Reactive Mesothelial Proliferations Research Articles

Transforming growth factor α and epidermal growth factor receptor in reactive and malignant mesothelial proliferations

Abstract Background.—Growth factors such as transforming growth factor α (TGF-α) and epidermal growth factor receptor (EGFR) play an important role in cell proliferation. The immunohistochemical expression of these factors has been extensively studied in malignant tumors including mesothelioma. However, the comparative expression of these growth factors in mesothelioma and reactive mesothelial proliferations has been less well studied. Objective.—To evaluate the possible role of TGF-α and EGFR in the clinically important distinction between reactive mesothelial proliferations and malignant mesothelioma. Methods.—The expression of TGF-α and EGFR was studied in 39 cases of mesothelioma and 30 cases of reactive mesothelial proliferations by means of immunohistochemistry. Results.—Fourteen (70%) of 20 reactive mesothelial proliferations tested and 29 (76%) of 38 mesotheliomas tested expressed TGF-α. One (3%) of 30 reactive mesothelial proliferations and 17 (45%) of 39 mesotheliomas expressed EGFR. Conclusions...

Transforming growth factor alpha and epidermal growth factor receptor in reactive and malignant mesothelial proliferations.

Growth factors such as transforming growth factor alpha (TGF-alpha) and epidermal growth factor receptor (EGFR) play an important role in cell proliferation. The immunohistochemical expression of these factors has been extensively studied in malignant tumors including mesothelioma. However, the comparative expression of these growth factors in mesothelioma and reactive mesothelial proliferations has been less well studied. To evaluate the possible role of TGF-alpha and EGFR in the clinically important distinction between reactive mesothelial proliferations and malignant mesothelioma. The expression of TGF-alpha and EGFR was studied in 39 cases of mesothelioma and 30 cases of reactive mesothelial proliferations by means of immunohistochemistry. Fourteen (70%) of 20 reactive mesothelial proliferations tested and 29 (76%) of 38 mesotheliomas tested expressed TGF-alpha. One (3%) of 30 reactive mesothelial proliferations and 17 (45%) of 39 mesotheliomas expressed EGFR. These results suggest an up-regulation of EGFR in mesothelioma as compared with reactive mesothelial proliferations. This up-regulation further suggests a possible use of EGFR as an adjunct immunohistochemical test in the differential diagnosis of mesothelioma and reactive mesothelial proliferations.

Paratesticular mesothelial proliferations

Varied mesothelial proliferations are found around the testes. Benign reactive mesothelial proliferations in hydrocoeles may be very florid and histologically worrisome, but these can usually be separated from malignant mesotheliomas of the tunica vaginalis because they are confined to a sharply demarcated zone near the luminal surface. In addition, benign inflamed hydrocoeles tend to show a distinct zonation with cellular areas near the luminal surface and more fibrotic areas beneath. The proliferating mesothelial cells in benign reactions often form lines that are parallel to the surface of the hydrocoele. Malignant mesotheliomas of the tunica vaginalis are usually grossly visible as single or multiple nodules. Histologically, they show an epithelial- or mixed epithelial- and sarcomatous-morphologic image, with evidence of stromal invasion. Well-differentiated papillary mesotheliomas are usually solitary exophytic nodules with a distinctive morphologic appearance and benign course, but they must be carefully separated from malignant mesotheliomas with a focally exophytic papillary growth pattern. By definition, well-differentiated papillary mesotheliomas do not exhibit stromal invasion. Peritesticular adenomatoid tumors are also very common; they are benign circumscribed cellular nodules with an appearance comparable to that of adenomatoid tumors in other body locations such as the uterine serosa.

Simian virus 40 and human tumors: It is time to study mechanisms.

Several studies found simian virus 40 (SV40) in 47% to 83% of human mesotheliomas. Mesotheliomas are malignant tumors of the pleura and peritoneum, firmly associated with asbestos exposure. In this issue, Gazdar and colleagues ¿Shivapurkar et al., 1999 found that SV40 is present only in the malignant cells and not in the surrounding stromal cells. Using the microdissection technique, they found SV40 in 54% of 93 mesotheliomas of the epithelial type. The surrounding reactive stromal cells, (20 lung cancers and 14 mesotheliomas of the sarcomatoid/fibrous type) did not contain SV40, confirming the specificity of their positive findings. Furthermore, SV40 was found in 14% of 14 non-malignant reactive mesothelial cell proliferations. In 12 cases of mesothelioma a noninvasive (or in situ) component was also identified. In all four cases in which SV40 sequences were present in the invasive component, sequences were also present in the accompanying noninvasive component. These data suggest that the virus resides in the mesothelial cells prior to tumor development. The data address the remaining concerns raised at an International Meeting organized by the NIH, FDA, and CDC in 1997 to definitively associate SV40 with human mesothelioma. It is time now to investigate the pathogenic mechanisms of this association, and if SV40-infected mesothelial cells are more susceptible to other carcinogens, such as asbestos. Furthermore, we must investigate the interaction between the host immune system and SV40-infected mesothelial cells, and study if the immunosuppressive activity of asbestos interferes with tumor rejection. These studies should lead to a better understanding of mesothelioma pathogenesis, and possibly to new therapeutic approaches aimed at interfering with the expression of the SV40 genome and/or at eliciting a strong immune response against SV40 infected mesothelial cells.

