Elfriede Bollschweiler

Histomorphologic Tumor Regression and Lymph Node Metastases Determine Prognosis Following Neoadjuvant Radiochemotherapy for Esophageal Cancer: Implications for Response Classification

Objective:We sought to quantitatively and objectively evaluate histomorphologic tumor regression and establish a relevant prognostic regression classification system for esophageal cancer patients receiving neoadjuvant radiochemotherapy. Patients and Methods:Eighty-five consecutive patients with localized esophageal cancers (cT2-4, Nx, M0) received standardized neoadjuvant radiochemotherapy (cisplatin, 5-fluorouracil, 36 Gy). Seventy-four (87%) patients were resected by transthoracic en bloc esophagectomy and 2-field lymphadenectomy. The entire tumor beds of the resected specimens were evaluated histomorphologically, and regression was categorized into grades I to IV based on the percentage of vital residual tumor cells (VRTCs). A major response was achieved when specimens contained either less than 10% VRTCs (grade III) or a pathologic complete remission (grade IV). Results:Complete resections (R0) were performed in 66 of 74 (89%) patients with 3-year survival rates of 54% ± 7.05% for R0-resected cases and 0% for patients with incomplete resections ortumor progression during neoadjuvant therapy (P < 0.01). Minor histopathologic response was present in 44 (59.5%) and major histopathologic response in 30 (40.5%) tumors. Significantly different 3-year survival rates (38.8% ± 8.1% for minor versus 70.7 ± 10.1% for major response) were observed. Univariate survival analysis identified histomorphologic tumor regression (P < 0.004) and lymph node category (P < 0.01) as significant prognostic factors. Pathologic T category (P < 0.08), histologic type (P = 0.15), or grading (P = 0.33) had no significant impact on survival. Cox regression analysis identified dichotomized regression grades (minor and major histomorphologic regression, P < 0.028) and lymph node status (ypN0 and ypN1, P < 0.036) as significant independent prognostic parameters. A 2-parameter regression classification system that includes histomorphologic regression (major versus minor) and nodal status (ypN0 versus ypN1) was established (P < 0.001). Conclusions:Histomorphologic tumor regression and lymph node status (ypN) were significant prognostic parameters for patients with complete resections (R0) following neoadjuvant radiochemotherapy for esophageal cancer. A regression classification based on 2 parameters could lead to improved objective evaluation of the effectiveness of treatment protocols, accuracy of staging and restaging modalities, and molecular response prediction.

Prognostic factors of resected adenocarcinoma of the esophagus

BACKGROUND The main purpose of this study was to determine prognostic factors in patients with surgical treatment of adenocarcinoma of the esophagus. METHODS Within a 12.5-year period, esophageal adenocarcinoma was resected in 165 patients by radical transhiatal esophagectomy (n = 134) or transthoracic en bloc esophagectomy (n = 31). Tumors were analyzed according to the 1992 UICC classification with respect to pTNM stage, residual tumor (R) status, grading, and ratio of infiltrated to resected lymph nodes (lymph node ratio); both univariate and multivariate analysis of prognostic factors were performed. RESULTS The 30-day mortality rate was 6.1%. A complete removal of the tumor was achieved in 83% of the patients. Lymph node metastases were not detected in mucosal cancer (pT1a) but were detected in 18% of submucosal cancer (pT1b), 77% of pT2, 83% of pT3, and 96% of pT4. The overall 5-year survival rate was 34%; for patients without postoperative residual tumor (R0) it was 41%, and for those without lymph node metastases (pN0, R0) 63%. The 5-year survival rate for patients (pN1) with less than 30% invaded lymph nodes was 45%, compared with 0% for more than 30% invaded nodes. Independent prognostic factors for R0 resected patients excluding postoperative fatal outcome were pT and lymph node ratio. CONCLUSIONS Long-term survival after resection of esophageal adenocarcinoma is mainly associated with complete tumor removal, limited esophageal wall penetration, and ratio of infiltrated to removed lymph nodes of less than 0.3.

Comparison between endoscopic and surgical resection of mucosal esophageal adenocarcinoma in Barrett's esophagus at two high-volume centers.

