Malignant Mesothelioma

Slide 1 · Malignant Mesothelioma

Pleural pathology • morphology • diagnostic reasoning

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Connect asbestos exposure and the long latency period to pleural mesothelioma.

Recognize diffuse pleural encasement and the three histologic patterns.

Interpret mesothelial and epithelial immunohistochemical panels.

Distinguish primary pleural mesothelioma from common mimics and apply WHO 2021 refinements.

Slide 3 · Pleural neoplasia: Primary versus secondary

Primary pleural malignancy includes mesothelioma; Primary mesothelial disease is uncommon.

Secondary pleural involvement by tumors arising elsewhere is more frequent.

Lung and breast primaries are common sources of metastatic pleural disease.

A pleural mass or effusion therefore requires evaluation of tumor origin.

Primary pleural tumormesothelioma

Versus

Secondary pleural depositsmetastatic carcinoma

Schematic — not a diagnostic specimen

Slide 4 · Mesothelial origin and pleural compartments

Pleural mesothelioma can arise from visceral or parietal pleura.

The visceral pleura covers the lung; The parietal pleura lines the thoracic cavity.

Diffuse spread in the pleural space underlies the characteristic encasing pattern.

Chest wall

Parietal pleura

Pleural space

Visceral pleura

Lung surface

Schematic — not a diagnostic specimen

Slide 5 · An anatomical rather than parenchymal cancer

Pleural origin

Diffuse pleural growth

Secondary lung invasion

The primary lesion originates at the pleural lining, not in the pulmonary alveoli.

Direct extension can subsequently invade the underlying lung.

Differentiating site of origin matters when pleural carcinoma is in the differential.

Slide 6 · Clinical entry point: A pleural syndrome

Chest pain, dyspnea, and recurrent pleural effusion are typical presenting features.

Symptoms reflect pleural disease and its effects on thoracic mechanics.

The clinical presentation alone is not specific enough for a mesothelioma diagnosis.

Lung

Pleural fluid

Fluid + encasing pleural disease

Schematic — not a diagnostic specimen

Slide 7 · Asbestos association is central to epidemiology

Heavy asbestos exposure is the dominant documented etiologic association.

Strong exposure links in historic shipbuilding and mining populations.

Exposure history should be obtained with attention to industry and elapsed time.

Heavy asbestos exposure

Pleural malignancy

25–45 years

Schematic — not a diagnostic specimen

Slide 8 · Historical occupational clusters

Coastal shipping industries in the United States and Great Britain.

Mining regions in Canada, Australia, and South Africa are also cited.

In selected high-exposure populations, up to 90% of mesotheliomas were asbestos-related.

The figure is context-specific; Do not generalize it to all contemporary patients.

Slide 9 · Long latency is diagnostically important

A 25–45-year interval for asbestos-associated mesothelioma.

An exposure decades earlier remains relevant in a new pleural malignancy.

The absence of recent exposure does not negate a historical asbestos link.

Heavy asbestos exposure

Pleural malignancy

25–45 years

Schematic — not a diagnostic specimen

Slide 10 · Exposure risk is not disease certainty

A lifetime mesothelioma risk of up to 7–10% in heavily exposed persons.

This estimate concerns heavily exposed groups, not the general population.

Most exposed persons do not necessarily develop the disease; Individual risk cannot be assigned from this figure alone.

Slide 11 · Smoking: A crucial etiologic distinction

Question

Mesothelioma

Lung carcinoma

Heavy asbestos exposure

Strong association

Established association

Smoking interaction

No apparent increase reported

Risk markedly magnified

Primary site

Pleura

Lung parenchyma

Slide 12 · Why asbestos workers may die of lung carcinoma

Asbestos exposure predisposes to both mesothelioma and pulmonary carcinoma.

The carcinogenic combination of asbestos and smoking is particularly strong for lung carcinoma.

The textbook therefore notes higher lung carcinoma mortality than mesothelioma in asbestos workers, especially smokers.

Slide 13 · Asbestos bodies and pleural plaques

Increased asbestos bodies in lung tissue support prior exposure.

Pleural plaques are another marker of asbestos exposure.

These exposure markers should not be confused with the diagnosis of invasive mesothelioma.

