Introduction

Ectopic salivary gland (SG) tissue may occur in different sites of the body: extra-cranially (larynx, gastrointestinal tract, middle ear, chest wall) [1,2,3,4,5,6] and intra-cranially, with sellar and extra-sellar localizations (e.g.: optic nerve sheath, cerebellopontine angle) [7,8,9]. Intrasellar ectopic SG rests are typically localized close to the neurohypophysis or in the pars intermedia, often communicating with the Rathke’s cleft [7], and maybe incidentally found at autopsy [10, 11]. Only a small minority come to clinical attention because of mass effects and/or endocrine dysfunction, in particular hyperprolactinemia [8, 12,13,14,15,16,17,18,19,20]. Symptomatic enlargement of ectopic SG rests may be non-neoplastic (NNESG) or due to benign or malignant salivary tumours (ST) that mimic other non-functioning lesions, and the diagnosis relies on pathology where surgery is indicated. In addition, because malignant ST derived from major or minor eutopic SG may reach the sella through local invasion or blood spread [21,22,23], an extra-sellar origin should be excluded before concluding to a primary ectopic SG malignancy [24]. Sellar salivary neoplasms represent an unusual challenge for specialists involved in the management of pituitary neuroendocrine tumours (Pit-NETs) [25] and other sellar/parasellar lesions.

A recent puzzling observation (illustrated in Fig. 1) prompted us to perform the first systematic review of the literature about sellar NNESG and ST, pointing out an additional diagnostic pitfall, i.e. an inflammatory submucosal SG mimicking a prolactinoma during transsphenoidal surgery (TS). Individual cases were classified into four groups: ectopic NNESG, benign and malignant ectopic ST (eST) and secondary localizations of eutopic ST. Clinical, neuroradiological, pathological characteristics, and therapeutic outcome were analysed. This review points out the importance of a multidisciplinary work-up to reach a correct diagnosis and optimize clinical management.

Fig. 1
figure 1

A puzzling case of sellar salivary gland (SG). A 19-year-old woman was referred in February 2019 because of a prolactinoma showing increasing pharmacological resistance. The diagnosis was made 3 years earlier in the setting of primary amenorrhea–galactorrhea and intermittent headache, plasma PRL 1763 ng/ml (N < 26.7) and a macroadenoma with a fluid hemorrhagic component at Magnetic Resonance Imaging (MRI) (A1, A2 coronal and sagittal T2-weighted). Menarche occurred within 5 months of treatment, with regular menses but an increasing and poorly tolerated drug requirement to obtain a sub-optimal control of hyperprolactinemia (CAB up to 3.5 mg/week). As MRI showed clear evidence of residual disease (B1, B2 pre-and post-Gadolinium coronal views), endoscopic TS was proposed. A small nodular lesion, consistent with a microadenoma, was removed. Unexpectedly, pathological examination revealed numerous groups of glandular berries composed of typical serous and mucinous cells, compatible with SG tissue, separated by a chronic inflammatory lymphoplasmacellular infiltrate (C1 hematoxylin–eosin). Immunostaining for lysozyme was positive in mucinous cells (C2). Bony spicules and flaps of respiratory mucosae were also present, with no evidence of pituitary cells. Immunostaining for PRL was negative (not shown). The first pathological diagnosis was NNESG. However, post-operative CAB withdrawal was followed by a progressive recurrence of symptomatic hyperprolactinemia (up to 245 ng/ml 4 months after surgery), with MRI evidence of residual/recurring disease. Careful revision of serial pre-operative imaging revealed in a single MRI study (2017) a small intrasphenoidal nodular lesion localized just beneath the adenomatous lesion, with spontaneous hypointensity in T2 (D1 coronal view) and hyperintensity in T1 before and after gadolinium (D2 sagittal view). This finding was consistent with a cystic SG, undergoing subsequent inflammation and shrinkage. The final diagnosis was a sub-mucosal SG, mimicking and masking the residual microprolactinoma during TS. As CAB was re-started up to the maximal well-tolerated dose (2.0 mg weekly) with an incomplete response (PRL 45 ng/ml), TS will be potentially re-considered if necessary.