Background and Objective:Esophagectomy has previously been the gold standard for patients with mucosal adenocarcinoma in Barretts esophagus (Barretts carcinoma, BC). Because of the minimal invasiveness and excellent results obtained with endoscopic resection (ER), the latter has become an accepted alternative. However, few data have so far been published comparing the 2 treatment methods. Methods:A total of 114 patients with mucosal BC who were treated surgically or endoscopically in 2 high-volume centers were included in this study. Between 1996 and 2009, 38 patients with mucosal BC received transthoracic esophageal resection with 2-field lymphadenectomy (median 29 lymph nodes removed; all pN0) in the Department of Surgery at the University of Cologne. Seventy-six patients with BC treated with ER followed by argon-plasma-coagulation of the remaining non-dysplastic Barretts esophagus in the Department of Gastroenterology in Wiesbaden were matched according to the following criteria: age, gender, infiltration depth (pT1m1–3), differentiation grade (G1/2 vs. 3) and follow-up period. Results:There were no significant differences between the 2 groups with regard to epidemiologic and tumor criteria. Complete remission (CR) was achieved in all patients in the surgery group and all but 1 patient in the ER group (98.7%; the patient died of other causes before CR was achieved). Major complications after surgery occurred in 32% of the patients, significantly more often than in the ER group (0% major complications, P < 0.001). The 90-day mortality rates were 0% in the ER group and 2.6% in the surgical group (1 of 38; P = 0.333). The median follow-up periods were 4.1 years in the ER group and 3.7 years in the surgical group. During this period, 1 patient in the ER group had a local recurrence and 4 had metachronous neoplasia (overall recurrence rate 6.6%). However, repeat endoscopic treatment was possible in all of the patients, and the long-term CR rates in the surgical and ER groups were 100% and 98.7%, respectively. No tumor-related mortality was observed in either group. Conclusions:For patients with mucosal BC, both surgery and ER are effective treatment modalities. Surgery is associated with a higher morbidity rate and shows a risk for procedure-related mortality. However, the recurrence rate is higher in patients treated with ER, so that thorough follow-up procedures are mandatory.

Prognosis of early esophageal cancer. Comparison between adeno‐and squamous cell carcinoma

Background. The purpose of this study was to compare the prognosis of patients with T1 squamous cell carcinoma (SCC) with those with Tl adenocarcinoma of the esophagus and to explain prognostic differences by an analysis of clinicopathologic characteristics.

Early gastric cancer: lymph node metastasis starts with deep mucosal infiltration.

Objective:The purpose of this study was to evaluate the frequency of lymph node metastasis according to the depth of tumor infiltration of the mucosa and submucosa. Background Data:Currently some endoscopists extend the indication for endoscopic mucosal resection in gastric cancer to the submucosa. However, the decision between endoscopic mucosectomy or gastrectomy with lymphadenectomy for early gastric cancer depends especially on the probability of lymph node metastasis. Methods:One hundred twenty-six patients either had subtotal resection (n = 29) or total gastrectomy (n = 97) for T1 gastric cancer. The median number of resected lymph nodes was 21 (1–63). In the histopathologic analysis of the specimens the tumors were differentiated according to their wall penetration in the upper (m1), middle (m2), lower (m3) third of the mucosa or submucosa (sm1, sm2, sm3). The greatest diameter of the lesions, the Grading and the Goseki-, Ming-, WHO-, and Laurén classification were determined. Results:Patients with m1 (n = 3) and m2 (n = 5) layer infiltration had no lymphatic metastasis compared with 13% for m3 (n = 39). The rate of lymphatic metastasis in submucosal carcinomas was 21% for sm1 (n = 29), 16% for sm2 (n = 23) and 40% for sm3 (n = 25). Carcinomas with papillary differentiation, Grading G1 or <1 cm in diameter had no lymph node metastasis. The size of tumor <2 cm or ≥2 cm showed independent influence on the rate of lymph node metastasis. Conclusions:Endoscopic mucosectomy in m3 carcinoma is questionable and in all submucosal carcinomas and lesions ≥2 cm it is not indicated.

Prognostic value of DNA ploidy and cerbB-2 oncoprotein overexpression in adenocarcinoma of Barrett's esophagus

Background. During the last two decades, a rising incidence of adenocarcinoma of the esophagus has been observed in the Western world. The prognostic relevance of tumor‐biological factors, such as DNA ploidy or c‐erbB‐2 overexpression, for overall survival following complete resection is still unknown.

High Specificity of Quantitative Excision Repair Cross- Complementing 1 Messenger RNA Expression for Prediction of Minor Histopathological Response to Neoadjuvant Radiochemotherapy in Esophageal Cancer

Purpose: The excision repair cross-complementing 1 (ERCC1) gene is coding for a nucleotide excision repair protein involved in the repair of radiation- and chemotherapy-induced DNA damage. We examined the potential of quantitative ERCC1 mRNA expression to predict minor or major histopathological response to neoadjuvant radiochemotherapy (cisplatin, 5-fluorouracil, and 36 Gy of radiation) followed by transthoracic en bloc esophagectomy in patients with locally advanced esophageal cancer (cT2–4, Nx, M0). Experimental Design: Tissue samples were collected by endoscopic biopsy before treatment. RNA was isolated from biopsies, and quantitative real-time reverse transcriptase PCR assays were performed to determine ERCC1 mRNA expression. Relative mRNA levels (tumor/normal ratios) were calculated as (ERCC1/β-actin in tumor)/(ERCC1/β-actin in paired normal tissue). ERCC1 expression levels were correlated with the objective histopathological response in resected specimens. Histomorphological regression was defined as major response when resected specimens contained <10% of residual vital tumor cells or in case a pathologically complete response was achieved. Results: Twelve of 36 tumors showed a major histopathological response, and 24 of 36 showed a minor histopathological response. Relative expression levels of ERCC1 of >1.09 were not associated with a major histopathological response (sensitivity, 62.5%; specificity, 100%) and 15 of 24 patients with minor histopathological response to the delivered neoadjuvant radiochemotherapy could be unequivocally identified. This association of dichotomized relative ERCC1 mRNA expression and histopathological response was statistically significant (P < 0.001). Conclusions: Relative expression levels of ERCC1 mRNA determined by quantitative real-time reverse transcriptase-PCR appear highly specific to predict minor response to our neoadjuvant radiochemotherapy protocol in patients with locally advanced esophageal cancer and could be applied to prevent expensive, noneffective, and potentially harmful therapies in a substantial number (42%) of patients.

