恶性血液病继发骨髓纤维化71例病理及临床研究

 【摘要】 目的 探讨继发性骨髓纤维化(secondary myelofibrosis,SMF)患者的临床及骨髓病理学特征。方法 对71例继发性骨髓纤维化患者的临床表现、外周血涂片、骨髓涂片及骨髓活检情况进行了回顾性研究,同时对不同疾病骨髓纤维化程度与巨核细胞数目作了相关分析。结果 分析71例SMF患者,其原发病情况为慢性粒细胞白血病(CML)20例(28.2%),急性淋巴细胞白血病（ALL）6例（8.5%）,急性髓系细胞白血病(AML)、骨髓增生异常综合症（MDS）、淋巴瘤各10例（14.1%）,多发性骨髓瘤（MM）、淋巴增殖性疾病（LPD）各4例（5.6%）,骨髓增殖性肿瘤（MPN）3例,慢性淋巴细胞白血病（CLL）2例,骨髓转移癌、传染性单核细胞增多症各1例。骨髓纤维化程度与巨核细胞数具有明显相关性（P＜0.05）。结论 继发性骨髓纤维化患者骨髓切片巨核细胞增生明显,且与纤维化程度有相关性。这可能与巨核细胞克隆性增殖释放的多种细胞因子积极参与骨纤的发生发展密切相关。     

急性全髓增殖症伴骨髓纤维化研究进展

急性全髓增殖症伴骨髓纤维化（acute panmyelosis with myelofibrosis，APMF）是一种全髓细胞增生伴骨髓纤维增生的疾病。WHO关于造血和淋巴组织肿瘤分型中将其作为独立的亚型，与其他类型急性髓系白血病相比，该病发病率低，相关研究较少。其主要特点为全髓增生、明显骨髓纤维化、全血细胞减少、红细胞形态正常、脾不大、进展迅速等。治疗包括支持治疗：输血，糖皮质激素，生长因子和在原始细胞明显增多时和进展为明显的急性髓细胞白血病（acute myelocytic leukemia，AML）时应用骨髓抑制性药物、造血干细胞移植和双磷酸盐。     

恶性血液病继发骨髓纤维化69例

目的探讨继发性骨髓纤维化（SMF）患者的临床及骨髓病理学特征。方法对69例SMF患者的临床表现、外周血涂片、骨髓涂片及骨髓活检情况进行回顾性分析,对不同疾病骨髓纤维化程度与巨核细胞数目进行相关性分析。结果69例SMF患者原发病分别为慢性粒细胞白血病（CML）20例（29．0％）,淋巴瘤14例（203％）,急性髓系白血病（AML）、骨髓增生异常综合征（MDS）各10例（14．5％）,急性淋巴细胞白血病（ALL）6例（8．7％）,多发性骨髓瘤（MM）4例（5．8％）,骨髓增殖性肿瘤（MPN）3例（4．3％）,慢性淋巴细胞白血病（CLL）2例（2．9％）。病理骨髓纤维化程度与巨核细胞数之间无相关性（r=0．024,P=0．848）。结论临床上多种血液系统疾病可以引起SMF。初诊的造血系统恶性疾病患者应同时行骨髓活检,特别是脾大、骨髓“干抽”的患者要考虑SMF的可能,骨髓病理学检查对临床诊断和鉴别诊断具有重要意义。     

骨髓纤维化74例临床分析

 目的 探讨骨髓纤维化（MF）的诊治方法,提高对该类疾病的认识。方法 回顾性分析1994年1月至2004年10月沈阳市红十字会医院74例MF患者的临床资料。结果 MF约占同期因血液系统异常行骨髓活检人数的1.86 %,病因依次为：慢性骨髓增生性疾病（CMPD）、原发性骨髓纤维化（IMF）、急性白血病（AL）、慢性肾功能不全及其他。结论 MF的主要病因为CMPD、IMF及慢性肾功能不全等内科疾病所致,凡疑为MF者必须进行骨髓活检确诊。     

