Intra-tumoral genomic heterogeneity is a well-established biologic property of human malignancies with emerging roles in cancer progression and therapy resistance. However, its impact on the clinical utility of genomic testing in patient management remains unclear. Furthermore, best practices to account for heterogeneity in the provision of highly accurate, clinically valid molecular testing have yet to be firmly established. Genomic biomarkers for the management of colorectal carcinoma are both well-established (ie, KRAS, NRAS) and emerging (BRAF, PIK3CA, and others) in respect to therapy selection and clinical trial eligibility. Critically, standard colorectal carcinoma management requires the exclusion of KRAS and NRAS mutations; thus optimal procedures to control for potential intra-tumoral heterogeneity are clinically important. Here, we assessed heterogeneity among three intra-tumoral sites within 99 colorectal carcinomas cases on a CLIA-validated oncology next generation sequencing assay and examined whether a pooling strategy overcame any discordant results. Overall, 11% of cases demonstrated discordant mutation results between sites; 2% of cases were discrepant for mutations within RAS genes while the remainder was discrepant in PIK3CA. Half of the discrepant cases were associated with borderline tumor cellularity assessment. Further, a sample pooling strategy across all three sites successfully detected the relevant mutation in all but one case. Our results indicate that intra-tumoral genomic heterogeneity of clinically relevant genes within colorectal carcinoma is a relatively infrequent occurrence and that a simple strategy to pool DNA from several tumor sites with adequate cellularity minimizes the risk of false negative results even further to ensure optimal patient management.
A 34-year-old male with a history of T cell-rich B-cell lymphoma relapsed 1 year after high-dose therapy with recurrent fevers, abdominal pain, and jaundice. He was cachetic with hepatosplenomegaly and ascites. Laboratory findings showed a white blood cell count of 2.7 ϫ 10 9 /L, hemoglobin 8.7 g/dL, platelets of 21 ϫ 10 9 /L, hyperbilirubinemia, and no evidence of hemolysis including a negative Coombs test. Bone marrow examination revealed marked hypercellularity and affirmed recurrent lymphoma (occupying 30%-40% of marrow). In addition, there was dysplasia of red cell precursors (panel A) and phagocytosis of bone marrow elements by lymphohistiocytes (panel B). A diagnosis of hemophagocytic lymphohistiocytosis (HLH) was made. Laboratory data consistent with HLH included albumin of 1.7 gm/dL, fibrinogen 65 mg/dL, ferritin Ͼ 15 000 ng/mL, and soluble IL-2 receptor Ͼ 6500 units/mL. The relapsed lymphoma was successfully treated with salvage therapy. A repeat bone marrow examination showed no lymphoma, normal hematopoiesis, an absence of dysplasia, and no phagocytosis. Several months later the patient relapsed and died.HLH can be familial or associated with viral infections, autoimmune disorders, and some malignancies. Treatment of the underlying disorder may reverse HLH, as was true in this case. The appearance of HLH with lymphoma is rare and often associated with a poor outcome.For additional images, visit the ASH IMAGE BANK, a reference and teaching tool that is continually updated with new atlas and case study images. For more information visit
Cytopenia is a common finding in hepatitis C patients. Hypersplenism or LT has an adverse impact on some blood cell counts. Lastly, hepatitis C patients present with a wide spectrum of BM findings including malignant neoplasms, which indicates a diagnostic value of BM examination in these patients.
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