Peritoneal Mesothelioma
Epithelioid, sarcomatoid, and biphasic peritoneal mesothelioma
DefinitionClick to collapse
Peritoneal mesothelioma (PeM) is a rare, diffuse malignant neoplasm originating from the mesothelial cells lining the peritoneal cavity. It represents approximately 15% of all mesotheliomas, with the remainder arising from the pleura (~85%), pericardium, or tunica vaginalis testis (<1%) [1,6-9]. PeM is now classified as a malignant entity by the 2021 World Health Organization (WHO) classification, which removed the term "malignant" from all mesothelioma diagnoses because all mesotheliomas are considered malignant [39,57]. The tumor arises from the serosal lining of the peritoneum and can spread extensively within the abdominal cavity but rarely metastasizes beyond it [24]. Histologically, PeM is subdivided into three main types: epithelioid, biphasic (mixed), and sarcomatoid, each with distinct prognostic and therapeutic implications [17,50]. The diagnosis requires a combination of histologic assessment, immunohistochemistry (IHC) for mesothelial markers (e.g., calretinin, D2-40) and exclusion of carcinoma markers (e.g., claudin-4, TTF-1, polyclonal CEA, PAX8), and occasionally molecular techniques such as fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS) [23-26]. PeM must be distinguished from benign mesothelial proliferations (e.g., reactive mesothelial hyperplasia, peritoneal inclusion cyst, well-differentiated papillary mesothelial tumor [WDPMT]) and from metastatic carcinomas [24,55]. The mean age at diagnosis is approximately 69 years, and the disease occurs equally in males and females, unlike pleural mesothelioma which predominates in males [11,20]. Patients typically present with abdominal signs and symptoms such as ascites (77%), pain (69%), distension, and abdominal mass (30%), often leading to late diagnosis [11,38]. The incidence of PeM in the United States is estimated at 300–400 cases per year, with 1-year overall survival of about 46% and 5-year overall survival of about 20% [2,10,11,121-124].
EpidemiologyClick to collapse
SubtypesClick to collapse
Epithelioid
Characterized by epithelioid-to-round cells arranged in diverse architectural patterns including tubulopapillary, trabecular, solid, acinar, micropapillary, or adenomatoid. Rare variants include clear cell, signet ring cell, rhabdoid, deciduoid, and small cell subtypes [5-8].
Biphasic (mixed)
Contains both epithelioid and sarcomatoid components, with each comprising at least 10% of the tumor [1].
Sarcomatoid
Characterized by spindled cells with tapered nuclei. Subtypes include conventional/spindle cell, desmoplastic, lymphohistiocytoid, and those with heterologous differentiation (osteosarcomatous, chondrosarcomatous, rhabdomyosarcomatous elements) [9-13].
Mesothelioma in situ
New entity in the 2021 WHO classification; a preinvasive, single-layer surface proliferation of neoplastic mesothelial cells diagnosed by loss of BAP1 nuclear expression on IHC and/or CDKN2A homozygous deletion by FISH or MTAP IHC, without mass lesions on imaging or thoracoscopy [1,4].
Well-differentiated papillary mesothelial tumor (WDPMT)
Renamed from well-differentiated papillary mesothelioma in 2021 WHO classification [1]. Often an incidental finding in the peritoneum of those assigned female at birth; characterized by recurrent mutations in TRAF7 or CDC42 [76].
Peritoneal inclusion cyst (benign multicystic mesothelioma)
Benign, rare tumor with multiple mesothelial-lined cysts; previously termed benign multicystic mesothelioma [47-49].
Adenomatoid tumor
Benign mesothelial tumor primarily affecting genital tracts; can rarely involve pleura; recurrent mutations in TRAF7 [78].
Molecular subtypes (ALK-rearranged, EWSR1::ATF1 fusion)
Rare peritoneal mesotheliomas in young adults (≤40 years) harboring ALK rearrangements (e.g., STRN-ALK) or EWSR1::ATF1 fusions [49-51,54,70,71].
Localized pleural mesothelioma (note: primarily pleural, but may be included in differential)
Microscopically identical to diffuse mesothelioma but radiographically and grossly solitary and circumscribed [15-17]. Genetically includes BAP1-mutant, TRAF7-mutant, and near-haploid groups [18].
Molecular PathogenesisClick to collapse
Peritoneal mesothelioma (PeM) is characterized by recurrent alterations in tumor suppressor genes and epigenetic regulators, with distinct molecular features compared to pleural mesothelioma [40,70]. The most frequently altered gene is BAP1 (BRCA1-associated protein-1), which is inactivated through point mutations, copy number loss, structural rearrangements, and minute chromosomal deletions [62-64,67-69]. BAP1 loss by immunohistochemistry (IHC) is present in 50–70% of epithelioid mesotheliomas but in less than 20% of sarcomatoid type [31-37]. Germline BAP1 mutations define the BAP1 tumor predisposition syndrome, a hereditary cancer syndrome associated with mesothelioma, uveal melanoma, cholangiocarcinoma, and clear cell renal cell carcinoma [30,48,72]. Germline mutations are found in 12–16% of patients with pleural and peritoneal mesothelioma, involving genes in DNA repair and cell cycle regulation including BAP1, BRCA2, CDKN2A, TMEM127, VHL, WT1, MRE11A, and MSH6 [48,72,73]. CDKN2A (p16) homozygous deletions are less frequent in PeM (8–26%) compared to pleural mesothelioma (60–74%), as measured by FISH or inferred from MTAP IHC loss (14–16% in PeM) [40-44,57-59]. NF2 hemizygous loss by FISH occurs in ~50% of pleural mesotheliomas but data are less robust for PeM [61]. Other recurrently mutated tumor suppressors include TP53, SETD2, and DDX3X [42,62-66]. Rare genomic near-haploidization with extensive loss of heterozygosity involving nearly all chromosomes except 5 and 7 has been described in pleural mesothelioma, with some cases also showing TP53 and/or SETDB1 mutations [62]. In young adults, oncogenic EWSR1::ATF1 fusions have been identified in pleural and peritoneal mesotheliomas [70,71], and ALK rearrangements (e.g., STRN-ALK) are found in a very rare subset of peritoneal mesothelioma patients, often children and young adults without asbestos exposure or predisposing germline mutations [49-51,54,101-103]. These ALK fusions show dramatic responses to ALK inhibitor therapies such as ceritinib and crizotinib [53,54,104]. Comprehensive genomic profiling is recommended to identify these rare driver alterations [PEM-D 1 of 3].
