Characterization of novel USP6 gene rearrangements in a subset of so-called cellular fibroma of tendon sheath.

Fibroma of tendon sheath (FTS) is an uncommon benign fibroblastic/myofibroblastic neoplasm that typically arises in the tenosynovial tissue of the distal extremities. Histologically, it is a well-circumscribed proliferation of spindle cells within collagenous stroma with peripheral slit-like vessels. Most examples are relatively hypocellular and more densely collagenous than nodular fasciitis; however, a cellular variant has been described, which has considerable morphologic overlap with nodular fasciitis and has been shown to harbor USP6 translocations in a subset of cases. The incidence of these rearrangements and the identity of the USP6 fusion partners have not been described in detail. In this study we evaluate 13 cases of cellular fibroma of tendon sheath by anchored multiplex PCR/next generation sequencing in order to detect potential gene fusions. Nucleic acids of adequate quality were obtained in 11 cases, demonstrating gene fusions in 7/11 (64%), all of which involve USP6 with a variety of partners, including PKM, RCC1, ASPN, COL1A1, COL3A1, and MYH9. Some unusual histomorphologic findings were present in a subset of cases including palisading growth pattern, epithelioid cells, and osteoclast-like multinucleated giant cells, particularly in the tumors with PKM and ASPN gene partners. Overall, the findings support a biologic relationship between cellular fibroma of tendon sheath and other lesions within the spectrum of USP6-rearranged neoplasms, particularly nodular fasciitis.

Spindle cell neoplasm with EML4-ALK gene fusion presenting as an intraosseous vertebral mass.

In this article, we describe a spindle cell neoplasm harboring an EML4-ALK gene fusion presenting as an intraosseous vertebral mass with extension into the adjacent soft tissue in a 65-year-old man. Histologically, the lesion was characterized by the presence of monotonous, cytologically bland spindle cells with loose myxoedematous stroma and interspersed areas of amianthoid-like collagen fiber deposition. Immunohistochemistry demonstrated strong diffuse staining for CD34 and S100, with absent immunoreactivity for SOX10. At 1 year of follow-up after resection, there is no evidence of local recurrence or metastatic disease. This case adds to the clinical and pathologic spectrum of the recently described group of kinase fusion-positive spindle cell neoplasms and represents the first reported intra-osseous example. The presence of ALK rearrangement in this lesion represents a potential therapeutic target, if clinically indicated.

Validation of a Congestive Hepatic Fibrosis Scoring System.

Congestive hepatopathy is a complication of right heart failure and chronically elevated right heart pressure. Histologic findings include sinusoidal dilatation, centrilobular hepatocellular plate atrophy, and fibrosis. We performed a validation study of a recently proposed scoring system (0 to 4 scale) for congestive hepatic fibrosis on 38 liver biopsies. Glutamine synthetase immunohistochemistry was also performed, and loss of centrizonal immunoreactivity correlated with increasing fibrosis score (P<0.01). Interobserver concordance for congestive hepatic fibrosis score based on Masson trichrome stain was initially fair (Fleiss κ=0.28, weighted concordance coefficient=0.60) and significantly improved (κ=0.40, weighted concordance coefficient=0.66) following a multiheaded microscope training session and inclusion of glutamine synthetase immunohistochemistry. Average congestive hepatic fibrosis score correlated with significantly higher right atrial pressure, severity of right atrial dilation, presence of right ventricular dilation, elevated serum alanine aminotransferase, platelet counts, prothrombin time, and model for end-stage liver disease score. In conclusion, the congestive hepatic fibrosis scoring system is reproducible among pathologists and correlates with clinical and laboratory markers of congestive hepatopathy.

Detecting disease-defining gene fusions in unclassified round cell sarcomas using anchored multiplex PCR/targeted RNA next-generation sequencing-Molecular and clinicopathological characterization of 16 cases.

