Benign Mesothelial Proliferations Research Articles

A Comparative Evaluation of Immunohistochemical Markers for the Differential Diagnosis between Malignant Mesothelioma, Non-Small Cell Carcinoma Involving the Pleura, and Benign Reactive Mesothelial Cell Proliferation

Histopathological diagnosis of malignant mesothelioma (MM) and differentiating it from tumors infiltrating the pleura is very difficult. Distinguishing benign reactive mesothelial cell proliferation from MM also presents problems. The objective of this study was to evaluate the significance of selected immunohistochemical stains in differentiating MM from non-small cell lung cancers infiltrating the pleura and from benign reactive mesothelial cell proliferation. The material encompassed 86 cases of MM, 54 cases of NSCLC infiltrating the pleura, and 43 cases of benign reactive mesothelial cell proliferation. The MM cases were reclassified according to the WHO criteria (2004): epithelioid, 61 cases (71%), including well-differentiated papillomatous, 3 cases; sarcomatous, 6 cases (6.8%); fibrous, 4 cases (4.7%); biphasic, 15 cases (17.5%). A panel of immunohistochemical stains was used in this study. It included broad-spectrum antibodies to cytokeratins (CKAE1/AE3, CKMNF116), vimentin, epithelial membrane antigen (EMA), mesothelial cells (HBME1, CK5/6, calretinin), adenocarcinoma cells (BerEp4, B72.3, CEA, TTF1), antibodies enabling the assessment of proliferation (Mib1) and cell-cycle regulating proteins (p53). Coexpression of cytokeratins and vimentin was found in 63.9% of MM cases and cell-membrane reactions with EMA were seen in 58.9%. Positive staining for HBME1, CK5/6, calretinin, BerEp4, B72.3, CEA and p53 was obtained in 76.7%, 51.2%, 66.7%, 1.2%, 6.2%, 1.2% and 51% of the cases, respectively. None of the MM cases stained for TTF1. MM by WHO subgroups: Coexpression of cytokeratins and vimentin occurred in 55.7% cases of epithelioid MM, 93.3% of biphasic MM, 66.6% of sarcomatous MM, and in 100% of fibrous MM cases. Positive staining for HBME1, CK5/6, and calretinin was seen only in the epithelioid and mixed subtypes of MM; the respective percentages of positive reactions were: HBME1, 90.2% and 73.3%; CK5/6 58.2% and 53.3%; calretinin, 72% and 75%. Non-small cell lung cancers infiltrating the pleura: Coexpression of cytokeratin and vimentin was found in 17.6% of the cases, positive staining of membranes for EMA, in 13% cases. Positive staining for HBME1 was observed in 22.6% of the cases, for CK5/6, in 9.3%, for calretinin, in 2%, for BerEp4, in 72.2%, for B72.3, in 64.1%, for CEA, in 58.5%, and for TTF1, in 43.8%. Benign reactive mesothelial cell proliferation: Protein p53 was present in 9.3% of cases, whereas no positive staining for EMA was found. Differentiation of MM from non-small cell carcinomas: Among the antibodies used in the study, anti-HBME1 had the highest sensitivity (76.7%) but lowest specificity (77.4%). Staining for calretinin showed high specificity (99.8%), as did CEA and TTF1 (98.8% and 100%), with moderate sensitivity (66.7%, 58.5% and 43.8%, respectively). BerEp4 showed the highest sensitivity (72.2%) and specificity (98.8%). In diagnosing mesothelioma it is necessary to use a panel of immunohistochemical stains, which should contain antibodies to markers for adenocarcinoma and mesothelioma. Due to the high costs of such a study, a two-stage method is advantageous. The best combination of sensitivity and specificity was found for BerEp4, CEA, and TTF1 and for calretinin and HBME1. In the diagnosis of spindle-cell pleural tumors and the fibrous form of MM and benign reactive mesothelial cell proliferation , markers of mesothelial cells are noncontributory. Immunohistochemical staining fails to identify a reactive process, but a diffuse, positive stain for EMA and the presence of protein p53 support the diagnosis of MM.

