A Case Report of Tongue Lymphoepithelial Carcinoma with a Histological Diagnostic Dilemma

Most head and neck lymphoepithelial carcinomas (LECs) arise in the nasopharynx and harbor Epstein–Barr virus (EBV). LEC is also a rare subtype of the oral squamous cell carcinoma (SCC). Morphologically, LEC is defined as resembling non-keratinizing nasopharyngeal carcinoma, undifferentiated subtype. The histological features and pathogenesis of oral LEC are not established. We describe a case of tongue LEC with histopathological diagnostic difficulties. A 72-year-old Japanese female presented with a whitish change on her left-side tongue. The diagnosis was atypical epithelium; neoplastic change could not be ruled out by a biopsy. Although the lesion was monitored at our hospital per her request, invasive carcinoma was detected 11 months later. Microscopically, conventional SCC was observed with the characteristic features as LEC confined to the deep part of the lesion. We briefly discuss this unusual histological finding and make a novel proposal for distinguishing oral LEC from LECs in other regions based on these histological findings.

Life without mismatch repair

Mismatch repair (MMR) is a critical defence against mutation, but we lack quantification of its activity on different DNA lesions during human life. We performed whole-genome sequencing of normal and neoplastic tissues from individuals with constitutional MMR deficiency to establish the roles of MMR components, tissue type and disease state in somatic mutation rates. Mutational signatures varied extensively across genotypes, some coupled to leading-strand replication, some to lagging-strand replication and some independent of replication, implying that the various MMR components engage different forms of DNA damage. Loss of MSH2 or MSH6 (MutSα), but not MLH1 or PMS2 (MutLα), caused 5-methylcytosine-dependent hypermutation, indicating that MutSα is the pivotal complex for repairing spontaneous deamination of methylated cytosines in humans. Neoplastic change altered the distribution of mutational signatures, particularly accelerating replication-coupled indel signatures. Each component of MMR repairs 1-10 lesions/day per normal human cell, and many thousands of additional events during neoplastic transformation.

Gastric Hyperplastic Polyps: A Benign Entity? Analysis of Recurrence and Neoplastic Transformation in a Cohort Study

<b><i>Introduction:</i></b> Hyperplastic polyps represent 30–93% of all gastric epithelial polyps. They are generally detected as innocuous incidental findings; however, they have a risk of neoplastic transformation and recurrence. Frequency and risk factors for neoplastic transformation and recurrence are not well established and are fields of ongoing interest. This study aims to evaluate the frequency of and identify the risk factors for recurrence and neoplastic change of gastric hyperplastic polyps (GHP). <b><i>Methods:</i></b> A single-centre retrospective cohort study including consecutive patients who underwent endoscopic resection of GHP from January 2009 to June 2020. Demographic, endoscopic, and histopathologic data was retrieved from the electronic medical records. <b><i>Results:</i></b> A total of 195 patients were included (56% women; median age 67 [35–87] years). The median size of GHP was 10 (3–50) mm, 62% (<i>n</i> = 120) were sessile, 61% (<i>n</i> = 119) were located in the antrum, and 36% (<i>n</i> = 71) had synchronous lesions. Recurrence rate after endoscopic resection was 23% (<i>n</i> = 26). In multivariate analysis, antrum location was the only risk factor for recurrence (odds ratio [OR] 3.0; 95% confidence interval [CI] 1.1–8.1). Overall, 5.1% (<i>n</i> = 10) GHP showed neoplastic transformation, with low-grade dysplasia in 5, high-grade dysplasia in 4, and adenocarcinoma in 1. In multivariate analysis, a size &#x3e;25 mm (OR 84; 95% CI 7.4–954) and the presence of intestinal metaplasia (OR 7.6; 95% CI 1.0–55) and dysplasia (OR 86; 95% CI 10–741) in adjacent mucosa were associated with an increased risk of neoplastic transformation. Recurrence was not associated with neoplastic transformation (OR 1.1; 95% CI 0.2–5.9). <b><i>Discussion:</i></b> Our results confirmed the risk of recurrence and neoplastic transformation of GHP. Antrum location was a predictor of recurrence. The risk of neoplastic change was increased in large lesions and with intestinal metaplasia and dysplasia in adjacent mucosa. More frequent endoscopic surveillance may be required in these subgroups of GHP.