Detection of disease-defining gene fusions in sarcoma has led to refining their classification, as well as to discover several new entities. The advent of anchored multiplex PCR/targeted RNA next-generation sequencing (AMP/RNA-seq) has allowed for the development of scalable platforms that can simultaneously examine multiple fusion transcripts without prior knowledge of specific fusion partners.In this study, we assess the utility of a FusionPlex sarcoma panel analysis by AMP/RNA-seq to detect disease-defining gene fusions in 16 cases of undifferentiated round cell sarcoma in which prior diagnostic work-up could not establish a definitive diagnosis. The clinical and pathologic features of these cases were correlated with the molecular findings. Validation of the method using 41 cases with known diagnoses showed analytic sensitivity and specificity of 98% and 100%, respectively. Of the 16 cases of undifferentiated round cell sarcoma, gene fusions were found in 9 (56%). These included three cases with CIC-DUX4 fusion, two cases with BCOR-CCNB3, and four single cases with CIC-NUTM2A, HEY1-NCOA2, EWSR1-NFATC2, and NUT-MGA1 fusions. Overall, despite some degree of morphologic overlap, all fusion-positive cases had distinct morphologic features, which can be helpful for their histologic classification. We also describe the first adult case of MGA-NUTM1 fusion sarcoma, as well as cartilaginous differentiation in a BCOR-CCNB3 fusion sarcoma, which has not been previously reported. Our study demonstrated that FusionPlex sarcoma panel analysis, in the appropriate morphologic context, is a sensitive and precise ancillary method for the detection of disease-defining gene fusions in undifferentiated round cell sarcomas, aiding in their definitive classification.

Amplification of DNA damage-inducible transcript 3 (DDIT3) is associated with myxoid liposarcoma-like morphology and homologous lipoblastic differentiation in dedifferentiated liposarcoma.

Dedifferentiated liposarcoma is defined as progression of atypical lipomatous tumor/well-differentiated liposarcoma to a higher grade usually non-lipogenic sarcoma, with amplification of 12q13-15. This region contains several genes involved in liposarcoma pathogenesis, including MDM2, CDK4, and DDIT3. While the former two are thought of as the main drivers in dedifferentiated liposarcoma, DDIT3 is typically rearranged in myxoid liposarcoma. Overexpression of DDIT3, along with MDM2 and CDK4, may contribute to the pathogenesis of dedifferentiated liposarcoma by interfering with adipocytic differentiation. Dedifferentiated liposarcoma with DDIT3 amplification has not been well characterized. In this study we evaluate the presence of DDIT3 amplification in 48 cases of dedifferentiated liposarcoma by cytogenomic microarray analysis and its correlation with demographic, clinical, and morphologic characteristics. Data from The Cancer Genome Atlas were also evaluated to determine a relationship between DDIT3 amplification and prognostic outcomes. Of the 48 cases, 16 (33%) had amplification of DDIT3; these patients were on average 11 years younger than patients without DDIT3 amplification (P < 0.05). Myxoid liposarcoma-like morphologic features were identified in 12/16 (75%) cases with DDIT3 amplification and in 7/32 (22%) cases without amplification (P < 0.05). Homologous lipoblastic differentiation was seen in 6/16 (38%) cases with DDIT3 amplification and 2/32 (6%) cases without it (P < 0.05). There was no significant correlation between DDIT3 amplification and tumor location, disease-specific or recurrence-free survival, and distant metastasis. DDIT3 amplification appears to interfere with the adipogenic molecular program and plays a role in inducing or maintaining a lipogenic phenotype in dedifferentiated liposarcoma. From a diagnostic standpoint, it is important to consider DDIT3-amplified dedifferentiated liposarcoma in the differential diagnosis of myxoid liposarcoma, particularly in small biopsies. Further studies evaluating the significance of DDIT3 amplification in the pathogenesis of dedifferentiated liposarcoma, as well as a potential predictor of tumor behavior in well-differentiated liposarcoma, are needed.

T-cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death-ligand 1 expression in patients with soft tissue sarcomas.