Asbestos bodiesin pulmonary tissue

Pleural plaquesexposure marker

Schematic — not a diagnostic specimen

Slide 14 · Asbestosis need not accompany mesothelioma

Pulmonary asbestosis denotes associated interstitial fibrosis.

Concurrent pulmonary asbestosis in only about 20% of pleural mesothelioma cases.

Absence of interstitial fibrosis does not exclude a pleural mesothelioma.

Slide 15 · Etiology and the molecular disease model

Strong asbestos association identifies an exposure pathway at the population level.

Mesotheliomas frequently show alterations of tumor-suppressor genes.

CDKN2A, NF2, and BAP1 as central genetic abnormalities.

The exact causal sequence from individual fiber exposure to each alteration is not established by this excerpt.

CDKN2A

Cell-cycle restraint

NF2

Cell signaling regulation

BAP1

Chromatin regulation

Schematic — not a diagnostic specimen

Slide 16 · CDKN2A: A frequent deletion

Homozygous chromosome 9p deletion can eliminate the tumor suppressor CDKN2A.

This event in about 80% of mesotheliomas.

The 80% value is the textbook estimate, not a substitute for cohort-specific testing performance.

Chromosome 9p

↓

Homozygous CDKN2A deletion

Loss of tumor-suppressor function

Schematic — not a diagnostic specimen

Slide 17 · Why a homozygous deletion matters

“Homozygous deletion” means loss of both genomic copies at the affected locus.

Loss of a tumor-suppressor locus removes a key growth-restraining function.

For diagnostics, gene deletion and absence of protein staining are different observations and assays.

CDKN2A copy 1

CDKN2A copy 2

Loss of both genomic copies

Schematic — not a diagnostic specimen

Slide 18 · NF2: Cell-signaling regulation

NF2 is a recurrently altered gene in sequenced mesothelioma genomes.

The NF2 product is a regulator of cell signaling.

Its disruption supports a model of disordered growth control, rather than a single-pathway diagnosis.

CDKN2A

Cell-cycle restraint

NF2

Cell signaling regulation

BAP1

Chromatin regulation

Schematic — not a diagnostic specimen

Slide 19 · BAP1: Chromatin-associated tumor suppression

BAP1 is a recurrent mesothelioma driver gene.

The protein interacts with BRCA1 and participates in chromatin regulation.

The genetic finding connects mesothelioma biology with altered gene-regulatory machinery.

CDKN2A

Cell-cycle restraint

NF2

Cell signaling regulation

BAP1

Chromatin regulation

Schematic — not a diagnostic specimen

Slide 20 · Germline BAP1 and inherited susceptibility

Aspect

Germline BAP1

Somatic BAP1

Where present

Constitutional tissues

Tumor-acquired cells

Teaching relevance

Inherited predisposition

Tumor pathogenesis

Implication

Familial risk assessment

Tumor characterization

Slide 21 · Molecular abnormalities are complementary

CDKN2A loss, NF2 alterations, and BAP1 alterations affect different regulatory processes.

No single alteration defines the entire morphologic spectrum.

Integrate molecular information with gross pathology, microscopic morphology, and immunophenotype.

CDKN2A

Cell-cycle restraint

NF2

Cell signaling regulation

BAP1

Chromatin regulation

Schematic — not a diagnostic specimen

Slide 22 · The distinctive gross growth pattern

Diffuse pleural mesothelioma spreads widely over pleural surfaces.

Tumor tissue can form a thick mantle that ensheathes the lung.

A soft, gelatinous, gray-pink gross appearance.

Gross color and texture alone cannot establish tumor type.

Lung

Pleural tumor mantle

Diffusely encasing

Schematic — not a diagnostic specimen

Slide 23 · A pleural rind restricts the enclosed lung

The lesion grows along pleural surfaces instead of behaving as a solitary intrapulmonary nodule.

An encasing pleural mantle anatomically constrains expansion of the underlying lung.

This provides a clinicopathologic explanation for dyspnea alongside associated effusion.

Lung

Pleural tumor mantle

Diffusely encasing

Schematic — not a diagnostic specimen

Slide 24 · Pleural fluid is part of the gross phenotype

Extensive pleural effusion frequently accompanies diffuse mesothelioma.

Repeated fluid accumulation can become a major symptom-producing feature.

