Case 1 -
Ectopic Pituitary Adenoma
Diane P. Kowalski
Yale University School of Medicine
New Haven, CT
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This is a 62-year-old woman with a history of significant life long developmental delay. She presented to her primary care physician complaining of a 2-month history of nasal congestion and posterior nasal pain. Family denied complaints of fever, chills, night sweats, weight loss or weakness. Cranial nerves were intact. She was tried on multiple treatments, including systemic steroids, antibiotics, decongestants and nasal steroids, without improvement of her symptoms. She was then referred to an ENT specialist. Nasal endoscopy revealed a submucosal polypoid mass in the nasopharynx. CT scan of the sinuses revealed a soft tissue density centered within the posterior ethmoid sinus, extending into the sphenoid sinus, eroding surrounding bone, with extension to the base of skull. Subsequent MRI revealed a 7 cm mass centered roughly in the sphenoid sinus region with involvement of the entire clivus. There was no evidence of intracranial extension. The tumor was felt to be unresectable.
Case 1 - Figure 1
MRI: Unresectable large sinonasal, skull base tumor, ptuitary fossa normal.
Case 1 - Figure 2
Low power of cellular tumor with surrounding fibrous tissue and respiratory mucosa
Case 1 - Figure 3
Medium power with uniform population of cells in nests with moderate eosinophilic cytoplasm
Case 1 - Figure 4
High power with minimal cytologic atypia and pseudorosettes
The differential diagnosis of tumors arising in the sinonasal region is wide. This case represents a
challenging diagnosis that required microscopic findings, immunohistochemistry, imaging findings and a
strong index of suspicion to confirm the diagnosis. This 62 year old patient was asymptomatic except for
complaints of nasal congestion and nasal pain.
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
Sections of tumor reveal a uniform population of cells with round to ovoid nuclei, inconspicuous
nucleoli and moderate eosinophilic cytoplasm. Cells form nests, ribbons and occasional pseudorosettes,
and are surrounded by fibrovascular stroma. Necrosis and significant cytologic atypia are not seen.
Rare mitoses are present. Unremarkable overlying respiratory mucosa is also present. The infiltrative
nature of the tumor could not be assessed. The imunohistochemical profile for this tumor showed that
tumor cells were diffusely positive for MAK6, and synaptophysin. Pit-1 was completed in consultation and
reported to be diffusely positive. Focal staining was seen with pankeratin (AE1/AE3), cytokeratin 7,
cytokeratin 20 and growth hormone (hGH). S-100 showed a non-sustentacular staining pattern. Negative
stains included neurofilament, follicle stimulating hormone (FSH), luteinizing hormone (LH),
adrenocortical hormone (ACTH), thyroid stimulating hormone (TSH), and prolactin. MIB-1 (Ki-67)
proliferative index was <5%. Reticulin stain showed disrupted vascular network.
- Primary Pituitary Adenoma
- Olfactory Neuroblastoma
- Neuroendocrine Carcinoma
- Paraganglioma Sinonasal Undifferentiated carcinoma
- ES/PNET Ectopic Pituitary Adenoma
Ectopic Pituitary Adenoma
The ability to make the correct diagnosis in this case requires the awareness of pituitary adenoma in
ectopic locations. The differential diagnosis of a sinonasal mass is lengthy and may be challenging.
Ectopic pituitary adenomas most commonly arises in the sphenoid sinus, and although not frequently
encountered, they should be considered in the differential of a sinonasal mass. In order to eliminate a
primary pituitary adenoma, and to arrive at the correct diagnosis, imaging studies are essential.
