Pseudomyxoma Peritonei: Symptoms, Types, Causes and Treatment

Pseudomyxoma peritonei (PMP) is a rare and enigmatic disease that presents a unique set of challenges for both patients and clinicians. Often characterized by the accumulation of mucinous (gelatinous) material in the abdominal cavity, PMP can lead to a significant decline in quality of life and, if left untreated, can be life-threatening. Despite advances in diagnosis and therapy, PMP remains poorly understood, and its subtle onset frequently leads to delayed recognition. In this article, we explore the key symptoms, classification types, underlying causes, and current as well as emerging treatment strategies for pseudomyxoma peritonei, drawing upon the latest research and clinical guidelines.

Symptoms of Pseudomyxoma Peritonei

Pseudomyxoma peritonei often unfolds silently, with early symptoms so subtle that the disease may go unnoticed for months or even years. When symptoms do appear, they are frequently vague and can easily be mistaken for more common abdominal or gynecological issues. Recognizing the main symptoms is crucial for timely diagnosis and intervention.

Symptom	Description/Manifestation	Frequency/Severity	Sources
Abdominal pain	Persistent, dull, or intermittent pain	Common, varies from mild to severe	1 2 3 4 5
Abdominal distention	Progressive increase in abdominal girth	Very common, often pronounced	2 3 4 5
Ascites	Accumulation of gelatinous/mucinous fluid	Common in advanced cases	2 3 4 5 11
Bowel obstruction	Symptoms of nausea, vomiting, constipation	May occur with advanced disease	2 3 4 16
Hernia/new mass	Palpable mass or new-onset hernia	Less common, sometimes presenting	3 4
Incidental finding	Discovered during imaging or surgery	Notable in early or asymptomatic	2 4 11

Table 1: Key Symptoms

Understanding the Symptom Spectrum

PMP is notorious for its lack of specific early warning signs. The clinical presentation is often driven by the slow but relentless accumulation of mucinous material secreted by tumor cells within the peritoneal cavity.

Progressive Abdominal Distention

• Abdominal distention is the most prominent and characteristic feature, driven by the progressive build-up of mucinous ascites.
• Patients may notice their clothes fitting more tightly or experience a sensation of fullness unrelated to food intake.
• As the disease advances, the abdomen can become markedly distended, resembling late-stage pregnancy in severe cases 2 3 4 5 11.

Non-specific Abdominal Pain

• Abdominal pain tends to be dull and persistent, though some patients report intermittent cramps.
• Pain may worsen as the mucin compresses abdominal organs and causes stretching of the peritoneum 1 2 3 5.

Bowel and Digestive Symptoms

• As mucin accumulates, it can compress portions of the intestine, leading to bowel obstruction.
• Symptoms may include nausea, vomiting, constipation, or changes in bowel habits 2 3 4 16.
• Nutritional compromise is possible if the disease is advanced and causes significant digestive dysfunction 3.

Hernia and Masses

• Occasionally, PMP presents as a new-onset hernia or a palpable pelvic or abdominal mass, often due to localized accumulation of mucin 3 4.
• Some patients, especially women, may present with findings suggestive of a pelvic tumor.

Incidental Discovery

• In a significant number of cases, PMP is discovered incidentally during imaging, surgery, or evaluation for unrelated symptoms 2 4 11.
• This reflects the disease’s indolent (slow-growing) nature and the lack of early, alarming symptoms.

Summary

The vague and gradual onset of symptoms means PMP can easily be missed or misattributed to other, more common abdominal conditions. Any persistent, unexplained abdominal distention, especially if accompanied by pain or changes in bowel habits, should prompt consideration of PMP in the differential diagnosis.

Types of Pseudomyxoma Peritonei

PMP is not a single disease entity but a spectrum, ranging from relatively indolent to aggressive forms. Understanding its classification is vital for prognosis and treatment planning.

Type / Category	Key Features / Pathology	Prognosis / Outcome	Sources
Low-grade (DPAM)	Abundant mucin, scant bland epithelial cells	Favorable, indolent	3 6 7 9
High-grade (PMCA)	Mucin with abundant malignant epithelial cells; cytologic atypia	Less favorable, aggressive	3 6 7 8 9
High-grade with signet ring cells	High-grade cytology, signet ring morphology	Poorest prognosis	6 8
Acellular mucin	Mucin pools without epithelial cells	Variable, generally better	6

Table 2: Types and Classifications

Modern Classification Systems

DPAM vs PMCA

• Disseminated Peritoneal Adenomucinosis (DPAM):

  • Characterized by copious extracellular mucin with very few, bland, non-malignant-appearing epithelial cells.
  • Represents the “low-grade” or less aggressive form.
  • Associated with better long-term survival and a more indolent course 3 6 7 9.

