Perioperative discordance in mesothelioma cell type after pleurectomy/decortication-a possible detrimental effect of neoadjuvant chemotherapy due to epithelial to mesenchymal transition?

Our plain-English summary of Perioperative discordance in mesothelioma cell type after pleurectomy/decortication-a possible detrimental effect of neoadjuvant chemotherapy due to epithelial to mesenchymal transition?, by L. Ventura, M. Lee, R. Baranowski, et al (Interdisciplinary Cardiovascular and Thoracic Surgery, 2023).

The study

• Authors: L. Ventura, M. Lee, R. Baranowski, J. Hargrave, M. Sheaff, D. Waller
• Journal: Interdisciplinary Cardiovascular and Thoracic Surgery
• Published: 2023;37(5)
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Objectives: The goal was to evaluate the accuracy of preoperative histological assessment and the factors affecting the accuracy and the subsequent effect on postoperative survival after surgical treatment for malignant pleural mesothelioma (MPM).

Methods: We analysed the perioperative course of patients who underwent surgery for MPM in a single institution over a 5-year period. The primary end point was to evaluate the proportion of histological discordance between preoperative assessment and postoperative histological diagnosis. The secondary end point was to evaluate its prognostic effect on postoperative survival after surgical treatment.

Results: One-hundred and twenty-nine patients were included in this study. Histological discordance between preoperative assessment and postoperative histological diagnosis was found in 27 of 129 patients (20.9%): epithelial to biphasic/sarcomatoid (negative discordance) in 24 and biphasic to epithelial (positive discordance) in 3 (P-value < 0.001). All 24 patients who exhibited epithelial-to-mesenchymal transition (EMT) had received neoadjuvant chemotherapy (P-value: 0.006). In the 34 patients who underwent upfront surgery, only 1 case (2.9%) of EMT was identified (P-value: 0.127). EMT was not associated with a less invasive method of biopsy (P-value: 0.058) or with the volume or maximum diameter of the biopsy (P-value: 0.358 and 0.518, respectively), but it was significantly associated with the receipt of neoadjuvant chemotherapy (P-value: 0.006). At a median follow-up of 17 months (IQR: 11.0-28.0), 50 (39%) patients are still alive. Overall survival was significantly reduced in those patients who received neoadjuvant chemotherapy and who exhibited discordance (EMT) compared to those who did not: 11 (95% CI: 6.2-15.8) months versus 19 (95% CI: 14.2-23.8) months (P-value < 0.001). In addition, there was no difference in overall survival between those who received neoadjuvant chemotherapy and those who had upfront surgery: 16 (95% CI: 2.5-19.5) months versus 30 (95% CI: 11.6-48.4) months (P-value: 0.203).

Conclusions: The association of neoadjuvant chemotherapy with perioperative histological discordance can be explained by EMT, which leads to worse survival. Therefore, there is an argument for the preferential use of upfront surgery in the treatment of otherwise resectable MPM.

© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.

