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Dr Sumit Kumar
Assistant Professor
NEIGRIHMS
 Malignant mesothelioma arises from serosal membranes of the pleura,
peritoneum, pericardium, or tunica vaginalis testes.
 This is a rare disease & highly lethal malignancy, account only 10-15%
of all mesothelioma.
 The peritoneum is the second most frequent site of origin of
mesothelioma, following the pleura.
 The pathogenesis of all forms of mesothelioma is strongly associated
with industrial pollutants, of which asbestos is the principal carcinogen
associated with the disease.
 it is not clear that Malignant peritoneal or pleural mesothelioma (MPM)
are similar because
• Share the same predominant risk factor (asbestos exposure),
• But,gene expression profiles of pleural and peritoneal
mesotheliomas are distinct.
Aspect Peritoneal Mesothelioma Pleural Mesothelioma
Incidence Less common More common
Gender Distribution Slightly higher in women More common in men(4-5:1)
Average Age of Onset Around 60-65 years( younger) Around 70 years
Asbestos Exposure
Associated with asbestos(amphibole)
exposure, but often lower levels
Strongly linked to significant
asbestos(chrysolite) exposure
Occupational Risk
Associated with specific industries
involving asbestos use
Linked to industries with heavy
asbestos use, like shipbuilding
Environmental Risk
Can occur through living in asbestos-
contaminated areas or secondary
exposure
Less common, near asbestos
mines or factories
Trends in Incidence
Rates may be stable or slightly
increasing
Rates may be decreasing due to
prevention efforts
Radiation exposure Less
More commonly associated than
peritoneal
Papoovavirus, simian
virus 40 (SV40)
Seen Seen
Tumor suppressor gene
BAP1 mutation
Frequently associated Associated
Positive prognostic
factor
BAP1
Negative prognostic factor
CDKN2A Deletion
NF2 Loss
 Majority of MPM are Diffuse but may be Localized.
 Diffuse MPM highly aggressive in contrast localized MPM has good
prognosis.
 Common sign and symptom:
• Abdominal distesion(30-80%)
• Pain(27-58%)
• Ascites
• Nausea
• Anorexia
• Weight loss
• Eary satiety
• Dysphagia
• Shortness of breath
 Mainly disease progression within the peritoneal cavity.
 May also extend into the pleural cavity during the latter stages of disease
progression, causing a pleural effusion.
 Lymph node metastases are found in approximately 20 to 28 % of patients
undergoing cytoreductive surgery for diffuse MPM.
 Distant metastases are very uncommon .
 In a multi-institutional registry-based series of 294 patients with MPM, only
12 had extra-abdominal metastases (4 %) .
 A number of paraneoplastic phenomena have been described in the
setting of mesothelioma, including]:
• Fever
• Thrombocytosis
• Malignancy-related thrombosis (
• Rarely, Coombs-positive hemolytic anemia.
baseline thrombocytosis an independent factor strongly associated with shortened
survival in patients with diffuse MPM .
Diffuse mesothelioma
Localized
mesothelioma
CECT: Thorax and abdomen
Diffuse and widespread involvement of
the peritoneal cavity, tumor infiltration,
and irregular/nodular thickening of the
peritoneum in a sheet-like fashion
Ascites
Omental caking
PET CT Scan
used for staging
MRI
Used mainly long-term follow-up
evaluation after initial treatment for
MPM who cannot receive iodinated
contrast
appears as a heterogeneous, solid
intraperitoneal mass on cross sectional
imaging but (generalized ascites,
omental caking, and peritoneal
nodularity) are characteristically absent
1 2 3 4 5
Liver
metastases
and
lymphadeno
pathy are
more
common
Peritoneal
Carcinomato
sis
a primary
neoplasm
arising within
the
peritoneum
Serous
Peritoneal
Carcinom
a arise from
ovarian
epithelial
rests that are
a remnant of
the ovary's
descent into
the pelvis
Ovarian
Carcinoma
In Women
diffuse
adenopathy
with a lack
of omental
involvement.
Lymphomato
sis
by smooth
peritoneal
thickening,
mesenteric
lymphadenopathy
with central
necrosis, ascites
with high
attenuation, and
splenomegaly.
Tuberculo
us
Peritonitis
Laboratory findings
Elevated level of hyaluronan, CA-125, AFP, CEA, and mesothelin (SMRP) correlated
with disease progression
Serum levels of SRMP are potentially more useful as a marker of disease activity in
patients with an established diagnosis
CA-125 and mesothelin may prove useful to follow response to therapy or for post-
treatment surveillance if they are initially elevated.
 Consider peritoneal mesothelioma in patients with abdominal malignancy.
 Ascitic fluid cytology is limited for diagnosis.
 Cytology often inconclusive for mesothelioma.
 Stromal invasion assessed via histology, not cytology.
 CT-guided or laparoscopic biopsy for tissue diagnosis.
 Differentiation using H&E sections and immunohistochemistry.
 Excise port sites due to mesothelioma's seeding tendency.
1 2 3
resembles normal
mesothelial cells,
forming
tubulopapillary or
trabecular
patterns
Epithelioid(mc)
consists of tightly
packed spindle
cells with
malignant osteoid,
chondroid, or
muscular elements
Sarcomatoid
both epithelioid and
sarcomatous
components each
contributing more
than 10 percent to
the overall
histology..
Biphasic (mixed
The prognosis is worse in sarcomatoid MPM, with a median survival of 13 months
compared to 55 months in the epithelioid subgroups.
Distinguishing benign from malignant mesothelial proliferations can be challenging, as
histologic evidence of invasion is the key parameter.
Positivity in Mesothelioma Negativity in Mesothelioma
Calretinin CEA
Cytokeratins 5/6 LeuM1
WT-1 Ber-Ep4
EGFR B72.3
CA125 Bg8
Thrombomodulin PAX-8
Mesothelin MOC-31
p16
D2-40
•At least two mesothelioma and two carcinoma markers are recommended for
differentiation.
•Electron microscopy is less helpful for differentiating sarcomatous mesothelioma from
soft tissue sarcoma in peritoneal primary tumors.
