Search

The bone marrow is a preferential site for both reactive and neoplastic histiocytic proliferations. The differential diagnosis ranges from reactive histiocyte hyperplasia in systemic infections, vaccinations, storage diseases, post myeloablative therapy, due to increased cell turnover, and in hemophagocytic lymphohistiocytosis, through extranodal Rosai-Dorfman disease to neoplasms derived from histiocytes, including histiocytic sarcomas (HS), Langerhans cell histiocytoses (LCH), Erdheim-Chester disease (ECD), and disseminated juvenile xanthogranuloma (JXG). One of the most important recent developments in understanding the biology of histiocytic neoplasms and in contributing to diagnosis was the detection of recurrent mutations of genes of the Ras/Raf/MEK/ERK signaling pathway, in particular the BRAFV600E mutation, in LCH and ECD. Here, we summarize clinical and pathological findings of 17 histiocytic neoplasms that were presented during the bone marrow symposium and workshop of the 18th European Association for Haematopathology (EAHP) meeting held in Basel, Switzerland, in 2016. A substantial proportion of these histiocytic neoplasms was combined with clonally related lymphoid (n = 2) or myeloid diseases (n = 5, all ECD). Based on the latter observation, we suggest excluding co-existent myeloid neoplasms at initial staging of elderly ECD patients. The recurrent nature of Ras/Raf/MEK/ERK signaling pathway mutations in histiocytic neoplasms was confirmed in 6 of the 17 workshop cases, illustrating their diagnostic significance and suggesting apotential target for tailored treatments.

Dear Editor,Myelofibrosis (MF), either primary (PMF) or secondary topolycythemia vera (post-PV MF), is associated with a dismalprognosis in terms of overall survival (OS) and quality of life(QoL) [1]. Its clinical management is still complicated, and atpresent,theonlycurativetreatmentisrepresentedbyallogenichematopoietic stem cell transplantation. However, the thera-peutic landscape of MF has dramatically changed with theintroduction of JAK1/2 inhibitors as ruxolitinib. The COM-FORT trials showed that ruxolitinib is effective in reducingsplenomegalyandMF-relatedsymptoms,thereforeimprovingQoL[2,3];morerecently,longer-termfollow-upstudiesdem-onstrated also an OS advantage [4, 5].Here, we describe the clinical and morphologic features offivepost-PVMFcasesselectedamong15MFpatientstreatedwith ruxolitinib in our institution. To our knowledge, onlyisolated reports described the morphologic changes occurringin ruxolitinib-treated patients, mostly focusing on modifica-tions in marrow fibrosis degree [6–9].The main clinical and morphologic features of these casespre- and on-treatment are summarized in Table 1. After amedian treatment of 22.1 months, all cases showed improve-mentinIPSS, constitutionalsymptoms, and spleensize, asso-ciated with a slight reduction in the JAK2 allele burden. Inaddition,pre-treatment leukocytosisnormalizedoratleast de-creased in two cases (patients 1 and 5, respectively). Regard-ing ruxolitinib dosage, it varied among the patients, as it waschosen initially according to their platelets counts and thenmodified mainly because of hematological toxicities. Fourpatients are still alive, and one died because of leukemic evo-lution after 22.1 months of treatment.Interestingly, three patients showed complex karyotypes,either before or on-treatment: however, differently fromPMF [10], this did not represent a negative predictive factorof response to therapy.How to evaluate bone marrow (BM) changes duringruxolitinibtherapyiscurrentlydebated.Wecomparedindetailcellularity, hematopoietic lineages, and stromal modificationsin both pre- and on-treatment BM biopsies.Beforetreatment,allcasesshowedmarkedlyincreasedcel-lularity(85–95%)andpolymorphicmegakaryocytes,formingloose and tight clusters; three cases displayed significant in-creasedmyeloid/erythroid(M:E)ratio(>8:1).ThreehadMF-2fibrosis and two MF-3. On-treatment biopsies showed de-creased cellularity in two cases, with reduction of both mye-loid and erythroid lineages. The M:E ratio normalized or atleast decreased in all patients, whereas megakaryocytes’ mor-phology showed only minor changes. In three cases, multifo-cal decrease of marrow fibrosis was documented but only inone the overall fibrosis downgraded from MF-3 to MF-2.In summary, although the small number of cases does notallow definite conclusions, the efficacy of ruxolitinib in post-PV MF is strongly suggested. As in PMF patients, clinicalresponse is quick and sustained in most cases. However