Keywords
ectopic pituitary adenoma - pituitary adenomas - inactive ectopic pituitary adenoma
- cavernous sinus meningioma
Introduction
Ectopic pituitary adenomas (EPAs) are rare tumors typically found in the sphenoid
sinus or nasopharynx.[1] They are likely to arise from residual pituitary fragments within the craniopharyngeal
duct and share similarities with typical pituitary adenomas in morphology, immunohistochemistry,
and hormonal activity.[2]
[3] Identifying these tumors presents significant challenges, especially when they are
located at the skull base, often leading to diagnostic ambiguities. Computed tomography
(CT) scans and magnetic resonance imaging (MRI) are crucial for their detection.[4]
When diagnosing an EPA, differential diagnoses include schwannomas (especially oculomotor
or trigeminal nerve types) in the cavernous sinus or parasellar region; meningioma
(cavernous sinus meningioma), a common extra-axial tumor in the parasellar region;
chordoma, a rare bone tumor extending into the sphenoid or cavernous sinus; craniopharyngioma,
a nonpituitary tumor in the sellar or parasellar region; pituitary hyperplasia, involving
diffuse enlargement of the pituitary gland; metastatic tumors that may affect the
cavernous or sphenoid sinus; lymphoma (primary or secondary) in the cranial or sinonasal
region; and primary neuroendocrine tumors in the sinonasal tract or skull base.[1]
[2]
[3]
Establishing a diagnosis requires tumor resection and a thorough pathological examination,
including immunohistochemical studies targeting neuroendocrine markers.[1]
[4] This report presents a unique case of an ectopic, nonfunctioning pituitary adenoma
located in the right cavernous sinus, extending into the base of the skull and sphenoid
sinus, and causing intermittent headaches in a young female school teacher.[5]
Case Report
A 37-year-old woman presented to the emergency department with persistent and worsening
headaches that were not responding to oral analgesics. Despite normal vital signs
and neurological exams during prior outpatient visits, her ongoing symptoms necessitated
neuroimaging. MRI revealed a large extra-axial solid mass in the right parasellar
region, extending into the right cavernous sinus, the base of the skull, and the sphenoid
sinus, resembling a cavernous sinus meningioma ([Fig. 1A–C]). She had no visual complaints, raised intracranial pressure, or other neurological
deficits. Preliminary laboratory tests, including pituitary hormone levels, were normal.
Digital subtraction angiography showed increased vascularity but made embolization
unfeasible due to difficulties in catheterizing the thin vessels ([Fig. 2A, B]). Guided by our senior author, a right temporal craniotomy was performed with the
goal of gross total tumor resection. After achieving a subtotal excision (> 70%),
unexpected bleeding from the slender vessels complicated the procedure. Intraoperatively,
the tumor was dark pink, highly vascular, and observed in the arachnoid, exerting
slight pressure on the optic nerve and abutting the 4th segment of the middle cerebral
artery, with no bony erosions. Options for addressing the residual tumor included
redo surgery or adjuvant stereotactic radiosurgery.
Fig. 1 (A–F) Preoperative (A: axial image, B: coronal image, C: sagittal image) and postoperative (D: axial image, E: coronal image, F: sagittal image). Magnetic resonance imaging (MRI) scans of the brain, allowing for
comparison at similar levels. The preoperative transverse (axial) T1-weighted MRI
scan of the brain showed a highly enhancing mass (5.4 × 4.5 × 4.5 cm) in the right
parasellar region, indicative of aggressive tumor pathology, likely a cavernous sinus
meningioma (A–C: red arrows). It extended into the right cavernous sinus, base of the skull, and
sphenoid sinus, exerting pressure on adjacent structures. Compression and displacement
of the left lateral ventricle were evident, with adjacent sulci showing signs of increased
mass effect (A, B). Three and a half months after surgery, the postoperative MRI scan revealed a resection
cavity surrounded by enhancement and gliosis, consistent with typical postsurgical
findings (D–F: blue arrow). The sulci were more defined, and correction of the midline shift was
observed, indicating successful lesion removal for symptomatic relief (D–F: blue arrow).
Fig. 2 (A, B) Preoperative findings from digital subtraction angiogram of the brain. A digital
subtraction angiogram of the brain revealed a tumor blush (blue dotted box) from the
right choroidal vessels. The right middle cerebral artery (MCA) Sylvian branches were
shifted superolaterally, and the right carotid siphon was open. The remainder of the
anterior and posterior circulation appeared normal in course, caliber, and branching
pattern, with normal capillary and venous patterns.
The frozen section suggested some intra-axial features, but the exact etiology remained
unclear. Postoperatively, the patient had an uneventful recovery and was discharged
on the 10th day in stable hemodynamic and neurological condition. Immunohistochemical
examination showed diffuse positivity for synaptophysin and CD99, focal positivity
for GATA binding protein 3 (GATA3), and positive pituitary-specific positive transcription
factor 1, consistent with a pituitary adenoma ([Fig. 3A, B]). Adjuvant stereotactic radiosurgery was performed for the residual lesion. Follow-up
visits approximately every 3 months over the past year have shown that she is symptom-free
with no new neurological complaints ([Fig. 1D–F] and [Fig. 4]).
