Review of xanthomatous lesions of the sella

Abstract

Xanthomatous lesions of the sellar region have traditionally been divided into two separate categories, xanthomatous hypophysitis (XH) and xanthogranuloma (XG) of the sellar region. The seminal article on XH, a condition typified by foamy histiocytes and lymphoplasmacytic infiltrates in the pituitary gland/sellar region, but usually little or no hemosiderin pigment, detailed three patients. However, most reports since that time have been single cases, making understanding of the entity difficult. In contrast, the seminal report on XG, characterized by sellar region cholesterol clefts, lymphoplasmacytic infiltrates, marked hemosiderin deposits, fibrosis, multinucleated giant cells around cholesterol clefts, eosinophilic granular necrotic debris, and accumulation of macrophages, included 37 patients, allowing more insights into etiology. Few examples could be linked to adamantinomatous craniopharyngioma, and although ciliated epithelium similar to that of Rathke cleft cyst (RCC) was identified up to 35% of the 37 cases, it could not be proven that XG was related to hemorrhage into RCC. Case reports since that time, however, occasionally linked XG to RCC when an etiology could be identified at all, and a few recognized that a spectrum exists in xanthomatous lesions of the sella. They review literature, adding 23 cases from our own experience, to confirm that overlap occurs between XH and XG, and that the majority—but not all—can be linked to RCC leakage/rupture/hemorrhage. It was suggested that progressive accumulation of hemosiderin pigment in the lesion, possibly caused by the multiple episodes of bleeding, could account for the transition of at least some cases of XH to XG.

Introduction

Xanthomatous hypophysitis (XH) and xanthogranuloma (XG) of the sellar region were originally described as quite separate entities. The seminal report on XH by Folkerth et al included three females, ages 12–30 years, all of whom presented with headache, 2 with altered menses, and the third with diabetes insipidus (Folkerth) 25. The lesions were characterized by fragments of normal anterior pituitary gland infiltrated by foamy histiocytes which were positive for the macrophage marker CD68 and negative for S‐100 and CD1a. No well‐formed granulomas, giant cells, hemosiderin, acid‐fast bacilli, or fungi were identified. Entrapped epithelium was sought via serial sectioning and keratin immunostaining, but was not found, and the origin remained elusive.

Following this seminal report in 1998, case reports followed 5, 16, 20, 22, 30, 31, 38, 60, 62. Tashiro et al further subdivided xanthomatous hypophyseal lesions into xanthomatous (XH) and xanthogranulomatous (XGH) hypophysitis, with the latter containing multinucleated giant cells, epithelioid histiocytes and occasional neutrophilic infiltrates in addition to the foamy xanthoma cells and lymphocytic infiltrates of XH. He also placed the frequencies of XH and XGH into the context of other types of hypophysitis. Specifically, of his 31 examples of hypophysitis, the overwhelming majority were lymphocytic hypophysitis 22, with 5 cases of granulomatous hypophysitis, and two cases each of XH and XGH. 80

At approximately the same time, Paulus et al in 1999, described an entity which he named xanthogranuloma of the sellar region (XG). Of his 37 described cases, 100% showed cholesterol clefts and lymphoplasmacytic infiltrates, 97% had marked hemosiderin deposits, 89% fibrosis, 86% foreign body giant cells around the cholesterol clefts, 78% eosinophilic granular necrotic debris and 59% accumulation of macrophages 67. Cyst‐like epithelium was focally identified in 35% of cases. He concluded that XG of the sellar region was different from adamantinomatous craniopharyngioma (ACP), with XG showing preferential occurrence in adolescents and young adults (mean age 27 years), predominant intrasellar location, more severe endocrinological deficits, longer preoperative history, lower frequency of calcification and visual disturbances, absence of dry or wet keratin in almost all cases and less brain invasion 67. The authors noted that the “superficial epithelium resembling a cyst wall, … occasional ciliated cells and the preferentially intrasellar localization of xanthogranulomatous lesions may suggest a relation to Rathke's cyst.” What led to reticence to definitively ascribe an association of XG with RCC, however, was the fact that “blood breakdown products and cholesterol deposits had only been reported a few times in association with Rathke cleft cyst (RCC)” 67.

Since that time, numerous additional case reports of XG 1, 2, 3, 8, 11, 29, 33, 39, 41, 55, 57, 59, 67, 69, 76, 77, 82, 83 have suggested that, when an etiology can be identified at all, it is a hemorrhagic RCC that is implicated. In addition, since the report of Paulus et al 67, numerous examples of hemorrhagic and non‐hemorrhagic RCCs mimicking pituitary apoplexy have been published, underscoring the fact that bleeding into RCC may be both subclinical and clinically relevant 9, 14, 40, 49, 68. The etiological mechanism behind hemorrhage into RCCs is obscure, but usually there is no identified antecedent traumatic or other inciting event. Also of note is the fact that, since the time of Paulus et al 67, numerous parallel examples of hemorrhage into other types of benign cysts such as arachnoid cysts 4, 15, 18, 21, 28, 36, 37, 48, 52, 65, 66, colloid cysts 7, 13, 23, 24, 61, 73, 75, 78 or even epidermoid or developmental cysts 6, 42, 44, 53, 56, 70, 71, 74, 79, 81 have been reported. Some of these bleeds have been linked to trauma, but many have been spontaneous events.

This review of the literature on XH, XGH and XG confirms the impression of others, particularly Burt et al 11, that xanthomatous lesions of the sella may represent a continuum. Infectious workup has been undertaken most frequently with cases of XH caused by the frequent presence of neutrophils in the debris, but has been negative to date. Although the caveat needs to be made that a transient sellar region infection might result in XH, the collective evidence from multiple cases in the literature would argue against this. Past hemorrhage is most strongly linked to XG, given the nearly ubiquitous presence of hemosiderin pigment. We review the literature and contribute 23 examples from our own experience at our joint adult and pediatric hospitals, detailing several cases that were previously reported briefly by us in the context of a series of RCCs 46, 47.

We expand clinical information on XH/XG to include intraoperative impressions by the experienced neurosurgeon, long‐term follow‐up, two patients with clearly documented growth of the cystic lesion over time based on serial magnetic resonance imaging (MRI) scans, five patients who required two surgical excisions of the sellar lesion for diagnosis or control, and one dramatic XG related to a known prolactinoma treated with cabergoline. Two patients had unusual combinations of epithelium types in the same surgical specimen; this overlap in sellar region masses, while generally not appreciated by pathologists, exists in cystic epithelial sellar region masses without XH or XG, and is also discussed.

