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1 PowerPoint Slides English Text Mandarin Chinese Translation Hematologic Malignancies: Diagnosis and Staging Part II: Lymphoma and Multiple Myeloma Hematologic Malignancies: Diagnosing and Staging, Part 2: Lymphoma and Multiple Myeloma VideoTranscript Professional Oncology Education Hematologic Malignancies: Diagnosing and Staging, Part 2: Lymphoma and Mulitple Myeloma Time: 20:19 Jorge Romaguera, M.D. Professor Lymphoma/Myeloma The University of Texas MD Anderson Cancer Center Hello. I am Dr. Jorge Romaguera. I am Professor of the Department of Lymphoma and Multiple Myeloma at the University of Texas MD Anderson Cancer Center. I will be speaking to you today about the diagnosis of staging of lymphomas and multiple myeloma. 恶性血液疾病 : 诊断与分期, 第 2 部分 : 淋巴瘤与多发性骨髓瘤视频文本专业人员肿瘤教学讲座恶性血液疾病 : 诊断与分期, 第 2 部分 : 淋巴瘤与多发性骨髓瘤时间 : 20:19 德克萨斯大学 MD Anderson 癌症中心淋巴瘤 / 骨髓瘤科教授 Jorge Romaguera, M.D. 大家好 我是 Jorge Romaguera 医生, 是德克萨斯大学 MD Anderson 癌症中心淋巴瘤和多发性骨髓瘤科的教授 今天我将向大家介绍淋巴瘤和多发性骨髓瘤的诊断与分期 Jorge Romaguera, M.D. Professor Lymphoma/Myeloma 1

2 Part II: Objectives Upon completion of this part, participants will be able to: Define lymphoma, including Hodgkin s and Non-Hodgkin s and multiple myeloma Discuss the clinical presentation of these diseases Discuss the hematologic, radiographic and pathologic findings for classification and staging of each Upon completion of this part of this talk, you will be able to define lymphoma, both Hodgkin s and non- Hodgkin s lymphoma as well as multiple myeloma. You will be able to discuss clinical presentation of the cases of these diseases --- [I apologize] --- as well as hematologic, radiographic, and pathologic findings for classification and staging of each. 在完成本部分讲座后, 大家将能够定义淋巴瘤, 包括霍奇金淋巴瘤和非霍奇金淋巴瘤, 以及多发性骨髓瘤 大家将能够讨论这些疾病的表现以及每种疾病分型和分期所需的血液学 放射成像以及病理学检查结果 Lymphoma Group of malignancies originating in the lymphatic system Types of lymphoma Hodgkin s lymphoma Non-Hodgkin s lymphoma (NHL) 85% B-cell lymphoma 15% T-cell lymphoma We will start first with lymphoma. This is a group of malignancies that originates in the lymphatic system. It is broadly divided in two categories, the Hodgkin s lymphoma and the non-hodgkin s lymphoma or malignant lymphoma. Here in North America, 85% of the malignant lymphomas are of the B-cell type and 15 are of a T-cell type. We will be discussing in this presentation mainly the B-cell type, which is the most common. 我们先来谈谈淋巴瘤 这是一组起源于淋巴系统的恶性疾病 淋巴瘤被粗略分为两类, 霍奇金淋巴瘤和非霍奇金淋巴瘤, 或者称为恶性淋巴瘤 在北美,85% 的恶性淋巴瘤都是 B 细胞型,15% 是 T 细胞型 我们在本次讲座中会主要讨论最常见的 B 细胞型 2

