Correlation between PSOGI pathological classification and survival outcomes of patients with pseudomyxoma peritonei treated using cytoreductive surgery and HIPEC: national referral centre experience and literature review

Patient selection and clinical management

In 2013 a program to provide CRS HIPEC to appropriately selected patients with peritoneal malignancy was established. The program has been delivered at a single national centre and has provided care to patients with pseudomyxoma peritonei from throughout the Republic of Ireland.

The decision to proceed to CRS + HIPEC was at the multidisciplinary meeting (MDT). An extensive clinical history including serum tumor marker status (TM) (carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (Ca19-9) and cancer antigen 125 (Ca-125)) was recorded. Radiologists with a special interest and experience in peritoneal malignancy reviewed oral and intravenous contrast-enhanced computed-tomography (CT) scans of chest/abdomen/pelvis [11]. An expert pathologist reviewed available tissue (mainly from previous appendicectomy or debulking specimens or radiologically guided biopsies).

Intraoperatively, the extent of the peritoneal disease was recorded using the peritoneal cancer index (PCI) scoring system [12]. Briefly, the abdomen is divided into 9 regions with 4 further regions for the small bowel, resulting in 13 in total. A score of 0–3 is calculated for each region where 0 indicates that no visible peritoneal disease, 1 where tumour nodules are <0.5 cm, 2 being nodules from 0.5 to 5 cm and 3 nodules >5 cm or confluent disease. The PCI score ranges from 0 to 39. The objective of CRS was to remove all macroscopic tumor deposits with HIPEC aiming to treat microscopic disease using a single dose of heated chemotherapy directly in contact with any tumour nodules or presumed residual microscopic disease [13]. Visceral resections were used where needed taking into consideration non-vital organ involvement by disease and the histology of the primary appendix tumour. Thus, a radical appendicectomy would suffice in patients with a LAMN, but a right hemi-colectomy with lymphadenectomy was performed in patients with a HAMN or mucinous adenocarcinomas +/−SRC). Peritonectomy procedures were performed as described by Sugarbaker [14]. The completeness of cytoreduction score (CC) was recorded where CC-0 implies no residual macroscopic disease, CC-1 where residual tumour nodules are <2.5 mm in size, CC-2 from 2.5 mm to 2.5 cm and CC-3 >2.5 cm [12]. For PMP, optimal CRS is considered where patients have had CC0 or CC1 cytoreduction as HIPEC can penetrate and eradicate tumour nodules up to 3 mm in size. After CRS completion, HIPEC was delivered using either the open “coliseum” technique or closed technique for 60 min at 41-43 °C using a delivery circuit (SunChip2, Gamida, France). The dosage protocols were based on the body surface area (mitomycin-C 10 mg/m²). Pelvic anastomosis, when needed, was performed after completion of HIPEC. Low pressure abdominal surgical drains were placed routinely. Patients were admitted to a critical care unit for at least 48 h for postoperative monitoring. Parenteral nutrition and mechanical and pharmacological anti-thrombotic prophylaxis were initiated in all cases. Perioperative mortality and complications were recorded using the Clavien–Dindo classification system [15]. All cases were rediscussed at the MDT once pathology results were available. Oncology review was advised for patients with pathological high-grade features. Follow-up varied according to the final pathology but at a minimum occurred every six months during the first year; yearly up until the tenth year. Follow-up by treating surgeon or medical oncologist at the treatment centre involving clinical examination, TM measurement and CT-scan evaluation. The date, site and treatment offered for recurrence was recorded. The date of death (regardless of the cause) was registered.

Pathological evaluation

The pathology specimens obtained from the intervention after the year 2016 were analyzed by an experienced pathologist (J.A) who classified peritoneal implants using the PSOGI classification [7]. Specimens removed before this period were reviewed and reclassified into the PSOGI classification groups.

Primary appendiceal lesions were categorized into benign lesions, LAMN, HAMN and mucinous adenocarcinoma. Pushing invasion is the main pathological feature that differentiates LAMN and HAMN lesions from mucinous adenocarcinomas which demonstrate an infiltrative growth pattern [16]. Mucinous adenocarcinomas with SRC (w/SRC) and signet ring cell carcinoma (SRCC) were defined by the presence of <50 % and >50 % of SRC respectively. The presence of cells with neuroendocrine differentiation (positive chromogranin/synaptophysin immunohistochemical staining) classified a lesion as Goblet cell carcinoma and was excluded from the current analysis [17].

Peritoneal lesions were classified into the following categories: acellular mucin (AM), low-grade mucinous carcinoma peritonei (LGMCP), high-grade mucinous carcinoma peritonei (HGMCP) and HGMCP with signet ring cells (HGMCP-SRC). AM was defined as mucin and a granulation-like response in the peritoneum with absence of epithelial cells. Mucinous deposits with <20 % of low-grade epithelial cells correspond to LGMCP category, to HGMCP, when >20 % of cells with high-grade features and to HGMCP-SRC when at >10 % of cells are SRC. Cases without mucin or mucinous epithelial cells could not be classified according the PSOGI criteria, and were excluded.

Statistical analysis

The primary objective was to evaluate OS and DFS in the different histological subgroups. The secondary objective was to evaluate the impact of PCI, CC score and preoperative TM status on outcomes.

The analysis of variance (ANOVA) test and non-parametric tests (Mann-Whitney U test or Kruskal–Wallis test) were used to analyse differences in continuous variables across the different categories. The Pearson’s chi-square was used to compare categorical data. The Kaplan–Meier method was used to perform survival analysis and the log-rank test for group comparisons. OS was considered as the period of time (in months) from the date of CRS/HIPEC to the date of death (regardless of the cause) and DFS, to the date of recurrence in cases with optimal CRS. Patients without events (death or recurrence) were censored at the day of last contact and patients who had postoperative deaths were excluded. Multivariate analysis was performed using a cox-regression model and identified possible confounding variables. Missing data was managed via deletion methods. Statistical significance was defined at p<0.05.

