Myelomastocytic leukemia versus mast cell leukemia versus systemic mastocytosis associated with acute myeloid leukemia: A diagnostic challenge

A 35-year-old woman presented in September 2006 with progressive urticaria, which was refractory to increasing doses of antihistamines and prednisone. Features of urticaria pigmentosa were not present. She presented 11 months later with fatigue and petechiae. An initial bone marrow (BM) biopsy was hypercellular with left-shifted myelopoiesis, mild reticulin fibrosis, and diffuse infiltration by mast cells (MCs). No compact dense MC infiltrates were detected on BM biopsy. Mastocytosis is currently defined as a clonal, neoplastic proliferation, and accumulation of MCs in one or multiple organs [1]. Clinical symptoms are caused by the release of chemical mediators and by infiltration of tissues by neoplastic MCs. In cutaneous mastocytosis, MC infiltration is limited to the skin and typically presents in childhood with urticarial symptoms. It has a benign clinical course and may regress spontaneously [2]. In adults, cutaneous disease is more frequently associated with indolent rather than aggressive forms of systemic mastocytosis (SM). Although a diagnosis of SM was considered, the lack of compact dense aggregates was considered atypical, and full criteria for SM were not met. In the 2008 WHO classification, SM is diagnosed when one major criterion and one minor criterion, or at least three minor criteria are present (Table I). The major diagnostic criterion for SM is fulfilled by the presence of multifocal dense MC infiltrates (≥15 MCs per aggregate) detected histologically in the BM or in another extracutaneous organ(s). Minor criteria include: (1) ≥25% of the MCs in the infiltrate are spindle-shaped or show atypical morphology or, ≥25% are immature or atypical on BM aspirate smears; (2) a serum tryptase level persistently greater than 20 ng/mL (this parameter is not valid if there is an associated clonal myeloid disorder); (3) detection of the characteristic D816V KIT mutation in BM, blood, or another extracutaneous organ; and (4) expression of CD2, CD25, or both in neoplastic MCs [1-3]. Indolent forms of systemic MC disease may be characterized by one or more “B” findings (Table II). If two or more B findings are present the disease is called smouldering SM. Treatment of mediator-related symptoms, when present, is commonly employed in all SM variants, whereas cytoreductive agents are not prescribed. In contrast, aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) are characterized by one or more “C” findings (Table II), which often require cytoreductive therapy. SM may also be associated with a clonal hematologic disease that is not of mast cell origin (SM-AHNMD), such as myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), acute leukemia, lymphoma, or plasma cell myeloma. In SM-AHNMD, full WHO diagnostic criteria for both SM and the AHNMD are met [4]. A BM aspirate smear showed intermediate size blasts with open chromatin, single prominent nucleoli, and agranular basophilic cytoplasm and metachromatic blasts with large deeply basophilic granules (Fig. 1). An abdominal ultrasound showed no organomegaly. Top row: Case 1, myelomastocytic leukemia; (A) BM aspirate demonstrates a metachromatic blast with abundant metachromatic granules, immature nuclear chromatin, and high N:C ratio (top left), a myeloblast with high N:C ratio, fine nuclear chromatin, and scant basophilic cytoplasm (top right), a dysplastic erythroid precursor with an enlarged nucleus, irregular nuclear contours, and pale basophilic cytoplasm (bottom left), and another metachromatic blast with an enlarged nucleus, fine nuclear chromatin, scent basophilic cytoplasm, and azurophilic granules (bottom right). (B) ×100 view of BM biopsy demonstrating no focal lesions (C) ×400 H&E BM biopsy demonstrating immature mononuclear cells with some cells showing granulocytic differentiation. (D) ×400 BM biopsy with IHC staining for tryptase highlighting the interstitial pattern of MC infiltration, an immunohistochemical stain for CD34 was negative (inset); (E) ×400 BM biopsy with IHC staining for CD25 showing cytoplasmic staining in scattered interstitial MC and no staining in adjacent blasts. Middle row: Case 2, myelomastocytic transformation in AML; (F) diagnostic BM aspirate showing numerous enlarged myeloblasts with high N:C ratio, fine nuclear chromatin, and scant basophilic cytoplasm along with scattered atypical MC (inset). (G) ×100 H&E diagnostic BM biopsy showing hypercellularity, FISH analysis demonstrated interphase nuclei with 1 red, 1 green, and 2 fusion signals, consistent with the t(8:21)(q22;q22) translocation fusion product (inset). (H) ×400 