BACKGROUND: Patients with metastatic sarcomas have poor outcomes and although the disease may be amenable to immunotherapies, information regarding the immunologic profiles of soft tissue sarcoma (STS) subtypes is limited. METHODS: The authors identified patients with the common STS subtypes: leiomyosarcoma, undifferentiated pleomorphic sarcoma (UPS), synovial sarcoma (SS), well-differentiated/dedifferentiated liposarcoma, and myxoid/round cell liposarcoma. Gene expression, immunohistochemistry for programmed cell death protein (PD-1) and programmed death-ligand 1 (PD-L1), and T-cell receptor Vß gene sequencing were performed on formalin-fixed, paraffin-embedded tumors from 81 patients. Differences in liposarcoma subsets also were evaluated. RESULTS: UPS and leiomyosarcoma had high expression levels of genes related to antigen presentation and T-cell infiltration. UPS were found to have higher levels of PD-L1 (P≤.001) and PD-1 (P≤.05) on immunohistochemistry and had the highest T-cell infiltration based on T-cell receptor sequencing, significantly more than SS, which had the lowest (P≤.05). T-cell infiltrates in UPS also were more oligoclonal compared with SS and liposarcoma (P≤.05). A model adjusted for STS histologic subtype found that for all sarcomas, T-cell infiltration and clonality were highly correlated with PD-1 and PD-L1 expression levels (P≤.01). CONCLUSIONS: In the current study, the authors provide the most detailed overview of the immune microenvironment in sarcoma subtypes to date. UPS, which is a more highly mutated STS subtype, provokes a substantial immune response, suggesting that it may be well suited to treatment with immune checkpoint inhibitors. The SS and liposarcoma subsets are less mutated but do express immunogenic self-antigens, and therefore strategies to improve antigen presentation and T-cell infiltration may allow for successful immunotherapy in patients with these diagnoses. Cancer 2017;123:3291-304. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Glandular differentiation in dedifferentiated chondrosarcoma: molecular evidence of a rare phenomenon.

Epithelial glandular differentiation in dedifferentiated chondrosarcoma has not been described. Our patient was a 64-year-old man with a history of prostate cancer status post-radiation and hormonal therapy. On screening bone scan, he was found to have increased uptake in his right femoral shaft. Biopsy revealed intermediate-grade conventional chondrosarcoma. Subsequent femoral resection was remarkable for an intermediate-grade chondrosarcomatous component juxtaposed to an area composed of anastomosing nests and cords of malignant epithelial cells showing nuclear atypia and increased mitotic activity. A fibroblastic-appearing spindle cell population was intimately associated with the epithelial cells. The epithelial cells labeled with 34bE12, AE1/AE3, EMA, and Vimentin (both spindled and epithelial components) while being negative for prostate-specific antigen, prostate specific acid phosphatase, cytokeratin 20, thyroid transcription factor-1, and CDX2. The patient developed local recurrence 9 months after the initial resection but has had no metastatic disease and consistently undetectable prostate-specific antigen levels. Deep parallel sequencing of the dedifferentiated component showed a nonsynonymous mutation at exon 4 of IDH1 gene at codon R132 leading to a substitution of arginine, with serine confirming glandular differentiation in dedifferentiated chondrosarcoma.

Prognostic relevance of Fédération Nationale des Centres de Lutte Contre le Cancer grade and MDM2 amplification levels in dedifferentiated liposarcoma: a study of 50 cases.

Dedifferentiated liposarcoma represents a form of liposarcoma composed of a non-lipogenic sarcoma associated with well-differentiated liposarcoma. The prognostic significance of histological grading of the dedifferentiated component remains to be elucidated due to vague grading criteria employed in previous studies. Molecular markers of tumor behavior, including amplification levels of murine double minute-2 (MDM2) and cyclin-dependent kinase-4 (CDK4) genes, have been explored in a limited number of cases. Here we investigate whether 'Fédération Nationale des Centres de Lutte Contre le Cancer' (FNCLCC) grade and MDM2 gene amplification levels have prognostic value in dedifferentiated liposarcoma in terms of local recurrence and disease-specific survival. Fifty cases were retrieved, reviewed and FNCLCC grade was scored for the dedifferentiated component. Testing for MDM2 gene amplification was performed by fluorescence in situ hybridization. Amplification was categorized as high level (≥20 copies) and as low level (<20 copies). Follow-up data was obtained through chart review. Log-rank test and Cox proportional hazard models were used to determine the effect of grade and level of MDM2 amplification on outcomes. Our series includes 50 patients (male n=28, female n=22) with an average age of 63 years (range, 28-88) and a median follow-up of 28 months (range, 2-120). Tumors were graded as grade 1 (6%), grade 2 (58%), and grade 3 (36%). When adjusted for age, sex, site, tumor size, and margin status, grade 3 patients had a higher recurrence rate than grades 1 and 2 (HR=2.07, 95% CI: 1.24, 7.62; P=0.015). Patients with high-level MDM2 amplification had higher recurrence rate on univariate analysis (P=0.028), but not on multivariate analysis (HR=1.69, 95% CI: 0.73, 3.94; P=0.221). FNCLCC grade 3 dedifferentiation confers a worse prognosis in dedifferentiated liposarcoma in terms of local recurrence. MDM2 amplification level remains a useful diagnostic tool in dedifferentiated liposarcoma, but has no prognostic value in terms of local recurrence.