A multicenter study of survival after neoadjuvant radiotherapy/chemotherapy and esophagectomy for ypT0N0M0R0 esophageal cancer.

Objective:To evaluate 5-year survival of patients with locally advanced esophageal cancer (LAEC) who have undergone multimodality treatment with complete histopathologic response. Background:Patients with LAEC may obtain excellent local-regional response to multimodality therapy. The overall benefit of a complete histopathologic response, when no viable tumor is present in the surgical specimen, is incompletely understood and existing data are limited to single-center studies with relatively few patients. The aim of this multicenter study was to define the outcome of patients with complete histopathologic response after multimodality therapy for LAEC. Methods:The study population included 299 patients (229 male, 70 female; median age: 60 years) with LAEC (cT2N1M0, T3-4N0-1M0; 181 adenocarcinomas, 118 squamous carcinomas) who underwent either neoadjuvant radiochemotherapy (n = 284) or chemotherapy (n = 15) followed by esophagectomy at 6 specialized centers: Europe (3) and United States (3). All patients in the study had stage ypT0N0M0R0 after resection. Results:Esophagectomy with thoracotomy (n = 255) was more frequent than with a transhiatal approach (n = 44). The median number of analyzed lymph nodes in the surgical specimens was 20 (minimum–maximum: 1–77). Thirty-day mortality rate was 2.4% and 90-day mortality rate was 5.7%. Overall 5-year survival rate was 55%. The disease-specific 5-year survival rate was 68%, with a recurrence rate of 23.4% (n = 70; local vs distant recurrence: 3.3% vs 20.1%). Cox regression analysis identified age as the only independent predictor of survival, whereas gender, histology, type of esophagectomy, type of neoadjuvant therapy, and the number of resected lymph nodes had no prognostic impact. Conclusion:Patients with histopathologic complete response at the time of resection of LAEC achieve excellent survival.

Response Evaluation by Endoscopy, Rebiopsy, and Endoscopic Ultrasound Does Not Accurately Predict Histopathologic Regression After Neoadjuvant Chemoradiation for Esophageal Cancer

Objective:To prospectively assess the sensitivity (sens), specificity (spec), positive predictive value (ppv), negative predictive value (npv), and accuracy (acc) for clinical response evaluation by endoscopy, rebiopsy, and endoscopic ultrasound (EUS) to determine histomorphologic regression UICC T-category downstaging after neoadjuvant chemoradiation for esophageal cancer. Background:Histomorphologic regression is meanwhile established as objective parameter for response and prognosis after neoadjuvant chemoradiation for esophageal cancer. Patients and Methods:Within a prospective observation trial, 80 patients with localized esophageal cancers (cT2-4,Nx,M0) received standardized neoadjuvant chemoradiation (cisplatin, 5-fluorouracil, 36 Gy) and were resected by transthoracic en bloc esophagectomy and two-field lymphadenectomy. Tumor regression was based on the percentage of vital residual tumor cells and classified in 4 categories as reported previously. Evaluation by endoscopy and EUS was performed based on WHO/UICC criteria before starting chemoradiation and before resection and rebiopsies were taken at the time of re-endoscopy. Results:Histomorphologic response was of significant (log rank) prognostic importance (P < 0.001), whereas clinical response evaluation by endoscopy (P = 0.1), rebiopsy (P = 0.34), and EUS (P = 0.35) was not. The results of the 3 diagnostic modalities to assess histomorphologic regression by endoscopy and rebiopsy UICC ypT-category downstaging for EUS are summarized: Endoscopy: sens 60%, spec 34%, ppv 49%, npv 44%, acc 47%. Rebiopsy: sens 36%, spec 100%, ppv 100%, npv 24%, acc 47%. EUS: sens 7%, spec 79%, ppv 18%, npv 57%, acc 50%. Conclusions:Histomorphologic regression is an objective response parameter of significant prognostic importance. The diagnostic accuracy of endoscopy, rebiopsy, and EUS is inadequate for objective response evaluation after neoadjuvant chemoradiation and can be omitted for this purpose in the clinical practice.

Is the prognosis for Japanese and German patients with gastric cancer really different

Background. Differing survival rates have been reported between patients having undergone surgical intervention for the treatment of gastric carcinoma in Japan and Western industrialized countries. Through the actual availability of the data compiled at a major Japanese medical center (National Cancer Center, Tokyo), it was possible, for the first time, to compare the patients and therapeutic results of a Japanese center (n = 1475) with that of a German center (Department of Surgery, Technical University of Munich, Munich; n = 453).