The presence of effusion is not specific: Inflammation and metastatic tumors also cause pleural fluid.

Lung

Pleural fluid

Fluid + encasing pleural disease

Schematic — not a diagnostic specimen

Slide 25 · Direct invasion of neighboring structures

Diffuse pleural tumor

Contiguous invasion

Underlying lung / thoracic tissues

Mesothelioma is locally aggressive and invades thoracic structures directly.

Robbins specifically describes extension into the adjacent lung.

Local anatomical spread should be distinguished from distant metastatic spread.

Slide 26 · Distant spread occurs in advanced disease

Primary pleural lesion

Hilar nodes

Liver / distant organs

Hilar lymph nodes may be involved as disease progresses.

Robbins also describes eventual spread to the liver and other distant sites.

The pathologic description links regional and distant spread to aggressive clinical behavior.

Slide 27 · Three principal microscopic patterns

Epithelioid, sarcomatoid, and biphasic are the three main histologic categories.

Epithelioid as the dominant pattern (60–80%).

Sarcomatoid (10–12%) and biphasic (10–15%) complete the textbook distribution.

Percentages reflect the cited description and may vary by case series.

Epithelioid

Sarcomatoid

Biphasic

Schematic — not a diagnostic specimen

Slide 28 · Mesothelial differentiation permits two patterns

Mesothelial tumor cells may adopt epithelium-like or mesenchymal-like morphologies.

The epithelioid phenotype forms cohesive structures; The sarcomatoid phenotype is spindle-cell dominant.

A biphasic tumor contains both histologic appearances.

Epithelioid

Sarcomatoid

Biphasic

Schematic — not a diagnostic specimen

Slide 29 · Epithelioid mesothelioma: Cell shape

Tumor cells may be cuboidal, columnar, or flattened.

The cells can organize into structures resembling glandular epithelium.

Cell shape by itself does not exclude pulmonary adenocarcinoma.

Tubules / lumina, simplified

Schematic — not a diagnostic specimen

Slide 30 · Epithelioid mesothelioma: Architecture

Tubular structures are a common epithelioid pattern in the Robbins description.

Papillary architecture is another important pattern.

These arrangements may mimic adenocarcinoma and motivate a discriminating immunopanel.

Tubules / lumina, simplified

Schematic — not a diagnostic specimen

Slide 31 · Why adenocarcinoma is a major mimic

Feature

Epithelioid mesothelioma

Pulmonary adenocarcinoma

Typical primary site

Pleura

Lung

Overlap

Tubules / papillae

Glandular morphology

Resolution

Mesothelial IHC + negative epithelial markers

Epithelial markers + clinical correlation

Slide 32 · Sarcomatoid mesothelioma: Spindle phenotype

Sarcomatoid mesothelioma resembles a fibrosarcoma microscopically.

It is commonly extensively fibrotic and paucicellular.

The spindle-cell phenotype can complicate both sampling and immunophenotypic recognition.

Spindle-cell / fibrotic architecture

Schematic — not a diagnostic specimen

Slide 33 · Sarcomatoid marker expression can be reduced

Expression of many typical mesothelial markers is lower in sarcomatoid cases.

Some tumors may show keratin staining while lacking the stronger mesothelial-marker profile.

Negative calretinin or WT1 staining alone therefore does not exclude sarcomatoid mesothelioma.

Epithelioid component

Calretinin: Often stronger

Sarcomatoid component

Mesothelial markers may be reduced

Schematic — not a diagnostic specimen

Slide 34 · Biphasic mesothelioma combines both components

The tumor has an epithelioid region and a sarcomatoid region.

The relative proportions may vary across the sampled lesion.

Robbins indicates clinical behavior resembling the sarcomatoid type.

Epithelioid

Sarcomatoid

Schematic — not a diagnostic specimen

Slide 35 · Histologic sampling changes what is visible

A limited biopsy may sample only one histologic compartment of a heterogeneous lesion.

Finding both components changes the morphologic classification.

WHO 2021 permits diagnosing biphasic mesothelioma on small biopsies with both components even when one is under 10%.

