Ectopic pituitary neuroendocrine tumors (PitNETs), also referred to as ectopic pituitary adenomas, are exceedingly rare neoplasms that develop outside the typical sellar region of the pituitary gland [1]. These tumors have been reported in various locations, including the sphenoid sinus, suprasellar region, clivus, cavernous sinus, periorbital area, and nasal sinuses [234]. Due to their atypical locations, ectopic PitNETs often present significant diagnostic challenges, frequently leading to misinterpretation as other intracranial neoplasms such as gliomas, meningiomas, chordomas, or other neuroendocrine tumors [4].

Misdiagnosis of intracranial tumors can result in delayed or inappropriate treatment, highlighting the critical importance of a comprehensive and systematic diagnostic approach, especially in cases with atypical presentations. In this case report, we describe an interesting case of a patient with an ectopic PitNET that was initially misdiagnosed as pineal parenchymal tumor based on findings from an endoscopic biopsy.

A 39-year-old male patient presented to neurosurgical outpatient department with a persistent headache that had been ongoing for 2 months. A CT scan revealed a 5 cm-sized heterogeneous mass in the suprasellar area, causing obstructive hydrocephalus (Fig. 1A). MRI further characterized the mass as a heterogeneously contrast-enhancing lesion extending superiorly into the third ventricle and compressing the midbrain posteriorly (Fig. 1B and C).

In addition to the large mass in the suprasellar area, MRI identified a small, nodular, contrast-enhancing mass in the pineal region which raised further diagnostic considerations (Fig. 1C). This finding suggested the possibility of a germ cell tumor, given the typical presentation of bifocal masses. The serum hormonal study, alfa-fetoprotein, and beta-human chorionic gonadotropin were within normal limits. To obtain a histopathologic diagnosis and guide surgical decision-making, a trans-ventricular endoscopic biopsy was performed (Fig. 1D).

The histopathologic diagnosis from the initial biopsy was consistent with a pineal parenchymal tumor of intermediate differentiation (PPTID) (Fig. 2). This was determined based on a mass in the pineal region with normal pituitary gland in MRI and immunohistopathologic findings, which included diffuse, uniform round cell proliferation with a vague pineocytomatous-like rosettes appearance. In PPTID, well-formed pineocytomatous rosettes are often absent. In addition, the tumor also showed diffuse positivity for synaptophysin and chromogranin, and was negative for pan-cytokeratin. These findings are more compatible with PPTID than with a metastatic neuroendocrine tumor, which generally showed a positive reaction to pan-cytokeratin. Given the aggressive nature of the tumor and its significant mass effect, surgical removal was considered necessary. A trans-sylvian approach, following an orbito-pterional craniotomy, was performed to access and resect the tumor. The suprasellar mass was nearly completely removed, while the enhancing nodule in the pineal region was left intact (Fig. 3).

However, immunohistopathological evaluation following surgical resection revealed the final diagnosis to be an ectopic PitNET, based on diffuse, uniform proliferation of round or oligo-like cells and additional diffuse positivity for SF1, CAM5.2, and GATA3 and was negative for PIT-1, T-PIT, and pituitary hormones, underscoring the diagnostic complexity of this case (Fig. 4). The list of primary antibodies used is shown in Table 1.

Ectopic PitNETs are pituitary adenomas that develop outside the sella turcica, without any anatomical connection to intrasellar tissues [1]. Due to the extreme rarity of this pathology, the diagnostic criteria, treatment protocol, and prognostic factors are not well established. Among the reported locations of ectopic PitNETs, sphenoid sinus (34.4%) and suprasellar region (25.6%) are the most common [14]. Rare cases have also been described in other locations such as cavernous sinus, nasopharynx, clivus, and interpeduncular cistern [1567].

The pathogenesis of ectopic PitNETs remains unclear. The most widely accepted hypothesis, from an embryological perspective, suggests that these tumors arise from remnants of embryonic cells during the migration of Rathke’s pouch from the craniopharyngeal canal to the sphenoid sinus, where it eventually fuses with the neurohypophysis [14]. However, this hypothesis is controversial, as ectopic PitNETs have also been reported in locations beyond the expected developmental tract, such as the petrosal temporal bone, superior orbital fissure, and temporal lobe.

