Genome‐wide analysis of acute leukemia and clonally related histiocytic sarcoma in a series of three pediatric patients

Bleeke, Matthias; Johann, Pascal; Gröbner, Susanne; Alten, Julia; Cario, Gunnar; Schäfer, Hansjörg; Klapper, Wolfram; Khoury, Joseph D.; Pfister, Stefan M.; Müller, Ingo

doi:10.1002/pbc.28074

Cited by 7 publications

(5 citation statements)

References 11 publications

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“…For example, in Case 1, the MAP2K1 and RAF1 mutations were (presumably) only present in the HS and not in the CMML, suggesting that these mutations may have contributed to the development of the HS from a common KRAS mutated HSPC or primary CMML clone. Similar situations of one or more shared genetic alterations and additional unique mutations in the histiocytic neoplasm and/or associated haematological malignancy have been reported in other cases [15,18,23,25–27,29,31,32,39,41,44,45,47,52–57,59,60,63–67,87–95]. The histiocytic neoplasms often harboured unique mutations in genes encoding proteins of the MAPK signalling pathway, including NRAS [52,55], KRAS [39,53,56], BRAF [15,23,44,45,54,92,94] and RAF1 [32], again demonstrating the importance of constitutive MAPK pathway activation in the pathogenesis of the histiocytic neoplasms [3,96].…”

Section: Discussionmentioning

confidence: 67%

Spectrum of histiocytic neoplasms associated with diverse haematological malignancies bearing the same oncogenic mutation

Kemps

Hebeda

Pals

et al. 2020

The Journal of Pathology CR

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Histiocytic disorders are a spectrum of rare diseases characterised by the accumulation of macrophage‐, dendritic cell‐, or monocyte‐differentiated cells in various tissues and organs. The discovery of recurrent genetic alterations in many of these histiocytoses has led to their recognition as clonal neoplastic diseases. Moreover, the identification of the same somatic mutation in histiocytic lesions and peripheral blood and/or bone marrow cells from histiocytosis patients has provided evidence for systemic histiocytic neoplasms to originate from haematopoietic stem/progenitor cells (HSPCs). Here, we investigated associations between histiocytic disorders and additional haematological malignancies bearing the same genetic alteration(s) using the nationwide Dutch Pathology Registry. By searching on pathologist‐assigned diagnostic terms for the various histiocytic disorders, we identified 4602 patients with a putative histopathological diagnosis of a histiocytic disorder between 1971 and 2019. Histiocytosis‐affected tissue samples of 187 patients had been analysed for genetic alterations as part of routine molecular diagnostics, including from nine patients with an additional haematological malignancy. Among these patients, we discovered three cases with different histiocytic neoplasms and additional haematological malignancies bearing identical oncogenic mutations, including one patient with concomitant KRAS p.A59E mutated histiocytic sarcoma and chronic myelomonocytic leukaemia (CMML), one patient with synchronous NRAS p.G12V mutated indeterminate cell histiocytosis and CMML, and one patient with subsequent NRAS p.Q61R mutated Erdheim–Chester disease and acute myeloid leukaemia. These cases support the existence of a common haematopoietic cell‐of‐origin in at least a proportion of patients with a histiocytic neoplasm and additional haematological malignancy. In addition, they suggest that driver mutations in particular genes (e.g. N/KRAS) may specifically predispose to the development of an additional clonally related haematological malignancy or secondary histiocytic neoplasm. Finally, the putative existence of derailed multipotent HSPCs in these patients emphasises the importance of adequate (bone marrow) staging, molecular analysis and long‐term follow‐up of all histiocytosis patients.