Epithelioid

Sarcomatoid

Schematic — not a diagnostic specimen

Slide 36 · Morphologic pattern comparison

Pattern

Typical appearance

Pitfall

Epithelioid

Cuboidal / columnar cells; tubules, papillae

Mimics adenocarcinoma

Sarcomatoid

Spindle cells; fibrotic, paucicellular

Markers may be weak or absent

Biphasic

Epithelioid + sarcomatoid areas

Sampling may miss a component

Slide 37 · Immunohistochemistry answers a lineage question

Pleural tumor morphology

Lineage IHC panel

Integrated diagnosis

IHC is used to distinguish mesothelial differentiation from epithelial carcinoma.

A diagnostic panel is more reliable than a single positive stain.

Interpret marker distribution together with tissue morphology and the clinical setting.

Slide 38 · Mesothelial-positive marker set

Keratins, calretinin, WT1, cytokeratin 5/6, and podoplanin as commonly positive.

These markers support mesothelial differentiation when their expected patterns are present.

Sensitivity is context- and histologic-subtype-dependent.

Calretinin

WT1

CK5/6

Podoplanin

Keratin

Schematic — not a diagnostic specimen

Slide 39 · Calretinin supports mesothelial differentiation

Calretinin is usually expressed in epithelioid mesothelioma.

The textbook illustration shows stronger staining in epithelioid than sarcomatoid areas.

Stain interpretation must account for internal controls and tumor architecture.

Epithelioid component

Calretinin: Often stronger

Sarcomatoid component

Mesothelial markers may be reduced

Schematic — not a diagnostic specimen

Slide 40 · WT1 is part of a composite mesothelial panel

Wilms tumor protein 1 (WT1) is included among the main mesothelioma markers.

A positive WT1 result is supportive, not uniquely diagnostic by itself.

Correlation with keratin, calretinin, and epithelial-marker results remains necessary.

Slide 41 · CK5/6 and podoplanin add complementary evidence

Cytokeratin 5/6 and podoplanin are additional mesothelial-associated markers.

Their value is greatest when concordant with the morphologic impression and other stains.

Marker selection should consider the differential diagnosis rather than indiscriminate screening.

Slide 42 · Keratins and lineage: A diagnostic nuance

Mesotheliomas are typically keratin-positive despite their varied cell shapes.

Keratin staining can remain useful when sarcomatoid tumors lose other mesothelial markers.

Keratin positivity also occurs in carcinomas, so it cannot independently resolve lineage.

Slide 43 · Claudin-4: An epithelial differentiation marker

Immunophenotype

Mesothelioma (typical)

Adenocarcinoma (typical)

Calretinin / WT1

Often positive

Not the characteristic mesothelial panel

Claudin-4

Negative

Often positive

Interpretation

Mesothelial lineage favored

Epithelial lineage favored

Slide 44 · BerEP4 provides an additional exclusion signal

BerEP4 is named by Robbins among epithelial differentiation markers.

Mesotheliomas are usually negative while adenocarcinomas may be positive.

Its diagnostic role complements other mesothelial-positive and epithelial-positive markers.

Slide 45 · Two-sided IHC panels are more interpretable

Panel axis

Representative stains

Interpretive role

Mesothelial-associated

Calretinin, WT1, CK5/6, podoplanin

Support mesothelial differentiation

Epithelial-associated

Claudin-4, BerEP4

Favor carcinoma when expressed

Broad keratin

Pan-keratin

Supports epithelial/mesothelial nature; not discriminatory alone

Slide 46 · Worked panel: A mesothelial profile

Diffuse pleural tumor with epithelioid tubulopapillary architecture.

Keratin, calretinin, and WT1 positive; Claudin-4 and BerEP4 negative.

In the described context, the composite profile favors epithelioid mesothelioma.

This is an educational composite, not a patient specimen.

Calretinin +

WT1 +

Claudin-4 −

BerEP4 −

Schematic — not a diagnostic specimen

Slide 47 · Worked panel: An epithelial profile

Pleural lesion with gland-forming malignant epithelial cells.

Claudin-4 and BerEP4 positive without a convincing mesothelial marker profile.

Adenocarcinoma becomes an important alternative diagnosis.

Primary site still requires clinicopathologic correlation.

Calretinin −

WT1 −

Claudin-4 +

BerEP4 +

Schematic — not a diagnostic specimen

Slide 48 · A solitary stain is not a diagnosis

No single marker in the Robbins list is described as sufficient in every case.

