Bone Marrow Histopathological Changes in Neoplastic and Non-Neoplastic Diseases

肿瘤和非肿瘤疾病的骨髓组织病理学变化

• 批准号: 8565402
• 负责人: Irina Maric
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8565402
• 关键词: Acute Erythroblastic Leukemia; American; Antimetabolites; Aspirate substance; Autologous; Biological; Biology; Blast Cell; Bone Marrow; Bone marrow biopsy; Bortezomib; British; C-KIT Gene; CD34 gene; Cells; Characteristics; Child; Chromosome 15; Chromosome Arm; Chromosome Markers; Chromosomes; Classification; Clinical; Clinical Management; Collaborations; Complex; Cyclophosphamide; Cytarabine; Cytogenetic Analysis; Cytogenetics; DNA Nucleotidylexotransferase; DNA Sequence Rearrangement; Development; Diagnosis; Diagnostic; Differential Diagnosis; Disease; Disease remission; Donor Lymphocyte Infusion; Dose; Dysmyelopoietic Syndromes; Environment; Erythroblasts; Erythroid; Erythroid Hyperplasia; Extramedullary; Factor VIII; Fetal Hemoglobin; Flow Cytometry; Folate; Frequencies; Functional disorder; Future; Genomic Instability; Glycophorin; Guidelines; Hematological Disease; Hemoglobin; Hemoglobin concentration result; Heterogeneity; Hospitalization; Idarubicin; Immunophenotyping; Infarction; Investigation; Karyotype; L Cells; Laboratories; Left; Life; Longitudinal Studies; Marrow; Melphalan; Metaphase; Molecular; Multiple Myeloma; Myelogenous; Myeloproliferative disease; Nature; Neoadjuvant Therapy; Neoplastic Plasma Cell; Neutropenia; Newly Diagnosed; Pathogenesis; Patients; Peroxidases; Pharmaceutical Preparations; Platelet Count measurement; Priapism; Reaction; Recovery; Recurrent pain; Refractory; Relapse; Reporting; Research Personnel; Risk; Role; Siblings; Sickle Cell Anemia; Spectrin; Staging; Stem cell transplant; Suggestion; Therapeutic; Transfusion; United States Food and Drug Administration; United States National Institutes of Health; Variant; White Blood Cell Count procedure; World Health Organization; acute chest syndrome; cancer cell; chemotherapy; chromosome 5q loss; fludarabine; follow-up; hydroxyurea; immunocytochemistry; insight; irradiation; leukemia; mean corpuscular volume observed; meetings; mortality; myeloblast; neoplastic; neoplastic cell; neutrophil; novel; novel therapeutics; older men; outcome forecast; peripheral blood; response; stem cells; von Willebrand Factor

We reported a unique combination of sickle cell anemia, hydroxyurea treatment, and short-latency leukemia of erythroid origin that presented a diagnostic challenge and underscored leukemogenic potential. A 33-year-old man with sickle cell anemia began treatment with hydroxyurea, 9.0 mg/kg daily, after 1 year of ambulatory pain and recurrent priapism requiring hospitalization. At baseline, the patient had a leukocyte count of 14 700 109 cells/L, hemoglobin level of 7.2 g/dL, and fetal hemoglobin level of 5.1%. Four years later, he was receiving hydroxyurea, 18 mg/kg daily, and the response was excellent (maximum fetal hemoglobin level, 35.6%; maximum mean corpuscular volume, 131.0 fL), although administration was interrupted by onset of transient neutropenia. The patient was later hospitalized and received transfusions for the acute chest syndrome. Hydroxyurea was withheld due to onset of neutropenia 2 weeks later. Follow-up again showed profound neutropenia (absolute neutrophil count, 0.120 109 cells/L), a leukocyte count of 0.670 109 cells/L, and a platelet count of 102 000 109 cells/L. Peripheral blood smear showed 44% blasts, consistent with normoblasts, megaloblastic changes, and marked dyserythropoiesis in numerous circulating nucleated erythrocytes. We ruled out delayed transfusion reaction and folate or B12 deficiency. Bone marrow biopsy showed hypercellularity with myeloid hypoplasia and erythroid hyperplasia with markedly left-shifted maturation and an increased erythroblast count. There was no increase in myeloblast count. Immunocytochemistry showed that blasts were positive for spectrin, hemoglobin, and CD117 and were negative for myeloperoxidase, CD34, glycophorin, terminal deoxynucleotidyl transferase, CD68, and factor VIII (von Willebrand factor), indicating malignant cells of early erythroid origin. Standard flow cytometry showed less than 2% myeloblasts. Pure erythroid leukemia (Di Guglielmo disease or French-American-British M6b AML) was suspected; however, massive