Risk of neoplastic change in large gastric hyperplastic polyps and recurrence after endoscopic resection

Background Gastric hyperplastic polyps (GHPs) have a risk of neoplastic transformation reaching 5 %. Current endoscopic resection techniques appear suboptimal with a high risk of local recurrence. This study assessed the outcomes of endoscopic resection for GHPs and identified risk factors for recurrence and neoplastic transformation. Methods This retrospective, multicenter, European study included adult patients with at least one GHP ≥ 10 mm who underwent endoscopic resection and at least one follow-up endoscopy. Patients with recurrent GHPs or hereditary gastric polyposis were excluded. All data were retrieved from the endoscopy, pathology, and hospitalization reports. Results From June 2007 to August 2018, 145 GHPs in 108 patients were included. Recurrence after endoscopic resection was 51.0 % (74 /145) in 55 patients. R0 resection or en bloc resection did not impact the risk of polyp recurrence. In multivariate analysis, cirrhosis was the only risk factor for recurrence (odds ratio [OR] 4.82, 95 % confidence interval [CI] 1.33 – 17.46; P = 0.02). Overall, 15 GHPs (10.4 %) showed neoplastic transformation, with size > 25 mm (OR 10.24, 95 %CI 2.71 – 38.69; P < 0.001) and presence of intestinal metaplasia (OR 5.93, 95 %CI 1.56 – 22.47; P = 0.01) being associated with an increased risk of neoplastic transformation in multivariate analysis. Conclusions Results confirmed the risk of recurrence and neoplastic transformation of large GHPs. The risk of neoplastic change was significantly increased for lesions > 25 mm, with a risk of high grade dysplasia appearing in polyps ≥ 50 mm. The risk of recurrence was high, particularly in cirrhosis patients, and long-term follow-up is recommended in such patients.

Follow-up evaluation of outliers with elevated spermine-spermidine acetyltransferase-1 activity.

e14536 Background: In the evolving role of biomarkers, proteinomic signatures related to up-regulation of polyamine synthesis including spermine/spermidine acetyltransferase-1 (SSAT-1) appear to be promising markers of malignancy. Acetylamantadine (AA) excretion, a measure of SSAT-1 up-regulation, has been shown to be a marker for malignant proliferation. In preliminary analyses of ostensibly normal individuals from Canada (Winnipeg) and Bangladesh (Dhaka), a proportion were identified to have evidence of SSAT-1 up-regulation above the expected non-malignant range (outliers). These outliers were assessed and followed for development of identifiable medical conditions. Methods: SSAT-1 up regulation was assessed in 60 ostensibly normal individuals by analysis of urinary excretion of AA after ingestion of amantadine 200 mg x 1 dose. AA was assayed using HPLC-mass spec techniques as previously described. Outliers who consented were followed-up by clinical examinations, routine biochemical and hematological tests and radiographs, where indicated. Results: Total AA average (median) excretion at 6 hrs in the Winnipeg cohort was 579+/-252 vs 1699+/-633 ng in the Dhaka cohort. Average urinary concentration at 6 hrs was 3.75+/-0.75 vs 21+/-20 ng/ml. In outliers consenting to follow-up, 1 case of invasive malignancy was identified, 6 cases of pre-malignant neoplastic change, chronic liver disease in 7 cases and chronic inflammation in 2 cases. In others, no malignant or inflammatory conditions have yet been identified. The range of SSAT-1 activity in individuals living in Bangladesh was significantly higher than in the Canadian cohort. Bangladesh volunteers live in an area of known to have high natural contamination with arsenic, a recognized carcinogen and they are exposed to high levels of air pollution. Conclusions: By this assay, high SSAT-1 activity has been confirmed in patients harbouring malignancy; however, pre-malignant and inflammatory conditions may result in a positive test. Follow-up of individuals with elevated SSAT-1 activity may reveal unrecognized malignancies, pre-malignant neoplasms, liver disease, inflammatory conditions and possibly false-positivity in individuals exposed to carcinogens such as arsenic. In further work, SSAT-1 up-regulation is being correlated with 5 other putative polyamine metabolite markers for accurate diagnosis of lung cancer.

The mutational landscape of normal human endometrial epithelium

All normal somatic cells are thought to acquire mutations. However, characterisation of the patterns and consequences of somatic mutation in normal tissues is limited. Uterine endometrium is a dynamic tissue that undergoes cyclical shedding and reconstitution and is lined by a gland-forming epithelium. Whole genome sequencing of normal endometrial glands showed that most are clonal cell populations derived from a recent common ancestor with mutation burdens differing from other normal cell types and manyfold lower than endometrial cancers. Mutational signatures found ubiquitously account for most mutations. Many, in some women potentially all, endometrial glands are colonised by cell clones carrying driver mutations in cancer genes, often with multiple drivers. Total and driver mutation burdens increase with age but are also influenced by other factors including body mass index and parity. Clones with drivers often originate during early decades of life. The somatic mutational landscapes of normal cells differ between cell types and are revealing the procession of neoplastic change leading to cancer.

The landscape of somatic mutation in normal colorectal epithelial cells

The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions leading to cancer. As for most cancer types, however, understanding of the earliest phases of colorectal neoplastic change, which may occur in morphologically normal tissue, is comparatively limited because of the difficulty of detecting somatic mutations in normal cells. Each colorectal crypt is a small clone of cells derived from a single recently-existing stem cell. Here, we whole genome sequenced hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed, some ubiquitous and continuous, others only found in some individuals, in some crypts or during some phases of the cell lineage from zygote to adult cell. Likely driver mutations were present in ∼1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium.