Cancers 2022, 14, 913. https://doi.org/10.3390/cancers14040913 www.mdpi.com/journal/cancers Article Heterogeneity of Small Intestinal Neuroendocrine Tumors Metastasis: Biologic Patterns of a Series with Virchow’s Node Involvement Maria Wedin 1 , Marina Tsoli 2 , Göran Wallin 1 , Eva Tiensuu Janson 3 , Anna Koumarianou 4 , Gregory Kaltsas 2 and Kosmas Daskalakis 1,5, * 1 Department of Surgery, Faculty of Medicine and Health, Örebro University, 70185 Örebro, Sweden; ma- ria.wedin@regionorebrolan.se (M.W.); goran.wallin@regionorebrolan.se (G.W.) 2 1st Department of Propaedeutic Internal Medicine, National and Kapodistrian, University of Athens, 11527 Athens, Greece; martso.mt@gmail.com (M.T.); gkaltsas@med.uoa.gr (G.K.) 3 Department of Medical Sciences, Uppsala University, 75185 Uppsala, Sweden; eva.tiensuu_janson@medsci.uu.se 4 Hematology-Oncology Unit, Fourth Department of Internal Medicine, Attikon Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece; akoumari@yahoo.com 5 2nd Department of Surgery, “Korgialenio-Benakio”, Red Cross General Hospital, 11526 Athens, Greece * Correspondence: kosmas.daskalakis@oru.se; Tel.: +46-737510629 Simple Summary: Virchow’s node metastasis (VM) refers to the involvement of the left supracla- vicular lymph nodes at the junction of the thoracic duct and the left subclavian vein. Generally, VM is considered by clinicians to be a strong indicator of metastatic abdominal malignancy, and its dis- mal prognostic significance has previously been described in patients with metastatic gastric and ovarian cancer. To date, comprehensive descriptions of patients with small intestinal neuroendo- crine tumors (SI-NETs) and rare metastatic manifestations, including that of VM, are sparse. In the present study from two tertiary referral centers, the prevalence of the VM secondary to SI-NET primaries was found to be 3.9%. VM was more often encountered in patients with higher-grade tumors and established disseminated disease to distant para-aortic lymph nodes. However, the presence of VM did not yield any negative prognostic impact in patient outcomes when compared to age- and sex-matched patients of similar grade with distant metastases confined in the abdomen Abstract: Small intestinal neuroendocrine tumors (SI-NETs) may rarely metastasize to the left su- praclavicular lymph nodes, also known as Virchow’s node metastasis (VM). Data on prevalence, prognostic significance, and clinical course of disease for SI-NET patients with VM is limited. In this retrospective analysis of 230 SI-NET patients treated at two tertiary referral centers, we found nine patients with VM (prevalence 3.9%). Among those, there were 5 females and median age at SI-NET and VM diagnosis was 61 and 65 years, respectively. Two patients had G1 tumors and five G2, while two tumors were of unspecified grade (median Ki67: 7%, range 2–15%). Four patients presented with synchronous VM, whereas five developed metachronous VM after a median of twenty-four months (range: 4.8–117.6 months). Hepatic metastases were present in seven patients, extrahepatic metastases (EM) in eight (six para-aortic distant lymph node metastases, one lung and one pancre- atic metastasis), whereas peritoneal carcinomatosis (PC) in two patients. We used a control group of 18 age- and sex-matched SI-NET patients from the same cohort with stage IV disease but no extra- abdominal metastases. There was no difference in best-recorded response to first line treatment ac- cording to RECIST 1.1 as well as progression-free survival (PFS) between patients with VM and those in the control group (Chi-square test p = 0.516; PFS 71.7 vs. 106.9 months [95% CI 38.1–175.8]; log-rank p = 0.855). In addition, median overall survival (OS) of SI-NET patients with VM did not differ from those in the control group (138.6 [95% CI 17.2–260] vs. 109.9 [95% CI 91.7–128] months; log-rank p = 0.533). In conclusion, VM, although relatively rare in patients with SI-NETs, is more often encountered in patients with G2 tumors and established distant para-aortic lymph node me- Citation: Wedin, M.; Tsoli, M.; Wallin, G.; Janson, E.T.; Koumarianou, A.; Kaltsas, G.; Daskalakis, K. Heterogeneity of Small Intestinal Neuroendocrine Tumors Metastasis: Biologic Patterns of a Series with Virchow’s Node Involvement. Cancers 2022, 14, 913. https://doi.org/10.3390/cancers 14040913 Academic Editors: Louis de Mestier and Jérôme Cros Received: 26 December 2021 Accepted: 9 February 2022 Published: 12 February 2022 Publisher’s Note: MDPI stays neu- tral with regard to jurisdictional claims in published maps and institu- tional affiliations. Copyright: © 2022 by the authors. Li- censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con- ditions of the Creative Commons At- tribution (CC BY) license (https://cre- ativecommons.org/licenses/by/4.0/).