erythroid recovery due to marrow infarctions occurring during the acute chest syndrome was also in the differential diagnosis. Cytogenetic analysis showed that 14 out of 20 marrow metaphase cells were abnormal, with significant karyotypic heterogeneity. The composite karyotype had 44 to 46 chromosomes with a recurring unbalanced rearrangement of chromosome arm 5q, deletion of chromosome arm 7q, loss of chromosomes 15 to 22 and Y, and 5 marker chromosomes, suggesting the myelodysplastic syndrome or AML. Clonal abnormalities enabled diagnosis of pure erythroid leukemia. Induction therapy with cytarabine and idarubicin produced a cytogenetic remission. Sibling-matched stem cell transplantation after cyclophosphamide therapy, fludarabine therapy, and irradiation was unsuccessful, and relapse occurred 4 months later. Flow cytometry demonstrated that 33% blasts were coexpressing CD117, CD38, and CD33. Bone marrow biopsy showed sheets of erythroblasts. Neither salvage chemotherapy nor donor lymphocyte infusion yielded a response. The patient died 9 months after diagnosis. To our knowledge, this is the first case of sickle cell anemia associated with AML of erythroid origin and a complex karyotype that meets the immunophenotype criteria for pure erythroid leukemia and, of note, therapy-related AML following the 2008 World Health Organization classification. This case is unique for development after 50 months of hydroxyurea treatment compared with an average AML latency of 8 years in myeloproliferative disorders. Short latency and genomic instability suggest a therapy-related cause, although complex karyotype AML is not characteristic of hydroxyurea treatment in the absence of a myeloproliferative disorder. The potential role of antimetabolites in therapy-related AML and suggestions for expanding hydroxyurea treatment to children and others with sickle cell anemia not meeting current U.S. Food and Drug Administration guidelines highlight the need for long-term studies with bone marrow cytogenetics to determine whether these rare cases represent true therapy-related AML in patients with sickle cell anemia. Even if risk for therapy-related AML was proven, it would need to be weighed against the intrinsic mortality of untreated sickle cell anemia. In another report, we described a novel finding of a CD38 negative extramedullary multiple myeloma (MM) with a prominent antigenic drift. Given that patients with MM live longer after the introduction of novel therapies, it seems reasonable to believe that this phenomenon will become increasingly common. Clinically, since the disease biology typically is more aggressive when there is extramedullary relapse, it is important for clinicians and diagnostic laboratories to be aware and suspect biological variations in this setting, so that appropriate therapy and clinical management decisions can be initiated without unnecessary delays. In the past, overall survival for patients with multiple myeloma (MM) was estimated at around 35 years. After the introduction of high-dose melphalan chemotherapy followed by autologous stem cell rescue, and novel agents (such as bortezomib and immunomodulatory drugs), the nature of treating MM has dramatically changed by nearly doubling overall survival. With such an improvement in the survival of patients with MM, the question remains whether disease biology and local microenvironment interactions evolve to facilitate more highly aggressive forms of the disease, such as extramedullary relapse. Indeed, the frequency of extramedullary disease seems to be higher in the relapse setting compared to newly diagnosed patients with MM. Although there is lack of scientific evidence, one may speculate that dynamic changes seen in the relapse setting may be supported by current novel therapeutics impacting local marrow microenvironment interactions, allowing neoplastic plasma cells to harbor and survive in a different environment. Such disease biology may not respond to conventional therapeutic strategies. Also, from a diagnostic standpoint, neoplastic cells in patients with relapsed and refractory MM may or may not express conventional markers due to altered biology. These findings suggest there may be gradually increasing diagnosis- and treatment-related challenges in relapsed MM in the future.

