Immunohistochemical expression of hormone receptors in melanoma of pregnant women, nonpregnant women, and men.

The survival advantage of women over men with cutaneous melanoma and the reports of accelerated progression of melanoma during pregnancy have led to studies of the effect of hormones and hormone receptors on the development and progression of melanoma. However, the results are inconclusive. We therefore evaluated the expression of estrogen receptor α, estrogen receptor ß, and androgen receptor in melanomas of stage- and age-matched pregnant women, nonpregnant women, and men by immunohistochemical analysis of formalin-fixed, paraffin-embedded archival tissues. In addition, we also assessed the mitotic rate using the antiphosphohistone H3 antibody by immunohistochemistry. Our data showed a trend of more frequent expression of estrogen receptor ß in the melanomas of pregnant patients than in the melanomas of male patients, without a significant difference observed between pregnant and nonpregnant women. However, no association between the expression of estrogen receptor ß and survival was observed. The small cohort may have limited the statistical power of the study, and large-scale studies are needed to elucidate the potential role of estrogen receptor ß as a prognostic marker of melanoma.

Residual tumor thickness at the tumor-normal tissue interface predicts the recurrence-free survival in patients with liver metastasis of breast cancer.

Tumor response to neoadjuvant therapy is a significant predictive indicator of recurrence-free survival. We measured tumor response using residual tumor thickness at the tumor-normal tissue interface (TNI) and evaluated its association with outcome in patients with liver metastasis of breast cancer. We included 48 patients who underwent neoadjuvant therapy followed by partial liver resection at MD Anderson Cancer Center between 1997 and 2010. The hematoxylin-eosin-stained tumor sections were evaluated for both pathologic response and the residual tumor thickness at the TNI by 3 pathologists who were blinded to the clinical information, treatment regimen, and patient outcome. The residual tumor thickness at the TNI was correlated with recurrence-free survival using Kaplan-Meier method and log-rank test. Cox proportional hazard model was used to identify predictors of recurrence-free survival. All patients were women with a median age of 43 years. The median duration of follow-up was 52.1 months. Residual tumor thickness less than or equal to 3 mm at the TNI correlated with major pathologic response and was associated with longer recurrence-free survival in both univariate and multivariate analyses. Residual tumor thickness at the TNI predicts recurrence-free survival and provides an objective outcome end point in patients who underwent neoadjuvant therapy and liver resection of metastatic breast cancer. We suggest using both the pathologic response and the residual tumor thickness at the TNI to measure tumor response to therapy to improve accuracy.

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas.

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.

Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma.

On the basis of multidimensional and comprehensive molecular characterization (including DNA methalylation and copy number, RNA, and protein expression), we classified 894 renal cell carcinomas (RCCs) of various histologic types into nine major genomic subtypes. Site of origin within the nephron was one major determinant in the classification, reflecting differences among clear cell, chromophobe, and papillary RCC. Widespread molecular changes associated with TFE3 gene fusion or chromatin modifier genes were present within a specific subtype and spanned multiple subtypes. Differences in patient survival and in alteration of specific pathways (including hypoxia, metabolism, MAP kinase, NRF2-ARE, Hippo, immune checkpoint, and PI3K/AKT/mTOR) could further distinguish the subtypes. Immune checkpoint markers and molecular signatures of T cell infiltrates were both highest in the subtype associated with aggressive clear cell RCC. Differences between the genomic subtypes suggest that therapeutic strategies could be tailored to each RCC disease subset.

Squamous cell carcinoma of parotid gland associated with concurrent lymphoepithelial cysts and lymphoepithelial lesion: case report and proposed histogenesis.

Lymphoepithelial cyst and lymphoepithelial lesion have similar histologic features and an affinity for the parotid gland. Though considered as different entities, both conditions arise from heterotopic salivary epithelial rests or inclusions in intra- or peri-parotid lymph nodes. We present a case of squamous cell carcinoma of parotid gland associated with concurrent lymphoepithelial cyst and lymphoepithelial lesion in a patient who was not infected with human immunodeficiency virus. We propose that lymphoepithelial cyst and lymphoepithelial lesion have a similar histogenesis.

Biobanking in genomic medicine.