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Methods

A systematic review of case reports and case series was performed according to the Cochrane Collaboration and PRISMA statements [26, 27]. A literature search without limits was conducted on Medline and Scopus up to September 2020, including international and non-English literature, using the following keywords: ectopic salivary gland/ salivary gland/salivary gland tumour AND pituitary/sella/sphenoidal/sphenoid sinus. Cross-references were used to identify additional papers, allowing to retrieve six additional cases. Titles and abstracts of all papers were screened to assess their relevance. Duplicates, reviews, animal studies, in vitro studies and congress reports were excluded. Based on available abstracts and full texts, all the papers describing NNESG and benign or malignant sellar ST were analyzed. The following data were extracted for each paper: (1) first author, year of publication; (2) case demographics (gender, age), (3) symptoms, (4) endocrine abnormalities, in particular, PRL values, (5) neuro-radiological findings at MRI and/or computed tomography (CT): localization, size, invasion, signal intensity/density, contrast enhancement, (6) pre-operative and final pathological diagnosis, (7) treatment and, (8) where available, status at last follow-up (recurrence, progression, hormone replacement therapy, death).

Results

Overall, 1024 potentially relevant studies were found, 978 were excluded at first screening and 46 were selected for full-text assessment (Fig. 2). Thirty-five papers were finally retained (1963–2020): 32 in English language, 1 in French, and 2 papers in Japanese or Korean with detailed English abstracts and figures footnotes. Overall, 44 individual cases of symptomatic sellar NNESG and ST were described, including 14 secondary sellar localizations of primary eutopic ST. Because PitNETs were originally reported as pituitary adenomas (PA) in all papers, we elected to maintain this terminology to report the pre-operative diagnosis.

Fig. 2
figure 2

Flowchart of the literature eligibility assessment process

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NNESG

Fifteen cases of NNESG were found (Table 1) [8, 12,13,14,15,16,17,18,19,20, 28]. Most patients were younger than 30 years (11/15, 73.3%), including a pediatric case. Most were females (12/15, 80%). The most frequent complaints were headache (12/15, 80%), visual symptoms—bitemporal hemianopsia, blurred vision, decreased visual acuity—(4/15, 26.6%), nausea (4/15, 26.6%), galactorrhea and menstrual irregularities (3/15, 20%). Endocrine dysfunction was frequent (8/15, 53.3%), including mild hyperprolactinemia (23.9–93.0 ng/ml, median 83.5) (3/15, 20%), growth hormone deficiency (2/15, 13.3%), panhypopituitarism (2/15, 13.3%) and/or central hypothyroidism (1/15, 6.7%). Pre-operative diabetes insipidus (DI) was present in 3/15 cases (20%). NNESG were variable in size (maximal dimension 0.6–4.6 cm, median 1.7). Intrasellar lesions were typically localized in the posterior pituitary (6/15, 40%), suprasellar extension was frequent (8/15, 53.3%), but hydrocephalus was rare (1/15, 6.7%) [28]. Lateral extension was uncommon (2/15, 13.3%), with cavernous sinus infiltration in the largest case [16]. Based on the neuroradiological description and/or pre-operative diagnosis, they presented as pseudo-tumorous solid lesions, with frequent cystic component(s) (7/15, 46.7%). At MRI, most lesions appeared as hyper- or iso-intense on T1 weighted imaging (T1) (7/15, 46.7% and 4/15 26.6%, respectively) but either hyper- or hypo-intense on T2 weighted imaging (T2) (4/15, 26.6% and 4/15, 26.6%, respectively), with inconstant contrast enhancement (4/15, 26.6%). Spontaneous hyperdensity was found at CT where available (n = 4). Pre-operative diagnosis was: PA (8/15, 53.3%), Rathke’s cleft cyst (RCC) (5/15, 30%), craniopharyngioma (2/15, 13.3%), exceptionally chordoma (the largest one) [16]. Two patients received bromocriptine but the lesion was unchanged despite PRL normalization [12, 20]. All patients were operated on, 80% through a TS route (12/15). Follow-up was limited (1–4 years, median 1 year, n = 10), but no recurrence or progression was reported, except a cystic relapse after 2 years, without pathological evidence of SG tissue [28]. At pathological examination, SG rests or cysts were found within or close to the posterior pituitary lobe, in 7 cases within the wall of a RCC (46.7%). NNESG were composed of acini with a low columnar or cuboidal epithelium, embedded in a fibrovascular stroma, without cellular atypia, with occasional inflammation (2/15, 13.3%). Anti-PGP immunoreactive nerve fibers were reported in one case, suggesting parasympathetic innervation [18]. Adjacent anterior pituitary cells were observed in a minority of cases (20%).

Table 1 Non-neoplastic enlarged ectopic sellar salivary glands (NNESG) reported in the literature
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Sellar ST

The individual characteristics of sellar ST according to their pathological classification are shown in Table 2.

