Histiocytic/Dendritic Cell Transformation of B-Cell Neoplasms: Pathologic Evidence of Lineage Conversion in Differentiated Hematolymphoid Malignancies

Abstract

B-cell lymphomas, such as low-grade follicular lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma, can transform to histiocytic/dendritic cell sarcoma (H/DS) in rare cases. The diagnosis of this unconventional neoplastic evolution relies on a combination of immunophenotypic analysis and genotypic studies. A genotype identical to that of the primary B-cell neoplasm in a secondary neoplasm with H/DS immunophenotype supports the lineage conversion to H/DS. Putative mechanisms for this unusual phenomenon include dedifferentiation, common immature progenitor, and transdifferentiation models, the latter of which is suggested by clinical laboratory data at the present time. Elucidation of the molecular mechanisms governing this lineage conversion may facilitate the understanding of carcinogenesis of not only hematopoietic but also nonhematolymphoid neoplasms. The clinical outcome of secondary H/DS is dismal, as observed in sporadic cases, and the optimal treatment remains to be determined.

A rare case of follicular lymphoma with transformation to diffuse large B-cell lymphoma and transdifferentiation to histiocytic sarcoma

“…There have been isolated reports of H/DC tumors occurring in patients with FL, CLL/SLL, and splenic marginal zone lymphoma. [6,10,11,[13][14][15] Rarely, FL involving the lymph node with co-existing DLBCL and HS in a bone marrow biopsy has been identified. [16] Therefore, it is important to biopsy and evaluate lymph nodes and bone marrow lesions.…”

Activating mutations of the oncogene EZH2 in cutaneous melanoma revealed by next generation sequencing

“…In contrast, the patient's follicular lymphoma demonstrated neither EZH2 (Y641) nor BRAF (V600) mutations. Transdifferentiation of lymphoma into Langerhans cell neoplasms, histiocytic sarcomas and dendritic cell sarcomas has been reported [29,30]. However, the expression of melanocytic markers including Melan-A in the index case, together with the lack of shared EZH2 and BRAF mutations between the melanoma and lymphoma, makes transdifferentiation unlikely in this case.…”

Tumor Heterogeneity in Lymphomas: A Different Breed

“…An example of transdifferentiation is shown in Figure 4. Reported cases include histiocytic/dendritic cell (H/DC) neoplasms in patients suffering from low-grade B-cell lymphomas, such as FL, Mantle cell lymphoma, hairy cell leukemia, or CLL/SLL [64], as well as Langerhans cell neoplasms in patients with lymphoblastic leukemia/lymphoma of either B-cell (B-LBL) [65] or T-cell (T-LBL) [66] origin (Table 2). Myeloid differentiation in a low-grade lymphoma patient sample may pose diagnostic problems because of a morphologic resemblance to large cell lymphoma, mimicking transformation.…”

“…In summary, experimental and clinical evidence indicates that different mechanisms may lead to H/DC neoplasms in patients suffering from lymphomas, the most frequent one being transdifferentiation from mature tumor lymphocytes (Table 2). For future studies that investigate transdifferentiation, it is essential to properly address this issue using molecular techniques, either by physically separating the 2 tumor types via immune-directed laser capture microdissection or by morphologydirected FISH for chromosomal aberrations [64].…”