Myeloid sarcoma in JAK2-positive myelodysplastic neoplasms with fibrosis: a case report and literature review.

Myeloid sarcoma (MS) occurs in patients with acute myeloid leukemia (AML). In rare cases, MS can represent a form of blast transformation in patients with myeloproliferative neoplasms (MPN), myelodysplastic neoplasms (MDS), or MDS/MPN. The most frequent chromosomal alterations in MS are t(8;21) or inv(16), with other alterations being reported. Cases of MS in Janus kinase 2 (JAK2)-positive MDS with fibrosis are exceedingly rare. Here, we describe such a case. To the best of our knowledge, this is the first report of a JAK2 V617F mutation-positive MDS case occurring concurrently with MS involving the posterior aspect of the left seventh rib. No clear association has been previously demonstrated between the intramedullary AML cytogenetics and extramedullary disease occurrence. Interestingly, samples from the intramedullary MDS and extramedullary mass in this patient presented the same JAK2 V617F mutation. Following a treatment regimen of azacitidine and venetoclax, the patient achieved complete remission. The chest CT scan showed that the seventh posterior rib mass disappeared. This case provides valuable information for the potential future treatment of this disease.

Association of immune evasion in myeloid sarcomas with disease manifestation and patients' survival.

Introduction: Myeloid sarcomas (MS) comprise rare extramedullary manifestations of myeloid neoplasms with poor patients' outcome. While the clinical relevance of the tumor microenvironment (TME) is well established in many malignancies, there exists limited information in MS. Methods: The expression of the human leukocyte antigen class I (HLA-I) antigens, HLA-I antigen processing and presenting machinery (APM) components and the composition of the TME of 45 MS and paired bone marrow (BM) samples from two independent cohorts were assessed by immunohistochemistry, multispectral imaging, and RNA sequencing (RNAseq). Results: A significant downregulation of the HLA-I heavy chain (HC; 67.5%) and ß2-microglobulin (ß2M; 64.8%), but an upregulation of HLA-G was found in MS compared to BM samples, which was confirmed in a publicly available dataset. Moreover, MS tumors showed a predominantly immune cell excluded TME with decreased numbers of tissue infiltrating lymphocytes (TILs) (9.5%) compared to paired BM (22.9%). RNAseq analysis of a subset of 10 MS patients with preserved and reduced HLA-I HC expression revealed 150 differentially expressed genes and a significantly reduced expression of inflammatory response genes was found in samples with preserved HLA-I expression. Furthermore, low HLA-I expression and low TIL numbers in the TME of MS cases were linked to an inferior patients' outcome. Discussion: This study demonstrated a high prevalence of immune escape strategies in the pathogenesis and extramedullary spread of MS, which was also found in patients without evidence of any BM pathology, which yields the rational for the development of novel individually tailored therapies for MS patients.

Acute Myeloid Leukemia with Myelodysplasia - Related Changes after Isolated Myeloid Sarcoma.

BACKGROUND: As a tumor mass, a myeloid sarcoma consists of myeloid blasts and presents at an anatomical site other than the bone marrow. In about one quarter of cases, myeloid sarcoma happens without an underlying acute myeloid leukemia or other myeloid neoplasm, and it may precede or coincide with AML or form acute blastic transformation of MDSs, MPNs, or MDS/MPNs. METHODS: Herein, we described a rare case of acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), with WT1 mutation and high expression of TP53 after isolated myeloid sarcoma of lymph nodes showing a higher proportion of blasts, dysplasia of both megakaryocytes and granulocytes. CONCLUSIONS: The case highlights the importance of a bone marrow examination, including morphology, immunophenotyping, cytogenetic, and molecular examination in all cases to exclude the possibility of myeloid sarcoma, especially the morphological feature of bone marrow dysplasia in the early stage before AML.

CNS erythroblastic sarcoma: a potential emerging pediatric tumor type characterized by NFIA::RUNX1T1/3 fusions.