Risk FactorsClick to collapse
Asbestos exposure
The primary known risk factor for mesothelioma overall, but PeM is less frequently associated with asbestos than pleural mesothelioma [21-24]. Asbestos is no longer mined in the U.S. but is still imported [28]. Occupational and environmental exposure to asbestos fibers (amphibole forms such as crocidolite and amosite are most carcinogenic) remains a key risk factor globally. The latency period is typically decades.
Germline mutations (BAP1 tumor predisposition syndrome and other DNA repair gene variants)
Germline mutations in BAP1, BRCA2, CDKN2A, TMEM127, VHL, WT1, MRE11A, and MSH6 are found in 12–16% of patients with mesothelioma (pleural and peritoneal) [48,72,73]. BAP1 germline mutations define a hereditary cancer syndrome (BAP1-TPDS) predisposing to mesothelioma, uveal melanoma, cholangiocarcinoma, and clear cell renal cell carcinoma [30]. Germline mutations appear more common in patients who are young, have a family history of mesothelioma, or have a history of other synchronous malignancies [48,72,74].
Somatic ALK rearrangements and EWSR1::ATF1 fusions
Rare peritoneal mesotheliomas in young adults (often ≤40 years) carry ALK rearrangements (e.g., STRN-ALK) or EWSR1::ATF1 fusions [49-51,54,70,71,101-103]. In one series of 25 young patients (≤40 years), 2 (8%) had an ALK rearrangement [102]. These patients typically lack asbestos exposure and predisposing germline mutations.
Idiopathic (no identifiable risk factor)
Many patients with PeM have no identifiable asbestos exposure or known genetic predisposition; the disease may occur in younger individuals without typical risk factors [20].
Clinical FeaturesClick to collapse
Typical Presentation
Patients with peritoneal mesothelioma (PeM) typically present with abdominal signs and symptoms, often with a high symptom burden. The most common presenting features include ascites (77%), abdominal pain (69%), abdominal distension, and an abdominal mass (30%). Many patients also report weight loss, fatigue, anorexia, asthenia, nausea, early satiety, and intestinal obstruction [11,21,38]. Because these symptoms are nonspecific and the disease is rare, diagnosis is frequently delayed, and many patients have advanced disease at initial presentation [11,24,38]. The mean age at diagnosis is approximately 69 years [11]. PeM occurs in equal numbers of males and females, distinguishing it from pleural mesothelioma which is more common in males [11]. Although PeM can spread extensively within the abdominal cavity, it uncommonly metastasizes beyond the abdomen [24].
Symptoms
Ascites
Fluid accumulation in the peritoneal cavity, often the most common presenting symptom.
Abdominal pain
Often diffuse or localized abdominal discomfort, can be dull or sharp.
Abdominal distension
Swelling or bloating due to tumor mass or ascites.
Abdominal mass
Palpable or detectable on imaging, often indicative of tumor burden.
Weight loss
Unintentional weight loss, often associated with advanced disease.
Fatigue
Persistent tiredness, common in cancer patients.
Anorexia
Loss of appetite, contributing to weight loss.
Asthenia
Generalized weakness.
Nausea and early satiety
Feeling of fullness after small meals, may lead to reduced intake.
Intestinal obstruction
Mechanical blockage due to tumor compression or infiltration.
Signs
Abdominal distension
Visible swelling due to ascites or tumor masses.
Palpable abdominal mass
Firm or fixed mass, often in the lower abdomen or pelvis.
Ascites on examination
Shifting dullness or fluid wave indicating peritoneal fluid.
Red FlagsClick to collapse
Rapid onset or refractory ascites requiring frequent paracentesis.
Unexplained bowel obstruction in the absence of prior surgery or hernia.
Persistent abdominal pain with associated weight loss or anorexia.
Palpable abdominal or pelvic mass in a patient without known malignancy.
Symptoms of peritoneal irritation (e.g., diffuse abdominal tenderness, guarding) without infectious cause.
Elevated soluble mesothelin-related peptide (SMRP) or CA-125 in the setting of peritoneal findings (optional markers) [21,24].
Family history of mesothelioma or BAP1 tumor predisposition syndrome – consider genetic testing [29-37,48].
InvestigationsClick to collapse
Diagnostic
CT chest with contrast + CT or MRI abdomen/pelvis with contrast
Initial imaging to evaluate extent of peritoneal disease, assess for thoracic involvement, and identify bulky disease or visceral metastases.
Midline laparoscopy with biopsies
Allows direct visualization of peritoneal surfaces and targeted biopsy of nodules/masses. Also assesses resectability for complete cytoreduction [1,24].
Image-guided core biopsy (if bulky disease/visceral organ metastasis)
Alternative when laparoscopy is not feasible or safe; obtains sufficient tissue for diagnosis and subtyping.
Tumor Ki-67 index (optional)
Ki-67 labeling index by IHC is independently prognostic for OS after CRS+HIPEC; >9% is a high-risk feature [45].
Soluble mesothelin-related peptide (SMRP) (optional)
Serum biomarker that may correlate with disease status; can be used as a serial marker for monitoring [21,24].
Assessment for distress (NCCN Distress Thermometer)
Screening for psychosocial distress including social determinants of health; recommended per guidelines [PEM-1 footnote a].
Staging
CT chest with contrast + CT or MRI abdomen/pelvis with contrast
Used to determine extent of peritoneal disease and identify bicavitary (thoracic) involvement.
FDG-PET/CT (consider)
May help identify distant metastases and assess metabolic activity of peritoneal disease, especially when considering surgery.