Materials and Methods

Cases were retrieved from departmental files databases, 2000‐present, by linking the text word xanthoma, hypophysitis, xanthomatous or xanthogranulomatous with pituitary gland and supplemented with cases from the authors’ personal files. Medical records were reviewed under the auspices of institutional review board #95‐149, Children's Hospital Colorado, with attention to presenting clinical symptoms and follow‐up at last visit. Neuroimaging studies were retrieved by the two neurosurgeons on the study, with intraoperative impression taken from the medical record (KOL, TH).

All tissues were formalin‐fixed, paraffin‐embedded, cut in routine fashion at 4 microns and stained with to Harris hematoxylin and eosin (H&E). Although there had been a variable workup at the time of diagnosis in terms of immunostaining and search for organisms, most had been assessed by CD68 for macrophages and pankeratin (AE1/AE3), with some additionally stained/immunostained for CD3 for T cells and CD20 for B cells (both Ventana, Tucson, AZ, predilute), alcian blue, CK7 (Dako, Carpinteria, CA, 1:800), CD5/6 (Dako, 1:50), synaptophysin (Ventana, predilute), trichrome, Gram stain for bacteria, periodic acid Schiff and methenamine silver. A few was assessed for beta catenin (Cell Marque, Rocklin, CA, 1:25) and BRAF VE1 (Spring Bioscience, 1:100). Mutational analysis for BRAF V600E was performed as previously described in two cases 45.

All cases had been diagnosed originally by the senior author (BKD), but slides were retrieved and re‐reviewed for the purposes of this study. Particular attention was given to identification of epithelium and mucin, with the latter often further confirmed by alcian blue histochemical staining. Definitions of XH and XG were as offered by the original authors, namely foamy histiocytes and lymphoplasmacytic infiltrates removed surgically from the sellar/pituitary region were necessary for diagnosis of XH and had to constitute either the overwhelming majority of, or the only aspect of, the surgical specimen. Most biopsies were small and the amount of anterior pituitary gland was variable.

The diagnosis of XG was rendered based on the additional presence of cholesterol clefts, giant cells and epithelioid histiocytes, almost always in association with hemosiderin and fibrosis; XG had to constitute the overwhelming majority of the resection materials. Where present, hemosiderin, calcification or metaplastic ossification was noted.

Literature was reviewed using the PubMed database, searching the text words XH, xanthogranulomatous hypophysitis and xanthogranuloma, with the latter linked with sella. Reports were reviewed with special attention to details regarding presence or absence of identifiable epithelium, hemosiderin and use of infectious stains or cultures.

Results

The search generated 23 examples in our files, detailed in the Table 1. Generally, small biopsies had been taken in examples of XH, with larger tissue volumes removed for cases that could be classified as XG. Based on the histological criteria, cases were diagnosed as XH or xanthogranuloma of the sella (XG), with several cases having predominantly XH components and very focal XG. Extensive fibrosis was confined to the XG cases. Cases were further classified as being definitively related to RCC rupture/leakage/bleeding if strips of columnar epithelium with ciliation were identified. They were also definitively related to RCC bleed/rupture/leakage if mucin plus epithelium with squamous metaplasia was found, even if the amount of ciliated epithelium was scant. In some instances, basal cell hyperplasia vs. true squamous metaplasia was difficult to determine. Cases were classified as possibly associated with RCC if only scant epithelium, with or without mucin, was found in the resection material. The XH or XG was considered without identifiable cause if no epithelial cells were found. If craniopharyngioma or other lesion type was identified, this was noted (see Table 1).

Table 1.

Xanthomatous hypophysitis/xanthogranulomas.