Erythroblastic sarcoma (ES) (previously called chloroma or granulocytic sarcoma) are rare hematological neoplams characterized by the proliferation of myeloid blasts at extramedullary sites, and primarily involve the skin and soft tissue of middle-aged adults. ES may be concomitant with or secondary to myeloid neoplasms (mostly acute myeloid leukemia (AML)) or in isolated cases (de novo) without infiltration of the bone marrow by blasts. ES share cytogenetic and molecular abnormalities with AML, including RUNX1T1 fusions. Some of these alterations seem to be correlated with particular sites of involvement. Herein, we report an isolated erythroblastic sarcoma with NFIA::RUNX1T1 located in the central nervous system (CNS) of a 3-year-old boy. Recently, two pediatric cases of CNS MS with complete molecular characterization have been documented. Like the current case, they concerned infants (2 and 3 years-old) presenting a brain tumor (pineal involvement) with leptomeningeal dissemination. Both cases also harbored a NFIA::RUNX1T3 fusion. ES constitutes a diagnostic challenge for neuropathologists because it does not express differentiation markers such as CD45, and may express CD99 which could be confused with CNS Ewing sarcoma. CD43 is the earliest pan-hematopoietic marker and CD45 is not expressed by erythroid lineage cells. E-cadherin (also a marker of erythroid precursors) and CD117 (expressed on the surface of erythroid lineage cells) constitute other immunhistochemical hallmarks of ES. The prognosis of patients with ES is similar to that of other patients with AML but de novo forms seem to have a poorer prognosis, like the current case. To conclude, pediatric ES with NFIA::RUNX1T1/3 fusions seem to have a tropism for the CNS and thus constitute a potential pitfall for neuropathologists. Due to the absence of circulating blasts and a DNA-methylation signature, the diagnosis must currently be made by highlighting the translocation and expression of erythroid markers.

Myeloid sarcoma and pathological fracture: a case report and review of literature.

Myeloid sarcoma is a rare clinical entity that presents as an isolated proliferation of leukemic cells, concurrently with or at relapse of acute myeloid leukemia (AML), myelodysplastic syndromes/neoplasms (MDS), chronic myeloid leukemia (CML), and myeloproliferative neoplasm (MPN). Myeloid sarcoma disrupts the normal architecture of its surrounding tissues. When it forms in long bones, it can cause their pathological fracture. We recently experienced a rare case of MDS presenting with myeloid sarcoma in the femur that eventually resulted in its pathological fracture. Detailed chromosomal analysis of the bone marrow cells suggested emergence of myeloid sarcoma during the fast-paced progression of MDS just after acquiring trisomy 22. A comprehensive review of previous cases of myeloid sarcoma-associated pathological fracture indicated possible involvement of structural rearrangements of chromosomes 9 and 22. Management of myeloid sarcoma should continue to improve, and clinicians should note that myeloid sarcoma with specific chromosomal alterations needs extra medical attention to prevent pathological fracture.

KAT6A::EP300 fusion in congenital myeloid sarcoma: Yet another novel molecular marker indicating spontaneous remission?: A case report.

RATIONALE: Acute myeloid leukemia (AML)/myeloid sarcoma (MS) is risk-stratified based on cytogenetics. Although most congenital AML/MS have a dismal prognosis, certain genetic variants such as t (8, 16) [KAT6A::cAMP response element-binding protein (CREB) - binding protein fusion] and more recently t (8, 22) [KAT6A::EP300 fusion] have shown spontaneous remissions. KAT6A located on chromosome 8p11 encodes KAT6A protein, a histone/lysine acetyltransferase enzyme. Numerous partner genes associated with KAT6A include cAMP response element-binding protein (CREB) - binding protein (16p13), EP300 (22q13), LEUTX (9q13), NCOA2, NCOA3, and ASXL2. PATIENT CONCERNS: In this article, we describe an otherwise healthy infant who presented with skin nodules on the face and scalp without any systemic or CNS involvement. A biopsy of the cutaneous lesion was consistent with congenital MS. DIAGNOSES: Through molecular testing, we found that our patient had the KAT6A::EP300 mutation. This is one of the rare recurrent cytogenetic abnormalities that are linked to congenital AML. INTERVENTION: Our patient underwent spontaneous remission with watchful waiting. OUTCOME: Our patient has remained in spontaneous remission for 24 months. LESSONS: Even though the KAT6A::EP300 mutation in adults is a poor prognostic marker, a similar mutation in congenital AML has a higher likelihood of spontaneous remission. Hence, conservative management might be an initial management strategy for clinically stable patients.