Tetramer guided, cell sorter assisted production of clinical grade autologous NY-ESO-1 specific CD8(+) T cells.

BACKGROUND: Adoptive T cell therapy represents an attractive modality for the treatment of patients with cancer. Peripheral blood mononuclear cells have been used as a source of antigen specific T cells but the very low frequency of T cells recognizing commonly expressed antigens such as NY-ESO-1 limit the applicability of this approach to other solid tumors. To overcome this, we tested a strategy combining IL-21 modulation during in vitro stimulation with first-in-class use of tetramer-guided cell sorting to generate NY-ESO-1 specific cytotoxic T lymphocytes (CTL). METHODS: CTL generation was evaluated in 6 patients with NY-ESO-1 positive sarcomas, under clinical manufacturing conditions and characterized for phenotypic and functional properties. RESULTS: Following in vitro stimulation, T cells stained with NY-ESO-1 tetramer were enriched from frequencies as low as 0.4% to >90% after single pass through a clinical grade sorter. NY-ESO-1 specific T cells were generated from all 6 patients. The final products expanded on average 1200-fold to a total of 36 billion cells, were oligoclonal and contained 67-97% CD8(+), tetramer(+) T cells with a memory phenotype that recognized endogenous NY-ESO-1. CONCLUSION: This study represents the first series using tetramer-guided cell sorting to generate T cells for adoptive therapy. This approach, when used to target more broadly expressed tumor antigens such as WT-1 and additional Cancer-Testis antigens will enhance the scope and feasibility of adoptive T cell therapy.

Molecular profiling of soft tissue sarcomas using next-generation sequencing: a pilot study toward precision therapeutics.

Next-generation sequencing (NGS) can provide in-depth detection of numerous gene alterations. To date, there are very few reports describing the use of this technique in soft tissue sarcomas. Herein, we aim to test the utility of NGS in identifying targetable mutations in these tumors. NGS was performed using a clinically validated multiplexed gene sequencing panel interrogating the full coding sequence of 194 cancer-related genes. A custom bioinformatics pipeline was developed to detect all classes of mutations directly from the NGS data, including single-nucleotide variants, small insertions and deletions, copy number variation, and complex structural variations. Twenty-five soft tissue sarcomas were analyzed; 18 of these patients had metastatic disease and 7 primary locally advanced tumors. Targetable mutations for which clinical trials are available were identified in 60% of the cases. MAP2K4, AURKA, AURKB, and c-MYC amplification were recurrent events in leiomyosarcomas. Frequent non-targetable variants included copy losses of the TP53 (24%), PTEN (16%), and CDKN2A (20%). Additional frameshift mutations, deletion mutations, and single-nucleotide variants involving numerous genes, including RB1, NOTCH1, PIK3CA, PDGFRB, EPHA5, KDM6A, NF1, and FLT4 genes, were also identified. NGS is useful in identifying targetable mutations in soft tissue sarcomas that can serve as a rationale for inclusion of patients with advanced disease in ongoing clinical trials and allow for better risk stratification.

Beta-human chorionic gonadotropin expression in recurrent and metastatic giant cell tumors of bone: a potential mimicker of germ cell tumor.

Giant cell tumors of bone (GCTs) are generally benign, locally aggressive neoplasms that rarely metastasize. The beta subunit of human chorionic gonadotropin (beta-hCG) is expressed in syncytiotrophoblasts and several nongynecologic neoplasms but has not been described in GCT. At our institution, we observed cases of elevated beta-hCG in patients with GCT leading to diagnostic difficulty and in one case, concern for metastatic choriocarcinoma. This study aims to determine the frequency of beta-hCG expression in GCT and any relationship to clinical aggressiveness. We evaluated tissue expression of beta-hCG by immunohistochemistry with 58% of cases staining for beta-hCG. Additionally, 2 of 11 patients with available serum and/or urine beta-hCG measurements demonstrated elevated beta-hCG due to tumor. It is important to be aware of beta-hCG expression by GCT and the potential for elevated urine and serum beta-hCG levels in patients with GCT so as to avoid misdiagnosis of pregnancy or gestational trophoblastic disease.

