LAUSR

Dear Editor, The association between plasma cell (PC) neoplasms (PCN) and neutrophilia is a rare but well-known phenomenon [1–3]. CHIP designates asymptomatic presence of clones in the peripheral blood and/or the bone marrow carrying somatic mutations of genes, typically mutated in myeloid neoplasms, with a not exactly predictable risk of progression towards cancer, bearing analogies to MGUS and monoclonal Blymphocytosis [4, 5]. We report on a patient with concomitant MGUS, neutrophilia, and CHIP, rising questions of the nature of neutrophilia in PCN as well as caveats of overinterpretation due to the simultaneous co-existence of MGUS and CHIP. A 60-year-old Caucasian male presented with fatigue and splenomegaly in 2008. Blood counts showed leukocytosis with mature neutrophilia [leukocytes of 32 g/L (reference, 412 G/L) with 90% neutrophils (28.8 G/L)]. Immunofixation electrophoresis revealed IgGκ monoclonal gammopathy (13.1 g/L (reference, 0.7–1.6 g/L)) without CRAB criteria. The bone marrow biopsy was hypercellular with increased maturing myelopoiesis and with 5% kappa-restricted PC (Fig. 1a–c). Neither mutations of JAK2 and CSF3R nor BCR-ABL1-, PDGFRA, PDGFRB, or FGFR1 rearrangements were detected. The neoplastic PCs were CD38+/CD138+/ CD19−/CD20−/CD56− on flow cytometry. No PCNcharacteristic structural genomic alterations could be detected. Exome sequencing (Illumina) and targeted re-sequencing (IonTorrent) on purity-controlled sorted cells showed identical muta t ions of DNMT3A [ c .2287_2288insGGCG, p.(Val763GfsTer2)] , TET2 [c.3879_3880insTAC, p.(Tyr1294dup)], and others (Fig. 1d) in the neutrophilic population (CD66+), in the PC (CD138+)—containing the kappa-restricted clone—and in the stem cell pool (CD34+). Consequently, we suspected clonal relationship between the neutrophilic and the PC population and even a putative common progenitor. However, we also noted that the mutations were present at similar allelic frequencies in the sorted, purified cell pools but also in their negatives (in each CD138−, CD66−, or CD34− pool), indicating a distinct clonal outgrowth represented equivalently in the background of each sorted and left-over cell populations. Based on this, the hypothesis of an additional pan-hematopoietic/pluripotent clone giving rise to approximately 15 to 20% of all neutrophils and PCs (most probably not the MGUS PCs) was set up. This hypothesis was sustained by the high prevalence of TET2 and DNMT3A mutations, which are very characteristic of CHIP [6]. Finally, the diagnosis of MGUS with associated mature neutrophilia and a co-existent pan-hematopoietic CHIP was established. The patient remained asymptomatic showing no significant disease progression for 10 years, which further strengthened our interpretation. The nature of neutrophilia in PCN is not fully understood [7]. It may be secondary to abnormal cytokine production by the neoplastic PCs [8, 9]. This is substantiated by one case showing elevated G-CSF levels in the serum and PC positivity on immunohistochemical stains [8] and appears to be a plausible paraneoplastic mechanism. In other reported cases, mutations of JAK2, SETB2, or CSF3R have been detected [1, 9], suggesting the possibility of concurrent chronic neutrophilic leukemia (CNL) and PCN. In our case, supported by the absence of CSF3R driver mutations and by the indolent clinical course, the diagnosis of MGUS with paraneoplastic neutrophilia and independent CHIP has been established, in line with the growing evidence that somatic mutations in hematopoietic cells with clonal expansions can be acquired with aging [4]. The originality of our case resides * Alexandar Tzankov [email protected]