Improving Cancer Survival

Serosal cavities – peritoneal, pleural, and pericardial – are frequently affected by cancer. The majority of tumors are carcinomas, particularly adenocarcinomas, originating from the lung, breast, female genital tract, and gastrointestinal tract. However, carcinomas of other origin – hematological cancers, germ cell tumors, melanomas, sarcomas, and childhood cancers originating from primitive tissues – may all be associated with malignant effusions. Additionally, malignant mesothelioma is a primary cancer of serosal cavities.

Serous effusions are not infrequently the first anatomic site sampled in a newly found or clinically suspected cancer, or the only site from which material is available in the event of disease recurrence (1). Indeed, many surgical pathologists have been reluctant to accept that serous effusion specimens constitute adequate material for diagnosing cancer, one of the most contentious areas of dispute being malignant mesothelioma. This ignores the fact that effusion specimens contain large numbers of viable tumor cells, which are often far better preserved than those in biopsy specimens. Moreover, educating clinicians to send non-fixed, large-volume specimens immediately to the laboratory provides pathologists with ideal material for diagnosing both new cancer and recurrent disease. Recently, an international group of experts published a consensus document detailing guidelines and ancillary methods for the diagnosis of malignant mesothelioma in effusions, supporting the relevance of these specimens in tumor diagnosis (2).

Beyond the issue of tumor diagnosis, effusions are becoming relevant in targeted therapy. Indeed, any molecular test that can be applied to biopsy material or surgical specimens may be applied to effusions. The use of paraffin-embedded cell blocks allows for the application of identical immunohistochemistry and in situ hybridization protocols as in biopsies, and the availability of high-quality fresh-frozen material makes molecular analyses feasible (3). This is likely to have greater relevance in the near future, when next generation sequencing will become part of the normal repertoire of pathology labs.

While many pathologists use primary and metastatic tumor interchangeably in molecular analyses, there is extensive literature documenting that these specimens have different molecular profiles (1)(2)(3), emphasizing the need to analyze the metastatic lesions that are to be targeted by therapy rather than the primary tumor. Metastases are not all equal either. Cancer cells in recurrent disease differ from those in metastases sampled at diagnosis and demonstrate complex patterns of clonal evolution that are evidence of the dynamic changes undergone by cancer cells during tumor progression, as exemplified by ovarian carcinoma effusions (4)(5). The prognostic relevance of cancer-associated molecules similarly differs among chemo-naïve effusions obtained at diagnosis and post-chemotherapy specimens (6).

Finally, I believe it is worth taking note of the rapidly increasing body of literature that implicates effusion-located cancer cells in the development of chemoresistance, most evidently in the case of ovarian carcinoma (7)(8)(9)(10)(11)(12)(13)(14). This appears to occur via diverse cellular mechanisms, including expression of postulated stem cell markers, partial epithelial-to-mesenchymal transition, modulation of cytokine levels, and inhibition of apoptosis. This should draw our attention to focusing on strategies that would sensitize these cells to chemotherapy and improve treatment of metastatic cancer.