乳腺恶性血液病的病理类型、临床特点及生存分析

目的:探讨乳腺恶性血液病的病理分型、患者的临床特征及预后。方法:回顾性分析2014年1月至2019年1月空军军医大学西京医院收治的33例乳腺恶性血液病患者的病理分型、临床特征及预后。结果:33例患者中,32例为女性,1例为男性,平均年龄为45.5岁(12-78岁)。经病理确诊29例(29/33,87.9%)为非霍奇金淋巴瘤,其中弥漫大B细胞淋巴瘤(18/29,62.1%)最为常见,其次是NK/T细胞淋巴瘤(3/29,10.3%),B淋巴母细胞白血病/淋巴瘤(2/29,6.8%),而伯基特淋巴瘤、滤泡淋巴瘤、原发皮肤间变大细胞淋巴瘤各1例(1/29,3.4%),其余3例未进一步分型。此外,1例(1/33,3.0%)霍奇金淋巴瘤,3例(3/33,9.1%)急性白血病复发累及乳腺。原发性乳腺恶性血液病为19例(57.6%),继发性为14例(42.4%),病变主要累及右侧乳腺(18例,54.5%),其次为左侧(10例,30.3%),双侧均累及的为少数(5例,15.2%)。19例原发性乳腺恶性血液病均为淋巴瘤,与14例继发性乳腺恶性血液病相比,其血小板计数明显升高(P=0.004),β2-MG显著降低(P=0.049),B症状少(P=0.017),Ann Arbor分期主要为Ⅰ-Ⅱ期(P<0.01),骨髓受累少(P<0.01)等特点。生存分析提示原发性乳腺恶性血液病患者比继发性患者生存期更长(HR=9.846,P=0.002)。恶性血液病累及骨髓可导致生存期显著缩短(HR=6.434,P<0.01)。结论:乳腺恶性血液病患者以中年女性为主,原发性乳腺恶性血液病比继发性发病率高(分别为57.5%和42.5%),最常见的病理类型为弥漫大B细胞淋巴瘤,病变主要累及右侧乳腺。与继发性乳腺恶性血液病相比,原发性乳腺恶性血液病患者具有血小板计数相对更高,β2-MG水平更低,往往不伴B症状,Ann Arbor分期主要为Ⅰ-Ⅱ期,骨髓不受累,且生存期显著延长等特点。此外,恶性血液病累及骨髓提示预后不良。     

免疫组织化学在淋巴组织疾病诊断中的应用与结果评价

目的提高对合理应用免疫组化标记及正确评价免疫组化结果重要性的认识。方法回顾性分析3例淋巴组织疾病的临床资料,进行组织形态学观察并增加相关抗体标记予以鉴别诊断。结果例l为弥漫大B细胞性淋巴瘤,梭形细胞变异型,误诊为未分化肉瘤与形态学观察遗漏中心和中心母细胞特征的淋巴样细胞,没考虑到淋巴瘤的梭形细胞形态变异以及免疫标记的选择失误有关。例2为急性淋巴结T区增生误诊为T细胞淋巴瘤与忽略患者临床信息及对免疫组化阳性细胞量变及强弱评价有误相关。例3为经典型霍奇金淋巴瘤误诊为间变性大细胞淋巴瘤与对霍奇金淋巴瘤组织形态认识不足及淋巴瘤标记抗体的配伍不当有关。结论淋巴组织疾病的诊断建立在形态学、免疫组化、临床资料和遗传学基础上,免疫组化标记的选择与结果的正确分析对淋巴瘤确诊至关重要。     

小剂量沙利度胺联合三氧化二砷治疗骨髓增生异常综合征疗效观察

目的评价小剂量沙利度胺联合三氧化二砷治疗骨髓增生异常综合征(RAEBⅠ型及Ⅱ型)的效果及其安全性。方法选择骨髓增生异常综合征(均为RAEBⅠ型或Ⅱ型)患者27例为治疗组,给予沙利度胺联合三氧化二砷治疗;同时选择同期诊断为骨髓增生异常综合征(均为RAEBⅠ型或Ⅱ型)患者25例为对照组,采用全反式维A酸及小剂量阿糖胞苷治疗,观察两组患者的临床疗效及不良反应。结果治疗3个月时的疗效评估,治疗组总有效率37.0%,对照组12.0%,差异无统计学意义(P0.05);治疗6个月时,治疗组总有效率77.8%,3年OS率为70.4%,明显优于对照组的20.0%和36.0%,差异均具有统计学意义(P0.05)。两组不良反应发生率比较无统计学意义(P0.05)。结论采用小剂量沙利度胺联合三氧化二砷治疗骨髓增生异常综合征的疗效好,毒副作用小,安全性高。     

