Gastric cancer (GC) is the fifth malignancy worldwide and the second most commonly diagnosed cancer in China (1, 2). Gastric linitis plastica (GLP) is a special phenotype of GC found in 7%–14% of cases and represents a particular entity (3). It is characterized macroscopically as a thickened stomach, with prominent diffusion of the tumor into the submucosal and muscular layers and microscopically by the association with signet ring cell features and diffuse and scirrhous histologic types (4, 5). GLP has a special predominance of distant lymph node metastasis, peritoneal metastasis, and ascites (6–8). As such, curative resection is possible in less than half of patients, and early recurrence is common, leading to a poor prognosis, median survival ranging from 6 to 12 months, and 5-year survival between 8% and 13% (9–13).

Despite these specific features, GLP still lacks a clear and standardized definition. GLP is used interchangeably with “Borrmann IV type carcinoma” and “scirrhous carcinoma” (12). However, these terms only include the partial characteristics of GLP and are often indiscriminately used to lead to confusion in the literature (6). The original definition of GLP is based on preoperative gastroscopy biopsies, CT scan, and postoperative surgical specimens. However, many GLP patients affected by advanced disease would not undergo gastrectomy, so that the typical definition based on postoperative surgical specimens would not always be possible. Moreover, the increasingly common practice of neoadjuvant chemotherapy or radiotherapy increases the need for preoperative diagnosis of GLP (14). In recent years, there has been an increasing development of liquid biopsy, defined as the preoperative sampling and analysis of GLP tissue (15). However, the repeatability and sensitivity of liquid biopsy are quite different. The concordance between fluid biopsy markers and clinical phenotypes is not satisfactory. Therefore, there is a need for a simple and specifically macroscopic criterion that could be used in clinical practice to aid surgeons and oncologists to arrive at a definite diagnosis preoperatively (16).

Several relatively quantitative criteria had been proposed in recent years. Pedrazzani et al. (11) defined GLP as a thickening and stiffening of the gastric wall that involved circumferentially at least one-third of the stomach. Then, Endo et al. (17) considered GLP as a gastric wall involving more than two-thirds of the stomach. Recently, Agnes et al. (6) proposed the definition as a thickening of the gastric wall that involved more than one-third of the gastric surface as a circumferential involvement of more than one area or a semicircular involvement of more than two areas. However, these definitions tended to be descriptive concepts and needed doctors to subjectively judge whether the tumor is more than one-third or two-thirds of the gastric surface by endoscope or CT scan, which made it difficult for surgeons and oncologists from different institutions to guarantee a uniform identification. Thus, the definition should be macroscopic, with a quantitatively critical value that the GLP phenotype is clearly identifiable preoperatively.

The Gastrointestinal Oncology Study Group of Japan Clinical Oncology Group (JCOG) grouped Borrmann IV with large Bormann III GC (≥8 cm in diameter) together in JCOG0210 and JCOG0501 due to the large Borrmann III with the same biological characteristics as Borrmann IV GC (18–20). In reference to Japanese studies, we proposed whether an observed tumor size ≥8 cm preoperatively by stomach enhanced CT scan could be used as a quantitative diagnosis for GLP on the premise of meeting the descriptive and pathological definition in China. The objective of this retrospective study was to propose a clearly quantitative diagnosis for GLP by survival analysis on the premise of satisfying the originally descriptive and pathological definition. Moreover, we explored clinicopathologic factors and evaluated the prognosis of GLP patients with or without neoadjuvant chemotherapy or radiotherapy. Our results would provide a firm foundation for the standardized and reproducible definition of GLP and help to define the best therapeutic options for it.

GLP is a long-known term that might date back to the 16th and 17th centuries (25). It was defined until 1947 by Arthur Stout (26) as a specific type of gastric carcinoma characterized macroscopically by a major segmental or diffuse thickening of the gastric wall and microscopically by the existence of poorly cohesive and/or signet ring cells. However, this definition tended to be a descriptive concept, missing detailed quantitative standards. Although in the following year, several relatively quantitative criteria were proposed. For example, Nakamura defined typical GLP as the involvement of more than one-fourth of the stomach (27), Pedrazzani et al. (11) proposed a critical value as one-third thickening and stiffening of the stomach (11), and Endo et al. (17) considered GLP as gastric wall involving a limit of two-thirds of the stomach. However, neither of these classifications was an accepted standard. These criteria needed doctors to subjectively judge whether the tumor was more than one-third or two-thirds of the gastric surface by endoscope or CT scan, which made these definitions difficult to be objective and reproducible.

Besides, GLP was interchangeably but not accurately termed “Borrmann IV type carcinoma,” “scirrhous carcinoma,” “Lauren carcinoma,” or “signet cell carcinoma” (28). In Japan, the term “scirrhous gastric cancer,” which commonly grouped Borrmann IV with large Borrmann III (≥8 cm in diameter) GC together, was often, but inconsistently, used confusedly with GLP to describe this phenotype of GC (18, 19, 29). Therefore, in our study, we explored whether an observed tumor size larger than 8 cm was used as a quantitative standard for GLP on the premise of satisfying the originally descriptive and pathological definition.