Weak or missing markers are especially problematic in sarcomatoid tumors.

Avoid equating “keratin-positive spindle lesion” with mesothelioma without a differential work-up.

Slide 49 · Solitary fibrous tumor: A pleural mimic

Feature

Mesothelioma

Solitary fibrous tumor

Distribution

Diffuse pleural spread

Often pedunculated / circumscribed

Keratin

Often positive

Typically negative

CD34 / STAT6

Not the characteristic profile

Typically positive

Asbestos relation

Strong association

No established relationship

Slide 50 · SFT carries NAB2::STAT6 rearrangement

Pleural spindle lesion

CD34 and nuclear STAT6

Consider solitary fibrous tumor

The adjacent Robbins section describes a characteristic NAB2::STAT6 fusion.

SFT typically shows CD34 and STAT6 positivity with keratin negativity.

These findings separate SFT from mesothelioma when morphology overlaps.

Slide 51 · Metastatic pleural carcinoma remains common

Secondary pleural tumors are far more common than primary pleural tumors overall.

Lung and breast are frequent primary sites in the Robbins pleural-tumor discussion.

Pleural implants often produce serous or serosanguineous fluid with neoplastic cells.

Primary pleural tumormesothelioma

Versus

Secondary pleural depositsmetastatic carcinoma

Schematic — not a diagnostic specimen

Slide 52 · Effusion cytology: Useful but context-dependent

Careful cytologic examination of fluid sediment when malignancy is suspected.

Identifying neoplastic cells does not by itself settle whether a pleural lesion is primary or metastatic.

Definitive tissue classification may require integrated morphologic and ancillary studies.

Slide 53 · WHO 2021: Modern terminology

Robbins section terminology

WHO 2021 terminology

Malignant mesothelioma

Diffuse mesothelioma (invasive diffuse disease)

Epithelioid / sarcomatoid / biphasic

Same three main subtypes

Historical disease label

Contemporary classification wording

Slide 54 · WHO 2021 recognizes mesothelioma in situ

Mesothelioma in situ is a preinvasive mesothelial lesion included in WHO 2021.

Flat or minimally papillary mesothelial cells alone are insufficient for diagnosis.

Molecularly supported malignant mesothelial proliferation must be assessed for invasion.

Single layer along pleural surface

No demonstrated invasion in sampled tissue

Schematic — not a diagnostic specimen

Slide 55 · BAP1 loss as a marker of malignancy

Loss of nuclear BAP1 expression can support a malignant mesothelial proliferation.

Interpretation requires retained staining in appropriate internal control cells.

BAP1 IHC loss is not equivalent to a demonstrated inherited BAP1 mutation.

Tumor mesothelial cells

Nuclear BAP1 absent

Internal control nuclei retained

Schematic — not a diagnostic specimen

Slide 56 · CDKN2A deletion and MTAP IHC

Mesothelial proliferation

CDKN2A FISH / MTAP IHC

Support malignant biology

Homozygous CDKN2A deletion can be detected by fluorescence in situ hybridization (FISH).

Loss of MTAP by IHC can serve as a surrogate in validated settings.

These assays address malignant-versus-reactive mesothelial proliferation rather than tumor lineage alone.

Slide 57 · Why the in situ diagnosis needs tissue

Specimen

What it may establish

What it cannot alone exclude

Effusion / cytology

Abnormal mesothelial cells; molecular marker findings

Underlying invasive tumor

Pleural biopsy

Architecture and stromal interface

Complete disease extent when undersampled

Slide 58 · WHO 2021 adds epithelioid grading

The WHO update introduces nuclear grading for diffuse epithelioid mesothelioma.

Architectural and cytologic/stromal features also carry prognostic relevance.

Grading is distinct from histologic subtype; Exact criteria require the WHO framework.

Histologic type

Epithelioid / sarcomatoid / biphasic

Grade within epithelioid disease

Schematic — not a diagnostic specimen

Slide 59 · Prognosis varies by histologic subtype

Histologic classification is clinically consequential, not merely descriptive.

Biphasic disease behaving similarly to sarcomatoid disease.

The WHO update also emphasizes prognostic heterogeneity within epithelioid disease.