EBV与非霍奇金淋巴瘤的相关性研究

目的探讨EBV与非霍奇金淋巴瘤的相关性。方法采用免疫荧光法检测62例非霍奇金淋巴瘤患者外周血血清中EBV-VCA-IGA,进而探讨EBV感染与非霍奇金淋巴瘤的相关性。结果92例非霍奇金淋巴瘤患者EBV-VCA-IGA阳性率为36%,B细胞来源非霍奇金淋巴瘤患者EBV-VCA-IGA阳性率为34%,T细胞来源非霍奇金淋巴瘤患者EBV-VCA-IGA阳性率为38%。结论EBV与非霍奇金淋巴瘤关系密切,监测EBV感染状况,对非霍奇金淋巴瘤的早期诊断及预后判断具有重要意义。     

原发性乳腺淋巴瘤研究进展

原发性乳腺淋巴瘤(primary breast lymphoma,PBL)是一种罕见的结外型淋巴瘤,最常见的病理类型为弥漫大B细胞淋巴瘤,近年来隆胸相关的间变大细胞淋巴瘤亦被界定为新的临床类型。其与乳腺癌相比,临床表现和影像学检查均无特异性,需依靠病理活检及免疫组化明确诊断,预后较差。目前PBL尚无标准治疗方案,但趋向于以环磷酰胺+阿霉素+长春新碱+泼尼松(cyclophosphamide+doxorubicin+vincristine+prednisolone,CHOP)方案化疗为主的综合治疗方案,避免采用扩大的手术治疗。     

原发性肾上腺非霍奇金淋巴瘤（附9 例报告）

目的:探讨原发性肾上腺淋巴瘤(Primary Adrenal Lymphoma,PAL)的临床特点、提高对PAL的认识。方法:回顾分析解放军总医院1995年12月至2007年6月收治的9例PAL的临床表现、实验室检查、影像学特点、组织病理类型以及治疗方法等临床资料,并结合国内外文献进行分析。结果:9例患者中,1例因常规体检发现,8例因腹痛、腹胀或腰痛就诊发现;其中单侧3例,双侧6例,实验室检查无明显异常,影像学检查仅发现肾脏肿瘤,但术后病理组织学诊断为非霍奇金淋巴瘤(non-Hodgkin’s lymphoma,NHL),其中8例弥漫大B细胞淋巴瘤,1例T细胞淋巴瘤;7例患者术后均接受了CHOP或RCHOP方案化疗为主的综合治疗,2例常规治疗;随访至2010年2月,1例弥漫性大B细胞淋巴瘤患者存活4年,1例在术后3年2个月死亡,余7均在2年内死亡。结论:PAL是一种罕见的、恶性程度较高的肿瘤,临床表现和影像学检查缺乏特异性,组织病理学及免疫组织化学是明确诊断的好方法。术前确诊肾上腺原发性非霍奇金淋巴瘤可避免手术,联合化疗应为治疗首选。     

积分系统参与MDS诊断的可行性研究

目的:骨髓增生异常综合征(MDS)是一种起源于造血干细胞,以高风险向急性髓系白血病转化为特点的难治性血细胞质、量异常的异质性疾病。对不明原因血细胞减少或者有巨幼红细胞血症的老年人,如果得不到明确的诊断就不会获得有效的治疗。探讨对伴有不明原因血细胞减少或大红细胞血症患者采用一种积分系统来预测诊断为骨髓增生异常综合征(MDS)的可行性。方法:应用四个因子即年龄≥65,红细胞平均体积(MCV),红细胞分布宽度(RDW),和乳酸脱氢酶(LDH)的一个积分系统来计算诊断MDS的概率。结果:调查了303个病人,他们都因为不明原因的血细胞减少或者大红细胞血症在过去三年(2010~2012)进行了骨髓检查,最终三分之二患者被诊断为MDS,9%为疑似MDS,采用积分系统前后的MDS诊断率分别为12%和48%。结论:此四个因子的积分系统可以用于指导MDS患者的诊断。提高MDS的诊断率,减少不必要的骨髓穿刺,减轻病人的疼痛和医疗费用。     

