Intracranial xanthogranulomas arise most commonly in the choroid plexus at the trigone of the lateral ventricle; xanthogranulomas of the sellar region are much rarer [
3]. The entity was first identified in 1988 [
5], and was placed on the spectrum of cystic pathology occurring in the sellar region, incorporating CPs, RCCs, colloid cysts, cystic adenomas, and dermoid cysts [
6]. Paulus et al. [
7] described xanthogranuloma of the sellar region as a distinct entity in 1999, identifying 37 cases wherein resected pituitary lesions consisted predominantly of xanthogranulomatous components once examined histologically. These lesions may be an individual disease entity, [
7] or represent the outcome after repetitive inflammation and haemorrhage into a previously typical RCC or CP.
Demographics
Previous literature has reported the prevalence of sellar and parasellar xanthogranulomas in pituitary tumour patients the western hemisphere to be in the region of 0.6% [
2]. The prevalence of xanthogranulomas in our study was 2% (6/295), in keeping with another recent series which reported just under 3% of their pituitary tumour database comprised of xanthogranulomatous lesions (6/223) [
3,
8]. Whilst it remains rare, as awareness of this disease entity has developed it appears to be more commonly identified on histology within the cohort of patients with cystic sellar and parasellar tumours.
Four patients in the studied cohort were female (67%). Larger case series have also identified a slight female preponderance, with one recent study identifying 16 (59%) females and 11 (41%) males within their 27-patient cohort [
4]. The mean age of patients in this study was 29, in keeping with the largest case series of xanthogranulomatous pituitary lesions to date, which stated a mean age 27 [
7]. Others have reported mean ages of their pituitary xanthogranuloma patients as slightly older (43–46 years) [
2,
9]. This discrepancy likely reflects the low numbers of cases in each cohort. However, a trend towards younger patients is noted, with only one case reported in a patient over the age of 70 [
7].
The most common presenting features in our cohort were visual deterioration and clinical endocrine dysfunction, at least one of which was present in 67% (n = 4) of cases. The most common visual deficit was a bitemporal hemianopia (n = 3). Three patients (50%) also presented with headaches. These clinical manifestations are similar to those reported in other series, with endocrine dysfunction, (e.g. diabetes insipidus, hypoadrenalism) often reported as the most common presenting feature [
3,
10,
11].
All patients with visual field deficits in our study regained normal vision post-operatively. Concordantly, almost all patients discussed in the literature are reported to have normal or near-baseline levels of vision or post-operatively. Conversely, endocrinological deficits are rarely reported to improve after surgery [
4,
9].
Endocrine effects
Four (67%) of our patient cohort presented with biochemical hyperprolactinaemia. Pre-operative trials of dopamine agonists had no effect on tumour size or serum prolactin and hyperprolactinaemia resolved in all cases after surgery. In total, one patient was free of any hormonal supplementation (case 6), and one demonstrated improvement in endocrine function, (case 1) at their most recent follow-up (Table
3).
These endocrine outcomes are slightly more promising than those previously reported, as in the majority of published cases endocrine function rarely improves after xanthogranuloma resection and most patients remain on long-term hormonal supplementation. For instance, Amano et al. reported that in their cohort of seven pituitary xanthogranuloma patients, 6 cases (86%) presented with pituitary hormonal dysfunction, and this persisted in all six patients after surgery (3 total resection, 3 sub-total resection) [
9].
In a larger analysis of parasellar xanthogranuloma patients, the most common presenting symptom was an endocrinological deficit (74%; n = 20/27), usually either isolated DI or panhypopituitarism. All 20 cases had persistence of their endocrine deficiency post-operatively, with a total of 21 patients (77%) requiring hormonal treatment despite adequate removal of the pituitary xanthogranuloma [
4].
The risk of permanent pituitary dysfunction with sellar xanthogranulomas may reflect the time interval between symptom onset and surgery, and/or the repetitive inflammatory and haemorrhagic nature of the lesions causing ongoing damage to normal pituitary parenchyma. Therefore, the ability to more confidently identify suspected cases of xanthogranulomatous pituitary masses is desirable, as this could justify expediting surgical intervention, potentially permitting more favourable endocrine outcomes [
2,
9]. It is also possible that meticulous dissection, focus on optic apparatus decompression, and preservation of the pituitary stalk when feasible may have contributed to the favourable endocrine outcomes achieved in a third of patients in our series. In our single case of permanent DI, a decision was taken to sacrifice the pituitary stalk in the aim of curative resection of a craniopharyngioma; this was probably not necessary given the pathology of xanthogranuloma, and could have been avoided if the diagnosis was suspected pre-operatively. Similarly, the high rate of anterior hypopituitarism following surgery compared to surgery for pituitary adenoma, highlights the need for clinical suspicion of the diagnosis pre-operatively to aid patient counselling.
