with signs of compression of adjacent structures and the pituitary stalk. A recent meta‐analysis by Covington et al identified visual disturbances (64%), headache (32%), hyperprolactinemia and amenorrhea (19%), and fatigue (12.5%) as the most common symptoms. Only a minority of patients (4.7%) manifested diabetes insipidus 23. A single case associated with multiple endocrine neoplasia type 2 syndrome has been reported 24.

Similar to the entities discussed earlier, granular cell tumors show similarities on neuroimaging to the most common nonfunctioning pituitary adenoma, and their differentiation at preoperative diagnosis may be problematic. The tumors are mostly well circumscribed, suprasellar lesions with hyperattenuation as compared with brain on non‐contrast computed tomography and strong enhancement after contrast administration 22, 23, 53. Intratumoral calcification has been reported 12, 95. On MRI sequences, the tumors are isointense to gray matter on both T1‐ and T2‐weighted sequences and lack the normal high intensity of the neurohypophysis 22, 23, 53. Enhancement patterns are mixed, with some tumors showing heterogeneous enhancement, whereas others enhanced homogeneously 23.

At gross examination, the tumors are typically firm, tan to gray in coloration. Similar to other tumors of the region including pituicytomas and spindle cell oncocytomas, granular cell tumors may be very vascular and bleed extensively during surgical exploration 95.

Histologically, granular cell tumors are characterized by a proliferation of large, polygonal cells arranged in sheets or small lobules surrounded by fine capillaries. The cells have a distinct eosinophilic cytoplasm with fine to coarse granularity. The nuclei are round with delicate chromatin and uniform nucleoli, and tend to be located in the periphery of the cells. The cytoplasmic granules are PAS‐positive and diastase‐resistant (Figure 9G). Touch and smear preparations of these tumors highlight the uniform appearance of the tumor cells characterized by uniform nuclei and abundant eosinophilic granular cytoplasm dispersed in a granular background 84. The tumor shows absent to low mitotic activity, and necrosis is rarely seen. A fine and delicate network of capillaries is present with occasional perivascular lymphocytic infiltrates.

Granular cell tumors are diffusely immunoreactive for vimentin and S100 protein, but only occasionally immunoreactive for GFAP. The macrophage/lysosome marker CD68 is consistently and strongly immunoreactive in all tumors, and some show immunoreactivity for alpha‐1‐antitrypsin (Figure 9H). Similar to other hypophysial tumors believed to originate from pituicytes, faint and focal EMA immunoreactivity has been demonstrated in a few cases of granular cell tumors. The tumors are negative for neuroendocrine markers chromogranin, synaptophysin and CD56. Most significantly, granular cell tumors are strongly immunoreactive for TTF‐1 (Figure 9I) as other pituicyte‐derived tumors 60, 73.

Electron microscopy shows characteristically abundant membrane‐bound, electron‐dense material in the cytoplasm, consistent with lysosomes. Intermediate filaments are scarce, and neurosecretory granules are absent.

Molecular studies of granular cell tumors are limited. In a recent study of three granular cell tumors of the pituitary, all tumors were negative for the mutant IDH1‐ (R132H) specific antibody and none had evidence of BRAF alterations (BRAF V600E mutation and BRAF‐KIAA fusion) 73.

Granular cell tumors are generally considered slow‐growing, benign neoplasms. However, a few cases of tumors with more aggressive behavior have been reported 43, 119. A case with infiltration of the optic chiasm demonstrated variable Ki‐67 proliferative index (1%–15%) in areas of the tumor and immunoreactivity for p53 119. In a large review of 42 cases of symptomatic granular cell tumors, Schaller et al observed that the outcome of patients treated conservatively was poor, with death within 2–26 months 95. In the same analysis, patient survival was largely increased with extended surgery or combination of surgery and radiation therapy.

Summary

Although far less frequent than the major “neoplastic resident” of the sellar region—pituitary adenomas—hypophysitis, pituicytoma, spindle cell oncocytoma and granular cell tumor of neurohypophysis have emerged as equally interesting entities. Given their relative rarity, many pathologists have limited personal experiences with these cases. In the case of hypophysitis, both frozen section and permanent section can be diagnostically challenging for the pathologist because of small specimen size, and often a battery of immunostaining as well as consultation with laboratory and clinical findings is necessary to arrive at the correct diagnosis of first, hypophysitis, and then secondary vs. primary hypophysitis. New types of hypophysitis that have been recently recognized include those related to IgG4 disease and one type of cancer therapy, usually utilized for patients with melanoma. Pituicytoma, spindle cell oncocytoma and granular cell tumor of neurohypophysis are now recognized as closely related to each other in origin, based on their shared nuclear immunoreactivity for TTF‐1.