Epithelioid Mesothelioma:
•Calretinin: Typically positive.
•Cytokeratins 5/6: Typically positive.
•WT-1: Typically positive.
•EGFR: Typically positive.
•CA125: Typically positive.
•Thrombomodulin: Typically
positive.
•Mesothelin: Typically positive.
•p16: Positive in some cases.
Sarcomatoid Mesothelioma:
•Calretinin: Can be positive but less
frequently.
•Cytokeratins 5/6: Can be positive but less
frequently.
•WT-1: Can be positive but less frequently.
•EGFR: Can be positive but less
frequently.
•CA125: Can be positive but less
frequently.
•Thrombomodulin: Can be positive but less
frequently.
•Mesothelin: Can be positive but less
frequently.
•D2-40: Positive in some cases.
It's essential to consider the mixed nature of biphasic mesothelioma when interpreting
staining results, as the markers may vary within different regions of the tumor.
 Malignant peritoneal mesothelioma (MPM) lacks a widely accepted staging
system.
 The Peritoneal Cancer Index (PCI) is commonly used to assess tumor extent.
 Patients with pleural effusion should undergo diagnostic tests (e.g.,
thoracentesis or video-assisted thoracoscopic surgery) to rule out pleural cavity
involvement.
 T stage is determined by PCI values as follows:
• T1: PCI 1-10
• T2: PCI 11-20
• T3: PCI 21-30
• T4: PCI 31-39
•Stage groupings associated with a progressive decrease
in survival:
Stage I – T1 N0 M0; five-year survival 87%
Stage II – T2-3 N0 M0; five-year survival 53 %
Stage III – T4 N0-1 M0, T1-4 N1 M01-, and T1-4 N0-
1 M1; five-year survival 29 %
 Well-Differentiated Papillary Mesothelioma (WDPM):
• Rare, non-invasive tumor predominantly in women.
• Small, well-structured papillary growths.
• Radiologic findings include calcification, thickening, nodules.
• Typically curable through surgery, but potential for recurrence and
progression.
• No link to asbestos exposure.
 Multicystic Mesothelioma:
• Rare cystic tumor, often in young women.
• Associated with prior surgery, endometriosis, or inflammation.
• Controversial origin; may be reactive.
• Indolent behavior with frequent recurrences.
• Can rarely transform into aggressive malignant mesothelioma.
Treatment of rare variants:
 Initial surgical resection alone rather than CRS and HIPEC
 Long-term follow-up is warranted in these cases because of their indolent
behavior.
Suspicion for peritoneal mesothelioma
Recurrent ascites and /or peritoneal thickening/masses
CECT –C+A+P
Midline laparoscopy with nodule/mass biopsies
Image guided biopsy
Peritoneal Mesothelioma
Diffuse peritoneal
mesothelioma
Peritoneal inclusion cyst or
well differentiated papillary mesothelial tumor
PET/CT scan
Unicavitary
epithelioid
Biphasic/sarcomatoid or
bicavitary epithelioid
Symptomatic/recurr
ent or microinvasive
Asymptomatic
& noninvasive
ECOG PS 0-2 ECOG PS 3-4
Systemic therapy Best supportive care
CRS +-HIPEC
Observation with
imaging survillance
Progression to symptomatic
/invasive disease
Next page
Medically operable and complete
cytoreduction possible
Imaging
Surveillance
PS 0-2
Medically inoperable and complete
cytoreduction not possible(including
high risk feature)
CRS +HIPEC PS 3-4
Adjuvant systemic
therapy if surgical
/pathologic high risk
feature and no
neoadjuvant therapy
Systemic Therapy
Medically operable
and complete
cytoreduction possible
BST
Recurrence
Perioperative systemic therapy should
be considered for high-risk features
such as:
• Ki-67 >9%,
• Nodal metastasis,
• High tumor burden (PCI>17),
• Completeness of cytoreduction
(CC) score >1,
• Biphasic disease, or
• Bicavitary disease
Patients with favourable prognostic
profile:
Complete cytoreduction,
Epithelioid subtype,
No lymph node involvement,
Ki-67 ≤9%,
PCI ≤17)
SCORE DEFINITION
CC-0 No residual tumor
CC-1 Residual tumor<2.5 mm
CC-2 Residual tumor 2.5-25mm
CC-3 Residual tumor>25mm
Conventional therapy
•Systemic chemotherapy, palliative surgery,
and whole abdominal irradiation
•Median survival was less than one year.
•Median survival for untreated patients is
approximately six month.
Evolution of modern therapy
•Aggressive surgical cytoreduction and
intraperitoneal chemotherapy with hyperthermia
•Centers with expertise reported median survival
for appropriately selected patients is 34 to 100
months
Rationale :
 MPM amenable to complete or near complete cytoreduction due to:
• Majority of cases confined to the peritoneal cavity.
• Also superficial and do not invade underlying tissues deeply.
 Direct intraperitoneal chemotherapy permits a several-fold increase in drug
concentration in the peritoneum compared with systemic administration
Patient selection :factor that decide the outcome
• Disease extent and depth of tumor invasion beyond the mesothelial
surface,
• The predicted completeness of cytoreduction,
• Histology (epithelioid better than sarcomatoid or biphasic),
• Age (less than 60 better than older),
• The presence of preoperative thrombocytosis, and Weight loss
 The presence of a >5 cm mass in the epigastric region and
 loss of normal architecture of the small bowel and its mesentery
• (matted adjacent small bowel loops,
• distorted and thickened configuration,
• segmental small bowel obstruction,
• small bowel mesenteric vessels difficult to define due to
obliteration of mesenteric fat)
Adequate Cytoreduction:
defined as all residual tumor nodules <2.5 cm in diameter
CRS: complete gross cytoreduction
include
a) Omentectomy,
b) Splenectomy,
c) Small and large bowel
resection,
d) Peritonectomy,
e) Hysterectomy,
f) Salpingectomy, o
g) Ophorectomy, and
h) Low anterior resection.
i) Implants on the capsule of the
liver or other solid viscera
•HIPEC (Hyperthermic Intraperitoneal
Chemotherapy) treats peritoneal
mesothelioma.
