KRAS mutation in secondary malignant histiocytosis arising from low grade follicular lymphoma

Abstract

BackgroundTransformation of follicular lymphoma most typically occurs as diffuse large B-cell lymphoma, however other forms of transformation such as classic Hodgkin lymphoma and lymphoblastic transformation can occur. Secondary malignant histiocytosis also represents a rare form of transformation, which is thought to occur due to a process of transdifferentiation whereby the lymphoma cells exhibit lineage plasticity and lose all evidence of B-cell phenotype and instead acquire the phenotype of a histiocytic neoplasm. Little is known about the underlying genetic alterations that occur during this unusual process. Comparative genetic analysis of pre- and post-transformation/transdifferentiation would be one tool by which we could better understand how this phenomenon occurs.Case presentationHere we report the clinical, immunophenotypic and genetic features of a rare case of secondary malignant histiocytosis, Langerhans cell-type (Langerhans cell sarcoma) arising from a previous low grade follicular lymphoma. FISH analysis confirmed the presence of IgH/BCL2 rearrangement in both the low grade follicular lymphoma (FL) and transformed Langerhans cells sarcoma (LCS) samples, demonstrating a clonal relationship. Comparative whole exome sequencing was then performed, which identified a KRAS p.G13D mutation in the LCS that was not present in the FL.ConclusionsThis report highlights genetic alterations, in particular an acquired somatic KRAS mutation, that may occur during transdifferentiation, with additional significance of KRAS mutation as a possible therapeutic target in cases which otherwise would have limited treatment options.Electronic supplementary materialThe online version of this article (10.1186/s13000-018-0758-0) contains supplementary material, which is available to authorized users.

A case of Langerhans cell sarcoma on the scalp: Whole‐exome sequencing reveals a role of ultraviolet in the pathogenesis

“…Through our analysis of this Langerhans cell neoplasm, we demonstrated for the first time that UV could affect not only the phenotype but also the genome of the Langerhans cells. LCS can arise through at least three mechanisms: de novo , progression from LCH, and transdifferentiation from a B‐cell neoplasm 4,10,12,19 . Our results suggest that de novo LCS, corresponding to our case, can occur as a UV‐related cancer, as is the case for skin cancers of various lineages (e.g., basal cell carcinoma, squamous cell carcinoma, and melanoma, etc.).…”

“…A literature searched revealed ten English‐language papers reporting genetic alterations in LCS 3–8,10–13 . Six case reports, 3–8 three of which included WES data, 4–6 indicated causative alterations such as mutations related to activation of the MAPK pathway ( BRAF , KRAS , MAPK2A1 or NRAS ), homozygous deletions of CDKN2A/(2B) , and/or a loss‐of‐function mutation of TP53 (Table 1). The present case also exhibited CDKN2A deletion and a pathogenic missense mutation in TP53 (Fig.…”

“…However, the underlying molecular features of LCS that could explain its aggressive behavior or pathogenesis, and lead to the development of more effective treatment strategies, are poorly understood, except for the reported presence of a few genetic alterations, such as mutations of MAPK‐related genes, CDKN2A or TP53 3–8 …”

CD30+ large B cell lymphoma with anaplastic features and complete loss of B cell marker expression arising from follicular lymphoma

“…[3][4][5][6][7] Follicular lymphoma can also transform into histiocytic/dendritic cell tumours, demonstrating that lineage infidelity is possible. [8][9][10] Rare reports of transformed follicular lymphoma with CD30 expression and anaplastic morphology exist, but all previously described cases retain expression of one or more B cell lineage-specific markers. 11,12 Case report A 60-year-old male initially presented in 2011 with bilateral axillary lymphadenopathy.…”

“…Transformation to other neoplasms that retain expression of immunophenotypical markers of the B cell transcriptional programme (Burkitt lymphoma, B lymphoblastic leukaemia/lymphoma, classical Hodgkin lymphoma) is also well described . Follicular lymphoma can also transform into histiocytic/dendritic cell tumours, demonstrating that lineage infidelity is possible . Rare reports of transformed follicular lymphoma with CD30 expression and anaplastic morphology exist, but all previously described cases retain expression of one or more B cell lineage‐specific markers …”