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In recent years, a novel small round cell sarcoma harboring EWSR1-NFATC2 translocation with immunomorphologic overlap with Ewing sarcoma (ES), myoepithelial tumors, and extraskeletal myxoid chondrosarcoma has emerged. There has not been a case series devoted to describing its detailed clinicopathologic and immunohistochemical characteristics. Six sarcomas harboring EWSR1-NFATC2 fusion transcripts by reverse transcription polymerase chain reaction and amplification of the fusion gene by fluorescence in situ hybridization were identified. The patients were 5 adult men and 1 adult woman. Three were primary bone tumors of the radius and 3 were primary soft tissue tumors. Most tumors showed monomorphic round to epithelioid cells in anastomosing cords and abundant myxohyaline to collagenous extracellular matrix. Two tumors had large areas of a solid, matrix-poor histomorphology. All tumors stained for CD99 and NKX2.2; while EMA, dot-like cytokeratin, and focal WT-1 and SMA were present in some tumors. All but 1 tumor showed poor histologic and radiologic responses to neoadjuvant ES-specific chemotherapy. Local or distant recurrences happened in 4 cases. EWSR1-NFATC2 sarcoma is a novel translocation-associated sarcoma. It presents as either a primary bone or soft tissue tumor, usually exhibits distinctive histopathologic features, and has predilection for long bones of adult men. It consistently shows recurrent fusion gene amplification readily detectable by EWSR1 breakapart fluorescence in situ hybridization, which serves as a diagnostic surrogate. It has potential for local and distant recurrence and histologic progression, and is resistant to Ewing sarcoma-specific chemotherapy.

Introduction: Disruption of E-cadherin function and increased expression of vimentin and the transcriptional oncogene, SOX2, are thought to characterize epithelial to mesenchymal transition (EMT) in HNSCC that contributes to invasive and metastatic behavior. To determine if such changes relate to prognosis or host immune response, expression of these markers and correlations with clinical characteristics, histologic worst pattern of invasion (WPOI) and tumor infiltrating lymphocytes (TIL) and survival were assessed., Methods: Immunohistologic expression of markers was determined in tissue microarrays from 274 previously untreated HNSCC patients. Expression was correlated with levels of TILs in microcores and WPOI in biopsy specimens. Correlations were assessed by Kruskal-Wallis testing and Spearman correlation coefficients where appropriate. Overall and relapse-free survival were analyzed with Cox proportional hazards models. Median follow up was 60.0 months., Results: Loss of E-cadherin expression was significantly associated with low or absent SOX2 expression (R = 0.433, p < 0.0001). SOX2 expression and low grade WPOI were significantly associated with favorable overall (OS) and relapse free (RFS) survival in multivariable analysis. E-cadherin expression did not correlate with TILs, however WPOI score correlated indirectly with CD4, CD8, and FoxP3 levels. When grouped by primary treatment, lower grades (1, 2) of WPOI predicted improved RFS and OS in patients treated with primary surgery but not for patients treated with chemoradiation., Conclusion: The findings suggest that SOX2 expression and WPOI are significant prognostic factors and that WPOI correlates with decreased T cell infiltration. The combination of markers and TILs might be useful in selecting patients for primary surgery., (Published by Elsevier Ltd.)

Background: Head and neck cancers include carcinomas of the oral cavity, larynx, sinonasal tract and nasopharynx. Studies on molecular expression of prognostic tumour markers in Ghana are scarce. The purpose of this study was to determine the expression of p53, p16, EGFR, Cyclin-D1 and HER2 among patients with non-oropharyngeal head and neck squamous cell carcinoma (HNSCC)., Methodology: Tissue microarrays from 154 histologically confirmed non-oropharyngeal HNSCC at the Komfo Anokye Teaching Hospital from 2006-2014 were constructed using duplicate cores of representative and viable areas from tumours. Expression of EGFR, p53, p16, Cyclin-D1 and HER2 was evaluated using immunohistochemistry., Results: For non-oropharyngeal HNSCC, majority of the cases (66.2%; 102/154) had stage IV disease. EGFR was the most expressed molecular marker (29.4%; 25/85) followed by p53 (24.0%; 29/121), p16 (18.3%; 23/126) and Cyclin-D1 (10.0%; 12/120). HER2 was not expressed in any of the cases. There was a significantly (p = 0.022) higher expression of Cyclin-D1 in tumours of the oral cavity (19.6%; 9/46) than in those of the larynx (4.7%; 2/43) and nose (3.2%; 1/31). Tumours in stages I-III were more frequently positive for p16 (28.6%; 12/42) than tumours in stage IV (13.1%; 11/84)., Conclusion: Expression of p53, EGFR, p16 and Cyclin-D1 in non-oropharyngeal HNSCC in Ghana is largely similar to what has been reported in published studies from other countries., Competing Interests: The authors have declared that no competing interests exist.