Imaging appearances
No typical radiological signs are thought to highlight xanthogranuloma as the most likely possibility in the differential diagnosis of sellar lesions [
6]. This is reflected in the fact that xanthogranuloma was not listed in the radiological differential diagnosis for any patients in our cohort. The most common radiological differential diagnosis was craniopharyngioma, which was documented as the most likely diagnosis for 3 patients, (50%) prior to their surgeries in the present study.
It has been speculated that cholesterol components within these lesions should be identifiable from their T1W hyper-intensity and T2W hypo-intensity on pituitary MR scans, [
6,
12]. However, fluid components within the cystic lesions can appear hyperintense on T2W images, and the development of more profound fibrosis (granulation) and haemorrhage can appear as both T1W and T2W hypointensities [
6]. These mixed signal intensities reflect the complex histologic components that make up granulomatous inflammatory lesions. Eighty-three percent (5/6) of cases in our cohort demonstrated a degree of T1W hyperintensity of their pituitary lesions. This is consistent with imaging descriptions in other case reports [
4,
10,
13], and may represent the cystic content and cholesterol clefts before any haemorrhage or degeneration of lesion has occurred. However, once a degree of necrosis or haemorrhage occurs, the lesions may then demonstrate heterogeneous signals on both T1W and T2W images, making their differentiation from other cystic lesions such as RCC and CPs extremely challenging.
All six patients in this case series demonstrated some degree of contrast enhancement of their parasellar lesions; three cases (50%) demonstrated peripheral rim enhancement of their pituitary lesion on post-contrast T1W scans. Amano et al. [
9] specified that 71% (5/7) of sellar xanthogranulomas in their series also demonstrated T1W peripheral rim enhancement. The other three cases in our cohort did also display contract enhancement, but in a more homogenous manner. RCCs do not typically enhance on MRI scans post-contrast, and calcification is rarely identified. CPs typically demonstrate heterogeneous contrast enhancement, and frequently do have calcification identifiable within the cystic lesion, particularly in the adamantinomatous sub-type. There was no calcification seen in any of the pre-operative MRI or CT head scans in our cohort, and thus far only 7 reported cases of pituitary xanthogranulomas have demonstrated calcification on imaging [
3,
10].
Furthermore, no cases in our cohort demonstrated cavernous sinus involvement, which has been reported for both RCCs and CPs [
14]. Cavernous sinus involvement remains as yet unreported in pituitary xanthogranulomas [
4,
9,
10,
13]. The absence of calcification and cavernous sinus invasion, in the setting of peripheral or global contrast enhancement, may therefore constitute a constellation of imaging features that necessitate consideration of xanthogranuloma in the pre-operative differential diagnosis.
Table
6 provides a summary of typical features of CPs, RCCs and pituitary xanthogranulomas on conventional MR imaging. However, these features are not universal to any of the lesions, and therefore there are currently no specific radiological criteria which can be used differentiate xanthogranuloma from other cystic sellar lesions with complete confidence.
Table 6
Summary of typical features of CP, RCC and pituitary xanthogranulomas on MRI
T1W | Hyperintense | Heterogeneous | Hyper- and/or hypointense |
T2W | Hypointense | Heterogeneous | Hyper- or hypointense |
Contrast enhancement | – | Diffuse or peripheral enhancement | Peripheral rim or homogeneous enhancement |
Calcification (on CT scan) | – | + | Rare |
Tumour epicentre | Usually sellar | Usually suprasellar | Suprasellar |
Cavernous sinus invasion | May be present | May be present | Unreported |
All lesions analysed in this study had tumour epicentres which were universally suprasellar, (Quadrants 1–2) which also appears to be a consistent finding in other case series [
3]. This contrasts to cystic pituitary adenomas and RCCs, which typically have an epicentre located in sellar quadrants, (quadrants 3 or 4). This supports the notion that pituitary xanthogranulomas may hold their origin in the hypothalamoinfundibular region [
2,
9]. A primarily sellar tumour epicentre may therefore suggest cystic adenoma or RCC as more likely diagnoses when assessing cystic pituitary lesions.
