Rodríguez-Pinilla, Socorro Marıá

Large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4) predominantly affects children and young adults (CAYA) and presents as localized disease with excellent prognosis. Although most tumors harbor IRF4 rearrangements (IRF4-R), the existence of cryptic rearrangements has been suggested. Whether IRF4-R LBCL in adults represents the same biological entity remains unclear. To address this question, 35 CAYA patients diagnosed with LBCL-IRF4 and 7 adult (>40-year-old) LBCL with IRF4-R were investigated by an integrative molecular approach. Targeted sequencing structural variant analysis (SV-NGS) confirmed the IRF4-R in 84% of investigated cases. In CAYA, an enrichment (55% vs 29% in adults) of translocations involving IGH, with a breakpoint cluster 3' to IRF4 (EXOC2) was observed, including a cryptic insertion of IGHM-IGHJ5 into IRF4 locus. Novel translocations, IRF4::MIR142 in two CAYA (7%) and IRF4::BATF in one adult, were discovered. Whole-exome sequencing analysis identified unreported mutations in LBCL-IRF4 as YY1 and ZC3H12A (11% each). The high incidence of mutations affecting the B-cell receptor/NF-KB pathways in LBCL-IRF4 was confirmed in cases with diffuse component only. None of the CAYA tumors were classified by LymphGen tool. Adult IRF4-R LBCL showed higher levels of genetic complexity and a distinct mutational profile with mutations on KMT2D and DTX1 (43% each), and MYD88-L265P (29%), and were predicted as EZB or MCD (29% each). These differential genetic features were in line with different clinical presentations (extranodal involvement and advanced stage). In conclusion, IRF4-R architecture and mutational profile differ according to age, supporting that not all cases should be classified as LBCL-IRF4.

ABSTRACTBackgroundPrimary cutaneous anaplastic large cell lymphoma (pcALCL) and lymphomatoid papulosis (LyP) are indolent CD30‐positive lymphoproliferative disorders that rarely express TCR‐γδ. However, primary cutaneous gamma‐delta T‐cell lymphoma (pcGDTCL), characterized by TCR‐γδ expression on neoplastic cells, is a rare, aggressive cutaneous T‐cell lymphoma with a poor prognosis. Accurate differentiation is essential due to distinct clinical behavior and treatment.MethodsWe identified 11 TCR‐γδ‐positive pcALCL cases from internal and consultation files, verified by two cutaneous lymphoma experts, with clinicopathologic data recorded.ResultsThe median age was 68 years (range 38–95). Most cases presented as a single dermal lesion on the upper extremities. All were ALK‐negative, CD30‐positive (> 90% tumor cells), TCR‐βF1‐negative, and diffusely TCR‐γδ‐positive. CD4−/CD8− (54.5%) and CD4+/CD8− (45.5%) immunophenotypes were observed. CD2 (63.6%) and CD3 (54.5%) were the most common T‐cell antigens. Ulceration, inflammation (both 45.5%), and necrosis (36.4%) were frequent. Angiotropism, angiocentricity, and myxoid stroma appeared in one case; epidermotropism in two. Four of ten tested were DUSP22‐rearranged, and TP63 was negative in all eight tested.ConclusionsMost ALK‐negative TCR‐γδ‐positive pcALCL were CD4−/CD8−, followed by CD4+/CD8−. DUSP22 rearrangement occurred in 40% of cases, similar to reports in typical pcALCL. Its prognosis and the role of DUSP22 are yet to be clarified.

Lymphomatoid papulosis (LyP) has several histopathologic presentations. LyP featuring gamma-delta (γδ) T-cell receptor expression may masquerade as and may be misdiagnosed as aggressive cutaneous T-cell lymphoma, particularly primary cutaneous γδ T-cell lymphoma (PCGDTL) or γδ mycosis fungoides. We performed a clinicopathologic analysis of the largest series of LyP featuring γδ T-cell expression. We identified 26 patients with a diagnosis of LyP with γδ T cells from our institutions, as well as through a comprehensive review of the literature, and characterized these cases. Most cases were treated with topical steroids or not treated at all. The majority of cases showed a CD4-CD8+ phenotype and featured at least one cytotoxic marker. Histopathologic features included an intraepidermal or dermal infiltrate with large cells and frequent angiotropism. One case was initially misdiagnosed as PCGDTL, requiring further therapy. Our case series, the largest international cohort of γδ T cell predominant LyP cases, confirms marked clinicopathologic heterogeneity that may contribute to misdiagnosis, reasserting the need to identify classic clinical features, CD30+ T-cell components, and markers of cytotoxicity when dealing with this differential diagnosis. A limitation of this study includes somewhat limited follow-up, histologic, and immunophenotypic information for some cases.