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DEK :: AFF2 fusion nonkeratinizing squamous cell carcinoma (NKSCC) is an emerging entity in the sinonasal tract, temporal bone, and skull base. However, the clinical behavior of these tumors has not been well studied. Here, we report the largest cohort of DEK :: AFF2 carcinomas to determine if morphology, mitotic rate, and/or Ki-67 IHC are associated with patient outcomes, including a comparison with high-risk human papillomavirus (HPV)-associated and independent patients. We solicited cases of molecularly or AFF2 immunohistochemistry (IHC) proven DEK :: AFF2 SCC from surgical pathologists to collect patient demographic, clinical, and outcome data. Using representative H&E slides, we characterized the morphology and counted mitoses. Ki-67 immunohistochemistry was performed. We also compared the DEK :: AFF2 survival rates to those in a cohort of AFF2 IHC-negative HPV-associated and HPV-independent SCC. DEK :: AFF2 carcinomas most commonly arose in the nasal cavity (13/30, 43%), and the average number of recurrences was 1.8 (range: 0 to 10). At the last follow-up, most patients were disease free (19/30, 63%) or were alive with disease (9/30, 30%). There was an average mitotic rate of 2 per 2 mm 2 (range: 0 to 9) and Ki-67 proliferation rate of 26% (range: 3% to 60%). Local recurrence was common, but morphology, mitotic activity, and Ki-67 index were not associated with recurrence or survival. On Kaplan-Meier survival analysis, DEK :: AFF2 patients had lower disease-free survival but otherwise had similar outcomes to conventional SCC patients. Our multi-institutional study shows that local recurrence is common in DEK :: AFF2 fusion nonkeratinizing SCC patients, but patients have survival rates similar to conventional SCC. Despite showing a range of different features and proliferation rates, traditional grading by morphology, mitotic rate, and/or Ki-67 activity does not seem to be predictive of outcome., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: DEK::AFF2 squamous cell carcinoma is a recently described cancer entity, with 29 cases reported to date. Occasionally, these carcinomas appear deceptively indistinguishable; however, specific morphological and phenotypic features suggest the presence of this rearrangement. However, the prognostic value of this diagnosis remains unclear. We aimed to report a new case series with histological, molecular, and clinical features., Methods: We collected data from 15 patients and investigated their phenotypes, including the expression profiles of CK7, P63/P40, PDL1, AFF2, and P16, morphological features, and associated prognostic data. We analyzed these data along with the previously published data., Results: Most of these cases exhibited indicative morphological features, such as exophytic and endophytic papillary growth, nuclear monomorphism, and abundant neutrophil-rich inflammatory infiltrates. Immunohistochemical analysis revealed the expression of AFF2 and squamous cell markers in all the patients. Overexpression of P16 was not detected, whereas CK7 and PDL1 were expressed variably. In our study cohort, a 50% progression or recurrence rate, 25% lymph node metastasis, 17% distant metastasis, and 18% disease-related death were identified, with a short follow-up time., Conclusion: DEK::AFF2 squamous cell carcinoma incidence is probably underestimated. The low-grade appearance of these tumors sometimes limits their detection. The rates of recurrence and metastasis seem to be high despite an often bland morphology. We propose AFF2 immunohistochemistry as an effective tool, and a diagnostic algorithm has been established to support accurate diagnosis of these tumors., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To investigate the clinicopathological features and differential diagnosis of olfactory carcinoma (OC). Methods: Twenty-one cases of sinonasal tumors, including those initially diagnosed as olfactory neuroblastoma (ONB) and those with uncertain diagnosis, were collected from the Department of Pathology, the First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital) from January 2016 to August 2022, among which 3 cases were reclassified as OC. The clinicopathological features were investigated, and the remaining 18 cases were used as control. Results: Of the three OC patients, 2 were male and 1 was female, with an average age of 57 years ranging from 35 to 74 years. Microscopically, the tumor cells were arranged in solid, nested or lobulated patterns with occasional palisading around the solid nests. The stroma was highly vascular with focal neurofibrillary areas. There were prominent rosettes or pseudorosettes formation. The tumor cells were mainly ovoid to spindly with scant to moderate amount of cytoplasm, one or several small nucleoli, and fine chromatin content. Brisk mitotic figures were seen. In all 3 cases of OC, there were scanty atypical glands and some were ciliated. Immunohistochemically, at least one epithelial marker and neuroendocrine marker were diffusely expressed in the tumor. Some of the tumor cells were positive for p40 and p63, and the sustentacular cells showed the expression of S-100 protein. All cases tested were negative for NUT, CD99 and desmin, with intact expression of SMARCA4 (BRG1) and SMARCB1 (INI-1). Ki-67 proliferation index varied from 20% to 80%. Follow-up after 16-18 months showed no mortality with tumor recurrence from 1 patient after 16 months. Conclusion: OC is a rare sinonasal tumor with neuroepithelial differentiation, its histomorphology is diverse, and the combination of immunohistochemical markers is essential for appropriate diagnosis.

A novel DEK-AFF2 fusion was recently reported in 4 nonkeratinizing squamous cell carcinomas of the sinonasal region and skull base, including 1 with exceptional response to immunotherapy, but it is not yet clear if this rearrangement defines a unique clinicopathologic category or represents a rare event. This study aims to characterize a larger cohort of carcinomas with DEK-AFF2 fusions to assess whether they truly constitute a distinctive entity. Among 27 sinonasal and skull base nonkeratinizing squamous cell carcinoma that were negative for human papillomavirus and Epstein-Barr virus, RNA sequencing identified DEK-AFF2 fusions in 13 cases (48%). Nine were centered in the nasal cavity, 2 in the middle ear/temporal bone, 1 in the nasopharynx, and 1 in the orbit. These tumors displayed recurrent histologic features including (1) complex endophytic and exophytic, frequently papilloma-like growth, (2) transitional epithelium with eosinophilic to amphophilic cytoplasm, (3) absent or minimal keratinization with occasional compact keratin pearls, (4) monotonous nuclei, and (5) prominent tumor-infiltrating neutrophils or stromal lymphocytes. This appearance not only overlaps with high-grade basaloid sinonasal carcinomas but also with benign papillomas and tumors reported as low-grade papillary Schneiderian carcinoma. However, DEK-AFF2 carcinomas showed frequent local recurrence, cervical lymph node metastases, and distant metastasis with 2 deaths from disease, confirming they are aggressive malignancies despite relatively bland histology. Overall, the distinctive molecular, histologic, and clinical features of DEK-AFF2 carcinomas suggest they represent a unique entity in the sinonasal region. This tumor merits increased pathologic recognition to better understand its prognostic and therapeutic implications., Competing Interests: Conflicts of Interest and Source of Funding: Supported in part by Jane B. and Edwin P. Jenevein, MD Endowment for Pathology at UT Southwestern Medical Center. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

