Extramedullary Manifestations Research Articles

Myeloid Sarcoma of the Colon Initially Presenting as a Paracolic Abscess in a Patient with Relapsed Acute Myeloid Leukemia.

Myeloid sarcoma, a rare extramedullary manifestation of acute myeloid leukemia (AML), can occur in various anatomic sites but seldom involves the gastrointestinal tract. We report the unusual case of a 49-year-old man with a history of AML who initially presented with abdominal pain and imaging findings suggestive of a paracolic abscess. However, the lesion rapidly progressed to a large descending colon mass with peritoneal involvement over five weeks. Surgical resection and histopathological examination confirmed a diagnosis of myeloid sarcoma. This case highlights the potential of myeloid sarcoma to mimic an inflammatory colonic process at initial presentation prior to manifesting as an overt mass lesion. Although exceedingly rare, myeloid sarcoma should be considered in patients with a history of AML presenting with colon lesions, particularly in those with an aggressive clinical course. Early recognition may expedite appropriate treatment and prevent unnecessary procedures. This report also underscores the importance of correlating imaging findings with clinical history and histopathology findings to establish an accurate diagnosis.

Waldenstrom Macroglobulinemia Recurrence with Bing–Neel Syndrome Presentation

Bing–Neel syndrome (BNS) is a rare condition that may occur in patients with Waldenstrom macroglobulinemia (WM) and is caused by lymphoplasmacytic infiltration into the central nervous system. BNS is an extramedullary manifestation of WM which may present with various neurological signs and symptoms that make the diagnosis difficult to achieve. We present a case of BNS in a 60-year-old patient diagnosed 6 years after recovering from Waldenstrom’s macroglobulinemia. We observed the patient for a secondary generalized focal motor seizure. Unenhanced brain CT revealed slight hyperdensity of left parietal subarachnoid spaces. The MRI of the brain and spinal cord showed leptomeningeal enhancement in both parietal lobes. The presence of monoclonal bands (light chain k and IgM) was found in cerebrospinal fluid, leading to the diagnosis of BNS. The patient started treatment with ibrutinib and remains clinically stable during a 1-year follow-up. However, the MRI showed the appearance of a new subcortical left parietal lesion. BNS is an extremely rare presentation of WM that should be recognized and considered early in the presence of unexplained neurological symptoms in patients with a history of WM, even if the patient appears to have recovered.

Atypical Presentation of Acute Suppurative Otitis Media with Facial Palsy: Extra Medullary Manifestation of AML in Temporal Bone

Atypical Presentation of Acute Suppurative Otitis Media with Facial Palsy: Extra Medullary Manifestation of AML in Temporal Bone

An unusual testicular mass: myeloid sarcoma as a rare extramedullary manifestation of acute myeloid leukemia

BackgroundWe report an unusual testicular mass with small bowel and retroperitoneal lymph node deposit proven to be myeloid sarcoma after complete histopathological and hematological workup. Myeloid sarcoma (MS) usually involves lymph nodes and head and neck regions. Uncommon sites like testis and ovary are rarely involved and pose a diagnostic challenge. Extramedullary myeloid sarcoma is most commonly associated with hematological malignancies like acute myeloid leukemia and myelodysplastic syndromes. It can precede or co-occur with AML. Considering it as a differential diagnosis in atypical presentation of testicular tumor helps in early treatment.Case presentationWe present a case of TMS with small bowel and retroperitoneal deposits presenting initially as intussusception and a vague scrotal pain. The patient underwent unilateral left radical inguinal orchidectomy. Surgical pathology revealed myeloid sarcoma of the testicle. And later jejunojejunostomy was done for small bowel deposit causing obstruction with retroperitoneal lymph node biopsy taken which revealed granulocytic sarcoma deposit. He developed peripheral blood involvement 4 weeks postoperatively, and bone marrow biopsy showed acute myeloid leukemia.ConclusionsWith very short median survival period of 7.5 months, high index of suspicion is required where multifocal lesions are observed in various sites as in our case.

Isolated Myeloid Sarcoma in the Nasal Cavity Without Bone Marrow Involvement in a 5-Year-Old Child

Isolated myeloid sarcoma is a rare extramedullary manifestation, characterized by the presence of myeloid blasts in the body and occurring without bone marrow involvement. While the isolated myeloid sarcoma involvement in the nasal cavity of adults has been reported sparsely, there have been no documented cases involving children in South Korea. Given its rarity, diagnosing isolated myeloid sarcoma is challenging without resorting to a biopsy accompanied by a comprehensive panel of immunohistochemistry. In this context, we present a case of a 5-yearold child diagnosed with isolated myeloid sarcoma situated within the right nasal cavity. Notably, this case is unique as there is no evidence of bone marrow invasion or underlying hematological disorders.