•After surgery, catheters are placed in the
abdomen.
•A solution with mitomycin or cisplatin
circulates through these catheters.
•It circulates for 90 minutes at temperatures
between 40-42°C.
•Some patients retain catheters for
postoperative intraperitoneal chemotherapy,
but most do not.
Parameter Data
Clinical Centers
Worldwide
29
Total Patients with MPM 405
Chemotherapy Agents
Used
Cisplatin, Mitomycin C,
Doxorubicin
Median Actuarial
Overall Survival
53 months
One-Year Survival Rate 81%
Three-Year Survival
Rate
60%
Five-Year Survival Rate 47%
Complete/Near
Complete
Cytoreduction
Achieved in 67% of
patients
Estimated Five-Year
Survival Rate
42%
table summarizing the data from the multi-institutional registry for peritoneal
mesothelioma (MPM) treatment with HIPEC:
Parameter Data
Clinical Centers Worldwide
Total Patients with MPM 211
Chemotherapy Agents
Used
Cisplatin, Mitomycin C,
Doxorubicin
Median Actuarial
Overall Survival
38 months
5-Year Survival Rate 41%
10-Year Survival Rate 26%
Prognostic factor for improved survival:
• Epithelioid histologic subtype,
• Absence of lymph node metastases,
• Complete or near complete resection
• (ie, completeness of cytoreduction
score [CC] 0 or 1 and
• The use of HIPEC. The use of
cisplatin versus mitomycin C
 CRS and HIPEC treatment is associated with an operative mortality rate that
ranges from 0 to 8 %, and rates of serious perioperative morbidity are between 10
and 45 %.
Common Complication:
• Abscess
• Fistula
• Bleeding,
• Wound infection,
• Sepsis.
• Cardiovascular and
• Respiratory events
A study of the NSQIP database demonstrates overall 30-day mortality was lower in
CRS/HIPEC compared with Whipple, right lobe hepatectomy, esophagectomy, and
trisegmental hepatectomy
NEO ADJUVANT
• Pemetrexed and platinum based
chemotherapy
• Bevacizumab should not be used in
NACT
Should Be Given In High Risk:
• Presence Of Deep Tissue Invasion,
• Biphasic Histology, Or
• Baseline Thrombocytosis.
ADJUVANT
For patients with optimal cytoreduction and no histopathologic features that would
suggest increased risk of early recurrence, no systemic therapy is recommended.
• Pemetrexed plus cisplatin is an
active regimen
• May add bevacizumab adj CT
• Concurrent supplementation with
vitamin B12 and folic acid is
needed to reduce toxicity.
Treatment Approach Number of Patients
Percentage of Total
Patients
Neoadjuvant
Chemotherapy +
Surgery
55 3.2%
Adjuvant
Chemotherapy +
Surgery
228 13.1%
Surgery Only 684 39.3%
Long-Term Outcomes Similar among all three groups
Initial Improvement
Patients receiving any chemotherapy seemed
to perform better, especially in the first year
Here's a table summarizing the data from the study comparing outcomes
for different treatment approaches in the United States National Cancer
Database
Treatment Approach Number of Patients
Five-Year Overall
Survival
Neoadjuvant
Chemotherapy
42 40%
Adjuvant Chemotherapy 16 67%
Perioperative CT 16 62%
No Chemotherapy 48 56%
Pemetrexed-Based
Regimens
62%
Progression-Free
Survival
Improved for Adjuvant Chemo (p = 0.006) and
Post-2005 treatment (p = 0.030), but not on
multivariate analysis.
no significant difference in survival between
patients receiving no chemotherapy and those
receiving either adjuvant alone or perioperative
Retrospective review of 126 patients with diffuse MPM
CRS plus HIPEC included cohorts
Pemetrexed-based regimens :
• Pemetrexed plus cisplatin
• Pemetrexed plus carboplatin
• Pemetrexed plus cisplatin and
bevacizumab
• Pemetrexed plus gemcitabine
Cisplatin plus irinotecan —
Gemcitabine plus cisplatin or
carboplatin
Vinorelbine
Targeted therapy
Immunotherapy
(ie, ipilimumab plus nivolumab)
Tremelimumab,
Tremelimumab and durvalumab;
Atezolizumab and bevacizumab
•Patient Enrollment in the Expanded Access Program:
• 1056 mesothelioma patients enrolled.
• 9.3% had peritoneal primary sites.
• 57 previously treated, 38 chemotherapy-naive.
•Treatment Received:
• Two treatment options: pemetrexed alone (32 patients) or pemetrexed in combination with
cisplatin (66 patients).
• Treatment was administered for six cycles or until disease progression.
• All patients received folic acid and vitamin B12 supplementation.
•Response and Survival Data:
• 73 patients with mesothelioma were evaluable for response (28 chemotherapy-naïve& 43
treated).
• 19 objective responses (four complete) for an overall response rate of 26%.
• 45% had stable disease.
• Disease control rate (objective responses plus stable disease) was 71%.
• Similar objective response rates were seen in both previously-treated and chemotherapy-
naive patients.
• Median overall survival for previously-treated patients was 13.1 months.
• Median OS for chemotherapy-naive patients had not been reached at the time of the
analysis.
•Comparison of Pemetrexed Alone and Pemetrexed-Cisplatin Combination:
• Response rate and median survival were higher with the pemetrexed-cisplatin combination
Parameter Data
Program International Pemetrexed Expanded Access
Patients with Peritoneal
Mesothelioma
29 evaluable patients
Treatment
Pemetrexed (500 mg/m2) and Carboplatin
(AUC 5) with vitamin B12, folate, and
dexamethasone supplementation
Objective Responses
7 patients (24%) with objective responses (1
complete)
Stable Disease 52% had stable disease
Comparison
Results comparable to Pemetrexed and
Cisplatin
Aspect MAPS Trial Results
Study Design Phase III
Number of Patients 448
Patient Eligibility Unresectable MPM
Chemotherapy Regimen
- Cisplatin (75 mg/m2) and pemetrexed (500 mg/m2) on day 1 of each of six 21-
day cycles
- Bevacizumab (15 mg/kg) on day 1, continued as maintenance every three weeks
after six chemotherapy cycles
Crossover Not allowed
Median Follow-Up 39 months
Progression-Free Survival (PFS)
Increased with bevacizumab combination compared to cisplatin-pemetrexed
alone (median PFS: 9.2 versus 7.3 months)
Overall Survival (OS)
Increased with bevacizumab combination compared to cisplatin-pemetrexed
alone (median OS: 18.8 versus 16.1 months)
Findings and Conclusions
Bevacizumab combination resulted in improved PFS and OS in MPM patients who
were not eligible for radical surgery
 The addition of bevacizumab to the pemetrexed-cisplatin regimen improved both PFS and OS
compared to pemetrexed-cisplatin alone in a large Phase III trial.