Confirmation of an intact sella turcica eliminates the possibility of a primary pituitary adenoma
extending inferiorly to involve the sphenoid sinus. A wide array of immunohistochemical stains is often
used in this differential in order to help differentiate other neuroendocrine tumors and small round cell
tumors. Olfactory neuroblastoma, which was given consideration in this case, typically has a nested
growth pattern, neurofibrillary stroma and small hyperchromatic nuclei. Keratin stains are usually
negative and sustentacular cells express S-100 at the periphery of the cell nests. Neurofilament will be
positive in cytoplasm and the neurofibrillary matrix. Imaging studies in olfactory neuroblastoma often
show a mass in the superior nasal cavity with involvement of the cribiform plate. Diffuse keratin
positivity, lack of S-100 sustentacular staining, negative neurofilament, and lack of clear
neurofibrillary stroma helped to eliminate this diagnosis. Sinonasal neuroendocrine carcinoma
(undifferentiated) is a high grade tumor with morphologic features similar to that seen in the lung. The
cells are small and hyperchromatic with high nuclear to cytoplasmic ratios. Numerous mitoses and
extensive necrosis, features not seen in pituitary adenoma, is common in neuroendocrine carcinoma. These
tumors are immunohistochemically positive for keratin and neuroendocrine markers, but will lack staining
with hormonal markers and Pit-1. Morphologically, the distinction between these two tumors should not be
difficult, despite overlapping immunohistochemical profiles. Sinonasal undifferentiated carcinoma, also
very high grade and morphologically distinct from ectopic pituitary adenoma, may show weak neuroendocrine
differentiation. This tumor is characterized by extensive vascular invasion, numerous mitoses and
frequent central necrosis of cell nests. Paragangliomas have rarely been reported in the sinonasal
region and therefore should enter this differential diagnosis. The nested cells in the highly vascular
paraganglioma are larger than ectopic pituitary adenoma, have abundant eosinophilic cytoplasm, and often
show significant pleomorphism. S-100 will stain the surrounding sustentacular cells in paraganglioma,
and hormonal markers will be negative. ES/PNET is always considered in the differential of small round
blue cell tumors of the sinonasal tract. Small biopsy specimens are most challenging. Classically,
ES/PNET is comprised of a uniform population of small cells with scant clear to eosinophilic cytoplasm,
fine chromatin and small nucleoli. Consideration of this tumor should lead to staining with CD 99, which
is intensely positive in the vast majority of cases, and staining for FLI1 protein. Additionally,
genetic testing for the t (11;22) translocation will aid in confirming this diagnosis. In this case of
ectopic pituitary adenoma, positive staining with hormonal markers, hGH, and Pit-1, confirmed the
Review of the Literature/Treatment Options (if applicable):
Ectopic pituitary adenomas (EPA) are extrasellar pituitary adenomas that have no direct communication
with the pituitary gland. They usually occur along the migration pathway of Rathke's pouch
Embryologic remnants of pituitary tissue can be retained in the sphenoid bone, sphenoid sinus and the
sella turcica and remain separate from the normal pituitary gland
The embryologic rests can show
hormonal activity for any of the major pituitary hormones, which suggests that any type of pituitary
tumor could arise from these rests
The sphenoid sinus is the most common site for ectopic
pituitary adenoma, followed by the suprasellar region, and less commonly the cavernous sinus, clivus,
nasal cavity, nasopharynx, and third ventricle
EPAs usually occur in the fourth to seventh
decades and more commonly in women
Presenting symptoms will depend on location and mass effect of
the tumor as well as hormonal activity. Symptoms associated with sphenoid sinus EPA may include nasal
obstruction, headache, pain, cranial nerve deficiencies, and evidence of hormonal activity, such as
Cushing's syndrome, acromegaly and thyroid abnormalities
EPA may be hormonally active in as many
as 50% of cases
CT and MRI are essential in the assessment of sphenoid EPAs. CT provides helpful
information regarding the bony landmarks of the sinuses and skull base. Bone remodeling and erosion is
not uncommon in EPAs
MRI will help evaluate the relationship to critical soft tissues such as
the pituitary gland, carotid arteries and cavernous sinuses . Most importantly, evaluation of the
sella turcica is essential to exclude a primary pituitary adenoma. Sphenoid sinus EPAs may occur in
association with empty sella . The association between empty sella and EPA is not understood.
Treatment consists of complete surgical removal; however, in large lesions, this may not be possible. In
this case, postoperative irradiation is indicated. This treatment appears to be effective as most
patients experience a benign course. However, Hosaka et al  reported malignant transformation of an
invasive EPA after multiple recurrences.
Helpful features to diagnose EPA include an endocrine growth pattern, very low mitotic rate, evidence
of neuroendocrine differentiation and pituitary hormone activity.
- Yang BT et al. Sphenoid sinus ectopic pituitary adenomas: CT and MRI findings. British Journal of Radiologu, 83 (2010), 218-224.
- Loyd RV et al. Ectopic Pituitary adenomas with normal pituitary glands. The American Journal of Surgical pathology 10(8):546-552, 1986.
- Wang H et al. Ectopic pituitary adenoma in the spheno-orbital region. Journal of neuro-ophthalmology 2010;30:135-137.
- Ivy SC et al. Pituitary adenoma presenting as sinonasal tumor:pitfalls in diagnosis. Human Pathology vol27, No 6 (June 1996).
- Ali R et al. Ectopic adenoma presenting as midline nasopharyngeal mass. Ir J Med Sci (2010) 179:593-595.
- Kurowska M et al. Acromegaly in a patient with normal pituitary gland and somatotrophic adenoma located in the sphenoid sinus. Polish Journal of Endocrinology vol 59, number4/2008, 348.
- Suzuki J et al. An aberrant ACTH-producing ectopic pituitary adenoma in the sphenoid sinus. Endocrine Journal 2004, 51 (1), 97-103.
- Matsuno A et al. Ectopic pituitary adenoma in the sphenoid sinus causing acromegaly associated with empty sella. ANZ J. Surg. (2001) 71, 495-498.
- Yoshiyasu I et al. Giant basal prolactinoma extending into the nasal cavity. Surg Neurol 1992;37;280-3.
- Hosaka, N et al. Ectopic pituitary adenoma with malignant transformation. The American Journal of Surgical Pathology 26(8): 1078-1082, 2002.
- Slonim SM et al. MRI appearances of an ectopic pituitary adenoma:case report and review of the literature. Neuroradiology (1993) 35:546-548.