Peritoneal dissemination is discovered in 10–20% of patients with gastric cancer.¹ Furthermore, peritoneal recurrence develops in 60% of patients with T3 or T4 tumor after curative resection.¹² The prognosis of patients with peritoneal metastasis is very poor and peritoneal dissemination is considered as an independent factor for poor prognosis.³ However, the recent introduction of peritonectomy and perioperative intraperitoneal chemotherapy has improved the survival of patients with peritoneal dissemination. Assessment of patients to select proper treatments for peritoneal dissemination is now important.#

The volume and distribution of peritoneal dissemination correlate with the prognosis, and several classifications of the grade of peritoneal dissemination have been proposed. There are two general types of classification. One is the preoperative assessment and another is for the postoperative assessment after cytoreductive surgery.#

According to the Japanese General Rules for Gastric Cancer Study, peritoneal status is described in terms of three classes, P1, P2 and P3.⁴ P1 means that the peritoneal dissemination is distributed locally in the upper abdomen above the transverse colon, P2 indicates several countable nodules on the distant peritoneum below the transverse colon, and P3 indicates numerous metastases observed on the distant peritoneum. The survival of 1061 patients with peritoneal dissemination after surgery were analyzed according to the Japanese classification. As shown in Fig. 1, survival of patients with peritoneal dissemination becomes worse as the P-grade increases.#

To help predict the response of peritoneal nodules to treatment with intraperitoneal chemo-hyperthermia, Yonemura et al. classified four types of implants: tubercular type, nodular type, diffuse infiltrating type and ovarian type.⁵ Tubercular type indicates small nodules less than 3mm in diameter, and this type responds well to intraperitoneal chemotherapy. The penetration depth of drugs through the peritoneal surface varies from 100mm to 2mm. CDDP and carboplatin have the deepest penetration distance of about 2mm.⁶ The large nodular type is composed of nodules greater than 3mm in diameter. The diffuse infiltrating type indicates that cancer cells diffusely infiltrate deeply into the submesothelial tissue, and strongly resist intraperitoneal chemotherapy.⁷#

By the Lyon classification, gastric carcinomatosis is classified into four stages: stages I and II, malignant tumor nodules less than 5mm in diameter localized in one part of the abdomen and diffuse to the whole abdomen, respectively; stage III, tumor nodules 5mm to 2cm in diameter; stage IV, large (>2cm in diameter) tumor deposit.⁸⁹ Mean survival times of stage I, II, III and IV were 13, 22, 10 and 7months, and the staging system closely correlates with prognosis.⁶⁸#

Sugarbaker proposed the Peritoneal Cancer Index (PCI).¹⁰ Carcinomatosis with limited extent (Japanese classification of P1 and P2) corresponds to PCI less than 13 and the stages I and II from the Lyon classification, and carcinomatosis with extensive extent (P3) corresponds to PCI of 13 or larger and stages III and IV from the Lyon classification.#

All three classifications are valuable for the estimation of the prognoses. The distribution of peritoneal dissemination on the mesentery of the small bowel is very important to perform complete cytoreduction by peritonectomy. Involvement of the mesentery of the small bowel sometimes becomes a cause of incomplete cytoreduction. Sugarbaker's PCI classification is complex, but enables one to describe the precise distribution of peritoneal dissemination on the small bowel and its mesentery.#

We clarified the mechanisms of peritoneal dissemination of gastric cancer by morphological and molecular studies.⁷ Peritoneal surfaces which are involved at the early phase of peritoneal dissemination contain the lymphatic orifices. The orifices are referred to as the lymphatic stomata and connect with the subperitoneal lymphatic channel and milky spots (Fig. 2). Milky spots are the minute organelles which contain lymphatic vessels, lymphocytes, and peritoneal macrophages. Milky spots distribute mainly on the greater omentum and pelvic peritoneum.#

Intraperitoneal free cancer cells specifically deposit in the lymphatic stomata and proliferate in the submesothelial lymphatic space. Hagiwara et al. reported that intraperitoneally inoculated P388 leukemia cells invade the peritoneal surface, where abundant lymphatic stomata exist.¹¹ The lymphatic stomata showed special distribution on the peritoneal surface. Numerous stomata are detected on the undersurface of the diaphragm, small bowel mesentery, greater omentum, appendix epiploicae of the large bowel and the pelvic peritoneum. Lymphatic stomata are located on the area within 1–3cm from the attachment of mesentery to the small bowel.#