235 Diagnostic value of proliferative markers Ki-67 and Repp 86 in distinguishing between malignant and benign mesothelial proliferations

235 Diagnostic value of proliferative markers Ki-67 and Repp 86 in distinguishing between malignant and benign mesothelial proliferations

Cell proliferation rate and telomerase activity in the differential diagnosis between benign and malignant mesothelial proliferations

The differential diagnosis of malignant mesothelioma (MM) from benign mesothelial lesions (BML) based on histopathological criteria is sometimes not satisfying and causes diagnostic problems for histopathologists. We aimed to investigate whether the immunohistochemically determined cell proliferation rate and telomerase activity, using Ki-67 and human telomerase reverse transcriptase (hTERT) immunohistochemistry, respectively, are useful in the differential diagnosis of MM from BML. Sixty-six cases of MM (33 epithelioid, 30 biphasic and 3 sarcomatoid) and 22 cases of BML (15 reactive mesothelial proliferations and 7 fibrous pleuritis/pericarditis) were included in this study. We evaluated the proliferative activity by Ki-67 and telomerase activity by hTERT immunohistochemistries for each case. The mean value of the Ki-67 proliferation index (PI) in MMs was significantly higher than that of BMLs. Biphasic MMs have higher a Ki-67 PI than epithelioid and sarcomatoid types. Ki-67 immunohistochemistry has a sensitivity of 74%, specificity of 86% and positive predictive value of 94% in detecting MM. hTERT immunohistochemistry detected MM with sensitivity and specificity of 68%. As a result, being cheap and simple methods, Ki-67 and hTERT immunohistochemistries can be used in differentiating malignant and benign mesothelial lesions in routine formalin-fixed, paraffin-embedded material.

Differential Diagnosis of Benign and Malignant Mesothelial Proliferations on Pleural Biopsies

Although much of the pathology literature focuses on differential diagnosis of diffuse malignant mesothelioma from other types of cancer, the primary diagnostic challenge facing the pathologist is often whether a mesothelial proliferation on a pleural biopsy represents a malignancy or a benign reactive hyperplasia. Based on previous medical publications, extensive personal consultations, and experience on the United States-Canadian Mesothelioma Reference Panel and the International Mesothelioma Panel, salient information was determined about interpretation of benign versus malignant mesothelial proliferations on pleural biopsies. Differentiation of benign reactive mesothelial hyperplasia from diffuse malignant mesothelioma is often difficult. Benign reactive mesothelial hyperplasia may mimic many features ordinarily associated with malignancy, and diffuse malignant mesothelioma may be cytologically bland. Entrapment of benign reactive mesothelial cells within organizing pleuritis may mimic tissue invasion. Various histologic clues favor a benign over a malignant mesothelial proliferation and vice versa. Invasion is the most reliable criterion for determining that a mesothelial proliferation is malignant. When there is any doubt that a pleural biopsy represents a malignancy, we recommend a diagnosis of atypical mesothelial proliferation.

Specificity of MOC-31 and HBME-1 immunohistochemistry in the differential diagnosis of adenocarcinoma and malignant mesothelioma: a study on environmental malignant mesothelioma cases from Turkish villages