Background: We examined the prognostic value of a panel of biomarkers in patients with squamous cell carcinoma of the head and neck (SCCHN) who were human immunodeficiency virus (HIV) positive (HIV-positive head and neck cancer) and HIV negative (HIV-negative head and neck cancer)., Methods: Tissue microarrays (TMAs) were constructed using tumors from 41 disease site-matched and age-matched HIV-positive head and neck cancer cases and 44 HIV-negative head and neck cancer controls. Expression of tumor biomarkers was assessed by immunohistochemistry (IHC) and correlations examined with clinical variables., Results: Expression levels of the studied oncogenic and inflammatory tumor biomarkers were not differentially regulated by HIV status. Among patients with HIV-positive head and neck cancer, laryngeal disease site (P = .003) and Clavien-Dindo classification IV (CD4) counts <200 cells/μL (P = .01) were associated with poor prognosis. Multivariate analysis showed that p16 positivity was associated with improved overall survival (OS; P < .001) whereas increased expression of transforming growth factor-beta (TGF-β) was associated with poor clinical outcome (P = .001)., Conclusion: Disease site has significant effect on the expression of biomarkers. Expression of tumor TGF-β could be a valuable addition to the conventional risk stratification equation for improving head and neck cancer disease management strategies., (© 2017 Wiley Periodicals, Inc.)

Purpose: There is a paucity of biomarkers to predict failure in human papillomavirus-positive (HPV + ) oropharyngeal squamous cell carcinoma (OPSCC) following curative therapy. E6/E7 viral oncoproteins are constitutively expressed in HPV + tumors and highly immunogenic, resulting in readily detected serum antibodies. The purpose of this study is to determine whether serum E6 and E7 antibody levels can potentially serve as a biomarker of recurrence in patients with HPV+OPSCC. Experimental Design: We evaluated E6/E7 antibody levels in patients with previously untreated, advanced stage (III, IVa-b), HPV+OPSCC receiving definitive chemoradiation under a uniform protocol from 2003 to 2010. Baseline and longitudinal serum samples were obtained from our archived repository. E6/E7 serum levels were measured using a glutathione- S -transferase capture ELISA and quantified by approximating the area under the dilution curve, and were analyzed using ANOVA and linear mixed model for longitudinal analysis. Results: We compared 22 HPV+OPSCC patients who developed recurrence with 30 patients who remained disease-free. There were no differences in T classification, N classification, disease subsite, or smoking status between the groups. In a longitudinal analysis, recurrent patients had significantly higher E6 and E7 serum antibody levels than the nonrecurrent patients over the follow-up period ( P = 0.02 and P = 0.002, respectively). Patients who recurred had a lower clearance of E7 antibody than patients who remained disease-free ( P = 0.0016). Conclusions: Patients with HPV+OPSCC whose disease recurs have a lower clearance of E6 and E7 antibodies than patients who do not have recurrence. The ratio of E7 antibody at disease recurrence compared with baseline is potentially a clinically significant measurement of disease status in HPV+OPSCC. Clin Cancer Res; 23(11); 2723-9. ©2016 AACR ., (©2016 American Association for Cancer Research.)