Cases associated with strips of columnar/ciliated epithelium identified histologically
Age, gender. date of surgery	Clinical history/preoperative findings	Intraoperative impression of neurosurgeon	Histological findings	Final diagnosis	Follow‐up
1. 10 F 2004	Increased drinking and urination for 4–6 months, MRI showed suprasellar mass, mass enlarged and became more cystic	“Classic” RCC with mucoid material, nodule identified within cyst, biopsied to rule out pituitary adenoma. No crystalline appearance, as would be expected with craniopharyngioma	Grumous debris, sheets of CD68+/CD1a− macrophages, moderate CD3+ T cells, PMNs, fibrotic cyst wall, strips of pseudostratified columnar ciliated epithelium; Gram stain negative, no mucin, no hemosiderin	Xanthomatous hypophysitis with definitive RCC epithelium	Last seen 9 yrs. post op, pan‐hypopituitarismcentral hypothyroidism adrenal insufficiency, diabetes insipidus
2. 4 F 2008	Presented with diabetes insipidus, MRI showed suprasellar pituitary stalk mass c/w histiocytosis or germ cell tumor	Grayish lesion that expressed thick, mucinous liquid. Unclear etiology	Scant grumous debris and mucin, lympho‐plasmacytic infiltrates, CD68+ histiocytes, PMNs, columnar epithelium abundant on touch preparation, strips of ciliated epithelium on permanent sections, no hemosiderin	Xanthomatous hypophysitis with Rathke cleft and definitive epithelium	Last seen 8 yrs. post op, hypothyroidism growth hormone deficiency, diabetes insipidus
4 F 2009	Biopsy 1 yr. prior, post‐op steroids, MRI showed decreased cyst size; MRI 2 months later showed interval enlargement of mass, sellar (0.6 x 0.8 cm) and suprasellar (0.6 x 1.4 x 0.6 cm), minimal nodular enhancement; infundibulum involved; altered signal in optic chiasm	Dense, firm tissue. Unclear etiology but no evidence of neoplasm	Fibrotic cyst wall, compressed non‐adenomatous anterior pituitary gland at edge, no adenoma, focal CD3+, CD68+ inflammatory cells, no definitive residual epithelium, no hemosiderin	Fibrosis + inflammation secondary to recurrent xanthomatous hypophysitis	As above
3. 25 M 2009	Hypogonadism, MRI showed intrasellar lesion	“abnormal debris located at junction between anterior and posterior gland”; anterior gland appeared normal; cholesterol debris, minute fragment of bone removed	Grumous debris, organizing hemorrhage, macrophages, probable squamous metaplasia + cuboidal ciliated goblet cell epithelium, giant cells and small granuloma surrounding cholesterol clefts, focal hemosiderin	Xanthogranuloma with RCC epithelium, with metaplastic ossification probable squamous metaplasia	Lost to follow‐up immediately post op
4. 14 F 2011	3 yrs. prior had onset first menstrual period but second did not occur until 4 months later and then completely amenorrheic until age 14 yrs., increased urination and thirst; MRI showed partially cystic/solid mass optic chiasm displaced	RCC vs. CP	Grumous debris, cholesterol clefts, CD68+ macrophages, PMNs, focal lympho‐plasmacytic collections, ciliated cuboidal epithelium with goblet cells, hemosiderin + hemosiderin laden macrophages	Xanthogranuloma with definitive RCC epithelium	Last seen 1 yr. post op and then lost to follow‐up when she left country
5. 39 F 2012	New onset headache, modestly elevated prolactin level, MRI cystic sellar/suprasellar mass c/w RCC	RCC infection not clinically suspected so cultures not performed	Grumous debris, sheets of CD68+ macrophages PMNs, lympho‐plasmacytic infiltrates, strips of columnar epithelium with squamous metaplasia; abundant mucin, very focal hemosiderin; Gram stain negative	Xanthomatous hypophysitis with definitive RCC epithelium, with squamous metaplasia	Last seen 3 yrs post op hypothyroidism diabetes insipidus
6. 63 F 2013	7–8 months of progressive loss of peripheral vision, panhypopituitarism, MRI showed peripherally enhancing particularly calcified sellar/suprasellar mass c/w craniopharyngioma	Fibrotic calcified mass filled with yellow mucoid material adherent to optic chiasm, vasculature, felt to be consistent with ACP	Grumous debris, cholesterol clefts, lymphoplasmacytic infiltrates, mucin, macrophages, dystrophic calcifications, ciliated epithelium with goblet cells, hemosiderin	Xanthogranuloma, with definitive RCC epithelium	Last seen 1 yr. post op, compressive optic neuropathy, peripheral vision loss
7. 33 F 2013	Workup for persistent headache resulted in MRI consistent with RCC	White mucoid material consistent with RCC	Scant grumous debris + mucin, PMNs, CD68+ macrophages, lymphoplasmacytic infiltrates, dystrophic mineralization, flattened cuboidal epithelium with focal ciliation + squamous metaplasia, no hemosiderin	Xanthomatous hypophysitis with definitive RCC epithelium, with squamous metaplasia	Last seen 3 yrs. post op obesity, diabetes insipidus, diagnosed with undifferentiated connective tissue disease by rheumatologist
33 F 2013	Recurrent xanthomatous hypophysitis	Thick mucoid yellow‐tinged material	Extensive squamous metaplasia, small strip columnar epithelium, PMNs, including within epithelium, CD68+ macrophages, lymphoplasmacytic inflammation, anterior gland fibrosis, minute amounts of mucin, Gram stain negative, no hemosiderin	Xanthomatous hypophysitis, recurrent, with Rathke cleft epithelium and predominant squamous metaplasia	As above
8. 43 F 2014	Repeated episodes of hypoglycemia and hypertension, unclear etiology, daily headaches, history of hypothyroidism going back many yrs., MRI showed small pituitary mass thought to be RCC	Grumous cyst fluid with shimmering crystals suggestive of ACP	Grumous debris, PMNs, fibrosis, lymphoplasmacytic infiltrates, cholesterol clefts, giant cells, columnar epithelium, focal squamous metaplasia, focal mucin + hemosiderin; Gram stain negative	Xanthogranuloma with definitive RCC epithelium, with squamous metaplasia	Last seen 5 mo. post‐op. obesity, Roux en Y gastric bypass procedure, hypothyroidism hypoglycemia last seen 6/6/2014
9. 15 M 2014	Slow growth beginning 10 yrs. prior, small stature, overactive bladder; 6 years prior, MRI showed cystic sellar/suprasellar lesion, no involvement of optic apparatus or hypothalamus; closely monitored over time with multiple interval MRIs and numerous ophthalmology and endocrinology visits; stable endocrino‐pathies; begun on Synthroid 4 months prior; re‐review of serial MRIs confirmed lesion was slowly growing in size, prompting surgery	Thick multicolored green, white and brown granular material compressing the pituitary gland, potentially consistent with craniopharyngioma	Grumous debris, PMNs, CD68+ macrophages, fibrosis, columnar epithelium, cholesterol clefts, giant cells, lymphoplasmacytic inflammation in anterior pituitary gland with preservation of acinar pattern, hemosiderin mostly in macrophages; Gram stain negative	Xanthogranuloma with definitive RCC epithelium, with squamous metaplasia, metaplastic ossification	Last seen 4 mo. post op. panhypopituitarism, no other neurological deficits
10. 79 M 2016	4 months prior, loss of bilateral vision, MRI suprasellar mass eventually documented	Intraoperatively completely suprasellar, could not be separated from pituitary stalk, consistent with ACP	Grumous debris, cholesterol clefts, CD68+ macrophages, giant cells, PMNs, fibrosis, ciliated columnar epithelium with squamous metaplasia, focal mucin no wet keratin, no nuclear beta catenin, BRAF VE1 negative, BRAF, exon 15 mutation absent, abundant hemosiderin; Gram, GMS, PAS, Fite stains negative	Xanthogranuloma associated with definitive RCC epithelium, with squamous metaplasia	Last seen 1 yr. post op pan‐hypopituitarism diabetes insipidus, subdural hematoma found during follow‐up, drained
Cases associated with scant epithelium with or without mucin
11. 16 F 2012	Presented with diabetes insipidus, amenorrhea; CT without intralesional calcification but with erosion of anteroinferior aspect of sella; MRI showed sellar region mass c/w pituitary abscess	Intraoperatively abscess suspected and lesion cultured; cultures negative	Scant debris, CD68+ macrophages, lymphoplasmacytic infiltrates, clusters ciliated columnar cells best seen on touch preparation; strips of columnar epithelium with crush artifact on permanent sections, no mucin, no hemosiderin	Xanthomatous hypophysitis, favor association with RCC	Last seen 4 years post op no recurrent infection; hyperprolactin‐emia, central adrenal insufficiency, hypothyroidism hypogonadism, diabetes insipidus