Compound Angiotrophic Biphasic Myeloid Sarcoma with JAK2 (V617F) and KRAS (G12C) mutations

Introduction. Myeloid sarcomas (MS) are extramedullary manifestations of myeloid neoplasms, associated with conditions like acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPN). MS presents as tumor masses in various body sites, often expressing myeloid or monocytic markers. This case report details an unusual biphasic MS relapse with a significant “intravascular” component. Materials and methods. A 59-year-old male with a history of JAK2-V617F positive MDS/MPN underwent allogeneic hematopoietic stem cell transplantation and presented with abdominal pain, skin lesions, and systemic symptoms. Biopsy of colonic masses was performed, and subsequent analysis was carried out. Results. The biopsy revealed a neoplasm with solid and intravascular components. The solid part was mainly composed of monocytic lineage cells expressing specific markers, with a small population of myeloid blasts. In contrast, the “intravascular” component was mainly myeloid blasts expressing different markers. Genetic analysis uncovered JAK2 (V617F) and KRAS (G12C) mutations. Despite treatment, the disease progressed, and the patient eventually passed away. Conclusions. Myeloid sarcomas are challenging to diagnose, often being mistaken for large cell lymphomas. They can manifest as isolated extramedullary relapses, with a unique molecular profile. This case stands out due to its biphasic nature, featuring distinct components with differing characteristics, which has not been documented previously in English literature. It underscores the intricate and diverse nature of myeloid sarcomas, emphasizing the need for further research to comprehend their biology and behavior effectively.

Acute myelomonoblastic leukemia in children, the particularities of extramedullary infiltration based on a clinical case

Childhood acute myeloidleukemia (AML) represents approximately 5% of childhood malignancies and 15% to 25% of pediatric acute leukemia. The extramedullary manifestation of infiltrating clonal blast populations in a variety of organs and tissues in acute myeloid leukemia (AML) is defined as a distinct entity in the 2016 WHO classification of myeloid neoplasms, myeloid sarcoma The rate of complete remission after induction chemotherapy was lower in patients with extramedullary infiltration, overall survival and event-free survival were not different between patients with and without extramedullary infiltration. Purpose of the study: Presentation of a clinical case of ALM type M4 with the presence of an extramedullary infiltrate in the tissue of the central nervous system in children. Materials and methods: The clinical, paraclinical, imaging data of the patient were studied in parallel with the specialized literature on similar cases. Results: Boy, 5 years old, goes to the doctor with accusations of bilateral palpebral edema, bilateral temporal region edema and bilateral exophthalmos , more pronounced on the left. In the general analysis of the blood: - Hemoglobin - 89 g/l , Leukocytes - 7.2 x 10^9/l; unsegmented neutrophil - 1%; segmented - 18%; lymphocytes - 44%; monocytes - 20%; blast cells - 16%; Platelets - 70 x 10^9/l;VSH - 44 mm/h. During the physical examination: the peripheral lymph nodes are palpable. No signs of central nervous system damage. It is supposed the diagnosis: Acute myeloid leukemia, sarcoma, or neuroblastoma. A medullary puncture: moderately cellular marrow was determined, with blastcells 15.2%. Morphologically, it is more similar to acute myelo-monoblastic leukemia FAB-M4. Computerized Tomography-multiple, hyperdense pathological foci, with localization with inand bilateral extraorbital, associated with exophthalmos. The formation from the sphenoid sinus extends to the nasopharynx , through the pterygopalatine fossa, with narrowing of the lumen and mass effect on the palatine tonsils. Immunophenotyping: CD45-/+ SS low 8% population, CD36+ 6%CD64+ monoblasts 8%, Promonocytes /monocytes – (CD64+/CD14+) 25%.He underwent treatment according to the AML BFM 2004 program with numerous complications, andcranial radiotherapy. At the moment, the child is in morphological remission. Conclusions. The differential diagnosis of hyperdense intracranial masses may include neuroblastoma, meningioma, lymphoma, metastases, or sarcomas. Correct and early diagnosis and initiation of specific treatment are essential to increase the survival rate in cases of acute leukemia in children.

