Title: PLEURAL MESOTHELIOMA: DIAGNOSIS
1PLEURAL MESOTHELIOMA DIAGNOSIS DIFFERENTIAL
DIAGNOSESMark R. Wick, MDUniversity of
Virginia Medical Centermrw9c_at_virginia.eduhttp//
www.markwickmd.com
2Classification of Mesothelial Tumors
- Malignant
- Epithelial
- Tubulopapillary/Pseudoglandular
- Solid
- Deciduized
- Anaplastic
- Small-cell
- Biphasic
- Sarcomatoid
- Desmoplastic
- Lymphohistiocytoid
- Borderline
- Well-differentiated papillary mesothelioma
- Multicystic mesothelial
neoplasm (multicystic mesothelioma) - Benign
- Adenomatoid tumor
3Categories of Diagnostic Difficulty
- Fibrous pleurisy vs. desmoplastic mesothelioma
- Atypical mesothelial hyperplasia vs. epithelial
MM - Epithelial MM vs. adenocarcinoma
- Sarcomatoid mesothelioma vs. sarcoma
- Biphasic MM vs. synovial sarcoma or metastatic
sarcomatoid carcinoma
4Pancytokeratin
5ANTIBODIES USED IN BATTIFORA STUDY
CB Citrate Buffer at pH 6.0
6Recommended Panel for Immunohistochemical
Diagnosis of Mesothelioma
Positive in AdenoCA
Positive in MM
- Calretinin
- CK 5/6
- WT-1
- Mesothelin
- Thrombomodulin
- CEA
- Ber-EP4
- BG-8
- MOC-31
- TAG-72
Based on a study of 13 antibodies in gt300 cases
7MESOTHELIAL MARKERS
8Mesothelin
9Thrombomodulin
10Calretinin
11Keratin 5/6
12WT-1
13Sensitivity/Specificity of Mesothelial Markers
14Specificity of Mesothelial MarkersCancer Subtypes
Lung Ovary Breast
15Podoplanin (D2-40)
16Podoplanin (D2-40) A Recently-Introduced
Mesothelial Marker
- Podoplanin is a transmembrane mucoprotein
recognized by antibody D2-40 - It binds to ERM (ezrin, radixin, moesin) protein
family to active RhoA kinase this initiates
epithelial-mesenchymal transition and may
facilitate invasiveness of malignant tumors
17Podoplanin (D2-40) A Recently-Introduced
Mesothelial Marker
- Adenocarcinomas of lung, ovary, breast, kidney,
stomach, and pancreas are negative - D2-40 calretinin-positivity increases
sensitivity for Dx of mesothelioma to 95 for
epithelioid tumors and 66 for sarcomatoid lesions
18Podoplanin (D2-40) A Recently-Introduced
Mesothelial Marker
- CAVEATS---
- D2-40 binds to synovial sarcoma and epithelioid
hemangioendothelioma or angiosarcoma as well,
representing potential diagnostic pitfalls (all
of those neoplasms may simulate mesothelioma
clinically histologically)
19CARCINOMA MARKERS
20CEA
21MOC-31
22Lewis-Y (BG8)
23BerEp4 in Adenocarcinoma
Basolateral cellular staining predominates
The great majority of tumor cells are labeled
24BerEp4 in Mesothelioma
Staining is usually scant and peripherocellular
25Specificity of Epithelial Markers
26Sensitivity of Epithelial Markers Cancer Subtype
Lung Ovary Breast
27Which How Many Antibodies to Use?
- Depends on the specific differential diagnosis
and the level of tumor differentiation - A panel of 2 pro-mesothelial and 2 carcinoma
markers suffices in most cases - Cases that still prove to be diagnostically
indeterminate will require an expanded panel of
antibodies, and possibly would benefit from
electron microscopy as well
28Moderately-differentiated Epithelial Mesothelioma
29The Diagnosis of MM is Possible in Cytologic
Preparations
30Adenocarcinoma of Lung in Pleural Fluid
31Atypical Mesothelial Hyperplasia vs. Mesothelioma
32AJSP, September 2000
3351 year old man with recurrent left pleural
effusion, of unknown etiology. Thoracoscopy was
not very remarkable, but pleural biopsies were
obtained.
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35HBME-1
36Mesothelial Reactions Show a Zonation
Phenomenon, Wherein the Proliferations are
Restricted to the Mesothelial Surface and
Immediate Submesothelial Zone, with No Evidence
of Invasion of Underlying Stroma
Pankeratin
37Pleuropulmonary cultures were subsequently
positive for Mycobacterium tuberculosis
38Fibrous Pleurisy vs. Desmoplastic Mesothelioma
39- 70 year old man with progressive shortness of
breath - Radiographs showed diffuse right pleural
thickening and distortion of the pleuropulmonary
architecture - Thoracentesis was negative for malignant cells
- The clinical diagnosis of empyema was made and
antibiotic therapy was administered, but without
benefit - Thoracotomy showed encasement of the right lung
by fibrotic tissue, involving both visceral
parietal pleura - A decortication was attempted
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41Parietal Pleural Biopsy
42Parietal Pleural Biopsy
Differential Diagnosis Desmoplastic MM vs.
