Bone Marrow Histopathological Changes in Neoplastic and Non-Neoplastic Diseases

我们报道了镰状细胞性贫血、羟基脲治疗和红系起源的短潜伏期白血病的独特组合，这对诊断提出了挑战，并强调了白血病发生的潜力。一名33岁男性镰状细胞性贫血患者，在出现1年的移动疼痛和复发性阴茎勃起需要住院治疗后，开始用羟基脲治疗，每日9.0 mg/kg。基线时，患者白细胞计数为14 700 109个/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，他开始接受羟基脲治疗，每日18mg /kg，效果非常好（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），尽管由于短暂性中性粒细胞减少症的发作而中断给药。该患者后来因急性胸综合征住院并接受输血。2周后由于中性粒细胞减少症发作，羟基脲被保留。随访再次显示中性粒细胞严重减少（绝对中性粒细胞计数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%的母细胞，与正母细胞、巨幼细胞的变化一致，在许多循环有核红细胞中有明显的红细胞生成。我们排除了延迟输血反应和叶酸或B12缺乏症。骨髓活检显示骨髓增生伴髓样增生和红样增生，成熟明显左移，红母细胞计数增加。成髓细胞计数未见增加。免疫细胞化学显示，原细胞中spectrin、血红蛋白、CD117阳性，髓过氧化物酶、CD34、糖蛋白、末端脱氧核苷酸转移酶、CD68、血管性血液病因子（vviii）阴性，提示早期红系恶性细胞。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，在急性胸综合征期间发生骨髓梗死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，核型异质性显著。复合核型有44 ~ 46条染色体，5q染色体臂反复出现不平衡重排，7q染色体臂缺失，15 ~ 22和Y染色体缺失，5条标记染色体，提示骨髓增生异常综合征或AML。克隆异常有助于诊断纯红系白血病。阿糖胞苷和伊达柔比星诱导治疗产生细胞遗传学缓解。经环磷酰胺治疗、氟达拉滨治疗和放射治疗后的兄弟姐妹匹配干细胞移植不成功，4个月后复发。流式细胞术显示33%的母细胞共表达CD117、CD38和CD33。骨髓活检显示成片的红细胞。补救性化疗和供体淋巴细胞输注均未产生反应。患者在确诊后9个月死亡。据我们所知，这是首例镰状细胞性贫血与红系AML相关的病例，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，符合2008年世界卫生组织分类的治疗相关AML。与骨髓增生性疾病的AML平均潜伏期为8年相比，该病例在羟基脲治疗50个月后的发展是独特的。虽然在没有骨髓增生性疾病的情况下，复杂核型AML并不是羟基脲治疗的特征，但短潜伏期和基因组不稳定性提示与治疗相关的原因。抗代谢物在治疗相关AML中的潜在作用，以及将羟基脲治疗扩大到儿童和其他镰状细胞性贫血患者的建议，不符合美国食品和药物管理局目前的指南，这些都强调了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性贫血患者真正的治疗相关AML。即使治疗相关AML的风险得到证实，也需要与未经治疗的镰状细胞性贫血的固有死亡率进行权衡。

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.