我们报告了镰状细胞性贫血、羟基脲治疗和红系起源的短潜伏期白血病的独特组合，这提出了诊断挑战并强调了致白血病的潜力。一名患有镰状细胞性贫血的 33 岁男性，在经历了 1 年的动态疼痛和需要住院治疗的复发性阴茎异常勃起后，开始接受羟基脲（每天 9.0 毫克/公斤）治疗。基线时，患者的白细胞计数为 14 700 109 个细胞/L，血红蛋白水平为 7.2 g/dL，胎儿血红蛋白水平为 5.1%。四年后，他每天接受 18 mg/kg 羟基脲治疗，尽管因短暂性中性粒细胞减少症的发作而中断给药，但反应良好（最大胎儿血红蛋白水平为 35.6%；最大平均红细胞体积为 131.0 fL）。该患者后来因急性胸部综合症住院并接受输血。由于两周后出现中性粒细胞减少症，羟基脲被停用。随访再次显示严重中性粒细胞减少（中性粒细胞绝对计数0.120 109细胞/L），白细胞计数0.670 109细胞/L，血小板计数102 000 109细胞/L。外周血涂片显示 44% 为原始细胞，与正常母细胞、巨幼细胞变化以及大量循环有核红细胞中明显的红细胞生成异常一致。我们排除了延迟输血反应和叶酸或 B12 缺乏症。骨髓活检显示细胞增多，伴有骨髓发育不全和红系增生，成熟明显左移，红细胞计数增加。成粒细胞计数没有增加。免疫细胞化学显示，母细胞血影蛋白、血红蛋白和 CD117 呈阳性，髓过氧化物酶、CD34、血型糖蛋白、末端脱氧核苷酸转移酶、CD68 和因子 VIII（冯·维勒布兰德因子）呈阴性，表明早期红系起源的恶性细胞。标准流式细胞术显示成髓细胞少于 2%。怀疑纯红系白血病（Di Guglielmo 病或法美英 M6b AML）；然而，急性胸部综合征期间发生的骨髓梗塞导致的大量红细胞恢复也在鉴别诊断中。细胞遗传学分析显示，20个骨髓中期细胞中有14个异常，具有显着的核型异质性。复合核型有 44 至 46 条染色体，其中 5q 染色体臂反复出现不平衡重排、7q 染色体臂缺失、15 至 22 号染色体和 Y 染色体缺失，以及 5 条标记染色体，提示骨髓增生异常综合征或 AML。克隆异常使得能够诊断纯红细胞白血病。阿糖胞苷和伊达比星的诱导治疗产生了细胞遗传学缓解。经过环磷酰胺治疗、氟达拉滨治疗和放疗后进行同胞匹配干细胞移植不成功，4个月后复发。流式细胞术表明 33% 的母细胞共表达 CD117、CD38 和 CD33。骨髓活检显示有成红细胞片。挽救性化疗和供体淋巴细胞输注均未产生反应。患者在诊断后 9 个月死亡。据我们所知，这是第一例与红系起源的 AML 相关的镰状细胞性贫血病例，其复杂核型符合纯红系白血病的免疫表型标准，值得注意的是，按照 2008 年世界卫生组织分类，与治疗相关的 AML 也符合。与骨髓增殖性疾病中 AML 平均潜伏期 8 年相比，该病例经过 50 个月的羟基脲治疗后发生的情况是独一无二的。短潜伏期和基因组不稳定提示与治疗相关的原因，尽管复杂核型 AML 不是在不存在骨髓增殖性疾病的情况下羟基脲治疗的特征。抗代谢药物在治疗相关 AML 中的潜在作用以及将羟基脲治疗扩大到儿童和其他不符合美国食品和药物管理局现行指南的镰状细胞贫血患者的建议，强调需要进行骨髓细胞遗传学的长期研究，以确定这些罕见病例是否代表镰状细胞贫血患者中真正的治疗相关 AML。即使治疗相关的 AML 风险得到证实，也需要与未经治疗的镰状细胞性贫血的内在死亡率进行权衡。 在另一份报告中，我们描述了具有显着抗原漂移的 CD38 阴性髓外多发性骨髓瘤 (MM) 的新发现。鉴于采用新疗法后 MM 患者的寿命更长，我们有理由相信这种现象将变得越来越普遍。在临床上，由于当发生髓外复发时，疾病生物学通常更具侵袭性，因此临床医生和诊断实验室必须了解并怀疑这种情况下的生物学变化，以便可以启动适当的治疗和临床管理决策，而不会造成不必要的延误。过去，多发性骨髓瘤 (MM) 患者的总生存期估计约为 35 年。在采用高剂量马法兰化疗、随后进行自体干细胞拯救和新药物（如硼替佐米和免疫调节药物）后，多发性骨髓瘤的治疗性质发生了巨大变化，总体生存率几乎翻了一番。随着多发性骨髓瘤患者的生存率得到如此提高，问题仍然是疾病生物学和局部微环境相互作用是否会进化以促进更具侵袭性的疾病形式，例如髓外复发。事实上，与新诊断的多发性骨髓瘤患者相比，复发情况下髓外疾病的发生率似乎更高。尽管缺乏科学证据，但人们可以推测，在复发环境中看到的动态变化可能受到当前影响局部骨髓微环境相互作用的新疗法的支持，使肿瘤性浆细胞能够在不同的环境中藏匿和生存。这种疾病生物学可能对传统的治疗策略没有反应。此外，从诊断的角度来看，由于生物学的改变，复发难治性多发性骨髓瘤患者的肿瘤细胞可能表达也可能不表达常规标记物。这些发现表明，未来复发性多发性骨髓瘤的诊断和治疗相关挑战可能会逐渐增加。