SMARCB1-deficient sinonasal carcinoma (SNC) is an aggressive malignancy characterized by INI1 loss mostly owing to homozygous SMARCB1 deletion. With the exception of a few reported cases, these tumors have not been thoroughly studied by massive parallel sequencing (MPS). A retrospective cohort of 22 SMARCB1-deficient SNCs were studied by light microscopy, immunohistochemistry, fluorescence in situ hybridization (n = 9), targeted exome MPS (n = 12), and Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing (FACETS) (n = 10), a bioinformatics pipeline for copy number/zygosity assessment. SMARCB1-deficient SNC was found in 13 (59%) men and 9 (41%) women. Most common growth patterns were the basaloid pattern (59%), occurring mostly in men (77%), and plasmacytoid/eosinophilic/rhabdoid pattern (23%), arising mostly in women (80%). The former group was significantly younger (median age = 46 years, range = 24-54, vs 79 years, range = 66-95, p < 0.0001). Clear cell, pseudoglandular, glandular, spindle cell, and sarcomatoid features were variably present. SMARCB1-deficient SNC expressed cytokeratin (100%), p63 (72%), neuroendocrine markers (52%), CDX-2 (44%), S-100 (25%), CEA (4/4 cases), Hepatocyte (2/2 cases), and aberrant nuclear β-catenin (1/1 case). SMARCB1 showed homozygous deletion (68%), hemizygous deletion (16%), or truncating mutations associated with copy neutral loss of heterozygosity (11%). Coexisting genetic alterations were 22q loss including loss of NF2 and CHEK2 (50%), chromosome 7 gain (25%), and TP53 V157F, CDKN2A W110∗, and CTNNB1 S45F mutations. At 2 years and 5 years, the disease-specific survival and disease-free survival were 70% and 35% and 13% and 0%, respectively. SMARCB1-deficient SNCs are phenotypically and genetically diverse, and these distinctions warrant further investigation for their biological and clinical significance., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The molecular pathogenesis of poorly differentiated sinonasal carcinoma received significant attention in recent years. As a consequence, several unclassified carcinomas in the morphologic spectrum of sinonasal undifferentiated carcinoma have been reclassified as distinctive genetically defined variants or entities. Among the latter are NUT-rearranged carcinoma and SMARCB1-deficient carcinomas. In this study, we further characterize a rare variant of sinonasal undifferentiated carcinoma-like tumors characterized by inactivation of the SWItch/Sucrose Nonfermentable chromatin remodeler SMARCA4 (BRG1) detectable by immunohistochemistry. Patients were 7 males and 3 females aged 20 to 67 years (median, 44). Tumors originated in the nasal cavity (6), nose and sinuses (2), or at unspecified site (2). Six tumors were initially misdiagnosed as small cell neuroendocrine carcinoma (SCNEC) or large cell neuroendocrine carcinoma (LCNEC). Histologically, the tumors were composed of small basaloid (3 cases) or large epithelioid (7) cells disposed into nests and solid sheets with extensive areas of necrosis. No glands or other differentiating features were noted. Abortive rosettes were seen in 1 case. Immunohistochemistry showed consistent expression of pankeratin and absence of CK5, p63, p16, and NUT in all tumors tested. Other tested markers were variably positive: CK7 (2/6), synaptophysin (9/10; mostly focal and weak), chromogranin-A (4/10; focal), and CD56 (3/5; focal). All tumors showed total loss of SMARCA4 and retained expression of SMARCB1/INI1. Co-loss of SMARCA2 was seen in 1 of 8 cases. Limited data were available on treatment and follow-up. Two patients received surgery (1 also radiotherapy) and 3 received chemotherapy. Metastases (cervical nodes, liver, bone, and lung/mediastinal) were detected in 3 patients; 2 were alive under palliative chemotherapy at 8 and 9 months while 1 died of progressive lung disease at 7 months. Three patients (1 with brain invasion) died soon after diagnosis (1 to 3 mo). In total, 4 of 6 patients (66%) with follow-up died of disease (median, 3 mo). This series characterizes SMARCA4-deficient sinonasal carcinoma as a genetically distinct aggressive entity in the spectrum of undifferentiated sinonasal carcinomas. These variants add to the spectrum of SWItch/Sucrose Nonfermentable-deficient sinonasal carcinomas, at the same time expanding the topographic distribution of SMARCA4-related malignancies.

Objectives: Sinonasal inverted papilloma (SIP) is a relatively rare disease, and its etiology is not understood. It is characterized by locally aggressive growth and a strong tendency to recur despite its benign histology., Aims: The aim of this study was to identify the presence of human papilloma virus (HPV) and its surrogate marker p16 in SIP tissue samples from a regional cohort., Material and Methods: Subjects were identified from our regional center cohort of 88 SIP patients treated between 1984-2014. From these subjects, 54 were included in this study. Of these, 53 biopsies were analyzed with PCR, and 54 samples were immunohistochemically stained for p16. DNA was extracted from histopathologically verified SIP. Genotype screening for 13 high risk-, 5 oncogenic and 6 low risk HPV types was performed using the PapilloCheck® HPV-screening test., Results: HPV analysis was successful for 38 of 53 samples. Of the 38 successfully analyzed samples, only 2 samples were positive for HPV 11. Notably, p16 was present in the epithelia in all samples, and in the papilloma lesions in 37 samples., Conclusion: Since only 2 out of 38 SIPs were positive for HPV (type 11), and at the same time p16 was positive in epithelia in all samples and in 37 of 38 papilloma lesions of the samples, it is concluded that p16 cannot be used as a surrogate marker for high-risk HPV-infection in SIP. We are currently planning a prospective, multicenter study in order to increase the study power and in order to be able to better evaluate the clinical implications of HPV-and p16 in SIP., (Copyright © 2019. Published by Elsevier Masson SAS.)

The field of head and neck pathology was just developing 50 years ago but has certainly come a long way in a relatively short time. Thousands of developments in diagnostic criteria, tumor classification, malignancy staging, immunohistochemistry application, and molecular testing have been made during this time, with an exponential increase in literature on the topics over the past few decades: There were 3506 articles published on head and neck topics in the decade between 1969 and 1978 (PubMed source), with a staggering 89266 manuscripts published in the most recent decade. It is daunting and impossible to narrow the more than 162000 publications in this field and suggest only a few topics of significance. However, the breakthrough in this anatomic discipline has been achieved in 3 major sites: oropharyngeal carcinoma, salivary gland neoplasms, and sinonasal tract tumors. This review will highlight selected topics in these anatomic sites in which the most profound changes in diagnosis have occurred, focusing on the information that helps to guide daily routine practice of surgical pathology., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Ectopic pituitary adenoma is a rare entity that is most commonly located in the sphenoid sinus. We report a case of a patient with ectopic pituitary adenoma with no functional expression associated with empty sella turcica, which gives rise to a broad differential diagnosis. Although it is a benign neoplasm, necrosis is encountered in a proportion of cases. Magnetic resonance imaging is the diagnostic method of choice for hypothalamic-pituitary-related endocrine diseases with endoscopic biopsy for histological confirmation. It is important to include pituitary markers in the immunohistochemical diagnostic panel., (Copyright © 2018 Sociedad Española de Anatomía Patológica. Publicado por Elsevier España, S.L.U. All rights reserved.)

Biphenotypic sinonasal sarcoma (BSNS) is a locally aggressive tumor occurring in the sinonasal region. It harbors both myogenic and neural differentiation and is characterized by PAX3 rearrangement with MAML3 as the most frequent fusion partner, but the partner of PAX3 remains unidentified in a subset of cases. About 70 cases have been reported so far. In this study, we report a series of 41 cases with clinical, pathologic, and molecular description. Twenty-five (61%) patients were female individuals, and the median age was 49 years. Tumors arose predominantly in the nasal cavity and ethmoidal sinuses. Local recurrences occurred in 8 cases of the 25 (32%). Histologic features were characteristic of BSNS, with 5 cases showing focal rhabdomyoblastic differentiation. Immunohistochemistry showed a constant positivity of S100 protein and PAX3 and negativity of SOX10. MyoD1 was focally positive in 91% of cases, whereas only 20% were positive for myogenin. Molecular analysis showed a PAX3-MAML3 transcript in 37 cases (90%). RNA sequencing was performed in the 4 negative cases for PAX3-MAML3 fusion, and it showed that 1 case harbored a PAX3-FOXO1 fusion, as previously described in the literature, and 2 novel fusions: PAX3-WWTR1 fusion in 2 cases and PAX3-NCOA2 fusion in 1 case. RNA sequencing results were confirmed by fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, and Sanger sequencing. The PAX3-NCOA2-positive case showed focal rhabdomyoblastic differentiation. In conclusion, we report 2 novel fusions (PAX3-WWTR1 and PAX3-NCOA2) in BSNS and show that MyoD1 is more sensitive than myogenin for demonstrating myogenic differentiation in this tumor.

Background and Objectives: We have previously indicated that EGFR has a role in carcinogenesis in a subgroup of sinonasal squamous cell carcinomas (SNSCC). In addition, EGFR activates 2 of the most important intracellular signalling pathways: PI3K/pAKT/mTOR/pS6 and MAP pathway kinases. The objective of this study was to evaluate the involvement of the EGFR/PI3K/pAKT/mTOR/pS6 pathway and its relationship with clinical-pathological parameters and follow-up of sinonasal squamous cell carcinoma., Material and Methods: The immunohistochemical expression of different components of the PI3K/AKT/mTOR/pS6 pathway and its relationship with various clinical-pathological parameters was studied in a series of 54 patients with SNSCC., Results: Loss of PTEN expression was observed in 33/54 cases (61%) and pAKT, mTOR and pS6 pre-expression was observed in 19/54 cases (35%), 8/54 cases (15%), and 47/54 cases (87%), respectively. Loss of PTEN expression was related to intracranial invasion and development of regional metastases (p=0.005). Overexpression of pS6 was associated with a decrease in survival (p=0.008), presence of local recurrences (p=0.055), and worsening of overall prognosis (p=0.007). No significant relationships were observed between pAKT and mTOR expression and the clinicopathological parameters studied., Conclusions: Alterations in the expression of EGFR/PI3K/pAKT/mTOR/pS6 pathway components are common in a subgroup of SNSCC. This study reveals that the absence of pS6 overexpression is associated with better clinical outcomes. Therefore, pS6 expression could be considered as an unfavourable prognostic marker., (Copyright © 2018. Publicado por Elsevier España, S.L.U.)