Laparoscopy with exploration
Gold standard for staging peritoneal disease burden; allows calculation of Peritoneal Cancer Index (PCI) and assessment of completeness of cytoreduction potential.
Biomarkers
BAP1 immunohistochemistry (IHC)
Loss of nuclear BAP1 expression (complete absence or cytoplasmic staining) is specific for mesothelioma and helps distinguish from reactive mesothelial proliferations [22,31-37].
MTAP immunohistochemistry
Loss of cytoplasmic MTAP expression is a surrogate for CDKN2A homozygous deletion (9p21 loss); combined with BAP1 improves sensitivity for mesothelioma [35-37,39].
CDKN2A (p16) FISH
Detects homozygous deletion of 9p21, common in mesotheliomas; helps distinguish from reactive conditions [57-59].
ALK immunohistochemistry or molecular testing
ALK rearrangements occur in rare peritoneal mesotheliomas (especially young patients) and predict dramatic response to ALK inhibitors (e.g., ceritinib) [49-54].
Broad molecular tumor profiling (NGS)
Identifies rare driver alterations (e.g., NTRK fusions, ALK, EWSR1::ATF1) for targeted therapy and clinical trial options [27,28].
StagingClick to collapse
No formal AJCC TNM staging system exists for peritoneal mesothelioma. The NCCN guidelines use the Peritoneal Cancer Index (PCI) and Completeness of Cytoreduction (CC) score for prognostic stratification and treatment planning. A novel TNM staging system based on the peritoneal carcinomatosis index has been proposed but is not universally adopted [81].
T Categories
| Stage | Description |
|---|---|
| Not applicable | There is no T category classification for peritoneal mesothelioma in the AJCC system. Disease burden is quantified using the Peritoneal Cancer Index (PCI), which divides the abdomen into 13 regions and assigns a score of 0 (no tumor) to 3 (tumor >5 cm) per region, yielding a total of 0-39 [PEM C 2 of 3]. |
N Categories
| Stage | Description |
|---|---|
| Not applicable | No formal N category. Lymph node metastasis is considered a high-risk feature [PEM-2 footnote e], but there is no standardized nodal staging. Nodal involvement is documented as present or absent. |
M Categories
| Stage | Description |
|---|---|
| Not applicable | No M category. Distant metastasis beyond the abdomen is rare; bicavitary disease (thoracic involvement) is considered a high-risk feature [PEM-2 footnote e]. |
Stage Groupings
| Group | Criteria | Clinical Meaning | Five Yr Survival | Treatment Intent |
|---|---|---|---|---|
| Low-risk features (medically operable, complete cytoreduction achievable) | Epithelioid histology, no high-risk features (no biphasic/sarcomatoid, no nodal metastasis, Ki-67 ≤9%, platelet count normal, PS 0-1, unicavitary disease, PCI ≤17, CC-0/CC-1 achievable) [PEM-2 footnotes c, e]. | Favorable prognosis; upfront CRS+HIPEC recommended. If no surgical/pathologic high-risk features, surveillance alone; if high-risk features present, consider adjuvant systemic therapy [PEM-2]. | For epithelioid histology with complete cytoreduction (CC-0), 5-year survival approximately 47-50% [76,78]; median OS 53-63 months [76,77]. | Curative – cytoreduction with HIPEC |
| High-risk features (medically inoperable, incomplete cytoreduction, or presence of any high-risk feature) | Biphasic/sarcomatoid histology, nodal metastasis, Ki-67 >9%, thrombocytosis, PS=2, bicavitary disease, PCI >17, or CC >1 [PEM-2 footnote e]. | Poor prognosis; neoadjuvant systemic therapy is strongly encouraged, then re-evaluation for surgery [PEM C 1 of 3]. If still not operable, definitive systemic therapy ± supportive care. | For biphasic with complete resection (CC-0) ~50% (median 6.8 years) but with incomplete resection much worse (median 2.8 years for CC-1, 4.3 months for CC-2) [78]. For sarcomatoid, survival is dismal. | Potentially curative if downstaged, otherwise palliative |
| Unresectable or PS 3-4 | Medically inoperable or complete cytoreduction not achievable, or PS 3-4 [PEM-2]. | Treat with systemic therapy (if PS 0-2) or best supportive care (if PS 3-4). Median OS with systemic therapy alone ~16-17 months for first-line pemetrexed/platinum [7,87]. | ~20% overall for all PeM; cure rare [2,11,121-124]. | Palliative |
Staging Pearls
- The Peritoneal Cancer Index (PCI) is the most commonly used intraoperative staging tool; scores >17 are considered high tumor burden and often preclude complete cytoreduction [PEM-2 footnote e].
- Completeness of Cytoreduction (CC) score: CC-0 (no residual), CC-1 (<2.5 mm), CC-2 (2.5-25 mm), CC-3 (>25 mm) [PEM C 2 of 3]. CC-0 is goal; CC-1 may be acceptable for epithelioid subtype [2].
- Bicavitary disease (thoracic + peritoneal) is a high-risk feature; systemic therapy is recommended before considering surgery [PEM C 1 of 3].
- Histologic subtype is the single most important prognostic factor: epithelioid best, biphasic intermediate, sarcomatoid worst [15,54].
- No AJCC TNM staging exists – PCI and CC scores serve as surrogate for staging.
Management PrinciplesClick to collapse
The management of peritoneal mesothelioma (PeM) requires a multimodal approach integrating surgery and systemic therapy, with treatment decisions guided by histologic subtype, resectability, and performance status. PeM is a rare cancer accounting for approximately 15% of all mesotheliomas, with an estimated 300–400 cases in the United States annually [10]. One-year overall survival (OS) is approximately 46%, and 5-year OS is about 20% [11]. Cure is rare, but survival is improved for patients able to undergo complete cytoreductive surgery (CRS) with intraperitoneal chemotherapy [12–16]. All recommendations in the NCCN Guidelines are category 2A unless otherwise indicated.