Fig. 3 Immunohistochemical slides (A), hematoxylin and eosin (H&E) stain, 100 × , and (B) immunoperoxidase stain, 200 × . Photomicrographs (A) show nests and trabeculae of
monomorphic tumor cells with eosinophilic granular cytoplasm and uniform round nuclei
(H&E stain, 100 × ). (B) Highlights diffuse strong synaptophysin positivity (immunoperoxidase stain, 200 × ),
and CD99, focal positivity for GATA binding protein 3 (GATA3), and positive pituitary-specific
positive transcription factor 1 (PIT1) consistent with a pituitary adenoma. The MIB-1
(Mindbomb homolog 1) labeling index indicated low proliferation (1–2% in the most
proliferative areas), and tumor cells were positive for PIT1 but negative for TPIT
(T-box pituitary transcription factor) and tyrosine hydroxylase. Additionally, tumor
cells were negative for markers such as AE1/AE3 (cytokeratin antibodies), NeuN (neuronal
nuclei), vimentin, GFAP (glial fibrillary acidic protein), Olig2 (oligodendrocyte
transcription factor 2), EMA (epithelial membrane antigen), S100 (S100 proteins),
STAT6 (signal transducer and activator of transcription 6), cytokeratin, LCA (leukocyte
common antigen), CD68 (cluster of differentiation 68), CD138 (syndecan-1), and IDH1R132H
(isocitrate dehydrogenase 1 R132H mutation).
Fig. 4 A Memphis Design timeline graph illustrating the stages of treatment and overall
impact. MRI, Magnetic Resonance Imaging.
Discussion
EPAs are rare tumors located outside the sellar region, with approximately 1,000 cases
reported since their first description in 1909.[1]
[3]
[6]
[7]
[8] Typically benign, EPAs lack a direct connection to normal pituitary tissue but can
occasionally be malignant. They frequently occur in the sphenoid sinus or suprasellar
regions and often present with nonspecific symptoms.[1]
[2]
[3]
[9] Although prolactinomas account for approximately 60% of pituitary adenomas, adrenocorticotropic
hormone (ACTH)-secreting adenomas are less common but are more frequent in EPAs.[1]
[7]
[8] EPAs are believed to arise from embryonic pituitary cell remnants that migrate along
the path of Rathke's pouch.[1]
[2]
[8] The exact pathogenesis of EPAs remains unclear, with speculation that these remnants
may have migrated to the sphenoid sinus and undergone neoplastic changes.
Diagnosis can be challenging due to the varied ways EPAs present. Isolated sphenoid
sinus lesions can mimic EPAs, often presenting with symptoms such as headache and
nasal obstruction.[3]
[9] Hormone-inactive EPAs, like the one observed in our case, may present with headaches,
sinus fullness, nasal congestion, and cranial nerve paralysis. These tumors are often
detected incidentally during routine imaging. Despite their potential for aggressive
behavior, our case was detected early and did not exhibit aggressive features.
Endocrine evaluations and imaging studies, including MRI and CT, assist in differentiating
EPAs, while endoscopic nasal examination is useful for detecting sphenoid sinus lesions.[2]
[10] An empty sella, commonly seen with EPAs, is indicative but not definitive.[7] Clival EPAs, which may present with mass effects or cranial nerve palsy, can be
mistaken for other clival lesions such as chordomas, which have distinct imaging features.[6]
[11] Nasopharyngeal EPAs may also be misdiagnosed as chronic sinusitis due to their rarity.
Accurate diagnosis requires ruling out primary hyperthyroidism and following standard
procedures for inappropriate thyroid-stimulating hormone secretion.[7]
[8]
[9] Suprasellar and cavernous sinus EPAs may be confused with intrasellar pituitary
adenomas, necessitating repeated MRI and careful review.[12]
ACTH-secreting EPAs, particularly in the suprasellar and cavernous areas, are more
challenging to differentiate from intrasellar Cushing's disease. Nuclear medicine
imaging, such as somatostatin receptor scintigraphy and 68 gallium-68 DOTATATE positron
emission tomography/CT (PET/CT), can assist in detection, though its effectiveness
varies.[13] Additionally, fluorine-18 fuorodeoxyglucose PET/CT is helpful in identifying recurrent
or residual tumors.[13] Due to the rarity of EPAs, diagnosis is often confirmed postsurgery. Diagnostic
features include a low mitotic count and specific immunohistochemical markers. Hormonally
inactive EPAs typically show chromophobic, monomorphic cells with minimal nuclear
atypia. The immunohistochemical profile often includes negativity for anterior pituitary
hormones and positivity for neuron-specific enolase, synaptophysin, CD99, and occasionally
GATA3.[1]
[2]
[3]
[14]
Treatment approaches for EPAs follow similar guidelines as those for intrasellar pituitary
adenomas, depending on the tumor's clinical manifestations and characteristics. Management
options include surgical intervention, radiotherapy, and drug therapy, depending on
endocrine changes, local compression, and surgical feasibility.[2]
[3]
[8]
[12]
Conclusion
EPA is an extremely rare condition, often leading to diagnostic delays. Accurate diagnosis
requires thorough hormone evaluation, detailed imaging, and a comprehensive preoperative
assessment. Clinical symptoms, imaging, histology, and immunohistochemical markers
must be integrated for an accurate diagnosis. Management should consider the tumor's
clinical manifestations, size, location, extent of invasion, and hormone secretion
profile. In our case, subtotal tumor resection followed by stereotactic radiosurgery
was performed. The patient responded favorably to the treatment and is currently doing
well.