postinduction BM aspirate showing numerous MC with enlarged bilobed nuclei and abundant cytoplasmic granules without increased blasts. (I) ×200 H&E postinduction BM biopsy showing a marked decrease in cellularity from the previous biopsy. (J) ×200 postinduction BM biopsy with IHC staining for mast cell tryptase which highlights the interstitial pattern of MC infiltration, an immunohistochemical stain for CD25 showed absent expression in mast cells and blasts (inset). Bottom row: Case 3, MCL; (K) ×100 BM aspirate showing metachromatic blast with enlarged nucleus, fine nuclear chromatin, basophilic cytoplasm, and scattered metachromatic granules (top) and multinucleated MC with small round nuclei, fine nuclear chromatin, and abundant cytoplasmic granules (bottom). (L) ×100 H&E BM biopsy showing hypercellularity and scattered giant cells, ×100 BM biopsy with IHC staining for mast cell tryptase, which highlights the diffuse pattern of MC infiltration (inset). (M) ×400 H&E BM biopsy showing numerous immature mononuclear cells and occasional multinucleated cells. (N) ×400 BM biopsy with IHC staining for CD117 showing strong membranous and cytoplasmic staining. (O) ×200 BM biopsy with IHC staining for CD25 showing lack of expression in MC. BM, bone marrow; N:C, nuclear to cytoplasmic; H&E, hematoxylin and eosin; IHC, immunohistochemical; MC, mast cell(s); FISH, fluorescence in situ hybridization; MCL, mast cell leukemia. Reactive tissue MC are small with round centrally located nuclei, indistinct to absent nucleoli, abundant cytoplasm, and faint cytoplasmic granules on H&E stained tissue sections; in Romanowsky stained smears, MCs contain tightly packed uniform metachromatic granules with round to oval shaped nuclei (Table III). Neoplastic MC morphology has been classified into three subtypes: (1) Metachromatic blasts with high nuclear to cytoplasmic ratio, fine nuclear chromatin, prominent nucleoli, and several metachromatic granules; (2) atypical MC type I with elongated cytoplasmic projections, oval eccentric nuclei, and hypogranulated cytoplasm; and (3) atypical MC type II with bi- or polylobed nuclei (Table III) [4, 5]. Recognition of neoplastic MC morphology has been shown to correlate with clinical outcome [4]. Atypical MC type I are more commonly seen in SM with a clinically indolent course whereas atypical MC type II and metachromatic blasts are more common in patients with MML and MCL, which are associated with a poor prognosis and short survival [1, 4, 5]. In light of the similarities in morphology between MCs and basophils, the differential diagnosis of MML also includes basophilic leukemia (BAL), a very rare neoplasm accounting for <1% of all AML cases [1]. Neoplastic cells are medium-sized blasts with round or oval bilobed nuclei, basophilic cytoplasm, and a variable number of metachromatic granules, and are morphologically indistinguishable from metachromatic blasts seen in MML [1]. Blasts typically express myeloid markers including CD13 and CD33 and are usually negative for CD117 and chymase, and express only low amounts of tryptase, which differentiates them from cells of the MC lineage [1]. Definitive diagnosis of BAL is now more easily undertaken with the introduction of basophil-specific immunohistochemical antibodies 2D7 and BB1 [6]. Two months later, she was admitted to the hospital for febrile neutropenia. A serum tryptase level was 156 ng/mL (reference range <12 ng/mL). A complete blood count (CBC) showed neutropenia with an absolute neutrophil count of 0.4 × 109/L and thrombocytopenia with a platelet count of 42 × 109/L. A peripheral blood smear contained 10% blasts and <1% metachromatic blasts (Table IV). On BM aspirate smears, 9% blasts and 5% metachromatic blasts were enumerated and multilineage dysplasia was seen; however, aspirate smears lacked particles and appeared hemodilute (Table IV). BM biopsy showed 5% immature mononuclear cells resembling blasts that expressed MPO, and dim CD117, and lacked CD34 and tryptase. The marrow was also infiltrated in an interstitial pattern by immature MCs (50%), expressing tryptase, CD25, and CD117, and lacking CD34 (Fig. 1). No dense MC aggregates were seen. Flow cytometry identified two distinct populations in the BM: a myeloblast population expressing CD13, CD33, dim CD45, CD117, and MPO, but lacking CD34, and a MC population expressing CD25 and CD117, and lacking CD34 and MPO. PCR was negative for the D816V KIT mutation by allele-specific PCR [7] and cytogenetics showed a normal karyotype (46,XX). The patient subsequently developed respiratory failure and was transferred to the intensive care unit where she received cladribine chemotherapy. Although recovering from respiratory failure, the