12. 61 F 2005	Underwent incomplete resection CP 53 yrs. prior at age 9 yrs. with post‐op radiation therapy + panhypopituitarism; developed ptosis of left eye 3 months prior, then presented emergently to outside ED with what was thought to be hemorrhage into sella, transferred emergently	Very large cyst with yellow‐tinged mucoid material consistent with RCC without hemorrhage	Grumous debris, cholesterol clefts, hemorrhage, rare PMNs, few pankeratin + low cuboidal cells overlying fibrotic cyst wall, Alcian blue positive mucin, focal hemosiderin; PAS/GMS negative for organisms	Xanthomatous hypophysitis, few cuboidal epithelial cells + mucin, favor association with RCC	Last seen 12 yrs. post op, pan‐hypopituitarism hypothyroidism hair loss
13. 39 F 2008	Episodic hyponatremia and persistent severe headaches lead to MRI c/w RCC	Serous fluid with inspissated mucous consistent with RCC variant	Macrophage‐rich debris scattered cholesterol clefts without giant cells, lymphocytes, small clusters pankeratin + cuboidal cells, pools of mucin, no hemosiderin	Xanthomatous hypophysitis, favor association with RCC	Last seen 3 ½ yrs. post op, headaches improved, hyponatremia
14. 66 F 2012	Suspected prolactinoma with increasing suprasellar cyst on MRI despite dopamine agonist therapy	Consistent with ACP	Grumous debris, cholesterol clefts, giant cells, squamous (vs. basal cell hyperplasia) epithelium, extremely focal overlying ciliated cells, possible mucin only on Alcian blue stain, no wet keratin, abundant hemosiderin	Xanthogranuloma associated with squamous epithelium with focal superficial ciliation, ciliated PCP vs. RCC with squamous metaplasia	Last seen 3 yrs. post op, pan‐hypopituitarism decreasing vision, increasing apathy; 4 yrs. post op died from untreated chronic subdural hematoma
66 F 2014	Mass recurred, was treated with radiation therapy but developed visual compromise resulted in repeat surgery	Consistent with recurrent ACP	Grumous debris, CD68+ macrophages, giant cells, cholesterol clefts, lympho‐plasmacytic infiltrates, scant squamous (vs. basal cell hyperplasia) epithelium, BRAF VE1 negative, abundant hemosiderin; no adenoma	Xanthogranuloma, recurrent	As above
Cases without identifiable epithelium or other identifiable etiology
15. 14 F 2004	Panhypopituitarism, headaches	Gritty yellow tissue found in anterior gland, thickening of dura	No debris, CD68+ macrophages, lymphoplasmacytic infiltrates, focal cholesterol clefts, giant cells, focal hemosiderin near giant cells, no mucin, no epithelium; CD1a, PLAP negative	Xanthomatous hypophysitis with very focal xanthogranuloma	Last seen 8 yrs. post op, pan‐hypopituitarism obesity
16. 15 F 2009	Amenorrhea, elevated prolactin level	Unknown	Grumous debris, focal cholesterol clefts, giant cells, focal hemosiderin near giant cells, lymphoplasmacytic infiltrates, no mucin or epithelium	Xanthomatous hypophysitis with focal xantho‐granuloma	Lost to follow‐up
17. 44 F 2009	11 yrs. prior developed galactorrhea post‐delivery, headaches, amenorrhea, MRI showed “very small” pituitary lesion, followed expectantly until referral	Cholesterol debris with focal bony/calcified material within lesion	Grumous debris, cholesterol clefts, giant cells, lympho‐plasmacytic infiltrates, focal hemosiderin metaplastic bone, no mucin or epithelium	Xanthogranuloma with metaplastic ossification	Last seen 7 yrs. post op for renal transplantation
18. 25 M 2014	Presented as child with pan‐hypopituitarism and sellar region mass diagnosed as sarcoid response to steroid therapy; episode of interim bleeding into sellar region mass with suspicion of RCC: no biopsy undertaken; mass continuously increased in size; eventual presentation with bitemporal hemianopsia	Optic nerve and pathway appeared slightly yellow and abnormal, but no clear neoplastic material was identified; lesion filled with necrotic debris	Grumous debris, cholesterol clefts, giant cells, lympho‐plasmacytic infiltrates, focal hemosiderin, no definitive mucin or epithelium on pankeratin	Xanthogranuloma	Last seen 3 months post op with persistent panhypo‐pituitarism hypogonadism hypothyroidism
19. 55 F 2015	5 yrs. prior had recurrent headache and nausea with onset of peripheral vision loss 2 yrs. prior; underwent transsphenoidal surgery at outside hospital, slides on review showed very minute amount grumous debris, follow‐up MRI 2 months prior showed residual lesion suspicious for RCC	Necrotic mucoid debris consistent with RCC	Grumous debris, sheets of macrophages, PMNs dystrophic calcification, very focal cholesterol clefts, no epithelium; Gram stain negative PCR negative for bacterial, fungal, nontuberculous mycobacteria or mycobacterial DNA	Xanthomatous hypophysitis with very focal xanthogranuloma	Last seen 1 yr. post op, with slight interval increase in pituitary cyst size; scheduled for re‐excision, cancelled, lost to follow‐up
Case associated with adamantinomatous craniopharyngioma and wet keratin
20. 10 M 2016	Presented with apoplexy‐like symptoms	Cystic lesion filling and expanding the sphenoid sinus with a small supradiaphragmatic communication to another large cystic region. Capsule appeared consistent with craniopharyngioma	Wet keratin debris, macrophages, cholesterol clefts, giant cells, fibrosis, focal hemosiderin, calcification, metaplastic ossification, lymphoplasmacytic infiltrates, XG 50% of resected material, focal ACP epithelium + wet keratin	Xanthogranuloma, with adamantinomatous CP	Last seen 8 mo. post op growth hormone deficiency, ACTH deficiency, hypothyroidism
Case associated with adamantinomatous craniopharyngioma, wet keratin, + ciliated columnar epithelium
21. 15 F 2016	Presented with homonymous hemianopsia, MRI lesion completely intrasellar	Intraoperatively bony portion of tumor adherent to optic tract	No grumous debris, focal organizing hemorrhage, macrophages, cholesterol clefts, giant cells, focal hemosiderin metaplastic ossification ciliated columnar epithelium transitioning to ACP + copious wet keratin, no nuclear beta catenin	Xanthogranuloma, associated with mixed adamantinomatous CP epithelium and RCC epithelium	Last seen 6 mo. post op growth hormone and ACTH deficiency, hypothyroidism
Case associated with squamous epithelium with keratohyaline layer, dry flaky keratin
22. 57 M 2013	Presented with acute vision loss in left eye; had significant fatigue and decreased libido over two years, 40 pound weight gain, polydipsia, polyuria, MRI consistent with CP	Mucoid material? PCP	Sheets of histiocytes, cholesterol clefts, lymphoplasmacytic infiltrates, squamous epithelium, dense fibrosis, calcification, embedded within brain tissue, very focal keratohyaline layer in <5% of epithelium, abundant dry keratin, focal grumous debris, little or no mucin, negative nuclear beta catenin, negative BRAF V600E mutation after dissection of epithelium	Xanthogranuloma, squamous epithelium with epidermoid cyst epithelium	2 yrs. post op panhypopituitarism, diabetes insipidus; developed chorea 2 yrs. post op, diagnosed with paraneoplastic syndrome caused by the small cell carcinoma, lung, Died 3 yrs. post op
Case associated with pituitary adenoma
23. 35 M 2016	Known, very large sellar/suprasellar calcified, cystic mass diagnosed 1 year prior, had bitemporal hemianopsia, failed cabergoline therapy, had massively elevated prolactin level	Old liquefied blood and necrotic debris with fibrous capsule	Grumous debris, occasional PMNs, cholesterol clefts, giant cells, hemosiderin containing macrophages, extensive fibrosis, lympho‐plasmacytic infiltrates, focal metaplastic ossification, calcification, scant viable prolactinoma compressed to fibrotic edge of lesion, extensive hemosiderin	Xanthogranuloma with scant residual prolactinoma	Last seen 4 mo post op, had persistent bitemporal hemianopsia, cancelled further appointments

