Introduction

Well-Differentiated Papillary Mesothelioma (WDPM) is one of the groups of peritoneal mesothelioma [1]. Deraco M et al. classified the disease as a borderline malignancy in malignant peritoneal mesothelioma (MPM), and occupies 10.4% (105/1103) of all MPM [2]. Most articles about WDPM reported that the biological characters of the disease show a benign course, but some cases progress to malignant transformation [3]. Accordingly, this disease has a broad spectrum of malignancy [4]. However, the incidence of WDPM is very rare, and no consensus for the recommendation of treatment option has been described. In the present article, we report the data of our experiences of 9 patients with WDPM, and propose some treatment options for the treatment of WDPM

Patients and Methods

From 2006 to 2023, 107 patients with MPM were referred to our hospitals, and 9 (8.4%), 84 (78.5%), 9 (8.4%) and 5 (4.7%) were pathologically classified into WDPM, epithelioid, biphasic, and sarcomatoid type, respectively, according to the classification of WHO from biopsied materials and resected specimens. Among 9 WDPM patients, 5 were male and 4 were female, and the age range from 35 to 65 with mean age of 45.1 years old (Table 1). Case one showed scattered nodules (5 small nodules of smaller than 5 mm in diameter on the small bowel mesentery and one nodule of 6 mm in diameter on the caecum) (Figure 1). Biopsied material showed typical papillary architecture containing fibrovasular cores with a single lining of cuboidal mesothelial cells without atypia or mitoses on the peritoneal surface. She was treated by Laparoscopic Hyperthermic Peritoneal Chemotherapy (LHIPEC) with 20mg of mitomycin C (MMC) and 100mg of cisplatinum (CDDP) (Tables 1,2). She is alive without recurrence 7 years after LHIPEC.

Figure 1: Scattered type of WDPM (case 1), 2-3 mm of several nodules were found on the small bowel mesentery.

The other 8 patients showed multifocal involvement of peritoneal surface with small nodules of 2-3 mm in diameter (Figure 2). Eight patients except case 6 were received laparoscopy and LHIPEC. Four patients (Case 1, 2, 5, and 7) were treated with LHIPEC alone, using MMC + CDDP for case 1 and 2 or MMC + Gemicitabine (1000mg/body) for case, 5 and 7. Neoadjuvant intraoperative chemotherapy (NIC) using 40mg of docetaxel plus 40mg of CDDP through intraperitoneal port system was performed in case 2, 3, 4, 7, and 8 (Table 3). In case 3, 4, 6, 8, and 9, laparotomy was performed and peritonectomy was done accompanying with intraoperative HIPEC. Complete macroscopic resection of peritoneal nodules (CCR-0) could be done in case 3, and 4, but in case 8, and 9, CCR-0 could not be performed due to diffuse involvement of small bowel mesentery. Specimens of all these 9 patients histologically shows a mesothelial proliferation with a papillary architecture, a myxoid appearance to the papillary cores , and a sigle layer of cytologically bland mesothelial cells covering the papillae, with small number of KI-67 labelled cells (Figure 5) and absence of invasion to other organs [5].

Figure 2: Diffuse type in WDPM (case 2), 2-3 mm of uncountable nodules were found on the greater omentum.

Table 1: Cases of well-differentiated papillary mesothelioma.

Table 2: PCI at NLHIPEC, intraoperative HIPEC, prognosis, subperitoneal invasion, and IP chemotherapy.

Table 3: Cycles of IP chemotherapy, treatment by Nivolumab, and removed peritonel sectors.

Methods of LHIPEC

Before LHIPEC, informed consent according to the institutional guideline was obtained from all patients. The patients were put under general anesthesia. A 12 mm blunt port was placed from the 2cm longitudinal incision above the umbilicus. A second trocar (12 mm) was placed in the right upper quadrant, following by a third trocar (12mm) in the left lower quadrant. A 5 mm trocar was added if necessary in the left upper quadrant. Most of the ascites was suctioned and the amount was measured with cytological examination. If there is no ascites, peritoneal wash cytology was done using aspirated saline recovered after intraperitoneal administration of 200 ml of saline.

Biopsy specimens were routinely taken from the peritoneal nodules. Quantitative evaluation of peritoneal metastasis in the entire abdominal cavity was done using the Peritoneal Carcinomatosis Index (PCI) based on the regions involved in the abdominal cavity and the lesion size [6]. Following the confirmation of the diagnosis and PCI determination, a longitudinal 5cm midline incision was made on the midline of the lower abdomen for open laparotomy. Three drainage tubes were place on the bilateral subdiaphragmatic space for the inlet tubes and on the rectovesical pouch for male and Douglas’ pouch for female patients for an outlet tube. One liter of saline was introduced into the peritoneal cavity, and the saline was completely washed out. The procedure was repeated for ten times to remove the peritoneal free cancer cells (PFCCs) [7]. Then, LHIPEC was performed at 43 to 43.5 centigrade for 60 minutes adding 4 liters of saline with 20mg of MMC plus 50mg of CDDP in case 1, 2, 8, and 9, and 1000 mg of gemcitabine plus 50mg of CDDP in case 3, 5, and 7, and 40mg of docetaxel plus 50mg of CDDP in case 4, respectively [8].

