Nuclear grade and necrosis predict prognosis in malignant epithelioid pleural mesothelioma: a multi-institutional study

Our plain-English summary of Nuclear grade and necrosis predict prognosis in malignant epithelioid pleural mesothelioma: a multi-institutional study, by L.E. Rosen, T. Karrison, V. Ananthanarayanan, et al (Modern Pathology, 2018).

The study

• Authors: L.E. Rosen, T. Karrison, V. Ananthanarayanan, A.J. Gallan, P.S. Adusumilli, F.S. Alchami, R. Attanoos, L. Brcic, K.J. Butnor, F. Galateau-Sallé, K. Hiroshima, K. Kadota, A. Klampatsa, N.L. Stang, J. Lindenmann, L.A. Litzky, A. Marchevsky, F. Medeiros, M.A. Montero, D.A. Moore, K. Nabeshima, E.N. Pavlisko, V.L. Roggli, J.L. Sauter, A. Sharma, M. Sheaff, W.D. Travis, W.T. Vigneswaran, B. Vrugt, A.E. Walts, M.Y. Tjota, T. Krausz, A.N. Husain
• Journal: Modern Pathology
• Published: 2018;31(4):598-606
• Cited by: 85 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

A recently described nuclear grading system predicted survival in patients with epithelioid malignant pleural mesothelioma. The current study was undertaken to validate the grading system and to identify additional prognostic factors. We analyzed cases of epithelioid malignant pleural mesothelioma from 17 institutions across the globe from 1998 to 2014. Nuclear grade was computed combining nuclear atypia and mitotic count into a grade of I-III using the published system. Nuclear grade was assessed by one pathologist for three institutions, the remaining were scored independently. The presence or absence of necrosis and predominant growth pattern were also evaluated. Two additional scoring systems were evaluated, one combining nuclear grade and necrosis and the other mitotic count and necrosis. Median overall survival was the primary endpoint. A total of 776 cases were identified including 301 (39%) nuclear grade I tumors, 354 (45%) grade II tumors and 121 (16%) grade III tumors. The overall survival was 16 months, and correlated independently with age (P=0.006), sex (0.015), necrosis (0.030), mitotic count (0.001), nuclear atypia (0.009), nuclear grade (<0.0001), and mitosis and necrosis score (<0.0001). The addition of necrosis to nuclear grade further stratified overall survival, allowing classification of epithelioid malignant pleural mesothelioma into four distinct prognostic groups: nuclear grade I tumors without necrosis (29 months), nuclear grade I tumors with necrosis and grade II tumors without necrosis (16 months), nuclear grade II tumors with necrosis (10 months) and nuclear grade III tumors (8 months). The mitosis-necrosis score stratified patients by survival, but not as well as the combination of necrosis and nuclear grade. This study confirms that nuclear grade predicts survival in epithelioid malignant pleural mesothelioma, identifies necrosis as factor that further stratifies overall survival, and validates the grading system across multiple institutions and among both biopsy and resection specimens. An alternative scoring system, the mitosis-necrosis score is also proposed.

In plain English

This retrospective study tested a published nuclear grading system for epithelioid malignant pleural mesothelioma, a cancer of the pleura (the lining around the lungs), using cases from 17 institutions worldwide. It included 776 patients diagnosed between 1998 and 2014. 79% were male and the mean age was 65. Tumor slides were scored for nuclear atypia and mitotic count, which were combined into grades I to III. They were also scored for necrosis (dead tumor tissue) and growth pattern. The study did not examine asbestos exposure. Median overall survival was 16 months: 27 months for grade I tumors, 14 for grade II and 8 for grade III. With necrosis the median was 10 months, against 19 without. Combining grade and necrosis gave four groups: grade I without necrosis (29 months), grade I with necrosis or grade II without necrosis (16 months), grade II with necrosis (10 months) and grade III (8 months). A mitosis–necrosis score also separated patients, but less well. The authors concluded that nuclear grade and necrosis predict survival. They noted that the analysis was retrospective and did not measure agreement between pathologists.

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 multi-institutional study of pathology slides and survival data. Survival was analyzed with Kaplan–Meier curves and Cox regression.
• Who was studied: 776 patients with epithelioid malignant pleural mesothelioma diagnosed between 1998 and 2014 at 17 institutions worldwide (1 to 170 cases per institution). Mean age was 65 years (range 29 to 91). 611 (79%) were male.
• Exposure: Asbestos exposure was not studied. The factors examined were tumor features seen under the microscope: nuclear atypia, mitotic count, the combined nuclear grade (I to III), necrosis and a predominantly solid growth pattern.
• Main results:
  • Median overall survival for all 776 patients was 16 months (95% CI 15.0 to 17.5).
  • Of the 776 tumors, 301 (39%) were nuclear grade I, 354 (45%) grade II and 121 (16%) grade III. Median overall survival was 8 months for grade III, 14 months for grade II and 27 months for grade I.
  • Necrosis was present in 235 (30%) cases. Patients whose tumors had necrosis had a median overall survival of 10 months, against 19 months without necrosis (HR 1.85, CI 1.57 to 2.17).
  • Within grade II tumors, patients with necrosis had a median survival of 10 months, against 16 months without (HR 1.42, 95% CI 1.13 to 1.78, P = 0.002). Within grade I tumors, the difference with and without necrosis (16 vs 29 months, HR 1.51, 95% CI 0.96 to 2.39, P = 0.076) was described as marginally significant.
  • Combining nuclear grade and necrosis gave four prognostic groups by median overall survival: grade I without necrosis (29 months); grade I with necrosis or grade II without necrosis (16 months); grade II with necrosis (10 months); grade III (8 months).
  • In multivariate analysis, nuclear grade, necrosis, age and sex were each significantly associated with overall survival. For necrosis present versus absent, HR was 1.23 (95% CI 1.02 to 1.48, P = 0.030).
  • A predominantly solid growth pattern was linked to shorter median survival on univariate analysis (12 vs 19 months). After adjustment, neither solid growth pattern nor type of surgery was independently associated with survival.
  • The mitosis–necrosis score separated patients by median overall survival: 22 months for score 0 (n = 299), 14 months for score I (n = 149) and 10 months for score II (n = 98). This separated patients less strongly than nuclear grade combined with necrosis.
  • After controlling for nuclear grade, age and sex, post-operative chemotherapy was associated with improved survival (HR 0.57, 95% CI 0.46 to 0.69). Pre-operative chemotherapy was not (HR 0.87, 95% CI 0.69 to 1.07, P = 0.18).
  • On univariate analysis, the mortality rate was 33% higher in males than in females (HR 1.33, 95% CI 1.10 to 1.60).
• The authors' conclusion: The authors concluded that nuclear grade and necrosis predict overall survival in epithelioid malignant pleural mesothelioma, and that adding necrosis to nuclear grade separates survival further. They proposed the mitosis–necrosis score as an alternative that is not as robust but still stratifies patients. They stated that both systems can be applied to biopsy and resection specimens.
• Limitations the authors state:
  • The analysis was retrospective, and agreement between pathologists in grading (interobserver variability) was not analyzed.
  • Type of surgery was not randomized, so survival differences between procedures may be confounded by other factors.
  • Staging information (T stage and N status) was incomplete and was not analyzed. Patients who had biopsy alone may have had more advanced disease than those who had resection.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Nuclear Grade, Necrosis, Prognosis, Epithelioid, Pleural Mesothelioma, Nuclear Grading, Nuclear Atypia, Mitotic Count.

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