Cutaneous squamous cell carcinoma (cuSCC) comprises 15-20% of all skin cancers, accounting for over 700,000 cases in USA annually. Most cuSCC arise in association with a distinct precancerous lesion, ...the actinic keratosis (AK). To identify potential targets for molecularly targeted chemoprevention, here we perform integrated cross-species genomic analysis of cuSCC development through the preneoplastic AK stage using matched human samples and a solar ultraviolet radiation-driven Hairless mouse model. We identify the major transcriptional drivers of this progression sequence, showing that the key genomic changes in cuSCC development occur in the normal skin to AK transition. Our data validate the use of this ultraviolet radiation-driven mouse cuSCC model for cross-species analysis and demonstrate that cuSCC bears deep molecular similarities to multiple carcinogen-driven SCCs from diverse sites, suggesting that cuSCC may serve as an effective, accessible model for multiple SCC types and that common treatment and prevention strategies may be feasible.
Helicobacter pylori colonises the stomach in half of all humans, and is the principal cause of gastric cancer, the second leading cause of cancer death worldwide. While gastric cancer rates correlate ...with H pylori prevalence in some areas, there are regions where infection is nearly universal, but rates of gastric cancer are low. In the case of Colombia, there is a 25-fold increase in gastric cancer rate in the Andean mountain (high risk) region compared to the coastal (low risk) region, despite similarly high (∼90%) prevalence of H pylori in the two locations. Our aim was to investigate the ancestral origin of H pylori strains isolated from subjects in these high- and low-risk regions and to determine whether this is a predictive determinant of precancerous lesions.
Multi-locus sequence typing was used to investigate phylogeographic origins of infecting H pylori strains isolated from subjects in the Pacific coast and Andes Mountains in the state of Nariño, Colombia. We analysed 64 subjects infected with cagA+ vacA s1m1 strains. Gastric biopsy slides from each individual were scored for histological lesions and evaluated for DNA damage by immunohistochemistry.
We show that strains from the high-risk region were all of European phylogeographic origin, whereas those from the low risk region were of either European (34%) or African origin (66%). European strain origin was strongly predictive of increased premalignant histological lesions and epithelial DNA damage, even in the low-risk region; African strain origin was associated with reduced severity of these parameters.
The phylogeographic origin of H pylori strains provides an explanation for geographic differences in cancer risk deriving from this infection.
In many organs, including the intestine and skin, cancers originate from cells of the stem or progenitor compartment. Despite its nomenclature, the cellular origin of hepatocellular carcinoma (HCC) ...remains elusive. In contrast to most organs, the liver lacks a defined stem cell population for organ maintenance. Previous studies suggest that both hepatocytes and facultative progenitor cells within the biliary compartment are capable of generating HCC. As HCCs with a progenitor signature carry a worse prognosis, understanding the origin of HCC is of clinical relevance. Here, we used complementary fate-tracing approaches to label the progenitor/biliary compartment and hepatocytes in murine hepatocarcinogenesis. In genotoxic and genetic models, HCCs arose exclusively from hepatocytes but never from the progenitor/biliary compartment. Cytokeratin 19-, A6- and α-fetoprotein-positive cells within tumors were hepatocyte derived. In summary, hepatocytes represent the cell of origin for HCC in mice, and a progenitor signature does not reflect progenitor origin, but dedifferentiation of hepatocyte-derived tumor cells.
Esophageal adenocarcinoma (EAC) develops in a step-wise manner, from low-grade dysplasia (LGD) to high-grade dysplasia (HGD), and ultimately to invasive EAC. However, there remains diagnostic ...uncertainty about LGD and its risk of progression to HGD/EAC. The aim is to investigate the role of Ki-67, immune-histochemical marker of proliferation, surface expression in patients with confirmed LGD, and risk stratify progression to HGD/EAC. A retrospective cohort study was conducted. Patients with confirmed LGD and indefinite for dysplasia (IND), with a mean follow-up of ≥1 year, were included. Pathology specimens were stained for Ki-67 and analyzed for evidence of surface expression. Our results reveal that 29% of patients with confirmed LGD who stained positive with Ki-67 progressed to HGD/EAC as opposed to none (0%) of the patients who stained negative, a statistically significant result (P = 0.003). Similarly, specimens from patients with IND were stained and analyzed revealing a nonsignificant trend toward a higher rate of progression for Ki-67 positive cases versus Ki-67 negative, 30% versus 21%, respectively. Ki-67 expression by itself can identify patients with LGD at a high risk of progression.