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by germline mutations in the FH gene, and is associated with increased incidence of leiomyomas and a potentially aggressive variant of renal cell carcinoma (HLRCC-associated RCC). Absent immunohistochemical expression of fumarate hydratase (FH) has previously been used to diagnose HLRCC-associated RCC, but immunohistochemical staining of leiomyomas is not standard practice. We performed immunohistochemistry (IHC) on whole sections from consecutive cutaneous leiomyomas from our archives to evaluate for both FH and succinate dehydrogenase B expression, in addition to clinicopathologic data collection and review of all hematoxylin and eosin-stained slides for blinded morphologic evaluation of features reported to be seen in HLRCC-associated uterine leiomyomas. Ninety-six cutaneous leiomyomas from 87 patients were identified; 12 of these specimens were from 7 patients with documented HLRCC. FH expression by IHC was absent in 9 specimens and retained in 85 specimens; 2 cases were equivocal with minimal FH expression. Seven of the 9 absent expression specimens were from patients with HLRCC, as were both of the equivocal specimens. The overall sensitivity and specificity of absent FH expression in leiomyomas for detection of patients with HLRCC were 70.0% and 97.6%, respectively. Inclusion of cases classified as equivocal increased sensitivity to 75.0%. Succinate dehydrogenase B expression was retained in 95 specimens and equivocal in 1 specimen. None of the evaluated morphologic features showed any association with leiomyomas in HLRCC. Loss of FH immunohistochemical expression in cutaneous leiomyomas is a sensitive and specific marker for detection of HLRCC, thus suggesting a role for prospective FH IHC in patients with these tumors to screen for HLRCC.

Aims: A recently characterized group of undifferentiated small round cell sarcomas harbours fusions of the genes CIC and DUX4. Studies report a distinctive gene expression profile for these sarcomas, including expression of E26 transformation-specific (ETS) family proto-oncogenic transcription factors ETV1, ETV4 and ETV5. To test the utility of an ancillary diagnostic technique for these tumours, we evaluated chromogenic RNA in-situ hybridization assays for ETV1, ETV4 and ETV5 as diagnostic adjuncts for this emerging group of highly malignant sarcomas., Methods and Results: We tested six confirmed CIC-DUX4 sarcomas and 105 lesions in the differential, including 48 Ewing sarcomas for expression of ETV1, ETV4 and ETV5, scoring expression utilizing a previously validated scale. ETV1 and ETV4 were positive in five of six cases, while ETV5 was positive in six of six. No Ewing sarcoma or other sarcoma tested showed coexpression of these transcripts, while one ETV1/ETV4/ETV5 triple positive previously unclassified round cell sarcoma was identified as harbouring a CIC rearrangement by break-apart fluorescence in-situ hybridization (FISH)., Conclusion: We identified overexpression of ETV1, ETV4 and ETV5 transcripts in situ in CIC-DUX4 sarcomas using a robust assay in routine archival sections. One previously unclassified round cell sarcoma showed ETV1/4/5 positivity, and was proved to harbour a CIC rearrangement by break-apart FISH. The sensitivity and specificity observed with our in-situ hybridization assay implies potential utility as an ancillary diagnostic technique, particularly when faced with limited biopsy samples., (© 2016 John Wiley & Sons Ltd.)

In this study, high-risk HPV (hrHPV) incidence, prognostic biomarkers, and outcome were assessed in HIV-positive (case) and HIV-negative (control) patients with head and neck squamous cell cancer (HNSCC). HIV-positive cases were matched to controls by tumor site, sex, and age at cancer diagnosis. A tissue microarray (TMA) was constructed and DNA isolated from tumor tissue. MultiPlex-PCR MassArray, L1-PCR, and in situ hybridization were used to assess hrHPV. TMA sections were stained for p16ink4a, TP53, RB, CCND1, EGFR, and scored for intensity and proportion of positive tumor cells. The HNSCC cohort included 41 HIV-positive cases and 41 HIV-negative controls. Tumors from 11 of 40 (28%) cases, and 10 of 41 (24%) controls contained hrHPV. p16 expression, indicative of E7 oncogene activity, was present in 10 of 11 HPV-positive cases and 7 of 10 HPV-positive controls. Low p16 and high TP53 expression in some HPV-positive tumors suggested HPV-independent tumorigenesis. Survival did not differ in cases and controls. RB expression was significantly associated with poor survival (P = 0.01). High TP53 expression exhibited a trend for poorer survival (P = 0.12), but among cases, association with poor survival reached statistical significance (P = 0.04). The proportion of HPV-positive tumors was similar, but the heterogeneity of HPV types was higher in the HIV-positive cases than in HIV-negative controls. High RB expression predicted poor survival, and high TP53 expression was associated with poorer survival in the HIV-positive cases but not HIV-negative controls., Implications: HIV infection did not increase risk of death from HNSCC, and HPV-positive tumors continued to be associated with a significantly improved survival, independent of HIV status. Mol Cancer Res; 15(2); 179-88. ©2016 AACR., (©2016 American Association for Cancer Research.)

