The Differential Diagnosis of Sinonasal/Nasopharyngeal Neuroendocrine/Neuroectodermally Derived Tumors

The Differential Diagnosis of Sinonasal/Nasopharyngeal Neuroendocrine/Neuroectodermally Derived Tumors Kathleen T. Montone, MD Context. The differential diagnosis of neuroendocrine neoplasms arising in the sinonasal tract is broad and includes lesions of epithelial, mesenchymal, and neuroectodermal origin. Objective. To review the differential diagnosis of sinonasal neuroendocrine and neuroectodermally derived tumors. Data Sources. The current literature was reviewed to provide updated information regarding the differential diagnosis and means for diagnosing neuroendocrine tumors including sinonasal neuroendocrine carcinoma, olfactory neuroblastoma, malignant melanoma, paraganglioma, pituitary adenoma, and Ewing family of tumors. Conclusions. The differential diagnosis of neoplasms with neuroendocrine differentiation in the sinonasal tract is broad, and diagnosis often includes not only histologic review but also immunohistochemical or molecular analysis. (Arch Pathol Lab Med. 2015;139:1498 1507; doi: 10.5858/arpa.2014-0383-RA) A variety of different neoplastic tumors including those with epithelial, mesenchymal, or neuroectodermal differentiation may arise in the sinonasal tract and should be considered in the differential diagnosis of sinonasal tract neoplasms. 1 4 Neuroendocrine/neuroectodermally derived sinonasal tumors are often a consideration when a pathologist is reviewing a sinonasal neoplasm (either benign or malignant). This review will describe the differential diagnosis of sinonasal tract neuroendocrine/neuroectodermal neoplasms (Table 1). NEUROENDOCRINE CARCINOMA Epithelial malignancies are the most common malignant tumors of the sinonasal tract; however, carcinomas with neuroendocrine differentiation are exceedingly rare in this site. 1 6 Classification of sinonasal tract neuroendocrine carcinomas is variable. The most common classification system for head and neck neuroendocrine carcinomas is the classification recommended by the World Health Organization (WHO), which is as follows: carcinoid tumor; atypical carcinoid; small cell carcinoma, neuroendocrine type; neuroendocrine carcinoma, not otherwise specified; and combined small cell carcinoma (neuroendocrine type) with non small cell carcinoma (usually adenocarcinoma or squamous cell carcinoma). 7 More recently, consideration Accepted for publication April 20, 2015. From the Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia. The author has no relevant financial interest in the products or companies described in this article. Presented in part at The Princeton Integrated Pathology Symposium: Head and Neck Pathology; February 9, 2014; Princeton, New Jersey. Reprints: Kathleen T. Montone, MD, Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, 3400 Spruce St, 6 Founders, Philadelphia, PA 19104 (e-mail: kmontone@upenn.edu). for classifying head and neck neuroendocrine carcinomas, using the recommended classifications for neuroendocrine tumors of the lung and pancreas/gastrointestinal tract, has been proposed 8 10 (Table 2). While large cell neuroendocrine carcinoma of the head and neck has not in the past been recognized in the WHO classification, it is established that this lesion does exist, and recent reviews 11 have suggested these lesions should be included in the future WHO classifications of head and neck neuroendocrine carcinomas. Sinonasal neuroendocrine carcinomas have histologic features similar to neuroendocrine carcinomas arising in other sites (Figure 1, A through C). Low- and intermediategrade tumors ( carcinoids and atypical carcinoids ) are extremely rare and limited data are available on these lesions. 10 High-grade lesions are most common and usually classified as small cell carcinoma. 5,6 Mixed neuroendocrine/ adenocarcinomas and neuroendocrine/squamous cell carcinomas have been described. 