Key: M, male; F, female; yrs., years; PMNs, polymorphonuclear cells/neutrophils; MRI, magnetic resonance imaging; CT, computerized tomography; post‐op, post‐operative; P, craniopharyngioma; RCC, Rathke cleft cyst; PCP, papillary craniopharyngioma; ACP, adamantinomatous craniopharyngioma,.

Of the 23 cases, 7 were pure XH (cases 1, 2, 5, 7, 11, 12, 13), 3 were overwhelmingly XH but with small foci of XG (cases 15, 16, 19), lending credence to the impression that there was a spectrum/overlap of XH to XG development and 13 were pure XG (cases 3, 4, 6, 8, 9, 10, 14, 17, 18, 20, 21, 22, 23).

Ten cases were definitively associated with RCC bleed/rupture/leakage, 4 were possibly associated with RCC bleed/rupture/leakage, and 5 were without any identifiable causation. Cases associated with RCC epithelium, either definitively (n = 10) or probably (n = 4), included XH (n = 7) and XG (n = 7) types in equal numbers, again suggesting a spectrum/overlap between the two xanthomatous types of lesions. One of the cases thought to probably be related to RCC was case 14 where squamous epithelium with extremely focal ciliated columnar cells was found, although the possibility of ciliated craniopharyngioma was raised based on histology.

Only one XG (case 20) had occurred secondary to adamantinomatous craniopharyngioma (ACP), with the XG occupying at least 50% of the resection materials (see Table 1). The single case associated with a pituitary adenoma (case 23) was an XG caused by the bleed in a known very large prolactinoma following cabergoline therapy; the XG constituted greater than 80% of the resection materials in this case. No case with squamous epithelium manifested a papillary configuration.

Two XGs were associated with unusual combinations of epithelium (cases 21, 22). Case 21, a 15‐year‐old girl had a lesion that contained significant amounts of ciliated columnar epithelium transitioning directly to squamous epithelium. Given the presence of balls of wet keratin in the epithelium and even more abundant wet keratin in the resection materials, this case was considered possibly a mixed/transitional adamantinomatous craniopharyngioma (ACP)/RCC. Case 22 contained cytologically bland squamous epithelium in which less than 5% of it manifested a prominent keratohyaline layer. This XG contained abundant dry flaky keratin on the histological sections and the lesion was considered predominantly an epidermoid cyst rather than papillary craniopharyngioma by histological criteria. However, clinically the case was not considered a typical epidermoid cyst by the neurosurgeon, based on mucoid cyst content he identified intraoperatively (see below).

Demographics for the cohort as a whole (n = 23) were 16 females vs. 7 males, age 4‐79 years. Young patients were over‐represented, with pediatric (16 years or less, n = 9), young adult (17–40 years, n = 5), and older adult (41–79 years, n = 9) cases. If only the definite plus probable RCC‐associated cases were assessed (n = 14), 11 females vs. 3 males were identified, and if the 5 cases with unknown cause were also included (n = 19), 15 females vs. 4 males emerged, that is, an even stronger female skew emerged.

The range of clinical presentations is detailed in the Table 1, but most came to clinical attention either caused by the headaches, diabetes insipidus or varying degrees of hypopituitarism. Four patients required two surgical resections of their sellar region masses (cases 2, 7, 14, 19, the latter with her first surgery at an outside hospital but with slides available for review) and 1 had had two surgeries but the first biopsy (seen by BKD) was completely non‐diagnostic and thus the biopsy may not have fully encompassed the original lesion (case 18). The second biopsy on this patient showed definitive XG.

Two patients had known growth of their sellar region lesion over a several‐year time course prior to their first surgical excision at our institution (cases 9, 18). Case 12, by history, had had an incomplete resection of a presumed craniopharyngioma 53 years prior (as a child and thus likely adamantinomatous craniopharyngioma; slides unavailable for review); no craniopharyngioma epithelium was found microscopically. Instead, low cuboidal epithelium and mucin allowed classification of probable RCC association.

While neuroimaging features were variable, they ranged from sellar ring‐enhancing masses somewhat simulating pituitary abscess (Figure 1a) to one case with a fluid‐fluid level appearance (Figure 1b); these cases were respectively, XH and XG. The neuroimaging features of case 2 prior to each of her surgeries in illustrated in Figure 2a,b). Case 9 had had a 10‐year history of slow growth and small stature, and serial magnetic resonance imaging scans (MRI) over a 4‐year time period clearly showed growth of the sellar region mass (Figure 2c) that prompted surgical resection at our institution.

Figure 1.

Coronal magnetic resonance images (MRI), with gadolinium of patients #1 and #4. a. Although the neuroimaging appearance was variable amongst xanthomatous lesions of the sella, many cases of xanthomatous hypophysitis manifest a ring‐enhancing appearance, prompting consideration of infection. b. This xanthogranuloma had the unusual appearance of a fluid–fluid level.

