Should the surgical decision be influenced by the diagnostic biopsy in mesothelioma?

Malignant pleural mesothelioma (MPM) is a fatal malignancy caused by exposure to asbestos that arises in the pleural lining of the lungs. MPM is generally associated with poor prognosis, with median overall survival time from 7 to 19 months after initial diagnosis (1,2).

The diagnosis of MPM is usually made during workup of thoracic symptoms. A chest radiograph and often a contrast-enhanced computed tomography scan are used to visualize hallmark radiographic features such as thickening of pleura, pleural effusion (found in ~70% of patients), loss of hemithoracic volume, irregular fissural thickening and localized mass lesions [for review, see (3)]. However, non-invasive radiographic evaluation cannot usually distinguish benign from malignant disease and only offers a sensitivity of 40% in detecting malignancy (4). Pleural fluid cytology is commonly non-diagnostic, detecting malignant cells in only 35% of cases (5). Therefore, definitive diagnosis usually requires a pleural biopsy for more definitive histological and immunohistochemical evaluation. Thoracoscopy is frequently used because it is sensitive for malignant disease and allows for direct visualization of biopsy sites, producing large and accurate samples in a disease where specimen size is important. Diagnosis is attained in 75% of specimens greater than 10mm in size compared with only 8% for specimens less than 10 mm (6). Surgical pleural biopsies, typically obtained via thoracoscopy, have become the gold standard diagnostic procedure for MPM with reported sensitivities of 95–98% with 100% specificity (6,7). Importantly, surgical biopsies are adequate to support immunohistochemical studies critical for differentiating among MPM subtypes and from histologically similar pleural malignancies (8-10).

There is no standard therapy for MPM. Treatment tends to be individualized, ranging from palliation of symptoms to cytotoxic chemotherapy to a variety of surgery-based multimodality regimens. Conservative management is most often indicated, based on considerations commonly encountered at diagnosis including advanced age, comorbidity, poor performance status and disseminated disease. Although MPM is poorly responsive to most classes of cytotoxic agents, treatment with combination platinum-antifolate chemotherapy is commonly applied in the first line based on several positive phase III studies (11,12). More recently, adding bevacizumab has been recommended for appropriate patients (13). Chemotherapy most often can be administered in the community, making it conveniently accessible for most patients.

Mesothelioma is categorized histologically into three subtypes: epithelioid, sarcomatoid, and biphasic (14). The epithelioid subtype is characterized by round or cube-shaped tumor cells. Epithelioid tumors are generally more indolent, less likely to metastasize, and more likely to be surgically resectable and responsive to chemotherapy. Correspondingly, epithelioid MPM is associated with better patient outcome. In contrast, the sarcomatoid subtype of MPM is comprised of spindle-shaped and more aggressively proliferating cells and is associated with rapid progression and short survival (15). For example, after therapeutic surgery, patients with epithelioid, biphasic and sarcomatoid MPM demonstrated respective median survival times of 15.3, 10.1 and 5 months and two-year survival rates of 31.7%, 7.6% and 0% (16).

Biphasic mesothelioma comprises both the epithelioid and sarcomatoid cell types. World Health Organization classification guidelines (17) define this subtype to include tumors ranging from 10% to 90% sarcomatoid component. These cut-points have been published without data-driven justification or update in successive editions of the guidelines (14,17,18). In studies where exhaustive review of final pathology blocks has been undertaken, patient prognosis has been found to depend on which cell type is more dominantly present (19), suggesting that implementing evidence-based subclassification of biphasic MPM may improve prognostic accuracy and allow surgical biopsy to better inform decisions on treatment. Because biphasic tumors are heterogeneous, the relative proportions of epithelioid and sarcomatoid cells may vary substantially with the pleural location of the biopsy, further reducing the accuracy of biopsy-estimated prognosis for patients diagnosed with this subtype. For example, thoracoscopic biopsy has been reported to misclassify 44% (20), 46% (21) and 58% (22) of biphasic tumors as epithelioid. These findings imply a larger number and distribution of pleural locations where surgical biopsies would need to be obtained to detect biphasic histology with reasonable sensitivity and specificity, particularly if future editions of WHO guidelines were to include subclassification based on a percentage score.