Table 2 Sellar/parasellar salivary tumours (ST) reported in literature
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Primary benign ectopic ST

Seven cases of benign sellar eST have been reported [7, 29,30,31,32], with a majority of pleomorphic adenomas (4/7, 57.1%) and single reports of monomorphic adenoma, oncocytoma and adenomyoepithelioma. They manifested at any age in both genders (4M, 3F, 17–81 years-old, median 44), with visual symptoms in all cases and inconstant headache (2/7, 28.6%). General symptoms—such as muscle weakness, fatigue, weight loss, anorexia, nausea and/or vomiting—were also present in all patients, and endocrine dysfunction reported as hypopituitarism (4/7, 57.1%), hyperprolactinemia (2/7, 28.6%) and/or DI (3/7, 42.8%). Accordingly, benign eST were large (2.5–4.0 cm, median 3.0), with a suprasellar extension in all cases—up to the optic chiasm (5/7, 71.4%) or the hypothalamus (2/7, 28.6%). MRI signal was not reported, but contrast enhancement was frequent (3/7, 42.8%) and calcifications or pseudo-hemorrhage could be found at CT. The most frequent pre-operative diagnosis was PA (n = 5), but craniopharyngioma, chordoma and benign teratoma were also considered. All patients were operated on—TS (4/7, 57.1%) or transcranially (TC) (3/7, 42.8%). Based on a variable follow-up duration (0.4–14 years, median 2.5, n = 6) recurrences were rarely reported after complete surgical removal, but occurred 4 and 14 years after partial removal [29,30,31]. Four patients received radiotherapy [29,30,31]. Noteworthy, the first pathological diagnosis was inaccurate in 3 cases (benign teratoma, chordoma, craniopharyngioma) [30,31,32].

Primary malignant ectopic ST

Primary malignant eST were reported in 8 cases [24, 29, 33,34,35,36,37] and consisted of adenoid cystic carcinoma (2/8, 25%), myoepithelioma (2/8, 25%), epithelial–myoepithelial carcinoma (1/8, 12.5%), papillary mucinous adenocarcinoma (1/8, 12.5%), low-grade acinic cell carcinoma (1/8, 12.5%) and adenocarcinoma (1/8, 12.5%). All patients were adult (3M, 5F, 34–68 years, median 51.5) and had visual symptoms, with frequent oculomotor nerve palsy/diplopia (5/8, 62.5%). Endocrine dysfunction was reported as hypopituitarism (4/8, 50%)—including one case of acute adrenal insufficiency, hyperprolactinemia (3/8, 37.5%) and DI (2/8, 25%). Accordingly, tumours were large (2.0–3.8 cm, median 2.5), growing up to the optic chiasm (4/8, 50%) or the floor of the 3° ventricle (3/8, 37.5%). An invasive growth was reported in some cases, eroding inferiorly into the sphenoid and ethmoid sinuses (1/8, 12.5%) or extending in the cavernous sinus (2/8, 25%)—in one case reaching the middle fossa [34]. Contrast enhancement was inconstantly reported (4/8, 50%) and, according to limited detailed MRI (n = 2), the tumour was isointense on T1 and slightly hyper- or hypointense on T2 [34, 36]. Pre-operative diagnosis was PA (n = 3) [29, 34, 37], craniopharyngioma (n = 2) [35, 36], but also inflammatory granulomatosis/hypophysitis, metastatic brain tumour and primary tumour of the cavernous sinus [34]. All patients were operated on—half of them through a TC approach—and subsequently irradiated (20–54 Gy). Two patients also received chemotherapy (isofosfamide/BCNU or temozolomide) for an epithelial–myoepithelial carcinoma and an aggressive myoepithelioma, respectively [24, 35], with a poor response. Except for one case of papillary mucinous carcinoma [33], all patients showed disease progression within 4 years (4/8, 50%) or died (6/8, 75%, 3 post-operative deaths). In one case, neuropathological misdiagnosis of PA was reported [29].