1 4,12 By immunohistochemistry, neuroendocrine carcinomas variably express cytokeratin and neuroendocrine markers (synaptophysin, neuron-specific enolase, chromogranin, CD56; Figure 1, D). Staining for calcitonin and thyroid transcription factor 1 (TTF-1) is rare in tumors of the sinonasal tract. The prognosis for sinonasal neuroendocrine carcinoma will vary with the tumor types and grades, with high-grade carcinomas having a worse prognosis. Improved survival has been seen in patients with a multimodality approach to treatment. 13 16 OLFACTORY NEUROBLASTOMA (ESTHESIONEUROBLASTOMA) Olfactory neuroblastoma (ONB) is a rare (,5% of sinonasal tract malignancies) malignant tumor of neuroectodermal origin that arises from the olfactory epithelium lining the superior one-third of the nasal septum, the cribriform plate, and the superior nasal turbinates. The 1498 Arch Pathol Lab Med Vol 139, December 2015 Sinonasal Neuroendocrine Tumors Montone

Table 1. The Differential Diagnosis of Neuroendocrine/Neuroectodermal Neoplasms of the Sinonasal Tract Neuroendocrine carcinoma Well differentiated (carcinoid) Moderately differentiated (atypical carcinoid) Poorly differentiated (small cell carcinoma or large cell neuroendocrine carcinoma) Olfactory neuroblastoma/esthesioneuroblastoma Malignant melanoma Ewing family of tumors (Ewing sarcoma/pnet) Paraganglioma Pituitary adenoma Abbreviation: PNET, primitive neuroectodermal tumor. Table 2. Proposed Sinonasal Neuroendocrine Carcinoma Classification 1. Well-differentiated neuroendocrine tumor/neuroendocrine carcinoma, grade 1 (carcinoid morphology;,2 mitoses per 10 HPFs; no necrosis) 2. Moderately differentiated neuroendocrine tumor/ neuroendocrine carcinoma, grade 2 (atypical carcinoid; 2 10 mitoses per 10 HPFs and/or necrosis) 3. Poorly differentiated neuroendocrine tumor/neuroendocrine carcinoma, grade 3 (small or large cell carcinoma;.10 mitoses per 10 HPFs; necrosis) Abbreviation: HPFs, high-power fields. tumor affects males and females equally and occurs over a wide age range with a bimodal distribution (ages 11 20 and 51 60 years). 1 4 Histologically, ONB characteristically shows a lobular architecture. Well-differentiated ONBs are composed of nests of small cells with uniform, round to oval nuclei and speckled chromatin pattern admixed with a neurofibrillary matrix. In contrast, poorly differentiated ONBs are characterized by cells with hyperchromatic, atypical nuclei with coarse chromatin, scant cytoplasm, and minimal fibrillary matrix (Figure 2, A through D). The best grading system (Hyams classification; Table 3) for ONB includes 4 grades with grade I being the most differentiated and grade IV being the least differentiated. 17 Grade I tumors have a lobular architecture with the presence of a prominent neurofibrillary matrix. The cells are small and cytologically uniform without mitotic activity. Pseudorosettes (Homer- Wright rosettes) are often present and necrosis is not seen. Figure 1. Sinonasal neuroendocrine carcinoma. A, Moderately differentiated (atypical carcinoid). B, Poorly differentiated (small-cell type). C, Poorly differentiated (non small cell). D, Poorly differentiated (non small cell, positive for CD56) (hematoxylin-eosin, original magnifications 350 [A] and 3100 [B and C]; diaminobenzidine with hematoxylin counterstain, original magnification 325 [D]). Arch Pathol Lab Med Vol 139, December 2015 Sinonasal Neuroendocrine Tumors Montone 1499

Figure 2. Olfactory neuroblastoma (ONB). A, Examination shows a cellular small round cell tumor with a nested appearance. B, Olfactory neuroblastoma showing medium-sized cells surrounded by neurofibrillary matrix. C, High-power view of ONB showing bland, hyperchromatic nuclei without prominent nucleoli. D, Low-power view of ONB shows a cellular small round cell neoplasm with numerous blood vessels. E, Olfactory neuroblastoma showing positive staining for chromogranin. F, Olfactory neuroblastoma showing sustentacular cell staining pattern with S100 immunostain (hematoxylin-eosin, original magnifications 3100 [A through C] and 350 [D]; diaminobenzidine with hematoxylin counterstain, original magnifications 350 [E] and 3100 [F]). 1500 Arch Pathol Lab Med Vol 139, December 2015 Sinonasal Neuroendocrine Tumors Montone

