Wednesday, January 22, 2014
Immunohistochemistry in the diagnosis of malignant mesothelioma
Immunohistochemistry is integral to the diagnosis of malignant mesothelioma and
is currently the most useful and standard ancillary procedure for distinguishing this
malignancy from other types of cancer.
The primary differential diagnosis for epithelioid mesothelioma in the pleura is with
metastatic lung adenocarcinoma. Immunohistochemistry has replaced electron
microscopy as the preferred ancillary method, and differential diagnosis now relies on
the detection of various mesothelial and carcinoma-related antigens/markers in cytology
cell block sections or in biopsy tissue (21, 40, 41, 44, 45, 63, 78, 79). Carcinoma-related
markers include carcinoembryonic antigen (CEA), LeuM1 (CD15), Ber-EP4, B72.3 and
BG8 (45, 63, 80-84) and – whenever lung adenocarcinoma is included in the differential
diagnosis – thyroid transcription factor-1 (TTF-1) (45) and/or napsin A (85, 86). Antigens
characteristically expressed by mesothelial cells include calretinin, Wilms’ tumour gene
product (WT-1), mesothelin, cytokeratin 5/6, HBME-1 antigen, thrombomodulin and
podoplanin (D2-40) antibody (63, 79, 87-113).
The exact combination and number of antigens to evaluate is dependent on the
differential diagnosis and the antibodies available. Currently, calretinin is considered
to have the greatest specificity for a diagnosis of malignant mesothelioma, followed
by WT1 and D2-40 (21, 44, 45, 79, 99). The International Mesothelioma Panel (IMP) (41)
recommends at least one cytokeratin (CK) marker plus at least two mesothelial markers
(for example, calretinin and WT1) together with at least two carcinoma-related markers
(for example, CD15 and TTF-1). The guidelines from the ERS and the ESTS (21) reiterate
this IMP approach, as do the Guidelines from the International Mesothelioma Interest
Group (IMIG)(45). When tumours other than lung cancer enter into the differential
diagnosis (for example, secondary prostate carcinoma) additional markers become
necessary. The ERS/ESTS guidelines do not recommend use of CK7/CK20 (114) for
diagnosis of mesothelioma (21).
As a practical reference for pathologists, the IMIG recommends that markers have
sensitivity or specificity greater than 80% for the lesions in question (45), whereas the
ERS/ESTS guidelines specify a minimum sensitivity of 60-70%. Interpretation of positivity
should take into account the localisation of the stain (for example, nuclear versus
cytoplasmic) and the percentage of cells stained: more than 10% has been suggested for
cytoplasmic membranous markers (45).
From the preceding discussion, it is clear that none of the antibodies used for the
diagnosis of mesothelioma is 100% specific or sensitive – hence the requirement for
panels of mesothelial and non-mesothelial antibodies. As one example of the diagnostic
pitfalls that can be encountered, up to 15% of a subset of high-grade carcinomas of the
breast can express calretinin, and these carcinomas may also express CK5/6 and lack
detectable oestrogen receptor protein – with the potential for misdiagnosis of pleural
metastases as malignant mesothelioma (115, 116).
Immunohistochemistry has a more restricted role for the diagnosis of sarcomatoid
malignant mesotheliomas than for malignant mesotheliomas with an epithelial
30
component, because many sarcomatoid malignant mesotheliomas express only
cytokeratins in addition to vimentin and, in some cases, smooth muscle markers
Expression of calretinin is variable (30-89%) in sarcomatoid areas of
mesothelioma. . The high percentage labelling recorded in some
studies is explicable by acceptance of cytoplasmic labelling for calretinin as a positive
result (117), whereas positive nuclear labelling is required in addition to any cytoplasmic
labelling (41, 44). Most sarcomatoid and desmoplastic malignant mesotheliomas
are strongly positive for cytokeratins (although CK-negative sarcomatoid malignant
mesotheliomas do occur), and CK labelling can also highlight invasion, such as genuine
invasion into subpleural fat by a desmoplastic malignant mesothelioma . The ERS/
ESTS guidelines recommend use of at least two broad-spectrum CK antibodies and
two markers with negative predictive value, to support a diagnosis of sarcomatoid
mesothelioma
The place of immunohistochemistry in the diagnosis of malignant pleural mesothelioma
is a constantly evolving area and specific information on antibodies and their source
should be obtained from the current literature. It also seems likely that molecular
approaches to diagnosis – such as profiling of microRNA expression in tumour
tissue or extrapleural samples – will supplement immunohistochemistry for the
diagnosis of mesothelioma, but these approaches are at an investigational phase of
evaluation and at present they cannot be recommended for routine use in diagnosis.
is currently the most useful and standard ancillary procedure for distinguishing this
malignancy from other types of cancer.
