Optimal detection of clinically relevant mutations in colorectal carcinoma: sample pooling overcomes intra-tumoral heterogeneity.

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.

Low grade B cell lymphoma arising in a background of multifocal extra-adrenal myelolipoma.

Myelolipomas are rare, benign, non-functioning tumors composed of an admixture of mature adipose tissue and hematopoietic elements. Extra-adrenal myelolipomas are extremely rare, but have been reported in multiple sites including the omentum, presacral, and retroperitoneal areas, along with the thorax, kidneys, liver and stomach. We report a case of a 68-year-old man with low-grade B-cell lymphoma arising in a background of recurrent multifocal extra-adrenal myelolipoma. Pathological evaluation of the lesion and bone marrow showed foci of lymphoid aggregate that were confirmed to be monoclonal B lymphoma by flow cytometry. To our knowledge, this is only the third reported case to feature such a rare combination of diseases. The clinical, radiological, and pathological differential diagnostic findings are discussed.

Lymphomatoid granulomatosis: a case report with unique clinical and histopathologic features.

Lymphomatoid granulomatosis is a rare lymphoproliferative disorder composed of rare-to-abundant atypical Epstein Barr virus infected B-cells admixed with numerous reactive T-cells. We report a case of a 42 year-old man presenting with fevers of unknown origin and acute renal failure. CT scan demonstrated lung opacities which progressed to numerous nodules throughout both lungs without any cavitations. Wedge lung biopsy showed nodular polymorphous mononuclear infiltrates containing scattered atypical large Epstein Barr virus positive B-cells consistent with lymphomatoid granulomatosis. The patient responded to chemotherapy, but later underwent relapse and transformation to diffuse large B-cell lymphoma. The clinical and histological features of lymphomatoid granulomatosis and differential diagnoses as related to this case are discussed.