间变大细胞淋巴瘤的临床进展

间变大细胞淋巴瘤(ALCL)是一种临床上少见的恶性淋巴瘤。形态学存在着一种标志的hall mark细胞;细胞免疫学上CD30(Ki-1)表达强阳性;标志性的染色体异常t(2;5)(p23;q35)。临床诊断时多为疾病晚期(Ⅲ~Ⅳ期),并常伴有B症状。成人患者,推荐采取放疗,同时辅以联合化疗;儿童患者病程类似Burkitt淋巴瘤,治疗方案一般使用高强度的治疗淋巴母细胞白血病或Burkitti淋巴瘤的方案。高危ALCL、复发难治ALCL可应用CD30单克隆抗体和ALK蛋白抑制剂等。临床上报道较少,对其认识仍有不足。近年来虽然对ALCL的研究取得了显著的进展,但至今尚未形成成熟规范的治疗方案。未来研究有望最终寻找到ALCL的最优化治疗方案。现就其在免疫和遗传学、形态学、临床表现、治疗和预后等方面的研究进展作一综述。     

m6A-RNA甲基化在弥漫大B细胞淋巴瘤中的研究进展

弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)是非霍奇金淋巴瘤(non-hodgkin lymphoma,NHL)中最常见的亚型,其发病机制错综复杂,至今尚未被充分阐明.因其具有较大的异质性导致患者预后差,针对DLBCL的治疗面临着巨大的挑战.近年来,表观遗传修饰成为DLB...     

ICE方案治疗复发难治性非霍奇金弥漫大B细胞淋巴瘤临床观察

目的:观察ICE方案(异环磷酰胺IFO,卡铂CBP,依托泊苷VP-16)治疗复发/难治性非霍奇金弥漫大B细胞淋巴瘤(Non-hodgkin's lymphoma,NHL)的疗效及安全性。方法:20例经系统化疗后复发或进展的非霍奇金弥漫大B细胞淋巴瘤(DLBCL)患者,采用ICE方案化疗至少2周期,IFO 5 g/m2,第2天,持续24小时静脉输注,CBP按AUC=5,max 800 mg,第2天,静脉输注,VP-16.100 mg/m2,第1-3天,静脉输注。结果:完全缓解(complete response,CR)5例,部分缓解(partial response,PR)8例,疾病稳定(stable disease,SD)4例,疾病进展(progress disease,PD)3例,总有效率(overall response rate,ORR,CR+PR)65%,化疗副作用主要为骨髓抑制(Ⅰ、Ⅱ度6例,Ⅲ、Ⅳ度14例),其他不良反应包括胃肠道反应、粘膜损伤、肝肾毒性及脱发等均可耐受。结论:ICE方案可用于非霍奇金弥漫大B细胞淋巴瘤的二线化疗方案。     

Anaplastic large cell lymphoma of the mediastinum diagnosed by transbronchial scratch cytology. A case report

BACKGROUND: Anaplastic large cell lymphoma (ALCL) is a subtype of non-Hodgkin's lymphoma characterized by CD30 antigen-positive, large neoplastic cells. We describe a case of ALCL suggested by cytologic examination of the tumor cells obtained from bronchial scratch preparations. CASE: A 26-year-old woman had had a dry cough since November 1996. Chest radiography in May 1997 revealed an abnormal shadow in the mediastinum extending to the pulmonary hilar region. The patient was hospitalized in June 1997. Computed tomography revealed a neoplastic lesion in the anterior mediastinum invading the right lung. Transbronchial scratch cytology revealed large, atypical lymphoid cells expressing CD30 and CD3 on immunocytochemical examination. A transcutaneous mediastinal biopsy was performed and a diagnosis of ALCL made. CONCLUSION: Differentiation from Hodgkin's disease was the most difficult point in this case. Detailed cytologic observation and CD3-positive immunocytology led to the correct diagnosis. The cell transfer technique of Sherman et al was very useful for immunocytologic staining. Thus, transbronchial scratch cytology was an especially valuable and effective procedure in this case.     

