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.

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.

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.

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.

Systemic mastocytosis with myeloid sarcoma and B-CLL: molecular and clonal heterogeneity in a rare case of SM-AHN with review of literature.

BACKGROUND: Systemic mastocytosis (SM) is a rare myeloproliferative disease that results from a clonal proliferation of abnormal mast cells in one or more extra-cutaneous organs. Systemic mastocytosis with an associated hematological neoplasm (SM-AHN) is the second most common subgroup and is diagnosed when WHO criteria for both SM and a hematological neoplasm of non-mast cell lineage are met. The SM-AHN category as currently proposed is highly heterogeneous in terms of pathogenesis, clinical presentation, and prognosis. CASE PRESENTATION: We present the first reported case of SM-AHN associated with two hematological malignancies of different lineages, a monocytic myeloid sarcoma and a B-cell chronic lymphatic leukemia. Cytogenetic and molecular analyses revealed a distinct clonal origin of the two associated malignancies. The SM-myeloid sarcoma clone demonstrated an abnormal karyotype, trisomy 8 and del(13)(q12.3q14.3), as well as mutations in KITD816V, DNMT3A and RUNX1. The DNMT3A mutation could be detected years before disease onset, supporting its potential role as early driver of leukemogenesis. No genetic aberrations could be identified in the CLL clone, which is assumed to present coincidentally. CONCLUSIONS: This report highlights the importance of full diagnostic work-up in SM patients in whom an associated hematological malignancy is suspected. Moreover, the importance of genetic analysis is highlighted, as it provides additional insights in the underlying clonal pathogenesis of different phenotypes, can aid in risk stratification, and may help identify potential therapy targets.

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.

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: Features in Cytological Preparations and the Utility of Rapid On-Site Evaluation (ROSE) in Triage.

INTRODUCTION: Myeloid sarcoma (MS) is a rare extramedullary tumor consisting of blasts of granulocytic, monocytic, erythroid, or megakaryocytic lineage that disrupts the architecture of the involved tissue. MS shows vast clinical, morphologic, immunophenotypic, and genetic heterogeneity posing a diagnostic dilemma, especially in small biopsy specimens such as fine-needle aspiration (FNA) and core biopsy. The objective of this study is to highlight the morphologic features of MS in cytological preparations and investigate the efficacy of pathologist-performed rapid on-site evaluation (ROSE) in assuring accurate triage. METHODS: A retrospective review was performed for cases of MS with concurrent cytology and ROSE results from 2006 to 2017. FNA smears and touch preparations were reviewed, and the results of ROSE, immunohistochemistry (IHC), flow cytometric immunophenotyping (FCI), cytogenetics/FISH, and histology were analyzed. RESULTS: A total of 15 cases were found including 6 (40%) with monocytic morphology comprising promonocytes and monoblasts and 9 (60%) with conventional myeloblastic morphology. The most common genetic subgroup was KMT2A-rearranged MS (33.3%) followed by extramedullary blast crisis of chronic myeloid leukemia (26.6%). ROSE provided sufficient preliminary information and ensured the procurement of adequate tissue for histology, IHCs, FCI, and cytogenetics/FISH, leading to an accurate and complete diagnosis of MS in all cases. DISCUSSION/CONCLUSION: MS is a rare malignancy that shows pronounced clinical, morphologic, immunophenotypic, and genetic heterogeneity that often overlaps with other neoplastic and non-neoplastic entities. Features including the presence of classic myeloblasts, promonocytes, monoblasts, nucleated red blood cells, left-shifted granulocytes, cytoplasmic granules, and pseudopods are helpful hints in cytological preparations. In the modern era where pathologists are increasingly expected to do extensive diagnostic, molecular, and therapeutic biomarker testing on tissue that is historically diminishing in size, ROSE is a highly effective tool to ensure effective triage of MS aiding in an accurate, timely, and complete diagnosis.

A ZBTB16-RARα Variant of Acute Promyelocytic Leukemia with Concurrent Myeloid Sarcoma Presenting as Sudden Onset Paraplegia.

BACKGROUND: The co-occurrence of myeloid sarcoma (MS) and acute promyelocytic leukemia (APL) is a rare clinical event. METHODS: A 56-year-old man presented with lower extremity paralysis that occurred 6 hours before admission. Magnetic resonance imaging revealed an epidural mass. RESULTS: Histopathological examination demonstrated an extramedullary myeloid malignancy. Bone marrow examination showed abnormal promyelocytes and dysplasia, and an immunophenotyping study indicated very strong myeloperoxidase activity, suggesting APL. CONCLUSIONS: The final diagnosis given was spinal MS with a ZBTB16-RARα variant of APL. The possibility that patients with rapidly progressive neurologic symptoms could have MS and concurrent APL should be considered.

Identification of RCC1-LCK as a novel fusion gene in pediatric erythroid sarcoma.

Erythroid sarcoma is a very rare subtype of myeloid sarcoma with undetermined biological features. Here, we present an infant with a multifocal erythroid sarcoma, diagnosed because the tumor cells were positive for glycophorin A. After acute myeloid leukemia-oriented chemotherapy and surgical resection followed by cord blood transplantation, he has successfully maintained complete remission without any late effects. Total transcriptome analysis of the tumor identified a novel fusion gene, RCC1-LCK, and high LCK expression levels, suggesting that LCK overexpression was involved in leukemogenesis in this case.

The transformation of isolated gastric myeloid sarcoma into acute myeloid leukemia presenting with a complex karyotype and TLS-ERG gene fusion: A case report.

RATIONALE: Isolated myeloid sarcoma (MS) is characterized by the rapid proliferation of myeloblasts of acute myeloid leukemia (AML), without any blood or bone marrow involvement. This disease can manifest with extramedullary organ involvement, such as the skin, lymph nodes, bone, brain, breast cervix, and visceral organs, while the occurrence of myeloid sarcomas in the stomach is rare. Isolated MS has been associated with acute myeloid leukemia (AML), but the rapid progression of MS to acute myeloid leukemia with a complex karyotype and TLS-ERG fusion gene is even rarer. PATIENT CONCERNS: A 33-year-old woman suffered from persistent epigastric pain accompanied by two months of anorexia and nausea, as well as 1-week of melena. DIAGNOSIS: This patient was initially diagnosed with gastric MS that eventually transformed into AML with a complex karyotype and TLS-ERG fusion gene, 4 months later. INTERVENTIONS: Only palliative care, including nutrition support, antacids, blood transfusion, anti-infection methods were used on this patient to determine the cachexia status and the family's requirement. OUTCOMES: Routine follow-up results demonstrated this patient had died due to cerebral hemorrhage five months after the diagnosis of MS. LESSONS: Comprehensive integration of patient history, imaging features, mass and bone marrow biopsy, and molecular cytogenetic may provide insights that could help us avoid the misdiagnosis of gastric MS. Isolated gastric MS can rapidly progress to AML with a poor prognosis if the patient does not receive appropriate treatment.