patient continued to be pancytopenic after cladribine therapy and became febrile 2 months later with Enterococcus bacteremia. She was noted to have massive hepatomegaly and a biopsy of the liver showed diffuse infiltration by immature mononuclear cells, which expressed MPO but not CD34. A population of tryptase positive MCs was also identified (10%). A repeat BM biopsy was performed and was consistent with the liver biopsy, both suggestive of leukemic transformation. Myelomastocytic leukemia (MML) is a rare disease that has previously been described in patients with advanced myeloid neoplasms (most commonly refractory anemia with excess blasts, a subtype of MDS, or AML) with elevated numbers of immature atypical MCs who do not meet full criteria for SM [8]. MML typically presents with an increase in myeloblasts (>5%) as well as >10% metachromatic blasts in the peripheral blood and/or BM but without focal dense MC infiltrates, without MC expression of CD2 or CD25, and without evidence of the D816V KIT mutation by PCR [2, 3, 8, 9]. Similar to patients with MDS or AML without MML, dysplastic features are seen in one or more myeloid cell lineages [3]. Mature MCs and basophils may also be observed. In Case 1, the finding of numerous metachromatic blasts together with the diffuse infiltration pattern suggested either MML or MCL, as metachromatic blasts are rarely observed in SM or SM-AHNMD (Table III). Although CD25 expression was detected on MCs and MCs were atypical (2 minor criteria), the patient lacked the following findings: (1) focal dense MC aggregates; (2) an activating codon 816 KIT mutation; and (3) serum tryptase level was excluded from consideration given that a clonal myeloid cell population was present. Therefore, full criteria for SM were not met which also excluded MCL from the differential diagnosis. Metachromatic blasts were clearly MCs, not basophils, as these cells expressed high levels of KIT and tryptase. Histopathologic features included: (1) 5% metachromatic blasts in BM smears; (2) greater than 5% blasts in peripheral blood/BM smears; and (3) an interstitial MC infiltrate on biopsy. Immunophenotyping confirmed both myeloblast and MC populations, of which the latter appeared to be greater than 30% on the BM biopsy; this discrepancy with the percentage of metachromatic blasts in the BM smears appears due to the lack of particles present on the smears. Thus, Case 1 had findings diagnostic of MML with the unusual finding of CD25 expression and a normal karyotype, findings not described previously in MML. Our review of the literature identified seven cases of MML [9-12]. Three of these cases were published in 1994, before the term “myelomastocytic leukemia” was adopted, but the reported clinical and histopathologic features were highly suggestive of MML. Two patients had MDS/RAEB and one patient had blast crisis of chronic myeloid leukemia. All patients had increased blasts and metachromatic cells, complex karyotypes, a poor prognosis and did not meet criteria for SM [12]. The remaining four cases were described between 1999 and 2006 [9-11]. All cases described the presence of metachromatic blasts. Two cases exhibited elevated blasts, diffuse MC infiltrates, and the absence of the D816V KIT mutation [9, 10]. One patient had a diagnosis of MDS/RAEB with complex karyotype [10]. The other patient had AML with t(8;21) variant and was shown to have AML1/ETO fusion genes in both myeloblasts and MC [9]. The remaining two cases were reported to have findings of MML and did not meet criteria for SM; however, specific data was not provided by the authors [11]. Her clinical status rapidly deteriorated and she expired shortly thereafter, ∼2 years after initial presentation. The diagnosis of MML was made posthumously. Advanced MC neoplasms are notoriously difficult to manage and no curative treatments are currently available. Treatment for advanced SM may include standard therapy for mediator symptoms [4] along with cytoreductive therapy including interferon-α with or without corticosteroids, and cladribine in those who have slowly progressing ASM [6]. However, major and partial responses are observed in only a subset of patients [4, 6]. The initial three cases of MML described had complex karyotypes and poor prognosis [12]. In the more recent literature, one patient with MML went into complete remission with polychemotherapy [10], and another patient went into complete remission following myeloablative stem cell transplantation [9]. A 64-year-old man with a medical history of diabetes mellitus, coronary artery disease, and hypertension presented to an outside hospital with fever, fatigue, and left flank pain in late August 2007. A BM biopsy showed