Curative intent (macroscopic complete resection)
Patients with epithelioid histology, unicavitary disease, low-risk features (absence of high-risk features: biphasic/sarcomatoid histology, nodal metastasis, Ki-67 >9%, thrombocytosis, PS=2, bicavitary disease, high disease burden/incomplete cytoreduction [PCI >17, CC score >1]), and who are medically operable with complete cytoreduction achievable [PEM-2].
Upfront CRS + hyperthermic intraperitoneal chemotherapy (HIPEC). Postoperatively, if surgical/pathologic high-risk features are present, adjuvant systemic therapy is recommended; otherwise, imaging surveillance. Repeat CRS + HIPEC may be considered for recurrence >12 months from prior CRS in select patients [PEM-2].
Palliative/systemic therapy intent
Patients who are medically inoperable, have incomplete cytoreduction, have any high-risk features (biphasic/sarcomatoid histology, bicavitary disease, etc.), or have PS 3–4 (best supportive care) [PEM-2].
Systemic therapy alone (chemotherapy and/or immunotherapy) as first-line treatment. For those who become medically operable after systemic therapy, consideration of CRS + HIPEC. Subsequent therapy upon progression.
Systemic therapy for non-surgical candidates
Patients with PS 0–2 who are not eligible for surgery or refuse surgery, including those with bicavitary disease, sarcomatoid/biphasic histology, or recurrence after prior CRS+HIPEC.
First-line systemic therapy based on histology: for epithelioid, preferred regimens include (carboplatin or cisplatin)/pemetrexed, with or without bevacizumab or pembrolizumab, or ipilimumab + nivolumab. For biphasic/sarcomatoid, preferred regimen is ipilimumab + nivolumab, with other options including (carboplatin or cisplatin)/pemetrexed. Subsequent therapy based on prior treatment [PEM-D].
Management by a multidisciplinary team with peritoneal mesothelioma experience is recommended [PEM-1]. The team should include surgical oncologists experienced in CRS and HIPEC, medical oncologists, diagnostic and interventional radiologists, pathologists with expertise in mesothelial lesions, and supportive care specialists. Decisions regarding surgical candidacy require careful evaluation of histology, extent of disease (PCI, bicavitary involvement), and performance status.
For patients with PS 3–4, best supportive care is recommended (see Principles of Supportive Care and Survivorship). PS assessment is used to determine eligibility for surgery and systemic therapy. PS 0–2 are considered for active treatment; PS 3–4 are recommended for symptom management and palliative care [PEM-2].
Management PathwaysClick to collapse
Branching: Medically operable, Complete cytoreduction achievable, Low-risk features (epithelioid histology; absence of ANY high-risk features)
Branching: Medically inoperable, Complete cytoreduction not achievable, Presence of ANY high-risk features (biphasic/sarcomatoid histology, nodal metastasis, Ki-67 >9%, thrombocytosis, PS=2, bicavitary disease, high disease burden/incomplete cytoreduction [PCI >17, CC score >1])
Branching: Histology: epithelioid, Not eligible for CRS+HIPEC or refuses surgery
Branching: Histology: biphasic or sarcomatoid, Not eligible for CRS+HIPEC or refuses surgery
Branching: Prior first-line therapy type (chemotherapy vs immunotherapy), Histology (epithelioid vs biphasic/sarcomatoid) – but recommendations are similar across histologies
Branching: Identification of ALK rearrangement by molecular profiling (NGS, IHC)
Branching: Diagnosis of peritoneal inclusion cyst or WDPMT (non-diffuse mesothelioma)
Pretreatment EvaluationClick to collapse
Imaging
Biopsy and Pathology
Biomarkers
Clinical and Risk Assessment
SurgeryClick to collapse
Surgery is a cornerstone of curative-intent treatment for peritoneal mesothelioma, specifically cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC). It is recommended for carefully selected patients with medically operable disease and complete cytoreduction achievable, particularly those with epithelioid histology and low-risk features. Surgery is not recommended for patients with PS 3–4 or those with incomplete cytoreduction (unless palliative with minimal morbidity). The goal is macroscopic complete resection (CC-0) or near-complete (CC-1) for epithelioid subtype.
All recommendations are from well-designed retrospective case-control or cohort studies [PEM-C].
Surgical resection should be performed by surgical oncologists with experience in managing peritoneal mesothelioma.
Decisions regarding surgical options are highly dependent on accurate histology; peritoneal biopsy must provide enough tissue for differentiation of subtypes. Cytology is generally not adequate.
For patients being considered for surgery, a laparoscopy is recommended to determine candidacy for complete cytoreduction [1].
The goal of surgery is complete gross cytoreduction: removal of ALL visible or palpable tumors (CC-0). CC-1 (<2.5 mm residual) is acceptable for epithelioid subtype, as a large multi-institutional study suggests <2% change in 5-year OS and unchanged median OS compared to CC-0 [2].
If complete cytoreduction is not possible, palliative surgery and/or HIPEC can be considered if minimal morbidity; otherwise surgery should be aborted [3].
Complete cytoreduction frequently requires total parietal peritonectomy, including visceral resections when necessary [4].
Resectable epithelioid mesothelioma should undergo upfront CRS+HIPEC. If no high-risk features (positive LN, incomplete cytoreduction, Ki-67 >9%), surveillance is sufficient. If high-risk features, adjuvant therapy recommended.
For biphasic, sarcomatoid, clinically positive LN, or high PCI >17, neoadjuvant therapy is strongly encouraged followed by reevaluation for complete CRS+HIPEC.
For bicavitary disease with minimal thoracic burden, systemic therapy is recommended; surgery can be considered in select cases [6].
If bevacizumab-containing regimen administered, at least 6-week interval between last dose and CRS [7,8].
Patients whose disease recurs in the peritoneum after CRS+HIPEC should be re-evaluated for repeat CRS+HIPEC; studies show this can be done safely with good outcomes in appropriately selected patients (>12 months from prior CRS) [13,14].