Proteomic analysis of anaplastic lymphoma cell lines: identification of potential tumour markers

Anaplastic large-cell lymphomas (ALCL) are high grade lymphomas of T or null phenotype often associated with the t(2;5) translocation leading to the expression of a chimeric protein consisting of the N-terminal portion of nucleophosmin (NPM) and the intracellular domain of the anaplastic lymphoma kinase (ALK). Although ALCL are recognized as distinct clinical, biological and cytogenetic entities, heterogeneities persist in this group of tumours, which exhibit a broad spectrum of morphological features. Particularly, the common type tumour consisting in large cells contrast with the small cell variant that is sometimes associated with a leukemic phase. The ALK-negative ALCL is often associated with a poor prognosis. Here, we investigated the proteome of these subtypes of tumours using patient-derived cell lines. We compared the proteome of the cytosolic fraction of NPM-ALK-positive versus NPM-ALK-negative cells on one hand, and the proteome of common cell type versus small cell variant on the other hand. The identification of a set of proteins differentially expressed in the subtypes of ALCL points to new diagnosis/prognosis markers. This study also provides interesting information on the molecular mechanisms responsible for the different subtypes of ALCL.     

Anaplastic large cell lymphoma in a human immunodeficiency virus-positive patient with cytologic findings in bladder wash: a case report

BACKGROUND: Anaplastic large cell lymphoma (ALCL) (Ki-1/CD-30 positive) is an uncommon lymphoproliferative disorder that may be of T cell or null cell type. ALCL has been reported in fine needle aspirations of lymph nodes and pleural or peritoneal fluid cytology. In human immunodeficiency virus (HIV)-positive patients, ALCL appears to be more common and run a more aggressive course. CASE: A 39-year-old black man, seropositive for HIV, presented with acute renal failure secondary to bilateral ureteral obstruction by a pelvic mass involving the urinary bladder. Bladder wash cytology and subsequent biopsy of the mass were diagnostic of ALCL. The ALCL was CD30+ and null cell type, with negative CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD45, CD79a, ALK-1, granzyme B, cytokeratin (AE1/AE3), placental alkaline phosphatase (PLAP) and S-100. The patient expired 9 months after the diagnosis, despite aggressive therapy. CONCLUSION: This is a rare occurrence of ALCL (CD 30 positive, null cell type) in the urinary bladder in an HIV+ patient. Presumptive diagnosis was made by bladder wash cytology and subsequently confirmed by biopsy. Urinary cytologic examination is a useful diagnostic tool. In HIV+/immunosuppressed patients with urinary symptoms and an obstructive mass, ALCL should be considered in the differential diagnosis.     

Altered PTEN expression; a diagnostic marker for differentiating normal, hyperplastic and neoplastic endometrium

Background

Primary non-Hodgkin lymphoma (NHL) of the breast represents 0.04–0.5% of malignant lesions of the breast and accounts for 1.7–2.2% of extra-nodal NHL. Most primary cases are of B-cell phenotype and only rare cases are of T-cell phenotype. Anaplastic large cell lymphoma (ALCL) is a rare T-cell lymphoma typically seen in children and young adults with the breast being one of the least common locations. There are a total of eleven cases of primary ALCL of the breast described in the literature. Eight of these cases occurred in proximity to breast implants, four in relation to silicone breast implant and three in relation to saline filled breast implant with three out of the eight implant related cases having previous history of breast cancer treated surgically. Adjuvant postoperative chemotherapy is given in only one case. Secondary hematological malignancies after breast cancer chemotherapy have been reported in literature. However in contrast to acute myeloid leukemia (AML), the association between lymphoma and administration of chemotherapy has never been clearly demonstrated.

Case Presentation

In this report we present a case of primary ALCL of the breast arising in reconstruction mamoplasty capsule of saline filled breast implant after radical mastectomy for infiltrating ductal carcinoma followed by postoperative chemotherapy twelve years ago.

Conclusion

Primary ALK negative ALCL arising at the site of saline filled breast implant is rare. It is still unclear whether chemotherapy and breast implantation increases risk of secondary hematological malignancies significantly. However, it is important to be aware of these complications and need for careful pathologic examination of tissue removed for implant related complications to make the correct diagnosis for further patient management and treatment. It is important to be aware of this entity at this site as it can be easily misdiagnosed on histologic grounds and to exclude sarcomatoid carcinoma, malignant melanoma and pleomorphic sarcoma by an appropriate panel of immunostains to arrive at the correct diagnosis of ALCL.     