伴SF3B1及JAK2基因突变的骨髓增生异常/骨髓增殖性肿瘤伴环形铁粒幼细胞和血小板增多合并骨髓纤维化一例并文献复习

目的:探讨骨髓增生异常/骨髓增殖性肿瘤伴环形铁粒幼细胞和血小板增多（MDS/MPN-RS-T）合并骨髓纤维化患者的临床特点及治疗。方法:回顾性分析南方医科大学深圳医院2018年5月收治的1例伴SF3B1及JAK2基因突变的MDS/MPN-RS-T合并骨髓纤维化患者的临床资料,并进行相关文献复习。结果:患者以头晕、乏力为主要症状,诊断为伴SF3B1及JAK2基因突变的MDS/MPN-RS-T合并骨髓纤维化,予羟基脲降细胞治疗及芦可替尼靶向治疗,效果良好。结论:MDS/MPN-RS-T是血液肿瘤系统新定义的克隆性造血干细胞疾病,具有两种疾病的双重特点,不易鉴别,易漏诊,其有效的治疗选择仍有待探索。     

急性全髓增殖症伴骨髓纤维化一例并文献复习

 目的　探讨急性全髓增殖症伴骨髓纤维化（APMF）临床特点,提高对该病的认识。方法　结合文献复习对1例APMF患者的临床资料进行分析,为该病的诊断和鉴别诊断提供思路。结果　APMF起病急,进展较快,以贫血、出血、感染为主要临床表现,脾大不明显,外周血呈全血细胞减少,可见原始细胞,红细胞形态多正常;骨髓穿刺易干抽,骨髓活检示骨髓中粒系、红系、巨核系三系增殖异常,可见病态造血,伴有显著骨髓纤维化。结论　APMF是一种全髓增殖伴有明显骨髓纤维化的疾病,由于骨髓纤维化引起的骨髓液抽吸困难,故诊断有赖于骨髓活组织检查。     

原发性骨髓纤维化转急性髓系白血病一例并文献复习

目的 提高对原发性骨髓纤维化(PMF)诊断、治疗及疾病转化的认识.方法 报告1例PMF转为急性髓性白血病(AML)的过程以及基因突变特点,并作相关文献复习.结果 患者符合WHO2008年PMF诊断标准,自初诊至转化为AML共2.5年.疾病转化前后JAK2V617F基因突变始终阳性,小剂量化疗疗效维持时间短.结论 PMF转化为AML后JAK2V617F基因突变阳性,药物治疗难以控制病情进展.     

原发性骨髓纤维化转急性髓系白血病一例并文献复习

 目的　提高对原发性骨髓纤维化（PMF）诊断、治疗及疾病转化的认识。方法　报告1例PMF转为急性髓性白血病（AML）的过程以及基因突变特点,并作相关文献复习。结果　患者符合WHO 2008年PMF诊断标准,自初诊至转化为AML共2.5年。疾病转化前后JAK2 V617F基因突变始终阳性,小剂量化疗疗效维持时间短。结论　PMF转化为AML后JAK2 V617F基因突变阳性,药物治疗难以控制病情进展。     

地西他滨治疗继发性急性髓系白血病伴母细胞性浆细胞样树突细胞肿瘤一例并文献复习

目的 探讨地西他滨治疗继发于骨髓增殖性肿瘤的急性髓系白血病(AML)及AML伴发母细胞性浆细胞样树突细胞肿瘤(BPDCN)患者的效果.方法 报道1例原发性骨髓纤维化转为AML伴BPDCN的患者的诊疗情况,并就相关文献进行复习.结果 地西他滨治疗后,该患者脾脏回缩,外周血、骨髓中原始细胞比例明显下降,输血频率下降,而且未再发现异常的BPDCN细胞;截至投稿时患者仍在随访观察中.结论 继发性AML伴BPDCN比较少见,地西他滨对该类患者,特别是伴脾大症状者有一定疗效.     