CONTEXT: Genomic medicine requires the identification of biomarkers and therapeutic targets, which in turn, requires high-quality biospecimens. Achieving high-quality biospecimens requires implementing standard operating procedures to control the variations of preanalytic variables in biobanking. Currently, most biobanks do not control the variations of preanalytic variables when collecting, processing, and storing their biospecimens. However, those variations have been shown to affect the quality of biospecimens and gene expression profiling. OBJECTIVE: To identify evidence-based preanalytic parameters that can be applied and those parameters that need further study. DATA SOURCES: We searched the Biospecimen Research and PubMed databases using defined key words. We retrieved and reviewed 212 articles obtained through those searches. We included 58 articles (27%) according to our inclusion and exclusion criteria for this review. CONCLUSION: -Preanalytic variables in biobanking can degrade the quality of biospecimens and alter gene expression profiling. Variables that require further study include the effect of surgical manipulation; the effect of warm ischemia; the allowable duration of delayed specimen processing; the optimal type, duration, and temperature of preservation and fixation; and the optimal storage duration of formalin-fixed, paraffin embedded specimens in a fit-for-purpose approach.

Squamous cell carcinoma of the oral tongue in young non-smokers is genomically similar to tumors in older smokers.

PURPOSE: Epidemiologic studies have identified an increasing incidence of squamous cell carcinoma of the oral tongue (SCCOT) in younger patients. EXPERIMENTAL DESIGN: DNA isolated from tongue tumors of young (<45 years, non-smokers) and old (>45 years) patients at was subjected to whole-exome sequencing and copy-number analysis. These data were compared with data from similar patients in the TCGA (The Cancer Genome Atlas) project. RESULTS: In this study, we found that gene-specific mutation and copy-number alteration frequencies were similar between young and old patients with SCCOT in two independent cohorts. Likewise, the types of base changes observed in the young cohort were similar to those in the old cohort even though they differed in smoking history. TCGA data also demonstrate that the genomic effects of smoking are tumor site-specific, and we find that smoking has only a minor impact on the types of mutations observed in SCCOT. CONCLUSIONS: Overall, tumors from young patients with SCCOT appear genomically similar to those of older patients with SCCOT, and the cause for the increasing incidence of young SCCOT remains unknown. These data indicate that the functional impact of smoking on carcinogenesis in SCCOT is still poorly understood.

Mutational landscape of aggressive cutaneous squamous cell carcinoma.

PURPOSE: Aggressive cutaneous squamous cell carcinoma (cSCC) is often a disfiguring and lethal disease. Very little is currently known about the mutations that drive aggressive cSCC. EXPERIMENTAL DESIGN: Whole-exome sequencing was performed on 39 cases of aggressive cSCC to identify driver genes and novel therapeutic targets. Significantly, mutated genes were identified with MutSig or complementary methods developed to specifically identify candidate tumor suppressors based upon their inactivating mutation bias. RESULTS: Despite the very high-mutational background caused by UV exposure, 23 candidate drivers were identified, including the well-known cancer-associated genes TP53, CDKN2A, NOTCH1, AJUBA, HRAS, CASP8, FAT1, and KMT2C (MLL3). Three novel candidate tumor suppressors with putative links to cancer or differentiation, NOTCH2, PARD3, and RASA1, were also identified as possible drivers in cSCC. KMT2C mutations were associated with poor outcome and increased bone invasion. CONCLUSIONS: The mutational spectrum of cSCC is similar to that of head and neck squamous cell carcinoma and dominated by tumor-suppressor genes. These results improve the foundation for understanding this disease and should aid in identifying and treating aggressive cSCC.

ALDH1 immunohistochemical expression and its significance in salivary adenoid cystic carcinoma.

BACKGROUND: Adenoid cystic carcinoma (ACC) cells with a high level of ALDH1, a known cancer stem cell (CSC) marker, had higher tumorigenic, invasive, and metastatic abilities. We examined the immunohistochemical expression of ALDH1 in ACC and its correlation with survival. METHODS: Archival paraffin blocks of ACC were analyzed. A tissue microarray was constructed and immunohistochemical expression of ALDH1 was analyzed using anti-ALDH1 monoclonal antibody. Correlations between ALDH1 expression and clinical and histological parameters were assessed by chi-square tests. Survival was assessed by the Kaplan-Meier method and log-rank test. RESULTS: Most of the tumors (63%) showed stromal staining only, 11% of the tumors showed both epithelial and stromal expression, and 26% of the tumors did not show either epithelial or stromal staining. Statistical analyses did not show any correlation between the pattern of ALDH1 expression and tumor histology, tumor size, or perineural invasion. There were no significant differences in survival among the 3 patterns of ALDH1 expression. CONCLUSION: Other factors, besides CSCs, may play important roles in tumorigenesis, cell differentiation, and tumor progression in these tumors.