Detection of Isolated Extramedullary AML Using Next-Generation Sequencing of Cell-Free DNA

Introduction Isolated extramedullary (IEM) manifestation of AML is a recurrent event especially after allogenic hematopoietic cell transplantation (alloHCT). To date, measurable residual disease (MRD) assessment for early detection and monitoring of this difficult-to-treat patient cohort has not been established. Using cell-free DNA (cfDNA) from plasma or serum for MRD measurement shows comparable sensitivity to bone marrow mononuclear cells (BMMCs) and improved sensitivity over peripheral blood mononuclear cells (PBMCs) in medullary AML (Nakamura et al., Blood, 2019). Here, we evaluate next-generation sequencing (NGS) for MRD assessment of cfDNA in a cohort of patients with IEM AML. Methods We retrospectively collected tumor tissue and matched BMMC/PBMCs and cfDNA serum or plasma samples from IEM AML patients at our institution. BMMC/PBMCs and IEM tumor tissue were sequenced with 35- to 48-gene panels at diagnosis and relapse. Amplicon-based NGS-MRD (sensitivity 0.01%) of matched cfDNA and BMMC/PBMCs was quantified at time of IEM manifestation and in all available samples collected up to 12 months before IEM manifestation using the known mutations from IEM AML tissue. Amplicon-based NGS and bioinformatic error-correction was conducted and analyzed as previously described (Thol et al., Blood, 2018). Results We identified a cohort of 15 IEM AML patients at our institution. One patient was diagnosed with IEM AML at first diagnosis, 14 patients suffered from IEM relapse. For three patients, matched BMMC/PBMCs and cfDNA samples were collected from a second IEM AML relapse during the disease course. 15 of 18 IEM AML episodes (83%) occurred as relapse after alloHCT. 42 AML-related mutations were identified in the IEM AML tissue with a median of three mutations per patient (range 1-5). 33 of 39 mutations (85%) found in IEM relapse tissue had been already present at first diagnosis. All mutations were then evaluated in cfDNA and BMMCs at the time of the IEM manifestation by sensitive NGS-MRD analysis for all 18 IEM AML episodes. For two IEM episodes, BMMCs were not available and PBMCs were used instead. 17 of 18 (94%) cfDNA samples were NGS-MRD positive at the time of IEM manifestation, while only 8 of 18 (44%) BMMC/PBMC samples were positive. 20 of 53 mutations (38%) at first and second IEM episode could only be detected using cfDNA, 15 mutations (28%) were detected in both cfDNA and BMMC/PBMCs and only one mutation was solely found in BMMCs. 17 mutations (32%) could not be detected by either method (Figure 1). The variant allele frequency (VAF) of mutations detected by both methods was significantly higher using cfDNA with a median VAF of 2.45% (range 0.12 - 24%) compared to BMMC/PBMCs with a median VAF of 0.048% (range 0.13 - 10%; p < 0.01). Median VAF of mutations that were only found in cfDNA was 0.63% (range 0.017 - 39.6) and did not significantly differ from the cfDNA VAF of mutations that were found by both methods (p=0.43), indicating that these mutations represented the major clone. However, no correlation was found between IEM tumor VAF and cfDNA VAF (r=0.01; p=0.95). For ten IEM episodes from nine patients at least one cfDNA sample was available within 12 months before IEM relapse. In six IEM episodes (60%) cfDNA samples were MRD positive, one at 6 months, one at 5 months, two at 3 months and two at 2 months before IEM relapse. In four IEM episodes (40%) cfDNA samples were MRD negative, one at 10 months, one at 5 months and two at 2 months before IEM relapse. Conclusion In summary, cfDNA analysis from serum or plasma of AML patients can identify the molecular characteristics of a large proportion of patients with IEM AML. More than one third of clinically relevant mutations could only be detected using cfDNA and were missed by NGS-MRD of BMMC/PBMCs. Our data suggest that MRD monitoring from cfDNA detects IEM relapse earlier than routine monitoring from PB or BM in a significant proportion of patients.

Protective Function of Human Skin Mesenchymal Niches for Acute Myeloid Leukemia-Initiating Stem Cells