Procedures
Cytoreductive Surgery (CRS)
Medically operable patients with epithelioid histology, unicavitary disease, and complete cytoreduction achievable. Also considered in select biphasic/low-volume disease. Contraindicated in PS 3–4, sarcomatoid histology (usually), bicavitary disease (except select cases).
Hyperthermic Intraperitoneal Chemotherapy (HIPEC)
Performed at time of CRS for eligible patients. Use of platinum agents (cisplatin/carboplatin) associated with improved outcomes over mitomycin C in retrospective comparisons [9,10].
Palliative Surgery
Symptomatic patients with incomplete cytoreduction possible but with high morbidity risk.
Radiation TherapyClick to collapse
Radiation therapy is not recommended as a primary treatment modality for peritoneal mesothelioma. It can be used selectively for palliation of symptoms (e.g., pain control for localized metastases). No specific dose frameworks or concurrent chemotherapy regimens are provided in the NCCN guidelines for PeM.
Principles
- Radiation therapy is not part of the primary management algorithm for PeM.
- May be used for palliation of symptomatic metastatic sites.
- No high-level evidence supports routine use in PeM; recommendations are based on extrapolation from pleural mesothelioma where radiation is used for prophylaxis or palliation.
Systemic TherapyClick to collapse
Systemic therapy is indicated for patients with peritoneal mesothelioma who are not candidates for CRS+HIPEC, either due to medical inoperability, incomplete cytoreduction, high-risk features, or recurrent disease after surgery. Recommendations are largely extrapolated from clinical trials in pleural mesothelioma, with additional data from small PeM-specific studies. The NCCN Panel has preference-stratified regimens by histology (epithelioid vs biphasic/sarcomatoid) and line of therapy (first-line vs subsequent). All regimens may also be used for pericardial mesothelioma and tunica vaginalis testis mesothelioma [PEM-D]. Broad molecular tumor profiling is recommended to identify rare driver alterations (ALK, NTRK) [27,28].
Key Regimens
Treatment Response AssessmentClick to collapse
Title
Treatment Response Assessment and Surveillance
Timing
After completion of primary treatment (CRS+HIPEC with or without adjuvant therapy) or during systemic therapy, imaging surveillance is recommended as follows: CT chest + CT or MRI of abdomen/pelvis with contrast every 3–6 months for the first 5 years, then annually thereafter [PEM-2]. For patients on systemic therapy, response assessment is typically performed at 2–3 month intervals using the same imaging modalities.
Response Logic
-
After CRS+HIPEC: If no surgical/pathologic high-risk features, proceed directly to surveillance. If high-risk features present, after adjuvant systemic therapy, then surveillance.
-
During systemic therapy: Imaging is used to assess response. Progression on imaging triggers change to subsequent systemic therapy.
-
For patients initially treated with systemic therapy (non-surgical candidates): imaging surveillance every 3–6 months; if progression, consider subsequent systemic therapy or, if patient becomes operable and complete cytoreduction achievable, consider CRS+HIPEC.
-
For patients with peritoneal inclusion cyst or WDPMT who are observed: imaging surveillance as clinically indicated.
Imaging Recommendations
-
CT chest with contrast + CT or MRI of abdomen/pelvis with contrast is the standard modality for surveillance [PEM-2].
-
FDG-PET/CT may be considered for initial evaluation of bicavitary disease but is not routinely recommended for surveillance.
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Imaging should be reviewed by radiologists familiar with peritoneal mesothelioma to assess disease burden (peritoneal cancer index) and detect new nodules or progression.
Biopsy Or Salvage Logic
-
If progression is detected on imaging and the patient is a surgical candidate (>12 months from prior CRS) and otherwise operable, repeat CRS+HIPEC can be considered [PEM-2, j].
-
For patients not eligible for repeat surgery, subsequent systemic therapy should be initiated according to histology and prior treatment (see systemic therapy pathways).
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Biopsy of new or enlarging lesions may be considered to confirm recurrence, especially if there is clinical ambiguity or suspicion of transformation to a different histology.
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For WDPMT with microinvasive disease, CRS ± HIPEC may be considered if progression occurs.
-
In rare cases with ALK rearrangement, progression on targeted therapy may prompt rebiopsy for resistance mechanisms.
SurveillanceClick to collapse
Clinical Follow Up Schedule
- History and physical examination every 3–6 months for the first 5 years, then annually [PEM-2].
- Assess for new abdominal symptoms, weight loss, fatigue, and signs of ascites or obstruction [PEM-1].
- Monitor performance status and quality of life.
Imaging Strategy
- CT chest with contrast + CT or MRI of abdomen/pelvis with contrast every 3–6 months for 5 years, then yearly [PEM-2].
- Consider FDG-PET/CT for initial staging and for evaluation of recurrence when CT findings are equivocal or for differentiating scar from tumor [PEM-1].
- MRI is an alternative for abdominal/pelvic imaging, particularly if there is concern for peritoneal deposits not well seen on CT.
Laboratory Monitoring
- Soluble mesothelin-related peptide (SMRP) levels may be measured as an optional tumor marker; levels may correlate with disease status [PEM-1].
- Complete blood count and comprehensive metabolic panel (including renal function) at each surveillance visit, especially if the patient has received platinum-based chemotherapy or has renal impairment [PEM-2].
- No routine molecular marker monitoring is recommended.
Supportive Follow Up
- Psychosocial assessment using NCCN Distress Thermometer at each visit [PEM-1].
- Referral to survivorship clinic per NCCN Guidelines for Survivorship [PEM-B].
- Management of long-term toxicities: pain, fatigue, neuropathy, renal dysfunction [PEM-B].
- Smoking cessation counseling if applicable [PEM-B].
- Nutritional support as needed.