a normocellular marrow with increased myeloblasts. He was initially diagnosed with myelodysplastic syndrome and was transfused four of packed blood cells. He was subsequently at where a a blood cell count of × and platelet count × 109/L. The peripheral blood smear showed blasts, and no MCs (Table IV). Blasts were intermediate to large in size with irregular nuclear cytoplasmic occasional large cytoplasmic granules, and A BM biopsy exhibited hypercellularity and blasts were enumerated on aspirate smears (Fig. 1, IV). Blasts expressed myeloid markers dim CD33, CD34, CD117, and as well as and A diagnosis of AML was analysis showed the was with and on a clinical A postinduction BM a previously interstitial MC infiltrate and blasts (Table IV). MCs were round with bilobed nuclei and fine granules (Fig. 1). MCs expressed CD117 and tryptase, and lacked expression of CD25 and CD2 (Fig. 1). PCR the KIT mutation previously reported to be A serum tryptase level was elevated at ng/mL (reference range ng/mL). remission of AML was with chemotherapy. this <1% blasts and 5% MCs were enumerated on the and the was detected by FISH in cells with bilobed nuclei not He received three of with BM at 1 and months postinduction were of leukemia and contained MCs. 11 months was to have blasts on a peripheral blood smear and a BM aspirate and biopsy showed AML with BM blasts and 5% MCs. analysis showed with A repeat serum tryptase level was normal at of patients with SM a hematologic disease, which is usually a clonal myeloid The of AML is a that myeloid which to acute leukemia when other commonly KIT and other are and have a for the of (1) a in and/or to hematologic cells with no on and (2) fusion which has limited on but normal hematologic KIT are associated with of MCs and are frequently in a of patients with such as AML with or In such D816V KIT is the common mutation [2, Case 2 was a diagnostic appeared to be a of t(8;21) AML with of SM after chemotherapy. However, lacked the following findings of (1) focal dense MC infiltrates on BM biopsy, (2) the activating codon D816V KIT (3) expression of CD2 and/or CD25 on MC, and (4) serum tryptase level not be considered due to the presence of the associated clonal myeloid Therefore, this did not meet criteria for the diagnosis of SM. The observed KIT has been reported in the of AML but has not been reported to in patients with SM. this KIT mutation was expressed in neoplastic MC and/or a in the myelomastocytic transformation in this patient The initial BM smears showed 5% MCs, with MCs seen on postinduction smears. the of the patient presented with both increased blasts and MCs. All these that the patient developed a myelomastocytic transformation in with of MML. Although Case 2 is of transformation to MML in the of was A review of the literature identified seven cases of with all of which met full WHO criteria for SM In only one patient did mastocytosis the In four the presence of MC was by blast accumulation at the of and in two cases the were remission of AML after polychemotherapy was in four of the SM to polychemotherapy was cell transplantation was employed and in complete remission in two and four patients of disease two patients at one at and 1 at months after the initial diagnosis was is also one published on a patient with AML with t(8;21) with myelomastocytic leukemia [9]. patient also received a stem cell in to cases with this patient went into complete remission for both AML and the MC disease [9]. A have the clonal origin of MCs in advanced MC neoplasms such as MML and SM-AHNMD and to the myeloid leukemic blasts [9, the clonal origin of MCs in MML FISH analysis with specific for AML1/ETO FISH was in both blasts and in MCs, the that MCs and myeloblasts from the in this patient [9]. data in has been with to the clonal origin of MC. In demonstrated the presence of the D816V KIT mutation in MCs but not in blasts from the either clonal of SM and AML or two developed in these patients confirmed the presence of the in blasts but not in MCs, and that no the between blasts and MCs be made FISH on MCs identified either a fluorescence or to the clonal origin of MCs in a patient with who stem cell of BM before and at and 1 the in and of MCs, but not in other cell consistent with a common origin of MCs with the leukemic these some into the clonal origin of neoplastic MCs, there is no MCs and myeloblasts are from a common or distinct such as single cell and more may and in this He with one of and on a clinical A BM after showed no evidence of leukemia and no elevated MCs. He received a stem cell transplantation from an with acute leukemia and went to BM was not performed at the of SM-AHNMD is in a with the AHNMD as if no SM were