Langerhans Cell Sarcoma Arising from Chronic Lymphocytic Lymphoma/Small Lymphocytic Leukemia: Lineage Analysis and BRAF V600E Mutation Study

Abstract

Background: the phenomenon that histiocytic/dendritic cell sarcomas may be transformed from lymphoproliferative diseases is dubbed 'transdifferentiation'. Langerhans cell sarcoma (LCS) transdifferentiated from chronic lymphocytic leukemia/small cell lymphoma (CLL/SLL) is extremely rare. The underlying mechanisms of LCS tumorogenesis and its transdifferentiation from CLL/SLL are largely unknown.

Aims: the authors strive to further characterize LCS, to understand the potential molecular changes in LCS and the underlying mechanisms of CLL/SLL transformation to LCS.

Materials and methods: a progressively enlarging right inguinal lymph node from a 68-year-old female patient with a history of CLL was biopsied and submitted for flow cytometry analysis, routine hematoxylin, and eosin (H and E) stain and immunohistochemical study. Furthermore, clonality study (fluorescent in situ hybridization (FISH) analysis with a CLL panel probes) and BRAF V600E mutation study (pyrosequencing and immunostain) were performed.

Results: two different neoplasms, LCS and CLL/SLL, were discovered to occur simultaneously in the same lymph node. These two entities were shown to be clonally related. More importantly, for the first time, BRAF V600E mutation was detected in LCS.

Conclusions: LCS can be transdifferentiated from CLL/SLL and BRAF V600E mutation may provide the foundation for alternative therapy of LCS.

Keywords: BRAF V600E mutation; Langerhans cell sarcoma; clonality; transdifferentiation.

Figure 1

Synchronous and clonally related LCS and CLL/SLL in a lymph node. (a) Sheets of small SLL/CLL cells admixed with large LCS cells in clusters (100×). (b) The LCS cells show high mitotic activity (400×). (c) The LCS cells demonstrate a much higher proliferation index (MIB-1, 40%) than that of CLL/SLL cells (20%). (d–i) The CLL/SLL cells show immunoreactivity for CD20 (D), CD5 (E) and CD23 (F) while the LCS cells are positive for CD1a (G), S100 (H) and langerin (I). (j) and (k) A FISH analysis using probes for centromere6 (green) and 6q23 (red) revealed the CLL/SLL (J) and the LCS cells (K) both lost the 6q23 signal

Figure 2

BRAF V600E mutation in LCS. The monoclonal antibody VE1 is able to detect BRAF V600E mutation in PCR-confirmed melanoma (B: as a positive control) using immunohistochemistry (A: negative control). The LCS cells, but not the CLL/SLL cells, in the present case show positivity for VE1 (C), suggesting BRAF V600E mutation in the LCS The BRAF V600E mutation is confirmed by pyrosequencing of the tumor DNA (D). A wild type control is displayed on the left (D, left), and the patient result is displayed on the right (D, right). A T to A mutation at the codon 600 of BRAF is present in approximately 25% of the DNA (D, right)