Over 70% of reported ectopic PitNETs are hormone-secreting, functioning tumors. Among these, adrenocorticotropic hormone (ACTH)-secreting adenomas are the most common type of ectopic PitNET, in contrast to typical PitNETs, where prolactinomas account for approximately 60%, followed by non-functioning and growth hormone-secreting tumors [18]. The relatively lower proportion of prolactinomas in reported cases of ectopic PitNETs may be attributed to their diagnosis primarily through surgical resection and final pathological examination [1]. The underlying pathophysiology behind the high prevalence of ACTH-secreting ectopic PitNETs remains unknown. Further studies are needed to elucidate the mechanisms contributing to this phenomenon and to better understand the distinct behavior of ectopic PitNETs compared to their typical counterparts.

Ectopic PitNETs typically present as isodense masses on CT scans and may occasionally show adjacent bone remodeling or, rarely, calcification. MRI scans typically demonstrate isointense signals on T1- and T2-weighted images, with a characteristic pattern of heterogeneous enhancement and slow washout [6].

Histopathological studies of ectopic PitNETs reveal findings similar to those of intrasellar pituitary adenomas, including the expression of neuroendocrine markers such as synaptophysin, CD56, neuron-specific enolase (NSE), and chromogranin [9]. However, these neuroendocrine markers are not unique to PitNETs and can also be observed in other pathologies, including neuroendocrine carcinoma or tumors originating from the pineal gland. Furthermore, some sinonasal tract pathologies, such as adenocarcinomas, sinonasal undifferentiated carcinoma, and melanomas, may also express these markers [9]. For differential diagnosis, PitNETs may show positive staining results of epithelial markers such as CAM5.2, transcription factors such as Pit-1, T-pit, and SF1, and pituitary hormones (prolactin, GH, ACTH, FSH, LH, and TSH). A high Ki-67 proliferation index and increased mitotic activity may guide pathologists toward considering diagnoses other than adenoma [10].

Most ectopic PitNETs are diagnosed following surgical resection and pathological evaluation, given the rarity of the condition and the challenges in confirming the diagnosis solely through imaging studies. As a result, treatment protocols for ectopic PitNETs remain limited and are largely guided by individual case reports. The treatment approach should be tailored based on serum hormonal studies, tumor location, extent of the tumor, and clinical manifestations. Early decompression is particularly crucial for patients presenting with mass effect or cranial nerve symptoms [5111213].

Hosaka et al. [3] reported an extremely rare case of malignant transformation in a recurring FSH-secreting ectopic PitNET located in the nasal cavity, which disseminated into the subarachnoid space and resulted in multiple brain metastases. Markers of tumor proliferation, such as proliferating cell nuclear antigen (PCNA), MIB-1, and p53 protein are important indicators of the malignant potential of ectopic PitNETs and should be carefully evaluated during pathological analysis [3].

Our case exemplifies the diagnostic challenges in differentiating ectopic PitNET from other diseases. The patient initially presented with a suprasellar and pineal bifocal mass, leading to an initial working diagnosis of a germ cell tumor (GCT). Endoscopic biopsy provided a preliminary histologic diagnosis of PPTID, attributed to the midline location adjacent to the pineal gland, positive staining for neuroendocrine markers, and, critically, the presence of vague but pineocytoma-like rosettes. Multiple pineocytomatous rosettes are hallmark findings of pineal parenchymal tumors, with differentiation between pineocytoma, pineoblastoma, and PPTID based on cellularity [14]. CAM5.2, which is expressed only in PitNET, was not assessed during the first endoscopic biopsy due to the normal appearance of the pituitary gland on MRI images. While it is unusual for PPTID to manifest in the suprasellar area, there are reports of PPTID with metastatic spread, which further reinforced the initial interpretation [1516]. The vague rosette-like structures and the absence of secretory hormones in the initial pathological examination are likely attributable to insufficient or damaged tissue obtained during the endoscopic biopsy, ultimately leading to the initial misdiagnosis. However, following surgical resection, the final histopathological evaluation confirmed the diagnosis as a suprasellar ectopic PitNET, based on diffuse, uniform round, oligo-like cell proliferation and the immunoexpression result showing the diffuse positivity of SF1, CAM5.2, and GATA3, indicating PitNET.

The enhancing nodule in the pineal gland, however, was not surgically removed, leaving its nature uncertain. It remains unclear whether this nodule represents regional metastasis from the same tumor, a different disease entity, or a nonspecific finding. Continued follow-up and monitoring will be essential to determine the significance of this lesion and its potential progression.

We report a rare case that highlights the challenges in differentiating ectopic PitNET from other intracranial tumors. The difficulty stems from its extrasellar location, overlapping clinical presentation, and similar immunohistopathological findings with other neuroendocrine and intracranial tumors. Accurate diagnosis requires a multidisciplinary approach that integrates clinical, imaging, and pathological findings, particularly in rare cases with atypical presentations.