Slide 60 · A practical integrated diagnostic pathway

Pleural lesion / effusion

Morphology + lineage IHC

Ancillary studies + integration

Start with pleural distribution and careful morphologic assessment.

Establish lineage through a balanced IHC panel, with attention to subtype-related marker loss.

Where needed, use validated BAP1/MTAP or CDKN2A assays to assess malignant mesothelial biology.

Reconcile the full result with clinical and sampling limitations.

Slide 61 · Clinical vignette: Remote shipyard exposure

A patient develops progressive dyspnea and recurrent unilateral pleural effusion.

Occupational history reveals heavy shipyard asbestos exposure more than three decades earlier.

The latency and pleural syndrome make mesothelioma a salient possibility.

A tissue-based diagnosis is still required; Occupational history is not diagnostic.

Heavy asbestos exposure

Pleural malignancy

25–45 years

Schematic — not a diagnostic specimen

Slide 62 · Case interpretation: The diagnostic next question

Pleural biopsy shows tubules formed by atypical epithelial-like cells.

The pattern can be mesothelioma or metastatic/pulmonary adenocarcinoma.

Apply a mesothelial-positive and epithelial-positive IHC panel before assigning origin.

Tubules / lumina, simplified

Schematic — not a diagnostic specimen

Slide 63 · Clinical vignette: Spindle-cell pleural tumor

A fibrotic, paucicellular pleural tumor shows predominantly spindle-shaped cells.

Sarcomatoid mesothelioma and solitary fibrous tumor are important considerations.

Evaluate keratin alongside CD34/STAT6 and integrate gross distribution.

Spindle-cell / fibrotic architecture

Schematic — not a diagnostic specimen

Slide 64 · Beyond the chest: Other serosal sites

Mesothelioma also occurs in the peritoneum, pericardium, and tunica vaginalis.

These locations should not be conflated with the usual pleural presentation.

Robbins additionally mentions the benign adenomatoid tumor in a separate genital-tract context.

Pleura

Peritoneum

Pericardium

Tunica vaginalis

Schematic — not a diagnostic specimen

Slide 65 · Peritoneal disease: Exposure and course

Heavy asbestos association in 60% of male peritoneal cases, lower among women.

In approximately half of cases, disease remains confined to the abdominal cavity.

Intestinal involvement can cause obstruction and profound nutritional consequences.

These are source-specific observations rather than contemporary staging criteria.

Slide 66 · A clinicopathologic explanation of symptoms

Chest pain is linked to the pleural site and invasive spread.

Dyspnea reflects the combined consequences of effusion and an encasing pleural lesion.

Recurrent effusions reflect continuing pleural disease rather than isolated fluid imbalance.

Lung

Pleural fluid

Fluid + encasing pleural disease

Schematic — not a diagnostic specimen

Slide 67 · Prognosis description

Aggressive disease with a historically poor outcome.

Its cited figures are approximately 50% mortality within 12 months and few survivors beyond two years.

These figures must be understood as textbook historical estimates, not personalized modern survival predictions.

Slide 68 · Management is multidisciplinary and evolving

Surgery, chemotherapy, and radiation as approaches used in selected patients.

Treatment selection depends on disease extent, histology, patient factors, and contemporary protocols.

This pathology lecture does not present the textbook list as a current treatment guideline.

Slide 69 · Four diagnostic anchors to retain

Clinical context: Remote asbestos exposure plus a progressive pleural syndrome.

Gross phenotype: Diffuse pleural spread and encasement of the lung.

Microscopy: Epithelioid, sarcomatoid, or biphasic differentiation.

Diagnosis: Integrate morphology with two-sided lineage IHC and appropriate ancillary testing.

Exposure history

Pleural anatomy

Histologic type

Integrated markers

Schematic — not a diagnostic specimen

Slide 70 · Source documents and classification framework

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th ed. (2026), Chapter 15, pp. 660–662.

Nicholson AG et al. 2021 WHO Classification of Tumors of the Pleura. J Thorac Oncol. 2022;17:608–622.

Dacic S. Pleural mesothelioma classification—update and challenges. Mod Pathol. 2022;35:51–56.

Diagnostic concepts should be checked against current local laboratory protocols and multidisciplinary guidance.