Citations

Abstract The PAX8/PPARγ (PPFP) fusion-oncogene is moderately specific for follicular thyroid carcinomas (FTC). It remains unknown whether this can be translated into improved diagnosis, classification, or outcome prediction. We studied a cohort of well-characterized follicular adenomas (FA), FTC, and Hürthle cell carcinomas (HCC) from patients with complete clinical follow-up, to determine whether PPARγ immunohistochemistry (as a surrogate of PAX8/PPARγ expression) helps to distinguish FA from FTC and to assess its diagnostic accuracy as an adjunct to frozen section. We also correlated PPARγ staining with clinical outcomes to assess its role as a prognostic marker. PPARγ staining was more common in FTC (31 of 54; 57%) than in HCC (one of 23; 4%) or FA (four of 31; 13%) (P < 0.000001). Adjunctive use of PPARγ immunohistochemistry improved diagnostic sensitivity of intraoperative frozen section from 84% to 96% (P < 0.05) but reduced specificity from 100% to 90% (P < 0.05). PPARγ staining was associated with favorable prognostic indicators (female gender, better tumor differentiation, and lesser risk of metastases). PPARγ staining may be helpful in the differential diagnosis of FA, FTC, and HCC, particularly when diagnostic sensitivity of histomorphology is reduced (e.g. during intraoperative frozen section). PPARγ staining also shows an association with favorable prognosis and may have a role in risk stratification.

Lymphoplasmacytic lymphoma (LPL) is characterized by t(9;14)(p13;q32) in 50% of patients who lack paraproteinemia. Waldenström macroglobulinemia (WM), which has an immunoglobulin M (IgM) paraproteinemia, is classified as an LPL. Rare reports have suggested that WM sometimes is associated with 14q23 translocations, deletions of 6q, and t(11;18)(q21;q21). We tested for these abnormalities in the clonal cells of WM patients. We selected patients with clinicopathologic diagnosis of WM (all had IgM levels greater than 1.5 g/dL). Southern blot assay was used to detect legitimate and illegitimate IgH switch rearrangements. In addition to conventional cytogenetic (CC) and multicolor metaphase fluorescence in situ hybridization (M-FISH) analyses, we used interphase FISH to screen for t(9;14)(p13;q32) and other IgH translocations, t(11;18)(q21;q21), and 6q21 deletions. Genomic stability was also assessed using chromosome enumeration probes for chromosomes 7, 9, 11, 12, 15, and 17 in 15 patients. There was no evidence of either legitimate or illegitimate IgH rearrangements by Southern blot assay (n = 12). CC (n = 37), M-FISH (n = 5), and interphase FISH (n = 42) failed to identify IgH or t(11;18) translocations. Although tumor cells from most patients were diploid for the chromosomes studied, deletions of 6q21 were observed in 42% of patients. In contrast to LPL tumors that are not associated with paraproteinemia and that have frequent t(9;14)(p13;q32) translocations, IgH translocations are not found in WM, a form of LPL tumor distinguished by IgM paraproteinemia. However, WM tumor cells, which appear to be diploid or near diploid, often have deletions of 6q21.

Translocations involving c -myc and an Ig locus have been reported rarely in human multiple myeloma (MM). Using specific fluorescence in situ hybridization probes, we show complex karyotypic abnormalities of the c -myc or L -myc locus in 19 of 20 MM cell lines and approximately 50% of advanced primary MM tumors. These abnormalities include unusual and complex translocations and insertions that often juxtapose myc with an IgH or IgL locus. For two advanced primary MM tumors, some tumor cells contain a karyotypic abnormality of the c -myc locus, whereas other tumor cells do not, indicating that this karyotypic abnormality of c -myc occurs as a late event. All informative MM cell lines show monoallelic expression of c -myc . For Burkitt's lymphoma and mouse plasmacytoma tumors, balanced translocation that juxtaposes c -myc with one of the Ig loci is an early, invariant event that is mediated by B cell-specific DNA modification mechanisms. By contrast, for MM, dysregulation of c -myc apparently is caused principally by complex genomic rearrangements that occur during late stages of MM progression and do not involve B cell-specific DNA modification mechanisms.