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Section: Discussionmentioning

confidence: 67%

Spectrum of histiocytic neoplasms associated with diverse haematological malignancies bearing the same oncogenic mutation

Kemps

Hebeda

Pals

et al. 2020

The Journal of Pathology CR

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“…The association between ALL and histiocytic disorders has been investigated. Several articles have shown that LCH and ALL share the same mutations or had the same T-cell receptor or immunoglobulin rearrangement, which proves clonal relationship between them ( 8 , 9 , 11 ). Some papers report on RAS and CDKN2A mutations detected in ALL cases, which subsequently developed histiocytosis ( 8 , 9 ).…”

Section: Discussion Of the Underlying Pathophysiology And Significancmentioning

confidence: 96%

Disseminated Juvenile Xanthogranuloma and Hemophagocytic Lymphohistiocytosis Developed During Treatment of Acute Lymphoblastic Leukemia: Case Report

et al. 2020

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The association between acute lymphoblastic leukemia (ALL), non-Langerhans cell histiocytosis (non-LCH), and hemophagocytic lymphohistiocytosis (HLH), to the best of our knowledge, has not been published to date. Juvenile xanthogranuloma (JXG), as a type of non-LCH, is usually a benign disease limited to the skin. Systemic involvement is rarely reported. The present case report describes a 15-year-old boy diagnosed with disseminated JXG involving skin and bone marrow concurrent with severe symptoms of HLH during ALL therapy. Examination of immunoglobulin heavy chain genes in B-cell precursor leukemic blasts and histiocytes in the skin and bone marrow revealed identical rearrangements, confirming clonal relationship between both diseases. Implementation of corticosteroids, vinblastine, etoposide, cyclosporine, and tocilizumab resulted in partial skin lesion resolution with no improvement of bone marrow function; therefore, hematopoietic stem cell transplantation (HSCT) was eventually performed. The patient's hematological and general status has improved gradually; however, remarkable recovery of skin lesions was observed after empirical antitubercular therapy. Mycobacterium spp. infection should be considered as a possible secondary HLH trigger. Triple association of ALL, non-LCH, and HLH highlights heterogeneity of histiocytic disorders and possible common origin of dendritic and lymphoid cells.

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“…A few cases of HS development in pediatric patients previously diagnosed with leukemia, including T-cell acute lymphoblastic leukemia (T-ALL) and phenotypic acute leukemia, have been reported in the literature, with the interval between malignancies ranging from 5 months to 1.5 years. 11 An analysis of 15 B-ALL and T-ALL patients who subsequently developed a histiocytic neoplasm reported that ALL patients subsequently diagnosed with HS demonstrated a much poorer prognosis than their counterparts in the cohort, with 75% of patients dying from the disease. 10 In several of these cases, the histiocytic neoplasm shared similar molecular alterations with the antecedent leukemia, supporting the hypothesis that this association may arise from the transdifferentiation of neoplastic B/T cells into neoplastic histiocytes.…”

Section: Discussionmentioning

confidence: 99%

Multimodal Management With Immunotherapy, Radiation, and Surgery of Histiocytic Sarcoma Following Acute Lymphoblastic Leukemia: An Unusual Presentation of a Rare Disease

Ahmad,

Vallance,

Sharma

et al. 2023

Journal of Pediatric Hematology/Oncology

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Histiocytic sarcoma (HS) is a rare neoplasm with no known cause. This sarcoma is characterized by morphology similar to that demonstrated by mature tissue histiocytes and mostly afflicts adults. HSs typically have a poor prognosis due to a rapidly progressive clinical course. Our patient’s case was unique due to its presentation four years after completion of treatment for B-cell acute lymphoblastic leukemia. The patient experienced progression with initial therapy for HS. With dual immunotherapy and radiation, however, the patient has remained clinically stable without detectable disease. Immunotherapy may be a successful and tolerable therapeutic option for histiocytic disease.

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Genome‐wide analysis of acute leukemia and clonally related histiocytic sarcoma in a series of three pediatric patients

Cited by 7 publications

References 11 publications

Spectrum of histiocytic neoplasms associated with diverse haematological malignancies bearing the same oncogenic mutation

Spectrum of histiocytic neoplasms associated with diverse haematological malignancies bearing the same oncogenic mutation

Disseminated Juvenile Xanthogranuloma and Hemophagocytic Lymphohistiocytosis Developed During Treatment of Acute Lymphoblastic Leukemia: Case Report

Multimodal Management With Immunotherapy, Radiation, and Surgery of Histiocytic Sarcoma Following Acute Lymphoblastic Leukemia: An Unusual Presentation of a Rare Disease

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