Search

Verrucous carcinoma of the esophagus (VCE) is a rare variant of squamous cell cancer, with a puzzling clinical, etiological, and molecular profile. The etiological involvement of human papillomavirus (HPV) in the cancer's natural history is controversial. This study considers 9 cases of VCE, focusing on patients' clinical history before surgery, histologic phenotype, immunophenotype (epidermal growth factor receptor [EGFR], E-cadherin, cyclin D1, p16, and p53 expression), HPV infection, and TP53 gene mutational status (exons 5-8). Using 3 different molecular test methods, not one of these cases of VCE featured HPV infection. The only case with synchronous nodal metastasis was characterized by a TP53 missense point mutation in association with high EGFR and low E-cadherin expression levels. In conclusion, HPV infection is probably not involved with VCE, while TP53 gene mutation, EGFR overexpression, and E-cadherin loss might fuel the tumor's proliferation and lend it a metastatic potential., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Worldwide, colorectal cancer (CRC) screening programs have significantly increased the detection of submucosal (pT1) adenocarcinoma. Completion surgery may be indicated after endoscopic excision of these potentially metastasizing early cancers. However, the postsurgical prevalence of nodal implants does not exceed 15%, leading to questions concerning the clinical appropriateness of any post-endoscopy surgery. Eastern scientific societies (Japanese Society for Cancer of the Colon-Rectum, in particular) include tumor budding (TB), defined as the presence of isolated single cancer cells or clusters of fewer than 5 cancer cells at the tumor invasive front, among the variables that must be included in histologic reports. In Western countries, however, no authoritative endorsements recommend the inclusion of TB in the histology report because of the heterogeneity of definitions and measurement methods as well as its apparent poor reproducibility. To assess the prognostic value of TB in pT1 CRCs, this meta-analysis evaluated 41 studies involving a total of 10137 patients. We observed a strong association between the presence of TB and risk of nodal metastasis in pT1 CRC. In comparing TB-positive (684/2401; 28.5%) versus TB-negative (557/7736; 7.2%) patients, the prevalence of nodal disease resulted in an odds ratio value of 6.44 (95% confidence interval, 5.26-7.87; P<.0001; I 2 = 30%). This increased risk of regional nodal metastasis was further confirmed after accounting for potential confounders. These results support the priority of histologically reporting TB in any endoscopically removed pT1 CRC to direct more appropriate patient management., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Adrenocortical carcinoma patient prognosis is extremely variable and poorly predictable. The newly introduced Helsinki Score is the first so far proposed diagnostic and prognostic system based on the combined evaluation of morphological (mitoses and necrosis) and immunohistochemical (Ki-67) parameters. The aim of the study was to validate the prognostic role of the Helsinki Score for adrenocortical carcinoma characterization. Thus, 225 adrenocortical carcinomas were reclassified using the Weiss Score and the Helsinki Score (3× mitotic count + 5 × necrosis + Ki-67 index). At univariate analysis, statistically significant prognostic values were observed at the log-rank test for mitotic count (cutoff values: <6 and ≥55; P<.0001), Ki-67 (cutoff values: <20 and ≥50; P<.0001), Weiss Score (cutoff values: <5 and ≥8; P<.0001), Helsinki Score (cutoff values: <13 and ≥19; P<.0001), histological variant (conventional versus oncocytic; P=.009), necrosis (P=.001), and stage (P=.005). Cox multivariate analysis using a backward stepwise selection method retained only Helsinki Score and Weiss Score as predictors of poor prognosis (P<.0001 and P=.0005, respectively). Helsinki Score (with a threshold of 28.5 points; area under the curve [AUC]=0.729, 95% confidence interval=0.66-0.79) and Ki-67 (with a threshold of 20.5%; AUC=0.727, 95% confidence interval=0.66-0.79) showed the best and equivalent AUCs predicting disease-related deaths determined using receiver operating characteristic statistics. In conclusion, the Helsinki Score is a valuable system to predict prognosis in adrenocortical carcinoma, outperforming the currently established prognostic parameters., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Dysregulation of host microRNA expression has been involved in the development and progression of human papillomavirus (HPV)-related tumors. Analysis of miR-146a expression in a series of 59 penile squamous cell carcinomas (PSCCs) showed that its levels were lower in high-risk HPV-positive than in HPV-negative PSCCs and inversely correlated with expression of epidermal growth factor receptor (EGFR), a known target for miR-146a. Analysis of genotype distribution for rs2910164, a common functional polymorphism of miR-146a, did not identify correlations with miR-146a levels and EGFR expression in PSCCs. In vitro experiments demonstrated that E6 of HPV type 16, but not low-risk HPV-6, down-regulated miR-146a in human foreskin keratinocytes and up-regulated EGFR. Ectopic expression of miR-146a decreased expression of EGFR and inhibited proliferation of keratinocytes and cervical carcinoma cells. EGFR is commonly overexpressed in penile cancer and in other squamous cell carcinomas. Molecular mechanisms leading to EGFR overexpression and activation are known for HPV-negative cancers and include amplification or mutations of the EGFR gene. The results of this study indicate that down-regulation of miR-146a may represent another mechanism of EGFR overexpression in PSCCs, which can be mediated by high-risk HPV E6 in HPV-related tumors., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Adrenocortical carcinomas (ACCs) with sarcomatous areas represent an extremely rare type of highly aggressive malignancy of unknown molecular pathogenesis. The current study was planned to gain insight into its molecular genetics using a targeted next-generation sequencing approach and to explore