Background

Pseudomyxoma peritonei (PMP) is a rare malignant clinical syndrome with an incidence of 2–4 per million people [1, 2]. The main feature of PMP is the extensive dissemination of copious mucus-containing tumor cells in the abdominal cavity. Mucus accumulation causes progressive abdominal distention, intestinal obstruction, malnutrition, cachexia, and ultimately death. As a rare disease, an early and accurate diagnosis of PMP is difficult, which often leads to the clinically advanced stage at the time of optimal clinical treatment.

However, the dilemma has been gradually solved since 1980s, when cytoreductive surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC) strategy was developed [3]. In the following 4 decades, CRS + HIPEC related studies were discussed at the International Congress on Peritoneal Surface Malignancies since 1998, producing several consensus statements and guidelines (Fig. 1). Currently, CRS + HIPEC is the recommended treatment for PMP, vastly enhancing the prognosis of patients.

Fig. 1
figure 1

The historical development of pseudomyxoma peritonei (PMP) management and consensuses and controversies among different clinical recommendations worldwide. Consensus, black frame; Controversy, red frame. PSOGI, Peritoneal Surface Oncology Group International; EURACAN, European Rare Cancer; PMP, pseudomyxoma peritonei; MTD, maximal tumor debulking; HIPEC, hyperthermic intraperitoneal chemotherapy; CC, completeness of cytoreduction; EPIC, early postoperative intraperitoneal chemotherapy; CRS, cytoreductive surgery

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Although several guidelines have been published, most of the data come from retrospective studies, producing only type 3 clinical evidence. As a result, there are still many controversies regarding the treatment of PMP, such as the HIPEC regimen, efficacy of systemic chemotherapy, and early postoperative intraperitoneal chemotherapy (EPIC).

In this review, we collected literature and consensus statements or guidelines on PMP published worldwide over the past 4 decades, aiming to summarize the consensuses and controversies in PMP clinical management and to better understand the difficulties in the clinical management of PMP.

Main text

Literature search method

We conducted traditional narrative review on the published PMP guidelines and consensuses, according to the methodology of a traditional narrative review [4, 5]. Figure 2 shows the selection process of this study. Literature search was performed using PubMed and Web of Science for published English literature. The search terms included “pseudomyxoma peritonei + guideline”, “pseudomyxoma peritonei + consensus”, “pseudomyxoma peritonei + PSOGI”, “pseudomyxoma peritonei + protocol”, and “pseudomyxoma peritonei + proposal”. To ensure the study quality, only consensus articles published by international or regional authoritative organizations were selected for analyses, including Peritoneal Surface Oncology Group International (PSOGI)/European Rare Cancer (EURACAN), Chicago Consensus Working Group (CCWG) from U.S.A., Chinese Anti-Cancer Association (CACA) from China; Latin American Registry of Peritoneal Diseases (LARPD) from Latin America; and Brazilian Society of Surgical Oncology (BSSO) from Brazil. Eventually, 39 articles were found and 16 were included in this study, including 10 articles from 2008 PSOGI consensuses, 1 special consensus on classification and terminology, and 5 international/regional consensuses. All these articles were analyzed and outlined according to the clinical diagnosis and treatment process of PMP, mainly following the logic of CRS + HIPEC. After synthesizing the studies, we provided a take-home-message paragraph to summarize the key points of this narrative review.

Fig. 2
figure 2

Flowchart of literature search process

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Development of consensus statements worldwide

Since the first consensus statement by the PSOGI was published in 2008, sequential HIPEC treatment after CRS has gradually become the standard treatment of PMP in many countries or regions. There have been several different versions of consensuses on PMP customized according to actual situations in different regions. Currently, there are 5 up-to-date consensuses in different regions, coming from PSOGI/EURACAN, CCWG (U.S.A.) [6], CACA (China) [7], LARPD (Latin America) [8], and BSSO (Brazil) [9].

As listed in Table 1, the greatest differences among the 5 consensuses are the exclusion criteria, HIPEC regimen, and systemic chemotherapy, which still exist in the PSOGI/EURACAN 2020 Guideline. Consensuses on the terminology, pathological classification, and preoperative evaluation are largely identical with only minor differences, similar to the PSOGI/EURACAN 2020 Guideline. However, only 1 consensus at most provided recommendations regarding maximal tumor debulking, EPIC, and adverse events. The follow-up plan also needs further exploration. It is obvious that the 2008 and 2016 PSOGI Consensuses had a significant impact on consensus making around the world, which implies the important leading role of the PSOGI in PMP management. Due to the promotion and influence of the PSOGI, more countries have begun to summarize their experiences with PMP treatment [10].

