Utility of molecular genetic analysis for the diagnosis of neoplasia in morphologically and immunophenotypically equivocal hematolymphoid lesions

The authors reviewed retrospectively the results of molecular genetic analysis of 175 hematolymphoid lesions to assess the diagnostic utility of genotyping (analysis for immunoglobulin or beta‐chain T‐cell receptor gene rearrangements). All cases had been genotyped, and most were also immunophenotyped. Cases were assigned to control (90 cases) or problem groups (85 cases), depending on the absence or presence respectively of diagnostic uncertainty remaining after conventional (morphologic and immunophenotypic) analysis. All control cases had unequivocal morphologic features of non‐Hodgkin's lymphoma (NHL) and had appropriate lineage‐specific gene rearrangements, but immunostaining was almost as sensitive in demonstrating phenotypes that were diagnostically abnormal as well as lineagespecifying. However, genotyping was clearly diagnostically useful in the problem cases, which included a heterogeneous mixture of nodal and extranodal biopsy specimens of malignant (mostly NHL) and benign lesions. Genotyping demonstrated the appropriate absence or presence of gene rearrangements in 58 of 81 problem cases (72%) ultimately diagnosed as benign or malignant respectively, excluding four cases of Hodgkin's disease; in 25 cases (31%) this was judged to be essential to diagnosis. In the remaining problem cases genotyping did not contribute positively to diagnosis, but in no case was genotyping misleading when cautiously interpreted with primary reliance on conventional analysis and with knowledge of known causes of potentially misleading results, both positive and negative. It is concluded that although genotyping is highly sensitive and specific for hematolymphoid neoplasia, it provides little or no benefit in cases that are unequivocally malignant by conventional analysis, in cases of suspected Hodgkin's disease (HD), or for the sole purpose of lineage assignment. However, in cases whose diagnosis is uncertain after conventional analysis, the high yield of useful information from genotyping with careful interpretation warrants its application.