[Clinicopathological features of olfactory carcinoma].

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.

DEK-AFF2 Carcinoma of the Sinonasal Region and Skull Base: Detailed Clinicopathologic Characterization of a Distinctive Entity.

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.

Genetic basis of SMARCB1 protein loss in 22 sinonasal carcinomas.

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 ß-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.

SMARCA4-deficient Sinonasal Carcinoma: A Series of 10 Cases Expanding the Genetic Spectrum of SWI/SNF-driven Sinonasal Malignancies.

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.

Don't stop the champions of research now: a brief history of head and neck pathology developments.

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.

Absence of high-risk human papilloma virus in p16 positive inverted sinonasal papilloma.

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.

[Ectopic pituitary adenoma associated with empty sella turcica]. / Adenoma hipofisario ectópico asociado a silla turca vacía.

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.

Metastatic SMARCB1 (INI-1)-Deficient Sinonasal Carcinoma Diagnosed by Endobronchial Ultrasound-Guided Fine-Needle Aspiration (EBUS-FNA): A Potential Diagnostic Pitfall and Review of the Literature.

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.

Clinicopathologic and Molecular Features of a Series of 41 Biphenotypic Sinonasal Sarcomas Expanding Their Molecular Spectrum.

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.

Predictive value of EGFR-PI3K-pAKT-mTOR-pS6 pathway in sinonasal squamous cell carcinomas. / Valor pronóstico de la ruta de EGFR-PI3K-pAKT-mTOR-pS6 en los carcinomas epidermoides nasosinusales.

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.

[Expression of CD117, MITF and NAT10 and their prognostic values in sinonasal mucosal melanoma].

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.

Expression of PAX3 Distinguishes Biphenotypic Sinonasal Sarcoma From Histologic Mimics.

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.

[Clinicopathologic and molecular genetic characterizations of biphenotypic sinonasal sarcoma].

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 ß-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.

HPV-related Multiphenotypic Sinonasal Carcinoma: An Expanded Series of 49 Cases of the Tumor Formerly Known as HPV-related Carcinoma With Adenoid Cystic Carcinoma-like Features.

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.

ETV6 Gene Rearrangements Characterize a Morphologically Distinct Subset of Sinonasal Low-grade Non-intestinal-type Adenocarcinoma: A Novel Translocation-associated Carcinoma Restricted to the Sinonasal Tract.

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.

Checkpoint inhibition for advanced mucosal melanoma.

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.

[Clinicopathologic features of non-keratinizing carcinoma of nasal cavity and paranasal sinus].

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: an expanded immunoprofile including consistent nuclear ß-catenin positivity and absence of SOX10 expression.

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 ß-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 ß-catenin and SOX10 helps to support the diagnosis of BSNS without the need for gene rearrangement studies.

Recently described neoplasms of the sinonasal tract.

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.