• Peritoneal Mucinous Carcinomatosis (PMCA):

  • Shows abundant malignant epithelial cells within the mucin, with obvious signs of cellular atypia and increased mitotic activity.
  • Represents the “high-grade” or more aggressive variant 3 6 7 8 9.
  • Patients with PMCA have a higher risk of recurrence and worse survival outcomes.

WHO/PSOGI Classifications

• Modern consensus guidelines (e.g., PSOGI) recommend using three categories:
  • Low-grade (synonymous with DPAM)
  • High-grade (synonymous with PMCA)
  • High-grade with signet ring cells: Signet ring cells indicate a particularly poor prognosis 6.
  • Acellular mucin: Refers to mucin deposits without epithelial cells; generally carries a better prognosis 6.

Molecular Subtypes

• Recent studies suggest molecular classifications, including oncogene-enriched, immune-enriched, and mixed subtypes, may offer additional prognostic information 8.

Implications for Prognosis

• Patients with low-grade/DPAM disease fare significantly better than those with high-grade/PMCA or signet ring cell–containing tumors 3 6.
• Accurate histological and molecular classification is essential to tailor therapy and counsel patients regarding expected outcomes.

Causes of Pseudomyxoma Peritonei

While the classic cause of PMP is perforation of an appendiceal mucinous tumor, research has revealed a broader range of possible origins and key molecular drivers.

Cause / Origin	Description / Mechanism	Relative Frequency	Sources
Appendiceal mucinous tumors	Perforation/spread of mucinous neoplasms in appendix	Most common	1 2 3 6 7 9 12 17
Ovarian mucinous tumors	Primary or secondary involvement of ovaries	Less common	3 9 10 12 13
Other GI tract neoplasms	Colorectal, gastric, pancreatic, biliary tumors	Rare	3 10 13
Urachal and other rare sites	Mucinous tumors of urachus, fallopian tube, etc.	Very rare	3 10 13
Molecular mutations	KRAS, GNAS, TP53 mutations in tumor cells	Key pathogenic drivers	7 8 12 18

Table 3: Causes and Pathogenesis

The Classic Pathway: Appendiceal Origin

• Appendiceal mucinous neoplasms are the primary source of PMP in the vast majority of cases 1 2 3 6 7 9 12 17.
• These tumors can be either low- or high-grade and, upon perforation or invasion of the appendiceal wall, seed mucin-producing epithelial cells throughout the peritoneum.
• The mucin accumulates due to the “redistribution phenomenon,” where gravity and peritoneal fluid flow cause deposits to settle in dependent areas like the omentum, diaphragmatic undersurface, and pelvis 16.

Ovarian and Other Origins

• Ovarian tumors can be a primary source, especially mucinous cystadenoma or carcinoma, or they may be secondarily involved by spread from the appendix 3 9 10 12 13.
• In women, differentiation between primary ovarian and secondary appendiceal PMP is crucial for management.
• Other rare origins include mucinous tumors of the colorectum, urachus, stomach, pancreas, gallbladder, fallopian tube, and even lung or breast in exceptional cases 3 10 13.

Molecular and Genetic Drivers

• Recent research has identified frequent KRAS and GNAS mutations in PMP tumors, regardless of origin 7 8.
  • KRAS mutations are seen in up to 100% of cases; GNAS mutations are present in 17–100%.
  • These mutations drive mucin production and tumor proliferation.
• TP53 mutations are associated with high-grade, more aggressive disease 7 8.
• Mucin genes, particularly MUC2, are overexpressed, leading to the copious extracellular mucin characteristic of PMP 2 12.
• The identification of these molecular alterations is fueling research into targeted therapies, such as vaccines against mutated GNAS 18.

Pathophysiology: A Disease of Mucin-Secreting Cells

• PMP is, at its core, a disease of MUC2-expressing goblet cells. The accumulation of mucin is not merely a byproduct but a central feature of the disease’s progression and morbidity 12.
• The inability of the peritoneum to clear this mucin leads to mechanical compression and dysfunction of abdominal organs.