Leukemia cutis (LC) or leukemic cell infiltration in skin is one of the common extramedullary manifestations in acute myeloid leukemia (AML) and signifies a poorer prognosis. However, the pathogenesis and maintenance of LC have been understudied, limiting our understanding of its impact on AML progression and relapse. We recently have shown that the AML cells infiltrated in the mouse skin during steady state and after chemotherapy were capable to regenerate AML after serial transplantation (Sandhow et al., J. Exp. Med, 2023). Further characterization of the skin mesenchymal stem cells (MSCs) suggests that skin MSCs could maintain AML-initiating stem cells (LSCs) and protect them from chemotherapy, even to a greater degree than their bone marrow (BM) counterparts. These data suggest the protective role of skin mesenchymal niche in AML LSCs during chemotherapy. However, it remains unexplored whether human skin MSCs exert the same functional impact on human AML cells. We here have explored the role of human skin MSCs in AML maintenance and survival during chemotherapy by RNA sequencing and in vitro co-culture of patient-derived AML cells with primary human skin MSCs in comparison with BM MSCs. We first by prospective characterization identified human skin MSCs with a phenotype of CD45-CD235a-CD31-CD44+CD146- from healthy donors. RNA sequencing and Q-PCR revealed expression of key hematopoietic stem cell (HSC) regulatory genes including THPO, SCF, CXCL12 and LAMA4 in human skin MSCs. Interestingly, while HSC maintenance genes such as THPO and KITLG were significantly upregulated in skin MSCs (p<0.0001 and p<0.05, respectively), HSC negative regulator SPP1 was downregulated (p=0.05), pointing to a possible better hematopoiesis-supportive function of skin MSCs. In line with this, our functional studies indicated that skin MSCs displayed a superior protective effect on human AML cell line THP-1 than their BM cell counterparts during cytarabine (Ara-C) treatment in the in vitro co-culture. There were more residual chemo-resistant AML cells, reflected in the higher number of CD36+ AML cells after treatment with Ara-C in cocultures with skin MSCs, compared to that with BM MSCs (p=0.0065). This result was confirmed by functional assays showing the increased number of cobblestone area-forming cells (p=0.0298) and colony-forming units (p=0.038) within the residual AML cells co-cultured with skin MSCs. To investigate the mechanisms involved in the protective function of human skin MSCs, we have performed RNA-sequencing of the human skin and BM MSCs before and after co-culture with AML cells. This has revealed potential unique molecular pathways between AML and skin MSCs. Furthermore, there were dramatically less altered genes in the skin MSCs compared to BM MSCs after 3 day-coculture with THP1 AML cells (221 vs 1761 altered genes with adjusted p values <0.05). These data indicate that skin MSCs are likely more resistant to AML-remodeling, which could in turn maintain AML cells in quiescence status, thereby protecting AML cells from Ara-C treatment. This speculation is currently under validation. In addition, gene set enrichment analysis showed upregulated genes associated with fatty acid metabolisms and ribosome in skin MSCs compared to BM MSCs, providing molecular evidence for a potential better metabolic support of skin MSCs for AML cells. Taken together, our preliminary data indicate an important role of human skin MSCs in supporting and protecting AML cells during Ara-C treatment. We are further investigating the underlying mechanisms.

Encouraging Outcome of AML with t(8;16) Following Allogeneic Stem Cell Transplantation in First Remission - a Retrospective Analysis on Behalf of the Acute Leukemia Working Party of the EBMT

In the 2022 European Leukemia Net (ELN) risk classification, acute myeloid leukemia (AML) with translocation t(8;16) was newly classified as AML defined by specific cytogenetic abnormalities, associated with unfavorable prognosis. Translocation (8;16)(p11;p13) is a rare abnormality in AML with female preponderance and occurs more frequently in secondary AML (sAML), especially therapy-related, than in de novo disease. Clinically, AML with t(8;16) is associated with high risk of bleeding, occurrence of extramedullary manifestations, myelomonocytic differentiation, and signs of hemophagocytosis in the bone marrow. The translocation leads to the fusion of acetyltransferase KAT6A (also known as MOZ or MYST3) and CREB binding protein ( CREBBP) genes, both of them involved in hematopoiesis. ELN risk stratification of AML with t(8;16) was based on studies that included relatively low numbers of patients receiving allogeneic stem cell transplantation (alloSCT). In the largest report by Kayser et al. ( Br J Haematol 2021) 21 patients (15 transplanted in first complete remission [CR1], median follow-up 5.5 years) were analyzed. A 5-year overall survival (OS) of 38% was achieved after alloSCT compared to 11% in patients who received chemotherapy only. The aim of our study was to evaluate the outcome of patients with AML harboring t(8;16) after alloSCT in a larger cohort from the EBMT registry. All types of donor, conditioning regimen and graft were included. Sixty patients were identified, of whom 44 had been transplanted in CR1. Median follow-up from alloSCT was 72.3 months, median age was 46.3 years, and 73.3% were female. Karnofsky performance status was >80% in 59 patients, one had missing data. At 2 years after alloSCT, OS and leukemia free survival (LFS) of the entire cohort were 42.7% and 42.2%, respectively, (28.6% and 14.3% in patients transplanted in advanced disease). Cumulative incidence of relapse (RI) and non-relapse mortality (NRM) at two years was 36.9% and 15.3%, respectively, in patients transplanted in CR1, and 78.6% and 7.1%, respectively, in patients transplanted in advanced disease. The 44 patients transplanted in CR1 were analyzed in detail. Basic characteristics were comparable to the entire cohort as described above. Twenty-two of the patients had de novo, 22 had sAML. According to the ELN 2017 classification (not yet including t(8;16) as a factor for poor prognosis), 54.5% had an intermediate and 45.5% an adverse cytogenetic risk. Furthermore, 38.8% had a complex karyotype. Donors were matched related in 34%, matched unrelated in 54%, haploidentical in 5% and cord blood in 7%. Conditioning was myeloablative in 52.3%, whereas 47.7% had received reduced intensity conditioning. Among patients transplanted in CR1, 2- and 5-year OS from alloSCT was 48% and 39.9%, the respective LFS was 46.8% and 35.5%. On multivariate analysis (MVA), harboring t(8;16) within a complex karyotype was the major risk factor for outcome, being associated with higher RI (hazard ratio [HR] 3.38, p=0.01), lower LFS (HR 4.17, p=0.016), and lower OS (HR 3.08, p=0.017). In contrast, patients with t(8;16) outside of a complex karyotype achieved excellent results (Figure 1). Besides a complex karyotype, MVA revealed sAML as an additional, independent risk factor with a higher RI (HR 3.73, p=0.026). Age was the major factor for NRM, reaching 5% vs. 26.5% in patients below or above the median (p=0.02). In conclusion, according to the largest series analyzed in this setting so far, overall results after alloSCT in AML with t(8;16) transplanted in CR1 were favorable, especially in patients without multiple additional cytogenetic abnormalities, achieving a low risk of relapse and a 5-year OS >60%. Hence, alloSCT in CR1 appears to abrogate the unfavorable prognostic value of this translocation. Whether or not t(8;16) does have any additional influence on the outcome of patients with a complex karyotype remains to be evaluated. Figure Legend Figure 1: Outcome of AML with t(8;16) with and without complex karyotype

