Variability in endometrial carcinoma pathology practice: opportunities for improvement with molecular classification.

We assessed the landscape of diagnostic pathology practice and how molecular classification could potentially impact management of patients with endometrial cancer by collecting patient samples, clinicopathologic data, and patient outcomes from EC patients diagnosed in 2016 at 10 Canadian tertiary cancer centers and 19 community hospitals. ProMisE molecular subtype (POLEmut, MMRd, p53abn, No Specific Molecular Profile (NSMP)) was assigned retrospectively. 1357 patients were fully evaluable including 85 POLEmut (6.3%), 380 MMRd (28.0%), 643 NSMP (47.4%), and 249 p53abn ECs (18.3%). Immunohistochemistry (IHC) for MMR proteins was undertaken at the time of primary diagnosis in 2016 in only 42% of the cohort (570/1357; range 3.5-95.4%/center). p53 IHC had only been performed in 21.1% of the cohort (286/1357; range 10.1-41.9%/center). Thus, based on the retrospective molecular subtype assignment, 54.7% (208/380) of MMRd EC had not been tested with MMR IHC (or MSI) and 48.2% (120/249) of p53abn ECs were not tested with p53 IHC in 2016. Molecular subtype diversity within histotypes was profound; most serous carcinomas were p53abn (91.4%), but only 129/249 (51.8%) p53abn EC were serous. Low-grade (Gr1-2) endometrioid carcinomas were mostly NSMP (589/954, 61.7%) but included all molecular subtypes, including p53abn (19/954, 2.0%). Molecular subtype was significantly associated with clinical outcomes (p < 0.001) even in patients with stage I disease (OS p = 0.006, DSS p < 0.001, PFS p < 0.001). Assessment of national pathologic practice in 2016 shows highly variable use of MMR and p53 IHC and demonstrates significant opportunities to improve and standardize biomarker reporting. Inconsistent, non-reflexive IHC resulted in missed opportunities for Hereditary Cancer Program referral and Lynch Syndrome diagnosis, and missed potential therapeutic implications (e.g., chemotherapy in p53abn EC, immune blockade for MMRd EC). Routine integration of molecular subtyping into practice can improve the consistency of EC pathology assessment and classification.

A blinded study of bone marrow examinations in patients with primary immune thrombocytopenia.

OBJECTIVE: The role of bone marrow examinations in patients with primary immune thrombocytopenia (ITP) is uncertain. The objectives of this study were to determine the inter-rater reliability of bone marrow examinations and to identify distinguishing morphological features of ITP bone marrows under controlled conditions. METHODS: Histological slides of bone marrow biopsy specimens and aspirates from 32 adult patients with severe primary ITP who had failed a median of two treatments, and 51 non-thrombocytopenic controls were retrieved from hospital archives. Slides were arranged in random order in a slide box and coded. Blinded to the diagnosis and platelet counts, three independent hematopathologists were asked to identify the ITP bone marrows and to evaluate megakaryocyte number, morphology, and distribution. RESULTS: Overall chance-corrected agreement on ITP classification among the three raters was poor [kappa (κ) = 0.30; 95% confidence interval 0.22-0.38]. Raters were generally unable to correctly identify the ITP bone marrows from controls. Increased number of megakaryocytes, while an uncommon finding, was more frequent among ITP patients compared with controls (6/32, 18.8%; vs. 2/51, 3.9%; P = 0.05), and abnormal megakaryocyte morphology often led individual raters to reach a diagnosis of ITP. Overall sensitivity and specificity of bone marrow examinations were 24% and 90%, respectively. CONCLUSIONS: This study confirms methodologically that bone marrow examinations are unreliable and frequently non-diagnostic in ITP. Thus, they are not useful for patients with typical disease. Rare subsets of patients with severe ITP demonstrated unique features such as increased number of megakaryocytes.