Treatment of Pseudomyxoma Peritonei

Treatment strategies for PMP have evolved dramatically in recent decades, moving from repeated debulking surgeries to aggressive, potentially curative approaches combining extensive surgery and heated chemotherapy.

Treatment Approach	Main Components / Description	Outcomes / Considerations	Sources
Cytoreductive Surgery (CRS) + HIPEC	Surgical removal of all visible tumor + heated intraperitoneal chemo	Best survival, potential cure	2 3 14 15 16 17
Repeat debulking	Removal of bulk tumor/mucin, but not complete excision	Palliative, higher recurrence	3 11 16
Systemic chemotherapy	IV chemo for unresectable or recurrent disease	Limited efficacy	4 11 16 17
Targeted therapies (experimental)	Peptide vaccines, mucin-targeted drugs	Promising, under investigation	2 8 18
Supportive care	Symptom management, nutritional support	For advanced/inoperable cases	3 16

Table 4: Treatment Strategies

Complete Cytoreductive Surgery (CRS) and HIPEC

• CRS + HIPEC is the gold standard and only potentially curative treatment 2 3 14 15 16 17.
• CRS involves meticulous surgical removal of all visible tumor and mucin deposits, often requiring multivisceral resections (e.g., peritonectomy, omentectomy, hemicolectomy, hysterectomy in females) 16.
• HIPEC (Hyperthermic Intraperitoneal Chemotherapy) delivers heated chemotherapy directly into the peritoneal cavity during surgery to eradicate microscopic disease 2 14 15 16.
• This combined approach has led to significant improvements in survival:
  • Median survival up to 16.3 years, with 5-year overall survival rates ranging from 23% to 82% 2 14 15.
  • HIPEC adds a survival benefit over surgery alone, especially with oxaliplatin- or cisplatin-based regimens 14.

Repeat Debulking and Palliative Interventions

• In cases where complete cytoreduction is not possible, repeat debulking surgeries may provide symptom relief but do not offer cure 3 11 16.
• The disease often recurs, and further surgery may be needed.

Systemic Chemotherapy

• Systemic (IV) chemotherapy is sometimes used for unresectable or recurrent PMP, but its efficacy is limited 4 11 17.
• Regimens such as FOLFOX (oxaliplatin and 5-FU) have been tried, often with modest benefit 4.

Targeted and Experimental Therapies

• Ongoing research is exploring mucin-targeted therapies and peptide vaccines targeting mutated GNAS or other molecular drivers 2 8 18.
• Early studies show potential for these approaches, particularly in patients with identified molecular targets 18.

Supportive and Multidisciplinary Care

• Supportive measures are essential for patients with advanced or inoperable PMP, including pain management, nutritional support, and interventions to relieve bowel obstruction 3 16.
• Treatment decisions should be made in specialized centers with expertise in peritoneal surface malignancies 2 17.

Prognosis and Follow-up

• Prognosis depends on histological grade, completeness of cytoreduction, and the presence of high-risk molecular features 3 6 7 8 15 16.
• Even with optimal treatment, PMP frequently recurs, requiring long-term surveillance 2 15.

Conclusion

Pseudomyxoma peritonei is a rare but formidable disease, characterized by the relentless accumulation of mucin in the abdomen due to mucin-secreting tumor cells—most commonly of appendiceal origin. Early symptoms are vague, and diagnosis is often delayed until advanced stages. Today, curative treatment is possible for many patients through aggressive surgery and heated intraperitoneal chemotherapy, with ongoing research into targeted molecular therapies offering hope for the future.

Key Points:

• Symptoms are often subtle and non-specific—abdominal distention and pain are the most common initial signs.
• Classification matters—PMP ranges from indolent (low-grade/DPAM) to aggressive (high-grade/PMCA, signet ring cell) forms, with significant impact on prognosis and treatment.
• Most cases originate from the appendix, but ovarian and other GI tumors can also cause PMP; KRAS and GNAS mutations are important molecular drivers.
• Treatment has evolved—CRS and HIPEC offer the best chance for long-term survival or cure, but recurrence is common, and multidisciplinary care is essential.
• Emerging therapies—Research is ongoing into personalized treatments targeting the molecular underpinnings of PMP.

A multidisciplinary, evidence-based approach is crucial for improving outcomes in this complex and challenging disease.