成人慢性粒细胞白血病骨髓纤维化的病理与预后关系的探讨

应用国产塑料包埋荆对40例慢性粒细胞白血病忠者的骨髓组织进行塑料包埋．并制成半薄切片，通过对其骨髓切片的观察和随访结果，发现慢性粒细胞白血病的骨髓纤维化发生率为57．5％；骨髓纤维化的程度与患者的临床预后关系密切：纤推化程度较轻的预后较好，生存期较长；纤维化程度较重的预后较差，生存期缩短．且易急变。骨髓纤维化是慢性粒细胞白血病预后不良的指征之一。     

Acute panmyelosis with myelofibrosis

Acute panmyelosis with myelofibrosis (APMF) is an ill-defined disorder that may either evolve as a clonal hematopoietic condition or as a sequel of toxic exposure to the bone marrow (BM). Therefore, controversy and discussion continues as to whether APMF may be considered as a hyperfibrotic (de novo) myelodysplastic syndrome (MDS), as acute myeloid leukemia (AML) or as a severe toxic myelopathy with accompanying myelofibrosis. In this context scant knowledge exists about BM findings, but especially evolution of this disorder according to sequential examinations. Clinically patients present with pancytopenia, a very few blasts in the peripheral blood and no or little splenomegaly. Initially BM histopathology is characterized by different degrees of reticulin-collagen fibrosis and wide ranges of cellularity with a prominent left-shifted and often macrocytic erythropoiesis associated with a reduction and maturation defects of the neutrophil series. Most conspicuous are abnormalities of the megakaryocytes including loose clustering, dislocation towards the endosteal border and appearance of atypical microforms with compact nuclei. Moreover, besides myelofibrosis in a number of patients the interstitial compartment displays a remarkable inflammatory reaction with lymphoid nodules, abundant iron-laden macrophages, perivascular plasmacytosis and increase in microvessels. Repeatedly performed BM biopsies reveal an accumulation of dispersed or clustered CD34⁺ and lysozyme-expressing blasts in keeping with the insidious transformation into acute leukemia. Prognosis is unfavorable with a median survival of less than 1 year. In conclusion, APMF has to be regarded as a condition that shows considerable overlappings with primary hyperfibrotic MDS, AML and toxic myelopathy (secondary MDS) with accompanying myelofibrosis and therefore can not be considered as a definite clinical entity.     

急性白血病治疗前后骨髓网硬蛋白纤维含量的初步研究

目的 应用经塑料包埋骨髓活组织切片技术研究骨髓网硬蛋白纤维与白血病细胞的消长关系。方法 采用Ｇomori染色行Ｍasson三色染色检测１６例急性白血病患者治疗前后骨髓网硬蛋白纤维含量变化。结果 １６例急性白血病患者治疗前后骨髓网硬蛋白纤维阳性例数有明显差异（Ｐ＜０．０５）。治疗后骨髓网硬蛋白纤维含量呈正常１１例，其中完全缓解（ＣＲ）８例，部分缓解（ＰＲ）３例；而治疗后骨髓网硬蛋白纤维呈异常５例，其中ＰＲ１例     

Acute panmyelosis with myelofibrosis: clinical, immunophenotypic and cytogenetic study of twelve cases

The clinical, cytogenetic, and immunophenotypic features in 12 adult patients with acute panmyelosis with myelofibrosis (APMF; ICD-0-3: 9931/3; C42.1) are reported (median age: 57 years; f/m = 1.4). The white cell count (WBC) was normal in 3 patients; 9 had leucopenia. The median hemoglobin value was 64.5 g/l, and median platelet count 12 x 10(9)/l. Bone marrow biopsy showed a hypercellular marrow in 10/12 patients with a significant infiltration of pathological blasts (range: 30 - 60%). All the cases had marked reticulin fibrosis. Immunophenotyping of bone marrow blast cells showed the expression of early (CD34) and lineage-unspecified antigens (HLA-DR) in 6/7, and 7/7 patients, respectively. "Early" myeloid antigens (CD13, CD33) were seen in 6/7 and 4/6 patients respectively. Monocyte antigen (CD14) was expressed in 3/7 patients. Megakaryocyte antigen (CD61) and erythroid cell antigen (GpA) were each expressed in only 1 patient. Two patients had expression of CD34, HLA-DR and "early" myeloid antigens by their bone marrow blast cells and 1 of these also had a co-expression of the antigens from a differentiated monocytic cell proliferation (lysozyme+, CD68+). Nonspecific chromosomal aberrations were recorded in 8/10 patients. The median survival was 2 months. These findings suggest an immature myeloid phenotype of blast cells in APMF. In 6/9 patients a leukemic cell differentiation into monocytic, megakaryocytic or erythroid lineage was also demonstrated.     