SMARCB1 (INI-1)-deficient sinonasal carcinoma is a rare entity within the subgroup of poorly differentiated sinonasal tract carcinomas. As there are only two papers describing the cytologic features of this entity, herein we describe the unique cytomorphologic features of a pulmonary metastasis of this tumor and include the differential diagnosis based on tumor location. The patient was a 53-year-old male who initially presented with sinus congestion and vision changes including left-eye proptosis and diplopia. The initial biopsy of the ethmoid-centered sinonasal mass was non-keratinizing squamous cell carcinoma based on strong immunoreactivity with p40 and absence of immunoreactivity for chromogranin, synaptophysin, p16, and EBER. However, the final diagnosis of the surgical resection was amended to SMARCB1 (INI-1)-deficient sinonasal carcinoma after additional immunohistochemical stains were performed. Post-primary resection, follow-up computed tomography imaging revealed significant interval progression of a solitary, initially indeterminate 1-cm lung nodule in the left upper lobe. Endobronchial ultrasound-guided fine-needle aspiration with concomitant core-needle biopsy was performed. Rapid on site evaluation of cytologic smears revealed a hypercellular specimen consisting of sheets of epithelioid cells with very scant to absent cytoplasm, ill-defined cell borders, enlarged fragile nuclei, and areas of nuclear molding. Mitotic figures were present. Other areas showed tumor cells with spindled to elongated nuclei and scant to ill-defined wispy cytoplasm. Both cytology cell block and core-needle biopsy histopathologic material showed the tumor cells to be negative for INI-1 nuclear staining as well as CK5/6, CAM5.2, p40, p63, CK7, AE1/3, and TTF-1. SMARCB1 (INI-1)-deficient sinonasal carcinoma can have a spectrum of morphologies and may mimic "small-round-blue-cell" and spindle-cell tumors on cytology preparations. Given the pulmonary location of the aspirate, familiarity with the cytomorphologic spectrum of SMARCB1 (INI-1)-deficient sinonasal carcinoma, inclusion of this entity within the differential diagnosis, and performance of immunohistochemistry will aid in arriving at the correct diagnosis., (© 2019 S. Karger AG, Basel.)

Objective: To investigate the correlation between the expression of CD117, MITF, NAT10 and clinical parameters in sinonasal mucosal melanoma (SNMM). Methods: Formalin-fixed paraffin-embedded tumor specimens of 80 cases of SNMM at the Eye, Ear, Nose and Throat Hospital, Fudan University, from December 1999 to November 2013 were analyzed for CD117, MITF and NAT10 expression by immunohistochemistry. Results: There were 40 men and 40 women. The median age was 61 years, age 26 to 85 years. There was no correlation of the expression of CD117, MITF and NAT10 with the patients' age, gender, tumor site, stage, therapy method and brain metastases ( P >0.05). The expression of MITF and NAT10 was associated with lymph node metastasis and the tumors were more likely to metastasize when MITF and NAT10 were positive. However, expression of CD117 had no correlation with lymph node metastasis. Log-rank test revealed that the expression of CD117 was correlated with both three-year and five survival rate ( P =0.012, P =0.023; respectively) and patients with tumor having low expression of CD117 had the worse outcome. COX test revealed that low CD117 expression, advanced age and lymph node metastasis were independent risk factors ( P <0.05). No significant association was found between the expression of CD117, MITF and NAT10 with disease free survival ( P >0.05). Conclusions: Patients with SNMM expressing low level of CD117 have decreased survival rate. Tumors with high level of MITF and NAT10 expression are more likely to metastasize. The expression level of CD117 can be used as an important indicator for the patient survival, and the expression of MITF and NAT10 can be used as a predictor of tumor metastasis.

Biphenotypic sinonasal sarcoma (BSNS) is a distinctive, anatomically restricted, low-grade spindle cell sarcoma that shows considerable histologic overlap with other cellular spindle cell neoplasms. This tumor type shows both myogenic and neural differentiation, which can be demonstrated by immunohistochemistry; however, the available diagnostic markers are relatively nonspecific. BSNS is characterized by PAX3 rearrangements, with MAML3 as the most common fusion partner. Our aim was to determine whether immunohistochemistry using a monoclonal PAX3 antibody could distinguish BSNS from potential histologic mimics, as well as to evaluate a widely available polyclonal PAX8 antibody, which is known to cross-react with other paired box transcription factor family members. Immunohistochemistry for PAX3 and PAX8 was performed on whole sections of 15 BSNS (10 with confirmed PAX3 rearrangement) and 10 cases each of the following histologic mimics: malignant peripheral nerve sheath tumor, monophasic synovial sarcoma, spindle cell rhabdomyosarcoma (RMS), solitary fibrous tumor, sinonasal hemangiopericytoma, and cellular schwannoma, as well as alveolar RMS (which harbors PAX3 or PAX7 gene rearrangements). BSNS showed consistent expression of PAX3 (15/15), all multifocal-to-diffuse and most with moderate-to-strong intensity of staining. One single case of spindle cell RMS showed PAX3 expression (1/10), and all other histologic mimics were completely PAX3-negative. In contrast, nuclear staining for PAX8 was present in all 15 BSNS, 7/10 malignant peripheral nerve sheath tumor, 3/10 cellular schwannomas, 2/10 sinonasal hemangiopericytomas, 1/10 synovial sarcoma, 1 spindle cell RMS, and 1 solitary fibrous tumor. All cases of alveolar RMS were positive for PAX8, and most were also positive for PAX3 (8/10). Immunohistochemical expression of PAX3 is highly sensitive (100%) and specific (98%) for BSNS. A polyclonal PAX8 antibody also stains BSNS (likely due to cross-reactivity with PAX3) but has much lower specificity (75%), with frequent expression in numerous mimics.

Objective: To investigate the clinicopathologic characteristics, immunophenotypes, molecular genetics, and diagnostic and differential diagnostic features of biphenotypic sinonasal sarcoma (BSNS). Methods: Three cases of BSNS were retrieved, the histomorphology, immunophenotype and molecular genetics were analyzed with review of literature. Results: There were 2 male and 1 female patient aged 45, 29 and 40 years, respectively.Computed tomography and magnetic resonance imaging examinations showed a large polypoid mass occupying the sinonasal cavity in all 3 patients. Microscopically, these tumors were un-circumscribed and composed of cellular spindle-shaped cells arranged in long and interlaced fascicles. A hemangiopericytoma-like growth pattern was frequently identified. The overlying hyperplastic respiratory epithelium invaginated down into the tumor forming a cystic (2 cases), glandular (1 case) structures and inverted in a papilloma-like (1 case)pattern, and foci of eosinophilic metaplasia were also noted in 2 of the three cases. The tumor nuclei were bland-appearing, mitoses were scarce and necrosis was absent. Immunohistochemically, the tumor cells showed co-expression of neural and myogenic markers in all the 3 cases, including that 3/3 showed diffuse and strong positivity of S-100 protein, 3/3 positivity of smooth muscle actin (1 diffuse and 2 focal), 1/2 diffuse positivity of calponin, 1/3 focal positivity of desmin, and 1/1 focal positivity of MyoD1.In addition, 1 detected for β-catenin showed focal nuclear positivity. None of the 3 showed positivity to cytokeratin, CD34 or SOX10 in the tumor cells.Ki-67 showed an index <5%, 10% and <2%, respectively. Fluorescence in situ hybridization analysis showed rearrangements of PAX3 gene in all 3 cases. In case 3, reverse transcription polymerase chain reaction, followed by Sanger sequencing, demonstrated an in-frame fusion between PAX3 and FOXO1.Follow-up information (range 3-15 months)showed no evidence of local recurrence or distant metastasis in three cases. Conclusions: BSNS is a newly described entity which can be readily confused with a variety of benign and malignant spindle cell tumors encountered in the sinonasal cavity; immunohistochemistry co-expression of neural and myogenic markers and PAX3 gene rearrangement can help distinguish this tumor from its many mimickers.

Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC), originally known as HPV-related carcinoma with adenoid cystic carcinoma-like features, is a peculiar neoplasm that is restricted to the sinonasal tract, exhibits features of both a surface-derived and salivary gland carcinoma (particularly adenoid cystic carcinoma), and is associated with high-risk HPV. Given the limited number of published cases, the full clinicopathologic spectrum of this neoplasm is unclear. Here, we present an updated experience of 49 cases. All cases of HMSC were obtained from the authors' files. Immunohistochemistry for p16, c-kit, and myoepithelial cell markers (S100, actin, calponin, p63, and/or p40) was performed along with RNA in situ hybridization for HPV (type 33-specific as well as a high-risk cocktail). Fluorescence in situ hybridization studies for fusions of MYB, NFIB, and MYBL1 was performed on a subset of cases. Clinical follow-up was obtained from medical records. A total of 49 cases of HMSC were collected. Twenty-eight (57%) were from women and 18 (43%) from men, ranging in age from 28 to 90 years (mean, 54 y). Of 40 cases with detailed staging information, 43% of HMSCs presented with a high T-stage (T3 or T4). Histologically, most grew predominantly as solid nests of basaloid cells exhibiting high mitotic rates and frequent necrosis, with histologic and immunohistochemical evidence of myoepithelial differentiation. Most cases also demonstrated foci of cribriform and/or tubular growth, along with an inconspicuous population of ducts. Thirty-four (69%) cases demonstrated an unusual pattern of surface involvement where markedly atypical squamous cells colonized tracts of the sinonasal mucosa. Less consistent histologic features included squamous differentiation within the invasive tumor (n=6), sarcomatoid transformation (n=5) including overt chondroid differentiation (n=3), and prominent epithelial-myoepithelial carcinoma-like growth (n=3). All cases were positive for p16 by immunostaining and HPV by RNA in situ hybridization. Thirty-three (67%) were positive for HPV 33. No cases tested for MYB, MYBL1, or NFIB gene fusions were positive. In the 38 cases with follow-up data, (mean follow-up, 42 mo) 14 recurred locally and 2 metastasized (lung, finger). There were no regional lymph node metastases, and no tumor-related deaths. HMSC is a distinct sinonasal neoplasm characterized by myoepithelial differentiation, frequent surface epithelial involvement, and the presence of high-risk HPV (especially type 33). Although it classically exhibits a cribriforming pattern that closely resembles adenoid cystic carcinoma, our expanded series highlights a histologic spectrum that is much broader than previously recognized, warranting a change in terminology. HMSC usually presents as a large and destructive sinonasal mass with high-grade histologic features, but it paradoxically behaves in a relatively indolent manner, underscoring the importance of distinguishing HMSC from true adenoid cystic carcinoma, squamous cell carcinoma, and other histologic mimickers.

Low-grade sinonasal adenocarcinomas (low-grade SNACs) of the sinonasal tract comprise a poorly characterized and histologically heterogeneous group of tumors. We describe three cases of a histologically distinct variant of low-grade SNAC characterized by ETV6 gene rearrangements. The patients included 2 women (aged 32 and 88 y) and a man (aged 75 y); all were initially treated with surgery alone. Follow-up ranged from 9 to 170 months with one patient having 2 local recurrences and none experiencing distant or regional metastases. Tumors were composed of cytologically bland columnar and cuboidal eosinophilic tumor cells with basally located nuclei arranged in tubular and tubulotrabecular patterns. Immunohistochemically, CK7, DOG1, GCDFP-15, and SOX10 were positive in all cases, and vimentin was positive in 2 cases. Scattered single cells or small groups of tumor cells were S-100 positive. Only one case had weak, focal expression of GATA3, and mammaglobin was consistently negative. Two cases had ETV6-NTRK3 gene fusions, whereas ETV6 had an unknown fusion partner gene in one case. The highly similar morphology, immunohistochemical profile, and genetics of the presented cases are suggestive of a specific disease. Although translocation-associated adenocarcinomas in the sinonasal tract have previously been described exclusively as salivary-type carcinomas, we present the first type of carcinoma characterized by recurrent genetic rearrangements and distinct phenotype occurring exclusively in the sinonasal tract with no known major salivary gland counterpart. We provisionally designate this tumor ETV6-rearranged low-grade SNAC. Identification of additional cases is necessary to fully appreciate the morphologic and biological spectrum of this disease.

Background: Whereas anti-PD-1 therapy has demonstrated a significant and durable response against advanced cutaneous melanoma, conventional chemotherapies have shown only minor benefit against advanced mucosal melanoma., Objectives: To investigate the efficacy of anti-PD-1 therapy in a small cohort of patients with mucosal melanoma of the head and neck., Materials & Methods: We analysed five patients with mucosal melanoma of the head and neck who received nivolumab or pembrolizumab, at an advanced stage. Expression of PD-L1 and PD-1 in all tumour samples was evaluated immunohistochemically., Results: All patients received at least two cycles of nivolumab or pembrolizumab. The most severe adverse events were categorised as CTCAE (common terminology criteria for adverse events) Grade 2. All patients showed progressive disease after restaging at three and six months, and no partial or complete response was observed. Immunohistochemical staining demonstrated PD-L1 expression in less than 5% of tumour cells., Conclusion: Systemic therapy with either nivolumab or pembrolizumab showed no clinical response, however, tumour progression was identified in all patients using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and immune-related response criteria (irRC) to evaluate tumour response.

Objective: To study the clinicopathologic features, immunophenotype, differential diagnosis and prognosis of non-keratinizing carcinoma of nasal cavity and paranasal sinus., Methods: Four hundred and forty-one cases of squamous cell carcinoma of the nasal cavity and sinuses diagnosed in Beijing Tongren Hospital from January 2008 to August 2015 were included. Twenty-six cases of non-keratinizing carcinomas were selected. The histopathologic features and the clinicopathologic data of these twenty-six cases were retrospectively analyzed. Immunohistochemistry (two-step EnVision method) was done to evaluate the expression of CK, vimentin, CK5/6, CK7, CK8/18, p16, p53, Ki-67 etc. In situ hybridization was used to detect Epstein-Barr virus mRNA(EBER), and flow-through hybridization was used to evaluate the presence of human papilloma virus (HPV). One of the cases which HPV is positive was detected by HPV in situ hybridization and RNAscope technology., Results: The mean age for the twenty-six patients (16 males, 10 females) was 51.2 years (range 22 to 79 years). Three patients had a history of inverted papilloma.Microscopically the tumors showed invasive papillary and inverted growth, and formed solid cell nests with different sizes. It was similar to papillary carcinoma of the urinary tract: the nuclei of the tumor were rounded and the nucleolus are clear. Three cases displayed transition between normal epithelium to neoplastic cells; in two cases (2/26), some tumor cells were spindle shaped. Twenty cases (20/20) were strongly positive for CK, p63; 17 cases (17/20) were strongly positive for CK5/6 and three cases (3/20) were focally positive. Sixteen cases were strongly positive for CK8/18 and three cases (3/20) were focally positive and one case was negative. Seven cases (7/20) were strongly positive for CK7 and 13 cases (13/20) were negative. Two cases (2/20) were focally positive for vimentin and eighteen (18/20) cases were negative. One case (1/20) was strongly positive for p16 and nineteen cases (19/20) were negative. Nineteen cases (19/20) were positive for p53 and one case (1/20) was negative. Ki-67 index was >50% in 11 cases. Twenty cases (20/20) were negative for AFP, NUT, S-100 protein, HMB45 and Melan A. One case was positive for HPV (6, 11, 16, 18), as detected by in situ hybridization. The HPV18 mRNA was detected by RNAscope technique. In situ hybridization were negative in all twenty cases. The mean follow-up time of the patients in this group was less than 5 years, and the prognosis needs further observation., Conclusions: Non-keratinizing squamous cell carcinoma is a rare neoplasm with distinct morphological characteristics. Its diagnosis is primarily based on the site of lesions and the histological features.Immunohistochemistry staining can aid the diagnosis and differential diagnoses. The tumor may originate from the epithelium of nasal cavity and sinus. This disease has no relation with HPV and EBV infection, and the treatment is primarily surgical excision combined with postoperative radiotherapy.