Figure 2.

Coronal magnetic resonance images (MRI), with gadolinium. a, b. This patient (#2) required two neurosurgical resections to control the growth of her sellar region mass; the appearance prior to each resection is shown. c. Patient #9 was one of two that was monitored over time with serial MRIs, which clearly show the growth of the lesion over time.

Intraoperative impressions were extremely varied and often, caused by the grumous cyst contents, either ACP or even infection was suspected at the time of operation by the neurosurgeon (see Table 1). Of note, however, several xanthomatous sellar region masses that proved histologically to be associated with RCC rupture/leakage/hemorrhage had been considered to be RCC by the experienced pituitary neurosurgeon. The most interesting dichotomy between intraoperative impression and histological results was seen in case 22. In this patient, the neurosurgeon had noted the cyst contents to be mucoid and not the typical dry flaky keratin of an epidermoid cyst (Figure 3). Thus, this case was not considered a typical epidermoid cyst by the neurosurgeon. Microscopically, however, the case had a cyst wall composed of squamous epithelium containing less than 5% keratohyaline layer, yet dry flaky keratin along with the grumous material, but little or no mucin, was histologically identified on the materials received by the pathologist (see Table 1). This case underscores the obvious fact that the pathologist may not receive all components of a cystic lesion for histological examination and that correlation of clinical/intraoperative/histological features of XH or XG adds to our understanding of the more complex examples (see Table 1).

Figure 3.

Intraoperative transnasal endoscopic images from patient #22 are illustrated. Intraoperative impressions of xanthomatous hypophysitis and xanthogranuloma of the sella were also quite varied but in several instances contributed significantly to the understanding of the lesion as a whole. Despite dry flaky keratin and focal keratohyaline layer in the squamous epithelium of the cystic lesion in this case, the neurosurgeon intraoperatively identified and photographed the mucoid material shown, which is not typical for epidermoid cyst contents. No mucin was received in the pathology specimen.

Cases with and without definitive identifiable etiology showed similar features, namely XH manifested grumous debris containing small cholesterol clefts and occasionally scattered neutrophils, but no giant cells (Figure 4a). While sometimes intact individual macrophages could be recognized within the grumous debris (Figure 4b), often these were more degenerated and could contain iron pigment (Figure 4c). Other examples of XH contained sheets of macrophages and lymphoplasmacytic infiltrates, sometimes immediately adjacent to residual mucin and a few neutrophils (Figure 4d). The three cases of predominantly XH with focal areas of XG contained grumous debris and CD68‐immunoreactive macrophages identical to pure XH (Figure 4e) but additionally showed small foci of classic XG (Figure 4f). Pure XG contained multinucleated giant cells around the cholesterol clefts (Figure 4g) and even hemosiderin (Figure 4h). Metaplastic ossification was found in several examples of XG even without ACP features (cases 3, 9, 17) (Figure 4i).

Figure 4.

Xanthomatous hypophysitis (XH) manifested grumous material, sometimes with a few cholesterol clefts or neutrophils embedded within it (a), admixed macrophages (b), occasional hemosiderin within macrophages as seen on Perl's iron stain (c), and more cohesive sheets of foamy histiocytes admixed with lymphoplasmacytic infiltrates (d). Macrophages within the grumous debris often showed degenerative features and thus were best highlighted by CD68 immunostaining for macrophages (e), as seen here in the predominant XH component of an example with a small focus of xanthogranuloma (XG) development (f). Where present in the surgical specimen in XH, the anterior pituitary gland showed inflammation and sometimes considerable disruption of architecture (g). XGs consisted of abundant cholesterol clefts surrounded by multinucleated giant cells (h) and embedded in fibrotic background. Occasional examples of either XG or XH showed metaplastic ossification (i). All H&E except CD68 immunostaining with light hematoxylin counterstain (e) and Perl's iron (c).

Representative examples of the columnar and ciliated epithelium in patients with definitive RCC association are shown in Figure 5a‐i and supplemental Figure 1a‐i. In 2 cases, the ciliated columnar epithelium was best seen on touch preparation (Figure 5b; Supporting Information Figure S1a). The occasional finding of neutrophils in the center of glandular epithelium (Figure 5c; Supporting Information Figure S1e) prompted concern for infection, particularly bacterial infection, in many of the XH cases, but Gram stains (and in one instance, polymerase chain reaction for bacteria, fungal, and mycobacterial organisms, case 19, see Table 1) were negative. However, an acknowledged limitation of Gram staining was the difficulty in identifying any rare possible single bacterial forms in the midst of copious grumous debris. Goblet cells (Figure 5e, f), squamous metaplasia vs. basal cell hyperplasia (Figure 5d,g) and even Russell bodies in the plasmacytic infiltrates (Figure 5h) are illustrated. Oil immersion photography was optimal for illustrating ciliation (Figure 5e,f,h) or apical cell borders (Figure 5a). When epithelium was more abundant, the range of epithelial types within the same case (Supporting Information Figure S1d–f) could be easily detected, as in case 10, an XG with abundant hemosiderin debris (Supporting Information Figure S1c). Also in these instances, the intercellular connections for squamous epithelium could be easily appreciated (Supporting Information Figure S1f).

Figure 5.

Most cases of XH and XG had strips of columnar epithelium (a), usually ciliated (b) and sometimes best seen on touch preparation (b), although ciliation could be easily identified on permanent sections, especially using oil immersion (c, e, f, h, i). Focal goblet cells in the epithelium could be found in the highly‐ciliated epithelium of several cases (e, f, h) and squamous metaplasia (d, g) had to be distinguished from basal cell hyperplasia. Collections of neutrophils contributed to the impression of possible infection (c), although infectious organisms could not be demonstrated. Russell bodies within plasma cells were often conspicuous (h). All H&E.

The XG examples unrelated to definitive RCC, or even possible RCC, included one ACP and one unusual ACP + RCC epithelium, possibly a mixed ACP/RCC. The neuroimaging features of these two cases were not, however, dramatically different from other XGs in our series (Supporting Information Figure S2). However, multinucleated giant cell reaction in this example, similar to the pure ACP, was to the wet keratin (Figure 6a), with only minute amounts of mucin in small glands (Figure 6b), and well‐developed strips of ciliated pseudostratified columnar RCC‐like epithelium (Figure 6c) transitioning to ACP epithelium with wet keratin (Figure 6d,e), albeit without nuclear beta catenin immunostaining (2 tissue blocks assessed), including adjacent to wet keratin (Figure 6f). BRAF VE1 was negative in the squamous epithelium. BRAF V600E mutational testing could not be performed caused by the prior decalcification of the tissue necessitated by the bony metaplasia.