Non-infectious, xanthogranulomatous inflammation of the frontal lobe have been shown to demonstrate restriction of diffusion on diffusion-weighted MR scans [
15]. The features of CPs and RCCs with diffusion weighted imaging (DWI) and MR spectroscopy have been assessed, [
11,
12] and therefore specific analysis of DWI appearances in patients with sellar xanthogranuloma is warranted. If clear differences in diffusion restriction between these lesions are identified, this modality has the potential to aid clinicians in differentiating pituitary xanthogranulomas from other cystic sellar lesions prior to surgery.
Histology
Similarities in histological appearances and the consistent presence of chronic inflammatory cells and debris in sellar xanthogranulomas has fuelled the theory that these lesions are on the same spectrum as RCC’s and CPs, potentially representing a secondary reaction caused by repeated inflammation and haemorrhage [
16]. RCCs consists of simple columnar/cuboidal epithelium, whereas CPs are divided into histological sub-types: adamantinomatous, (stratified squamous epithelium with keratin nodules +/− calcification) or papillary (squamous epithelium).
At least two or more of the characteristic features of xanthogranulomas, such as cholesterol clefts, foamy macrophages, granulomas, necrosis, and/or haemosiderin deposition [
4,
7,
9] were identified in all patients within the study group. In addition, squamous metaplasia was present in 67% (4/6) of patients. Le et al. [
17] reported that 39%; (11/28) of RCCs displayed squamous metaplasia, and that xanthogranulomatous components were identified in 13/28 confirmed RCCs (47%). Conversely, xanthogranuloma-like features were highlighted in comparatively fewer (n = 5/25; 20%) CPs. Amano et al. identified components of RCCs (cuboidal/columnar epithelium, squamous metaplasia) within 86% (n = 6/7) of resected pituitary lesions which otherwise composed primarily of xanthogranlomatous material [
9]. The authors proposed that pituitary xanthogranulomas may represent a final inflammatory state, resulting from secondary reactions caused by repeated haemorrhage, inflammation and degeneration of RCCs.
However, identification of residual RCC/CP components within pituitary xanthogranulomas is not reported consistently in histological studies across the literature [
1,
6,
9,
13]. Furthermore, xanthogranuloma histology features are similar across multiple sites both intracranially and elsewhere in the body, and thus they may represent a unique disease entity [
6,
18].
However, this may be a function of heterogeneity within the tissues sent for analysis from pituitary lesions, and thus it remains possible that xanthogranulomas represent one condition a spectrum of cystic sellar and parasellar lesions, or a stereotyped response to repeated inflammation and haemorrhage within a biological structure [
18]. Future studies of cystic pituitary lesions must ensure that sufficient quantities of tissue are sent for histological analysis, to minimise the risk of sampling bias when analysing these microscopically heterogeneous lesions.
Treatment
Whilst radiotherapy for intracranial xanthogranulomas at other sites has been utilised, its use in sellar lesions is yet to be evaluated, partly due to the diagnostic uncertainty inherent when planning treatment of cystic lesions in this region. GTR is considered gold standard treatment for these lesions. The endoscopic endonasal approach is generally favoured over transcranial approaches when feasible [
6]. In all patients in our cohort, visual function was normal post-operatively, in contrast to endocrine outcomes, which improved in 2 patients after long-term follow-up. Recurrence or re-growth was not reported in any case during the present study’s follow-up period, and recurrence is rarely noted in other case reports, regardless whether total or subtotal resection was performed at the initial operation [
1,
4]. Given these factors, tumour mass reduction to decompress the optic chiasm, with sparing of the pituitary stalk if not involved in the lesion, may be regarded as the appropriate surgical target when planning resection of a suspected xanthogranuloma [
9].
However, GTR is advocated for RCCs and CPs. Therefore, until definitive clinical or radiological diagnostic features to identify pituitary xanthogranulomas prior to surgery are elucidated, GTR may need to continue to be the surgical goal for cystic sellar/parasellar lesions. As the long-term prognosis of xanthogranulomatous pituitary lesions after surgical removal is yet to be evaluated, close clinical and radiologic follow-up is indicated [
2,
16,
18].