Myeloid sarcoma: more and less than a distinct entity.

Myeloid sarcoma (MS) is a distinct entity among myeloid neoplasms defined as a tumour mass of myeloid blasts occurring at an anatomical site other than the bone marrow, in most cases concomitant with acute myeloid leukaemia (AML), rarely without bone marrow involvement. MS may also represent the blast phase of chronic myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS). However, the clinical and molecular heterogeneity of AML, as highlighted by the 2022 World Health Organization (WHO) and International Consensus (ICC) classifications, indirectly define MS more as a set of heterogeneous and proteiform diseases, rather than a homogeneous single entity. Diagnosis is challenging and relies mainly on histopathology, immunohistochemistry, and imaging. Molecular and cytogenetic analysis of MS tissue, particularly in isolated cases, should be performed to refine the diagnosis, and thus assign prognosis guiding treatment decisions. If feasible, systemic therapies used in AML remission induction should be employed, even in isolated MS. Role and type of consolidation therapy are not univocally acknowledged, and systemic therapies, radiotherapy, or allogeneic hematopoietic stem cell transplantation (allo-HSCT) should be considered. In the present review, we discuss recent information on MS, focusing on diagnosis, molecular findings, and treatments also considering targetable mutations by recently approved AML drugs.

Myeloid sarcoma: An overview.

Myeloid Sarcoma (MS) is a high grade, hematological malignancy defined as an extramedullary tumor mass of myeloid blasts with or without maturation that effaces tissue architecture. It is a highly heterogenous condition that represents a variety of myeloid neoplasms. This heterogeneity of MS, together with its rarity, have greatly hampered our understanding of the condition. Diagnosis requires tumor biopsy, which should be accompanied by bone marrow evaluation for medullary disease. It is presently recommended that MS be treated similar to AML. Additionally, ablative radiotherapy and novel targeted therapies may also be beneficial. Genetic profiling has identified recurrent genetic abnormalities including gene mutations associated with MS, supporting its etiology similar to AML. However, the mechanisms by which MS homes to specific organs is unclear. This review provides an overview of pathogenesis, pathological and genetic findings, treatment, and prognosis. Improving the management and outcomes of MS patients requires a better understanding of its pathogenesis and its response to various therapeutic approaches.

Myeloid sarcoma in a newborn: A rare manifestation of congenital acute myeloid leukemia.

Cutaneous myeloid sarcoma is rarely present prior to the diagnosis of congenital acute myeloid leukemia (AML); the former is typically diagnosed with or after the leukemia. We report a 2-day-old male born with multiple cutaneous red to violaceous nodules. Histopathologic and immunohistochemistry findings from a skin nodule were suspicious for myeloid sarcoma. Bone marrow biopsy was initially negative for aberrant blasts; however, at age 4 months, AML with a KMT2A gene rearrangement was identified via bone marrow biopsy.

RNA sequencing of myeloid sarcoma, shed light on myeloid sarcoma stratification.