P26 Leukaemia cutis as the first manifestation of acute myeloid leukaemia

Abstract Leukaemia is the most frequent malignancy of childhood, accounting for approximately 30% of all malignancies. Acute leukaemia may present in a variety of extramedullary manifestations, the commonest being leukaemia cutis (LC). LC is the infiltration of the epidermis, dermis or subcutis by neoplastic leukocytes with skin lesions preceding the development of leukaemia in the peripheral blood or bone marrow in just 2–3% of cases. A 6-month-old baby girl was reviewed due to multiple skin lesions which appeared on her left forearm 2 months previously, and spread widely, showing over 50 in the following weeks. They were well-circumscribed, nontender, violaceous nodules. She was clinically well and thriving with no lymphadenopathy or organomegaly. Blood tests and abdominal ultrasound were normal. A skin biopsy of a nodule demonstrated an infiltrate of medium-sized atypical cells involving the dermis and subcutis. Immunostaining showed CD45 expression and the Ki67 proliferation index was high, in keeping with a leukaemic infiltration. Cytogenetics performed on the skin biopsy showed KMT2A rearrangement by FISH. Bone marrow aspirate confirmed the diagnosis of acute myeloid leukaemia with monoblastic morphology, and cytogenetics confirmed the rearrangement as a KMT2A–MLLT10 fusion, which is classified as poor cytogenetic risk. Cerebrospinal fluid analysis was negative. It is vital to get a histological diagnosis (with cytogenetics) in a child presenting with violaceus nodular lesions even if the child is well. Importantly, LC can present with a normal full blood count. A bone marrow aspiration is paramount to confirm the diagnosis. Once leukaemia is diagnosed, cytogenetics plays a key role in stratifying treatment intensity.

Skin mesenchymal niches maintain and protect AML-initiating stem cells.

Leukemia cutis or leukemic cell infiltration in skin is one of the common extramedullary manifestations of acute myeloid leukemia (AML) and signifies a poorer prognosis. However, its pathogenesis and maintenance remain understudied. Here, we report massive AML cell infiltration in the skin in a transplantation-induced MLL-AF9 AML mouse model. These AML cells could regenerate AML after transplantation. Prospective niche characterization revealed that skin harbored mesenchymal progenitor cells (MPCs) with a similar phenotype as BM mesenchymal stem cells. These skin MPCs protected AML-initiating stem cells (LSCs) from chemotherapy in vitro partially via mitochondrial transfer. Furthermore, Lama4 deletion in skin MPCs promoted AML LSC proliferation and chemoresistance. Importantly, more chemoresistant AML LSCs appeared to be retained in Lama4-/- mouse skin after cytarabine treatment. Our study reveals the characteristics and previously unrecognized roles of skin mesenchymal niches in maintaining and protecting AML LSCs during chemotherapy, meriting future exploration of their impact on AML relapse.