A total of 2,684 Borrmann III and Borrmann IV GC patients without preoperative chemotherapy or radiochemotherapy from the 7,709 GC database in our department were included in the analysis grouped by observed tumor size. It was shown that patients’ observed tumor size of more than 8 cm was a critical value for distinguishing prognosis from different tumor sizes based on survival analysis. Moreover, we proposed a preoperative observed tumor size larger than 8 cm by CT scan as a quantitatively diagnostic criterion of GLP on the prerequisite of meeting the requirement of originally descriptive and pathological definition. According to our quantitative standard, of the 2,684 patients in our study, 343 (12.8%) met the diagnostic criteria of GLP. GLP patients presented with more advanced stage and had extremely poor 3-year survival. More of these patients underwent total gastrectomy, with a stronger propensity toward peritoneal metastasis. These clinical characters of GLP according to our quantitative definition were consistent with previously classical theory and literature. But the results about median age and male-to-female ratio in our study did not show incidence characteristics such as younger age at diagnosis and female predominance as reported previously (3, 30). The reason for that perhaps was our sample selection bias. The tumor stage of these GLP patients enrolled in our study was relatively early. Those GLP patients with definite peritoneal metastasis or poor physical condition who had no opportunity of surgery generally would not be admitted to hospital in our department.

Borrmann classification was based on the macroscopically endoscopic/endoluminal aspect of the tumor, which was a subjective judgment, especially for Borrmann type IV (31). Borrmann IV GC was described as diffuse and infiltrative characteristics often lacking clear demarcation of the tumor edge (23). Borrmann IV and large Borrmann III (≥8 cm in diameter) GC were grouped in JCOG0210 and JCOG0501 due to the large Borrmann III with the same biological characteristics as Borrmann IV GC (18, 19). However, the patients with Borrmann IV tumors localized in less than two-thirds of the stomach were reported to have similar survival as patients with other non-scirrhous GC (17), which indicates that definitions based exclusively on the Borrmann classification underrepresent GLP. In our study, of 302 Borrmann IV GC, 11.9% (36/302) patients’ observed tumor sizes were less than 3 cm and 47.7% (114/302) patients’ sizes were less than 5 cm. The 3- and 5-year OS rates of Borrmann IV GC patients were 50.4% and 40.8%, respectively, and the 3- and 5-year DFS rates were 47.8% and 42%, which were inconsistent with the classical theory about linitis plastica. Therefore, not all of the Borrmann IV GC could be defined as GLP. Our team set an observed tumor size larger than 8 cm as a quantitative diagnostic criterion for GLP regardless of Borrmann type.

In addition, we took the observed tumor size preoperatively as a supplementary diagnostic standard for GLP, not pathology tumor size postoperatively in our study. It was observed that tumor size, not pathology tumor size, was an independent predictor of prognosis for Borrmann III and IV GC. Moreover, there is the need for a preoperatively quantitative critical value that the GLP phenotype is clearly identifiable, not postoperative one. The observed tumor size by stomach enhanced CT scan would guarantee a relative uniform identification of GLP and could be simply used in clinical practice preoperatively for oncologists and surgeons from different institutions (16, 21).

Moreover, the optimum treatment strategy for GLP is unknown (32). It is not clear whether patients with GLP could gain benefit from neoadjuvant chemotherapy or chemoradiation (33). Our results suggested that neoadjuvant chemotherapy or chemoradiation for GLP followed by gastrectomy did not bring obvious survival benefits. But our study sample size was small, the follow-up time was short, and the statistical error made our negative clinical curative effect need further research. The JCOG0501 trial, a phase III study of neoadjuvant chemotherapy with S-1/cisplatin in scirrhous type GC, showed that the addition of neoadjuvant chemotherapy did not appear to affect the survival rate of the scirrhous type GC patients and was not recommended (18). However, 80% of the patients enrolled in the group were N0/N1 stage in the JCOG0501 study. The high proportion of the early stage probably resulted in a negative conclusion. It was worth rethinking whether neoadjuvant chemotherapy could benefit the survival of patients with locally advanced GLP, especially in China. Therefore, more high-level evidence-based medical studies are expected to evaluate the value of neoadjuvant therapy of GLP.

Nevertheless, our study had some limitations. The major limitation of this retrospective study was the selection bias of samples source. Our department is gastric surgery, where admitted patients could undergo surgical treatment. Therefore, those GLP patients with tumor distant metastasis or poor physical condition would be refused admission to our outpatient department. Even if GLP patients are hospitalized in our department, these patients generally have no accompanying ascites or peritoneal metastasis preoperative, which leads to the tumor stage of GLP enrolled in our study relatively early. Moreover, the data were collected retrospectively with a limited number of patients in our single-center study, not multicenter. Therefore, there is a need for large-scale clinical validation.

In summary, we considered patients’ observed tumor size of more than 8 cm by stomach enhanced CT as a critical value for distinguishing the prognosis of Borrmann III and IV GC. We proposed a preoperatively observed tumor size larger than 8 cm as a supplementary quantitative diagnosis for GLP on the premise of satisfying the originally descriptive and pathological definition. Moreover, neoadjuvant chemotherapy or chemoradiation for GLP patients followed by gastrectomy did not bring obvious survival benefits. In a word, this was a preliminary conclusion in a single-center study, which required us to enlarge the sample size to verify it. Next, we will focus on evaluating the value of neoadjuvant therapy of GLP in future studies.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

YH and HC conceived and designed the study and helped draft the manuscript. YX, XL, HZ, and MZ performed all data collection and conducted the statistical analysis. YW and DX revised the manuscript. All authors contributed to the article and approved the submitted version.

This study was funded by a grant from the National Natural Science Foundation of China (No. 81802439).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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