Faculty Bibliography

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.

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.

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.

Cutaneous carcinosarcoma (CCS) is an extraordinarily rare neoplasm with a biphasic morphological pattern exhibiting both epithelial and sarcomatoid components. Although its histogenesis and biological aspects remain poorly understood, previous studies have postulated that this tumor may arise from single cancer stem cells which subsequently differentiate into distinct tumor lineages. In this study, we explored a wide array of mutational hot spot regions, through high-depth next-generation sequencing of 47 cancer-associated genes in order to assess the mutational landscape of these tumors and investigate whether the epithelial and mesenchymal components shared the same genetic signatures. Results from this study confirm that despite their striking phenotypic differences, both elements of this infrequent tumor indeed share a common clonal origin. Additionally, CCS appears to embrace a heterogeneous spectrum with specific underlying molecular signatures correlating with the defining epithelial morphotype, with those carcinosarcomas exhibiting a squamous cell carcinoma epithelial component exhibiting diverse point mutations and deletions in the TP53 gene, and those with a basal cell carcinoma morphotype revealing a more complex mutational landscape involving several genes. Also, the fact that our findings involve several targetable gene pathways suggests that the underlying molecular events driving the pathogenesis of CCS may represent future potential targets for personalized therapies.

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.

We report a case of combined squamomelanocytic tumor of the skin. Clinically, the lesion was felt to be a squamous cell carcinoma. Histologically, it was characterized by large epithelioid cells admixed with basaloid cells with central squamous differentiation. Immunohistochemical staining showed both cell populations to be reactive with Melan A, BEREP4, and Pan Keratins. Ultrastructural studies revealed simultaneous features of squamous differentiation (dense cytoplasmic tonofilaments with well-developed desmosomes) and melanocytic differentiation (mature/pigmented melanosomes) in the same cell population. This is the second reported case in the English literature with documented biphenotypic or divergent differentiation at the ultrastructural level. The behavior of squamomelanocytic tumor is uncertain given the rarity of reported cases.

Primary cutaneous carcinosarcoma is a rare biphenotypic neoplasm exhibiting both epithelial and sarcomatous elements. Even though its origin and biological aspects remain poorly understood, it has been postulated that this tumor may arise from progenitor cells, which subsequently differentiate into distinct tumor components. We have investigated the histological and immunohistochemical staining patterns of a cutaneous carcinosarcoma case, as well as its ultrastructural aspects. In addition, sarcomatous and epithelial tumor components were separated by laser capture microdissection and subjected to targeted, high-depth, next-generation sequencing of a 46-cancer gene panel to asses the gene mutational pattern amongst both components. There were transitional cells at the epithelial/mesenchymal transition that labeled with putative progenitor cell markers (K19, c-kit, CD34 and Bcl-2). There was shared reactivity to antibodies directed against the progenitor cell marker EpCAM (epithelial cell adhesion molecule) in both components. Ultrastructurally, individual cells were demonstrated to have overlapping features of epithelial and mesenchymal differentiation. The mutational analysis revealed point mutations in exon 5 of TP53, which were identical in both the epithelial and sarcomatous components, and which were concordant with p53 expression at a tissue level. The aforementioned histological, ultrastructural, immunohistochemical and mutational pattern is strongly suggestive of a common clonal origin to the distinct elements of this tumor.

BACKGROUND:The hallmark of lung ischemia-reperfusion injury (IRI) is the production of reactive oxygen species (ROS), and the resultant oxidant stress has been implicated in apoptotic cell death as well as subsequent development of inflammation. Dietary flaxseed (FS) is a rich source of naturally occurring antioxidants and has been shown to reduce lung IRI in mice. However, the mechanisms underlying the protective effects of FS in IRI remain to be determined. METHODS:We used a mouse model of IRI with 60 min of ischemia followed by 180 min of reperfusion and evaluated the anti-apoptotic and anti-inflammatory effects of 10% FS dietary supplementation. RESULTS:Mice fed 10% FS undergoing lung IRI had significantly lower levels of caspases and decreased apoptotic activity compared with mice fed 0% FS. Lung homogenates and bronchoalveolar lavage fluid analysis demonstrated significantly reduced inflammatory infiltrate in mice fed with 10% FS diet. Additionally, 10% FS treated mice showed significantly increased expression of antioxidant enzymes and decreased markers of lung injury. CONCLUSIONS:We conclude that dietary FS is protective against lung IRI in a clinically relevant murine model, and this protective effect may in part be mediated by the inhibition of apoptosis and inflammation.