We quantified field cancerization of squamous cell carcinoma in the upper aerodigestive tract with epigenetic markers and evaluated their performance for risk assessment. Methylation levels were analyzed by quantitative methylation-specific PCR of biopsied specimens from a training set of 255 patients and a validation set of 224 patients. We also measured traditional risk factors based on demographics, lifestyle, serology, genetic polymorphisms, and endoscopy. The methylation levels of four markers increased stepwise, with the lowest levels in normal esophageal mucosae from healthy subjects without carcinogen exposure, then normal mucosae from healthy subjects with carcinogen exposure, then normal mucosae from cancer patients, and the highest levels were in cancerous mucosae (P < 0.05). Cumulative exposure to alcohol increased methylation of homeobox A9 in normal mucosae (P < 0.01). Drinkers had higher methylation of ubiquitin carboxyl-terminal esterase L1 and metallothionein 1M (P < 0.05), and users of betel quid had higher methylation of homeobox A9 (P ¼ 0.01). Smokers had increased methylation of all four markers (P < 0.05). Traditional risk factors allowed us to discriminate between patients with and without cancers with 74% sensitivity (95% CI: 67%-81%), 74% specificity (66%-82%), and 80% area under the curve (67%-91%); epigenetic markers in normal esophageal mucosa had values of 74% (69%-79%), 75% (67%-83%), and 83% (79%-87%); and both together had values of 82% (76%-88%), 81% (74%-88%), and 91% (88%-94%). Epigenetic markers done well in the validation set with 80% area under the curve (73%-85%). We concluded that epigenetics could improve the accuracies of risk assessment.
Methylation statuses of these 2 CGIs were significantly associated with the presence of lymph node metastasis of ESCCs. These CGIs are promising markers to predict the presence of lymph node metastases.
The intratumoral heterogeneity (ITH) of the tumor microenvironment (TME) has yet to be addressed in esophageal squamous cell carcinoma (ESCC). Here, we studied the ITH of CD8 and PD‐L1 status in ESCC, and examined the potential of the tumor surface for representing the TME. In total, 67 surgically resected clinical Stage II ESCC specimens were analyzed. The CD8‐cell density, PD‐L1 tumor proportion score (TPS), and combined positive score (CPS) were calculated in three (superficial, middle, and deep) areas of each specimen. ITH was quantified by distance‐standardized coefficient variations of the three values. The CD8 and PD‐L1 status of each area was dichotomized and tumor‐surface capabilities for predicting the entire tumor status were estimated. Variables were compared according to the presence of neoadjuvant chemotherapy (NAC). The ITH, especially PD‐L1 heterogeneity, differed markedly among specimens. The concordance rates of CD8 and PD‐L1 (CPS and TPS) status among the three different areas were 71.6%, 74.6%, and 73.1%, respectively. The sensitivity and the specificity of the tumor surface for predicting the CD8 status of the whole tumor were high, especially in the NAC− group (both 1.0). The tumor surface also showed high capabilities for representing the whole PD‐L1 status, while yielding moderate positive predictive values (0.70). The ITH degrees and predictive capabilities did not differ according to NAC. Taken together, the ITH of CD8 and PD‐L1 differed among ESCC specimens, while not being markedly affected by NAC. The use of a biopsy specimen from the tumor surface might be feasible for TME evaluation.
Pretreatment stenosis yielded marked survival and oncological impacts on patients undergoing surgery for esophageal cancer. The prognostic significance of eso-phageal stenosis was consistent in both early-and advanced-stage diseases (
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