 However, results from other trials evaluating antiangiogenic agents have been inconsistent.
•Study Details:
• Largest prospective multicenter study in peritoneal mesothelioma.
• Combination treatment: Gemcitabine (1250 mg/m2 on days 1 and 8) plus
Pemetrexed (500 mg/m2 on day 8, before gemcitabine).
• 20 chemotherapy-naive but highly selected patients with peritoneal
mesothelioma.
• Median of six treatment cycles administered.
•Patient Response:
• Three partial responses (15% response rate).
• 35% of patients had stable disease.
• Disease control rate: 50%.
•Survival Data:
• Median time to disease progression: 10.4 months.
• Median overall survival: 26.8 months.
• One-year survival rate: 67.5%.
•Toxicity:
• Hematologic toxicity: Substantial, including grade 3 or 4 neutropenia (60%),
febrile neutropenia (10%), and grade 4 anemia (5%).
• Common grade 3 and 4 non-hematologic toxicities: Fatigue (20%),
constipation (10%), vomiting (10%), dehydration (10%).
 There are no consensus- based guidelines from the NCCN or elsewhere
that cover immunotherapy for peritoneal mesothelioma.
(DETERMINE)
Randomized phase IIb trial
Tremelimumab, CTLA-4 Target,
previously treated pleural or
peritoneal (n = 26) mesothelioma.
• No statistically significant
difference in OS between the
tremelimumab and placebo groups
JAVELIN trial
phase Ib,
53 patients with pleural or peritoneal
mesothelioma treated with
avelumab
•5 patients had a confirmed
objective response (9 %), and
responses were durable
(median 15.2 months)
Parameter Value
Drug Combination Atezolizumab + Bevacizumab
Phase Phase II
Patient Population
Advanced Peritoneal Mesothelioma with
prior platinum-pemetrexed
chemotherapy progression or
intolerance (n = 20)
Primary Endpoint Confirmed Objective Response Rate
Objective Response Rate 40% (8 of 20 patients)
Median Response Duration 12.8 months
One-Year Progression-Free 61%
Response Independence
Independent of PD-L1 Overexpression or
Deficient Mismatch Repair
Grade 3 or Worse Toxicities
Hypertension (40%), Anemia (2%),
Thrombocytopenia (1%), Pancreatitis
(1%), Ileus (1%), Abdominal Pain (1%),
Thromboembolic Event (1%),
Transaminase Elevation (1%)
a) PD-L1 expression
b) MSI-H
c) dMMR
 Candidates for cytoreductive surgery
• Patients with diffuse MPM, no extraperitoneal disease spread, a good
performance status, and who can be predicted to achieve complete surgical
cytoreduction
• Cytoreductive surgery (CRS) and hyperthermic intraoperative peritoneal
perfusion with chemotherapy (HIPEC) is the treatment choice.
• Following CRS/HIPEC, for those patients whose tumors display high-risk
features (eg, the presence of deep tissue invasion, biphasic histology,
baseline thrombocytosis), systemic chemotherapy advised.
 Not candidates for cytoreductive surgery
• Systemic chemotherapy rather than debulking surgery with or without
chemotherapy
• When the chemotherapy regimen includes pemetrexed, concurrent
supplementation with vitamin B12 and folic acid is needed to reduce toxicity.
• All patients with peritoneal mesothelioma should be referred for germline
testing
SUMMARY AND RECOMMENDATIONS
• Malignant peritoneal mesothelioma (MPM) is an aggressive neoplasm that
arises from the lining mesothelial cells of the peritoneum and spreads rapidly
within the confines of the abdominal cavity. (See 'Introduction' above.)
• ● As with mesothelioma arising in other sites, there is a strong relationship
between asbestos exposure and the development of MPM. However, the link
between exposure to asbestos and peritoneal mesothelioma is less strong than
it is for pleural mesothelioma, particularly among women. A germline BRCA-
associated protein 1 (BAP1) mutation may predispose individuals to develop
MPM. (See 'Epidemiology and risk factors' above.)
• ● The majority of cases of MPM present with diffuse peritoneal involvement.
Common
 complaints include abdominal distention and/or increasing abdominal girth, abdominal pain, nausea, anorexia, and weight loss.
Rarely, patients present with a paraneoplastic syndrome (fever, thrombocytosis, hypoglycemia). (See 'Clinical features' above.)
• ● The imaging patterns and features of MPM are shown equally well on CT and magnetic resonance imaging. The pattern of
involvement is usually diffuse and widespread involvement of the peritoneal cavity with tumor infiltration and irregular/nodular
thickening of the peritoneum in a sheet-like fashion, usually with moderate to extensive ascites. Less commonly, there is a focal
pattern of involvement with a dominant intraperitoneal mass with or without associated peritoneal studding. (See 'Radiographic
imaging' above.)
• ● None of the radiographic findings is sufficiently specific for MPM to avoid the need for tissue diagnosis. Ascitic fluid cytology is
often inconclusive, especially in distinguishing between malignant and benign mesothelial proliferations. CT-guided core needle
biopsy or laparoscopic biopsy may provide sufficient material to establish the diagnosis, which usually requires a panel of
immunohistochemical stains. (See 'Diagnosis and histology' above.)
• ● There are no tumor markers with sufficient sensitivity or specificity to be useful in the diagnostic evaluation of a patient with
suspected MPM. (See 'Laboratory findings' above.)