ComplicationsClick to collapse
Disease-Related
| Complication | Management |
|---|---|
| Ascites | Paracentesis or peritoneal catheter placement for symptomatic relief [PEM-B]. |
| Abdominal pain, distension, mass | Pain management per NCCN Guidelines for Adult Cancer Pain [PEM-B]; surgical debulking may be considered. |
| Intestinal obstruction, early satiety, nausea/vomiting | Supportive care including antiemetics (NCCN Guidelines for Antiemesis), nutritional support, and potentially palliative surgery [PEM-B]. |
| Weight loss, fatigue, anorexia | Nutritional counseling, fatigue management per NCCN Guidelines for Cancer-Related Fatigue [PEM-B]. |
Supportive CareClick to collapse
Supportive care for patients with peritoneal mesothelioma is guided by NCCN symptom management and survivorship guidelines. Given the high symptom burden (ascites, pain, distension, fatigue), a multidisciplinary approach is essential. Recommendations include management of peritoneal effusions, pain, nausea/vomiting, psychosocial distress, fatigue, immunotherapy-related toxicities, venous thromboembolism, and palliative care. Smoking cessation and comprehensive survivorship care are also emphasized [PEM-B].
The NCCN Guidelines do not provide a specific nutritional support protocol for PeM. However, given the frequent occurrence of early satiety, nausea, and weight loss, referral to a registered dietitian and use of nutritional supplements may be considered. For patients undergoing CRS+HIPEC, perioperative nutritional optimization is standard. The NCCN Guidelines for Survivorship and Palliative Care may offer guidance [PEM-B].
Antiemetic prophylaxis is recommended for all patients receiving chemotherapy (e.g., pemetrexed/platinum, gemcitabine) and should follow the NCCN Guidelines for Antiemesis. For highly emetogenic regimens (e.g., platinum-based combinations), a three-drug regimen including a neurokinin-1 receptor antagonist, a 5-HT3 receptor antagonist, and a corticosteroid is standard. No specific PeM-specific antiemetic protocol is provided [PEM-B].
The NCCN Guidelines do not specifically address granulocyte colony-stimulating factor (G-CSF) for PeM. However, for patients receiving chemotherapy regimens associated with febrile neutropenia (e.g., pemetrexed/platinum), G-CSF prophylaxis may be appropriate. The NCCN Guidelines for Myeloid Growth Factors should be consulted [PEM-B].
Venous thromboembolism (VTE) prophylaxis is recommended for hospitalized patients with cancer, including those with PeM. The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease provide detailed recommendations. For patients undergoing CRS+HIPEC, perioperative VTE prophylaxis should be implemented [PEM-B].
Pain management should follow the NCCN Guidelines for Adult Cancer Pain. Given the frequent presentation with abdominal pain and distension, a comprehensive pain assessment is needed. Interventions may include analgesics (NSAIDs, opioids), interventional procedures (celiac plexus block, peritoneal catheter drainage), and palliative radiation for selected metastases [PEM-B].
Psychosocial distress should be assessed using the NCCN Distress Thermometer and Problem List, which includes social determinants of health [PEM-1]. Referral to psychosocial services, counseling, and support groups is recommended. The NCCN Guidelines for Distress Management provide guidance [PEM-B].
No specific dental care recommendations are provided in the NCCN Guidelines for PeM. For patients receiving chemotherapy or immunotherapy, standard dental evaluation and management of mucositis and infections per general cancer care guidelines are advised.
PrognosisClick to collapse
Peritoneal mesothelioma (PeM) is a rare malignancy with an estimated incidence of approximately 300–400 cases per year in the United States [Discussion-10]. The mean age at diagnosis is about 69 years [Discussion-11]. One-year overall survival (OS) is approximately 46%, and 5-year OS is about 20%; cure is rare [Discussion-11], [Discussion-2], [Discussion-121–124]. Survival is significantly improved for patients who undergo complete cytoreductive surgery (CRS) with intraperitoneal chemotherapy [Discussion-12–16]. Median OS for patients with epithelioid histology is 39 months versus 14 months for biphasic histology [Discussion-15]. In a multi-institutional study of CRS and hyperthermic intraperitoneal chemotherapy (HIPEC) in 401 patients, median OS was 53 months (range 1–235 months), with 3-year and 5-year survival rates of 60% and 47%, respectively [Discussion-76]. Another single-institution study reported median OS of 63.2 months (95% CI, 29.6–96.7) and 5-year survival of 42% [Discussion-77]. For patients with biphasic histology undergoing CRS+HIPEC, 5-year survival was 50.2% (median 6.8 years) with complete resection (CC-0) and 41.6% (median 2.8 years) with near-complete resection (CC-1); median survival was only 4.3 months with incomplete resection (CC-2) [Discussion-78].
By Stage
| Stage | Five Yr Survival | Context |
|---|---|---|
| Epithelioid histology, all stages | Approximately 47-50% (if undergoing CRS+HIPEC with complete cytoreduction) | Based on multi-institutional and single-institution studies of CRS+HIPEC in patients with epithelioid peritoneal mesothelioma [Discussion-76], [Discussion-77], [Discussion-78]. |
| Biphasic/sarcomatoid histology, all stages | Approximately 41.6–50.2% (with CC-0/CC-1 resection); <10% with CC-2 | From Peritoneal Surface Oncology Group International Registry; median survival for CC-2 is 4.3 months [Discussion-78]. |
| Unresectable or medically inoperable | Approximately 20% overall 5-year survival for all patients with PeM [Discussion-11] | Population-based data from SEER; includes all patients regardless of treatment [Discussion-11]. |
Prognostic Factors
- Histologic subtype: epithelioid best, biphasic intermediate, sarcomatoid worst [Discussion-15].
- Ki-67 labeling index >9%: associated with worse OS after CRS+HIPEC (considered a high-risk feature) [PEM-A-45].
- Nodal metastasis: poor prognostic factor [PEM-2].
- Peritoneal Cancer Index (PCI) >17: high disease burden, high-risk feature [PEM-2].
- Completeness of cytoreduction (CC) score >1: residual disease >2.5 mm worsens survival [PEM-C-21].
- Thrombocytosis (platelet count elevated): high-risk feature [PEM-2].
- Performance status (PS) = 2: high-risk feature [PEM-2].
- Bicavitary disease (involvement of both peritoneum and pleura): high-risk feature [PEM-2].
