Case 1 -

Ectopic Pituitary Adenoma Diane P. Kowalski Yale University School of Medicine New Haven, CT

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Clinical History 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 Case 1 - Figure 5 High power with single mitoses Case 1 - Figure 6 Pan keratin 9 (AE1/AE3) Case 1 - Figure 7 Cytokeratin 7 Case 1 - Figure 8 Cytokeratin 20 Case 1 - Figure 9 Synaptophysin Case 1 - Figure 10 S-100 Introduction: 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. Differential Diagnoses: Primary Pituitary Adenoma Olfactory Neuroblastoma Neuroendocrine Carcinoma Paraganglioma Sinonasal Undifferentiated carcinoma ES/PNET Ectopic Pituitary Adenoma Final Diagnosis: Ectopic Pituitary Adenoma Case Discussion: 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 diagnosis. 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 [1, 2, 3, 4]. 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 [1, 2]. 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 [1, 2, 3]. 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 [2, 3, 4, 5, 6, 7, 8, 9]. EPAs usually occur in the fourth to seventh decades and more commonly in women [1, 2]. 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 [2, 3, 4, 5, 6, 7, 8, 9]. EPA may be hormonally active in as many as 50% of cases [1, 2]. 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 [1, 11]. MRI will help evaluate the relationship to critical soft tissues such as the pituitary gland, carotid arteries and cavernous sinuses [11]. 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 [8]. 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 [10] reported malignant transformation of an invasive EPA after multiple recurrences. Conclusion(s): Helpful features to diagnose EPA include an endocrine growth pattern, very low mitotic rate, evidence of neuroendocrine differentiation and pituitary hormone activity. References: 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.