Ber-EP4 for differentiating adenocarcinoma from reactive and neoplastic mesothelial cells in serous effusions. Comparison with carcinoembryonic antigen, B72.3 and Leu-M1.

To evaluate the efficacy of Ber-EP4 in distinguishing epithelial cells from mesothelial cells in routine cytologic preparations. Paraffin-embedded cell blocks of serous effusions from 32 patients (11 metastatic adenocarcinomas, 16 reactive mesothelial proliferations and 5 malignant mesotheliomas) were immunostained with Ber-EP4. For comparison, cell block preparations of adenocarcinomas and mesotheliomas were also immunostained with the most commonly applied markers of adenocarcinoma: carcinoembryonic antigen (CEA), B72.3 and Leu-M1. In addition, cytocentrifuge preparations of 14 reactive effusions and 2 metastatic adenocarcinomas were stained prospectively with Ber-EP4. All adenocarcinomas showed intense membrane staining, while all mesothelial proliferations, both benign and malignant, were negative. The Ber-EP4-positive immunostaining was remarkably clean, with very minimal nonspecific staining. CEA stained 11/11 adenocarcinomas, B72.3 stained 10/11, and Leu-M1 stained 8/11; mesotheliomas were negative with all three antibodies. Ber-EP4 is at least as useful as CEA, B72.3 and Leu-M1 in the diagnosis of serous effusions. It has the advantage of high sensitivity and ease of interpretation because of the high percentage of tumor cells stained, characteristic membranous staining and lack of cross-reaction with background inflammatory cells.

Comparison of silver-staining nucleolar organizer region (AgNOR) counts and proliferating cell nuclear antigen (PCNA) expression in reactive mesothelial hyperplasia and malignant mesothelioma

Previous workers have used counts of colloidal silver-stained nucleolar organizer regions (AgNORs) to help distinguish reactive from malignant mesothelial processes. We sought to compare the demanding technique of AgNOR counting with the identification of proliferating cell nuclear antigen (PCNA) in 10 pleural malignant mesotheliomas and 11 reactive mesothelial proliferations. The mean AgNOR count was significantly higher in malignant compared to reactive lesions (5.10 [95% confidence interval, CI 4.35-5.84] vs 3.68 [95% CI 3.17-4.19], p = 0.004), as was the PCNA index (26.9 [95% CI 17.37-36.49] vs 9.67 [95% CI 4.94-14.39], p = 0.004). Less overlap was seen with PCNA indices and no reactive mesothelial proliferations had a PCNA index greater than 20%, suggesting that scores over this level may be a specific indicator of malignancy in this setting. There was only a weak correlation between the 2 proliferation indices suggesting that PCNA and AgNORs are present at somewhat different times of the cell cycle and/or persist in the post-S phase cell for variable lengths of time.

Diffuse Histiocytic Proliferation Mimicking Mesothelial Hyperplasia in Endocervicosis of the Female Pelvic Peritoneum

Two cases of a diffuse histiocytic proliferation that mimicked mesothelial hyperplasia in the pelvic peritoneum of premenopausal women with endocervicosis are presented. The lesions were found incidentally on laparoscopic examination for pelvic pain and appeared as small friable excrescenses attached to the serosal surface of the pelvis. Histologic examination revealed a dense proliferation of round to oval cells with abun dant eosinophilic cytoplasm and large, hyperchromatic nuclei showing focal invagina tions and occasional mitoses. The cells appeared to infiltrate the surrounding connec tive tissue in single files and were closely associated with sloughed strands of small, cuboidal mesothelial cells as well as with larger glands lined by mucinous epithelium. Immunohistochemical studies showed cytoplasmic staining of these cells with MAC387, HAM56, and alpha-1-antichymotrypsin antibodies, thus supporting their histiocytic nature. The close association of the histiocytic proliferation with the endo cervicotic glands raises the possibility that the process may have resulted as a reaction to rupture and extrusion of the mucous contents of the glands into the surrounding stroma. These lesions must be distinguished from reactive or neoplastic mesothelial proliferations involving the female pelvic peritoneum. Int J Surg Pathol 1(2):101-106, 1993

P53 expression is common in malignant mesothelioma.

The p53 tumour suppressor gene has been shown to be frequently mutated in a wide range of human neoplasms. This is accompanied by increased levels of p53 protein which become immunologically detectable in pathological material. We have investigated the possibility that the differential diagnosis between reactive and neoplastic mesothelium might be resolved using a polyclonal serum raised to human p53 protein, CM-1. None of 20 cases of reactive mesothelial proliferation showed p53 immunoreactivity while 70% (14 of 20) of cases of malignant mesothelioma showed p53 staining. We can thus infer that abnormalities of p53 appear to be a common event in malignant mesothelioma and that p53 immunostaining may be of value in the distinction of malignant mesothelioma from reactive hyperplasia.