Fibrous pleuritis
43Initial Diagnosis
- Based mainly on the clinical diagnosis of
empyema, an initial diagnosis of fibrous pleurisy
was made with no immunohistochemical evaluation
44Evolution
- The patient died one year after thoracotomy
- Autopsy confirmed the persistence of fibrotic
tissue encasing both lungs and extending into the
mediastinum - Multiple nodular lesions with a fibrotic
consistency were also seen in the vertebrae
45Autopsy Findings--- Bone
46Reevaluation of SurgicalMaterial with Keratin
Staining
47Parietal Pleura
48Autopsy Lung
49Final Diagnosis
- Desmoplastic Mesothelioma
50SARCOMATOID MESOTHELIOMA VS. SIMULATORS
51DIFFERENTIAL DIAGNOSIS OF SARCOMATOID MESOTHELIOMA
- True sarcomas
- Metastatic sarcomatoid melanoma
- Metastatic or pleurotropic sarcomatoid
carcinoma from other sites (e.g., lung, kidney)
52SARCOMATOID PLEURAL MESOTHELIOMA (SPM)
Clinicopathological Features
- Overwhelming majority of patients with SPM are
adults over the age of 40 yrs. extremely rare
reports of similar tumors in adolescents - Symptoms and signs highly variable shortness of
breath, flu-like symptoms, weight loss, or
recalcitrant chest pain of a constant or
pleuritic nature - Persistent unilateral pleural effusion a common
finding on chest radiographs, in the absence of
active collagen vascular disease or infection - High protein content of pleural fluid
- Only 50 of patients have history of asbestos
exposure
53SPM VS. TRUE PLEURAL SARCOMAS
- EM and IHL criteria for this differential
diagnosis are completely different than those
attending EPM vs. metastatic adenocarcinoma the
issue here is a simple inclusion or exclusion of
epithelial differentiation - Ultrastructural identification of SPM is based
on intercellular junctions IHL profile shows
reactivity for keratin and/or EMA - SPM may also demonstrate positivity for desmin
and MSA, representing a trap in the possible
misdiagnosis of a pleural sarcoma
54LYMPHOHISTIOCYTOID MESOTHELIOMA
- Currently considered a form of sarcomatoid
mesothelioma that may simulate fibroinflammatory
pleuritis or a lymphoproliferative disorder - The speaker is struck with the similarity between
LHM and lymphoepithelioma-like carcinoma of
various organs, but LHM is EBV antigen-negative - LHM is a rare form of mesothelioma, with lt10
well-documented cases in the literature
55KERATIN IN SARCOMATOID MESOTHELIOMAS
- Using current technology (a monoclonal antibody
cocktail and epitope retrieval), ALL
sarcomatoid mesotheliomas should be reactive for
keratin
Keratin Mixture MAK-6, CAM5.2, AE1/AE3
Aside from synovial sarcoma, all primary pleural
sarcomas rarely demonstrate keratin- immunopositiv
ity
56MESOTHELIAL MARKERS IN SARCOMATOID MESOTHELIOMA
- HMBE-1 Virtually always negative
- Mesothelin Virtually always negative
- CD141 Present in 20-30 of cases
- Calretinin Depending on the series that is
cited and the methods/reagents that are used,
anywhere from 30 to 100 of sarcomatoid
mesotheliomas are said to be calretinin-positive.