Imaging features of nodular hepatic multiple myeloma localizations: a review of the literature

INTRODUCTION: Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells confined to the bone marrow. Extramedullary manifestations of multiple myeloma can occur in many different sites, including soft tissues and internal organs. Although rare, it is important to keep in mind the radiological features of nodular lesions of hepatic MM, especially in the presence of suggestive clinical manifestations. Considering that there are few studies describing this phenomenon, starting from a case report we conducted a review of the available literature on this topic. Therefore, the main purpose of this study is to describe the radiological characteristics of liver MM lesions using ultrasonography (US), computerized tomography (CT) and magnetic resonance imaging (MRI) scans.EVIDENCE ACQUISITION: A search on PubMed was conducted up to the end of January 2023. We included articles that reported radiological findings of nodular liver lesions in MM patients using at least one of ultrasound, computed tomography, and magnetic resonance imaging.EVIDENCE SYNTHESIS: Among the studies, the most frequent US pattern was hypoechoic nodules. Most studies described intrinsically hypodense lesions in unenhanced CT scans and varying degrees of enhancement in the arterial phase, suggesting hypervascularized lesions. We found only six articles in scientific literature reporting the MRI features of hepatic nodular myelomatous lesions, with very heterogeneous results.CONCLUSIONS: The vast majority of nodular manifestations of hepatic MM collected in our study were multiple, and only five studies, including ours, described them using the major imaging modalities available.

Myeloid sarcoma of the larynx as manifestation of the terminal stage of myeloproliferative disease

A rare clinical observation of advanced myeloid sarcoma developed through blast transformation of post-polycythemia vera myelofibrosis as extramedullary manifestation of acute myeloid leukemia affecting larynx, laryngopharynx, trachea, soft tissues of the neck, pleura, and skeletal bones is presented.

Leukemia Cutis as the Presenting Sign of Acute Myeloid Leukemia in an HIV+ patient

Leukemia Cutis (LC) is a rare extramedullary cutaneous manifestation of leukemia that varies in terms of clinical presentation, leukemia type, and timing of presentation in relation to systemic leukemia. LC typically presents following diagnosis of systemic leukemia and during an active flare or relapse. An estimated 3.7% of patients with Acute Myeloid Leukemia (AML) develop LC. A 61-year-old male with poorly controlled HIV presented with a rash that began one month prior on his cheek as a red papule, which he believed was an ingrown hair. On exam, pink and yellow firm papules and nodules covered his entire body surface except the groin and axilla. One nodule held a peau d’orange appearance. The rash was overall asymptomatic, and he reported only increased fatigue. His CD4 count and viral load were 136 and 330,000 respectively. One punch biopsy revealed negative cultures for fungus, bacteria, and acid-fast bacilli. Two biopsies sent for pathologic evaluation revealed AML of the skin. Bone marrow biopsy confirmed AML. Clinically the presentation of LC is nonspecific, and systemic symptoms rarely appear in conjunction with LC. High clinical suspicion and histopathologic examination are necessary for diagnosis of LC.

Leukaemia Cutis in a Patient with Chronic Myeloid Leukaemia with Blast Crisis

Leukaemia cutis is a rare but important extra-medullary manifestation of Leukaemia. It develops due to the infiltration of neoplastic leukocytes or their precursors into the epidermis, dermis or subcutaneous tissue. Cutaneous presentation of Leukaemia cutis can precede, follow, present simultaneously with or may present in the absence of systemic Leukaemia. Here we present a pictorial of a 30-year-old male patient known to have Chronic Myeloid Leukaemia with blastic transformation to Acute myeloid Leukaemia with multiple cutaneous lesions, diagnosed as Leukaemia cutis. J MEDICINE 2023; 24: 65-66

Assessment of Bone Disease in Multiple Myeloma Patients After Autologous Stem Cell Transplant

Background : Detection of lytic bone lesions is crucial in the workup for multiple myeloma (MM) and very often dictates the decision to start treatment. Modern imaging techniques such as MRI, PET, and CT offer superior detection of myeloma bone disease and extramedullary manifestations of plasma cell dyscrasias. Autologous stem cell transplant (ASCT) is regarded as frontline therapy in candidate patients. Recent advances in understanding of myeloma bone disease showed that the receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) system plays a key role in this regard. Objectives : to assess the response of bone disease in patients with multiple myeloma using whole body low dose CT (WBLD CT) scan after different modalities of treatment including autologous stem cell transplant. Patients and method : This is a prospective cohort study in which patients with multiple myeloma had baseline WBLD CT scan with basic evaluation. They were then received induction chemotherapy with and then grouped into two groups according to the modality of consolidation (ASCT vs no ASCT). Both groups had second WBLD CT and were compared for the osteolytic lesions concerning size and site. Results : 20 patients were included in the study (12 males, 8 females), 8 treated with chemotherapeutic protocols (mainly bortezomib based) (group A) while 12 patients underwent ASCT during their course of treatment (group B). The improved score was found only in two patients, one in each group. Conclusion : myeloma bone disease needs to be assessed initially and promptly prevented and treated since it increases morbidity and mortality. Using newer imaging modalities like WBLD CT, MRI, PET scan is encouraged over conventional X ray skeletal survey.

Unusual Extramedullary Manifestation in Multiple Myeloma: Bilateral Synchronous Testicular Infiltration.

