Sarcomatoid differentiation during progression of malignant pleural mesothelioma

Background:

Malignant pleural mesothelioma (MPM) is an aggressive tumor with a high local recurrence rate despite multimodal treatment. We evaluated the prognostic impact of morphological and immunohistochemical changes in sequential biopsies obtained during disease progression.

Methods:

Tissue microarrays were constructed from samples of 36 MPM patients taken before induction-chemotherapy, during surgery and at tumor recurrence. Immunohistochemical staining and scoring for calretinin, cytokeratin 5/6 (CK5/6) and Wilm's tumor-1 (WT-1), mesothelin, osteopontin, and fibulin-3 was performed. Results were correlated with clinico-pathological characteristics including overall survival (OS) and. A multivariate analysis was performed.

Results:

In 28% of patients with epithelioid or biphasic MPM, a transition towards biphasic or sarcomatoid growth pattern during disease progression was observed. This dedifferentiation was associated with significantly decreased immunoreactivity for WT-1, calretinin, mesothelin as well as a shorter OS.

Patients with epithelioid or biphasic MPM in the diagnostic biopsy had a significantly better OS (29 months) in comparison to patients with sarcomatoid MPM (5 months). On multivariate analysis, male gender and high fibulin-3 in the pre-chemotherapy samples were independent predictors for shorter OS.

Conclusion:

In 28% of patients disease progression is accompanied by sarcomatoid differentiation, suggesting that factors such as molecular alterations involved in epithelial-to-mesenchymal transition are contributing to disease course and clinical outcome. Alternatively, induction chemotherapy might contribute to this transition by promoting selection and outgrowth of therapy resistant tumor cells. Eventually, the different tumor biology of this subgroup may be taken into account for the consideration of alternative patient handling.