Angiosarcoma (AS) is an uncommon vascular malignancy with an aggressive clinical course. Radiation-associated angiosarcoma (RAAS) and Stewart-Treves syndrome are associated with MYC gene amplification and protein overexpression, while other radiation-associated vascular lesions including atypical vascular lesions (AVL) are not associated with MYC overexpression. In contrast, de novo AS represent a group of molecularly heterogeneous tumours, for which MYC expression has not been extensively examined. In this study, MYC immunohistochemistry (IHC) was performed on representative whole tissue sections of a large retrospective cohort of de novo AS, RAAS, Stewart-Treves syndrome, and AVL and evaluated using a semi-quantitative scoring method. MYC is strongly expressed in the majority of RAAS and Stewart-Treves syndrome. De novo AS demonstrate variable MYC expression, with high-grade tumours showing significantly higher MYC expression than low-grade tumours. In contrast, MYC expression in AVL is predominantly negative but may occasionally show focal staining. These results indicate that unequivocal strong MYC IHC staining supports the diagnosis of RAAS. In rare cases of RAAS without strong MYC expression, however, particularly relatively low-grade tumours for which the differential diagnosis includes AVL, the distinction between these lesions should be made on morphological grounds using previously established criteria (i.e., significant atypia, deep invasion, infiltrative growth, etc.). Increased MYC expression in high-grade de novo AS suggests that MYC overexpression may play a role in the pathogenesis of these tumours, and MYC IHC may be a prognostic and/or therapeutic biomarker in a subset of these tumours., (Copyright © 2016 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Gene fusions between CIC and DUX4 define a rare class of soft tissue sarcomas poorly understood at the molecular level. Previous karyotyping and fluorescence in situ hybridization studies support chromosome 8 trisomy as a recurrent alteration; however, other driving alterations are largely unknown. Thus, we analyzed 11 formalin-fixed, paraffin-embedded CIC-DUX4 sarcoma tissue samples (including 3 sample pairs) using targeted Ion Torrent-based multiplexed polymerase chain reaction next-generation sequencing to characterize potential somatic driver alterations in 409 genes. Although we did not identify recurrent somatic mutations (point mutations or insertions/deletions), copy number analysis showed recurrent, broad copy number alterations, including gain of chromosome 8 and loss of 1p. In one sample pair (untreated primary and local recurrence resections), we identified similar copy number profiles and a somatic ARID1A R963X nonsense mutation exclusively in the local recurrence sample. In another sample pair (pre- and post-radiation treatment specimens), we observed single-copy loss of chromosome 7q exclusively in the posttreatment recurrence sample, supporting it as an acquired event after radiation treatment. In the last sample pair (near-concurrent, postchemotherapy primary and distant metastasis), molecular profiles were highly concordant, consistent with limited intertumoral heterogeneity. In summary, next-generation sequencing identified limited somatic driver mutations in CIC-DUX4 sarcomas. However, we identified novel, recurrent copy number alterations, including chromosome 1p, which is also the locus of ARID1A. Additional functional work and assessment of larger cohorts are needed to determine the biological and clinical significance of the alterations identified herein., Competing Interests: Disclosures/Conflicts of Interest The remaining authors have no disclosures., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To determine biomarkers of recurrence and survival in patients with spindle cell variant squamous cell carcinoma (SpSCC) of the head and neck., Study Design: Retrospective case control study., Setting: Tertiary academic center., Subjects and Methods: Thirty-two SpSCC patients (mean age, 68.8) between 1987 and 2009 were identified and reviewed. A tissue microarray (TMA) was constructed from tumor specimens. Tumor biomarkers under study included p16, epidermal growth factor receptor (EGFR), p53, EZH2, cyclin D1, CD104, HGFa, p21, and cMET. An additional TMA was constructed from patients with non-SpSCC oral cavity squamous cell carcinoma for comparative purposes. The main outcomes were overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS)., Results: In the SpSCC cohort, tumors positive for cMet had worse OS (P < .001). Patients positive for cMet (P = .007), cyclin D1 (P = .019), and p16 (P = .004) had worse DSS. Recurrence-free survival was also worse in patients with tumors positive for cMet (P = .037), cyclin D1 (P = .012), and p16 (P < .001). Compared with the oral cavity cohort, there was a significantly larger proportion of patients in the SpSCC group with tumors staining positive for cMet and a lower proportion of tumors positive for cyclin D1., Conclusion: cMet, cyclin D1, and p16 are predictive tumor biomarkers for risk of recurrence and worse DSS in patients with SpSCC., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.)