In contrast, there are no lymphatic stomata on the liver capsule, the surface of the spleen and the serosal surface of the small bowel and stomach. Accordingly, the serosal surface of these organs are involved only at the late phase of peritoneal dissemination in gastric cancer. In gastric cancer when the PCI is determined, the peritoneal surface having stomata or milky spots should be carefully and meticulously examined.#

In contrast, it should be noted that the liver and splenic capsule are usually involved in mucinous carcinomatosis (pseudomyxoma peritonei). Sugarbaker described two distinct patterns of dissemination designated as random-proximally distributed and redistributed patterns.¹² The former is found in moderate and high-grade cancer such as gastric and colon cancer. In the random-proximally distributed pattern, peritoneal seeding occurs close to the primary tumor because spilled cells can attach and grow at or near the site of the first peritoneal contact. In contrast, redistributed dissemination is seen when low-grade cancer cells with a mucinous histology are released into the peritoneal cavity. These cancer cells have low invasive capacity and adhesive activities. They follow the flow of peritoneal fluid absorption and grow in the omental milky spots and diaphragmatic stomata. By gravity the cells accumulate in the dependent areas, such as the cul-de-sac of Douglas and the mesentery of the appendix. Furthermore, as they grow on the peritoneal surface, they do not invade into the deep subperitoneal layer.#

With respect to the surgical cytoreduction of the primary tumor, peritoneal dissemination and regional lymph nodes, survival of patients who had undergone a complete cytoreduction (R0) was superior than that of patients with residual disease (R1) or non-resection group.⁷ Survival of patients with P1, P2 and P3 disease are shown in Figs. 3–5. Cytoreduction by resection of the primary tumor and lymph node metastases improved survival in not only P1 or P2 disease but also in P3 disease. However, complete cytoreduction showed no survival advantage in patients with peritoneal dissemination plus any other stage IV factors, such as liver metastasis, N3 status or T4 status (Fig. 5). Accordingly, complete cytoreduction improves survival only in patients with peritoneal dissemination alone. In patients with peritoneal dissemination, qualified surgeons should not hesitate to perform complete cytoreduction by total gastrectomy plus resection of metastatic nodules in selected patients in whom the operation is technically feasible. However, complete cytoreduction is not indicated for those having peritoneal dissemination plus other stage 4 factors.#

Sugarbaker proposed the classification of completeness of cytoreduction (CCR).¹⁰ The assessment of CCR was performed by the surgeon at the end of the cytoreduction, and classified into three categories: CCR-0 indicates no macroscopic residual tumor, CCR-1 indicates residual disease of less than 2.5mm in diameter, and CCR-2 indicates residual disease greater than 2.55mm in diameter. Glehen et al. reported the results of 506 colorectal cancer patients with peritoneal dissemination, analyzed by the CCR-classification.¹³ Patients in whom cytoreductive surgery was completed had a median survival of 32months, compared to 8.4months for patients in whom complete cytoreductive surgery was not possible. The CCR index was proved to be a positive independent prognostic factor by multivariate analyses.#

Peritonectomy consists of two surgical procedures, parietal and visceral peritonectomy. The parietal peritoneum can be completely removed, while for organs involved by visceral peritoneal dissemination, mesenteric mesothelium can be peeled away, combined with resection of involved organs. Unlike ordinary procedures, peritonectomy permits removal of all visible peritoneal dissemination to attain complete cytoreduction. As shown in Tables 1 and 2, for gastric cancer the incidence of complete cytoreduction by peritonectomy was 67% (26/39), but that by the ordinary resection was 28% (18/65). Peritonectomy improved the incidence of complete cytoreduction for colon cancer, ovarian cancer, and appendiceal mucinous neoplasms. Fig. 6 shows the survival of 57 gastric cancer patients who had undergone peritonectomy. Survival of 35 CCR-0 patients was significantly better than that of 22 CCR-1 or CCR-2 patients. Furthermore, complete cytoreduction was an independent prognostic factor.#

In conclusion, quantitative prognostic indicators that macroscopically classify peritoneal dissemination prior to gastrectomy are useful in the management of carcinomatosis from gastric cancer. Further prognostic information is available using an assessment of completeness of cytoreduction after the surgery is complete.#