the status of epithelial-mesenchymal transition (EMT)-associated markers (E-/P-/N-cadherins, MMP-2/-9 and caveolin-1), downstream transcriptional regulators of EMT-related signaling pathways (ZEB-1/-2, Slug), stem cell factors (Oct3/4, LIN28, SOX2, SO17, NANOG, CD133, nestin), and markers of adrenocortical origin/tumorigenesis (SF-1, β-catenin, p53) in phenotypically diverse tumor components of 6 cases. Thirteen pathogenic variants of ACC-associated TP53 and CTNNB1 genes were detected in epithelial and/or nonepithelial components in 4 out of 6 tumors. Three cases had identical mutations in distinct components, 1 of which contained TP53/CTNNB1 in 3 out of 5 components, whereas 1 harbored a single TP53 mutation only in the nonepithelial component. By immunohistochemistry, SF-1 and E-/P-/N-cadherins were found positive only in the epithelial component of all cases, whereas the nonepithelial components were mainly enriched for nestin, ZEB-1, and MMP-2/-9. β-Catenin demonstrated an aberrant nuclear localization in the sarcomatoid component of 5 cases, whereas p53 was strongly positive in nonepithelial constituent in 4 of 6 cases. In summary, we have shown that Wnt/β-catenin signaling pathway dysregulation and mutational inactivation of TP53 are common genetic events in sarcomatoid ACCs, a subset of which being monoclonal in origin. These tumors are enriched for EMT-related markers and stem cell factors, potentially conferring a poor prognosis, which might be exploited as novel therapeutic targets., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Among colorectal cancers, the prevalence of signet ring cell carcinoma (SRCC) is lower than 1%; to date, only 6 cases of early SRCCs arising in colonic adenoma have been reported. In spite of the well-established understanding of the phenotypic and genetic changes occurring in conventional colonic carcinogenesis, the molecular landscape of colon SRCC is still far to be elucidated. We describe the histologic and immunohistochemical phenotype and the molecular profile of a case of intramucosal SRCC developed within a 4.5-cm large sigmoid adenoma. The DNA sequencing of the 2 microdissected neoplastic components (adenomatous and SRCC) showed the same G12V KRAS mutation. Interestingly, although the adenomatous epithelium showed unequivocal p53 overexpression, no signet ring cancer cells featured p53 nuclear immunostain. This molecular pattern supports the unique histogenesis of the 2 coexisting neoplastic oncotypes, also suggesting that the signet ring cell component is derived from the molecular de-differentiation (p53 loss) of the preexisting adenomatous lesion., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Lipoblastoma (LB) is a rare benign adipocytic tumor of childhood occasionally showing histological similarities to myxoid liposarcoma (ML) or well-differentiated liposarcoma (WDL). p16 immunohistochemistry has proved to be useful in distinguishing various types of liposarcomas, in particular WDL from lipoma, with higher sensitivity and specificity than MDM2 and CDK4 immunohistochemistry. In this study, we reported the histologic features of a series of 30 LB with emphasis on the potential diagnostic pitfalls and investigated the immunohistochemical expression of p16. Moreover, p16 immunostaining was performed in 16 liposarcomas (11 WDL and 5 ML), 16 lipomas, and 16 cases of liponecrosis in order to evaluate its usefulness in the differential diagnosis of challenging lesions occurring in older children. Overall, p16 immunostaining was positive in 3 LBs and in 12 out of 16 liposarcomas (10 WDL and 2 ML), with a sensitivity of 75%, a specificity of 90%, a positive predictive value of 80%, and a negative predictive value of 87%. All lipomas were p16 negative, whereas 5 liponecroses were positive. Accounting altogether the benign lesions versus liposarcomas, p16 showed a sensitivity of 75%, a specificity of 87%, a positive predictive value of 60%, and a negative predictive value of 93%. Our data suggest that a negative p16 immunostaining may be helpful in excluding a liposarcoma when occurring in unusual clinical contexts, such as in adolescence or late recurrence. However, such finding should be interpreted with caution since also some liposarcomas lack p16 and occasional LBs are positive., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Among patients with gastric cancer (GC) and gastroesophageal cancer (G-EC), HER2 amplification identifies those who may benefit from trastuzumab. HER2 status assessment, however, is influenced by preanalytic, analytic, and postanalytic variables. In a series of 5426 microarray cancer tissue cores obtained from 1040 GC/G-ECs (824 GC, 216 G-EC) and 720 synchronous nodal metastases, we evaluated both the performances of 2 different immunohistochemistry (IHC) protocols and the HER2 status intratumor variability. The prevalence of HER2 amplification and protein overexpression were assessed by chromogenic in situ hybridization and by 2 IHC protocols (CB11 and 4B5). HER2 was amplified in 114 (11%) of 1040 cases; in 6 (5.3%) of 114 cases, gene amplification only involved nodal metastasis. HER2 amplification prevailed in intestinal-type (P = .001) and low-grade (P < .001) tumors, showing no correlation with patients' age/sex, tumor location, stage, and Ming histotype. Overall, 12.5% and 13.7% of cases IHC scored 2+/3+ using the CB11-IHC and the 4B5-IHC protocol, respectively. HER2 amplification was not associated with protein overexpression (score 0/1+) in 11.4% and 6.2% of cases using the CB11-IHC and the 4B5-IHC protocol, respectively. The 4B5-IHC protocol proved more sensitive than CB11-IHC (93.9% versus 88.6%) and just as specific (96.1% versus 96.9%). Tested by chromogenic in situ hybridization, intratumor HER2 status was "substantially" consistent in different tissue cores obtained from the same case (κ = 0.78). Similar results were obtained for HER2 protein expression (CB11-IHC, κ = 0.78, and 4B5-IHC, κ = 0.83). Immunohistochemistry testing, however, fails in identifying about 10% of HER2-amplified cancers, potentially excluding these patients from anti-HER2 therapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)