Original Article Gastroenterol Res. 2019;12(2):72-77 Desmoplasia and Detached Papillae in Early Esophageal Adenocarcinoma: A Histologic Study on Endoscopic Submucosal Dissection Specimens Zhongbo Jina, Dongwei Zhanga, Qin Zhangb, Jinping Laia, Ashwin Akkia, Ashwini Esnakulaa, Jesse Kresaka, David Hernandez Gonzaloa, Peter V. Draganovc, Hao Xied, Xiuli Liua, e Abstract vascular invasion (P ≥ 0.05 for all). Multivariate analysis confirmed that only desmoplasia was predictive of lymphovascular invasion Background: Desmoplasia and detached papillae were only rarely (odds ratio 8.0, P = 0.02) in intramucosal adenocarcinoma and sub- mentioned in intramucosal adenocarcinoma of esophagus or stomach. mucosally or beyond invasive adenocarcinoma specimens combined. This study aimed to examine these two features in early esophageal Conclusions: In conclusion, desmoplasia occurs in about a quarter adenocarcinoma. of esophageal intramucosal adenocarcinomas and three quarters of Methods: All endoscopic submucosal dissections specimens per- submucosally or beyond invasive adenocarcinomas, and is associated formed for Barrett’s esophagus neoplasm during the year 2013 to 2016 with lymphovascular invasion in early esophageal adenocarcinoma. were reviewed. These 44 cases included in this study were eight Bar- Keywords: Barrett’s esophagus; Intramucosal adenocarcinoma; Sub- rett’s esophagus with high-grade dysplasia, 21 intramucosal adenocar- mucosally invasive adenocarcinoma; Desmoplasia; Lymphovascular cinoma, and 15 submucosally or beyond invasive adenocarcinoma. invasion Results: Desmoplasia occurred in 73% submucosally or beyond in- vasive adenocarcinoma, higher than intramucosal adenocarcinoma (24%) and high-grade dysplasia (0%) (P < 0.00001 for each). The frequency of detached papillae in intramucosal adenocarcinoma and Introduction submucosally or beyond invasive adenocarcinoma specimens was 71.4% and 73.3%, higher than high-grade dysplasia (0%, P < 0.0001 Advances in endoscopic therapy in the past decade have broad- for both). Univariate analysis identified desmoplasia as risk factors ened the pool of patients with Barrett’s esophagus (BE)-asso- for lymphovascular invasion in intramucosal adenocarcinoma speci- ciated neoplasia for endoscopic intervention and diminished mens (odds ratio 12, P = 0.048), and desmoplasia and tumor thick- the need for esophagectomy in this patient population [1]. ness for lymphovascular invasion in intramucosal adenocarcinoma Esophagectomy should be reserved for patients with a long and submucosally or beyond invasive adenocarcinoma specimens segment of intramucosal adenocarcinoma (IMAC) or those in combined (odds ratio 9.0, P = 0.005; odds ratio 2.7, P = 0.01, respec- whom endoscopic therapies fail or are inappropriate, such as tively). Age, gender, the largest dimension and the average thickness the patients with a high risk of nodal metastases. In addition, of endoscopic submucosal dissection specimens, tumor size, detached recent research has suggested that early Barrett’s carcinoma papillae, and poor differentiation were not associated with lympho- with “low-risk” submucosal invasion may be treated with en- doscopic resection with a curative intent [2]. Thus, a correct diagnosis of early esophageal adenocarcinoma and risk strati- Manuscript submitted February 3, 2019, accepted March 19, 2019 fication in this population using cancer characteristics obtained aDepartment of Pathology, Immunology and Laboratory Medicine, University from endoscopic mucosal resection (EMR) and/or endoscopic of Florida, Gainesville, FL, USA submucosal dissection (ESD) specimens become critical in the bDepartment of Pathology, The Third Central Hospital of Nankai University, subsequent management and treatment of these patients. Tianjin, China Histological diagnosis of IMAC and SMAC is challeng- cDivision of Gastroenterology, Hepatology and Nutrition, Department of Med- ing. IMAC is defined as a neoplasm that has invaded into the icine, University of Florida, Gainesville, FL, USA d surrounding lamina propria or muscularis mucosae (MM) but Division of Hematology and Oncology, Mayo Clinic, Rochester, MN, USA not into the submucosa. Four criteria were used to establish eCorresponding Author: Xiuli Liu, Department of Anatomic Pathology, Im- munology and Laboratory Medicine, University of Florida, Gainesville, FL a diagnosis of intramucosal adenocarcinoma: single cell in- 32610, USA. Email: [email protected] vasion of the lamina propria in more than one focus; sheets of cells obliterating the lamina propria; small angulated, so- doi: https://doi.org/10.14740/gr1154 called abortive glands invading the lamina propria; or a