Biphenotypic sinonasal sarcoma (BSNS) is a recently recognized low-grade sarcoma that exhibits both neural and myogenic differentiation. This unique dual phenotype stems from recurrent rearrangements in PAX3, a transcription factor that promotes commitment along both lineages. While identification of PAX3 rearrangements by fluorescence in situ hybridization (FISH) can confirm a BSNS diagnosis, this assay is not widely available. This study evaluates whether an expanded immunohistochemical panel can facilitate recognition of BSNS without molecular analysis. Eleven cases of BSNS were identified from the surgical pathology archives of two academic medical centers. In 8 cases, the diagnosis was confirmed by FISH using custom probes for PAX3. In 3 cases, FISH failed but histologic and immunophenotypic findings were diagnostic for BSNS. All 11 BSNS (100%) were at least focally positive for S100 as well as calponin and/or smooth muscle actin. In addition, 10 (91%) of 11 expressed nuclear β-catenin, 8 (80%) of 10 expressed factor XIIIa, 4 (36%) of 11 expressed desmin, and 3 (30%) of 10 expressed myogenin. All 11 tumors were negative for SOX10. While no single marker resolves immunohistochemical overlap between BSNS and its histologic mimickers such as nerve sheath tumors, an extended immunohistochemical panel that includes β-catenin and SOX10 helps to support the diagnosis of BSNS without the need for gene rearrangement studies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Surgical pathology of the sinonasal region (i.e., nasal cavity and the paranasal sinuses) is notoriously difficult, due in part to the remarkable diversity of neoplasms that may be encountered in this area. In addition, a number of neoplasms have been only recently described in the sinonasal tract, further compounding the difficulty for pathologists who are not yet familiar with them. This manuscript will review the clinicopathologic features of some of the recently described sinonasal tumor types: NUT midline carcinoma, HPV-related carcinoma with adenoid cystic-like features, SMARCB1 (INI-1) deficient sinonasal carcinoma, biphenotypic sinonasal sarcoma, and adamantinoma-like Ewing family tumor., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Primary soft tissue tumors arising in the sinonasal tract are rare. While many mesenchymal neoplasms have been reported in the nasal cavity, sinuses, and nasopharynx, few are distinctive to this anatomic region. Some tumor types are relatively more common in this area, such as schwannoma and rhabdomyosarcoma. Nasopharyngeal angiofibroma and sinonasal hemangiopericytoma are unique entities of the sinonasal tract, as well as the recently characterized biphenotypic sinonasal sarcoma. This review discusses the clinical, morphologic, and immunohistochemical features and currently known molecular data of the more frequently encountered soft tissue tumors of the sinonasal tract., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The differential diagnosis for small round cell tumors in the sinonasal tract is diverse and as the body of literature documenting not only uncommon presentations but also availability of ancillary studies grows, so does the need for a reminder to take a conservative and thorough approach before rendering a diagnosis. Small tissue samples are particularly problematic, with limitations that include volume of tumor cells available for studies, lack of architectural context and a non-specific gross description. Incorporation of patient history and presentation, radiologic findings, clinical impression and concurrent studies often guide the course of studies performed by the pathologist. If these are non-specific, the pathologist may need to perform ancillary studies, including a broad panel of immunohistochemical stains and molecular studies. If tissue is limited, a precise classification may not be achievable. Although the expectation to render a definitive diagnosis is high, the pathologist should never feel compelled to go further with a diagnosis than the tissue itself supports., (Copyright © 2016 Elsevier Inc. All rights reserved.)

It is now well established that human papillomavirus (HPV) is an important causative factor in a subgroup of head and neck cancer. In the head and neck, while HPV is strongly associated with squamous cell carcinoma arising in the oropharynx, there is a growing interest in HPV-associated neoplasms of non-oropharyngeal origin including those which arise within sinonasal and nasopharyngeal mucosa. This article reviews current literature on the association of HPV with Scheiderian papillomas, sinonasal squamous cell carcinoma, sinonasal undifferentiated carcinoma, carcinoma with adenoid cystic-like features, and nasopharyngeal carcinoma. Several clinical implications of HPV detection in sinonasal and nasopharyngeal carcinomas are briefly discussed., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Various hematolymphoid lesions involve the sinonasal tract, including aggressive B, T, and NK-cell neoplasms; myeloid sarcoma; low-grade lymphomas; indolent T-lymphoblastic proliferations; and Rosai-Dorfman disease. Differentiating aggressive lymphomas from non-hematopoietic neoplasms such as poorly differentiated squamous cell carcinoma, olfactory neuroblastoma, or sinonasal undifferentiated carcinoma may pose diagnostic challenges. In addition, the necrosis, vascular damage, and inflammatory infiltrates that are associated with some hematolymphoid disorders can result in misdiagnosis as infectious, autoimmune, or inflammatory conditions. Here, we review hematolymphoid disorders involving the sinonasal tract including their key clinical and histopathologic features., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Sarcomas arising in the sinonasal region are uncommon and encompass a wide variety of tumor types, including the newly described biphenotypic sinonasal sarcoma (BSNS), which is characterized by a monomorphic spindle cell proliferation with dual neural and myogenic phenotypes. Most BSNSs harbor a pathognomonic PAX3-MAML3 fusion driven by t(2;4)(q35;q31.1), whereas the alternative fusion partner gene remains unidentified in a subset of PAX3-rearranged cases. As NCOA1 on 2p23 is a known partner in PAX3-related fusions in other tumor types (ie, alveolar rhabdomyosarcoma), we investigated its status by fluorescence in situ hybridization (FISH) and reverse transcription polymerase chain reaction assays in 2 BSNS cases showing only PAX3 gene rearrangements. Novel PAX3-NCOA1 fusions were identified in these 2 index cases showing an inv(2)(q35p23) by FISH and confirmed by reverse transcription polymerase chain reaction. Five additional BSNS cases with typical morphology were studied by FISH, revealing a PAX3-MAML3 fusion in 4 cases and only PAX3 rearrangement in the remaining case without abnormalities in MAML3 or NCOA1 gene. Except for 1 case with surface ulceration, all other tumors lacked increased mitotic activity or necrosis, and all cases immunohistochemically coexpressed S100 protein and actin, but lacked SOX10 reactivity. Interestingly, the 2 PAX3-NCOA1-positive cases showed desmin reactivity and displayed a small component of rhabdomyoblastic cells, which were not seen in the more common PAX3-MAML3 fusion cases. In conclusion, we report a novel PAX3-NCOA1 fusion in BSNS, which appears to be associated with focal rhabdomyoblastic differentiation and should be distinguished from PAX3-NCOA1-positive alveolar rhabdomyosarcoma or malignant Triton tumor. SOX10 immunohistochemistry is a useful marker in distinguishing BSNS from peripheral nerve sheath tumors.

Alveolar rhabdomyosarcoma (ARMS) is a common soft tissue tumor in children which can rarely metastasize to the breast in adults. Here we report the rare case of a 42-year-old Asian woman, who was diagnosed with ARMS of the nasopharynx and paranasal sinuses, and got a complete remission (CR) after surgery and chemoradiotherapy. Then the patient relapsed in the unilateral breast seventeen months later. Histology and immunohistochemistry of the primary sites and the breast lesions, combined with FISH, have been performed to confirm the diagnosis of metastatic alveolar rhabdomyosarcoma. With a rational therapeutic regimen of surgery, chemotherapy and radiotherapy, the patient has got a complete remission again.

Introduction: Primary mucosal melanoma of the sinonasal tract is a rare neoplasm, accounting for less than 1% of all melanomas. It has an aggressive and unpredictable biologic behavior characterized by frequent incidence of local recurrence, local and distant metastasis of the disease., Case Report: This report summarizes the results of the previous research concerning sinonasal mucosal melanoma, and by the example of the two patients suffering from mucosal melanoma, we described clinical and histopathological features of this rare neoplasm and our experience in its diagnosis and treatment., Conclusion: Only histopathological analysis complemented by immunobistochemical analysis contributes to early and accurate diagnosis of the disease.

Leiomyoma is an extremely rare tumor in sinonasal area. The reason for this is due to minimal amount of the smooth muscle in the area. The origin of this tumor is not clear and its etiology has not been proven in the literature. A 58-year-old woman who experienced nasal obstruction and epiphora visited our clinic. A huge mass was noted in right nasal cavity originating from the lacrimal bone area. The authors conducted endoscopic sinus surgery and obtained the specimen. Immunochemistry showed leiomyoma in the nasal cavity, which expressed estrogen receptor. There was no progesterone receptor expressed. The authors describe a sinonasal leiomyoma with estrogen receptors, not ever reported in previous article.

Sinonasal-type hemangiopericytomas, which comprise less than 0.5% of all sinonasal neoplasms, arise unilaterally in the nasal cavity as polypoid masses with a mean diameter of about 3 cm. A 34-year-old female patient was admitted due to nasal obstruction and epistaxis. A polypoid mass covered with intact mucosa that originated both from the right inferior concha and lateral nasal wall was detected by nasal endoscopy. The tumor, extending from the oropharynx to the nasopharynx, was measured as 3,5x3x2 cm. Although exhibiting characteristic histopathological features and typical clinical symptoms, this case with unexpected immunohistochemical findings can provide a viewpoint on the nature of this kind of tumors.