NYESO-1/LAGE-1s and PRAME are targets for antigen specific T cells in chondrosarcoma following treatment with 5-Aza-2-deoxycitabine.

BACKGROUND: Chondrosarcoma has no proven systemic option in the metastatic setting. The development of a non-cross-resistant strategy, such as cellular immunotherapy using antigen-specific T cells would be highly desirable. NY-ESO-1 and PRAME are members of the Cancer Testis Antigen (CTA) family that have been identified as promising targets for T cell therapy. LAGE-1 is a cancer testis antigen 90% homologous to NY-ESO-1, sharing the 157-165 A*0201 NY-ESO-1 epitope with its transcript variant, LAGE-1s. A number of CTA's have been induced using 5-Aza-2-Deoxycitabine (5-Aza-dC) in other cancers. We sought to evaluate the feasibility of targeting chondrosarcoma tumors using NY-ESO-1/LAGE-1s and PRAME specific T cells using 5-Aza-dC to induce antigen expression. METHODS: We used 11 flash frozen tumors from the University of Washington tumor bank to test for the expression of NY-ESO-1, PRAME, LAGE-1s and LAGE-1L in chondrosarcoma tumors. Using four chondrosarcoma cell lines we tested the expression of these CTA's with and without 5-Aza-dC treatments. Finally, using NY-ESO-1/LAGE-1s and PRAME specific effectors that we generated from sarcoma patients, we evaluated the ability of these T cells to lyse A*0201 expressing chondrosarcoma cell lines in vitro both with and without 5-Aza-dC treatment. RESULTS: A minority (36%) of chondrosarcoma tumors expressed either NY-ESO-1 or LAGE-1s at >10% of our reference value and none expressed PRAME at that level. However, in all four of the chondrosarcoma cell lines tested, NY-ESO-1 and PRAME expression could be induced following treatment with 5-Aza-dC including in cell lines where expression was absent or barely detectable. Furthermore, NY-ESO-1/LAGE-1s and PRAME specific CD8+ effector T cells were able to specifically recognize and lyse A*0201 expressing chondrosarcoma cell lines following 5-Aza-dC treatment. CONCLUSION: These data suggest that adoptive immunotherapy in combination with 5-Aza-dC may be a potential strategy to treat unresectable or metastatic chondrosarcoma patients where no proven systemic therapies exist.

NY-ESO-1 is a ubiquitous immunotherapeutic target antigen for patients with myxoid/round cell liposarcoma.

BACKGROUND: Myxoid/round cell liposarcoma (MRCL) is the second most common liposarcoma subtype, accounting for >33% of liposarcomas and approximately 10% of all soft tissue sarcomas. Although MRCL is a chemosensitive subtype, patients with metastatic disease have a poor outcome. NY-ESO-1 is a cancer-testis antigen (also known as cancer germ cell antigen) that has been successfully targeted in vaccine trials and in adoptive T-cell therapy trials for the treatment of several solid tumors. METHODS: The authors investigated the feasibility of targeting NY-ESO-1 in patients with MRCL by evaluating the prevalence of NY-ESO-1 expression in tumors using immunohistochemistry and quantitative reverse transcriptase-polymerase chain reaction analysis. NY-ESO-1-specific tumor recognition by NY-ESO-1-specific T-cells also was analyzed using a chromium release assay. RESULTS: A search of the University of Washington Sarcoma Tissue Bank identified paraffin-embedded tumor samples from 25 patients with MRCL. NY-ESO-1 expression was observed in every MRCL tumor assessed (100%); in 18 tumors (72%), staining was homogenous. In all but 2 tumors, staining was sufficiently robust (2+) that such patients would be eligible for clinical trials of NY-ESO-1-directed therapy. By using NY-ESO-1 specific, CD8-positive T-cells, the in vitro sensitivity of myxoid liposarcoma cell lines to antigen-specific lysis was demonstrated. CONCLUSIONS: The current results establish NY-ESO-1 as an important target antigen for the treatment of patients with MRCL.

Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma.