A 73-year-old man with multiple myeloma (initial diagnosis 21 months earlier) was referred to our center for a whole-body 18 F-FDG PET/CT. We detected a bilateral synchronous testicular manifestation, which was confirmed by histopathology after orchiectomy. Besides hypermetabolic lesions in the spine and ribs (most likely old fractures), known osteolysis showed no uptake. Extramedullary manifestation occurs in 13% to 20% of cases, among these 4% demonstrate testicular manifestation, which is associated with poor survival rates. Optimal therapy management is still unclear, due to limited data. To the authors' knowledge, so far only 3 comparable cases have been described.

Treatment and Disease Characteristics of Chronic Myeloid Leukemia in Blast Crisis: The European Leukemianet Blast Crisis Registry

Introduction Despite improvements in the treatment of chronic myeloid leukemia (CML), an important minority of patients (pts) will still develop blast crisis (BC). BC is highly aggressive, and if not treated promptly, will inevitably lead to patient's death. Due to its rarity and heterogeneous clinical presentation, no standard treatment is available for BC, and specifically addressed clinical trials are difficult to perform. Furthermore, it is unclear if the biology of BC has changed since the advent of tyrosine kinase inhibitors (TKI). To better understand BC and its treatment we sought to collect clinical and biological data of pts diagnosed with BC and started an international registry within the European LeukemiaNet (ELN) in 2018. Materials and methods The European Blast Crisis Registry with participants in 9 countries (Germany, Poland, Czech Republic, France, Italy, Sweden, Austria, Russia, and Armenia) gathers routinely collected clinical data in an online database. Pts are eligible for the registry if they had a diagnosis of BCR::ABL1 positive BC after January 1st, 2015 and were at least 18 years old at the time of BC. Both de novo BC and BC developing from a precedent CML in chronic phase are included. The Mann-Whitney and exact Fisher tests were used to compare variables. Overall survival (OS) was calculated according to Kaplan Meier. Significance was set at p<.05. Results At the cutoff date of July 2nd, 2022, 200 patients (60% male) with confirmed BC were recruited. Median age at diagnosis of CML and at diagnosis of BC was 45 years (yrs, range, 13-86) and 48 yrs (range, 18-86), respectively. BC occurred de novo in 37% of pts. At the time of CML diagnosis 47 pts had at least one additional cytogenetic abnormality (ACA) beside the t(9;22)(q34;q11), with 5 pts having 3 different ACAs. The most frequent ACA was +8 (10 pts) followed by +der(22) (6 pts). For pts diagnosed with a previous history of CML, median time between CML and BC was 31.3 months (range, 1-378 months). Before BC, 76% of patients were treated with TKI, most frequently with imatinib (78%). Median number of TKI treatments for chronic phase CML were 2 (range, 1-5). At the time of BC, mutations of BCR::ABL1 occurred in 25% of pts. The most frequent mutations were E255K and T315I, seen in 9 pts each. Mutations occurred more frequently in pts with evolution to BC after chronic phase (25% vs 8%, p<.001). The morphology of BC was myeloid (mBC) in 58% of the pts and lymphoid (lyBC) in 35%; 7% had a mixed or megakaryoblastic phenotype. Thirty-five and 16 pts had extramedullary manifestations (EMM) and central nervous system (CNS) involvement, respectively. Treatment data of BC are available for 191 pts and show the expected heterogeneity. Median lines of therapy for BC were 3. Most common was TKI+chemotherapy (Ctx)+allogeneic stem cell transplantation (alloTx) (49%), 19% received TKI+Ctx, 10% TKI alone, 5% TKI+alloTX, 1% Ctx+alloTx, 6% Ctx alone and 1 pt each alloTx upfront or no treatment. Pts receiving dasatinib (p=.004), Ctx (p=.005) and alloTx (p<.001) were younger. Imatinib was more used in de novo BC (p<.001), whilst ponatinib in pts with a previous CML (p=.016). Shorter time between CML and BC correlated significantly with a higher use of Ctx (p=.005). The type of therapy was not significantly associated with EMM/CNS involvement or BC phenotype, although slightly more pts with lyBC received Ctx (93% vs 82% p=.054). Best responses within the first 6 months of treatment are available in 82 pts (4 received an alloTx) and are: 18% MR5, 6% in MR4.5, 2% MR4 and 10% MMR; 24% had no response. With a median follow up of 27.0 months from diagnosis of BC, median OS was 23.7 months. Pts with EMM and CNS involvement had a similar outcome compared with pts with no EMM/CNS (median OS 46.0 vs 60.0 months for EMM/CNS vs none respectively, p=.56). The morphology of BC had a significant influence on survival. LyBC had a 2-yrs survival of 62% (95%-confidence interval (CI): 46-72%), mBC had a 2-yrs survival of 39% (95%-CI: 28-50%), p=.01). Sex had no influence on survival, morphology of BC or treatment received. Conclusions This analysis on a large cohort of CML pts in BC demonstrates a high degree of heterogeneity with regard to presentation and treatments. The outcome of lyBC is more favorable as compared to mBC, whilst the presence of CNS involvement and EMM had no significant impact on survival. Focused trials are warranted to identify the best treatment option for this still difficult disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Density of the Spleen in Low-Dose CT Scans Is Associated with High-Risk Disease Features and Shorter Survival in Newly Diagnosed Multiple Myeloma Patients