Table 1 Consensus statements or guidelines worldwide
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Consensus on diagnosis and treatment

Consensus on the pathological diagnosis and classification

PMP pathological classification criteria and diagnostic terminology are confusing because there are multiple classification systems in the world. This confusion is indicative of the diverse clinical manifestations, variable pathological characteristics, and elusive features of PMP. Only through long-term and painstaking research can we properly understand its key pathogenesis and mechanism of progression before formulating appropriate clinical prevention and treatment strategies. The commonly used pathological classification methods in the literature include the Ronnett three-tier system [11], the Bradley two-tier system [12], and the WHO two-tier system [13]. The simultaneous use of different classification systems may have the following disadvantages: (1) the research results of different centers are heterogeneous and are thus not conducive to the comparison of identical or similar studies; (2) as a rare disease, it is not conducive to the organization of relatively scarce research resources for collaborative studies; (3) Ronnett's three-tier system includes non-appendiceal PMP; and (4) both the Bradley and WHO systems leave out the classification of signet ring cells. Because of these shortcomings, the PSOGI failed to reach a consensus on the PMP pathology classification in 2008 [14].

An expert consensus on the pathological classification and diagnostic terms of PMP is particularly important (Table 2, Fig. 3), as it not only relates to the diagnosis and prognosis of PMP but also determines the treatment strategy. The fundamental treatment principle of PMP is to adopt different treatment strategies for PMP of different pathological grades. At the 12th International Conference on Peritoneal Carcinoma in Berlin in 2012, experts had heated discussions on PMP pathological classification and diagnostic terminology. It was not until 2016 that a written consensus on PMP pathology classification and diagnostic terminology was published [15]. According to this consensus, PMP is divided into 4 categories: (1) acellular mucin; (2) low-grade mucinous carcinoma peritonei (LMCP) or disseminated peritoneal adenomucinosis (DPAM); (3) high-grade mucinous carcinoma peritonei (HMCP) or peritoneal mucinous carcinomatosis (PMCA); and (4) high-grade mucinous carcinoma peritonei with signet ring cells (HMCP-S) or peritoneal mucinous carcinomatosis with signet ring cells (PMCA⁃S). It should be noted that DPAM and PMCA are synonyms for LMCP and HMCP, respectively, which are no longer recommended as standard pathological terminology [16].

Table 2 The 2016 PSOGI, 2017 AJCC, and 2019 WHO pathological classification and terminology of the PMP
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Fig. 3
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Pathological classification of pseudomyxoma peritonei in the 2016 consensus of the Peritoneal Surface Oncology Group International. a, b: Acellular mucin, without identifiable tumor cells in the disseminated peritoneal mucinous deposits; c, d Low-grade mucinous carcinoma peritonei, with tumor cells forming band-, island-, wave- or cluster-shaped tissue. Cancer cells present with a monolayer or pseudostratified arrangement, with slight nucleus atypia and rare mitotic figures; e, f High-grade mucinous carcinoma peritonei, with a complex structure presenting band-, island-, gland-, cribriform-shaped tissue, abundant cellularity, and at least local regional severe atypia; g, h High-grade mucinous carcinoma peritonei with signet ring cells, with abundant signet ring cells floating in the mucous pools. All sections were stained with H&E

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In 2017, the 8th Edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual included the intraperitoneal dissemination of acellular mucin in appendix mucinous tumors in M1a, while the intraperitoneal dissemination containing cellular mucin was divided into M1b. The AJCC further divided M1b into 3 grades: (1) G1, well-differentiated mucinous tumors; (2) G2, moderately differentiated mucinous tumors; and (3) G3, poorly differentiated mucinous tumors. In 2019, WHO published another taxonomy similar to 2017 AJCC staging system, and 2016 PSOGI classification (Table 2).

Currently, the 2016 PSOGI classification system is widely recognized by peritoneal carcinomatosis (PC) experts around the world. The latter-developed two taxonomies, the 2017 AJCC staging system and 2019 WHO classification of tumor, are similar to the 2016 PSOGI taxonomy in the classification criteria. However, it must be realized that the significance of the 2016 PSOGI Consensus is to end controversies regarding PMP pathology classification and diagnostic terminology. The relationship between the PSOGI pathological grading and outcome stratification still requires further study [17].

