Evan as advancements in medicine’s ability to diagnose and treat mesothelioma have had a positive impact in the lives of many people, the disease is still often diagnosed only in its advanced stages where the common treatments for mesothelioma are not considered effective. In the push to develop more effective therapies, there has been considerable research into the discovery of which disease factors are indicative of a good prognosis vs. a poor one, with many of these studies identifying positive surgical margins, where malignant cells are discovered in the margins of resected tissue, and mediastinal lymph node involvement, where the lymph nodes in the mediastinum show evidence of metastasis, as poor prognostic indicators. However, the fact that a number of patients with pleural mesothelioma do not show any evidence of these factors and still experience poor treatment response and limited survival time has puzzled physicians and saddened many a patient and his or her family.

In response to this issue, a group of Italian researchers conducted a retrospective study on a number of pleural mesothelioma patients that investigated if occult disease was at work, that is, if mesothelioma was present, but remained hidden from the available diagnostic procedures. Using improvements in the ability of immunohistochemical staining to identify microscopic disease, these researchers discovered just that.

Overview of the Study

The researchers conducted a retrospective analysis of the results of 41 patients who were treated with trimodal therapy for pleural mesothelioma. Within the cohort, there were 30 men and 11 women and the average age was 58 years-old. The treatment protocol specified that each patient would undergo surgery, in this case, extrapleural pneumonectomy, followed by adjuvant chemotherapy and radiation.

The EPP was the first step in the protocol. There were 24 right-side EPPs performed, as well as 17 left-side EPPs. After surgery, the patient was examined for any macroscopic evidence of residual tissue in the margins. If an area was suspected, a sample was taken, analyzed microscopically with hematoxylin and eosin (H&E) staining and then preserved and archived. There were also a number of random samples taken from the areas surrounding the surgery and from local and medinstinal lymph nodes. These, too, were analyzed with H&E staining for the presence of malignant cells and then preserved and archived for future re-analysis. In cases where margins were found positive for mesothelioma, part of the subsequent radiation therapy would be directed to these areas.

The chemotherapy regimen included cisplatin + etoposide or gemcitabine and was given four to 10 weeks after the EPP. The radiotherapy regimen was then delivered post-chemo. The total dose was between 30 and 40 Gy, and was delivered in 1.5 Gy fractions.

The results from the H&E staining were then compared with an analysis conducted using immunohistochemical (IHC) staining. In this phase, the samples were stained with anti-calretinin and anti-mesothelin monoclonal antibodies and then analyzed for each antigen’s presence. A sample was considered positive for mesothelioma if at least five cells reacted to both antibodies.

The single endpoint to the study was overall survival time and that was measured from the time of EPP to the last follow-up or to the patient’s death. Due to the nature of the study itself, disease-free interval and time-to-progression were not evaluated.

Results

Histological analysis revealed 34 cases of epithelial mesothelioma, four cases of biphasic mesothelioma and three sarcomatoid cases. Staging was completed post-operatively and the following results were returned: 14 cases of Stage I disease, 6 cases of Stage II disease and 21 cases of Stage III disease—a clear indication that pleural mesothelioma is often diagnosed in its advanced stages. Patients with Stage IV disease were expressly excluded from this study by design.

The median survival for the entire cohort was 13 months, but differences in the presence of certain prognostic variables resulted in a wide range of median survival times when these variables were accounted for. Overall, the authors identified the presence of the following factors as indicative of poor prognosis: non-epithelial histology, stage, positive resection margins and lymph node metastases.

The initial H&E analysis identified 16 patients with positive surgical margins. Their 2-year median survival was only 13%, while patients with negative margins demonstrated a median 2-year figure of 49%. 12 patients in the cohort were discovered to have lymph node involvement and their median 2-year figure was only 8%, while those without nodal involvement had a 44% 2-year figure.

IHC analysis revealed additional patients with microscopic occult disease, as well as additional patients with lymph node metastases. When these additional findings were included in the analysis, these variables became even more significant predictors of prognosis.

Conclusion

The authors conclude that IHC is definitely an effective tool for the identification of occult disease and microscopic lymph node metastases for patients with pleural mesothelioma. In the cohort under study, IHC identified a number of additional patients who were in fact positive for marginal and nodal malignancy, indicating its greater specificity over traditional H&E staining. Its use for the diagnosis and staging of mesothleioma is an important development, as it will give physicians a greater ability to properly identify each patient’s individual status.

Labels: mesothelioma