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

Abstract

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.

Atypical cutaneous histiocytic eruption in a patient with chronic myelomonocytic leukemia: A case report

“…In Vitte et al's series, 70% of the MPDCP group had accompanying infiltrates of indeterminate dendritic cells (IDCs). Cutaneous IDCT have been reported in three patients with CMML, where the cutaneous IDCT was suggested to be clonally related to the CMML by NGS demonstrating shared KRAS , TET2/ASLX1/ZRS2 , and NRAS mutations in the three cases, respectively 10‐12 . Although the morphology of the cells in our case, with the histiocytes having reniform, convoluted, and grooved nuclear profiles, may be in keeping with IDCs, the majority of the cells did not stain for S100 or CD1a.…”

MAP2K1‐driven mixed Langerhans cell histiocytosis, Rosai‐Dorfman‐Destombes disease and Erdheim‐Chester disease, clonally related to acute myeloid leukemia

“…To date the most frequently diagnosed histiocytosis‐AHN is juvenile or adult xanthogranuloma 8 . Myeloid neoplasms outnumber lymphoid malignancies in both L‐ and C‐group histiocytosis‐AHN patients, whereas histiocytic sarcoma (M‐group) patients more often develop low‐grade B‐cell lymphoma or T‐acute lymphoblastic leukemia 8,9 . In C‐group histiocytoses‐AHN, 71% of the AHN was of mononuclear‐phagocyte lineage (ie, juvenile or chronic myelomonocytic leukemia, acute monocytic or myelomonocytic leukemia), the same as histiocytoses 8 …”

“…Interestingly, many reports describe a clonal relationship between the two diseases 9 . Histiocytoses associated with myeloid neoplasms generally gain alterations in genes recurrently mutated in myeloid neoplasms and clonal hematopoiesis (eg, JAK2 ) 14 or histiocytoses (eg, BRAF , KRAS ), 9‐15 as well as cytogenetic anomalies 16 .…”

“…Interestingly, many reports describe a clonal relationship between the two diseases 9 . Histiocytoses associated with myeloid neoplasms generally gain alterations in genes recurrently mutated in myeloid neoplasms and clonal hematopoiesis (eg, JAK2 ) 14 or histiocytoses (eg, BRAF , KRAS ), 9‐15 as well as cytogenetic anomalies 16 . On the other hand, the shared genetic alteration of lymphoid neoplasms arising in histiocytosis patients are generally reported for lymphomas (eg, BCL2 , MYC , CDKN2A ), suggesting an underlining mechanism of transdifferentiation or for a common hematopoietic precursor 9‐17 …”

“…Hematological (and especially myeloid) neoplasms may arise in up to 10% of adult histiocytosis patients, with a higher frequency comparing to the general population 7 and eventually share clonal alteration(s) with histiocytosis. Such association correlate with a poor patients' prognosis as well as difficulties in the management 7‐9 …”