• ● There is no uniformly accepted staging system for MPM. Given the very low risk of extra-abdominal spread, a radiographic
staging workup is generally not needed in the absence of symptoms. (See 'Staging and the staging workup' above.)
• ● There are two rare variants of peritoneal mesothelioma, well-differentiated papillary mesothelioma and multicystic
mesothelioma (peritoneal inclusion cyst), which are both characterized by a localized presentation and indolent behavior.
mesothelioma peritoneal.pptx
mesothelioma peritoneal.pptx

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mesothelioma peritoneal.pptx

  • 1. Dr Sumit Kumar Assistant Professor NEIGRIHMS
  • 2.  Malignant mesothelioma arises from serosal membranes of the pleura, peritoneum, pericardium, or tunica vaginalis testes.  This is a rare disease & highly lethal malignancy, account only 10-15% of all mesothelioma.  The peritoneum is the second most frequent site of origin of mesothelioma, following the pleura.  The pathogenesis of all forms of mesothelioma is strongly associated with industrial pollutants, of which asbestos is the principal carcinogen associated with the disease.  it is not clear that Malignant peritoneal or pleural mesothelioma (MPM) are similar because • Share the same predominant risk factor (asbestos exposure), • But,gene expression profiles of pleural and peritoneal mesotheliomas are distinct.
  • 3. Aspect Peritoneal Mesothelioma Pleural Mesothelioma Incidence Less common More common Gender Distribution Slightly higher in women More common in men(4-5:1) Average Age of Onset Around 60-65 years( younger) Around 70 years Asbestos Exposure Associated with asbestos(amphibole) exposure, but often lower levels Strongly linked to significant asbestos(chrysolite) exposure Occupational Risk Associated with specific industries involving asbestos use Linked to industries with heavy asbestos use, like shipbuilding Environmental Risk Can occur through living in asbestos- contaminated areas or secondary exposure Less common, near asbestos mines or factories Trends in Incidence Rates may be stable or slightly increasing Rates may be decreasing due to prevention efforts Radiation exposure Less More commonly associated than peritoneal Papoovavirus, simian virus 40 (SV40) Seen Seen Tumor suppressor gene BAP1 mutation Frequently associated Associated
  • 4. Positive prognostic factor BAP1 Negative prognostic factor CDKN2A Deletion NF2 Loss
  • 5.  Majority of MPM are Diffuse but may be Localized.  Diffuse MPM highly aggressive in contrast localized MPM has good prognosis.  Common sign and symptom: • Abdominal distesion(30-80%) • Pain(27-58%) • Ascites • Nausea • Anorexia • Weight loss • Eary satiety • Dysphagia • Shortness of breath
  • 6.  Mainly disease progression within the peritoneal cavity.  May also extend into the pleural cavity during the latter stages of disease progression, causing a pleural effusion.  Lymph node metastases are found in approximately 20 to 28 % of patients undergoing cytoreductive surgery for diffuse MPM.  Distant metastases are very uncommon .  In a multi-institutional registry-based series of 294 patients with MPM, only 12 had extra-abdominal metastases (4 %) .
  • 7.  A number of paraneoplastic phenomena have been described in the setting of mesothelioma, including]: • Fever • Thrombocytosis • Malignancy-related thrombosis ( • Rarely, Coombs-positive hemolytic anemia. baseline thrombocytosis an independent factor strongly associated with shortened survival in patients with diffuse MPM .
  • 8. Diffuse mesothelioma Localized mesothelioma CECT: Thorax and abdomen Diffuse and widespread involvement of the peritoneal cavity, tumor infiltration, and irregular/nodular thickening of the peritoneum in a sheet-like fashion Ascites Omental caking PET CT Scan used for staging MRI Used mainly long-term follow-up evaluation after initial treatment for MPM who cannot receive iodinated contrast appears as a heterogeneous, solid intraperitoneal mass on cross sectional imaging but (generalized ascites, omental caking, and peritoneal nodularity) are characteristically absent
  • 9. 1 2 3 4 5 Liver metastases and lymphadeno pathy are more common Peritoneal Carcinomato sis a primary neoplasm arising within the peritoneum Serous Peritoneal Carcinom a arise from ovarian epithelial rests that are a remnant of the ovary's descent into the pelvis Ovarian Carcinoma In Women diffuse adenopathy with a lack of omental involvement. Lymphomato sis by smooth peritoneal thickening, mesenteric lymphadenopathy with central necrosis, ascites with high attenuation, and splenomegaly. Tuberculo us Peritonitis
  • 10. Laboratory findings Elevated level of hyaluronan, CA-125, AFP, CEA, and mesothelin (SMRP) correlated with disease progression Serum levels of SRMP are potentially more useful as a marker of disease activity in patients with an established diagnosis CA-125 and mesothelin may prove useful to follow response to therapy or for post- treatment surveillance if they are initially elevated.
  • 11.  Consider peritoneal mesothelioma in patients with abdominal malignancy.  Ascitic fluid cytology is limited for diagnosis.  Cytology often inconclusive for mesothelioma.  Stromal invasion assessed via histology, not cytology.  CT-guided or laparoscopic biopsy for tissue diagnosis.  Differentiation using H&E sections and immunohistochemistry.  Excise port sites due to mesothelioma's seeding tendency.
  • 12. 1 2 3 resembles normal mesothelial cells, forming tubulopapillary or trabecular patterns Epithelioid(mc) consists of tightly packed spindle cells with malignant osteoid, chondroid, or muscular elements Sarcomatoid both epithelioid and sarcomatous components each contributing more than 10 percent to the overall histology.. Biphasic (mixed The prognosis is worse in sarcomatoid MPM, with a median survival of 13 months compared to 55 months in the epithelioid subgroups. Distinguishing benign from malignant mesothelial proliferations can be challenging, as histologic evidence of invasion is the key parameter.