Consensus on the preoperative evaluation

A consensus on the preoperative evaluation for PMP was reached in the 2008 PSOGI Consensus, which greatly facilitated patient diagnosis and selection, mainly including 4 aspects [7]. (1) Serum tumor markers, which mainly combined testing of carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125), and carbohydrate antigen 199 (CA199). CEA, CA125, and CA199 are helpful indicators for evaluating the degree of tumor invasion, ascites production and tumor burden, and the proliferation of cancer cells, respectively. (2) A computed tomography (CT) examination + 3D reconstruction is the optimal choice for routine preoperative examination. Typically, CT scan of PMP revealed a right lower abdominal cystic or cystic-solid mass frequently with calcification (Fig. 4a); copious mucinous ascites in the abdominal cavity (Fig. 4b); extensive organ invasion or compression (Fig. 4c–f); (3) Laparoscopic exploration and exfoliative cytology are both optional.

Fig. 4
figure 4

Typical computed tomography characteristics of pseudomyxoma peritonei. Computed tomography shows the following: a Enlargement of the appendiceal cavity and calcification of the appendiceal wall; b Abdominal girth enlargement caused by a large volume of intraperitoneal mucus deposits presenting as a “jelly belly”; c Thickened greater omentum presenting as an “omental cake”; d Small intestines compressed by mucus causing “central displacement”; e Scallop impression on the surface of the liver; f Contour deformation of the spleen

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Consensus on the intraoperative evaluation

The peritoneal cancer index (PCI) score is a standard parameter used to evaluate tumor burden during comprehensive abdominal exploration. According to the Sugarbaker standard PCI score [18], the abdomen is divided into 13 areas (Fig. 5a), including 9 abdominopelvic regions and 4 additional regions in the small intestine. Lesion size (LS) is scored according to the following rules: LS-0, no visible tumor; LS-1, tumor diameter ≤ 0.5 cm; LS-2, tumor diameter 0.5–5.0 cm; and LS-3, tumor diameter > 5.0 cm or confluence. The total score of the 13 regions ranges from 0 to 39 points. The PCI scoring system helps to evaluate tumor load in the abdominal cavity and has important significance for confirming regions in the peritoneum that need to be removed or stripped or whether an optimal CRS can be performed. A high PCI score is an independent factor for poor PFS [19].

Fig. 5
figure 5

Scoring criteria of the intraoperative peritoneal cancer index and postoperative completeness of cytoreduction. a peritoneal cancer index score; b completeness of cytoreduction score

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The completeness of cytoreduction (CC) score (Fig. 5b) is the main prognostic factor for PC patients. It is suitable for PMP, colon cancer peritoneal metastasis, peritoneal sarcomatosis, peritoneal malignant mesothelioma, and ovarian cancer peritoneal metastasis [20]. The CC scoring standard has become not only an objective quantitative index and independent prognostic factor for evaluating the effect of tumor resection but also an important part of the standardized CRS. The specific evaluation is as follows: CC-0, no residual tumor nodule after cytoreduction; CC-1: residual tumor diameter < 2.5 mm; CC-2: residual tumor diameter 2.5 mm-2.5 cm; and CC-3: residual tumor diameter > 2.5 cm or the residual tumor cannot be removed or palliatively removed.

Consensus on the standard operating procedures of CRS + HIPEC

The implementation of standardized CRS and complete resection of all visible malignant tumors is the basis for long-term survival. Sugarbaker elaborated on the PMP peritonectomy procedure as early as 1995 [21]. Complete CRS may require a 6-step peritonectomy to completely remove all tumors implanted on the peritoneum. These 6 procedures include greater omental excision + splenectomy; left upper peritoneal resection; right upper peritoneal resection; lesser omental excision + cholecystectomy + omental bursa peritonectomy; pelvic peritonectomy + sleeve resection of the sigmoid colon; and antrectomy. In 2003, Sugarbaker further improved the surgical principles and technical specifications for peritoneal resection in the pelvic peritoneum, left upper peritoneum, right upper peritoneum, greater omentum + spleen, and lesser omentum + gallbladder [22]. After 4 decades’ clinical practice, the surgical procedures and details have been refined and standardized, which are accepted by PC centers all over the world (Fig. 6).

