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

Abstract

Background: Transformation 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 presentation: Here 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.

Conclusions: This 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.

Keywords: Follicular lymphoma; KRAS; Langerhans cell sarcoma; Transdifferentiation.

Fig. 1

Diagnostic low grade follicular lymphoma. Excisional biopsy reveals a nodular lymphoid proliferation of small lymphocytes with elongated nuclei (a H&E, 100X; b H&E, 600X). Flow cytometric analysis identifies a surface lambda light chain-restricted B-cell population that is CD10+ and CD5-

Fig. 2

Diffuse large B-cell lymphoma. A transbronchial biopsy of the lung mass shows a diffuse proliferation of CD20+ large cells with large nuclei, open chromatic, occasional nucleoli associated with frequent apoptotic bodies (a H&E, 600X; b CD20 IHC, 600X). A bone marrow core biopsy shows an abnormal paratrabecular lymphoid infiltrate comprising of small lymphocytes with elongated nuclei (c H&E, 200X; d H&E, 600X). Flow cytometric analysis of the bone marrow aspirate (not shown) identified a monotypic, surface lambda light chain-restricted B-cell population that was dim CD10+ and CD5-, consistent with bone marrow involvement by follicular lymphoma

Fig. 3

Recurrent low grade follicular lymphoma. A needle core biopsy reveals an abnormal infiltrate of small lymphocytes that are predominantly CD20+ B cells with coexpression of CD10, BCL6 and BCL2, consistent with low grade follicular lymphoma (a H&E, 200X, b CD20 IHC, 200X; c CD10, 200X, d BCL2 IHC, 200X). Dual color dual fusion FISH analysis confirms the presence of IgH/BCL2 fusion signals resulting from t(14;18) in 62% of cells analyzed (Inset)

Fig. 4

Langerhans cell sarcoma. The inguinal lymph node biopsy shows a complete effacement of the lymph node architecture by an abnormal polymorphous infiltrate of histiocytes, small lymphocytes, neutrophils, eosinophils and rare plasma cells, with scattered and focal sheets of atypical large cells with convoluted nuclei (a H&E, 100X, b H&E, 600X). The large cells are CD1a + and S100+ (c CD1a IHC, 600X; d S100 IHC, 600X). The morphology and phenotype is consistent with a diagnosis of Langerhans cell sarcoma. The large cells were CD20-, CD19- (not shown), PAX5- (not shown) and CD10- (e CD20 IHC, 600X; f CD10 IHC, 600X)

Fig. 5

Dual color dual fusion FISH analysis demonstrates multiple IgH/BCL2 fusion signals resulting from t(14;18) in 21% of cells analyzed. The fusion signals are present only in the large sarcoma cells with but not in any of background inflammatory cells

Fig. 6

Exome sequencing performed on the Langerhans cell sarcoma sample revealed a G13D mutation results in an amino acid substitution at position 13 in KRAS, from a glycine to an aspartic acid (Variant allele frequency: 0.24) (b). This KRAS p.G13D mutation was not present in the previous follicular lymphoma (a)