The primary aim of our study was to investigate the incidence of endometrial pathologies, especially endometrial cancer, in women with breast cancer treated with tamoxifen (TAM), aromatase inhibitors ...(AIs), or receiving no treatment (NT). The secondary aim was to identify, in this cohort, ultrasonographic findings that represent robust indications for hysteroscopy and endometrial biopsy, to avoid unnecessary second-level diagnostic procedures.
Multicenter retrospective cohort study (Clinical Trial ID: NCT03898947).
Data were collected from different Italian centers: Regina Elena National Cancer Institute of Rome, Arbor Vitae Centre of Rome, Gaetano Martino University Hospital of Messina, and Villa Sofia-Cervello Hospital of Palermo.
We selected and consecutively included patients with a history of breast cancer who had undergone hysteroscopy for ultrasonographic or clinical indications between January 2007 and December 2016.
Diagnostic hysteroscopy with endometrial biopsy or operative hysteroscopy, when clinically indicated.
A higher percentage of patients in the TAM and AI groups had a normal endometrium compared with those in the NT group, whereas the incidence of endometrial polyps was higher in the NT group than in the others; no significant differences were observed among the 3 groups for other benign conditions or for premalignant and malignant uterine diseases, such as endometrial atypical hyperplasia and adenocarcinoma.
TAM treatment does not seem to be associated with a higher rate of endometrial cancer in women with breast cancer compared with women treated with AIs or NT.
There is increasing evidence to support a multistep model of the process of human hepatocarcinogenesis. Precursor lesions are characterized by the appearance of dysplastic lesions in the form of ...microscopic dysplastic foci and macroscopic dysplastic nodules. There are 2 types of small hepatocellular carcinoma (HCC) (≤2 cm in diameter): (1) early HCC with an indistinct margin and (2) progressed HCC with a distinct margin. Pathologic diagnostic criteria for early HCC have recently been set up based on a consensus between Eastern and Western pathologists.
To review the nomenclature, pathology, and biomarkers of precursor and early lesions of HCC.
Literature review and illustrations from case materials were used.
Dysplastic foci are composed of large and small cell changes. Small cell change is considered to be a more advanced precursor lesion than large cell change, and large cell change is a rather heterogeneous lesion that may represent both reactive change and true dysplasia. Dysplastic nodules can be categorized as low or high grade according to the degree of atypia. High-grade dysplastic nodules have been reported to show molecular changes similar to HCC and have a high risk of malignant transformation. Early HCC, which may correspond to microinvasive carcinomas of other organs, is a well-differentiated HCC, and differential diagnosis between early HCC and high-grade dysplastic nodule is difficult. Identification of stromal invasion and application of a panel of markers (glypican-3, heat shock protein 70, and glutamine synthetase) is helpful for diagnosis of early HCC. Detection of precursor lesions of HCC is important in recognizing patients with higher risk of developing HCC, and diagnosis of early HCC can improve patient survival by allowing for early and adequate treatment.
The objective of this study is to measure interobserver variability in the classification of laryngeal mucosal premalignant lesions by reassessing the histopathology of previously diagnosed cases and ...to determine the possible therapeutic consequences of disagreement among observers. Histopathological assessment of 110 laryngeal mucosal premalignant lesions was done by three pathologists. Each slide had to be classified according to the World Health Organization, Squamous Intraepithelial Neoplasia, and the Ljubljana Squamous Intraepithelial Lesions systems. After the independent assessment, a joint meeting took place. To assess the relation between histopathological grading and subsequent clinical management, we created a two- and a three-grade system besides one comprising all options. For all analyses, the SAS/STAT statistical software was used. The highest unweighted κ-values concerning the all-options system are observed for the Squamous Intraepithelial Neoplasia classification (0.28, 95% confidence interval 0.23-0.33), followed by the World Health Organization and Ljubljana classifications. For the two-grade system the Ljubljana classification shows the highest unweighted κ-values (0.50, 95%, 0.39-0.61), followed by the World Health Organization and Squamous Intraepithelial Neoplasia classifications. For the three-grade system, the unweighted κ-values are similar. The implementation of weighted κ-values led to higher scores within all three classification systems, although these did not exceed 0.55 (moderate agreement). Given the high level of consensus, simultaneous pathological assessment may be said to provide added value in comparison with independent assessment. In the current study, no clear tendency is observed in favor of any one classification system. The proposed three-grade system could be an improved histopathological tool because it is easier to correlate with clinical decision making and because it yields better unweighted κ-values and proportions of concordance than the all-options system. Furthermore, clinical management could benefit from assessment by more than one pathologist in suspected cases of dysplasia or carcinoma.