3 Risk Factors for Lymphoma Cause of NHL unknown Inherited familial: small percentage Environmental Chemical suspected (e.g., pesticides/herbicides) High-dose radiation exposure suspected Immunosuppression Immune deficiency (AIDS, post-organ transplant) Viral and bacterial Infections (HIV, HTLV-1 virus, Epstein-Barr virus, Helicobacter pylori bacteria) The cause of non-hodgkin s lymphoma is not known. It is not accepted to be inherited as other cancers are, although there is a suspicion that there might be some familial inheritance risk. There are environmental factors that have been associated, mainly herbicides. Also the Agent Orange which was used in the Vietnam War, also the creosol that was applied to the telephone posts several --- a decade or two ago. There is a suspicion that highdose radiation exposure might predispose to non- Hodgkin s lymphoma. It is known that immune deficiency states such as AIDS, acquired immunodeficiency disease --- syndrome, is a risk factor for developing lymphoma. It is also known that Helicobacter pylori predisposes in a very small population of patients to the development of indolent lymphoma in the stomach. There is also a suspicion of Epstein-Barr virus being behind the lymphomagenesis of several lymphomas. The one that is mostly discussed is the child --- childhood Burkitt s lymphoma, the African type. 非霍奇金淋巴瘤的病因不明 和其他癌症不同, 人们并不认为非霍奇金淋巴瘤具有遗传性, 尽管也有怀疑可能有某种程度的家族遗传风险 有环境因素被发现与之相关, 主要是除草剂, 还有在越战中使用的橙剂, 以及一二十年以前用于电话杆的木焦油酚 接触高剂量放射被怀疑可能造成非霍奇金淋巴瘤易患性 已经知道免疫缺陷状态, 例如艾滋病, 即获得性免疫缺陷综合症, 是发生淋巴瘤的风险因素 还知道幽门螺旋菌会让非常少的患者人群容易罹患胃内惰性淋巴瘤 还怀疑 EB 病毒是导致数种淋巴瘤的元凶 讨论最多的是非洲儿童伯基特淋巴瘤 3

4 Signs and Symptoms Enlarged (usually non-tender) lymph nodes that do not disappear in 2 weeks or respond to antibiotics Constitutional symptoms (< 20%) Weight loss Fever Night sweats You will know or suspect lymphoma if you have a --- an enlarged lymph node that does not disappear after two weeks and is not responding to antibiotics. Usually this lymph node will be non-tender. And it might or not be associated with unexplained weight loss or unexplained fever or drenching night sweats so that you have to change your clothes or your night spread --- sheets. 如果淋巴结肿大持续两周, 而且抗生素治疗无效, 则可以确定或怀疑存在淋巴瘤 通常这样的淋巴结没有触痛 可能伴有也可能不伴有原因不明的体重下降, 或原因不明的发烧, 或夜间大汗淋漓, 需要更换衣物或床单 Lymphoma: Diagnosis Biopsy Fine needle aspiration (FNA) Excisional/incisional Bone marrow Laboratory tests CBC and differential Serum chemistries Imaging studies Chest x-ray Computed tomography (CT) scan of neck/chest/ abdomen/pelvis Positron emission tomography (PET) scan in selected cases To diagnose lymphoma, you will need a biopsy. It could be incisional or excisional. And fine-needle aspiration is also recommended in order to do some of the additional markers and recent studies that have been added to the armamentarium. But you do have a --- you do need a biopsy. This will be able to make --- make you able to subclassify the lymphoma. You will need a bone marrow, both for staging purposes, to see how advanced the disease is. And, in some cases where you present with symptoms but no enlarged lymph nodes, this might be the only place where you have lymphoma. As part of the initial tests, once you have a diagnosis, you will have to evaluate for other prognostic factors, such as elevated levels of lactate dehydrogenase in the serum. You will also want to know how the blood count is to see if there has been an effect of the lymphoma in the platelet count as well as the hemoglobin. You will also want to do imaging studies as part of the workup to find the 诊断淋巴瘤需要进行活检 可以是切开式活检或切除 式活检 还建议进行细针穿刺, 以便进行其他的标记物或新近添加的其他检查 但无论怎样, 活检是必需的 这样就可以对淋巴瘤进行细分类 需要有骨髓, 用于分期, 查看疾病的程度如何 此外, 有时有表现症状却没有肿大的淋巴结, 则骨髓可能是唯一发现淋巴瘤的部位 作为初始检测的一部分, 一旦确诊之后, 必需评估其他预后因素, 例如血清乳酸脱氢酶升高的程度 还需要了解血细胞计数的情况, 查看淋巴瘤是否影响到了血小板计数和血红蛋白水平 检查时还需要进行成像检查, 了解疾病的扩散程度 这包括胸片 颈 胸 腹和骨盆的计算机断层成像 对大细胞非霍奇金淋巴瘤或霍奇金淋巴瘤, 则还可以使用较 4