Background: HPV-associated HNSCCs have a distinct etiologic mechanism and better prognosis than those with non-HPV associated HNSCCs. However, even within the each group, there is heterogeneity in survival time. Here, we test the hypothesis that specific candidate gene methylation markers (CCNA1, NDN, CD1A, DCC, p16, GADD45A) are associated with tumor recurrence and survival, in a well-characterized, prospective, cohort of 346 HNSCC patients., Methods: Kaplan-Meier curves were used to estimate survival time distributions. Multivariable Cox Proportional Hazards models were used to test associations between each methylation marker and OST/RPFT after adjusting for known or identified prognostic factors. Stratified Cox models included an interaction term between HPV and methylation marker to test for differences in the associations of the biomarker with OST or RPFT across HPV status., Results: Methylation markers were differentially associated with patient characteristics. DNA hypermethylation of NDN and CD1A was found to be significantly associated with overall survival time (OST) in all HNSCC patients (NDN hazard ratio (HR): 2.35, 95% CI: 1.40-3.94; CD1A HR: 1.31, 95% CI: 1.01-1.71). Stratification by HPV status revealed hypermethylation of CD1A was associated with better OST and recurrence/persistence-free time (RPFT) (OST HR: 3.34, 95% CI: 1.88-5.93; RPFT HR: 2.06, 95% CI: 1.21-3.49), while hypomethylation of CCNA1 was associated with increased RPFT in HPV (+) patients only (HR: 0.31, 95% CI: 0.13-0.74)., Conclusions: This study is the first to describe novel epigenetic alterations associated with survival in an unselected, prospectively collected, consecutive cohort of patients with HNSCC. DNA hypermethylation of NDN and CD1A was found to be significantly associated with increased overall survival time in all HNSCC patients. However, stratification by the important prognostic factor of HPV status revealed the immune marker, CD1A, and the cell cycle regulator, CCNA1 to be associated with prognosis in HPV (+) patients, specifically. Here, we identified novel methylation markers and specific, epigenetic molecular differences associated with HPV status, which warrant further investigation.

Background: The role of human papillomavirus (HPV) in sinonasal inverted papillomas (IPs) is controversial. Determining the prevalence of HPV infection and its impact on the molecular biology of these tumors is critical to characterizing its role in the pathogenesis of IPs., Methods: A total of 112 paraffin-embedded IPs from 90 patients were studied. A tissue microarray was constructed and stained for p16, p53, epidermal growth factor receptor (EGFR), and cyclin D1. HPV presence and types were determined using PGMY 09/11 primers and integration using HPV 11 detection of integrated papillomavirus sequences by ligation-mediated polymerase chain reaction (DIPS-PCR)., Results: HPV was detected in 11 of 90 (12%) patients. HPV 11 was found in 9 samples. HPV 6 and HPV 27 were found in 1 sample each. EGFR staining proportion was higher in HPV-positive IPs vs HPV-negative specimens (56.2% vs 23.6%; p = 0.009). Differences in p16, p53, and cyclin D1 staining were not significant. HPV-positive lesions tend to progress to malignancy (p = 0.064). Three samples were analyzed for integration. Viral integration was found in both malignant tumors but not in the precursor IP., Conclusion: Degradation of p53 and p16/cyclin D1 dysregulation are not important mechanisms in low-risk HPV-related IP. The low prevalence of HPV in this series indicates it is not a main etiological factor for IPs; however, when present, low-risk HPV may contribute to the biology of IPs through an increase of EGFR expression and a predisposition for malignant progression by integration into the cellular genome., (© 2015 ARS-AAOA, LLC.)