Integrating transcriptomic sequencing with conventional cytogenetics, we identified WWTR1 (WW domain-containing transcription regulator 1) (3q25) and CAMTA1 (calmodulin-binding transcription activator 1) (1p36) as the two genes involved in the t(1;3)(p36;q25) chromosomal translocation that is characteristic of epithelioid hemangioendothelioma (EHE), a vascular sarcoma. This WWTR1/CAMTA1 gene fusion is under the transcriptional control of the WWTR1 promoter and encodes a putative chimeric transcription factor that joins the amino terminus of WWTR1, a protein that is highly expressed in endothelial cells, in-frame to the carboxyl terminus of CAMTA1, a protein that is normally expressed only in brain. Thus, CAMTA1 expression is activated inappropriately through a promoter-switch mechanism. The gene fusion is present in virtually all EHEs tested but is absent from all other vascular neoplasms, demonstrating it to be a disease-defining genetic alteration. A sensitive and specific break-apart fluorescence in situ hybridization assay was also developed to detect the translocation and will assist in the evaluation of this diagnostically challenging neoplasm. The chimeric WWTR1/CAMTA1 transcription factor may represent a therapeutic target for EHE and offers the opportunity to shed light on the functions of two poorly characterized proteins.

Chondroid tenosynovial giant cell tumor: a clinicopathological and immunohistochemical analysis of 5 new cases.

Tenosynovial giant cell tumor (TGCT) arises from the synovium of joints or tendon sheaths. Chondroid metaplasia in TGCT is rare with only 4 well-documented cases reported in the literature. The authors describe the morphological features and immunophenotype of 5 new cases of chondroid TGCT emphasizing a broader range of matrix patterns in these tumors and an expanded immunophenotype, specifically, staining for clusterin and podoplanin which have recently been found to be expressed in conventional TGCTs. Chondroid metaplasia was extensive in 3 cases. Matrix patterns included chondromyxoid, chondro-osseous, hyaline-like, and lace-like calcification similar to that seen in chondroblastoma. The authors conclude that chondroid TGCT is a rare, distinct synovial tumor with a predilection for the temporomandibular joint that has a similar immunophenotype as conventional TGCT. Chondroid metaplasia may be extensive and have a variety of matrix patterns. Chondroid TGCT needs to be distinguished from other chondroid lesions, including chondroblastoma and chondrosarcoma.

An immunohistochemical study of XIAP expression in pleomorphic adenoma and carcinoma ex pleomorphic adenoma.

BACKGROUND: X-linked inhibitor of apoptosis protein (XIAP) is a member of the inhibitor of apoptosis proteins family of caspase inhibitors. Expression of XIAP in various neoplasms has been associated with aggressive behavior. The biological progression from pleomorphic adenoma (PA) to carcinoma ex pleomorphic adenoma (CXPA) has been poorly understood. We studied XIAP expression by immunohistochemistry in PA and CXPA. MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded representative sections of 14 cases of PA and seven cases of CXPA (four invasive and three intracapsular) were stained with anti-XIAP (# 610763; BD Biosciences, San Jose, CA, USA) following citrate-based antigen retrieval. Granular cytoplasmic staining was considered positive and intensity was assessed from weak (1+) to strong (3+). PAs were morphologically evaluated for cellularity, cytological atypia and mitotic activity. RESULTS: Of the seven PAs composed mostly of myxohyaline stroma with scattered ductal elements, two tumors showed no staining and five showed rare (<1%) 1+ positive cells. Of seven more cellular PAs, five had sheets of tumor cells comprising more than 50% of the tumor and two had sheets comprising more than 80% of the tumor (cellular PA), focal to diffuse 2+ to 3+ staining was observed. Tumor cells with strong staining often exhibited cytological atypia in the form of nuclear enlargement and contour irregularity, prominent nucleoli and eosinophilic cytoplasm. Mitotic activity was occasionally seen in cellular areas expressing XIAP. All cases of CXPA demonstrated diffuse 3+ staining in the carcinomatous component and 1+ to focally 3+ staining in cellular areas of the underlying PA. CONCLUSION: Increased expression of XIAP from PA to cellular PA to CXPA and in atypical cells within cellular areas of PA adds to our growing understanding of defective apoptotic pathways in malignant transformation in this group of salivary gland tumors and suggests an adenoma to adenocarcinoma model of progression. Further correlation with other oncogene expression may provide insight into the multiple molecular pathways that are affected in these tumors. Targeted therapy of XIAP may play a future role in the management of CXPA.