Introduction Whole body low-dose computed tomography (WBLDCT) is standard of care in the diagnostic work-up of suspected multiple myeloma. While the focus of clinical routine evaluation lies on the detection of osteolytic lesions or extramedullary myeloma manifestations, the entire informative capacity of WBLDCT scans seems underestimated. Here, the analysis of non-focal signal alterations might provide further diagnostic insights, and a recent study by Terao et al. described tumor-burden dependent loss of the splenic signal in diffusion-weighted MRI in newly diagnosed myeloma (NDMM) patients. However, due to limited availability of MRI, most NDMM patients receive WBLDCT at initial diagnostic work-up. Therefore, we asked if non-focal signal alterations of the spleen in WBLDCT scans (i.e., radiographic tissue density of the organ) in NDMM patients might correlate with disease characteristics, cytogenetics and clinical outcomes. Methods In this retrospective analysis, we screened clinical records of NDMM patients diagnosed and treated at our institution (LMU University Hospital Munich, Germany) between 01/2010 and 12/2020. Clinical and laboratory data from initial diagnosis until first relapse were integrated with segmentation analyses of WBLDCT scans taken within 90 days before diagnosis. Plasma cell dyscrasias others than MM as well as cases with CT scans taken >90 days before diagnosis or CT scans containing contrast media were excluded. Results A total of 231 consecutively treated NDMM patients were included with a median age of 66 years (range 25-89). Cytogenetic analyses were available in 177 (77%) patients of which 38 had high-risk (HR) aberrations including t(4;14), t(14;16) and del(17p). In 44 (19%) of patients a gain(1q) was found. Patients were classified according to ISS and R-ISS: ISS-1 84 (43%), ISS-2 56 (28%), ISS-3 57 (29%) and R-ISS-1 38 (22%), R-ISS-2 119 (70%), R-ISS-3 13 (8%). Induction therapy consisted of a doublet regimen in 61 (26%), a triplet regimen in 167 (72%) and a quadruplet regimen in 3 (1%) patients. From the entire cohort, 141 (61%) patients received high-dose melphalan and autologous stem cell transplantation (auto-SCT), and 46 (20%) patients underwent tandem auto-SCT. Maintenance therapy after auto-SCT was applied to 49 (35% of auto-SCT) patients. Spleen density gradually increased with ISS and R-ISS stages. Thus, ISS3 and R-ISS3 displayed a significantly increased spleen density compared to ISS1 and R-ISS1 patients (ISS3 40.7 HU vs. ISS1 35 HU, p=0.003; R-ISS3 45.4 vs. R-ISS1 32.5 HU, p=0.004, Fig. 1A). We further found spleen density to be significantly higher in patients with HR cytogenetics (HR vs SR HU, p=0.03), in particular with t(4;14) (p=0.04), but not with del(17p), t(14;16) or gain(1q). Moreover, it positively correlated with serum lambda light chain levels in patients with lambda paraproteinemia (r = 0.26, p = 0.02), but not with kappa light chain or immunoglobulin levels. Based on an optimal log-rank test separation algorithm, NDMM patients with a spleen density of > 53.5 HU (Spleenhigh) had a shorter survival compared to Spleenlow patients (median PFS: 18.9 vs 32.1 months, p=0.01, Fig. 1B; median OS: not reached, p=0.02). PFS and OS differences were similar in subgroup analysis of transplant-eligible (PFS: p=0.08; OS: p=0.04) and transplant-ineligible patients (PFS: p=0.02, OS: p=0.04). In multivariate cox regression analyses including Spleenhigh/low and R-ISS stages, spleen density remained an independent factor for shorter survival (HRPFS 2.45, 95%CI 1.21-4.49, p=0.007; HROS 3.24, 95%CI 1.06-8.23, p=0.02). Conclusion Our data suggest that high density of the splenic tissue in WBLDCT is associated with high-risk features and inferior survival of NDMM patients. Increased cell numbers or deposition of light chains within the spleen might represent modes of action. If validated in future prospective studies, spleen WBLDCT density may complement existing risk-stratification tools. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal