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Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. One of the major clinical challenges is adequate diagnosis and treatment of central nervous system (CNS) involvement in this disease. Intriguingly, there is little solid evidence on the mechanisms sustaining CNS disease in ALL. Here, we present and discuss recent data on this topic, which are mainly derived from preclinical model systems. We thereby highlight sites and routes of leukemic CNS infiltration, cellular features promoting infiltration and survival of leukemic cells in a presumably hostile niche, and dormancy as a potential mechanism of survival and relapse in CNS leukemia. We also focus on the impact of ALL cytogenetic subtypes on features associated with a particular CNS tropism. Finally, we speculate on new perspectives in the treatment of ALL in the CNS, including ideas on the impact of novel immunotherapies.

Abstract Objectives Leukemia cutis is a conflicting term to describe neoplastic hematopoietic infiltrates in the skin. Cutaneous myeloid or lymphoid proliferations often present a serious differential diagnostic challenge for pathologists. Methods This review aims to outline the confusion associated with the term leukemia cutis and discuss in detail the foremost common differential diagnoses in daily practice. The review is based on a summary of the relevant literature as well as on the authors’ experience. Results It addresses precursor cell myeloid and lymphoid tumors that are strictly considered true leukemia cutis but also more mature neoplasms, including some recently described mature extramedullary myeloid proliferations. Finally, a practical, comprehensive stepwise approach combining traditional immunohistochemical marker panels, novel lineage- or mutational-specific markers, and other ancillary tests is suggested to reach an entity-specific diagnosis. Conclusion The proper combination of ancillary techniques can help the pathologist to provide an accurate diagnosis of these challenging skin lesions.

The cure rate of acute lymphoblastic leukemia (ALL), the commonest childhood cancer, has been sharply improved and reached almost 90% ever since the central nervous system (CNS)-directed therapy proposed in the 1960s. However, relapse, particularly in the central nervous system (CNS), is still a common cause of treatment failure. Up to now, the classic CNS-directed treatment for CNS leukemia (CNSL) has been aslant from cranial radiation to high-dose system chemotherapy plus intrathecal (IT) chemotherapy for the serious side effects of cranial radiation. The neurotoxic effects of chemotherapy and IT chemotherapy have been reported in recent years as well. For better prevention and treatment of CNSL, plenty of studies have tried to improve the detection sensitivity for CNSL and prevent CNSL from happening by targeting cytokines and chemokines which could be key factors for the traveling of ALL cells into the CNS. Other studies also have aimed to completely kill ALL cells (including dormant cells) in the CNS by promoting the entering of chemotherapy drugs into the CNS or targeting the components of the CNS niche which could be in favor of the survival of ALL cells in CNS. The aim of this review is to discuss the imperfection of current diagnostic methods and treatments for CNSL, as well as new attempts which could be significant for better elimination of CNSL.

Skin lesions have been reported in about 10–12% of hairy cell leukemia (HCL) patients. Most are etiologically related to autoimmune or infectious processes, although secondary cutaneous neoplasms and drug-induced lesions are also reported. However, leukemia cutis with the direct infiltration of the skin by leukemic cells is extremely rare in HCL patients. This paper reviews the epidemiology, pathogenesis, clinical symptoms, diagnosis, and approach to treating skin lesions in HCL. A literature review of the MEDLINE database for articles in English concerning hairy cell leukemia, skin lesions, leukemia cutis, adverse events, infectious, cutaneous, drug reactions, neutrophilic dermatoses, secondary neoplasms, and vasculitis was conducted via PubMed. Publications from January 1980 to September 2020 were scrutinized. Additional relevant publications were obtained by reviewing the references from the chosen articles.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a common leukemia characterized by clonal expansion of mature CD5+/CD23 + B cells in the blood, bone marrow (BM) and lymphoid tissues. CLL can undergo extramedullary and extranodal infiltration, with one study noting an incidence of only 0.3 per 100,000 people, and in 17.6% of CLL patients in another report. The most common extranodal sites of leukemic involvement are the skin and central nervous system; however, other organs, including liver, lungs, kidney, gastrointestinal tract, bone, prostate and heart, are occasionally involved. The prognostic significance of extra-medullary CLL is still under debate, but the prognosis in such patients seems to be better in the era of novel targeted drugs. Following a diagnosis of extranodal CLL, survival appears to depend on the site of infiltration. This review presents an overview of CLL in patients with extramedullary and extranodal leukemic lesions, focusing on its epidemiology, pathogenesis, prognosis, clinical characteristics and treatment results.

Infiltration of T cell acute lymphoblastic leukemia (T-ALL) into the meninges worsens prognosis, underscoring the need to understand mechanisms driving meningeal involvement. Here, we show that T-ALL cells expressing CXCR3 exploit normal T cell function to infiltrate the inflamed meninges. CXCR3 deletion hampered disease progression and extramedullary dissemination by reducing leukemic cell proliferation and migration. Conversely, forced expression of CXCR3 facilitated T-ALL trafficking to the meninges. We identified the ubiquitin-specific protease 7 as a key regulator of CXCR3 protein stability in T-ALL. Furthermore, we discovered elevated levels of CXCL10, a CXCR3 ligand, in the cerebrospinal fluid from patients with T-ALL and leukemia-bearing mice. Our studies demonstrate that meningeal stromal cells, specifically pericytes and fibroblasts, induce CXCL10 expression in response to leukemia and that loss of CXCL10 attenuated T-ALL influx into the meninges. Moreover, we report that leukemia-derived proinflammatory cytokines, TNF-α, IL-27, and IFN-γ, induced CXCL10 in the meningeal stroma. Pharmacological inhibition or deletion of CXCR3 or CXCL10 reduced T-ALL cell migration and adhesion to meningeal stromal cells. Finally, we reveal that CXCR3 and CXCL10 upregulated VLA-4/VCAM-1 signaling, promoting cell-cell adhesion and thus T-ALL retention in the meninges. Our findings highlight the pivotal role of CXCR3-CXCL10 signaling in T-ALL progression and meningeal colonization.

Extramedullary infiltration (EMI), as a concomitant symptom of acute myeloid leukemia (AML), is associated with low complete remission and poor prognosis in AML. However, the mechanism of EMI remains indistinct. Clinical trials showed that increased miR-29s were associated with a poor overall survival in AML [ 14 ]. Nevertheless, they were proved to work as tumor suppressor genes by encouraging apoptosis and inhibiting proliferation in vitro. These contradictory results led us to the hypothesis that miR-29s may play a notable role in the prognosis of AML rather than leukemogenesis. Thus, we explored the specimens of AML patients and addressed this issue into miR-29c&b2 knockout mice. As a result, a poor overall survival and invasive blast cells were observed in high miR-29c&b2-expression patients, and the wildtype mice presented a shorter survival with heavier leukemia infiltration in extramedullary organs. Subsequently, we found that the miR-29c&b2 inside leukemia cells promoted EMI, but not the one in the microenvironment. The analysis of signal pathway revealed that miR-29c&b2 could target HMG-box transcription factor 1 (Hbp1) directly, then reduced Hbp1 bound to the promoter of non-muscle myosin IIB (Myh10) as a transcript inhibitor. Thus, increased Myh10 encouraged the migration of leukemia cells. Accordingly, AML patients with EMI were confirmed to have high miR-29c&b2 and MYH10 with low HBP1. Therefore, we identify that miR-29c&b2 contribute to the poor prognosis of AML patients by promoting EMI, and related genes analyses are prospectively feasible in assessment of AML outcome.

Background We here report the first case of leukemic lung infiltration diagnosed by transbronchial lung cryobiopsy (TBLC). TBLC is likely to be a superior method to transbronchial forceps biopsy because TBLC can get larger specimens, resulting in a higher chance of containing the leukemic cells infiltrated tissues. TBLC is generally considered a superior diagnostic method compared to transbronchial lung forceps biopsy (TBLB) because it utilizes cryotechnology to obtain larger specimens, increasing the likelihood of capturing tissues infiltrated with leukemic cells. Case presentation A 69-year-old male patient with acute myeloid leukemia presented with a fever. His initial chest CT scans revealed consolidative lesions, raising suspicion of fungal infection such as angioinvasive aspergillosis or mucormycosis. TBLC and TBLB were conducted to achieve a precise diagnosis, and eventually, leukemic lung infiltration was identified exclusively in the tissues obtained from TBLC. Two cycles of chemotherapy was administrated to patient, showing improvements in symptoms and chest CT findings. Conclusions TBLC has greater potential as a differential diagnostic method for pulmonary lesions than TBLB in leukemia patients facing therapeutic challenges due to its higher diagnostic yield.