Objectives: Expression of strong nuclear STAT6 is thought to be a specific marker for solitary fibrous tumors (SFTs). Little is known about subtle expression patterns in other mesenchymal lesions., Methods: We performed immunohistochemical studies against the C-terminus of STAT6 in tissue microarrays and whole sections, comprising 2366 mesenchymal lesions., Results: Strong nuclear STAT6 was expressed in 285 of 2,021 tumors, including 206 of 240 SFTs, 49 of 408 well-differentiated/dedifferentiated liposarcomas, eight of 65 unclassified sarcomas, and 14 of 184 desmoid tumors, among others. Expression in SFTs was predominately limited to the nucleus. Other positive tumors typically expressed both nuclear and cytoplasmic STAT6. Complete absence of STAT6 was most common in pleomorphic liposarcoma and alveolar soft part sarcoma (60% and 72% cases negative, respectively)., Conclusions: Strong nuclear STAT6 is largely specific for SFTs. Physiologic low-level cytoplasmic/nuclear expression is common in mesenchymal neoplasia and is of uncertain significance., (Copyright© by the American Society for Clinical Pathology.)

Metanephric adenoma (MA) is a rare benign renal tumor comprised of a neoplastic proliferation of primitive metanephric tubular cells. A previous study identified BRAF V600E mutations in approximately 90% of MA and found that similar BRAF exon 15 mutations are exceedingly rare in other common renal tumors, including renal cell carcinoma and oncocytoma. A recent follow-up study has validated mutation-specific immunohistochemistry (IHC) for detection of BRAF V600E mutations in a small cohort of MA. Here, we extend these findings to a larger, independent cohort of MA, demonstrating an overall 88% sensitivity and 100% specificity for BRAF V600E IHC. In addition, we report 2 cases of MA with novel BRAF exon 15 mutations, including a V600D missense mutation and a compound V600D and K601L missense mutation. Finally, we evaluate BRAF V600E IHC in a large tissue microarray cohort of common renal tumors and find no significant expression in several renal cell carcinoma subtypes. These data support a role for BRAF V600E IHC in diagnostically challenging cases of MA and expand the spectrum of BRAF exon 15 mutations in this uncommon but unique renal neoplasm.

PAX2 and PAX8 are transcription factors involved in embryogenesis that have been utilized as immunohistochemical indicators of tumor origin. Specifically, PAX2 is a marker of neoplasms of renal and müllerian origin, while PAX8 is expressed by renal, müllerian, and thyroid tumors. While studies examining these transcription factors in a variety of tumors have been published, data regarding their expression in salivary gland neoplasms are limited. The goal of this study was to assess expression of PAX2 and PAX8 in a large cohort of salivary gland tumors. Utilizing tissue microarrays, samples of normal salivary glands (n = 68) and benign and malignant salivary gland neoplasms (n = 442) were evaluated for nuclear immunoreactivity with PAX2 and PAX8. No expression was observed with either marker in the normal salivary glands, and PAX8 was negative in all neoplasms. Focal expression of PAX2 was observed in one example each of oncocytoma and acinic cell carcinoma. These results indicate that evaluation of PAX2 and/or PAX8 expression would be valuable in differentiating primary salivary gland tumors from metastases known to express PAX2 and/or PAX8.

Salivary duct carcinoma is a highly aggressive salivary gland malignancy that may be misdiagnosed as high-grade mucoepidermoid carcinoma. We utilized tissue microarrays with 78 examples of mucoepidermoid carcinoma and 47 salivary duct carcinomas to evaluate the utility of an immunohistochemical panel consisting of androgen receptor, Her2/neu, p63, and cytokeratin 5/6 in distinguishing these entities. Among all cases in the cohorts, androgen receptor was highly specific for salivary duct carcinoma, while cytokeratin 5/6 and p63 were specific for mucoepidermoid carcinoma. While the rate of unequivocal Her2/neu overexpression among the salivary duct carcinomas was low (8.9 %), discrimination of salivary duct carcinoma was enhanced when this marker was used in combination with androgen receptor due to profound sensitivity. The immunohistochemical panel was particularly efficacious at distinguishing the problematic subset of high-grade mucoepidermoid carcinomas from salivary duct carcinoma. Utilization of this set of immunohistochemical markers allows reliable differentiation of salivary duct and mucoepidermoid carcinoma, a distinction with important prognostic and therapeutic implications.