present, and [4]. described a patient with who was initially with and in hematologic complete remission with MCs in the BM, and lesions on of the of stem cell the patient was with and four of in a decrease in MC numbers by in and absence of the D816V KIT mutation detection on BM If the D816V KIT mutation be identified in both the SM and AHNMD there may be a for these KIT for both disease However, as single therapy with not to neoplastic cells, are to these with standard such as cladribine or A woman presented with abdominal and An abdominal ultrasound showed hepatomegaly and a was for a count of 2 × and platelet count of × with MCs on peripheral smear (Table IV). A BM biopsy showed a hypercellular marrow with MCs and blasts on aspirate smears (Table IV). BM showed immature MCs with nuclear and oval nuclei with occasional nuclear as well as forms (Fig. 1). MCs expressed tryptase, and CD117 and lacked expression of CD2, and CD25 (Fig. 1). analysis showed a normal BM was negative for the KIT D816V mutation by allele-specific PCR A diagnosis of MCL was MCL WHO criteria for and is characterized by MCs in the BM aspirate smears, with dense focal and diffuse infiltrates of atypical immature MC in the BM biopsy [2]. after a course of cladribine was She persistently pancytopenic without MCs. A BM biopsy after demonstrated MCs and scattered multinucleated giant MCs with an showing tryptase and CD117 but lacking expression of CD2 and MCs showed an interstitial and diffuse pattern on BM biopsy. She was with of and A postinduction BM biopsy showed hypercellularity with MCs. She was on and for 2 without clinical or She was subsequently on a 2 clinical of the KIT that a serum tryptase level was elevated at A peripheral blood smear after a of showed >10% MCs and a BM showed a hypercellular marrow with MCs with a expression pattern from previous A repeat serum tryptase level was increased at She was to have progressive disease, was from the and expired months after initial presentation. MCL is a rare subtype of SM characterized by leukemic of MC and an aggressive rapidly progressing clinical course MCL, by criteria for SM with features including (1) leukemic infiltration of the BM and other extracutaneous organs by neoplastic MCs, (2) at least MCs in BM and/or blood smears, and (3) findings [1, Case met criteria for SM given that diffuse and multifocal dense MC infiltrates were present, of all MC were and serum tryptase was persistently and no associated clonal myeloid was “C” findings are commonly associated with MCL and in this BM characterized by and as well as MCL is the only advanced for which a diagnosis on an aspirate smear is to the diagnosis A review of the literature by in identified cases of MCL, which were to cases when WHO criteria were The clinical and survival in these cases was to that of Our review of the literature identified a more recent of cases of MCL, which met WHO criteria for MCL Three patients had MCL and seven patients had the as defined by MCs. identified the D816V KIT mutation in patients and one patient had a KIT patients had MCs that expressed CD2 and/or with Case which lacked both CD2 and CD25 of treatments were employed including corticosteroids, and stem cell transplantation with complete remission in only one patient who stem cell transplantation after failure of two previous treatments MCL is a WHO defined however, in this may to to the major WHO criterion for multifocal dense infiltrates be present, whereas MCL is defined by diffuse MC infiltrates [1]. Thus, in MCL is to that the MC infiltrate is dense and multifocal but also has an diffuse MCs typically show marked serum tryptase levels are persistently and MCs often express CD2 and/or in of all the KIT mutation D816V is Therefore, in the absence of multifocal dense infiltrates, cases of MCL meet three of the minor criteria as is for the WHO diagnosis of SM. Although the aggressive of MCL consideration of polychemotherapy and/or BM the with these is limited in and has not been including and have exhibited partial in patients with advanced SM characterized by in one or more findings Advanced MC neoplasms are a of that often a clinical which not them to be on the of clinical findings Therefore, and a in the diagnosis of these neoplasms (Table and the disease prognosis and The diagnosis of MC neoplasm a high of clinical and with a with specific in the of these rare The diagnostic criteria are in with the diagnosis of these myeloproliferative However, as with some cases and more described such as MML do not into the WHO The authors for on these the for this and the and all authors the and and clinical and performed and FISH performed

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