Rodriguez, Erika F.

Abstract Introduction The risk of malignancy (ROM) remains an area of interest for further evaluation in reporting systems including in International System for reporting serous fluid cytopathology (TIS), which is a standardized system for reporting effusion cytology. Herein, we report our findings in further investigation of ROM in TIS by studying on paired pleural effusion specimens and corresponding pleural biopsies with emphasis on negative for malignancy, and atypia of undetermined significance categories. Materials and Methods The Johns Hopkins Hospital pathology database was retrospectively searched for patients with a pleural biopsy (PBX) and a paired pleural effusion (PF) cytology specimens over a 4‐year period. We employed the TIS categories. The following statistical parameters were evaluated: sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and ROM. Results A total of 223 patient cases were included. Effusions TIS reclassification and ROM were as follows: 1.8% non‐diagnostic (ROM 75%), 75.8% negative for malignancy (ROM 23%), 4.9% atypical cells of undetermined significance (ROM 45%), 2.2% suspicious for malignancy (ROM 80%), and 15.2% malignant (ROM 100%). Overall accuracy, sensitivity, specificity, PPV and NPV were calculated and were 79.4%, 45%, 97.7%, 91.2% and 77%, respectively. Among, discordant cases diagnosed negative for malignancy on PF and positive for malignancy on PBX, there were significant number of lymphomas, mesotheliomas, and sarcomas. Lung cancer was the most common carcinoma; however, rare types of carcinomas were noted. Cells blocks and immunohistochemistry (IHC) studies were utilized to confirm either malignant conditions or rule out malignancy in both cell blocks and histology biopsies. Conclusion This study demonstrates the high specificity and ROM for ‘malignant’ and ‘suspicious for malignancy’ categories in the TIS reporting system and highlights the modest negative predictive value for the ‘negative for malignancy’ category. Although Tissue biopsies are usually considered as ‘gold standard’, any definitive diagnosis of malignancy of body fluid should be considered positive for malignancy in further clinical decision‐making.

Abstract Objectives To demonstrate clinicopathologic features and evaluate the clonality of double PIK3CA alterations in colorectal cancers (CRCs). Methods Clonality was examined in 13 CRCs with double PIK3CA alterations (1.7% of CRCs or 9.6% of PIK3CA-mutated CRCs). Multiregional analyses were performed to confirm subclonal PIK3CA alterations. Results PIK3CA alterations were detected within exon 9 (51%), exon 20 (23%), exon 1 (15%), and exon 7 (6.0%). CRCs with exon 7 alterations showed a significantly higher incidence of double PIK3CA alterations. Most double PIK3CA alterations consisted of a hotpsot alteration and an uncommon alteration; they were often clonal and present within a single tumor population. Multiregional analyses of CRCs with predicted subclonal double-alterations revealed multiclonal CRCs with divergent PIK3CA variant status originating from a common APC- and KRAS-mutated founder lineage of adenoma. Conclusions The findings supported multiclonal CRCs resulting from parallel evolution during the progression from adenoma to adenocarcinoma within the mitogen-activated protein kinase pathway, as previously demonstrated, or the mammalian target of rapamycin pathway. Further studies are warranted to elucidate clinical significance and potential targeted therapy for CRC patients with double PIK3CA alterations and impacts on clinical decision-making in patients with multiclonal CRCs harboring divergent PIK3CA mutational status.