Statistical analysis and data management was done using SPSS version 23.0 (IBM) and R-studio.

Characteristics of cohort and overall outcomes

The pathology of the primary appendix tumour was available and documented in 91 patients. Following PSOGI’s description, these were classified into LAMN in 53 (58.2 %); HAMN in 5 (4.8 %), well-differentiated mucinous adenocarcinoma in 14 (15.4 %); moderate-to-poorly differentiated mucinous adenocarcinoma in 14 (15.4 %), mucinous adenocarcinoma with SRC in 3 (3.3 %) and SRCC in 1 (1.1 %). Evaluation of peritoneal implants stratified patients into 29 cases of AM (29.6 %), 43 LGMCP (43.9 %); 22 HGMCP (22.4 %) and 4 HGMCP-SRC (4.1 %). A significant correlation between primary appendiceal lesions and the pathology of the associated peritoneal disease (p<001) was observed. In total, 92 % of AM cases originated from an appendiceal LAMN whereas 94.6 % of LGMCP cases came from a LAMN (64.9 %) or a well-differentiated mucinous adenocarcinoma (29.7 %). HGMCP cases were more frequently associated with a moderate-to-poorly-differentiated mucinous adenocarcinoma (52.6 %) and 75 % of HGMCP-SRC were associated with a mucinous adenocarcinoma with SRC (50 %) or a SRCC (25 %).

The mean age was 58 years and 65/98 (62.5 %) were female. Overall, 20/65 (30.8 %) women were referred after gynecological debulking surgery due to initial suspicion of an ovarian neoplasm. Table 1 summarizes the clinical characteristics of the cohort. The median PCI score was 19 (IQR 9–28) and optimal CRS (CC0/1) was achieved in 82.7 %. The median length of stay (LOS) was 15 days (IQR 12–20) and the rate of severe postoperative complications defined by Clavien–Dindo>3 was 18.3 %. There was one postoperative death from a myocardial infarction. There was no relationship between histological subgroups and postoperative morbidity (p=0.679), nor LOS (p=0.128). The median follow-up was of 30.2 months (IQR 15.8–58.1 months). Three patients were lost to follow-up and 10/95 patients died during the follow period. The 2- and 5-year survival rates of the entire cohort were 92.1% and 88.8 %, respectively. Disease recurrence was detected in 22/77 (28.6 %) patients. The most frequent site of recurrence was peritoneal (in 19, 86.3 %), followed by 3 cases of multisite recurrence (13.6 %). Median DFS was not reached; 2- and 5-year DFS rates were of 79.1% and 61.6 % respectively (see Table 1).

The distribution of factors such as PCI, CC score, TM status, lymph node metastasis and adjuvant SCT administration was unequal across the different pathological subgroups (see Table 1).

Correlation between PSOGI classification and survival

The PSOGI classification predicted OS in the univariate analysis (see Table 1 and Figure 1A). No deaths were observed in the AM subgroup; 2 in the LGMCP; 6 in the HGMCP and 1 in the HGMCP-SRC subgroup. The 5-year OS rates across the groups were 100 % in AM, 93.6 % in LGMCP, 53.6 % in HGMCP and 66.7 % in HGMCP-SRC (Log-Rank p<0.001). Pairwise comparisons revealed differences to be significant between AM vs. HGMCP (p=0.001) and AM vs. HGMCP-SRC (p=0.004) and LGMCP vs. HGMCP (p=0.003). Median OS was only reached in the LGMCP subgroup (76.1 months, see Figure 1A).

Figure 1:

Overall survival (a) and disease-free survival (b) curves according to the PSOGI classification. (A) 5-year overall survival rates of 100 % in AM patients, 96.3 % in LGMCP, 53.6 % in HGMCP and 66.7 % in HGMCP-SRC (p<0.001). (B) 5- year disease-free survival rates of 100 % in AM patients, 55.8 % in LGMCP, 18.9 % in HGMCP and 0 % in HGMCP-SRC (p<0.001).

The predictive effect of the PSOGI classification on DFS was also significant on univariate analysis (see Table 1 and Figure 1B). Again, no relapses were observed in the AM group, whereas 11, 8 and 3 were observed in the LGMCP, HGMCP and HGMCP-SRC subgroups, respectively. Recurrences in the LGMCP and HGMCP-SRC subgroups were peritoneal and 3/8 patients in the HGMCP had a multisite recurrence (37.5 %), p=0.048. Median DFS was not reached in AM and LGMCP patients, but was 25 months in HGMCP and 10.2 months in HGMCP-SRC. The 5-year DFS rates were 100 %, 55.8%, 18.9% and 0 % in AM, LGMCP, HGMCP and HGMCP-SRC, respectively. These differences were significant in the Log-Rank test (p<0.001). Pairwise comparisons between the four histological groups found significant differences across the four groups except between HGMCP vs. HGMCP-SRC (p=0.624).

Multivariate analysis results are shown in Table 2. Once adjusted for other possible confounding variables (i.e. PCI, CC score, preoperative TM status … ), the PSOGI classification was no longer significantly associated to OS (p=0.870) nor to DFS (p=0.922).

Influence of other factors on survival

Multivariable cox regression analysis was performed to study the influence of other factors on OS and DFS, results are shown in Table 2. None of the factors analyzed were significantly associated with OS. Higher PCI scores were significantly associated with shorter DFS with hazards ratio (HR) of 1.078 (1.034–1.125, p<0.001). Also, preoperative elevation of Ca19-9 was associated with shorter DFS (HR 18.66 (1.013–343), p=0.049).