Fig. 6
figure 6

Main procedures of cytoreductive surgery. a A midline incision from xiphoid to pubic symphysis; b Total anterior parietal peritonectomy. ① Right abdominal wall. ② Right parietal peritoneum. c Greater omentectomy. ③ Greater omentum; d Exploration of the lesser omentum and stomach. ④ Stomach; e Appendectomy. The appendix significantly distended with serosa infiltrated; f Complete pelvic peritonectomy. ⑤ Ureter. ⑥ External iliac artery

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Consensus on the perioperative management

When PMP patients receive CRS + HIPEC, perioperative safety management is of paramount importance. The main high-risk factors for PMP patients include heavy tumor burden, multiple previous operations and chemotherapies, long anesthesia and operation time, extensive resections, high-volume bleeding and blood infusion, and central venous catheter. The main adverse events include perioperative venous thrombosis, anastomotic leakage, bleeding, infection, and postoperative hypermyoglobinemia. Therefore, the clinical consensus on the perioperative management of CRS + HIPEC has also become important for preventing complications. The most important aspect of perioperative management is the graded evaluation system of adverse events. The current consensus is that the perioperative period of peritoneal surface tumors includes 9 categories, 48 adverse events [23, 24] (Additional file 1: Table S1) and the classification of grade I-IV adverse events as follows: Grade I, confirmed diagnosis but without intervention; Grade II, confirmed diagnosis requiring medical intervention; Grade III, confirmed diagnosis, conservative treatment, usually requires an imaging examination for disease evaluation; and Grade IV, definitive diagnosis, emergency intervention, reoperation or ICU treatment required.

Controversies on the management of pseudomyxoma peritonei

Intraoperative procedures and technical details have been refined and standardized thanks to intensive collaborative efforts among PC centers around the world. The detailed and standardized procedures of peritonectomy and organ resection have been fully illustrated in Cytoreductive Surgery & Perioperative Chemotherapy for Peritoneal Surface Malignancy: Textbook and Video Atlas [25]. The published PC textbooks as well as the refinement and updating of expert consensuses have greatly contributed to the standardization of CRS. In contrast, several controversies remain to be solved regarding HIPEC regimens, such as drug choices, dosages, pharmacokinetics, and efficacies.

Controversies on HIPEC regimens

Controversies on HIPEC regimens have existed since their first application in 1980, and such controversies have inevitable negative impacts on the integration and comparison of clinical data and treatment efficacies among the PC centers. Among the frequently applied HIPEC regimens, most are based on oxaliplatin and mitomycin C. The representative oxaliplatin-based regimens are the “Elias high dose oxaliplatin regimen”, the “Glehen medium dose oxaliplatin regimen”, and the “Wake Forest University oxaliplatin regimen” (Table 3). However, considering the high rates of lethal hemorrhagic complications, lower-dosage oxaliplatin-based HIPEC regimens have been developed [26,27,28,29]. A consensus is almost impossible to reach due to the lack of high-level evidence from well-designed randomized controlled trials. Similarly, the dosage and intraperitoneal concentration of mitomycin C are also under heated debate [30, 31]. It is believed that the “Dutch High Dose Mitomycin C Regimen: ‘Triple Dosing Regimen’” is the preferred regimen for maintaining a stable intraperitoneal drug concentration. Other regimens, for example, the “Sugarbaker regimen” [32] and the “American Society of Peritoneal Surface Malignancy Low Dose Mitomycin C Regimen: ‘Concentration-Based Regimen’” [33], are also suggested by the PSOGI expert panel.

Table 3 Frequently used HIPEC regimens in the international peritoneal cancer centers
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To date, HIPEC regimen-related studies have been mostly single- or multicenter large-sample analyses [17, 19, 34,35,36,37,38,39,40,41,42,43,44,45,46,47,48]. In 2018, Levine et al. published the first multicenter randomized controlled trial on appendix-derived PMP. The study compared the safety, quality of life (QOL), 3-year disease-free survival (DFS), and 3-year overall survival (OS) after HIPEC (oxaliplatin 200 mg/m2 vs. mitomycin C 40 mg) [49]. In terms of hematotoxicity, no significant differences in hemoglobin or platelet counts were found, while white blood cell counts were significantly lower in the mitomycin C group between postoperative days 5–10. Short-term QOL was similar, but the oxaliplatin group had higher scores regarding physical well-being and emotional well-being than the mitomycin group. In addition, no significant differences were found regarding the 3-year DFS and OS rates between the 2 groups.