Figure 6.

Case 21 had a XG with abundant cholesterol clefts and giant cells associated with wet keratin (a), although focal small glands contained mucin and showed adjacent mononuclear cell inflammation in the specimen (b). The columnar, focally pseudostratified epithelium contained occasional goblet cells (c) and showed abrupt change to squamous epithelium containing wet keratin (d, e). Despite this, no nuclear beta catenin was found on immunostaining, even adjacent to wet keratin (f).

No nuclear beta catenin immunostaining (2 sections assessed) was found in the example of epidermoid cyst with squamous epithelium and less than 5% epithelium with keratohyaline layer (case 22). Both this case and case 10 were assessed for BRAF V600E mutation and were found to be negative, after microdissection of the epithelium to ensure optimal testing.

Clinical follow‐up time periods were highly variable but many had been followed for more than 1 year postoperatively, some as long as 8 (cases 2, 15), 9 (case 1) or 12 (case 12) years. Most continued to have endocrinological deficits at last follow‐up (see Table 1).

Literature on XH and XG was tabulated (Supporting Information Tables S1 and S2, respectively). Combining reports from the literature, and our own series, no infectious etiology has been identified for XH despite the neutrophilic infiltrates. Cultures, and even polymerase chain reaction testing (PCR) have occasionally been sent, either in our cases or those in the literature (Supporting Information Table S1), but results have been negative. In our literature review, XH cases contained not only foamy histiocytes, grumous debris, neutrophils and lymphoplasmacytic infiltrates, although almost never was hemosiderin found except for a single case of Cheung et al 16. In contrast, the literature, especially the original description by Paulus et al 67, shows that lymphoplasmacytic infiltrates and hemosiderin pigment, along with cholesterol clefts with giant cell reaction and fibrosis, are standard features of XG.

Several authors had identified the spectrum that existed between not only between various types of hypophysitis in general 80, but also xanthomatous lesions in particular 11 which was reinforced by our series.

Discussion

The etiology of XH and XG are heterogeneous but occasional examples have previously been linked with rupture/leakage/hemorrhage of RCC (Supporting Information Tables S1 and S2). As noted above, given the increased literature on hemorrhage, either spontaneous or rarely post‐traumatic, into other types of benign cysts in the nervous system, the possibility of hemorrhage into a benign cyst has become more plausible than it was when XG and XH were first described 25, 67. Infectious etiologies have been diligently sought, especially in XH because of the neutrophilic infiltrates, intraoperative findings of grumous cyst content (see Table 1), and the MRI features of ring enhancement (Figure 1a). In all cases, XH has failed to be linked with an infectious agent. Presumably the neutrophils seen in the grumous debris of XH, and occasionally XG, represent acute reaction to blood breakdown products or cyst contents, akin to the findings in cases of aseptic meningitis secondary to cyst rupture. The complex cyst contents especially in XG occasionally yielded a fluid–fluid level appearance preoperatively (Figure 1b).

The female predominance of both XH and XG had been well described in the literature prior to our series (Supporting Information Tables S1 and S2), but our inclusion of cases from our pediatric hospital practice further underscored the relatively young age of many of the patients with either condition. We also documented the need for a second surgical resection to control the condition in four patients (Figure 2a,b). In a 5th patient, two surgical procedures were required because the first was non‐diagnostic. The growing nature of the sellar lesion over time had been seen in two patients on serial MRI scans (Figure 2c).

The largest subset of either XHs or XGs in our cohort could be attributed to RCC rupture/leakage/hemorrhage, based on the presence of strips of columnar to ciliated columnar epithelium in the resected materials (Figure 5; Supporting Information Figure S1). Four more examples were considered likely to have arisen from a similar etiology (Table 1; Supporting Information Figure S1). Several had squamous metaplasia (Table 1).

Neither our study, nor case reports, assist in understanding the incidence of xanthomatous development in RCCs or how frequently squamous metaplasia occurs in RCCs with xanthomatous features. However, Le et al identified a “prominent xanthomatous component, consisting of chronic inflammation, giant cell reaction, hemosiderin‐laden macrophages, and cholesterol clefts” in 13 of 28 RCC cases, of which squamous metaplasia was seen in 9 (69%) 51. Conversely, “of the 11 cases with squamous metaplasia, prominent xanthomatous features were seen in 9 cases (82%)” 51. Thus, xanthomatous features are at least not rare in RCCs.

In our cohort, other definitive underlying lesions associated with XH or XG development were uncommon. A single example of XG was caused by the ACP (case 20). Another XG occurred in a child with both ciliated columnar epithelium and squamous epithelium containing wet keratin (i.e., combined ACP/RCC epithelium) (case 21). A third XG was a highly unusual lesion in an adult with squamous epithelium devoid of keratohyaline layer except for less than 5% of the epithelium, mucoid cyst contents intraoperatively (Figure 3), and almost exclusively dry flaky keratin on the histological specimen (i.e., potentially a combined PCP/epidermoid cyst, case 22). The fourth unusual XG was a very large prolactinoma with hemorrhage following cabergoline therapy in which the XG was the overwhelmingly dominant component (case 23). The most interesting cases of these four cases were the two with mixed types of epithelium (cases 21, 22). Specifically, the finding of cases with mixed epithelial types has been seen in cystic sellar lesions outside the setting of XH and XG. Thus, the finding of a few unclassifiable/transitional cases amongst our XH and XG cohort is not unique and deserves additional comment.

The occurrence of 2 types of epithelium in the same lesion, and potential overlap between ACP and PCP, may be surprising, especially to the research community. The discovery of beta catenin mutation almost exclusively in adamantinomatous craniopharyngioma 12, 27, 34, 35 and BRAF V600E mutation in papillary craniopharyngioma 10, 27, 35 suggests quite polar origins for epithelial cystic lesions of the sella, although at least one report of co‐existent BRAF and beta catenin mutation in the same lesion exists 50.