  • 13. Positivity in Mesothelioma Negativity in Mesothelioma Calretinin CEA Cytokeratins 5/6 LeuM1 WT-1 Ber-Ep4 EGFR B72.3 CA125 Bg8 Thrombomodulin PAX-8 Mesothelin MOC-31 p16 D2-40 •At least two mesothelioma and two carcinoma markers are recommended for differentiation. •Electron microscopy is less helpful for differentiating sarcomatous mesothelioma from soft tissue sarcoma in peritoneal primary tumors.
  • 14. Epithelioid Mesothelioma: •Calretinin: Typically positive. •Cytokeratins 5/6: Typically positive. •WT-1: Typically positive. •EGFR: Typically positive. •CA125: Typically positive. •Thrombomodulin: Typically positive. •Mesothelin: Typically positive. •p16: Positive in some cases. Sarcomatoid Mesothelioma: •Calretinin: Can be positive but less frequently. •Cytokeratins 5/6: Can be positive but less frequently. •WT-1: Can be positive but less frequently. •EGFR: Can be positive but less frequently. •CA125: Can be positive but less frequently. •Thrombomodulin: Can be positive but less frequently. •Mesothelin: Can be positive but less frequently. •D2-40: Positive in some cases. It's essential to consider the mixed nature of biphasic mesothelioma when interpreting staining results, as the markers may vary within different regions of the tumor.
  • 15.  Malignant peritoneal mesothelioma (MPM) lacks a widely accepted staging system.  The Peritoneal Cancer Index (PCI) is commonly used to assess tumor extent.  Patients with pleural effusion should undergo diagnostic tests (e.g., thoracentesis or video-assisted thoracoscopic surgery) to rule out pleural cavity involvement.  T stage is determined by PCI values as follows: • T1: PCI 1-10 • T2: PCI 11-20 • T3: PCI 21-30 • T4: PCI 31-39 •Stage groupings associated with a progressive decrease in survival: Stage I – T1 N0 M0; five-year survival 87% Stage II – T2-3 N0 M0; five-year survival 53 % Stage III – T4 N0-1 M0, T1-4 N1 M01-, and T1-4 N0- 1 M1; five-year survival 29 %
  • 16.  Well-Differentiated Papillary Mesothelioma (WDPM): • Rare, non-invasive tumor predominantly in women. • Small, well-structured papillary growths. • Radiologic findings include calcification, thickening, nodules. • Typically curable through surgery, but potential for recurrence and progression. • No link to asbestos exposure.  Multicystic Mesothelioma: • Rare cystic tumor, often in young women. • Associated with prior surgery, endometriosis, or inflammation. • Controversial origin; may be reactive. • Indolent behavior with frequent recurrences. • Can rarely transform into aggressive malignant mesothelioma. Treatment of rare variants:  Initial surgical resection alone rather than CRS and HIPEC  Long-term follow-up is warranted in these cases because of their indolent behavior.
  • 17. Suspicion for peritoneal mesothelioma Recurrent ascites and /or peritoneal thickening/masses CECT –C+A+P Midline laparoscopy with nodule/mass biopsies Image guided biopsy Peritoneal Mesothelioma Diffuse peritoneal mesothelioma Peritoneal inclusion cyst or well differentiated papillary mesothelial tumor PET/CT scan Unicavitary epithelioid Biphasic/sarcomatoid or bicavitary epithelioid Symptomatic/recurr ent or microinvasive Asymptomatic & noninvasive ECOG PS 0-2 ECOG PS 3-4 Systemic therapy Best supportive care CRS +-HIPEC Observation with imaging survillance Progression to symptomatic /invasive disease Next page
  • 18. Medically operable and complete cytoreduction possible Imaging Surveillance PS 0-2 Medically inoperable and complete cytoreduction not possible(including high risk feature) CRS +HIPEC PS 3-4 Adjuvant systemic therapy if surgical /pathologic high risk feature and no neoadjuvant therapy Systemic Therapy Medically operable and complete cytoreduction possible BST Recurrence
  • 19. Perioperative systemic therapy should be considered for high-risk features such as: • Ki-67 >9%, • Nodal metastasis, • High tumor burden (PCI>17), • Completeness of cytoreduction (CC) score >1, • Biphasic disease, or • Bicavitary disease Patients with favourable prognostic profile: Complete cytoreduction, Epithelioid subtype, No lymph node involvement, Ki-67 ≤9%, PCI ≤17)
  • 20. SCORE DEFINITION CC-0 No residual tumor CC-1 Residual tumor<2.5 mm CC-2 Residual tumor 2.5-25mm CC-3 Residual tumor>25mm
  • 21. Conventional therapy •Systemic chemotherapy, palliative surgery, and whole abdominal irradiation •Median survival was less than one year. •Median survival for untreated patients is approximately six month. Evolution of modern therapy •Aggressive surgical cytoreduction and intraperitoneal chemotherapy with hyperthermia •Centers with expertise reported median survival for appropriately selected patients is 34 to 100 months
  • 22. Rationale :  MPM amenable to complete or near complete cytoreduction due to: • Majority of cases confined to the peritoneal cavity. • Also superficial and do not invade underlying tissues deeply.  Direct intraperitoneal chemotherapy permits a several-fold increase in drug concentration in the peritoneum compared with systemic administration Patient selection :factor that decide the outcome • Disease extent and depth of tumor invasion beyond the mesothelial surface, • The predicted completeness of cytoreduction, • Histology (epithelioid better than sarcomatoid or biphasic), • Age (less than 60 better than older), • The presence of preoperative thrombocytosis, and Weight loss
  • 23.  The presence of a >5 cm mass in the epigastric region and  loss of normal architecture of the small bowel and its mesentery • (matted adjacent small bowel loops, • distorted and thickened configuration, • segmental small bowel obstruction, • small bowel mesenteric vessels difficult to define due to obliteration of mesenteric fat) Adequate Cytoreduction: defined as all residual tumor nodules <2.5 cm in diameter
  • 24. CRS: complete gross cytoreduction include a) Omentectomy, b) Splenectomy, c) Small and large bowel resection, d) Peritonectomy, e) Hysterectomy, f) Salpingectomy, o g) Ophorectomy, and h) Low anterior resection. i) Implants on the capsule of the liver or other solid viscera •HIPEC (Hyperthermic Intraperitoneal Chemotherapy) treats peritoneal mesothelioma. •After surgery, catheters are placed in the abdomen. •A solution with mitomycin or cisplatin circulates through these catheters. •It circulates for 90 minutes at temperatures between 40-42°C. •Some patients retain catheters for postoperative intraperitoneal chemotherapy, but most do not.