Controversies on HIPEC methods

There is a consensus that the efficacy evaluation of different HIPEC regimens relies largely on randomized clinical trials. However, an unified HIPEC method, duration, and temperature are required to guarantee the accuracy and reliability of both multicenter clinical trials and retrospective analyses of large samples, which vary vastly among different centers (Table 3). The randomized trial conducted by Levine et al. provided valuable experience for HIPEC regimen-related clinical trials. With the strengthening cooperation among PC centers worldwide and the promotion of standardized CRS + HIPEC technology, a larger randomized clinical trial of higher quality might promote a HIPEC regimen with better efficacy and less toxicity. The PSOGI/EURACAN 2020 Guideline voted 2 favored regimens for clinical trials, i.e., the “Glehen Medium Dose Oxaliplatin Regimen” and the “Dutch High Dose Mitomycin C Regimen: ‘Triple Dosing Regimen’”. However, neither reached the consensus threshold (51.0%) (Table 3).

Controversies on EPIC

EPIC is usually performed from postoperative days 1 to 4/5 without heating and is easier to perform than HIPEC. Theoretically, EPIC has the advantage of reducing or even eliminating tumor cells trapped in fibrin deposition. Therefore, EPIC could be an adjuvant therapy to reduce postoperative recurrence when combined with HIPEC. Retrospective analyses have also supported that EPIC significantly prolongs the 5-year survival rate [50] and is an independent prognostic factor for prolonged DFS and OS [51, 52]. Despite the reported good efficacy of EPIC, its safety is unclear. Lam et al. [53] and Tan et al. [54] reported that CRS + HIPEC + EPIC increased postoperative adverse events. However, Huang and colleagues [51, 52] reported the opposite results. Considering safety issues and the lack of high-level clinical evidence, 37.5% of experts in the PSOGI/EURACAN 2020 Guideline did not recommend EPIC immediately after CRS + HIPEC, with 60.7% supporting EPIC. At present, one multicenter, prospective randomized clinical trial is being conducted at the Memorial Sloan Kettering Cancer Center to evaluate efficacy and toxicity between CRS + HIPEC and CRS + EPIC [55], the results of which might provide strong evidence for the efficacy and toxicity of EPIC.

Controversies on systemic chemotherapies

Systemic chemotherapy in PMP includes neoadjuvant systemic chemotherapy, adjuvant systemic chemotherapy, and palliative systemic chemotherapy. Although the level of evidence is low, the expert panel of the PSOGI/EURACAN 2020 Guideline reached a consensus on the application of palliative systemic chemotherapy in patients with unresectable tumors or who are not suitable for surgery. In addition, its combination with bevacizumab might contribute to prolonged PFS. With respect to neoadjuvant [19, 56,57,58,59,60,61,62,63,64] and adjuvant [57, 65,66,67] chemotherapy, no definite survival benefits were proven in low-grade PMP, high-grade PMP, or high-grade PMP with signet ring cells, which is quite controversial. According to the PSOGI expert panel, neoadjuvant or adjuvant chemotherapy should not be totally abandoned in low-grade PMP (92.7% and 74.5%, respectively) and can be considered in patients with high-grade PMP with signet ring cells (76.4% and 85.5%, respectively). If neoadjuvant or adjuvant systemic chemotherapy is needed, a combination of fluoropyrimidine and an alkylating agent (e.g., oxaliplatin) is recommended (87.3% for both).

Conclusions

In conclusion, the up-to-date reached consensuses in PMP clinical management includes: (1) pathological classification; (2) terminology; (3) preoperative evaluation and eligibility for surgical treatment; (4) intraoperative evaluation; (5) standard CRS procedures and intraoperative criteria for non-resectability; and (6) SAE classification system. Gathering almost all PMP experts from all over the world, the PSOGI/EURACAN 2020 Guideline is the most authoritative clinical guideline for practice. At the same time, there are still several controversies existing: (1) HIPEC regimens; (2) systemic chemotherapy; and (3) EPIC.

PSOGI plays an important role in standardizing terminology and technical details, as well as in promoting exchanges and developing the PC discipline around the world. However, we should recognize that evidence of a consensus from the PSOGI is derived mainly from retrospective studies with low-level clinical evidence, and the Delphi methodology is not a substitution for randomized clinical trials. This is also the root cause for controversies regarding the HIPEC regimen, systemic chemotherapy, and EPIC. In the near future, consensuses or guidelines are still indispensable for the development in the management and study of PMP.