At the completion of HIPEC, intraperitoneal port system was introduced. Second and third sessions of LHIPEC was done in case 1, 2, and 7 at 6 and 12 months and in case 9 at 6 and 12 months after the first session of LHIPEC. At every LHIPEC, PCI were examined. PCI counts at the 1^st LHIPEC and the second LHIPEC or laparotomy after LHIPEC and IP chemotherapy were compared. Complications after LHIPEC were graded according to the classification established by Clavien PA and colleagues [9]. Two weeks after LHIPEC, Intraperitoneal (IP) chemotherapy from IP port system was performed. Forty mg of docetaxel and CDDP in 500 ml of saline was injected from IP port by two weeks interval (Table 3).

Statistical Analyses and the Approval By Ethical Committee

All patients were followed and no patients were lost to follow-up. Outcome data were obtained from medical records and patients’ interview. All statistical analyses were performed using SPSS software statistical computer package version 17 (SPSS Inc., Chicago, USA). The amount of ascites and PCI of the first and second LHIPEC were analyzed by student T-test. Statistical significance was defined as a p-value ≤0.05. The present study, entitled as a study of a comprehensive treatment for peritoneal surface malignancy was approved by the ethical committee of Kishiwada Tokushukai Hospital (H-19-2).

Results

Mean operation time of LHIPEC was 152 ± 15minutes, ranging from 142 to 212minutes. Intraoperative complications were not encountered. There was no mortality and morbidity of grade 3, or 4 after LHIPEC. Mean hospital stay was 3.5 days (range 3.7).

Changes of PCI.

PCI of the first LHIPEC was 24.1 ± 8.9, and that after LHIPEC plus IP chemotherapy using docetaxel and CDDP were 16.9 ± 8.3 (N=8). IP chemotherapy was done 3-24 cycles. There was a significant reduction of PCI after LHIPEC plus IP chemotherapy (P=0.0124). In case 1, 2, 5, and 7, treated with LHIPEC alone, all patients are alive without recurrence (case 1) or with disease (case 2, 5, and 7). Patients (case 3 and 4) received CCR-0 resection by peritonectomy were treated with LHIPEC and IP chemotherapy.

Histologic Findings

Microscopic examination showed that a papillary pattern accompanied by a glandular pattern, and the papillary areas were lined by a single cuboidal mesothelial cells (Figure 3), with one case (Figure 4, Case 8), having a mild nuclear atypia. In general, the mesothelial cells lacked mitotic activity. In addition, less than 1% of cells were positive for MIB-1 antibody (Figure 5). Immunohistologic studies showed a positive calretinine, CK7 (Figure 6) and D2-40 (Figure 7) and a negative CEA. In case 8, submesothelial invasive tumor of higher cytologic grade was detected in one of 23 sections from resected specimen.

Figure 3: Hematoxilin-eosin staining of case 4 (left) and case 1 (right).

Figure 4: Mild nuclear atypia was found in Case 8.

Figure 5: Immunohidtochemical findings by Ki-67 antibody (Case 8: left, and Case 1: right).

Figure 6: CK7 immunoreaction in case 4.

Figure 7: D2-40 immunoreaction in case 1.

Figure 8: Invasion foci found in Case 6. Atypical cells mimicking MPM invade into the submesothelial tissue (case 8).

Prognosis

Patients (case 1, 2, 5, and 7) treated by LHIPEC alone were alive with WDPM (case 2, 5, and 7) from 11 to 77 months or without WDPM (Case 1) after 92 months (Table 2). PCI of case 1 at the 1^st LHIPEC was 3, but it was 0 at the second laparoscopy, performed 6 months after the 1^st LHIPEC. PCI of case 2 at the 1^st LHIPEC was 30 (Figure 9), and WDPM was completely disappeared at the 2^nd laparoscopy (Figure 10). However, PCI of case 7 was not changed at the 1^st LHIPEC (PCI of 36) and 2^nd LHIPEC (PCI of 36). PCIs of Case 3 and 4 at the 1^st LHIPEC were 15, and 16, and those at the laparotomy became 3 and 13. Accordingly, complete resection could be done in the two cases, and they are alive without recurrence. In contrast, PCIs of case 8 and 9 at the laparotomy were 26 and 23, and those could not be reduced by LHIPEC and IP chemotherapy to the levels to perform complete resection. Additionally, small bowel mesentery in these 2 cases was diffusely involved, Case 8 died of mesothelioma recurrence in pleural cavity and abdominal wall, and the histology showed MPM (Figure 11). Case 9 is alive with mesothelioma recurrence in peritoneal cavity and the pathologic diagnosis was biphasic type of DMPM. Case 5 committed suicide.

Figure 9: Laparoscopic finding of pelvic peritonealsurface Case 2.