Hungarian experience with non-Hodgkin's lymphoma in childhood

Between 1990 and 2004, 230 children with non-Hodgkin's lymphoma (NHL) were treated according to the Berlin-Frankfurt-Münster (BFM) protocols (NHL-BFM-90 and -95) in Hungary. The aim of the present study was to summarize our experience with these protocols, to assess the survival rates and to compare the Hungarian data with the international results. The male-to-female ratio was 2.59:1, the mean age at the time of diagnosis was 10 years and 1 month. Ninety-one children had lymphoblastic/T-NHL (LB/T-NHL), 108 B-NHL and 31 anaplastic large cell lymphoma (ALCL). Twenty-eight patients had relapse after a mean time of 13 months from the time of the initial diagnosis. In the above mentioned period, 16 children underwent autologous stem-cell transplantation. Nine patients with B-NHL got anti-CD20 immunotherapy. The five-year overall survival (OS) of our patients is 77.8%+/-3%, the event-free survival (EFS) is 75.1%+/-3%. The 5-year OS and EFS rates were not statistically different in the three histology groups (OS: 71.6%+/-5%, 82.7%+/-4% and 80.3%+/-7%; EFS: 68.7%+/-5%, 81.1%+/-4% and 73.9%+/-8% in LB/T-NHL, B-NHL and ALCL, respectively). We can conclude that non-Hodgkin's lymphoma has a quite good prognosis among the malignant pediatric diseases. The cure rate is over 75%. The Hungarian results are comparable with other international data. In the last five years the mortality during induction was reduced from 10% to 2% and the OS is about 10% better than it was before. In case of relapse or residual disease, therapeutic results can be improved with stem-cell transplantation with or without immunotherapy.     

CD-30(Ki-1)-positive anaplastic large cell lymphoma in a pleural effusion. A case report with diagnosis by cytomorphologic and immunocytochemical studies.

BACKGROUND: Reports on cytodiagnosis of Ki-1-positive anaplastic large cell lymphoma (ALCL) are rare. This report describes one such case diagnosed by cytologic examination of a pleural effusion and confirmed by immunocytochemistry. CASE: An 87-year-old male presented with breathlessness, fever and a cough. Computed tomographic scan of the thorax showed a small, right, pleura-based nodule with infiltration of the immediate surroundings in addition to a massive, right-sided pleural effusion. Cytologic examination of pleural fluid revealed a heterogeneous population of cells comprising small mature lymphocytes, and numerous medium and large atypical lymphoid cells having frequent nuclear irregularity. Occasional very large cells resembling Reed-Sternberg cells or multinucleated cells with a horseshoe or wreathlike arrangement of nuclei (doughnut cells) were also present. Cytomorphology was suggestive of Ki-1 anaplastic large cell lymphoma (ALCL). Immunocytochemistry revealed intense positivity for CD-30, positivity for LCA and EMA in a variable number of cells and a negative result for cytokeratin except for occasional cells. CONCLUSION: Cytologic examination of pleural fluid can serve as a useful tool for the initial diagnosis of Ki-1-positive ALCL.     

