Advances in Intraluminal Exfoliative Cytology of Gastric Cancer: Oncologic Implication of the Sixth Metastatic Route (Metastasis VI)

Abstract

Historically, analysis of intragastric exfoliative cytology (IEC) of gastric cancer (GC) was used with a diagnostic intent only. With the successful advent of endoscopic biopsy, the rate of detection of GC has improved worldwide and, as a consequence, IEC has been progressively abandoned. Today, however, there is a renewed interest in this field of research, as witnessed by several pertinent publications. As discussed in this review, in fact, currently the importance of analyzing IEC in patients with early and advanced GC seems to reside in its clinicopathological and prognostic significance. In fact, compared to non-sloughing tumors, GC exhibiting intragastric exfoliation was recently associated with an aggressive tumor phenotype (characterized by deeper infiltration of the gastric wall, lymph nodal or distant metastases, angiolymphatic and perineural invasion) and poorer prognosis. Adoption of IEC examination in routine practice might help identify patients at higher risk of developing local recurrence and peritoneal metastasis from early and advanced GC, optimizing their treatment and improving quality of life and life expectancy.The study of intragastric exfoliative cytology (IEC) of gastric carcinoma (GC) started in 1882 when Rosenbach reported for the first time the presence of tumor cells in the gastric lavage of individuals affected with this type of malignancy (1). Coinciding with the worldwide success and spread of Papanicolaou staining, the heyday of IEC was from the 1940s to the 1960s; since the 1970s, succumbing to the more accurate results in diagnosis provided by the combination of endoscopy with biopsy, it was progressively abandoned (2, 3). Over recent years, however, a renewed interest in IEC has been generated. In 2013, in fact, Xie and colleagues found isolated cancer cells infiltrating the mesogastrium of resected GC specimens; such a finding in the mesogastrium led the authors to identify a metastatic pathway different from the four traditional routes (direct invasion, hematogenous spread, lymphatic dissemination, trancoelomic seeding) and to call it Metastasis V (4, 5). Concomitantly, our and other study groups have decided to focus on and persist in IEC for GC: for the first time in history, however, what was investigated was not the diagnostic role of IEC but other unreported aspects, such as its clinicopathological, prognostic and predictive significance (5-8), as well as prophylactic or therapeutic potential (9, 10). Compared with its non-exfoliative counterpart, in fact, GC exhibiting intraluminal seeding has been associated with traditional aggressive features of malignancy (depth of gastric wall invasion, lymph nodaI and distant metastasis, lymphovascular and perineural emboli) and poorer prognosis (shorter survival and time to tumor progression) (11)(12). Of interest, such results have been confirmed so far for early (13) and advanced (3) GC tumors, as well as GC submitted to neoadjuvant therapy ( 14). For such oncologicaI discoveries and implications, IEC of GC was recently identif...

Prognostic Role of Intragastric Cytopathology and Microbiota in Surgical Patients with Stomach Cancer

“…In the last decade, cytologic and molecular investigation of GL has provided interesting findings in terms of diagnosis, screening, prognosis, and treatment of GC patients. [ 7 8 9 10 11 12 13 14 15 16 17 28 29 30 ] Concerning the cytologic aspect, as suggested by numerous authors, the oncologic value of GL derives from its privilege of collecting GC products released directly by the tumor avoiding hepatic clearance, a condition known under the name of Metastasis VI. [ 8 9 31 ] In the presence of a patent gastrointestinal tube, the exfoliation of malignant cells into the gastric lumen (Metastasis VI) strongly suggests the possibility that other cell elements have already migrated or infiltrated the surrounding tissue following the classical routes of metastasis (invasion through vascular or lymphatic channels, lymph nodes, direct contact, intraperitoneal or mesogastric seeding).…”

“…[ 7 8 9 10 11 12 13 14 15 16 17 28 29 30 ] Concerning the cytologic aspect, as suggested by numerous authors, the oncologic value of GL derives from its privilege of collecting GC products released directly by the tumor avoiding hepatic clearance, a condition known under the name of Metastasis VI. [ 8 9 31 ] In the presence of a patent gastrointestinal tube, the exfoliation of malignant cells into the gastric lumen (Metastasis VI) strongly suggests the possibility that other cell elements have already migrated or infiltrated the surrounding tissue following the classical routes of metastasis (invasion through vascular or lymphatic channels, lymph nodes, direct contact, intraperitoneal or mesogastric seeding). [ 9 ] On the other hand, when obstruction by GC has occurred especially at cardia or pylorus, a number of cancerous cells, surviving for a long time due to a phenomenon called anoikis resistance, could colonize the gastric lumen, deposit on gastric or esophageal mucosa, and promote a metastasis.…”

“…[ 5 6 ] Since the last decade, cytologic and molecular analysis of gastric lavage (GL) of GC patients has provided interesting results. [ 7 8 9 10 11 12 13 14 15 16 17 ] Gastric bacterial microbiota (MB) represents another original issue for GC research drawing medical attention. [ 18 19 20 21 22 ] The stomach lumen, in fact, is not sterile and physiologically hosts a rich MB (approximately 10 2 –10 4 colony forming units per gram content) mainly composed of the genus Lactobacillus, Clostridium, Propionibacterium, Streptococcus , and Staphylococcus .…”

Combined Analysis of Intragastric Malignant Exfoliation and Ca 72.4 Concentration in Stomach Adenocarcinoma: The “GL1 Ca 72.4” Parameter

“…The findings derived from the GJ/GL of GC subjects have prompted us to identify this biologic fluid as a distinct route of tumor spreading, naming it “endoluminal pathway” or “metastasis VI” (Fig. 9) [16, 17]. Substantially, we followed the example given by Xie and colleagues [36-38] when they found malignant cells in the mesogastrium of resected GC specimens, assessing the gastric mesentery as the fifth metastatic route (“Metastasis V”) used by GC.…”

“…As of 2020, concerning diagnostic and prognostic purposes, GJ/GL have been examined through 2 main fields of application: cytopathology and molecular biology. As for the former, detection and analysis of malignant cells exfoliated in GJ/GL of GC patients have gained growing interest over the last years [16-19]. Concerning the latter, recently we observed a shift of interest from traditional tumor antigens (CEA, Ca 19.9, Ca 50, and Ca 72.4) to more sophisticated molecules, such as micro­RNAs (miRNAs), long noncoding RNAs (lncRNAs), and other noncoding RNA sections (ncRNAs) [20-28].…”