Grade Table 3. Lobular Architecture Preservation Hyams Grading System for Olfactory Neuroblastoma Mitotic Index Nuclear Pleomorphism Fibrillary Matrix Rosettes Necrosis I Present Zero None Prominent HW rosettes None II Present Low Low Present HW rosettes None III May or may not be present Moderate Moderate Low FW rosettes Rare IV May or may not be present High High Absent None Frequent Abbreviations: FW, Flexner-Wintersteiner; HW, Homer-Wright. Figure 3. A, Sinonasal melanoma infiltrating the sinonasal submucosa. This tumor has a more epithelial cytologic appearance. B, Sinonasal melanoma showing large atypical epithelioid-type cells with abundant eosinophilic cytoplasm and prominent nucleoli. This melanoma was a recurrence, with the original primary tumor occurring 16 years prior. C, Sinonasal melanoma showing a spindle cell morphology and necrosis. D, Sinonasal melanoma showing a small round cell morphology. Scattered melanin pigment is also seen in this case. E, Sinonasal melanoma with a small round cell morphology. This case was originally classified by an outside hospital as olfactory neuroblastoma but was reclassified as melanoma on re-review and additional immunohistochemical staining (hematoxylin-eosin, original magnifications 3100 [A, C, D, and E] and 3200 [B]). Arch Pathol Lab Med Vol 139, December 2015 Sinonasal Neuroendocrine Tumors Montone 1501

Figure 4. Ewing family of tumors. A, Low-power view of a core biopsy of a maxillary sinus mass in a 16-year-old adolescent boy, showing nests of small round blue cells. B, Higher-power view showing a monotonous neoplasm without significant mitotic activity or necrosis. C, Immunohistochemistry for FLI1 reveals strong nuclear expression. EWS1 rearrangements were confirmed by fluorescence in situ hybridization studies (hematoxylin-eosin, original magnifications 325 [A] and 3100 [B]; diaminobenzidine with hematoxylin counterstain, original magnification 3100 [C]). Figure 5. Paraganglioma. A, Low-power view of a sinonasal paraganglioma showing nested appearance. B, Higher-power view of a paraganglioma showing nuclear size variation with bland nuclei and no mitotic activity (hematoxylin-eosin, original magnifications 350 [A] and 3100 [B]). 1502 Arch Pathol Lab Med Vol 139, December 2015 Sinonasal Neuroendocrine Tumors Montone

Figure 6. Ectopic parathyroid adenoma (PA). A, Low-power view of PA in the sphenoid sinus. B, Higher-power view of PA showing cells with small round nuclei and no atypia. C, Growth hormone expression in PA. D, Ectopic PA with more epithelioid morphology. E, Ectopic PA expressing prolactin (hematoxylin-eosin, original magnifications 325 [A] and 3100 [B and D]; diaminobenzidine with hematoxylin counterstain, original magnification 3100 [C and E]). Grade II tumors usually show less prominent matrix and more cellular atypia with mitoses. Grade III tumors may retain a lobular architecture but the cells are more atypical with increased mitoses and necrosis. True neural rosettes Arch Pathol Lab Med Vol 139, December 2015 (Flexner-Wintersteiner) may be present. Grade IV tumors are the most undifferentiated and difficult to diagnose because there is often loss of lobular architecture. Cytologic atypia, necrosis, and mitotic activity are often present. Sinonasal Neuroendocrine Tumors Montone 1503

Table 4. Different Diagnosis of Sinonasal Neuroendocrine/Neuroectodermal Tumors Diagnosis Incidence, % of All Sinonasal Tract Malignancies Clinical Features Histologic Features SNEC, grade 1,1 Nasal obstruction, epistaxis, headache, sinusitis Similar to carcinoid tumors in other sites SNEC, grade 2,1 M. F Nasal obstruction, epistaxis, headache, sinusitis SNEC, grade 3,1 M ¼ F Nasal obstruction, epistaxis, headache, sinusitis ONB 5 F. M Nasal obstruction, epistaxis, anosmia, headache Melanoma 5 M. F Obstruction, mass, pain, epistaxis Histologically similar to atypical carcinoid tumors in other sites Histologically similar to small cell carcinomas in other sites Low-grade tumors show lobular/nested architecture, neurofibrillary matrix, low mitotic rate, no necrosis, pseudorosettes (Homer-Wright); high-grade tumors show loss of lobular/nested architecture, necrosis, mitoses, atypia, minimal neurofibrillary matrix, true neural rosettes (Flexner-Winsteiner) Variable histology: epithelioid, spindle cell, small cell 