BACKGROUND: Myeloid sarcoma (MS) is a rare, extramedullary tumor consisting of myeloid blasts. Little is known about the genetic background of MS and the prognostic value of genetic abnormalities in MS. In particular, the broad variety of gene fusions that occur in MS is marginally covered by traditional testing methods due to lack of fresh tumor specimens. METHODS: Here, we analyzed the clinical and genetic features of 61 MS cases. We performed RNA sequencing (RNA-seq) on formalin-fixed paraffin-embedded (FFPE) or fresh samples to analyze fusion genes in 26 cases. In addition, we performed genetic abnormalities-based risk stratification using fusion genes and gene mutations. RESULTS: A total of 305 fusion genes were identified in 22 cases, including the following five recurrent fusion genes: RUNX1-RUNX1T1, CBFß-MYH11, ETV6-MECOM, FUS-ERG, and PICALM-MLLT10. The prognosis in the adverse-risk group was significantly worse than that in the favorable/intermediate-risk group (median survival: 12 months vs. not reached; p = 0.0004). CONCLUSION: These results indicated the efficacy of RNA-seq using FFPE-derived RNA as a clinical routine for detecting fusion genes, which can be used as markers for risk stratification in MS.

Gene Mutations and Targeted Therapies of Myeloid Sarcoma.

OPINION STATEMENT: Myeloid sarcoma, a rare malignant tumor characterized by the invasion of extramedullary tissue by immature myeloid cells, commonly occurs concomitantly with acute myeloid leukemia, myelodysplastic syndromes, or myeloproliferative neoplasms. The rarity of myeloid sarcoma poses challenges for diagnosis and treatment. Currently, treatments for myeloid sarcoma remain controversial and primarily follow protocols for acute myeloid leukemia, such as chemotherapy utilizing multi-agent regimens, in addition to radiation therapy and/or surgery. The advancements in next-generation sequencing technology have led to significant progress in the field of molecular genetics, resulting in the identification of both diagnostic and therapeutic targets. The application of targeted therapeutics, such as FMS-like tyrosine kinase 3(FLT3) inhibitors, isocitrate dehydrogenases(IDH) inhibitors, and the B cell lymphoma 2(BCL2) inhibitors, has facilitated the gradual transformation of traditional chemotherapy into targeted precision therapy for acute myeloid leukemia. However, the field of targeted therapy for myeloid sarcoma is relatively under-investigated and not well-described. In this review, we comprehensively summarize the molecular genetic characteristics of myeloid sarcoma and the current application of targeted therapeutics.

Myeloid sarcoma with NPM1 mutation may be clinically and genetically distinct from AML with NPM1 mutation: a study from the Bone Marrow Pathology Group.

Myeloid sarcoma (MS) is currently considered equivalent to de novo acute myeloid leukemia (AML); however, the relationship between these entities is poorly understood. This retrospective multi-institutional cohort study compared 43 MS with NPM1 mutation to 106 AML with NPM1 mutation. Compared to AML, MS had more frequent cytogenetic abnormalities including complex karyotype (p = .009 and p = .007, respectively) and was enriched in mutations of genes involved in histone modification, including ASXL1 (p = .007 and p = .008, respectively). AML harbored a higher average number of gene mutations (p = .002) including more frequent PTPN11 mutations (p < .001) and mutations of DNA-methylating genes including DNMT3A and IDH1 (both p < .001). MS had significantly shorter overall survival (OS) than AML (median OS: 44.9 vs. 93.2 months, respectively, p = .037). MS with NPM1 mutation has a unique genetic landscape, and poorer OS, compared to AML with NPM1 mutation.

First study comparing genetic profiles of MS and AML with a common disease-defining lesion.NPM1^Mut MS may be genetically distinct from NPM1^Mut AML.NPM1^Mut MS may have inferior overall survival compared to NPM1^Mut AML.

Malignant Progression of an Ancestral Bone Marrow Clone Harboring a CIC-NUTM2A Fusion in Isolated Myeloid Sarcoma.