However, several groups since the 1990s have emphasized that a percentage of cystic sellar masses were impossible for even the very experienced neuropathologists on the study to categorize. Burger et al, in their seminal 1995 article on PCPs, commented that 4 of their 48 patients had sellar region lesions which were difficult to classify, including 4 that had features of both papillary and adamantinomatous differentiation and 2 cases in which the “distinction from Rathke's cleft cyst was achieved only with difficulty” 19. In 3 of the 4 tumors with mixed ACP and PCP features, “there were alternating areas of clearly defined adamantinomatous and papillary squamous differentiation within the same tumor; in the fourth the epithelium was intermediate in appearance” 19. Our case 21 of the 15‐year‐old female with alternating areas of ACP and squamous epithelium additionally contained strips of ciliated columnar epithelium, but otherwise is quite similar in its overlap (Figure 5). Our case was immuno‐negative for nuclear beta catenin (Figure 5f). It also was negative for BRAF VE1 immunohistochemistry in the squamous epithelium; BRAF V600E mutational testing could not be performed caused by the prior decalcification of the tissue necessitated by the bony metaplasia.

Burger et al also noted that “goblet cells similar to those seen in Rathke's cleft cyst were present in 16 of their tumors (33%), disposed either singly or in small groups within the squamous epithelium” but rare ciliated cells were identified in only two of their PCPs (4%) 19. Thus, ciliation is rare in PCP and usually focal whenever it is identified.

A number of case reports since that time of ciliated epithelium overlying squamous epithelium have been described, with the lesions designated “ciliated craniopharyngioma” 17, 19, 26, 54, 58, 63, 72. Sato et al reviewed the literature, felt that ciliated PCP might arise from a RCC, and suggested that “basal cells of RCC transform to papillary type craniopharyngioma after squamous metaplasia, explaining the presence of the cilia and goblet cells” 72. While one example of repeated hemorrhage into a ciliated craniopharyngioma has been reported 58, and while we had one case in which we considered the diagnosis of ciliated craniopharyngioma (case 14), it would not appear that ciliated CP is particularly prone to hemorrhage or to XH/XG formation.

Harrison et al in 1994 had noted that 6 of their 16 epithelial cystic lesion of the sellar region manifested overlapping features and 3 could not be classified into distinct RCC, craniopharyngioma, or epidermoid cyst categories 32. Harrison et al felt there was a possible continuum between ectodermal sellar region lesions such as RCC, ACP, PCP and even epidermoid cysts, based on these overlapping cases 32. One of their overlapping cases exactly parallels our case 22 from the current study. In the cyst from case 22, bland squamous epithelium without keratohyaline granules constituted the overwhelming majority of the epithelium, with only a very focal keratohyaline layer found in less than 5% of the epithelium. Despite the focality of the keratohyaline layer, there was abundant dry flaky keratin in the material received for pathological examination. This same case contain predominantly mucoid material intraoperatively, not epidermoid‐cyst‐like dry flaky keratin (Figure 3), underscoring the need to correlate intraoperative and histological findings. No nuclear beta catenin was found on immunostaining in case 22 and BRAF V600E mutational testing was negative after microdissection of the epithelium.

Zada et al more recently cited histological overlap between cystic epithelial sellar lesions, particularly “transitional” RCCs with squamous epithelium and PCPs with ciliated or mucinous goblet cells. They also felt that, when considering these “transitional” cases along with older animal studies, these collectively provided “additional support for a theory of sequential progression in epithelial cystic lesions” 84. These authors proposed that “subsequent inflammatory, metaplastic and neoplastic processes may promote further progression along pathological continuum ranging from benign epithelial cysts to aggressive neoplastic CPs” 84.

The unanswered question is where along the line does possible mutation (in either beta catenin or BRAF V600E) occur if such a transition, or continuum, of epithelial types exists, and is mutation always a prerequisite to this morphological transformation? One case of ciliated craniopharyngioma, reported by Coy et al 17, was assessed for BRAF VE1 immunostaining, and was found to be positive, suggesting that even if evolution from RCC to ciliated PCP exists, there may be an oncogenic event that accompanies PCP development. In similar fashion, a case of an ACP developing 34 months following surgery for a RCC reported by Park et al showed no nuclear beta catenin in the RCC specimen, but nuclear beta catenin was identified in the recurrent ACP specimen and “restricted to whorl‐like structures or surrounding ghost cells” 64. Kim et al were unable to demonstrate BRAF V600E mutations in RCC with squamous metaplasia, so perhaps any oncologic event, if it occurs, is either not a prerequisite or very focal 43. Clearly, more of these unclassifiable/transitional cases will have to be assessed for both nuclear beta catenin and BRAF V600E mutational status before conclusions can be drawn.

In conclusion, our study suggests that one plausible explanation for at least some cases of XH and XG is that they too exist in a spectrum. Possibly, only the subset of XH with significant (or repeated) hemorrhage goes on to develop giant cell reaction around the extensive cholesterol cleft formation and significant hemosiderin deposits. This would account for the relative absence/paucity of hemosiderin in XH, both in our cases and the literature, and the nearly ubiquitous presence of hemosiderin in XG (see Table 1; Supporting Information Tables S1 and S2). Both XH and XG in most—but not all—cases can be linked to RCC leakage/rupture/hemorrhage. We further verify, along with Paulus et al 67, that ACP is not a frequent antecedent to development of XG.

Supporting information

Additional supporting information may be found in the online version of this article at the publisher's web‐site:

Figure S1. Additional cases definitively associated with RCC showed well‐developed ciliated epithelium alone (a, b) or combinations of strips of ciliated epithelium with squamous epithelium, as in case 10, where the xanthogranuloma showed abundant hemosiderin amongst the cholesterol clefts (c), ciliated columnar epithelium (d), occasional glands containing grumous debris and neutrophils (e) similar to those in Figure 5c, and well‐developed squamous epithelium with obvious well‐developed intercellular bridges (f). Cases probably related to RCC rupture/leakage/hemorrhage either contained only scant ciliated cells, seen here on touch preparation (g), or small amounts of poorly preserved epithelium, seen here on pankeratin (AE1/AE3) immunostaining (h), or mucin in association with flattened epithelium (i). All H&E except AE1/AE3 immunostaining with light hematoxylin counterstain (h).

Figure S2. Sagittal (a) and coronal (b) MRI, with gadolinium showing the features of XG associated with adamantinomatous craniopharyngioma (a) or mixed adamantinomatous/ciliated columnar epithelium (b).

Figure S3. Sagittal (a) and coronal (b) MRI, with gadolinium showing the unusual features of the XG associated with the prolactinoma (case 23).

Table S1. Xanthomatous hypophysitis: literature review.

Table S2. Xanthogranulomas of sella: literature review.