50% amelanotic PNET/Ewing sarcoma Unknown, likely,1% Nasal obstruction, epistaxis Small round cells; bland nuclei; low mitotic rate, focal necrosis Paraganglioma,1 Polypoid lesion, epistaxis, obstructive mass, headache; rare tumors are functioning... Pituitary adenoma NA...... Abbreviations: EWS, Ewing sarcoma; F, female; HPF, high-power field; IHC, immunohistochemistry; M, male; NA, not applicable; NEC, neuroendocrine carcinoma; NSE, neuron-specific enolase; ONB, olfactory neuroblastoma; PNET, primitive neuroectodermal tumor; SDHB, succinate dehydrogenase subunit B; SNEC, sinonasal neuroendocrine carcinoma; TTF-1, thyroid transcription factor 1. Hyams grade I and II tumors are most often considered low grade and Hyams grade III to IV are high grade. 17 19 By immunohistochemistry, ONBs are positive for neuronspecific enolase, chromogranin, synaptophysin, and CD56 (Figure 2, E). S100 highlights the peripheral sustentacular cells (Figure 2, F). Tumors are rarely positive for cytokeratin. A recent study has shown that ONBs are frequently strongly positive for calretinin and negative for p63 and this immunohistochemical phenotype helps differentiate ONBs from other small round cell neoplasms. 20 Prognostic factors include Hyams grade, neck lymph node metastasis, and distant metastasis. 18,19 While ONB should be considered in the differential diagnosis of small round cell tumors of the sinonasal tract, there could be a tendency to overdiagnose small round cell tumors of the head and neck as ONBs. In a 2002 study from The University of Texas MD Anderson Cancer Center (Houston) the investigators felt that round cell tumors in the sinonasal tract may be overdiagnosed as ONB. 21 In their study of 12 patients originally given the diagnosis of ONB at an outside institution, they agreed with the ONB diagnosis in only 2 instances. For the patients they felt had been misdiagnosed, there was significant variation in treatment with increased patient morbidity in 8 patients. The tumors that had been initially misdiagnosed as ONBs included malignant melanoma (2), neuroendocrine carcinoma (3), pituitary adenoma (3), and sinonasal undifferentiated carcinoma (2). MALIGNANT MELANOMA Sinonasal melanoma is an uncommon tumor constituting about 5% of all neoplasms of the sinonasal tract and less than 5% of all melanomas. 1 4,21 24 Melanoma of the sinonasal tract has an equal incidence in males and females and is more commonly seen in patients older than 40 years. In the nasal cavity, tumors are most commonly encountered on the septum followed by the lateral nasal wall and the middle and inferior turbinates. The maxillary sinus is the most common paranasal sinus affected. The risk factors for sinonasal melanomas are largely unknown. Mucosal melanosis is associated with tumor development in oral sites but has only rarely been documented in patients with sinonasal melanoma. An autopsy study 25 found that melanocytes are normally present in the sinonasal mucosa and the number of these cells increases with age, perhaps explaining a reason why sinonasal melanomas are rarely encountered in younger patients and show increased incidence with increasing age. Microscopically, as with cutaneous melanomas, sinonasal mucosal melanomas may take on a variety of histologic appearances 1 4,21 24 (Figure 3, A through E). Lesional cells can be spindled or epithelioid and a mixture of both cell types can also be seen. Spindle cell melanomas are 1504 Arch Pathol Lab Med Vol 139, December 2015 Sinonasal Neuroendocrine Tumors Montone

Table 4. Extended Immunohistochemistry Prognosis Comments Positive for cytokeratin, synaptophysin, chromogranin, NSE, CD56 Positive for cytokeratin, synaptophysin, chromogranin, NSE, CD56; may rarely express calcitonin and TTF-1 Positive for cytokeratin, synaptophysin, chromogranin, NSE, CD56 Unknown due to rarity reported survival at 5 y, approximately 60% 70%, based on small numbers Unknown due to rarity reported survival at 5 y, approximately 60 70%, based on small numbers Survival generally,18 mo Low mitotic rate (,2 mitoses in 10 HPFs) and no necrosis Mitoses 2 10 in 10 HPFs and/or necrosis Mitoses. 