Histological diagnosis of malignant mesothelioma (MM) and differentiation from adenocarcinoma is often difficult. A number of clinical, radiologic, histologic and histochemical criteria have been used as diagnostic aids, but most cases cannot be readily classified on the basis of these characteristics. In recent years, a panel of immunohistochemical anti-bodies have been increasingly applied for the differential diagnosis of these two tumors. MOC-31 has been recently used as specific for adenocarcinomas while reacting with a minimal number of benign and malignant mesothelial proliferations, and HBME-1 has also been presented as a mesothelial cell marker. In this study, we aimed to show the importance of these two antibodies among the environmental MM cases from Southeastern Turkey. Fifty five cases of MM and twenty adenocarcinomas were included in this study. Histochemical (PAS, PAS-D, mucicarmine) and immunohistochemical (Keratin, EMA,CEA, MOC-31, HBME-1) stains have been performed on each case. Keratin was positive in all cases. EMA stained 50 of 55 MM and all the adenocarcinoma cases. According to our results, dPAS, mucicarmen, CEA and MOC-31 positivity was statistically significant in the diagnosis of adenocarcinoma whereas HBME-1 was demonstrable in most MM cases (52/55) and 11 adenocarcinoma cases. This study confirmed that in the diagnostic distinction between MM and adenocarcinoma, immuno-histochemistry is an important diagnostic tool, however, a panel of antibodies must be used rather than any single antibody. HBME-1 should be included in this panel; MOC-31 can be used where CEA is not available or to doublecheck the reactivity of this antibody.

Malignant mesothelioma eight years after a diagnosis of atypical mesothelial hyperplasia.

The separation of mesothelial hyperplasia from early malignant mesothelioma remains one of the most difficult problems in histopathology. Inconclusive cases are termed "atypical mesothelial hyperplasia" and treated expectantly. A 49...

Monoclonal antibody Ber-EP4: its use in the differential diagnosis of malignant mesothelioma and carcinoma in cell blocks of malignant effusions and FNA specimens.

Formol sublimate-fixed cell blocks derived from 129 malignant pleural (and some peritoneal) effusions, 8 benign effusions with reactive mesothelial cells, and 23 FNA specimens, were immunostained with monoclonal antibody Ber-EP4 to assess its ability to distinguish malignant mesothelioma (MM) from carcinoma. Only 2 of 44 (4%) well-characterized MM were Ber-EP4+, while none of 8 benign mesothelial proliferations reacted with the antibody. Fifty-seven percent of 23 pulmonary adenocarcinomas (AC) and 60% of 43 pulmonary carcinomas of all other histological types were Ber-EP4+. Of 40 metastatic AC originating from breast, gastrointestinal tract, ovary, endometrium, and kidney, 80% were Ber-EP4+. The predictive value of positive Ber-EP4 staining in distinguishing AC from MM was 96%. The predictive value of a negative Ber-EP4 in excluding MM was 70%, when the differential diagnosis was adenocarcinoma. These results suggest that Ber-EP4 is helpful in differentiating MM and AC if used together with other discriminating antibodies.

P53 immunostaining in the distinction between benign and malignant mesothelial proliferations using formalin-fixed paraffin sections.

The distinction between reactive mesothelium and mesothelioma in pleural biopsy specimens is notoriously difficult, and conventional immunohistochemical markers have provided no relief. The object of this study was to examine the frequency of immunohistochemically detectable p53 overexpression in routinely processed, paraffin-embedded tissue from pleural mesotheliomas and from pleura showing reactive mesothelial hyperplasia, using a polyclonal antibody to formalin-resistant p53 epitopes, and to consider the diagnostic utility of this antibody in the distinction between mesothelioma and reactive mesothelium in pleural biopsy specimens. Immunostaining was enhanced by pepsin predigestion prior to the application of the primary antibody. Positivity occurred in 10/16 epithelial mesotheliomas, 9/19 biphasic mesotheliomas, 2/12 sarcomatous mesotheliomas but in none of 20 reactive pleura. Immunostaining was particularly intense in some of the biopsy specimens, which may be due to the rapidity with which these small pieces of tissue were fixed. In conclusion, this study suggests that p53 immunostaining can help to distinguish epithelial or biphasic mesothelioma from reactive mesothelial hyperplasia in formalin-fixed, paraffin-embedded pleural biopsy specimens.

