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

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.

Heterogeneity in Malignant Pleural Mesothelioma

“…Histologically, temporal and spatial intra-tumor heterogeneity in MPM manifests with a morphological spectrum, ranging from epithelioid to sarcomatoid tumors with the biphasic subtype containing a combination of both epithelioid and sarcomatoid components, each constituting at least 10% of the tumor. Adding to the complexity of histological subtyping, morphological biomarkers in epithelioid MPM, including nuclear atypia and number of mitoses, have been used to determine a total score which independently correlates with overall survival [ 10 ]. This further supports the existence of tumor heterogeneity, even within morphological well-defined subgroups of MPM.…”

Genomic Deletion of BAP1 and CDKN2A Are Useful Markers for Quality Control of Malignant Pleural Mesothelioma (MPM) Primary Cultures

“…The biphasic histological subtype consists of epithelioid and sarcomatoid components, with each contributing to at least 10% of the tumor. Further, histomorphological features such as mitotic numbers and nuclear atypia have been included to conclude a total score [ 31 ]. This heterogeneity within morphological subgroups further adds to the complexity of the definitive identification of MPM [ 32 ].…”

Pleura revisited: From histology and pathophysiology to pathology and molecular biology

“…Apart from this gross distinction, detailed morphological aspects of the epithelioid type also have prognostic significance although their report is not yet recommended by WHO. Applying a nuclear grade and also evaluating necrosis in epithelioid mesothelioma gives a stratification of survival as follows: 29 months for nuclear grade I tumours without necrosis, 16 months for nuclear grade I tumours with necrosis and grade II tumours without necrosis, and 8‐10 months for nuclear grade II tumours with necrosis and nuclear grade III tumours …”