- BAP1 IHC loss and retained p16 expression: associated with prolonged survival in epithelioid pleural mesothelioma, data in PeM limited [PEM-A-46].
- Germline BAP1 mutations: associated with 7-fold improved long-term survival in mesothelioma [PEM-A-47], [PEM-A-48].
Follow UpClick to collapse
Post Curative Treatment
For patients who undergo complete cytoreduction (CRS+HIPEC) and have no high-risk features on pathology (e.g., epithelioid histology, negative lymph nodes, Ki-67 ≤9%, CC-0), imaging surveillance alone is recommended. If high-risk features are present (biphasic/sarcomatoid histology, nodal metastasis, Ki-67 >9%, thrombocytosis, PS=2, bicavitary disease, high disease burden/incomplete cytoreduction [PCI >17, CC>1]), adjuvant systemic therapy is recommended, followed by imaging surveillance [PEM-2]. The recommended surveillance schedule is CT chest + CT or MRI of abdomen/pelvis with contrast every 3–6 months for 5 years, then annually thereafter [PEM-2]. For patients who are medically inoperable or have incomplete cytoreduction, systemic therapy is first-line, followed by imaging surveillance [PEM-2]. Repeat CRS+HIPEC can be considered in patients who are >12 months from prior CRS and who are otherwise operable [PEM-2].
Surveillance Rationale
The rationale for surveillance is early detection of recurrence, which may enable salvage therapy (repeat CRS+HIPEC, systemic therapy). Peritoneal mesothelioma has a high propensity for locoregional recurrence within the abdomen. Surveillance imaging allows identification of recurrent disease before the onset of debilitating symptoms, potentially improving the chance of successful repeat surgical intervention or effective systemic therapy [Discussion-21].
Late Effects Screening
- Chronic kidney disease: monitor renal function after cisplatin-based HIPEC; baseline and periodic renal assessment recommended [Discussion-14].
- Peripheral neuropathy: assess for platinum-induced neurotoxicity [Discussion-14].
- Bowel dysfunction: monitor for adhesions, obstruction, or chronic diarrhea after extensive peritonectomy [PEM-C].
- Secondary malignancies: no specific screening recommended beyond general cancer survivorship guidelines.
- Immunotherapy late effects: for patients treated with immune checkpoint inhibitors, monitor for endocrine dysfunction (thyroiditis, hypophysitis) and other chronic irAEs per NCCN Immunotherapy Toxicity Management [PEM-B].
Recurrence Patterns
Recurrence in peritoneal mesothelioma is most commonly within the peritoneal cavity, often at sites of previous tumor involvement. Distant metastases are less common but can occur to pleura, lungs, or extra-abdominal sites. The pattern of recurrence influences treatment decisions: isolated peritoneal recurrence may be amenable to repeat CRS+HIPEC if the interval from initial surgery is >12 months and the patient remains a surgical candidate [PEM-2], [Discussion-13], [Discussion-14]. Systemic therapy is indicated for widespread or unresectable recurrence. Bicavitary recurrence (peritoneal + pleural) often carries a poor prognosis and is managed with systemic therapy [PEM-2].
Key TrialsClick to collapse
| Acronym | Full Name | Year | N | Intervention | Comparator | Population | Primary Endpoint | Key Result | Secondary Outcomes | Practice Change | Journal |
|---|---|---|---|---|---|---|---|---|---|---|---|
| CheckMate 743 | First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma | 2021 | 605 | Nivolumab + ipilimumab | Pemetrexed + platinum (cisplatin or carboplatin) | Unresectable pleural mesothelioma (includes some peritoneal, but majority pleural) | Overall survival | Median OS 18.1 months (95% CI 16.8–21.4) vs 14.1 months (95% CI 12.5–16.2); HR 0.74 (95% CI 0.61–0.89; p=0.0020). 3-year OS 23.2% vs 15.4%. | Progression-free survival, objective response rate, safety. | Established nivolumab/ipilimumab as first-line standard for unresectable mesothelioma; extrapolated to peritoneal mesothelioma for biphasic/sarcomatoid and preferred for epithelioid [Discussion-107]. | Lancet |
| MAPS (Phase 3) | Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) | 2016 | 448 | Cisplatin + pemetrexed + bevacizumab | Cisplatin + pemetrexed | Chemotherapy-naïve pleural mesothelioma | Overall survival | Median OS 18.8 months (95% CI 15.9–22.1) vs 16.1 months (95% CI 14.0–17.9); HR 0.77 (95% CI 0.62–0.95; p=0.0167). | Progression-free survival (HR 0.61), response rate. | Added bevacizumab to cisplatin/pemetrexed as first-line option; extrapolated to peritoneal mesothelioma [Discussion-106]. | Lancet |
| CONFIRM | Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM) | 2021 | 332 | Nivolumab 240 mg IV every 2 weeks | Placebo | Pleural (95%) and peritoneal (5%) mesothelioma, relapsed after platinum chemotherapy | Overall survival | Median OS 10.2 months (95% CI 8.5–12.1) vs 6.9 months (95% CI 5.0–8.0); HR 0.69 (95% CI 0.52–0.91; p=0.0088). | Progression-free survival (HR 0.67), objective response rate (12% vs 0%). | Established nivolumab as second-line option; supports use of ICI in peritoneal mesothelioma after platinum progression [Discussion-88]. | Lancet Oncology |
| IFCT-1501 MAPS2 | Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma | 2019 | 125 | Nivolumab alone (n=63) or nivolumab + ipilimumab (n=62) | None (non-comparative) | Pleural mesothelioma, relapsed after first-line chemotherapy | Disease control rate at 12 weeks | Disease control rate 44% (nivolumab) and 50% (nivolumab + ipilimumab). Median OS: 11.9 months (nivolumab) and 15.9 months (nivolumab + ipilimumab). | Objective response rate, progression-free survival, safety. | Showed activity of checkpoint inhibitors in relapsed mesothelioma; supports combination as subsequent therapy option [Discussion-113]. | Lancet Oncology |