Colorectal cancer (CRC) is a common and often lethal tumor. Over the last 25 years, remarkable progress has been made in understanding its biological and molecular features and in elucidating the ...steps involved in colon carcinogenesis. This, in turn, has led to a more rational and effective clinical approach to the treatment of CRC. While colorectal adenoma is the most frequent precancerous lesion, other potentially premalignant conditions, including chronic inflammatory bowel diseases and hereditary syndromes, such as familial adenomatous polyposis, Peutz-Jeghers syndrome and juvenile polyposis, involve different sites of the gastrointestinal tract with an overall incidence of less than 5%. In all such cases, disease recognition at an early stage is essential to devise suitable preventive cancer strategies. These topics are addressed in this review, along with the most important epidemiological, pathogenetic and clinical features that lead to malignant transformation. Novel biomarkers for early cancer prediction, detection, prognostic evolution, and the response to treatment are critically assessed as well. Continued improvements in our knowledge of the molecular basis of CRC and the transfer of this information into daily clinical practice will reduce the burden of this disease.
Secreted protein acidic and rich in cysteine (SPARC) has been implicated in multiple aspects of human cancer. However, its role in bladder carcinogenesis and metastasis are unclear,with some studies ...suggesting it may be a promoter and others arguing the opposite. Using a chemical carcinogenesis model in Sparc-deficient mice and their wild-type littermates, we found that loss of SPARC accelerated the development of urothelial preneoplasia (atypia and dysplasia), neoplasia, and metastasis and was associated with decreased survival. SPARC reduced carcinogen-induced inflammation and accumulation of reactive oxygen species as well as urothelial cell proliferation. Loss of SPARC was associated with an inflammatory phenotype of tumor-associated macrophages and fibroblasts, with concomitant increased activation of urothelial and stromal NF-κB and AP1 in vivo and in vitro. Syngeneic spontaneous and experimental metastasis models revealed that tumor- and stroma-derived SPARC reduced tumor growth and metastasis through inhibition of cancer-associated inflammation and lung colonization. In human bladder tumor tissues, the frequency and intensity of SPARC expression were inversely correlated with disease-specific survival. These results indicate that SPARC is produced by benign and malignant compartments of bladder carcinomas where it functions to suppress bladder carcinogenesis, progression, and metastasis.
Interval colorectal cancers may arise from missed or incompletely excised precursors or from a unique rapid progression pathway. We compared the clinicopathologic and molecular profiles of interval ...and matched non-interval colorectal cancer to determine whether interval colorectal cancers harbor any unique genetic characteristics. Fifty one of 982 colorectal cancer (5.2%) were categorized as interval colorectal cancer, defined as colorectal cancer detected in a diagnostic examination prior to the next recommended colonoscopy and at least 1 year after the last colonoscopy. Clinicopathologic characteristics of interval colorectal cancer were compared to non-interval colorectal cancer matched 1:1 on age, gender, and tumor location. Molecular profile of a subset of interval colorectal cancer (n = 20) and matched (1:2) non-interval colorectal cancer (n = 40) were evaluated using next generation sequencing. Interval colorectal cancer were more likely to occur in the right colon (55% vs. 35%; p = 0.02) and in patients > 70 years of age (55% vs. 34%; p = 0.002). Clinicopathologic features and aberrant DNA mismatch repair protein expression were not significantly different between interval and matched non-interval colorectal cancer. The frequency and spectrum of genetic alterations was also similar in interval and matched non-interval colorectal cancer. Similar findings were seen when analysis was restricted to interval colorectal cancer diagnosed <5 years after last colonoscopy (n = 42). Interval and non-interval colorectal cancers share similar clinicopathologic and genetic profiles when matched for tumor location. Interval colorectal cancers and are more likely to develop from missed or incompletely excised precursors rather than a unique rapid progression pathway.
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