Demineralized bone matrix and fat autograft in a rabbit model of frontal sinus obliteration.

OBJECTIVE: In this study, we investigate the efficacy of demineralized bone matrix (DBM) as a material for frontal sinus obliteration in a rabbit model. STUDY DESIGN AND SETTING: Twenty-four New Zealand White rabbits were divided into four groups, and the study was carried out to two time periods. Twelve rabbits underwent frontal sinus obliteration with fat autograft, and 12 rabbits underwent the procedure with DBM. At 12 weeks, six control and six study rabbits were killed. The remaining 12 rabbits were killed at 36 weeks. All specimens underwent radiologic evaluation with spiral CT followed by histologic examination for evidence of bony growth. RESULTS: Sinuses obliterated with DBM showed replacement of the sinus cavity by trabecular bone. Histology demonstrated significant progressive replacement of DBM by cancellous bone from 12 weeks (53.3%) to 36 weeks (78.8%). There were no complications observed as a result of the materials used. CONCLUSION AND SIGNIFICANCE: DBM is a prospective material for frontal sinus obliteration. Long-term studies and human trials will further elucidate the role of this material.

Base of skull chordomas in children and adolescents: a clinicopathologic study of 73 cases.

Chordomas in children and adolescents comprise <5% of all chordomas and most frequently develop in the skull base. These tumors are believed to behave more aggressively than chordomas in adults and may have unusual morphology. This study examines a large series of pediatric skull base chordomas treated with a standardized protocol to characterize the behavior and morphology of these tumors. There were 31 males and 42 females ranging from 1 to 18 (mean 9.7) years. Forty-two cases (58%) were conventional chordomas, some of which had unusual histopathologic features. Chondroid chordomas comprised 23% of cases. Fourteen tumors (19%) were highly cellular and had a solid growth pattern with no myxoid matrix or lobular architecture. Eight of these had cytologic features of conventional chordoma cells including physaliferous cells (cellular chordoma). The remaining cellular tumors were composed of poorly differentiated epithelioid cells set in a fibrous stroma and lacked physaliferous cells (poorly differentiated chordoma). All variants studied by immunohistochemistry showed positive staining for cytokeratin, epithelial membrane antigen, S100 protein, and vimentin. Mitoses and necrosis were seen in all variants. Follow-up data were available for all patients and ranged from 1 to 21 (mean 7.25) years. The survival rate was 81%. All but 1 patient with poorly differentiated chordoma died of disease. Overall, base of skull chordomas in children and adolescents treated with proton beam radiation have better survival than chordomas in adults. However, poorly differentiated chordomas are highly aggressive tumors.

Aggressive angiomyxoma of male genital region. Report of 4 cases with immunohistochemical evaluation including hormone receptor status.

Aggressive angiomyxoma (AA), first described by Steeper and Rosai (Am J SurgPathol. 1983;7:463-475), is a rare locally infiltrative tumor that usually arises in the pelvic and perineal soft tissues of young women. Approximately 150 cases have been reported in women. Aggressive angiomyxoma has a high rate of local recurrence because of its infiltrative growth and anatomical location making complete excision with wide margins difficult. To our knowledge, 39 cases of AA occurring in men have been reported in the literature. Sites frequently involved include the scrotum, spermatic cord, inguinal region, and perineum. The gross and microscopic appearances and clinical course are similar to those described in female cases. Immunohistochemistry evaluating estrogen and progesterone receptors (ER and PR, respectively), although frequently positive in the female cases, has rarely been studied in the male cases. We report the clinicopathologic features of 4 additional cases of AA in men with particular emphasis on hormone (ER/PR) receptor status. Hormone reactivity is significant in that AA may arise from specialized hormonally responsive stromal cells of the perineum and may potentially play a therapeutic role in unresectable tumors. From our small series, hormone positivity (1 case of ER+, 3 cases of PR+) does occur in the male cases of AA, and a large number of cases should be examined to determine the frequency at which these tumors express hormone receptors.

Glomus tumor of the thigh: confluent with the periosteum of the femur.

True glomus tumor is rare. In the majority of cases it involves the hand, preferring the fingertips or nail beds. We report a patient with glomus tumor of the mid-thigh who presented with severe localized pain and limp. The imaging features are discussed and the English literature reviewed.