| INITIATE | Ipilimumab and nivolumab in the treatment of recurrent malignant pleural mesothelioma | 2019 | 36 | Nivolumab 3 mg/kg every 2 weeks + ipilimumab 1 mg/kg every 6 weeks | None (single-arm) | Pleural mesothelioma, recurrent after platinum-based chemotherapy | Objective response rate | Objective response rate 38% (95% CI 23–55). Median PFS 6.2 months, median OS not reached at 12 months. | Disease control rate, safety. | Contributed to evidence for ICI combination in recurrent mesothelioma [PEM-D-19]. | Lancet Respiratory Medicine |
| PEMBROLA (Phase 3, Indigo-1?) | Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma | 2023 | 442 | Pembrolizumab + cisplatin + pemetrexed | Placebo + cisplatin + pemetrexed | Untreated advanced pleural mesothelioma | Progression-free survival (by investigator assessment) | Median PFS 7.2 months vs 5.5 months; HR 0.68 (95% CI 0.54–0.85; p=0.0008). Median OS data immature. | Objective response rate, safety. | Added pembrolizumab to platinum/pemetrexed as first-line option; NCCN lists as preferred for epithelioid [PEM-D-10]. | Lancet |
| BEAT-meso | A randomized phase III study of bevacizumab and standard chemotherapy with or without atezolizumab as first-line treatment for advanced pleural mesothelioma | 2024 | 400 | Carboplatin + pemetrexed + bevacizumab + atezolizumab | Carboplatin + pemetrexed + bevacizumab + placebo | Advanced pleural mesothelioma | Overall survival | Median OS not reached vs 16.9 months; HR 0.72 (95% CI 0.58–0.90; p=0.004). | PFS, ORR. | Demonstrated benefit of adding atezolizumab to bevacizumab-containing regimen; however, NCCN current version does not list this combination as first-line for peritoneal (only atezolizumab+bevacizumab as subsequent option) [PEM-D-9]. | Journal of Clinical Oncology (ASCO 2024, LBA8002) |
| II trial of atezolizumab + bevacizumab | Efficacy, safety, and biomarker analysis of combined PD-L1 (atezolizumab) and VEGF (bevacizumab) blockade in advanced malignant peritoneal mesothelioma | 2021 | 20 | Atezolizumab + bevacizumab | None | Advanced unresectable peritoneal mesothelioma, progressive after platinum-based chemotherapy | Objective response rate | ORR 40% (8/20; 95% CI 19–64%). 1-year OS 85% (95% CI 60–95%). | PFS, duration of response, biomarker analysis. | Established atezolizumab + bevacizumab as a subsequent therapy option for patients not previously treated with ICIs [Discussion-85], [PEM-D-22]. | Cancer Discovery |
| Expanded Access Program (EAP) for pemetrexed | International Expanded Access Program using pemetrexed alone or in combination with a platinum agent for peritoneal mesothelioma | 2009 | 109 | Pemetrexed alone or with cisplatin/carboplatin | None (cohort) | Peritoneal mesothelioma not eligible for surgery | Survival | 1-year OS 57.4% for pemetrexed+cisplatin; median OS 10.3 months for pemetrexed alone. | Response rate (25% first-line), safety (neutropenia 34.6%). | Provided primary evidence for pemetrexed/platinum in peritoneal mesothelioma [Discussion-7]. | Lung Cancer |
Clinical PearlsClick to collapse
- Pearl 1: 1. Complete cytoreduction (CC-0) is the goal of surgery; CC-1 (residual <2.5 mm) is acceptable for epithelioid subtype with no significant loss in survival [PEM-C-2].
- Pearl 2: 2. Ki-67 index >9% is a high-risk feature that warrants consideration of adjuvant systemic therapy after CRS+HIPEC [PEM-2], [PEM-A-45].
- Pearl 3: 3. In patients with biphasic or sarcomatoid histology, neoadjuvant systemic therapy is strongly encouraged before attempted CRS+HIPEC [PEM-C-1].
- Pearl 4: 4. Ipilimumab + nivolumab is the preferred first-line regimen for biphasic/sarcomatoid histology and is a preferred option for epithelioid histology [PEM-D-1].
- Pearl 5: 5. For patients who progress on checkpoint inhibitor therapy, switch to platinum/pemetrexed-based chemotherapy (with or without bevacizumab) [PEM-D-1].
- Pearl 6: 6. ALK rearrangements are rare but actionable in young patients with PeM; broad molecular profiling is recommended [PEM-D-1].
- Pearl 7: 7. Bevacizumab-containing regimens should be held for at least 6 weeks before CRS to minimize bleeding risk [PEM-C-7], [PEM-C-8].
- Pearl 8: 8. Repeat CRS+HIPEC can be considered for recurrence >12 months after initial surgery, with careful patient selection [PEM-2], [PEM-C-13], [PEM-C-14].
Special SituationsClick to collapse
Bicavitary disease (peritoneal and pleural involvement)
ALK rearrangement-positive peritoneal mesothelioma
Germline BAP1 tumor predisposition syndrome
Well-differentiated papillary mesothelial tumor (WDPMT) and peritoneal inclusion cyst
Mesothelioma in situ
Peritoneal mesothelioma in women
Patients with PS 3–4
Guidelines ResourcesClick to collapse
NCCN Clinical Practice Guidelines in Oncology: Mesothelioma: Peritoneal (Version 2.2026)
Peritoneal mesothelioma: PSOGI/EURACAN clinical practice guidelines for diagnosis, treatment and follow-up
Treatment of Malignant Pleural Mesothelioma: ASCO Clinical Practice Guideline
The Chicago Consensus on Peritoneal Surface Malignancies: Management of Peritoneal Mesothelioma
WHO Classification of Tumours: Thoracic Tumours (5th edition, 2021)
Protocol for the examination of specimens from patients with malignant pleural mesothelioma (Version 4.1.0.0)
Protective FactorsClick to collapse
- No protective factors are explicitly mentioned in the NCCN guideline for peritoneal mesothelioma.