Secondary malignant sellar ST

Secondary ST were reported in 14 patients, deriving in most cases from minor salivary glands situated in the sphenoid sinus (n = 6), nasopharynx (n = 2), palate (n = 1) and paranasal sinus (n = 1)—but also from the parotid gland (4/14, 28.6%) [21,22,23, 29, 38,39,40,41,42,43,44,45,46]. A majority were adenoid cystic carcinoma (ACC) (11/14, 78.6%), with single reports of ductal adenocarcinoma, mixed salivary tumour, and a monomorphic multi-recurrent parotid adenoma extending to the sella. Most primary ST reached the sella through the sphenoid sinus (9/14, 64.3%) or dural infiltration (1/14, 7.1%), but metastatic blood spread could occur (4/14, 28.6%). In 4 cases sellar involvement was delayed (5–26 years after the primary tumour) [22, 23, 40, 45]. Adults were affected at any age (6M, 8F, 28–85 years, median 45). Most patients had visual defects (10/14, 71.4%), cranial nerve palsy (7/14, 50%) with frequent diplopia (6/14, 42.8%) and/or trigeminal sensory symptoms (3/14, 21.4%). Endocrine dysfunction (hypopituitarism, hyperprolactinemia, DI, syndrome of inappropriate antidiuretic hormone secretion—SIADH) was documented in a minority of cases (5/14, 35%) despite suggestive symptoms in additional cases. Tumours were large, frequently invasive with skull base erosion (6/14, 42.8%) or cavernous sinus infiltration (5/14, 35.7%)., and inconstant suprasellar invasion (5/14, 35.7%). Pre-operative diagnosis was PA (n = 3) [22, 29, 43]—with an apoplectic presentation in one case [40]—but also craniopharyngioma, meningioma, neurinoma and metastasis [40, 45]. Surgery was proposed in all but one patient, who received first-line radiotherapy for tumour inoperability [21]. One patient who initially declined surgery was operated on 5 years after radiotherapy but the tumour had reached a considerable volume with extensive bone destruction and multiple cranial nerve palsy [43]. Patients underwent TS/endoscopic (n = 7), TC (n = 4) or undetermined (n = 2) surgery, and frequent post-operative radiotherapy (n = 8). Follow-up was available in 8 cases, 6 patients died within 4 years, in one case from early post-operative meningitis [43].

Discussion

This is the first systematic review on salivary diseases and neoplasia localized to the sellar region. The puzzling case of an apparently intrasellar NNESG removed during TS surgery prompted us to further analyse these conditions, which are not mentioned in exhaustive reviews on sellar/parasellar lesions [47, 48] or single-center experiences reporting rare sellar-suprasellar masses [47, 49, 50]. Indeed, nearly half of the reports were published in the last decade (17/35 papers), in particular those concerning NNESG (7/11 papers, 11/15 cases) and benign primary eST (4/5 papers, 4/7 cases). Strikingly, pre-operative neuroimaging was inconclusive or misleading in all cases. The heterogeneity of radiological descriptions, in part reflecting a variety of pathological histotypes [51], confirms the lack of strongly suggestive features, although cystic components of variable protein content were frequent in NNESG. Where present, DI or rapidly evolving symptoms may help to distinguish such conditions from non-secreting Pit-NETs, but usually suggest alternative diagnosis (craniopharyngiomas, hypophysitis or metastasis). Thus, similar to other rare lesions coming up as pathological surprises [52], they are extremely difficult to consider at the time of pre-operative evaluation. Of note, the pathological diagnosis may also be inaccurate at first observation.

Salivary rests in the pituitary are relatively common incidental findings at autopsy (3.4–8.8%) [10, 11]. This may be explained by pre-existing seromucous glands from the primitive oral cavity remaining in the Rathke’s pouch during migration and persisting during postnatal life [17], similar to ectopic pituitary tissue reported at various locations along its migratory path, including the roof of the nasopharynx [53]. Experimental studies also suggest that Rathke’s pouch components may occasionally differentiate into salivary and adenohypophyseal tissues during organogenesis [54] and that parotid gland tissue may trans-differentiate into pituitary hormone-producing cells under the influence of hypothalamic factors [55]. Embryological development would thus explain why NNESG are found close to the posterior pituitary lobe and sometimes within RCC’s wall [16,17,18]. In this latter case, the role of salivary remnants in the development of clinical symptoms is not always clear-cut, and some may be incidental findings in the setting of a symptomatic RCC rather than true NNESG [17]. Similarly, we recently observed incidental salivary rests adjacent to an apoplectic gonadotroph PitNET (Suppl Fig. 1), although in our experience this is extremely rare. Alternatively, active secretion from ectopic salivary rests within the cyst was proposed to contribute to RCC enlargement, possibly triggered by parasympathic innervation [18].