SMARCB1 (INI-1) is a tumor-suppressor gene located on chromosome 22q11.2. Its gene product is ubiquitously expressed in nuclei of all normal tissues. SMARCB1 gene inactivation has been implicated in the pathogenesis of a diverse group of malignant neoplasms that tend to share "rhabdoid" cytomorphology. This group of SMARCB1-deficient tumors is now further expanded by a subset of carcinomas arising in the sinonasal tract. SMARCB1 immunostaining was performed on 142 sinonasal carcinomas. Tumors that showed loss of expression were further characterized for SMARCB1 deletions by fluorescence in situ hybridization. Nine of 142 (6%) primary sinonasal carcinomas showed loss of SMARCB1 expression by immunohistochemistry. Five patients were women, and patients ranged in age from 33 to 78 years (mean 59 y). The SMARCB1-deficient tumors were characterized by nests, sheets, and cords of cells without any histologic evidence of specific (eg, squamous or glandular) differentiation. The tumors comprised varying proportions of basaloid and rhabdoid cells. The SMARCB1-deficient carcinomas had been diagnosed as nonkeratinizing squamous cell carcinomas (n=3), sinonasal undifferentiated carcinomas (n=2), myoepithelial carcinoma (n=2), nonintestinal adenocarcinoma (n=1), and carcinoma, not otherwise specified (n=1). Fluorescence in situ hybridization analysis revealed SMARCB1 deletions in 6 of 8 (75%) carcinomas. The SMARCB1-deficient carcinomas did not harbor human papillomavirus or NUT-1 alterations. Six patients presented with T4 disease, 5 patients developed local recurrences and/or distant metastases, and 4 died of their disease. Inactivation of the SMARCB1 tumor-suppressor gene appears to be involved in the pathogenesis of a subset of sinonasal carcinomas, further expanding the family of SMARCB1-deficient neoplasms and further delineating a bewildering group of poorly/undifferentiated, aggressive carcinomas arising at this site. The ability to detect SMARCB1 loss by immunohistochemistry, particularly when dealing with poorly differentiated carcinomas with basaloid or rhabdoid features, should facilitate a more comprehensive understanding of these sinonasal carcinomas including clinical behavior and response to targeted therapies.

Poorly differentiated sinonasal carcinomas are a heterogenous group of aggressive neoplasms that encompasses squamous cell carcinoma including basaloid variant, lymphoepithelial carcinoma, sinonasal undifferentiated carcinoma, and neuroendocrine-type small cell carcinoma. We herein describe 3 cases of a hitherto unreported variant combining features of basaloid carcinoma with variable intermingled rhabdoid cells. Patients were 2 women (aged 28 and 35) and a man (52 y) who presented with sinonasal masses. All had advanced local disease with bone involvement (pT4). None had a history of irradiation or a family history of rhabdoid tumors. Treatment was surgery and adjuvant chemoradiation. One patient developed liver, lung, pleural, and pericardial metastases (63 mo) and is currently (70 mo) alive under palliative treatment. Another developed recurrent cervical lymph node metastases and died of disease 8.5 years later. The youngest patient was disease-free at last follow-up 7 years later. Histologic features were very similar in all 3 cases and showed intimate admixture of compact basaloid cell nests with peripheral palisading, perivascular pseudorosettes, and a few scattered rhabdoid cells. Rhabdoid cells were more extensive in the metastasis in 1 case but formed a minor inconspicuous component in the primary tumors in all cases. Striking features common to all cases were (1) basaloid "blue" appearance at low power, (2) papilloma-like exophytic component, (3) extensive pagetoid surface growth with prominent denuding features, and (4) replacement of underlying mucous glands mimicking an inverted papilloma. Clear-cut origin from benign papilloma and overt squamous differentiation were lacking. Diffuse (2) or partial (1) p16 expression was noted, but all cases lacked human papillomavirus DNA by molecular tests. In situ hybridization was negative for Epstein-Barr virus. Immunohistochemistry showed diffuse expression of pancytokeratin. CK5 and vimentin showed intermingling of CK5/vimentin basaloid and CK5/vimentin rhabdoid cells. Complete loss of nuclear SMARCB1 expression was seen in all cases including also the denuding carcinoma in situ-like surface lesions. To our knowledge, this variant of sinonasal carcinoma has not been reported before. The identical features in all 3 cases suggest a specific disease rather than a nonspecific dedifferentiated phenotype. Awareness of this rare variant and thus reporting of additional cases is necessary for defining its full morphologic and biological spectrum.

Introduction and Objectives: Intestinal-type sinonasal adenocarcinomas are malignant epithelial tumours. Around 8-25% of all sinonasal malignant tumours are intestinal-type adenocarcinomas, which are related to wood dust exposure. Four histological subtypes have been described: papillary, colonic, solid and mucinous. We performed a pathological and immunohistochemical study in order to describe characteristics with prognostic, diagnostic and therapeutic value, and also to compare our results with previous studies., Methods: Sixty six tumour samples were analysed and protein expression of p53, p16, E-cadherin, β-catenin, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2/neu) and cyclooxygenase-2 (COX-2) was performed by tissue microarray blocks., Results: The 63% of cases were p53 positive; 37% showed nuclear staining with β-catenin and 100% with E-cadherin, while 98% showed membrane staining with β-catenin, 7% with EGFR, 8% with HER2/neu and 52% with COX-2; and 59% of the cases lost p16 expression., Conclusions: Intracranial invasion was the worst prognostic associated event. Solid and mucinous tumours were the most aggressive histological subtypes. Intracranial invasion was more frequent in mucinous subtype tumours. Immunohistochemical results were similar in all tumour subtypes, except for mucinous tumours, which showed weak expression of E-cadherin and β-catenin. Comparing with previous studies, we found a lower expression of EGFR, HER2/neu and COX-2. The p16 expression was associated with worse survival and metastatic disease., (Copyright © 2012 Elsevier España, S.L. All rights reserved.)

Background: Nonsalivary adenocarcinomas are the most interesting tumors found in the sinonasal area. They are rare tumors arising from surface epithelium. The clear cell type of this tumor is even more rare. We present cytologic findings of clear cell sinonasal adenocarcinoma and related pitfalls., Case: A 52-year-old woman presented with a left-cheek facial mass of 3-4 years' duration, with progressive enlargement, nasal discharge and discoloration of the lateral side of her left eye. Computed tomography was performed, revealing an expansile mass involving the nasal cavity, left maxillary sinus, ethmoid sinus with extension to sphenoid sinus, left side of oral cavity and left orbit. Fine needle aspiration performed through the upper buccogingival canine fossa showed clusters of epithelial cells with clear cytoplasm, round nuclei, inconspicuous nucleoli and slight pleomorphism. Some normal ciliated columnar epithelial cells are identified in the vicinity of neoplastic cells. The mass was reported to be a clear cell neoplasm, and excision of the whole mass was performed., Conclusion: Cytologic findings of this rare tumor overlap with those of salivary gland-type tumors with clear cell change and should be added to the list of head and neck tumors with clear cell change.

Objectives: The WHO 2005 histological classification separates sinonasal adenocarcinoma (ADC) into three classes: intestinal-type adenocarcinoma (ITAC), low-grade sinonasal ADC and high-grade sinonasal ADC. The goal of this study was to check the relevance of this classification on the prognosis of patients treated for ADC., Patients and Methods: All the files of patients treated consecutively in the ENT department of the Montpellier University Hospital for ADC between 1980 and 2003 were retrospectively re-examined. Each case was reviewed for anatomical and pathological data based on the immunohistochemistry results according to the WHO 2005 classification, with a study of a panel of markers: cytokeratin 7 (CK7), cytokeratin 20 (CK20), Villin, CDX2 and EGFR. The epidemiologic data, the methods of treatment and the follow-up were studied. The survival probabilities were calculated using the Kaplan-Meier method and the survival graphs were compared using a log-rank test., Results: Sixty-two files were reviewed. Twelve patients were reclassified into the adenoid cystic carcinoma category and excluded from the study. In the 50 remaining cases, there were 36 ITAC cases, four low-grade ADC cases and 10 high-grade dedifferentiated carcinomas. For all of the ADC cases, the total survival at 5 years and without recurrence was 64 and 52%, respectively. The analysis of the three subgroups showed a total survival of 72.2% for ITAC, 100% for low-grade and 20% for high-grade ADC with a significant difference (p=0.044). This immunohistochemical distinction was mainly based on the expression of CK20 found in 98% of the ITAC cases and absent in low- and high-grade ADC patients., Conclusion: The WHO 2005 classification for sinonasal ADC provides a valuable prognosis by showing a difference in the progression profile between ITAC, low-grade ADC and high-grade ADC. Moreover, broader studies should be conducted to investigate the different subtypes of ITAC.

