ORIGINAL ARTICLE Signet Ring Cells in Esophageal and Gastroesophageal Junction Carcinomas Have a More Aggressive Biological Behavior Philippe R. Nafteux, MD, ∗ Toni E. Lerut, MD, PhD, ∗ Patrick J. Villeneuve, MD, ∗ Jeroen M. Dhaenens, MD, ∗ Gert De Hertogh, MD, PhD,† Johnny Moons, MScN, ∗ Willy J. Coosemans, MD, PhD, ∗ Hans G. Van Veer, MD, ∗ and Paul R. De leyn, MD, PhD ∗ Objectives: To clarify the biologic behavior of esophageal signet ring cell (SRC) carcinomas of the esophagus and gastroesophageal junction (GEJ). To evaluate the accuracy of pretreatment biopsies in diagnosing true SRC carcinoma. Background: In contrast with gastric cancer, little is known about the biologic behavior and prognosis of SRC. Methods: All adenocarcinoma (ADC) of the esophagus and GEJ-patients undergoing primary resection between 1990 and 2009 were included (n = 920). Specimens containing SRCs (n = 114) were classified according to World Health Organization criteria (>50% SRC or <50% SRC). Results: Thirty-two patients showed more than 50% SRC and 71 patients showed less than 50% SRC. Overall cancer-specific 5-year survival was worse for SRC (22.4%, P < 0.0001) and for SRC > 50% (13.6%, P = 0.0001) compared with ADC. Complete resection was achieved in 86.5% of patients (n = 697) in ADC, 69.5% (n = 57) in SRC < 50%, and 78.1% (n = 25) in SRC > 50% (vs ADC, respectively, P < 0.0001 and P = 0.1801). In 379 pN + R0 patients, the median number of positive lymph nodes was comparable between ADC and SRC < 50% (4 vs 5, P = 0.207) or SRC > 50% (4 vs 8, P = 0.077). Compared with ADC, SRC > 50% showed more pN3’s (30% vs 61%, P = 0.006), higher recurrence (56% vs 42% for ADC, P = 0.003), and local-regional recurrences (29% vs 16%, P = 0.002). Pretreatment biopsies were unreliable to define the presence of SRC > 50% (sensitivity = 56.3%, positive predictive value = 43.9%). Conclusions: SRCs are aggressive neoplasms associated with poorer prog- nosis than other ADCs after primary esophagectomy. As our data suggest that pretreatment biopsies failed to reliably define presence of SRC > 50%, presence of SRCs in pretreatment biopsies seems to be of no use to define treatment strategy or prognosis. Keywords: esophageal cancer, gastroesophageal junction cancer, signet ring cell (Ann Surg 2014;00:1–7) E sophagus and gastroesophageal junction (GEJ) adenocarcinoma (ADC) is an aggressive neoplasm with a poor prognosis. 1–3 Surgery is the treatment of choice for localized esophageal ADC. Signet ring cell (SRC) carcinoma is a unique histologic subtype of ADC, characterized by accumulation of abundant intracellular mucin with a compressed nucleus displaced toward one extremity of the cell, giving the appearance of a signet ring. According to the World Health Organization (WHO), a true SRC carcinoma (SRC > From the Departments of ∗ Thoracic Surgery and †Pathology, University Hospitals Leuven, Leuven, Belgium. Disclosure: The authors have no disclosure to report for this work. This work has not been supported by any grants or funding. Reprints: Philippe R. Nafteux, MD, Department of Thoracic Surgery, Uni- versity Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. E-mail: Philippe.Nafteux@uzleuven.be. Copyright C  2014 by Lippincott Williams & Wilkins ISSN: 0003-4932/14/00000-0001 DOI: 10.1097/SLA.0000000000000689 50%) is defined as an ADC in which the predominant component (>50% of the tumor) consists of isolated or small groups of SRC in the stroma. 4 When signet-cell histology represents less than 50% of tumors cells, it is considered ADC. SRC carcinomas as defined by WHO are found in a variety of organs, including urinary bladder, colon, lung, and breast, among others. The stomach is the most frequent upper gastrointestinal site of primary signet-cell cancer, with prevalence increasing by more than 400% in the United States since the 1970s. 5 SRC > 50% rep- resents 32% to 70% of all gastric ADC in recent published series, 6–8 representing an important research topic in gastrointestinal oncology. Survival in cases of SRC > 50% seems to be worse than in classical gastric ADC, which is likely attributable to several fac- tors including (1) the higher prevalence of peritoneal carcinomatosis and lymph node (LN) metastases at initial diagnosis, (2) the lower rate of R0 resections related to the infiltrating pattern of SRC > 50% growth leading to positive vertical margins despite extensive surgery, and (3) reduced disease-free intervals attributable to peri- toneal carcinomatosis. 9 Despite these observations, there is a paucity of published literature specifically relating to the biologic factors and overall prognosis of esophageal SRC > 50%—information guiding therapy is currently extrapolated from gastric cancer literature. The aims of this study were (1) to compare esophageal and GEJ adenocarcinoma and signet ring cell (SRC) carcinoma with reference to prognosis and clinicopathologic features to better understand the behavior of esophageal SRC and (2) to evaluate the accuracy of pretreatment biopsies in diagnosing true SRC carcinoma according to the WHO criteria. MATERIALS AND METHODS Patient Characteristics Institutional ethics board approval from the Faculty of Medicine of the KU Leuven was obtained (ML8394). All cases of ADC during the period 1990 to 2009 undergoing primary surgery were retrieved from our prospectively built database. Lesions of the subcardia (Siewert III) were excluded, as were patients having under- gone induction therapy. Upon review, 920 patients were included for further analysis. Cases containing SRCs (n = 114) were identified by examination of pretreatment biopsy and final pathology reports and were all but 1 reviewed by a senior pathologist (G.D.H.). The pres- ence of SRCs was confirmed in 113 patients. The WHO pathology classification defines an SRC carcinoma (SRC > 50%) as an ADC in which more than 50% of the tumor consists of isolated or small groups of SRCs in the stroma. 4 As we were interested in evaluating the impact of the presence of SRCs, we decided to create 3 groups on the basis of the definition of the WHO: the true SRC carcinoma group (SRC > 50%) and a group of tumors containing SRCs without reaching the cutoff value of 50% of the tumor volume as defined by WHO (SRC < 50%). The remaining 806 ADC patients (without SRCs in biopsy or resection specimen) served as control group. Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Annals of Surgery  Volume 00, Number 00, 2014 www.annalsofsurgery.com | 1