10 in 10 HPFs; may be small cell or large cell in type Positive for chromogranin, NSE, synaptophysin, S100 (sustentacular pattern), CD56, calretinin Rarely positive for cytokeratin Negative for p63 5-y survival:.70%, based on stage and grade Pathologically graded with Hyams grading (grade 1 4); grades 1 and 2 are low grade and grades 3 and 4 are high grade; staged with Kadish grading system (stage A, B, and C) Positive for S100, HMB-45, Melan-A, tyrosinase Rare positivity for cytokeratin, myogenin, desmin Positive for vimentin, CD99, FLI1 6 Positivity for neuroendocrine markers, cytokeratins, S100 Negative for desmin Positive for chromogranin, synaptophysin, NSE, S100 (sustentacular pattern) Negative for cytokeratin Positive for cytokeratin (pan-cytokeratin, CAM 5.2), synaptophysin, chromogranin, pituitary hormones (singly or multiply, most common is prolactin) 5-y survival:,30% Rarely show BRAF mutations; more commonly demonstrate NRAS and c- KIT mutations Unknown; possibly better than Ewing family of tumors in other sites Predicted risk of malignancy approximately 25% Too small patient numbers to determine survival rates NA Most show rearrangement of the EWS gene on chromosome 22 most commonly with the FLI1 gene on chromosome 11 May be associated with mutations in genes coding for succinate dehydrogenase subunits, particularly SDHB Often can be confused with low-grade NEC and low-grade ONB; IHC for pituitary hormones can aid in the diagnosis composed of pleomorphic spindle cells with hyperchromatic nuclei, which may or may not contain prominent nucleoli. Epithelioid melanoma may grow in a solid, nested, or trabecular pattern and is characterized by large pleomorphic, epithelioid cells; abundant eosinophilic cytoplasm; and nuclei with prominent cherry red nucleoli and nuclear pseudoinclusions. In addition, sinonasal melanomas may be composed of small round cells with scant cytoplasm and can be misdiagnosed as small cell carcinomas or ONB. While a clue to diagnosis is intracytoplasmic melanin pigment, sinonasal melanomas are often amelanotic. Pagetoid spread (melanoma in situ) into the overlying respiratory mucosa may be present, although primary lesions are often not identified. 21 24 Immunohistochemistry for melanoma markers such as S100, HMB-45, and Melan-A, are useful for establishing the diagnosis. While BRAF mutations are characteristic of cutaneous melanomas, their presence is rare in sinonasal melanomas; however, sinonasal melanomas have been shown to harbor NRAS (and rarely c-kit) mutations. 26 28 Most patients (but not all) with sinonasal melanoma have a poor prognosis with a reported 5-year survival rate of less than 20%. 21 24 There are rare cases of patients with longterm survival, and recurrences as late as 20 years after primary diagnosis may be seen. Prognostic factors for sinonasal mucosal melanomas have not been as widely studied as for cutaneous lesions, most likely because these lesions are rare and often present late in the disease course. EWING FAMILY OF TUMORS (PRIMITIVE NEUROECTODERMAL TUMOR/EWING SARCOMA) The Ewing family of tumors consists of aggressive malignancies that can rarely arise in the sinonasal tract. 1 4,29 They are most commonly seen in children and young adults with a male predominance. Approximately 40% of cases present with maxillary sinus involvement. Microscopically, these tumors are characterized by sheets of monotonous cells with individual cell necrosis, and inconspicuous nucleoli (Figure 4, A and B). Foci of coagulative necrosis may be seen. Periodic acid Schiff stain shows the presence of cytoplasmic glycogen. By immunohistochemistry, almost all tumors express vimentin and MIC2 (CD99). Some tumors may express neuron-specific enolase and synaptophysin. Rare tumors express cytokeratin, S100, and glial fibrillary acid protein (GFAP). Desmin stains negatively. Approximately 85% of primitive neuroectodermal tumors (PNETs)/Ewing sarcomas show a characteristic translocation involving fusion of the EWS gene on chromosome 22 with the FLI1 gene on chromosome 11 (t(11;22)(q24;q12)). 1 4,29 The FLI1 protein product produced by the fusion transcript can be detected by immunohistochemistry (Figure 4, C). While PNETs/Ewing sarcomas are aggressive neoplasms, recent data suggest a better prognosis for those in the sinonasal tract. 29 PARAGANGLIOMA Paragangliomas (PGLs) of head and neck sites are uncommon, representing less than 1% of all tumors in the Arch Pathol Lab Med Vol 139, December 2015 Sinonasal Neuroendocrine Tumors Montone 1505