Myeloid sarcoma is a rare condition consisting of extramedullary myeloid blasts found in association with acute myeloid leukemia or, in the absence of bone marrow involvement. We identified an infant with isolated myeloid sarcoma whose bone marrow was negative for involvement by flow cytometry. Sequencing revealed the fusion oncogene CIC-NUTM2A and identified the sarcoma to be clonally evolved from the bone marrow, which carried the fusion despite the absence of pathology. Murine modeling confirmed the ability of the fusion to transform hematopoietic cells and identified receptor tyrosine kinase (RTK) signaling activation consistent with disruption of the CIC transcriptional repressor. These findings extend the definition of CIC-rearranged malignancies to include hematologic disease, provide insight into the mechanism of oncogenesis, and demonstrate the importance of molecular analysis and tracking of bone marrow involvement over the course of treatment in myeloid sarcoma, including patients that lack flow cytometric evidence of leukemia at diagnosis. IMPLICATIONS: This study illustrates molecular involvement of phenotypically normal bone marrow in myeloid sarcoma, which has significant implications in clinical care. Further, it extends the definition of CIC-rearrangements to include hematologic malignancies and shows evidence of RTK activation that may be exploited therapeutically in cancer(s) driven by these fusions.

Clinicopathological characteristics, genetics and prognosis of patients with myeloid sarcoma: a single-center study.

AIM: Myeloid sarcoma (MS) is a rare tumour comprising myeloid blasts occurring at an anatomical site other than the bone marrow. We sought to investigate both paediatric and adult patients with MS diagnosed at our institution and determine possible correlations among their clinicopathological, phenotypic, molecular and prognostic features. METHODS: This study retrospectively evaluated the data of 45 patients diagnosed with MS at Ege University Faculty of Medicine Hospital, Turkey, over a 17-year period. RESULTS: The male-to-female ratio was 1.5:1, and the median age was 39.12 years. The most commonly involved sites were the skin, lymph nodes, soft tissues and bone. Immunohistochemically, CD68-KP1 was the most commonly expressed marker, followed by CD33, myeloperoxidase, CD117, lysozyme, CD68-PGM1 and CD34. Of the patients, 26 (57.7%) presented with de novo MS, 7 (15.5%) had simultaneous acute myeloid leukaemia and 12 (26.8%) had a previous history of haematological disorders. Kaplan-Meier survival analysis revealed that the 2-year and 5-year overall survival (OS) rates were 46.4% and 39.8%, respectively; the median OS duration was 11 months. Increasing age had a negative prognostic relationship with survival (p = 0.04). Chromosomal abnormalities were detected in approximately 6/10 (60%) of paediatric patients and 6/9 (66.7%) of adult patients. t(8;21)(q22;q22) translocation was identified in 20% of paediatric patients. CONCLUSIONS: MS diagnosis is usually challenging; an expanded immunohistochemical panel should be used for an accurate diagnosis. Although MS generally has a poor prognosis, increasing age appears to be associated with a worse outcome.

Myeloid Sarcoma of the Breast as Blast Phase of JAK2-Mutated (Val617Phe Exon 14p) Essential Thrombocythemia: A Case Report and a Systematic Literature Review.

INTRODUCTION: Myeloid sarcoma (MS) is a mass-forming proliferation of myeloid blasts. Frequently, it arises as blast phase of pre-existing myeloproliferative, myelodysplastic disorders or consequent to bone marrow transplant. Its molecular characterization has become an increasingly important requirement for the diagnostic definition of this solid leukemia. CASE PRESENTATION: Our case report concerns an MS arising in the breast of a woman with a previous diagnosis of JAK2-mutated essential thrombocythemia (Val617Phe exon 14p) mimicking, on histology, a lobular carcinoma of the breast. The immunohistochemical study of the neoplasm provided the key that solved the diagnostic doubt and the immunohistochemical evaluation of NPM protein expression, which turn out to be negative, provided a clear indication on the molecular status and prognosis of the disease. A year later, the neoplasm relapsed in the pelvic area. DISCUSSION: This diagnostic challenge led us to review the literature of the past 10 years concerning MS of the breast. To the best of our knowledge, this was the first case of MS of the breast occurring in a patient with a history of essential thrombocythemia and recurred in the pelvic region.