  • 25. Parameter Data Clinical Centers Worldwide 29 Total Patients with MPM 405 Chemotherapy Agents Used Cisplatin, Mitomycin C, Doxorubicin Median Actuarial Overall Survival 53 months One-Year Survival Rate 81% Three-Year Survival Rate 60% Five-Year Survival Rate 47% Complete/Near Complete Cytoreduction Achieved in 67% of patients Estimated Five-Year Survival Rate 42% table summarizing the data from the multi-institutional registry for peritoneal mesothelioma (MPM) treatment with HIPEC: Parameter Data Clinical Centers Worldwide Total Patients with MPM 211 Chemotherapy Agents Used Cisplatin, Mitomycin C, Doxorubicin Median Actuarial Overall Survival 38 months 5-Year Survival Rate 41% 10-Year Survival Rate 26%
  • 26. Prognostic factor for improved survival: • Epithelioid histologic subtype, • Absence of lymph node metastases, • Complete or near complete resection • (ie, completeness of cytoreduction score [CC] 0 or 1 and • The use of HIPEC. The use of cisplatin versus mitomycin C
  • 27.  CRS and HIPEC treatment is associated with an operative mortality rate that ranges from 0 to 8 %, and rates of serious perioperative morbidity are between 10 and 45 %. Common Complication: • Abscess • Fistula • Bleeding, • Wound infection, • Sepsis. • Cardiovascular and • Respiratory events A study of the NSQIP database demonstrates overall 30-day mortality was lower in CRS/HIPEC compared with Whipple, right lobe hepatectomy, esophagectomy, and trisegmental hepatectomy
  • 28. NEO ADJUVANT • Pemetrexed and platinum based chemotherapy • Bevacizumab should not be used in NACT Should Be Given In High Risk: • Presence Of Deep Tissue Invasion, • Biphasic Histology, Or • Baseline Thrombocytosis. ADJUVANT For patients with optimal cytoreduction and no histopathologic features that would suggest increased risk of early recurrence, no systemic therapy is recommended. • Pemetrexed plus cisplatin is an active regimen • May add bevacizumab adj CT • Concurrent supplementation with vitamin B12 and folic acid is needed to reduce toxicity.
  • 29. Treatment Approach Number of Patients Percentage of Total Patients Neoadjuvant Chemotherapy + Surgery 55 3.2% Adjuvant Chemotherapy + Surgery 228 13.1% Surgery Only 684 39.3% Long-Term Outcomes Similar among all three groups Initial Improvement Patients receiving any chemotherapy seemed to perform better, especially in the first year Here's a table summarizing the data from the study comparing outcomes for different treatment approaches in the United States National Cancer Database
  • 30. Treatment Approach Number of Patients Five-Year Overall Survival Neoadjuvant Chemotherapy 42 40% Adjuvant Chemotherapy 16 67% Perioperative CT 16 62% No Chemotherapy 48 56% Pemetrexed-Based Regimens 62% Progression-Free Survival Improved for Adjuvant Chemo (p = 0.006) and Post-2005 treatment (p = 0.030), but not on multivariate analysis. no significant difference in survival between patients receiving no chemotherapy and those receiving either adjuvant alone or perioperative Retrospective review of 126 patients with diffuse MPM CRS plus HIPEC included cohorts
  • 31. Pemetrexed-based regimens : • Pemetrexed plus cisplatin • Pemetrexed plus carboplatin • Pemetrexed plus cisplatin and bevacizumab • Pemetrexed plus gemcitabine Cisplatin plus irinotecan — Gemcitabine plus cisplatin or carboplatin Vinorelbine Targeted therapy Immunotherapy (ie, ipilimumab plus nivolumab) Tremelimumab, Tremelimumab and durvalumab; Atezolizumab and bevacizumab
  • 32. •Patient Enrollment in the Expanded Access Program: • 1056 mesothelioma patients enrolled. • 9.3% had peritoneal primary sites. • 57 previously treated, 38 chemotherapy-naive. •Treatment Received: • Two treatment options: pemetrexed alone (32 patients) or pemetrexed in combination with cisplatin (66 patients). • Treatment was administered for six cycles or until disease progression. • All patients received folic acid and vitamin B12 supplementation. •Response and Survival Data: • 73 patients with mesothelioma were evaluable for response (28 chemotherapy-naïve& 43 treated). • 19 objective responses (four complete) for an overall response rate of 26%. • 45% had stable disease. • Disease control rate (objective responses plus stable disease) was 71%. • Similar objective response rates were seen in both previously-treated and chemotherapy- naive patients. • Median overall survival for previously-treated patients was 13.1 months. • Median OS for chemotherapy-naive patients had not been reached at the time of the analysis. •Comparison of Pemetrexed Alone and Pemetrexed-Cisplatin Combination: • Response rate and median survival were higher with the pemetrexed-cisplatin combination
  • 33. Parameter Data Program International Pemetrexed Expanded Access Patients with Peritoneal Mesothelioma 29 evaluable patients Treatment Pemetrexed (500 mg/m2) and Carboplatin (AUC 5) with vitamin B12, folate, and dexamethasone supplementation Objective Responses 7 patients (24%) with objective responses (1 complete) Stable Disease 52% had stable disease Comparison Results comparable to Pemetrexed and Cisplatin
  • 34. Aspect MAPS Trial Results Study Design Phase III Number of Patients 448 Patient Eligibility Unresectable MPM Chemotherapy Regimen - Cisplatin (75 mg/m2) and pemetrexed (500 mg/m2) on day 1 of each of six 21- day cycles - Bevacizumab (15 mg/kg) on day 1, continued as maintenance every three weeks after six chemotherapy cycles Crossover Not allowed Median Follow-Up 39 months Progression-Free Survival (PFS) Increased with bevacizumab combination compared to cisplatin-pemetrexed alone (median PFS: 9.2 versus 7.3 months) Overall Survival (OS) Increased with bevacizumab combination compared to cisplatin-pemetrexed alone (median OS: 18.8 versus 16.1 months) Findings and Conclusions Bevacizumab combination resulted in improved PFS and OS in MPM patients who were not eligible for radical surgery  The addition of bevacizumab to the pemetrexed-cisplatin regimen improved both PFS and OS compared to pemetrexed-cisplatin alone in a large Phase III trial.  However, results from other trials evaluating antiangiogenic agents have been inconsistent.