The speakers experience is approximately 75,
albeit with only multifocal labeling - WT1 Present in lt20 of cases
- CK 5/6 Present in 20-30 of cases
- _______________________________________________
- These reactants are also seen in
non-mesotheliomatous tumors, both epithelial
mesenchymal in nature
57IMMUNOPHENOTYPES OF SPM AND SARCOMATOUS PLEURAL
TUMORS
- CD34 is seen preferentially seen in solitary
fibrous tumors (SFTs) of the pleura, in common
with other fibrogenic non-epithelial
proliferations (e.g., DFSP) HOWEVER, malignant
variants of SFT are only inconsistently
CD34-positive - Keratin, on the other hand, is expressed by SPM
and sarcomatoid carcinoma, but not by sarcomatous
pleural neoplasms except for synovial sarcoma - Typical immunohistologic panel for differential
diagnosis of SPM true sarcomas would include
antibodies to keratin (anti-CK mixture CK5/6,
CK7, CK19), EMA, Ber-EP4, vimentin, desmin,
actin, S100 protein, CD34, CD57, CD141, WT-1,
calretinin
58DIVERGENT DIFFERENTIATION IN SPM A MORPHOLOGICAL
TRAP
- Bone
- Cartilage
- Smooth muscle
- Angiosarcoma-like foci
59PLEURAL SYNOVIAL SARCOMA A TRAP IN THE DIAGNOSIS
OF BIPHASIC SARCOMATOID MESOTHELIOMA
- Synovial sarcoma (SS) has biphasic and
monophasic spindle-cell subtypes, in analogy to
mesotheliomas - Both synovial sarcoma and SPM are potentially
immunoreactive for keratin, EMA, calretinin, and
CD141, in both epithelioid spindle cell
elements - WT1-positivity was restricted to SPM in one study
(Miettinen M, et al. Am J Surg Pathol 2001 25
610-617), but showed poor sensitivity Simple
keratins (7 19) were, on the other hand,
globally present in the cells of SPMs but only
focal in SS - CK 5/6 was seen in 30 of SPM cases in a study
by Attanoos et al. (Histopathology 2000 37
224-231), but has not been reported in SS - t(X18) SST-SSX transcripts are restricted to
SS
60PLEURAL EPITHELIOID HEMANGIOENDOTHELIOMA
SIMULATOR OF EPITHELIOID MESOTHELIOMA
- Like angiosarcoma, epithelioid hemangioendotheliom
a (EH) may rarely present primarily in the pleura - Even though it is a mesenchymal, low-grade
malignant neoplasm, it usually simulates
epithelial mesothelioma rather than the
sarcomatoid subtype of the latter tumor - EH is immunoreactive for von Willebrand factor,
CD34, CD31, CD141, and may demonstrate
aberrant keratin-positivity (10)
CD31
61MESOTHELIOMA VS. SARCOMATOID CARCINOMA
62HOW OFTEN IS SARCOMATOID CARCINOMA A PLEUROTROPIC
(PSEUDOMESOTHELIOMATOUS) LESION?
- Hartmann Schutze (Cancer Res Clin Oncol 1994
120 331-347) studied 72 autopsy cases of
pseudomesotheliomatous carcinomas of pleura - 38 of cases manifested multifocal or global
spindle-cell differentiation, yielding an
appearance which simulated that of biphasic or
sarcomatoid mesothelioma - Anatomic sites of origin for the tumors included
the lung, kidney, breast, colon, bladder, and
thymus in all instances, the primary tumor was
undetected clinically
63SARCOMATOID CARCINOMASThe Concept of
Monophasic Biphasic Tumors
- Biphasic neoplasms demonstrate focally overt
epithelial differentiation (squamous, adeno-,
adenosquamous, undifferentiated CA), and
typically fit the generic description of
carcinosarcomas sarcoma-like elements may show
divergent differentiation - Monophasic tumors lack definably epithelial
features on conventional microscopy and are
MFH-like, or they may show divergent sarcoma-like
constituents - Because of sampling limitations in small
biopsies, both forms of SC are potentially
confused with true sarcomas
64RADIOGRAPHIC APPEARANCE OF SARCOMATOID
SARCOMATOUS PLEURAL LESIONS
65SARCOMATOID CARCINOMAS OF THE LUNG INVOLVING
PLEURA Additional Details
- May contain heterologous tissues (striated
muscle, cartilage, etc.) in some biphasic
lesions, but that potentiality is also shared by
mesothelioma - Sarcomatoid carcinomas do NOT retain most
specialized immunohistologic markers of
differentiation, such as CEA, Ber-EP4, etc. - Distinction between pleurotropic sarcomatoid
carcinoma and mesothelioma is extremely difficult
or impossible in some cases
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68Calretinin
69Bg8
70p63
71Mesothelioma vs. Sarcomatoid Squamous Carcinoma
Immunohistology
- Keratin 5/6 not useful because both tumor types
are positive - Bg8 is sometimes still useful as a carcinoma
discriminant in sarcomatoid carcinomas - Calretinin is absent in SCC
- p63 is seen in the majority of SCCs, but is not
present in mesotheliomas
72DOES THE DDX OF MM AND OTHER MALIGNANT PLEURAL
TUMORS HAVE PRACTICAL IMPORTANCE?
- Pragmatically speaking, it does not, if lymphoma
is excluded from consideration the prognosis of
patients with MM, primary pleural sarcoma,
metastatic melanoma, and pseudomesotheliomatous
carcinoma is equally adverse and treatment is
closely similar (and similarly ineffective) - The main reason (beyond academic curiosity) for
making this distinction resides in the
medicolegal implications that are associated with
MM
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