Ectopic invasive ACTH-secreting pituitary adenoma mimicking chordoma: a case report and literature review

Pituitary adenoma originates from anterior pituitary cells and is the most common tumor in the sellar region, accounting for about 10–15% of all intracranial tumors [1, 2]. Most pituitary adenomas located in the sellar turcica, and those occurring outside the sellar without direct connection to the normal pituitary tissues, are called ectopic pituitary adenomas (EPA). EPA is an extremely rare tumor with about 100 cases reported in the English literature [3‐6]. The majority of EPA cases are benign, but a few cases can be malignant or undergo a malignant transformation. In this report, we present a case of EPA of large size and obvious invasiveness, alongside a review of the literature on this rare tumor.

A 47-year-old female was admitted to our hospital with a ten-day history of hematuria. During admittance, the patient presented with bloody nasal discharge, dizziness and headache. Paranasal sinus CT and brain MRI scans were performed. The patient denied weight gain or loss during recent years. The cardiopulmonary and neurological examinations were normal. The antithyroglobulin antibody (TGAB) level was markedly increased to 1156 IU/ml (normal range, 0-115 IU/ml). All serum tumor markers were within the normal ranges. A non-contrast CT scan of the paranasal sinus revealed an ill-defined mass (mean CT value, 38 HU) in the sphenoid sinus and clivus, eroding the adjacent bone (Fig. 1A-B). The mass did not contain any necrosis, hemorrhage or calcification. Brain MRI showed a heterogeneous mass with hypointensity on T1-weighted images, hyperintensity on T2-weighted images and isointensity on diffusion-weighted images (Fig. 1C-E). The mass was 5.8 × 3.6 × 3.7 cm in size, extending both anteriorly into the sphenoid sinus and superiorly into the bilateral cavernous sinuses (Fig. 1F). The mass was located outside of the sellar turcica, without any continuity with the intrasellar pituitary gland (Fig. 1G-H). No obvious deviation of the pituitary stalk was observed. Chordoma was suspected. The patient underwent partial tumor resection via transsphenoidal endoscopy (Fig. 2A). During the operation, it was found that the mass was grey-white and closely related to the surrounding structure. The sphenoid sinus wall, sphenoid floor and clivus were destroyed to varying degrees, and the nasal mucosa was also invaded. The tumor was partially resected (Fig. 3). Postoperative histological analyses demonstrated tumor cells arranged in sheets and nests, with prominent delicate vascularized stroma, confirmed a pituitary adenoma (Fig. 2B). Immunohistochemistry was positive for synaptophysin (Syn), chromogranin A (CgA), neuronspecific enolase (NSE), and adrenocorticotropic hormone(ACTH). The proliferation index, expressed as a percentage of Ki-67 antigen-positive nuclei, was around 3% (Fig. 2C). Ectopic invasive pituitary adenoma (ACTH-secreting EPA) was confirmed. After the operation, the patient recovered well and symptoms such as headache and dizziness were relieved. The serum TGAB level was decreased to 937 IU/ml (normal range, 0-115 IU/ml). The serum cortisol and plasma ACTH were within the normal ranges. Two months after the operation, she received external beam radiation with a total dose of 50.4 Gy in 28 fractions over 28 days.

EPA occurs outside the sellar turcica, which is very rare clinically. Since it was first reported in 1909 [7], only approximately 100 such cases have been reported in the English literature [8, 9]. EPA can present both intracranially and extracranially. In most patients, EPA arises in sphenoid sinus and suprasellar regions with nonspecific symptoms [10]. EPA can also occur in other sites, such as the clivus, cavernous sinus, parasellar, nasal cavity, nasopharynx and the third ventricle [11, 12]. In the present case, a mass of 5.8 × 3.6 × 3.7 cm in size was found located in the sphenoid sinus and clivus. It destroyed bone, invaded muscle and encased blood vessels. The patient presented with bloody nasal discharge and headache. Several hypotheses regarding the origin and pathogenesis of EPA have been proposed, but the exact etiology is still controversial. It is broadly accepted that the tumor arises from the embryonic residues of pituitary cells along the path of migration of Rathke’s pouch [6, 13]. The ectopic anterior pituitary cells deposit in these sites and then undergo tumor transformation, resulting in the formation of EPA.

Similar to intraseller pituitary adenomas, EPA may also be classified as either functioning or nonfunctioning tumors. Functioning EPA is relatively easy to determine due to its hormonal symptoms. The endocrine disorder caused by EPA is directly related to its secreted hormone type, including Cushing’s syndrome, acromegaly, amenorrhea, lactation, decreased libido and hyperthyroidism. In previous reports [8, 14], the majority of EPA cases were functioning tumors. The patient in our case demonstrated ACTH immunoreactivity but with nonspecific symptoms. Although lack of full-workups of pituitary function, it is similar to a previous case report [15]. This type of tumor is usually incidentally discovered in routine imaging for other conditions. EPA may show aggressive behavior. Bone invasion [15], tumor seeding [16], and malignant transformations [17‐19] have also been reported in several case series. The mechanism of this aggressive behavior is unclear. Bone invasion or erosion is common and found in most reported malignant cases. In our case report, three features (destroying bone, invading muscle, encasing blood vessel) were consistent with the aggressive criteria.

Preoperative imaging examination plays an important role in the evaluation of EPA. The typical imaging phenotype of EPA can be deciphered from a comprehensive literature review of published reports. Compared to CT, MRI has higher soft tissue resolution and is the first choice for EPA. MRI can clearly show the location, size and extent of the tumor, as well as the relationship between tumor and normal pituitary tissue, which provides important guidance for preoperative localization, treatment management and prognosis evaluation. The MRI findings of EPA are not characteristic, therefore accurate preoperative diagnosis remains a challenge. In the tumor, small foci of hypointensity on T1-weighted images and hyperintensity on T2-weighted images are reported [20]. Histologically, these foci correspond to enlarged spaces filled with secreting granules. The enhancing solid components and non-enhancing secretion filled space are mixed to form a characteristic cribriform pattern, which may be a suggestive sign. When differential diagnosis is difficult, surgical intervention and biopsy should be considered.

Treatment of EPA is similar to intrasellar pituitary adenomas and is dependent on the patient’s clinical manifestation and tumor size, location and invasion. For cases with noticeable endocrine changes or severe local compression, surgical treatment should be considered but individualized according to the specific location of the lesion. Tumor occurrence or poor surgical candidates may be supplemented by radiotherapy and drug therapy [21, 22]. In our case, the patient underwent partial tumor resection. The follow-up MRI-scan revealed residual, viable tumor and the patient accepted stereotactic radiosurgery.

Because of the rarity of this disorder, accurate preoperative diagnosis for EPA remains challenging. The final diagnosis depends on the combined application of clinical symptoms, imaging phenotype, histology and immunohistochemical markers. Treatment management should be individualized. Our case report advances our understanding of the imaging phenotype of EPA on CT and MRI.