Molecular Genetics in the Diagnosis and Biology of Lymphoid Neoplasms

2017 Society for Hematopathology/European Association for Haematopathology Workshop Report

Megan S. Lim, MD, PhD; Nathanael G. Bailey, MD; Rebecca L. King, MD; Miguel Piris, MD


Am J Clin Pathol. 2019;152(3):277-301. 

In This Article

Histiocytic Neoplasms

Histiocytic and dendritic neoplasms arise from cells that function in phagocytosis and/or antigen processing and presentation. Many arise from myeloid precursors or are of mesenchymal origin. Genetic alterations in the RAF/MEK pathway are identified in Langerhans cell histiocytosis (LCH).[87–89] Erdheim-Chester disease (ECD) and disseminated juvenile xanthogranuloma have diagnostic and therapeutic implications. Interesting associations exist between histiocytic/dendritic neoplasms and a variety of lymphoid neoplasms (FL, CLL, B- or T-lymphoblastic neoplasms, or PTCL) that share clonal relationship and/or chromosomal alterations suggesting a transdifferentiation event.

Langerhans Cell Histiocytosis

Three cases of LCH (cases 135, 336, and 368) were submitted to the workshop. All cases harbored the BRAF V600E mutation. In case 368, molecular studies performed on bone marrow with histiocytic/dendritic aggregates that showed only minimal morphologic atypia contributed to the establishing a diagnosis of LCH. In some recent studies, which did not utilize molecular analysis or BRAF immunohistochemistry, this pattern of bone marrow involvement was felt to be reactive to cytokine production and relatively common in pediatric patients with LCH.[90] As there are no widely accepted histopathologic criteria to define bone marrow involvement in LCH, molecular studies and/or BRAF immunohistochemistry may contribute to assessing bone marrow involvement.

Erdheim-Chester Disease

A case of ECD (case 336) was submitted to the workshop Table 6 with an unusual presentation masquerading as sclerosing mesenteritis with subsequent appearance of a mixed ECD/LCH of the skin. Biopsies demonstrated xanthomatous cells in the mesenteric tissue that were initially interpreted as fat necrosis. Multiplexed allele-specific PCR assay testing of both the mesenteric and skin of cheek biopsy specimens demonstrated the presence of the BRAF c.1799T>A (V600E) mutation. Subsequent findings of LCH and a xanthomatous component in the skin prompted BRAF analysis, establishing a clonal link between the mesenteric and skin lesions. Recent literature describes mixed patterns of LCH/ECD occurring simultaneously or sequentially at different anatomic sites.[91]

ALK-positive Histiocytosis

An unusual ALK-positive histiocytic proliferation (case 380) in a 4-month-old female infant was submitted to the workshop. The patient presented with hepatomegaly and mild leukocytosis. Biopsy of the liver demonstrates multiple aggregates of large atypical histiocytes with some sinusoidal infiltrative pattern. By immunohistochemistry, the atypical histiocytes were positive for CD31, CD68, CD163, factor XIII, and S100 (patchy). They also uniformly expressed ALK (membranous and granular cytoplasmic positivity) with negligible nuclear positivity, consistent with a variant ALK translocation. The cells were negative for CD1a, CD30, and CD34. Ki-67 labeling of lesional histiocytes was low. Bone marrow examination revealed rare aggregates of atypical histiocytes positive for CD163 and ALK. Rare cases of ALK-positive histiocytoses have been described.[92] The clinical behavior seems indolent and the clinical outcomes appear favorable. This case highlights the highly diverse human tumors that can be transformed by the ALK oncogene. Given the availability of a highly effective small molecular inhibitor to ALK, there is some rationale for evaluating all neoplasms of potential mesenchymal origin for the presence of ALK rearrangements.