head and neck area, with most of these tumors arising in the carotid body or jugular bulb. 30 Sinonasal/nasopharyngeal PGLs are very rare and while usually not functional, they may present with elevation of catecholamines. 31,32 Histologically, PGLs are characterized by a nested ( zellballen ) appearance of neuroendocrine cells surrounded by a fine vascular network (Figure 5, A and B). The tumor cell nests are usually smaller than those seen in ONB. Cytologically, PGL tumor cells are large, polygonal and have abundant eosinophilic/metachromatic granular cytoplasm, and uniform nuclei with open chromatin. The distinction between benign and malignant PGLs cannot be made without evidence of metastasis. Malignant neoplasms, however, more commonly have necrosis, vascular invasion, and mitotic activity. By immunohistochemistry, PGLs are positive for chromogranin and synaptophysin. S100 highlights the sustentacular cells similarly to ONB. Paragangliomas are negative for cytokeratin. Recently studies 33 have shown expression of GATA-3 in PGLs. Most recent studies on PGLs have concentrated on genetic syndromes associated with PGL. 34 36 In fact, it is believed that up to 50% of head and neck PGLs may be associated with a genetic syndrome. To date more than 10 susceptibility genes have been identified in patients with PGL, including, most commonly, mutations in the genes coding for succinate dehydrogenase subunits (SDHA, SDHB, SDHC, SDHD) and mutations in VHL, RET, and NF1. 36 The association of PGLs with germline SDHB mutations has been of recent interest. Most patients with SDHB mutations have extra-adrenal tumors with most located in the pelvis, abdomen, and head and neck areas. 36 Most patients are in their third decade of life at presentation, with almost 100% penetrance by age 70 years. 36 Patients with SDHB mutations have an increased risk of having malignant/recurrent PGLs, and SDHB mutations have also been associated with gastrointestinal stromal tumors, papillary thyroid carcinomas, and renal cell carcinomas. 36 Screening for SDHB mutations can be performed by using immunohistochemistry for SDHB, with loss of expression being associated with mutation. 37 Mutations in other genes encoding SDH subunits, particularly SDHD, have also been associated with head and neck paragangliomas, but paragangliomas associated with SDHD mutations are almost always benign. 36 PITUITARY ADENOMA Pituitary adenomas may rarely involve the sinonasal tract either by direct extension from an intracranial lesion or ectopically (likely arising from remnants of Rathke pouch). Lesions can be seen in males or females and can present at any age. Most commonly, ectopic pituitary adenomas are located in the sphenoid sinus but may locally extend into the nasal cavity and nasopharyngeal area. 38,39 Histologically, ectopic pituitary adenomas resemble intracranial pituitary adenomas. The lesional cells can take on a variety of different growth patterns including nested, trabecular, and glandular patterns 39 (Figure 6, A, B, and D). A fine vascular network is often seen surrounding tumor cell nests. Cytologically, the pituitary adenoma cells are often polygonal with granular eosinophilic or basophilic cytoplasm and finely speckled chromatin pattern. Mitotic activity is almost never seen but rarely necrosis may be present. By immunohistochemistry, the lesional cells are Table 5. Immunohistochemistry in the Differential Diagnosis of Sinonasal Neuroendocrine Tumors Sinonasal neuroendocrine carcinoma Cytokeratin: positive Neuroendocrine markers (synaptophysin, chromogranin, CD56): positive S100: variable Other melanoma markers (Melan-A, HMB-45, tyrosinase): negative Olfactory neuroblastoma Cytokeratin: usually negative (rare cases positive) Neuroendocrine marker: positive S100: sustentacular pattern of staining Other melanoma markers (Melan-A, HMB-45, tyrosinase): negative Calretinin: positive Malignant melanoma Cytokeratin: usually negative (rare cases positive) S100: positive Other melanoma markers (Melan-A, HMB-45, tyrosinase): positive Ewing family of tumors Cytokeratin: usually negative (rare cases positive) Neuroendocrine markers: variably positive S100: variable Other melanoma markers (Melan-A, HMB-45, tyrosinase): negative CD99: positive FLI1: may be positive Paraganglioma Cytokeratin: negative Neuroendocrine markers: positive S100: sustentacular pattern of staining Other melanoma markers (Melan-A, HMB-45, tyrosinase): negative GATA-3: positive SDHB: loss of expression in patients with SDH mutations Pituitary adenoma Cytokeratin: positive (.80%) Neuroendocrine markers: positive S100: negative Pituitary hormones: positive (most commonly prolactin [60%]) Abbreviation: SDHB, succinate dehydrogenase subunit B. commonly positive for cytokeratin (pan-cytokeratin or CAM 5.2), neuroendocrine markers, and pituitary hormones, which may be expressed singly or multiply with prolactin being the most common hormone produced (60% of cases) 39 (Figure 6, C and E). Pituitary adenoma should come into the differential diagnosis of any low-grade neuroendocrine neoplasm in the sinonasal tract. It is a diagnosis of utmost importance, since these lesions are often positive for cytokeratin and can be classified as lowgrade neuroendocrine carcinomas if not considered in the differential diagnosis of a cytokeratin-positive neuroendocrine tumor of the sinonasal tract. Confirmation of production of pituitary hormones will be useful for establishment of diagnosis. In summary, there are a variety of benign and malignant neoplasms that arise in the sinonasal tract/nasopharyngeal area with neuroendocrine/neuroectodermal differentiation. These lesions can have overlapping clinical and pathologic features and should be considered in the differential diagnosis of sinonasal tract neoplasms (Tables 4 and 5). 1506 Arch Pathol Lab Med Vol 139, December 2015 Sinonasal Neuroendocrine Tumors Montone

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A catecholamine-secreting skull base sinonasal paraganglioma presenting with labile hypertension in a patient with previously undiagnosed genetic mutation. JNeurolSurgRep. 2012;73(1):19 24. 33. So JS, Epstein JI. GATA3 expression in paragangliomas: a pitfall potentially leading to misdiagnosis of urothelial carcinoma. Mod Pathol. 2013;26(10):1365 1370. 34. Schiavi F, Savvoukidis T, Trabalzini F, et al. Paraganglioma syndrome: SDHB, SDHC, and SDHD mutations in head and neck paragangliomas. Ann N Y Acad Sci. 2006;1073:190 197. 35. Boedeker CC, Neumann HP, Maier W, Bausch B, Schipper J, Ridder GJ. Malignant head and neck paragangliomas in SDHB mutation carriers. Otolaryngol Head Neck Surg. 2007;137(1):126 129. 36. Fishbein L, Nathanson KL. Pheochromocytoma and paraganglioma: understanding the complexities of the genetic background. Cancer Genet. 2012;205(1 2):1 11. 37. Gill AJ, Benn DE, Chou A, et al. Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes. Hum Pathol. 2010;41(6):805 814. 38. Langford L, Batsakis JG. Pituitary gland involvement of the sinonasal tract. Ann Otol Rhinol Laryngol. 1995;104(2):167 169. 39. Thompson LD, Seethala RR, Müller S. Ectopic sphenoid sinus pituitary adenoma (ESSPA) with normal anterior pituitary gland: a clinicopathologic and immunophenotypic study of 32 cases with a comprehensive review of the english literature. Head Neck Pathol. 2012;6(1):75 100. CAP 16 Abstract Program Submission Dates Announced Abstract and case study submissions to the College of American Pathologists (CAP) 2016 Abstract Program will be accepted beginning on Friday, January 8 through 5 p.m. Central time Friday, March 11, 2016. Accepted submissions will appear on the Archives of Pathology & Laboratory Medicine Web site as a Web-only supplement to the September 2016 issue. The CAP 16 meeting will be held from September 25 to 28 in Las Vegas, Nevada. Visit the CAP 16 Web site (www.cap.org/cap16) for additional abstract program information as it becomes available. Arch Pathol Lab Med Vol 139, December 2015 Sinonasal Neuroendocrine Tumors Montone 1507