The primary differential diagnosis for epithelioid mesothelioma in the pleura is with
metastatic lung adenocarcinoma. Immunohistochemistry has replaced electron
microscopy as the preferred ancillary method, and differential diagnosis now relies on
the detection of various mesothelial and carcinoma-related antigens/markers in cytology
cell block sections or in biopsy tissue (21, 40, 41, 44, 45, 63, 78, 79). Carcinoma-related
markers include carcinoembryonic antigen (CEA), LeuM1 (CD15), Ber-EP4, B72.3 and
BG8 (45, 63, 80-84) and – whenever lung adenocarcinoma is included in the differential
diagnosis – thyroid transcription factor-1 (TTF-1) (45) and/or napsin A (85, 86). Antigens
characteristically expressed by mesothelial cells include calretinin, Wilms’ tumour gene
product (WT-1), mesothelin, cytokeratin 5/6, HBME-1 antigen, thrombomodulin and
podoplanin (D2-40) antibody (63, 79, 87-113).
The exact combination and number of antigens to evaluate is dependent on the
differential diagnosis and the antibodies available. Currently, calretinin is considered
to have the greatest specificity for a diagnosis of malignant mesothelioma, followed
by WT1 and D2-40 (21, 44, 45, 79, 99). The International Mesothelioma Panel (IMP) (41)
recommends at least one cytokeratin (CK) marker plus at least two mesothelial markers
(for example, calretinin and WT1) together with at least two carcinoma-related markers
(for example, CD15 and TTF-1). The guidelines from the ERS and the ESTS (21) reiterate
this IMP approach, as do the Guidelines from the International Mesothelioma Interest
Group (IMIG)(45). When tumours other than lung cancer enter into the differential
diagnosis (for example, secondary prostate carcinoma) additional markers become
necessary. The ERS/ESTS guidelines do not recommend use of CK7/CK20 (114) for
diagnosis of mesothelioma (21).
As a practical reference for pathologists, the IMIG recommends that markers have
sensitivity or specificity greater than 80% for the lesions in question (45), whereas the
ERS/ESTS guidelines specify a minimum sensitivity of 60-70%. Interpretation of positivity
should take into account the localisation of the stain (for example, nuclear versus
cytoplasmic) and the percentage of cells stained: more than 10% has been suggested for
cytoplasmic membranous markers (45).
From the preceding discussion, it is clear that none of the antibodies used for the
diagnosis of mesothelioma is 100% specific or sensitive – hence the requirement for
panels of mesothelial and non-mesothelial antibodies. As one example of the diagnostic
pitfalls that can be encountered, up to 15% of a subset of high-grade carcinomas of the
breast can express calretinin, and these carcinomas may also express CK5/6 and lack
detectable oestrogen receptor protein – with the potential for misdiagnosis of pleural
metastases as malignant mesothelioma (115, 116).
Immunohistochemistry has a more restricted role for the diagnosis of sarcomatoid
malignant mesotheliomas than for malignant mesotheliomas with an epithelial
30
component, because many sarcomatoid malignant mesotheliomas express only
cytokeratins in addition to vimentin and, in some cases, smooth muscle markers
Expression of calretinin is variable (30-89%) in sarcomatoid areas of
mesothelioma. . The high percentage labelling recorded in some
studies is explicable by acceptance of cytoplasmic labelling for calretinin as a positive
result (117), whereas positive nuclear labelling is required in addition to any cytoplasmic
labelling (41, 44). Most sarcomatoid and desmoplastic malignant mesotheliomas
are strongly positive for cytokeratins (although CK-negative sarcomatoid malignant
mesotheliomas do occur), and CK labelling can also highlight invasion, such as genuine
invasion into subpleural fat by a desmoplastic malignant mesothelioma . The ERS/
ESTS guidelines recommend use of at least two broad-spectrum CK antibodies and
two markers with negative predictive value, to support a diagnosis of sarcomatoid
mesothelioma
The place of immunohistochemistry in the diagnosis of malignant pleural mesothelioma
is a constantly evolving area and specific information on antibodies and their source
should be obtained from the current literature. It also seems likely that molecular
approaches to diagnosis – such as profiling of microRNA expression in tumour
tissue or extrapleural samples – will supplement immunohistochemistry for the
diagnosis of mesothelioma, but these approaches are at an investigational phase of
evaluation and at present they cannot be recommended for routine use in diagnosis.
0 comments:
Post a Comment