In current practice, prediction of overall tumor subtype and associated prognosis based on the diagnostic biopsy lacks accuracy in most cases to guide the surgical decision. However, the landscape for MPM treatment is changing toward more molecular and immune based approaches, presenting opportunities to use tumor biopsies for novel analyses that may help direct care, while circumventing the limitations of histological interpretation. Specifically, the diagnostic biopsy may be utilized to determine a molecular subtype, derive a molecular prognostic score or predict efficacy of novel targeted biologic or immune modulation therapies emerging as alternatives or adjuncts to surgical intervention.

Surgical biopsies usually provide sufficient tissue to support a range of histologic and molecular testing, including immunohistochemistry, genomic and transcriptomic analyses. Tumor RNA isolated from biopsy specimens can support prognostic testing based on gene expression signatures. For example, a gene ratio test involving expression levels of 4 genes has been rigorously validated in a prospective study (23). The test demonstrates high repeatability and reproducibility, successfully discriminating high and low risk patients based on outcomes following surgery-based therapy. Importantly, the test was further validated using formalin-fixed paraffin-embedded tissue samples, which supports its applicability to routinely collected clinical material (24). In addition, recent RNA-Seq profiling of over two hundred MPM tumors led to identification of distinct molecular clusters that align approximately with tumor histology, reflect gene expression signatures indicative of epithelial to mesenchymal transition and stratify survival (25). Thus, RNA isolated from the diagnostic pleural biopsy specimens can potentially provide a more robust indication of subtype and prognosis than does evaluation of their histology.

Tumor DNA isolated from a biopsy specimen may be subjected to targeted sequencing to detect known driver mutations indicative of prognosis or predictive of response to certain classes of targeted drugs. Although no targetable oncogenes have yet been identified as drivers of MPM, multiple novel significantly-mutated genes have recently been demonstrated (25) and are currently being investigated for their functional role, prognostic relevance and potential for biologic targeting. Technologies are also under development to use specific detected mutations to predict the availability of neoantigens for directed therapy (26).

Although MPM is characterized by relatively low mutation burden (25), early phase trials of immune checkpoint inhibitor therapy indicate activity in MPM. For example, KEYNOTE-028 (27) demonstrated 20% partial response and 52% stable disease rates using anti-programmed cell death receptor 1 (PD-1) antibody pembrolizumab. Lizotte and colleagues studied the immune profile of fresh MPM tumor biopsies obtained by fine needle aspiration using flow cytometry (28). Lizotte et al. found that non-epithelioid tumors demonstrated a more immunosuppressive microenvironment and were more likely to express PD-L1, but patient response in KEYNOTE-028 was unrelated to PD-L1 immunohistochemistry. Ongoing trials of anti-PD1 therapy for MPM include a pre-treatment biopsy to allow discovery of predictive biomarkers relevant to MPM that may ultimately be measurable in biopsy specimens.

Currently, histological analysis of the diagnostic pleural biopsy provides only modest prognostic information, but in the absence of definitive pathological staging and subtyping remains one of few indicators relevant to the surgical decision. In the context of evolving molecular technologies that require diminishing quantities of specimens, and of novel biologic and immune-based therapies, significant potential exists for accurate prognostic and predictive information to be ascertained from molecular analysis of biopsy material prior to determining treatment strategy. As the spectrum of available treatment options continues to expand, surgical intervention might be discouraged where surgical biopsy-based assays predict efficacy for less invasive or morbid alternatives such as targeted biologics or immune modulation. Conversely, prediction of resistance to such therapeutic approaches may shift the risk-benefit analysis in favor of surgical resection.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (David Waller and Annabel Sharkey) for the series “Mesothelioma Surgery” published in Shanghai Chest. The article has undergone external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/shc.2018.03.15). The series “Mesothelioma Surgery” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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