The differential diagnosis of epithelial‐type mesothelioma from adenocarcinoma and reactive mesothelial proliferation

Three monoclonal antibodies (mAbs) have been applied to 14 adenocarcinomas, eight mesotheliomas, and nine reactive mesothelial proliferations. One of these, AUA1, is a novel antibody in this context. It was found in 13/14 of the adenocarcinomas but not in benign or malignant mesothelial tissue, making it a potential substitute for carcinoembyronic antigen (CEA) in the differential diagnosis of mesotheliomas from adenocarcinomas. In addition, the lesions were stained using an argyrophil technique to identify nucleolar organizer regions. The results of counting these showed a small but significant overlap in their numbers between malignant and benign mesothelial proliferations. Although there was a difference overall in the numbers of nucleolar organizer regions in adenocarcinomas and mesotheliomas, on the one hand, and benign hyperplasias, on the other, this overlap considerably reduces their value in assessing individual difficult cases.

Immunohistochemical Differentiation of Sarcomatoid Mesotheliomas from Other Spindle Cell Neoplasms

A sizable proportion of pleural malignant mesotheliomas are sarcomatoid (22%) or biphasic (24%) and may need to be distinguished from other spindle cell neoplasms that occur as primary or metastatic tumors of the chest wall or lungs. To determine the utility of immunohistochemistry in the differentiation of sarcomatoid malignant mesotheliomas from other spindle cell neoplasms, the authors studied the immunostaining patterns of nine antibodies in four sarcomatoid mesotheliomas, one desmoplastic mesothelioma, two epithelial mesotheliomas, four spindle cell squamous carcinomas, and eight sarcomas of various differentiation. Three of the four sarcomatoid mesotheliomas and the desmoplastic mesothelioma had positive results for cytokeratin, which distinguishes them from sarcomas but not from spindle cell squamous carcinomas. The immunostaining pattern of 14 examples of benign spindle cell mesothelial proliferation was similar to that of the sarcomatoid mesotheliomas, which supports the theory that these tumors are mesothelial in origin. Although other antibodies occasionally may be helpful, depending on the differentiation of the sarcoma, cytokeratin immunostaining appears to be the best method to discriminate sarcomatoid mesotheliomas from sarcomas.

The diagnostic distinction between malignant mesothelioma of the pleura and adenocarcinoma of the lung as defined by a monoclonal antibody (B72.3)

The correct distinction between malignant mesothelioma of the pleura and adenocarcinoma of the lung has become increasingly complex, with a variety of histochemical, immunohistochemical, and ultrastructural studies to be performed on biopsy material. The reliability of immunohistochemical studies has been hampered by the use of polyclonal antisera to "carcinoembryonic antigen (CEA)" and keratin. Hybridoma technology now offers monoclonal antibodies (MAbs) in unlimited quantity and standardized quality to selective ranges of specific antigenic determinants. MAb B72.3, generated against a membrane-enriched fraction of human metastatic breast carcinoma, was used to distinguish malignant mesothelioma of the pleura from adenocarcinoma of the lung in tissue sections and was compared in terms of diagnostic utility with polyclonal anti-keratin and anti-CEA to make the same distinction. Reactivity with MAb B72.3 in at least 10% of tumor cells or more was noted in 19 of 22 adenocarcinomas of the lung (P greater than 0.0001), whereas none of the 20 cases of malignant mesothelioma demonstrated comparable reactivity. Furthermore, MAb B72.3 showed no reactivity with benign mesothelial proliferations. MAb B72.3 thus appears to be an appropriate diagnostic adjunct capable of discriminating between these malignancies.

Benign mesothelial proliferation with effusion: Clinicopathologic entity that may mimic malignancy

The clinical and pathologic features of five cases of a previously poorly defined syndrome, benign mesothelial proliferation with effusion, are described. Although this is a benign process, both the gross and the microscopic findings may mimic metastatic papillary adenocarcinoma. Three of five patients had dysynchronous Involvement in more than one body cavity developing over intervals of one, two, and six years. The clinical course is unpredictable and is usually associated with a good prognosis, but two of three patients with pericardial involvement required pericardectomy for pericardial tamponade. The entity of benign mesothelial proliferation with effusion and its distinction from true malignant conditions are discussed.