Primary poorly differentiated (small round and non-small) sinonasal neoplasms comprise histogenetically and biologically diverse entities with overlapping morphologic features. Because of the limited initial biopsy tissue materials, differential diagnostic difficulties may arise and complicate timely management of some cases. We used immunohistochemical and molecular marker analyses in a large cohort of these tumors to optimize their early diagnosis and classification. Fifty-two tumors of the skull base and sinonasal regions and, for comparison, 19 poorly differentiated neoplasms of other head and neck sites were analyzed by a panel of immunohistochemical markers including those of epithelial, mesenchymal, melanocytic, and neuroectodermal origin using tissue microarray. Reverse transcriptase-polymerase chain reaction analysis of messenger RNA for EWS-FLI1 and PAX-FKHR fusion transcripts and the human achaete-scute homolog-1 gene was performed on 24 of the 52 sinonasal tumors and the 19 tumors of other sites for comparison. The immunohistochemical results substantiated the phenotypic assessment and the initial diagnosis in 49 of the 52 tumors. In 4 instances the integrated markers and phenotypic analyses led to reclassification of 3 tumors and confirmed the histogenesis of a mesenchymal tumor with aberrant cytokeratin expression. Molecular analysis of the EWS-FLI1 fusion gene transcript revealed 4 (9.3%) of the 43 tumors to be positive; all were Ewing sarcomas. The human achaete-scute homolog-1 gene transcript was identified in 10 (23.8%) of 42 tumors: 3 of 6 neuroblastomas, all 4 neuroendocrine carcinomas, and 1 each in sinonasal undifferentiated carcinoma, rhabdomyosarcoma, and melanoma. The PAX-FKHR fusion transcript was not detected in any tumors. We conclude that (1) an integrated morphologic and biomarker algorithm may better optimize the early diagnosis of poorly differentiated sinonasal and skull-base tumors; (2) molecular analysis may assist in future biological stratification of certain classes of these tumors; and (3) the human achaete-scute homolog-1 gene transcript is a nonspecific marker for the diagnosis of neuroblastoma.

Purpose: To report a case of orbital chordoma, emphasizing the clinical, operative, and histopathologic findings, and to review similar English-language reports., Methods: This is a single case report with histopathologic correlation. Search of the English-language literature and review of referenced citations was performed., Results: After treatment with resection and proton beam radiation, our patient is alive, without recurrence at 3-year follow-up. Biopsy of the recurrent tumor was consistent with chordoma. The original biopsy had S100 and pancytokeratin-positive tumor cells, with abundant clear to eosinophilic cytoplasm. Focal EMA positivity was present. Literature review identified 14 additional cases., Conclusion: Orbital chordoma is rare. Extraocular motility disturbances occur solely with intracranial lesions as well as those extending into the orbit, but globe displacement is the most common sign of orbital involvement. This tumor often recurs in the path of previous resection. Diagnosis is confirmed by distinctive histopathologic features and positive staining for S100, pancytokeratin, and EMA. Treatment and outcome analysis of orbital chordoma is difficult due to its rarity and lack of reported follow-up and may need to be extrapolated from reported skull base cases.

Objective: We describe the clinicopathologic features of 6 cases of myofibroblastic sarcoma (MS) occurring in the nasal cavity and paranasal sinus., Study Design: The paraffin-embedded tissues of 6 cases of MS were stained immunohistochemically and examined by electron microscopy., Results: Clinically, a painless enlarging mass was the most common symptom, followed by the nasal obstruction, epistaxis, copious rhinorrhea, and proptosis. Histologically, the tumors showed a diffusely infiltrative growth pattern and consisted mainly of spindle cells with abundant eosinophilic cytoplasm. The hypocellular myxoid areas and the hypercellular fibrous areas were identified. Immunohistochemically, all 6 tumors were positive for vimentin, alpha-smooth muscle actin, calponin, and fibronectin. Ultrastructural examination in 3 cases showed characteristic features of myofibroblast. Follow-up in 6 patients revealed high local recurrence rate (6 out of 6)., Conclusion: Myofibroblastic sarcoma of the nasal cavity and paranasal sinus exhibit diverse histologic appearances and a strong aggressive behavior.

Context: Adenocarcinomas of the sinonasal tract are classified into 4 categories: salivary-type, intestinal-type, nonintestinal-type, and metastatic. Signet-ring cell carcinoma is the rarest form of intestinal-type adenocarcinoma. Only isolated cases have been reported in the literature., Objective: To evaluate clinical attributes, morphology, and immunohistochemistry in signet-ring cell carcinoma of the sinonasal tract., Design: Seventy-three cases of primary sinonasal adenocarcinomas were retrieved from the files. Only 5 signet-ring cell adenocarcinomas (tumors composed of more than 90% signet-ring cells) were identified. In all cases, clinical data and histologic slides were available and were reviewed. Consecutive tissue sections were immunostained with monoclonal antibodies against MUC2, MUC5AC, MUC5B, MUC6, p53 protein, and MIB-1., Results: Four of our 5 patients were woodworkers. They were treated by surgical excision and radiotherapy. Patient follow-up ranged from 11 to 84 months. Three patients presented an unfavorable evolution and died of metastatic spread. Microscopically, the tumors produced abundant mucin deposits, which accumulated in large extracellular pools. Tumor cells were predominantly signet-ring cells floating in the pools of mucin. The mucins profile was MUC2+, MUC5AC+, MUC5B+, and MUC6-. Eighty percent of cells were immunostained by p53 protein antibody and 60% cells with MIB-1 antibody., Conclusions: The mucin profile is similar to the profile described in digestive tract adenocarcinoma. It is not useful to differentiate between metastatic adenocarcinoma and primary intestinal-type sinonasal adenocarcinoma. Clinical data and immunochemistry with p53 protein and MIB-1 confirm that sinonasal signet-ring cell carcinoma is a high-grade and aggressive tumor.

The aim of this study was to investigate the expression of p16 in relation with the histopathologic features and the clinical course in patients with sinonasal melanoma. Thirty-seven sinonasal melanomas were immunostained for p16. Seventeen tumours were investigated for loss of the 9p21 region using interphase fluorescence in situ hybridization (FISH). Twenty-seven melanomas (72.9%) showed loss of p16 expression. All cases with spindle or mixed cytology showed loss of p16, whereas this was present in 50% of epithelioid tumours (p=0.01). Loss of p16 expression was more frequently seen in melanomas with alveolar architecture (87.5%) than in tumours with diffuse architecture (68.9%) (p=0.4). There was no correlation between p16 expression and presence of lymph node or distant metastases (p=0.57 and 0.24, respectively). In addition, p16 status did not influence overall survival (p=0.2). The FISH results were in good agreement with immunohistochemistry: 11 tumours out of 17 showed deletion of the 9p21 region and 10 of these showed loss of protein expression. Loss of p16 expression is a frequent event in sinonasal melanoma and it is mainly related to deletion of 9p21 region. At variance from cutaneous melanoma, loss of p16 is not correlated with the prognosis of patients affected by sinonasal melanoma.

Alveolar rhabdomyosarcoma is an uncommon tumor. It is a rare malignancy in adults and rarely occurs in paranasal sinuses in those aged older than 50 years. This report describes a locally invasive and destructive alveolar rhabdomyosarcoma arising in the ethmoid sinus of a 57-year-old woman. The small round blue cell tumors are positive for myogenin by immunohistochemistry and have a karyotype of 45, XX, -5, -13, der(16)t(1;1) (q21;q13) by cytogenetic analysis. Fluorescence in situ hybridization demonstrated a complex translocation with break apart of the FKHR region, which supports a diagnosis of alveolar rhabdomyosarcoma. This report characterizes this tumor through microscopic and cyto-genetic analysis and emphasizes the importance of considering rhabdomyosarcoma in the differential diagnosis of small round cell tumors of the head and neck region in the middle-aged adults.

Objective: To clarify the role of immunohistochemistry in the diagnosis of psammomatoid ossifying fibroma (PSOF), conventional cemento-ossifying fibroma (COF), and psammomatous meningioma (PM) of the craniofacial skeleton., Study Design: The histology and immunohistochemistry of 4 PSOFs, 6 COFs, and 7 PMs was studied. Antibodies included EMA, cytokeratins, smooth muscle actin (SMA), desmin, vimentin, CD34, CD10, S-100 protein, and glial fibrillary acidic protein (GFAP)., Results: All PSOFs showed multiple round ossicles homogeneously distributed within a fibroblastic stroma. Psammomatous meningiomas had meningothelial features. All tumors, except 1 COF, were positive for EMA. All of them expressed vimentin, and none showed cytokeratins. Staining for SMA and S-100 protein was variable. CD10 was positive in all cases except 2 meningiomas. CD34 and GFAP stained only 1 case of meningioma each., Conclusions: The diagnosis of PSOF should rest on histologic features. An incorrect diagnosis of meningioma based on the expression of EMA should be avoided.

D2-40 is a monoclonal antibody, which reacts with a fixative-resistant epitope of lymphatic endothelium. Sinonasal-type hemangiopericytoma (SHP) and tumors of the (conventional) hemangiopericytoma/solitary fibrous tumor family (HP/SFT) are characterized by prominent vasculature. However, data concerning D2-40 labeling of these tumors are very sparse. In the present study, we investigated D2-40 staining in tissue specimens of 17 patients with SHP (male to female ratio of 2.4:1, median age of 63 years) and compared the immunolabeling with 20 cases of HP/SFT, including three SFT cases from nasal mucosa. D2-40 was detected in vascular channels of all SHP patients examined. By contrast, all cases of HP/SFT did not reveal any vascular channel being positive for D2-40, neither in the nasal cases nor in the remaining patients. This study presented for the first time data on D2-40 labeling in a series of SHP, HP/SFT, and supports the distinction of SHP from HP/SFT.