never- Articles © The authors | Journal compilation © Gastroenterol Res and Elmer Press Inc™ | www.gastrores.org 72 This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited Jin et al Gastroenterol Res. 2019;12(2):72-77 ending/anastomosing gland pattern similar to endometrial ad- the original pathological report. In addition, all slides were re- enocarcinomas of the uterine corpus [3]. It appears that there viewed by one gastrointestinal pathologist (X.L.) to confirm are two schools of thoughts regarding the diagnosis of SMAC; the diagnosis, measure tumor thickness and tumor size, margin one requires the presence of unequivocal or “textbook worthy” status, and assess the presence of LVI, stromal changes, and stromal desmoplasia [3]; and the other one depends on the in- detached papillae. The diagnosis of IMAC was based on the filtration of neoplastic cells into the submucosa [4]. Although criteria described previously [3]. Multifocality of IMAC was desmoplastic response to tumor was reported in areas of tumor defined as the presence of ≥ two discrete IMACs separated by infiltration into the duplicated MM space [5], the frequency non-carcinomatous mucosa either grossly or microscopically and significance of this feature in early esophageal adenocarci- after reviewing and matching the pathological reports and cor- noma have not been examined. responding slides. The diagnosis of SMAC was based on infil- The aims of this study were to determine: 1) The frequen- tration of neoplastic cells into the submucosa [4]. Submucosa cy of stromal changes and detached papillae in early esopha- is defined as loose connective tissue containing area below a geal adenocarcinoma in ESD specimens; 2) The association of thickened double MM [4], space with mucus glands, or space these two features with lymphovascular invasion (LVI). with large-caliber arteries. The tumor grade was assigned ac- cording to the definitions of the American Joint Committee on Cancer: G1, well-differentiated; G2, moderately differentiated; Materials and Methods G3, poorly differentiated; G4, undifferentiated. Tumor thick- ness was measured microscopically from the surface of the tu- Study population mor to the area of the deepest invasion. In cases with multifocal IMAC, the thickness of the thickest lesion was measured and used for the entire case. LVI is defined as the presence of tumor Approval was obtained from the Institutional Review Board at emboli in endothelial cell-lined spaces in the invasive front of University of Florida, Gainesville, FL. The study population the tumors [8]. Cases that had clusters of tumor cells immedi- comprised 44 patients who had undergone ESD at the Shands ately adjacent to endothelial cell-lined spaces or tumor cells in Hospital Barrett’s Esophagus Unit from 2013 to 2016. empty spaces without endothelial lining were considered pos- sible LVI and were subjected to immunohistochemistry for D2- Clinicodemographics of the ESD cohort 40, ERG, and/or CD31. In addition, desmoplasia, defined as the presence of activated fibroblasts and myofibroblasts with extra- cellular matrix deposition (Fig. 1a) was evaluated. Cases with Data were collected on demographic and clinical and endo- only myxoid stromal change (Fig. 1b) were considered desmo- scopic variables using medical charts, including age at the plasia-negative. Further, the presence or absence of detached time of ESD procedure, gender, the presence of BE mucosal papillae, defined as clusters of tumor cells without attachment irregularities, i.e., mucosal ulceration, nodules and plaque-like to the surface or luminal epithelium (Fig. 1c, d), was recorded. lesions. Biopsy results prior to ESD were also recorded. Statistical analysis ESD technique and specimen preparation Descriptive statistics were computed for all variables. These All procedure was performed under general anesthesia by a included means and standard deviations (SD) for continuous single endoscopist (P.V.D.) as previously reported [6]. All ESD factors and frequencies for categorical factors. Comparisons specimens were pinned out flat on a cork or foam board and between two groups were made by using the two-tailed t test fixed in 10% neutral buffered formalin for overnight. The larg- (or Wilcoxon rank sum test as appropriate) for continuous vari- est size and average thickness of the ESD specimen of all cases ables and Chi-square test (or the Fisher exact test as appropri- was measured after fixation and recorded in the macroscopic ate) for categorical variables. Logistic regression was used in description. All specimens were examined for the presence of univariate and multivariable analysis. Variables with P < 0.1