Tyrosine phosphorylation in human lymphomas

In a previous study, we showed that the high level of protein tyrosine phosphorylation present in lymphomas containing an anaplastic lymphoma kinase (ALK) can be demonstrated in routinely processed paraffin tissue sections using immunolabelling techniques. In the present study we investigated whether oncogenic tyrosine kinase activation also occurs in other categories of lymphoma by staining 145 cases of lymphoma covering those tumours with a range of different subtypes including those with morphological similarity to ALK-positive anaplastic large cell lymphoma (ALCL). Twelve cases of the borderline malignant disorder lymphomatoid papulosis were also studied. Twenty seven of the 28 cases of ALK-positive ALCL showed the extensive cytoplasmic labelling for phosphotyrosine in the neoplastic cells. The remaining case containing moesin-ALK exhibited membrane-associated phosphotyrosine expression. There was no nuclear phosphotyrosine labelling in any of the ALK-positive ALCL, even though ALK was present within the cell nuclei in 23 of the tumours. Variable degrees of phosphotyrosine labelling, usually membrane-restricted, were observed in 7/40 cases of ALK-negative ALCL, 9/29 cases of diffuse large B-cell lymphoma, 3/6 cases of mediastinal B-cell lymphoma, 2/7 cases of Hodgkin's lymphoma, 3/6 cases of peripheral T-cell lymphomas unspecified, 4/6 cases of B-cell chronic lymphocytic leukaemia, 2/6 cases of follicular lymphomas and 2/12 cases of lymphomatoid papulosis studied. However none of these phosphotyrosine-positive cases showed the strong cytoplasmic labelling comparable to that seen in ALK-positive lymphoma. We conclude that activation of a tyrosine kinase is probably not a major oncogenic event in lymphomas other than ALK-positive ALCL.     

Anaplastic large cell lymphoma presenting as a pleural effusion and mimicking primary effusion lymphoma. A report of 2 cases

BACKGROUND: Systemic anaplastic large cell lymphoma (ALCL) is predominantly a nodal disease, but extranodal involvement can occur during the disease course or as the primary presentation. We report two rare cases of ALCL presenting with a pleural effusion, mimicking primary effusion lymphoma (PEL). CASES: Two patients, a 47-year-old woman and an 81-year-old man, presented with a pleural effusion for investigation. The pleural fluid contained abundant, large, lymphoid cells with marked nuclear atypia. These neoplastic cells strongly expressed CD30 and EMA and showed a T-cell phenotype (CD3+CD45RO+ for case 1 and CD4+ for case 2). Case 1, in addition, showed ALK1 expression. The tumor cells in both cases were negative for human herpes virus type 8 (HHV8) and Epstein-Barr virus (EBV). ALCL shows overlapping cytologic features with PEL, but the T-cell phenotype, ALK1 expression in case 1, lack of association with HHV8 and EBV, HIV seronegativity and subsequent discovery of nodal disease in case 2 were all in favor of ALCL over PEL. CONCLUSION: In rare cases a pleural effusion is the presenting feature of ALCL, and distinction from PEL depends on correlation with clinical findings, detailed immunophenotyping and study of the status of HHV8 and EBV.     

Pharmacological inhibitors of anaplastic lymphoma kinase (ALK) induce immunogenic cell death through on-target effects

Immunogenic cell death (ICD) is clinically relevant because cytotoxicants that kill malignant cells via ICD elicit anticancer immune responses that prolong the effects of chemotherapies beyond treatment discontinuation. ICD is characterized by a series of stereotyped changes that increase the immunogenicity of dying cells: exposure of calreticulin on the cell surface, release of ATP and high mobility group box 1 protein, as well as a type I interferon response. Here, we examined the possibility that inhibition of an oncogenic kinase, anaplastic lymphoma kinase (ALK), might trigger ICD in anaplastic large cell lymphoma (ALCL) in which ALK is activated due to a chromosomal translocation. Multiple lines of evidence plead in favor of specific ICD-inducing effects of crizotinib and ceritinib in ALK-dependent ALCL: (i) they induce ICD stigmata at pharmacologically relevant, low concentrations; (ii) can be mimicked in their ICD-inducing effects by ALK knockdown; (iii) lose their effects in the context of resistance-conferring ALK mutants; (iv) ICD-inducing effects are mimicked by inhibition of the signal transduction pathways operating downstream of ALK. When ceritinib-treated murine ALK-expressing ALCL cells were inoculated into the left flank of immunocompetent syngeneic mice, they induced an immune response that slowed down the growth of live ALCL cells implanted in the right flank. Although ceritinib induced a transient shrinkage of tumors in lymphoma-bearing mice, irrespective of their immunocompetence, relapses occurred more frequently in the context of immunodeficiency, reducing the effects of ceritinib on survival by approximately 50%. Complete cure only occurred in immunocompetent mice and conferred protection to rechallenge with the same ALK-expressing lymphoma but not with another unrelated lymphoma. Moreover, immunotherapy with PD-1 blockade tended to increase cure rates. Altogether, these results support the contention that specific ALK inhibition stimulates the immune system by inducing ICD in ALK-positive ALCL.Subject terms: Cancer, Cancer models