PLEURAL MESOTHELIOMA: DIAGNOSIS

1
PLEURAL MESOTHELIOMA DIAGNOSIS DIFFERENTIAL
DIAGNOSESMark R. Wick, MDUniversity of
Virginia Medical Centermrw9c_at_virginia.eduhttp//
www.markwickmd.com
2
Classification 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

3
Categories 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

4
Pancytokeratin
5
ANTIBODIES USED IN BATTIFORA STUDY
CB Citrate Buffer at pH 6.0
6
Recommended 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
7
MESOTHELIAL MARKERS
8
Mesothelin
9
Thrombomodulin
10
Calretinin
11
Keratin 5/6
12
WT-1
13
Sensitivity/Specificity of Mesothelial Markers
14
Specificity of Mesothelial MarkersCancer Subtypes
Lung Ovary Breast
15
Podoplanin (D2-40)
16
Podoplanin (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

17
Podoplanin (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

18
Podoplanin (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)

19
CARCINOMA MARKERS
20
CEA
21
MOC-31
22
Lewis-Y (BG8)
23
BerEp4 in Adenocarcinoma
Basolateral cellular staining predominates
The great majority of tumor cells are labeled
24
BerEp4 in Mesothelioma
Staining is usually scant and peripherocellular
25
Specificity of Epithelial Markers
26
Sensitivity of Epithelial Markers Cancer Subtype
Lung Ovary Breast
27
Which 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

28
Moderately-differentiated Epithelial Mesothelioma
29
The Diagnosis of MM is Possible in Cytologic
Preparations
30
Adenocarcinoma of Lung in Pleural Fluid
31
Atypical Mesothelial Hyperplasia vs. Mesothelioma
32
AJSP, September 2000
33
51 year old man with recurrent left pleural
effusion, of unknown etiology. Thoracoscopy was
not very remarkable, but pleural biopsies were
obtained.
34
(No Transcript)
35
HBME-1
36
Mesothelial 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
37
Pleuropulmonary cultures were subsequently
positive for Mycobacterium tuberculosis
38
Fibrous 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

40
(No Transcript)
41
Parietal Pleural Biopsy
42
Parietal Pleural Biopsy
Differential Diagnosis Desmoplastic MM vs.
Fibrous pleuritis
43
Initial Diagnosis

• Based mainly on the clinical diagnosis of
  empyema, an initial diagnosis of fibrous pleurisy
  was made with no immunohistochemical evaluation

44
Evolution

• 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

45
Autopsy Findings--- Bone
46
Reevaluation of SurgicalMaterial with Keratin
Staining
47
Parietal Pleura
48
Autopsy Lung
49
Final Diagnosis

• Desmoplastic Mesothelioma

50
SARCOMATOID MESOTHELIOMA VS. SIMULATORS
51
DIFFERENTIAL DIAGNOSIS OF SARCOMATOID MESOTHELIOMA

• True sarcomas
• Metastatic sarcomatoid melanoma
• Metastatic or pleurotropic sarcomatoid
  carcinoma from other sites (e.g., lung, kidney)

52
SARCOMATOID 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

53
SPM 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

54
LYMPHOHISTIOCYTOID 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

55
KERATIN 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
56
MESOTHELIAL 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

57
IMMUNOPHENOTYPES 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

58
DIVERGENT DIFFERENTIATION IN SPM A MORPHOLOGICAL
TRAP

• Bone
• Cartilage
• Smooth muscle
• Angiosarcoma-like foci

59
PLEURAL 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

60
PLEURAL 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
61
MESOTHELIOMA VS. SARCOMATOID CARCINOMA
62
HOW 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

63
SARCOMATOID 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

64
RADIOGRAPHIC APPEARANCE OF SARCOMATOID
SARCOMATOUS PLEURAL LESIONS
65
SARCOMATOID 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

66
(No Transcript)
67
(No Transcript)
68
Calretinin
69
Bg8
70
p63
71
Mesothelioma 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

72
DOES 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

73
(No Transcript)