A subset of small round cell sarcomas remains difficult to classify. Among these, a rare tumor harboring a t(4;19)(q35;q13.1) with CIC-DUX4 fusion has been described. The aim of this study is to better understand its clinicopathologic features. Four cases of CIC-DUX4 sarcoma, all arising in adults (3 women, 1 man, aged 20 to 43 y), were identified using conventional cytogenetic, reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) methods. All 4 tumors demonstrated CIC-DUX4 fusion transcript by both RT-PCR and FISH and CIC rearrangement by FISH. Cytogenetic results from 2 tumors showed t(4;19)(q35;q13.1) occurring as part of a simple karyotype in 1 tumor and as part of a complex karyotype in the other, the latter from a postchemotherapy specimen. Both tumors harbored trisomy 8 and lacked any other known sarcoma-associated translocation. No EWS or SYT rearrangements were detected by RT-PCR or FISH. The tumors had small round cell morphology with a distinctive constellation of histologic features including extensive geographic necrosis, mild nuclear pleomorphism with coarse chromatin and prominent nucleoli, clear cell areas, and focal myxoid matrix. Only focal staining for CD99 was present in each tumor. Two had very focal cytokeratin staining. All tumors were negative for desmin, myogenin, TLE-1, and S100 protein, whereas nuclear INI-1 staining was retained. The tumors were highly aggressive, and all patients died of disseminated disease within 16.8 months. CIC-DUX4 sarcoma represents a novel translocation-associated sarcoma with distinctive histopathologic features and rapid disease progression.

Context: Sclerosing hemangiomas (SH) are lung tumors characterized by surface cuboidal cells and round stromal cells. The cell of origin remains controversial, though immunohistochemical and ultrastructural studies suggest primitive respiratory epithelium. Napsin A, a human aspartic proteinase found primarily in type II pneumocytes and alveolar macrophages, is emerging as a helpful immunohistochemical marker in characterizing the origin of lung neoplasms, and may be of use in evaluating SH., Objective: To evaluate napsin A immunohistochemical staining in SH to further characterize the cell of origin., Design: Six cases of SH were stained for napsin A, as well as thyroid transcription factor 1 and cytokeratin in selected cases., Results: Surface and round cells were positive for thyroid transcription factor 1 in all cases stained with this marker. Cytokeratins were positive in surface cells in all cases stained with this marker; 2 cases had focal cytokeratin staining in round cells. Round cells had focal napsin A staining in 1 case (17%); surface cells were napsin positive in all cases., Conclusions: The observation of thyroid transcription factor 1 positivity in both surface and round cells in all SH suggests primitive respiratory epithelium as the cell of origin of SH. Our napsin A findings support this, with positivity in surface cells of all tumors (100%), and focal round cell staining in only 1 (17%). In fact, surface cells may represent entrapped type II pneumocytes, which normally express napsin A in a granular cytoplasmic pattern, similar to surface cells. The coexpression of thyroid transcription factor 1 and napsin A also introduces a caveat in differentiating primary pulmonary adenocarcinomas from SH in small biopsy specimens.

Background: Craniofacial osteosarcoma differs from long bone osteosarcoma in that patients are older, tumors are often low grade, and prognosis is more favorable. Although most are sporadic, some tumors occur in association with prior radiation therapy. The purpose of the current study was to compare clinicopathologic and prognostic features of primary and radiation-associated osteosarcoma., Methods: The study group consisted of 15 primary and 6 radiation-associated osteosarcomas. Clinical and follow-up data were obtained in every case. Tissue microarrays were immunohistochemically stained for p53, pRB, Ki-67 (MIB-1), and ezrin. DNA was sequenced for TP53 mutations., Results: All radiation-associated osteosarcomas were high grade and half were fibroblastic. In contrast, 47% of primary craniofacial osteosarcomas were high grade and only 1 was fibroblastic. All radiation-associated osteosarcomas recurred, half the patients died of disease, 2 were alive with unresectable tumors, whereas only 1 was alive without disease. In contrast, 80% of patients with primary tumors were alive without disease, 33% had local recurrences, and 13% died of disease. Radiation-associated tumors overexpressed p53 more often (33% vs. 13%), more often had TP53 mutations (33% vs. 8%), had higher proliferative activity (67% vs. 0% showing >50% MIB-1 staining), and expressed ezrin more frequently (83% vs. 40%) than primary tumors. Compared with a control group of 24 high- and 7 low-grade primary extremity osteosarcomas, radiation-associated tumors marked as the high-grade tumors., Conclusions: Craniofacial radiation-associated osteosarcomas are high-grade tumors that behave more aggressively than most primary craniofacial osteosarcomas. In addition, they demonstrate higher expression rates of adverse prognostic indicators, further highlighting the distinction., (Copyright 2006 American Cancer Society.)