In plain English

This study reviewed 129 patients with malignant pleural mesothelioma who had pleurectomy/decortication or extended pleurectomy/decortication by one London surgeon, 2017 to 2021. The article did not examine asbestos exposure. Tumour cell type on the pre-surgery biopsy differed from that in the removed tumour in 27 of 129 patients (20.9%), in 24 (18.6%) shifting from epithelioid toward biphasic or sarcomatoid. The article reports this shift in 24 of 93 (25.8%) chemotherapy-first patients, a group it elsewhere numbers 95, and in 1 of 34 surgery-first patients, counts exceeding its total of 24. Biopsy method, size and volume were not significantly linked to the mismatch. Chemotherapy-first patients whose tumours shifted had overall survival of 11 months (95% CI 6.2–15.8) from diagnosis, against 19 months (95% CI 14.2–23.8) for those whose did not (p less than 0.001). Survival after chemotherapy first, 16 months (95% CI 12.5–19.5), and surgery first, 30 months (95% CI 11.6–48.4), was not significantly different (p 0.203). The authors proposed that chemotherapy might cause the shift, and suggested considering surgery first for early-stage resectable epithelial disease pending randomized trials.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective single-institution analysis of surgical patients, registered as a clinical audit; slides were reviewed again after the fact by 2 pathologists
• Who was studied: 129 patients (108 male, 21 female; median age 68.0, IQR 63.0–73.0) who had radical surgery for malignant pleural mesothelioma at Barts Thorax Centre, St Bartholomew's Hospital, London, January 2017 to December 2021. They were referred from 49 centres, with biopsies reported by 46 pathology centres.
• Exposure: Not asbestos: the factor studied was neoadjuvant platinum/pemetrexed chemotherapy given before surgery (95 patients, median 2 cycles), compared with upfront surgery followed by adjuvant chemotherapy (34 patients)
• Main results:
  • In all 129 patients, the cell type in the resection specimen differed from the biopsy in 27 (20.9%)
  • Among all 129 patients, 24 (18.6%) had negative discordance (from epithelioid on biopsy toward biphasic or sarcomatoid after resection) and 3 (2.3%) had positive discordance
  • In patients given neoadjuvant chemotherapy, the article reports negative discordance in 24 of 93 (25.8%) and positive discordance in 2 of 93 (2.15%) (P 0.006). The article elsewhere numbers this group as 95, and its Table 4 totals 95.
  • In patients who had upfront surgery, 1 case (2.8%) of epithelial-to-mesenchymal transition was reported (P 0.127). Added to the 24 in the chemotherapy group, this gives more than the 24 negative-discordance cases the article reports overall.
  • Discordance was not significantly linked to biopsy method (P 0.058), and biopsy diameter and volume did not differ between the discordant and concordant groups
  • At a median follow-up of 17 months, 50 patients (39%) were alive
  • Among patients given neoadjuvant chemotherapy, overall survival from diagnosis was 11 months (95% CI 6.2–15.8) for those with discordance, against 19 months (95% CI 14.2–23.8) for those without (P less than 0.001)
  • Overall survival did not differ significantly between neoadjuvant chemotherapy (16 months, 95% CI 12.5–19.5) and upfront surgery (30 months, 95% CI 11.6–48.4) (P 0.203)
  • Survival was shorter when the resected tumour had more than 20% sarcomatoid component: 12 months (95% CI 8.7–15.3) versus 18 months (95% CI 13.6–22.4) (P 0.007)
  • After adjusting for other factors, discordance was associated with worse overall survival than concordance (HR 2.130; 95% CI 1.210–3.747; P 0.009)
• The authors' conclusion: The authors hypothesized that platinum chemotherapy may induce epithelial-to-mesenchymal transition, shifting tumours toward sarcomatoid cell types. They called for multiple, multi-site biopsies and for considering re-biopsy after chemotherapy. They concluded that upfront pleurectomy/decortication should be considered for early-stage (T1/T2N0M0) resectable epithelial disease while randomized trial results are pending.
• Limitations the authors state:
  • Only limited data on the comparative volumes of diagnostic tissue
  • Biopsies came from many hospitals, and there was no independent quality-control review of the histological data
  • Biopsy reports came from many pathologists who were potentially less experienced than those who reported the resection specimens
  • The decision to give neoadjuvant treatment was made by referring centres, which could cause selection bias
  • The number of sites from which biopsy material was taken was not recorded

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleurectomy/Decortication (P/D), Neoadjuvant Therapy, Pleural Mesothelioma, Biphasic Mesothelioma, Sarcomatoid, P-Value, Biopsy.

Related studies

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• Mesothelin promotes epithelial-to-mesenchymal transition and tumorigenicity of human lung cancer and mesothelioma cells — X. He, L. Wang, et al. (2017)
• Multi-walled carbon nanotubes directly induce epithelial-mesenchymal transition in human bronchial epithelial cells via the TGF-β-mediated Akt/GSK-3β/SNAIL-1 signalling pathway — M. Polimeni, G.R. Gulino, et al. (2016)
• FGF2 and EGF induce epithelial-mesenchymal transition in malignant pleural mesothelioma cells via a MAPKinase/MMP1 signal — K. Schelch, C. Wagner, et al. (2018)
• Epithelial to Mesenchymal Transition in Human Mesothelial Cells Exposed to Asbestos Fibers: Role of TGF-β as Mediator of Malignant Mesothelioma Development or Metastasis via EMT Event — S. Turini, L. Bergandi, et al. (2019)
• Blockage of epithelial to mesenchymal transition and upregulation of let 7b are critically involved in ursolic acid induced apoptosis in malignant mesothelioma cell — E.J. Sohn, G. Won, et al. (2016)

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