Depletion of STAT5 blocks TEL–SYK-induced APMF-type leukemia with myelofibrosis and myelodysplasia in mice

The spleen tyrosine kinase (SYK) was identified as an oncogenic driver in a broad spectrum of hematologic malignancies. The in vivo comparison of three SYK containing oncogenes, SYK^wt, TEL–SYK and IL-2-inducible T-cell kinase (ITK)-SYK revealed a general myeloexpansion and the establishment of three different hematologic (pre)diseases. SYK^wt enhanced the myeloid and T-cell compartment, without leukemia/lymphoma development. ITK–SYK caused lethal T-cell lymphomas and the cytoplasmic TEL–SYK fusion induced an acute panmyelosis with myelofibrosis-type acute myeloid leukemia (AML) with up to 50% immature megakaryoblasts infiltrating bone marrow, spleen and liver, additional MPN features (myelofibrosis and granulocyte expansion) and MDS stigmata with megakaryocytic and erythroid dysplasia. LKS cells were reduced and all subsets (LT/ST/MPP) showed reduced proliferation rates. SYK inhibitor treatment (R788) of diseased TEL–SYK mice reduced leukocytosis, spleen and liver infiltration, enhanced the hematocrit and prolonged survival time, but could not significantly reduce myelofibrosis. Stat5 was identified as a major downstream mediator of TEL–SYK in vitro as well as in vivo. Consequently, targeted deletion of Stat5 in vivo completely abrogated TEL–SYK-induced AML and myelofibrosis development, proving Stat5 as a major driver of SYK-induced transformation. Our experiments highlight the important role of SYK in AML and myelofibrosis and prove SYK and STAT5 inhibitors as potent treatment options for those diseases.     

Clinicopathological Impact of the Interaction Between Megakaryocytes and Myeloid Stroma in Chronic Myeloproliferative Disorders: A Concise Update

In this report an attempt has been made to discuss some of the issues pertinent to myelofibrosis complicating chronic myeloproliferative disorders (CMPDs) that are significantly associated with megakaryocyte function. In this context, biochemical, clinical and particularly morphological features were reviewed. Morphological findings based on elaborate techniques were in keeping with the assumption that in chronic myeloid leukemia (1) the number of CD61-positive megakaryocytes, and in particular their precursors were the parameters most closely associated with myelofibrosis (2) an increased content of reticulin fibers in follow-up biopsies significantly correlated with laboratory data indicative of a high tumor burden (anemia, peripheral blasts, hepatosplenomegaly) and thus a more advanced stage of the disease process (3) even a slight increase in reticulin, i.e. doubling of the normal fiber density was associated with a worse prognosis independent of therapeutic regimens given (4) Dynamics of myelofibrosis was significantly influenced by treatment. In this context, calculation of the myelofibrosis progression index (MPI) revealed a higher score following interferon therapy compared with busulfan. In addition, in idiopathic myelofibrosis (5) the evolution of myelofibrosis was unpredictable and according to the MPI, progression occurred at a relatively low rate (6) proliferation and dilatation of sinusoids accompanying intravascular hematopoiesis and collagen type IV deposits were predominant features in later (fibro-osteosclerotic) stages in the course of disease (7) transmural migration of megakaryocytes demonstrated by three dimensional reconstruction revealed a mole-like tunneling through the thickened sinusoidal wall. A very careful assessment of the numerous correlations between bone marrow features and laboratory data will allow clinicians and pathologists to gain a better insight into the mutual relationships between hematological and morphological findings in CMPDs.