Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: evidence for transdifferentiation of the follicular lymphoma clone

Abstract

Rare cases of histiocytic and dendritic cell (H/DC) neoplasms have been reported in patients with follicular lymphoma (FL), but the biologic relationship between the 2 neoplasms is unknown. We studied 8 patients with both FL and H/DC neoplasms using immunohistochemistry, fluorescence in situ hybridization (FISH) for t(14;18), and polymerase chain reaction (PCR)/sequencing of BCL2 and IGH rearrangements. There were 5 men and 3 women (median age, 59 years). All cases of FL were positive for t(14;18). The H/DC tumors included 7 histiocytic sarcomas, 5 of which showed evidence of dendritic differentiation, and 1 interdigitating cell sarcoma. Five H/DC tumors were metachronous, following FL by 2 months to 12 years; tumors were synchronous in 3. All 8 H/DC tumors showed presence of the t(14;18) either by FISH, or in 2 cases by PCR with the major breakpoint region (MBR) probe. PCR and sequencing identified identical IGH gene rearrangements or BCL2 gene breakpoints in all patients tested. All H/DC tumors lacked PAX5, and up-regulation of CEBPbeta and PU.1 was seen in all cases tested. These results provide evidence for a common clonal origin of FL and H/DC neoplasms when occurring in the same patient, and suggest that lineage plasticity may occur in mature lymphoid neoplasms.

Figure 1

Transcription factor expression in histiocytic sarcomas. (A,B) Staining for CEBP beta in cases 5 and 1. Tumor cells show strong nuclear expression. Note negative blood vessel in panel B. (C,D) Staining for PU.1 in cases 4 and 1. Neoplastic cells (C) show sinusoidal localization. Note negative adjacent lymphocytes. Histiocytic cells have pleomorphic nuclei and prominent nucleoli. (E,F) Staining for PAX5 in cases 8 and 1. No nuclear staining is observed. Follicular lymphomas demonstrated normal expression of PAX5 (not shown). Original magnification for all figures ×400 (hematoxylin counterstain).

Figure 2

Case 4: synchronous FL and interdigitating cell sarcoma (IDCS). (A) An inguinal lymph node biopsy showed both FL, grade 1, and IDCS. The latter process occupied the majority of the lymph node biopsy, with only focal areas of FL. Magnification ×200. (B) The IDCS showed strong staining for S100 protein. Magnification ×200. (C) Cells of IDCS showed nuclear staining for CEBP beta, negative in FL lymphocytes. Magnification ×400. (D) The IDCS showed splitting of the BCL2 signals (arrow), consistent with presence of the t(14;18), using a breakapart fluorescence in situ hybridization (FISH) probe. A control sample shows no splitting of the BCL2 signals. Magnification ×1250.

Figure 3

Case 7: synchronous FL and histiocytic sarcoma with dendritic cell differentiation. (A) A mass in the tongue and neck showed both FL, grade 1, and H/DC sarcoma. The FL was associated with lingual lymphoid tissue (arrowheads), while the H/DC neoplasm was associated with the epithelium (arrows). Magnification ×20. (B) The FL was positive for CD20, CD10, and Bcl2. Magnification ×200. (C) The H/DC was positive for CD163 and focally for CD1a, as well as CD68 and S100 (not shown). There was no evidence of infiltrating FL cells, as shown in the CD20 stain. Magnification ×400. (D) The H/DC neoplasm showed fusion of the BCL2 and IGH signals (arrows), consistent with presence of the t(14;18), using dual-fusion FISH (D-FISH) probes. A control sample shows no fusion. Magnification ×1250.

Figure 4

Results of sequencing of IGH gene rearrangements or JH/BCL2 breakpoint regions. All of the sequences are arranged with the specimen sequence at the top, compared with the lower IMGT gene bank sequence. The dashes indicate the sequence is identical to the gene bank sequence, and the nucleotides indicate areas where they differ. Illustrated are cases 1 and 4 (Fr2) and cases 2 and 5 (Fr 3). While the FL and H/DC paired samples from case 2 are similar, the H/DC tumor biopsied 12 years after the FL demonstrates additional mutations. Sequencing of BCL2/JH breakpoint region obtained with MBR probe is illustrated in case 8.