Gray zone lymphoma: chromosomal aberrations with immunophenotypic and clinical correlations

Abstract

The term gray zone lymphoma has been applied to tumors that demonstrate transitional morphologic and immunophenotypic features between classical Hodgkin's lymphoma and diffuse large B-cell lymphoma, especially primary mediastinal large B-cell lymphoma. Histopathological and genetic data are limited for these unusual cases. We analyzed cases of gray zone lymphoma (n=27), mediastinal composite lymphoma (n=3) and mediastinal synchronous/metachronous lymphoma (n=3) by morphology, immunophenotyping and fluorescence in situ hybridization. Mediastinal involvement was assured in 24/33 patients (73%). The patient cohort showed a male predominance (M:F ratio; 20:13) and a median age of 32 years (range, 16-91 years). Patients with mediastinal disease were significantly younger (median age: 29.5 years) than patients presenting without evident mediastinal disease (median age: 55 years). Gains including amplifications in 2p16.1 (REL/BCL11A locus) were observed in 33% of all patients, whereas alterations affecting the JAK2/PDL2 locus in 9p24.1 were present in 55%. Further studies revealed rearrangement of the CIITA locus at 16p13.13 in 8/30 cases (27%) and 7/26 cases (27%) demonstrated gains of 8q24 (MYC). Genetic aberrations involving 2p16.1, 9p24.1 and 8q24 showed a higher incidence in cases with evident mediastinal involvement. However, this was not statistically significant when compared with cases without known mediastinal involvement. Twelve of the 27 cases of gray zone lymphoma were morphologically more reminiscent of classical Hodgkin's lymphoma, whereas the other gray zone lymphomas presented with morphological features more closely resembling large B-cell lymphoma. Both morphological groups of gray zone lymphoma were similarly positive for Cyclin E (75 and 93%) and p63 (50 and 53%, respectively) expression. These findings further support a close relationship between gray zone lymphoma, classical Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma, and suggest that some cases of gray zone lymphoma without mediastinal disease may share similar genetic alterations.

Figure 1

Morphological and immunophenotypic features of gray zone lymphoma. Gray zone lymphoma with morphologic features of classical Hodgkin’s lymphoma and immunophenotypic features of primary mediastinal large B-cell lymphoma (case no. 5; left hand panels). Characteristic Hodgkin–Reed–Sternberg cells in an inflammatory background with numerous eosinophils (H&E) (a). Tumor cells are partially positive for CD30 (b), negative for CD15 (c), and positive for CD20 (d) and Cyclin E (e). Gray zone lymphoma with morphologic features of primary mediastinal large B-cell lymphoma and immunophenotypic features of classical Hodkgin’s lymphoma (case no. 20; right hand panels). Sheets of relatively monomorphic large tumor cells with abundant pale cytoplasm (H&E) (f). Tumor cells are positive for CD30 (g) and CD15 (h), but are negative for CD20 (i) and Cyclin E (j) (original magnification a–j: ×40).

Figure 1

Morphological and immunophenotypic features of gray zone lymphoma. Gray zone lymphoma with morphologic features of classical Hodgkin’s lymphoma and immunophenotypic features of primary mediastinal large B-cell lymphoma (case no. 5; left hand panels). Characteristic Hodgkin–Reed–Sternberg cells in an inflammatory background with numerous eosinophils (H&E) (a). Tumor cells are partially positive for CD30 (b), negative for CD15 (c), and positive for CD20 (d) and Cyclin E (e). Gray zone lymphoma with morphologic features of primary mediastinal large B-cell lymphoma and immunophenotypic features of classical Hodkgin’s lymphoma (case no. 20; right hand panels). Sheets of relatively monomorphic large tumor cells with abundant pale cytoplasm (H&E) (f). Tumor cells are positive for CD30 (g) and CD15 (h), but are negative for CD20 (i) and Cyclin E (j) (original magnification a–j: ×40).

Figure 2

Immunoglobulin gene rearrangement studies for kappa loci in both lymphomas, classical Hodgkin’s lymphoma (a, b) and primary mediastinal large B-cell lymphoma (c, d) of a mediastinal metachronous lymphoma (no. 32). Clonal peaks of identical size were detected in both tube A (a, c) and tube B (b, d) from both specimens examined. Peaks were seen at 144bp in tube A, and 272bp and 278bp in tube B. This result implies a clonal relationship between the classical Hodgkin’s lymphoma and the primary mediastinal large B-cell lymphoma. No significant peaks were detected for the IGH locus (data not shown).

Figure 3

Representative results of interphase FISH analysis for detection of chromosomal imbalances or rearrangements involving the gene loci of REL/BCL11A (2p16) (a) and CIITA (16p13.13) (b) in cases of gray zone lymphoma. Detection of multiple signals indicating amplification of 2p16 (a, yellow arrows, case 18) and detection of red and green break-apart signals indicating a chromosomal breakpoint affecting the CIITA locus in 16p13.13 (b, red arrows, case 27).