Background: Despite their histological resemblance to colorectal adenocarcinomas, there is little information about the molecular events involved in the pathogenesis of intestinal-type sinonasal adenocarcinomas (ITACs)., Aims: To evaluate the possible role of DNA mismatch repair (MMR) gene defects or disruptions of the E cadherin-beta catenin complex in ITAC by investigating the immunohistochemical expression of the MMR gene products, beta catenin, and E cadherin in a group of sporadic ITACs., Methods: Ten sporadic cases of ITAC were stained with antibodies against MLH1, MSH2, MSH3, MSH6, beta catenin, and E cadherin., Results: Nine cases showed strong nuclear expression of MLH1, whereas one case showed moderate staining. All 10 cases were strongly positive for MSH2 and MSH3. MSH6 was strong in nine cases, and moderate in one. Membranous beta catenin expression was strong in all 10 cases, and no case showed cytoplasmic or nuclear staining. E cadherin was strong in seven cases, and moderate in three cases., Conclusions: The preserved nuclear expression of MLH1, MSH2, MSH3, and MSH6 suggests that mutations or promoter methylation of MMR genes do not play a role in the pathogenesis of ITAC. The strong membranous staining for E cadherin and beta catenin and lack of abnormal cytoplasmic or nuclear expression is in keeping with the preservation of E cadherin-beta catenin complexes and beta catenin pathways.

Background: Intestinal-type sinonasal adenocarcinoma (ITAC) is an uncommon neoplasm, which resembles adenocarcinoma of the gastrointestinal tract. ITAC occurs sporadically or in association with occupational exposure to hardwood dust and other agents., Aims: To investigate the phenotype and possible pathogenetic mechanisms of primary sinonasal and nasopharyngeal adenocarcinomas by staining for cytokeratin 7 (CK7), CK20, CDX-2, and villin., Methods: Twelve sporadic sinonasal and nasopharyngeal adenocarcinomas were stained with monoclonal antibodies to CK7, CK20, CDX-2, and villin. The ITACs were classified as papillary, colonic, solid, mixed, or mucinous types., Results: The diagnosis of ITAC was confirmed in 10 cases: five were colonic type and five were papillary. One was a sinonasal papillary low grade adenocarcinoma, and one a papillary nasopharyngeal adenocarcinoma, and these tumours were CK7 positive, but CK20, CDX-2, and villin negative. All ITACs were positive for CK20, CDX-2, and villin, and six were CK7 positive. One ITAC had a focus of intestinal metaplasia away from the invasive carcinoma., Conclusions: Sinonasal ITACs have a distinctive phenotype, with all cases expressing CK20, CDX-2, and villin. Most ITACs also express CK7, although a proportion of tumours are CK7 negative. ITAC seems to be preceded by intestinal metaplasia of the respiratory mucosa, which is accompanied by a switch to an intestinal phenotype. Although ITACs are morphologically similar, differences in cytokeratin expression patterns suggest two distinct types. The expression pattern of CK7, CK20, CDX-2, and villin positive may be useful in separating these tumours from other non-ITAC adenocarcinomas of the sinonasal tract and nasopharynx.

We present the clinicopathological, histological and immunohistochemical findings of six cases of primary tubulopapillary low-grade adenocarcinoma of the sinonasal tract with ultrastructural examination in one case. Due to its unique features, we believe that primary tubulopapillary low-grade adenocarcinoma of the sinonasal tract represents a tumour entity different from any tumours generally recognised in the sinonasal region. Our cases had an equal sex incidence, with an age range of 44-76 years. The tumour has a tendency to recur, but none of our six patients developed metastases. We feel that it is important to separate this tumour entity from other types of sinonasal adenocarcinomas that exhibit a papillary growth pattern, as they frequently pursue a much more aggressive clinical course than the tumours in this study.

Context: Smooth muscle tumors (SMTs) of the sinonasal tracts are very rare mesenchymal neoplasms, and the literature includes very limited data correlating histologic parameters with clinical outcome. As the behavior of SMTs is site-dependent, defining applicable criteria to distinguish among low-grade leiomyosarcoma, SMT of uncertain malignant potential (SMTUMP), and cellular leiomyoma is sometimes difficult and arbitrary., Objective: To correlate the clinicopathologic features of 12 well-differentiated sinonasal SMTs with MIB-1 index and clinical outcomes so as to better classify this group of tumors., Design: Twelve cases of sporadic well-differentiated SMTs arising from the sinonasal tract were retrieved from both institutions. High-grade leiomyosarcomas were excluded from this analysis. The histologic parameters assessed included circumscription, mucosal ulceration, cellularity, nuclear atypia, mitotic count, necrosis, and destruction of adjacent bony structures. The histologic classification of these tumors was based on the guidelines for SMTs of deep soft tissues, using greater than 4 mitotic figures (MF)/10 high-power fields (HPF) to separate SMTUMP from leiomyosarcoma and the presence of 1 to 4 MF/10 HPF to distinguish between leiomyoma and SMTUMP. Immunostaining of MIB-1 index was performed in 7 cases with available material., Results: This study showed a 1:1.5 male-female ratio and a mean age of 40 years (range, 20-67 years). The most frequent symptoms were nasal stuffiness and/or epistaxis. The tumors involved nasal cavity in 8 cases (67%), paranasal sinus alone in 2 cases (16.5%), and both nasal cavity and paranasal sinuses in 2 cases (16.5%). The tumors ranged in size from 0.3 to 5.5 cm (mean, 2 cm) and were classified as follows: 7 leiomyomas, 2 SMTUMPs, and 3 low-grade leiomyosarcomas. All 7 leiomyomas, 1 SMTUMP, and 1 leiomyosarcoma originated from vessel walls. Bone involvement was seen in both the SMTUMPs (1 of 2) and leiomyosarcomas (2 of 3). Focal infiltrative growth was observed only in the 3 leiomyosarcomas, 1 of which also showed microscopic coagulative tumor necrosis. Mitotic figures ranged from 0 to 10 (mean, 2.3), with absence of mitosis in all 7 leiomyomas, 1 to 4 MF/10 HPF in the 2 SMTUMPs, and more than 4 MF/10 HPF in the 3 low-grade leiomyosarcomas. The MIB-1 index was low (or=15%) proliferative index. All 12 patients were treated by surgical excision, and only 1 patient with leiomyosarcoma received postoperative radiation. In all 12 tumors, there was neither local recurrence nor distant metastasis after an average of 93 months of follow-up (range, 4-221 months)., Conclusion: Well-differentiated sinonasal SMTs are rare and occur in adults with a slight female predilection. The lesions confined within the nasal cavity were more common than those involving a single paranasal sinus or both nasal cavity and paranasal sinuses. Despite variations in location, clinical manifestation, histologic features, and MIB-1 index, these tumors appear to follow a favorable course. Complete surgical excision appears to provide adequate treatment for these patients.

Sinonasal undifferentiated carcinoma (SNUC) is a highly aggressive malignant neoplasm that is often difficult to distinguish from other poorly differentiated carcinomas arising in the sinonasal tract. To search for a differential cytokeratin (CK) expression that could be useful for diagnostic purposes, we compared the expression of a large panel of CKs in a series of 6 SNUCs, 10 poorly differentiated squamous cell carcinomas (SCCs), 10 nonkeratinizing squamous cell carcinomas (NKSCCs), and 5 nasopharyngeal-type undifferentiated carcinomas (NPTCs). SCC, NKSCC, and NPTC frequently showed immunoreactivity for CK5/CK6, CK8, CK13, and CK19. In addition, SCC and NKSCC expressed CK14, which was not detected in NPTC, and SCC expressed CK7 (60% of cases) and CK4 (30% of cases), which were absent in NKSCC and NPTC. Three NKSCCs were associated with a Schneiderian papilloma, and the results of the immunostaining were similar in the two components, with the exception of CK4 and CK7, which were expressed by the papilloma and not by the carcinoma. In contrast to other carcinomas, SNUC was characterized by the exclusive expression of CKs of simple epithelia, such as CK8 (100% of cases), CK7 (50% of cases), and CK19 (50% of cases). Thus, there are significant differences in the pattern of CK expression between SNUC, SCC, NKSCC, and NPTC, which could be of diagnostic aid. Moreover, these findings support the hypothesis that SNUC is a separate entity from SCC and NPTC of the sinonasal tract.