Dissecting and Reconstructing Matrix in Malignant Mesothelioma Through Histocell-Histochemistry Gradients for Clinical Applications

Our plain-English summary of Dissecting and Reconstructing Matrix in Malignant Mesothelioma Through Histocell-Histochemistry Gradients for Clinical Applications, by M.L. Balancin, C.M. Baldavira, T.G. Prieto, et al (Frontiers in Medicine, 2022).

The study

• Authors: M.L. Balancin, C.M. Baldavira, T.G. Prieto, J. Machado-Rugolo, C. Farhat, A.K. Assato, A.P.P. Velosa, W.R. Teodoro, A.M. Ab'Saber, T.Y. Takagaki, V.L. Capelozzi
• Journal: Frontiers in Medicine
• Published: 2022;9:871202
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesotheliomas (MM) are known for their heterogenous histology and clinical behavior. MM histology reveals three major tumor cell populations: epithelioid, sarcomatoid, and biphasic. Using a dissecting approach, we showed that histochemical gradients help us better understand tumor heterogeneity and reconsider its histologic classifications. We also showed that this method to characterize MM tumor cell populations provides a better understanding of the underlying mechanisms for invasion and disease progression.

Methods: In a cohort of 87 patients with surgically excised MM, we used hematoxylin and eosin to characterize tumor cell populations and Movat's pentachrome staining to dissect the ECM matrisome. Next, we developed a computerized semi-assisted protocol to quantify and reconstruct the ECM in 3D and examined the clinical association between the matricellular factors and patient outcome.

Results: Epithelioid cells had a higher matrix composition of elastin and fibrin, whereas, in the sarcomatoid type, hyaluronic acid and total collagen were most prevalent. The 3D reconstruction exposed the collagen I and III that form channels surrounding the neoplastic cell blocks. The estimated volume of the two collagen fractions was 14% of the total volume, consistent with the median estimated area of total collagen (12.05 mm2) for epithelioid MM.

Conclusion: Differential patterns in matricellular phenotypes in MM could be used in translational studies to improve patient outcome. More importantly, our data raise the possibility that cancer cells can use the matrisome for disease expansion and could be effectively targeted by anti-collagen, anti-elastin, and/or anti-hyaluronic acid therapies.

Copyright © 2022 Balancin, Baldavira, Prieto, Machado-Rugolo, Farhat, Assato, Velosa, Teodoro, Ab'Saber, Takagaki and Capelozzi.

In plain English

This retrospective study examined archived tumor tissue from 87 patients with malignant mesothelioma treated between 2008 and 2018 in São Paulo, Brazil. The article calls them surgically excised, but lists surgery for only 62 (71.3%). About half (44 patients, 50.6%) were recorded as exposed to asbestos. That exposure was inferred indirectly, and findings were not analyzed by asbestos exposure. The authors measured the material surrounding tumor cells (the extracellular matrix) with staining and computer-assisted image analysis. Epithelioid tumor areas had more cells, elastin and fibrin. Sarcomatoid areas had more hyaluronic acid and total collagen. A 3D reconstruction of one tissue block showed collagen types I and III forming channels around tumor cell clusters. Grouping patients by these measurements produced three clusters. One, of 13 patients, had an odds ratio of 3.462 (95% confidence interval 1.115 to 10.746) for what the authors called better overall response than the largest cluster. Parts of the survival reporting are contradictory. The authors concluded that tumor cells may use the matrix to spread and that anti-collagen, anti-elastin or anti-hyaluronic acid therapies could target it.

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 study of archived tumor tissue (tissue microarrays), using histochemical staining, computer-assisted image quantification, 3D reconstruction of collagen, cluster analysis and survival analysis
• Who was studied: 87 patients with malignant mesothelioma, selected from 246 cases found by searching for the word 'mesothelioma'. The cases were treated between 2008 and 2018 at three institutions of the Hospital das Clínicas complex, University of São Paulo, Brazil. Median age was 60, 59 (67.8%) were male, and all were stage III/IV. The article describes the cohort as surgically excised, but reports that 71.3% (62 patients) had undergone surgical resection. The methods mention that extrapleural cases were staged separately, but their number is not given.
• Exposure: Asbestos exposure was recorded for 44 of 87 patients (50.6%) and absent for 43 (49.4%). It was inferred from indirect data such as residential location and employment history, plus online searches for litigation or links to former asbestos-industry worker groups. No fiber types, products or doses are given. The measured factors were tumor cellularity and matrix components (hyaluronic acid, fibrin, elastin, total collagen).
• Main results:
  • Compared with sarcomatoid areas, epithelioid tumor areas had higher cell density (71.14 vs 53.22 mean cells per mm2, P = 0.0001), elastin (6.08 vs 2.30 area fraction per mm2, P = 0.0001) and fibrin (4.13 vs 1.29, P = 0.0001).
  • Sarcomatoid tumor areas had more hyaluronic acid (10.73 vs 6.57 area fraction per mm2, P = 0.05) and total collagen (32.71 vs 12.05, P = 0.0001) than epithelioid areas.
  • In the 3D reconstruction of one chosen tissue block, collagen types I and III made up an estimated 14% of the total volume and formed channels around blocks of tumor cells.
  • Cluster analysis of the five tissue measurements divided patients into three groups. Cluster 1 (24 patients) coincided with sarcomatoid histology, cluster 2 (13 patients) was suggested to be biphasic, and cluster 3 (50 patients) coincided with epithelioid histology.
  • In logistic regression with cluster 3 as the reference group, cluster 2 had an odds ratio of 3.462 (95% CI 1.115 to 10.746, P = 0.032) for what the authors called better overall response. Cluster 1 did not differ significantly from cluster 3 (odds ratio 1.154, 95% CI 0.302 to 4.406, significance 0.834).
  • The authors reported that the clusters separated patients into groups with different survival times on Kaplan-Meier curves (log-rank P less than 0.01).
  • Cluster analysis identified three different subsets within mesotheliomas classified as epithelioid by histology alone (chi-square P = 0.02).
  • BAP1 protein was positive in 17 (22%) epithelioid-sarcomatoid and 3 (3.9%) epithelioid cases. The comparison with clusters was not statistically significant (P = 0.48).
• The authors' conclusion: The authors concluded that different matrix patterns in malignant mesothelioma could be used in translational studies to improve patient outcome. They also said their data raise the possibility that cancer cells use the matrix for disease expansion and could be targeted by anti-collagen, anti-elastin and/or anti-hyaluronic acid therapies.
• Limitations the authors state:
  • Only collagen types that stain with Picrosirius (types I and III) were reconstructed. The method was chosen for its affordability.
  • Tissue samples taken from the same patient differed from one another, and the predominant pattern was used.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Histology, Epithelioid, Sarcomatoid, Biphasic Mesothelioma, Disease Progression, Hyaluronic Acid.

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