Multicystic mesothelial proliferation. Immunohistochemical, ultrastructural and DNA analysis of five cases.

We investigated the clinicopathological findings in five cases of multicystic mesothelial proliferation (MMP). All masses consisted of multiloculated cysts attached to pelvic organs and sometimes growing into the upper abdominal cavity. The cystic spaces were lined by flattened or cuboidal cells. The stroma showed fibrosis, oedema and chronic inflammation. Immunohistochemistry revealed strong positive staining for cytokeratin and epithelial membrane antigen, and focal positivity for vimentin and carcinoembryonic antigen. The endothelial markers were negative. Electron microscopy showed abundant surface microvilli and well-developed basal lamina. DNA analysis identified euploid cell populations in all cases. All but one case had a previous history of abdominal surgery. Despite the worrying appearance the clinical outcome was favourable in all cases; there was one recurrence. Clinical and pathological data support the hypothesis that MMP represent a reactive mesothelial proliferation and not a neoplastic process.

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.

Multilocular peritoneal inclusion cysts (so-called cystic mesotheliomas).

Twenty-five cases of multilocular peritoneal inclusion cysts (MPIC) were investigated. All but four cases were associated with a history of a previous abdominal or pelvic operation, or evidence of endometriosis or pelvic inflammatory disease, or combinations of these findings. All of the lesions were attached to pelvic organs, 44% also occupied the upper abdominal cavity, and 16% involved the retroperitoneum. In three cases free-floating cysts were present as well. The median diameter of the lesions was 13 cm. The cyst locules were lined by one to several layers of flat to cuboidal mesothelial cells that occasionally formed papillae, had a hobnail shape, or had undergone squamous metaplasia. The stroma was characterized by chronic inflammation and often acute inflammation. In most of the cases there was mural proliferation of the mesothelial cells, occasionally simulating a malignant mesothelioma. Twelve lesions were complicated by postoperative local recurrence; in four of these cases the recurrences were multiple; neither the size of the lesion nor the presence of mural mesothelial proliferation influenced the outcome. The clinical and pathologic data in this series suggest that the MPIC is a nonneoplastic reactive mesothelial proliferation.

Keratin protein immunoreactivity ofsarcomatoid and mixed types of diffuse malignant mesothelioma: An immunoperoxidase study of 30 cases

To define the role of keratin protein immunohistochemistry in the pathologic diagnosis of the sarcomatoid type of diffuse malignant mesothelioma (DMM), we examined 30 DMM (16 pure sarcomatoid type and 14 mixed sarcomatoid-epithelial type) by an indirect immunoperoxidase technique using three commercially available antibodies to keratin proteins. The sarcomatoid (spindle-cell) areas of all 30 cases of sarcomatoid DMM were immunoreactive for keratin proteins. In 14 of 16 cases of sarcomatoid DMM, 50% or more of the tumor cells were reactive with one or more antibodies; however, polyclonal bovine muzzle and monoclonal AE1/AE3 antibodies were distinctly superior to polyclonal human callus keratin antibody in the detection of spindle tumor cells. In contrast with the staining patterns observed for DMM, 39 spindle-cell malignancies and tumor-like processes of 10 histogenetic types were unreactive with the three antibodies. Those spindle-cell tumors and reactive mesothelial proliferations that may enter into the differential diagnosis of sarcomatoid DMM are discussed. We conclude that keratin protein immunohistochemistry is a sensitive and highly useful method for the pathologic diagnosis of the sarcomatoid type of DMM and its distinction from other spindle-cell neoplasms.

Ultrastructural studies of malignant cells in fluids.

An ultrastructural study was performed on 104 sequential fluids in which more than eight malignant cells per ten high-power fields were found by routine light microscopy. The study included fluids associated with mesotheliomas, melanomas, lymphomas, squamous-cell carcinomas, small-cell anaplastic (oat-cell) carcinomas, and adenocarcinomas. Electron microscopic examination reliably separated lymphoid from epithelial malignancies and benign from reactive and malignant mesothelial cell proliferations. It also suggested or identified a primary site for the adenocarcinomas. Ultrastructural examination of fluids can be a valuable adjunct to routine light microscopy of cytology specimens. No false-positive diagnoses were encountered. Sampling was the most significant limitation for this technique.

Reactive mesothelial proliferation: a necropsy study.

To establish a histological standard against which surgical biopsy material could be compared, the degree of mesothelial proliferation was studied in 100 unselected necropsies. A minor degree of mesothelial hyperplasia was identified in 10 cases, usually close to areas of fibrous adhesions. Pleural plaques were present in 33 patients but there was no evidence of associated mesothelial proliferation. No mesothelial changes were noted in patients with empyema or pleural metastases. These findings indicated that the degree of mesothelial hyperplasia in common disorders of the pleura is relatively slight. Significant mesothelial proliferation in needle biopsies should therefore be viewed with considerable suspicion and, where clinically appropriate, be followed by further investigation.