The mechanisms leading to NNESG are not fully elucidated but the development of mucinous cysts [14, 18, 19] and/or chronic inflammation [12, 19] are frequently observed. In normal conditions, the lack of neuro-vegetative innervation of the posterior pituitary may prevent the secretion of mucinous material, or local lymphatic/venous reabsorption may remove secretions [20]. Symptomatic NNESG may grow up into the opto-chiasmatic cistern, but exceptionally reach considerable dimensions or appear invasive [16]. Because they more frequently affect young (73.3%) and/or female patients (80%), who present with headache and symptomatic hyperprolactinemia [12,13,14,15,16,17,18,19,20], NNESG may represent a rare differential diagnosis of cystic sellar lesions in such patients. Hyperprolactinemia likely results from functional disruption of the physiological dopaminergic inhibition, although direct stimulation by EGF, which is abundantly produced by SG, may be hypothesized [56, 57]. This explains why hyperprolactinemia is moderate and promptly normalized by dopamine-agonists in the absence of tumour shrinkage [12, 20]. Less frequently, pre-operative DI or hypopituitarism are present—including growth retardation [15]—and require appropriate hormone replacement therapy. In our patient, the lateral localization of the lesion associated with post-operative recurrence of hyperprolactinemia lead us to reconsider our first diagnosis of intrasellar NNESG with surgical aspiration of prolactinoma cells escaping pathological examination. Furthermore, we found no previous observation of NNESG coexisting with a PitNET. Based on careful revision of serial pre-operative MRI, transient evidence of an intrasphenoidal cyst was noticed, placed on the TS route to the prolactinoma. As only pathological minor salivary glands are seen by radiological imaging [58, 59], we finally concluded for residual inflammation in a submucosal SG following spontaneous reabsorption of the cyst. This pitfall should therefore be considered in the presence of SG acini contaminating surgical fragments obtained by TS, as it may open the possibility of a second TS approach. Once made a definitive diagnosis of NNESG, recurrences have been exceptionally reported [28]. In such cases, a neoplastic origin may not be totally ruled out [28].

ST involving the sellar region have been reported more frequently than NNESG. Patients were adults of any age, mass effects were almost invariably present and amenorrhea–galactorrhea or hyperprolactinemia were occasionally reported. Malignant forms were characterized by a mild female predominance and a major frequency of ocular palsy and symptoms suggestive of hypopituitarism or DI. Similar to primary eutopic ST, they include a variety of histotypes [51, 58], and a minority of eST were found in association with or close to a RCC [7, 33].

Primary benign sellar eST were mostly represented by pleomorphic adenomas. Where specified, they presented as medium/large-sized heterogeneous sellar/suprasellar masses, sometimes with intratumoural hemorrhage or calcifications, potentially mimicking PA, craniopharyngioma, teratoma or chordoma. Hypopituitarism and DI were frequently documented in this group. Post-operative radiotherapy was often proposed due to the risk of recurrence after incomplete surgical removal, although but delayed regrowth could occur [31]. Long-term follow-up is therefore recommended.

Malignant ST usually presented as large, heterogeneous, typically invasive sellar/parasellar masses, and rapid progression could suggest pituitary metastasis or other malignancies. They included a variety of histotypes. Adenoid cystic carcinomas (ACC) accounted for nearly 80% of secondary forms versus 25% of primary malignant eST. With a few exceptions, both were diagnosed earlier (4th–5th decade) than common eutopic ACC (5th–7th decade), which are usually slowly growing [51]. This suggests that sellar ACC may have a different natural history. However, further information is needed to compare the prognosis of sellar ST with similar eutopic histotypes. Radical surgical resection followed by radiotherapy was the treatment of choice in most cases, although first-line (chemo-)radiotherapy was also proposed [33, 46]. Incomplete surgical removal favored tumour progression and/or metastatic spread, with a poor response to radiotherapy and chemotherapy [36]. Of note, one patient died 8 days after surgery for unexplained hypotension [33]. As pituitary function was poorly evaluated in these patients, hypopituitarism could be left untreated.

Conclusion

Sellar/parasellar lesions derived from SG tissues are rare but challenging conditions. An appropriate pathological characterization is essential for a correct multidisciplinary approach, which should consider and treat their frequent endocrine complications. Where required, hormone replacement therapy is essential to improve patient’s quality of life and prevent the risk of acute adrenal insufficiency. In addition to surveillance for the early recognition of ST recurrences or metastasis, life-long endocrinological follow-up is necessary for the presence of permanent dysfunction or after radiotherapy, which may induce delayed hypopituitarism. Multicenter collection and long-term follow-up would be useful to better define disease evolution and optimal clinical management of these unusual conditions.