  • 35. •Study Details: • Largest prospective multicenter study in peritoneal mesothelioma. • Combination treatment: Gemcitabine (1250 mg/m2 on days 1 and 8) plus Pemetrexed (500 mg/m2 on day 8, before gemcitabine). • 20 chemotherapy-naive but highly selected patients with peritoneal mesothelioma. • Median of six treatment cycles administered. •Patient Response: • Three partial responses (15% response rate). • 35% of patients had stable disease. • Disease control rate: 50%. •Survival Data: • Median time to disease progression: 10.4 months. • Median overall survival: 26.8 months. • One-year survival rate: 67.5%. •Toxicity: • Hematologic toxicity: Substantial, including grade 3 or 4 neutropenia (60%), febrile neutropenia (10%), and grade 4 anemia (5%). • Common grade 3 and 4 non-hematologic toxicities: Fatigue (20%), constipation (10%), vomiting (10%), dehydration (10%).
  • 36.  There are no consensus- based guidelines from the NCCN or elsewhere that cover immunotherapy for peritoneal mesothelioma. (DETERMINE) Randomized phase IIb trial Tremelimumab, CTLA-4 Target, previously treated pleural or peritoneal (n = 26) mesothelioma. • No statistically significant difference in OS between the tremelimumab and placebo groups JAVELIN trial phase Ib, 53 patients with pleural or peritoneal mesothelioma treated with avelumab •5 patients had a confirmed objective response (9 %), and responses were durable (median 15.2 months)
  • 37. Parameter Value Drug Combination Atezolizumab + Bevacizumab Phase Phase II Patient Population Advanced Peritoneal Mesothelioma with prior platinum-pemetrexed chemotherapy progression or intolerance (n = 20) Primary Endpoint Confirmed Objective Response Rate Objective Response Rate 40% (8 of 20 patients) Median Response Duration 12.8 months One-Year Progression-Free 61% Response Independence Independent of PD-L1 Overexpression or Deficient Mismatch Repair Grade 3 or Worse Toxicities Hypertension (40%), Anemia (2%), Thrombocytopenia (1%), Pancreatitis (1%), Ileus (1%), Abdominal Pain (1%), Thromboembolic Event (1%), Transaminase Elevation (1%)
  • 38. a) PD-L1 expression b) MSI-H c) dMMR
  • 39.  Candidates for cytoreductive surgery • Patients with diffuse MPM, no extraperitoneal disease spread, a good performance status, and who can be predicted to achieve complete surgical cytoreduction • Cytoreductive surgery (CRS) and hyperthermic intraoperative peritoneal perfusion with chemotherapy (HIPEC) is the treatment choice. • Following CRS/HIPEC, for those patients whose tumors display high-risk features (eg, the presence of deep tissue invasion, biphasic histology, baseline thrombocytosis), systemic chemotherapy advised.  Not candidates for cytoreductive surgery • Systemic chemotherapy rather than debulking surgery with or without chemotherapy • When the chemotherapy regimen includes pemetrexed, concurrent supplementation with vitamin B12 and folic acid is needed to reduce toxicity. • All patients with peritoneal mesothelioma should be referred for germline testing
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  • 47. SUMMARY AND RECOMMENDATIONS • Malignant peritoneal mesothelioma (MPM) is an aggressive neoplasm that arises from the lining mesothelial cells of the peritoneum and spreads rapidly within the confines of the abdominal cavity. (See 'Introduction' above.) • ● As with mesothelioma arising in other sites, there is a strong relationship between asbestos exposure and the development of MPM. However, the link between exposure to asbestos and peritoneal mesothelioma is less strong than it is for pleural mesothelioma, particularly among women. A germline BRCA- associated protein 1 (BAP1) mutation may predispose individuals to develop MPM. (See 'Epidemiology and risk factors' above.) • ● The majority of cases of MPM present with diffuse peritoneal involvement. Common
  • 48.  complaints include abdominal distention and/or increasing abdominal girth, abdominal pain, nausea, anorexia, and weight loss. Rarely, patients present with a paraneoplastic syndrome (fever, thrombocytosis, hypoglycemia). (See 'Clinical features' above.) • ● The imaging patterns and features of MPM are shown equally well on CT and magnetic resonance imaging. The pattern of involvement is usually diffuse and widespread involvement of the peritoneal cavity with tumor infiltration and irregular/nodular thickening of the peritoneum in a sheet-like fashion, usually with moderate to extensive ascites. Less commonly, there is a focal pattern of involvement with a dominant intraperitoneal mass with or without associated peritoneal studding. (See 'Radiographic imaging' above.) • ● None of the radiographic findings is sufficiently specific for MPM to avoid the need for tissue diagnosis. Ascitic fluid cytology is often inconclusive, especially in distinguishing between malignant and benign mesothelial proliferations. CT-guided core needle biopsy or laparoscopic biopsy may provide sufficient material to establish the diagnosis, which usually requires a panel of immunohistochemical stains. (See 'Diagnosis and histology' above.) • ● There are no tumor markers with sufficient sensitivity or specificity to be useful in the diagnostic evaluation of a patient with suspected MPM. (See 'Laboratory findings' above.) • ● There is no uniformly accepted staging system for MPM. Given the very low risk of extra-abdominal spread, a radiographic staging workup is generally not needed in the absence of symptoms. (See 'Staging and the staging workup' above.) • ● There are two rare variants of peritoneal mesothelioma, well-differentiated papillary mesothelioma and multicystic mesothelioma (peritoneal inclusion cyst), which are both characterized by a localized presentation and indolent behavior.