5 World Health Organization (WHO) Classification of B-cell Lymphoma Indolent Aggressive Very Aggressive Small lymphocytic lymphoma Lymphoplasmacytic/ Waldenström s macroglobulinemia (WM) Marginal zone lymphoma Follicle center lymphoma, follicular, grade I-II Primary cutaneous follicle center lymphoma Multiple myeloma Mantle cell lymphoma Follicle center lymphoma, follicular, grade III Diffuse large B-cell lymphoma (DLBCL) Primary mediastinal large B-cell lymphoma Lymphomatoid granulomatosis Primary cutaneous DLCL- leg type Burkitt s lymphoma Intravascular large B-cell lymphoma Jaffe ES. Hematol Am Soc Hematol Educ Program 2009:523 extent of disease. This will include a chest x-ray, computed tomographies of the neck, chest, abdomen, and pelvis, and more recently a positron emission tomography in the cases that have large cell non-hodgkin s lymphoma or Hodgkin s lymphoma. There have been many classifications of lymphoma. The most recent one, the World Health Organization Classification from a year or two ago, is mainly a pathologic classification. Although for the clinician it helps to separate them into the slower indolent growth lymphomas, the more aggressive lymphopro --- lymphoproliferative processes, and the very aggressively fast-growing lymphomas. The indolent lymphomas are those mentioned in the table: small lymphocytic lymphoma; Waldenström s, which is intermediate between lymphoma and a plasmacytic process; the marginal zone lymphomas; the follicle center cell lymphoma follicular grades I and II, which are by far the most common indolent lymphomas; and the follicle center primary cutaneous lymphomas. Other aggressive lymphoproliferative disorders, multiple myeloma is included, but I will discuss this separately. Mantle cell lymphoma is one of the aggressive lymphomas. The follicle center cell follicular grade III is considered aggressive and should be treated as such. The diffuse large B-cell lymphoma is one of the two most common lymphomas along with the follicle center follicular grade I and II, and other more unusual presentations such as primary mediastinal large-cell lymphoma, lymphomatoid granulomatosis, primary cutaneous large-cell lymphoma of the leg type. Under the very aggressive group, the fast growing lymphomas with also a predilection for extranodal presentation are the Burkitt s and the intervascular large B-cell lymphoma. 新的正电子发射断层扫描 淋巴瘤的分类有很多种 最新的是一两年前颁布的世界卫生组织分类, 其中主要是病理学分类 但对临床医生来说, 这种分类有助于将淋巴瘤分为进展较慢的惰性淋巴瘤, 进展较快的淋巴增生过程, 以及进展很快的快速生长淋巴瘤 惰性淋巴瘤是表格中列出的这些种类 : 小淋巴细胞性淋巴瘤 ; 巨球蛋白病, 这是介于淋巴瘤和浆细胞疾病之间的一种疾病 ; 边缘区淋巴瘤 ; 滤泡等级为 I 度和 II 度的滤泡中心细胞淋巴瘤, 这是目前最常见的惰性淋巴瘤 ; 和滤泡中心原发性皮肤淋巴瘤 进展较快的淋巴增生疾病包括多发性骨髓瘤, 但我会单独讨论这一题目 套细胞淋巴瘤是进展较快的淋巴瘤之一 滤泡等级为 III 度的滤泡中心细胞淋巴瘤被认为是进展较快的疾病, 并应做相应的治疗 弥漫性大 B 细胞淋巴瘤是两种最常见的淋巴瘤之一 另一种是滤泡等级为 I 度和 II 度的滤泡中心细胞淋巴瘤 其他较不常见的表现包括原发性纵膈大细胞淋巴瘤 淋巴瘤样肉芽肿病 原发性皮肤大细胞淋巴瘤腿型 在进展很快的快速生长淋巴瘤里, 淋巴瘤快速生长同时易于出现淋巴结外表现的有伯基特淋巴瘤和血管内大 B 细胞淋巴瘤 5

6 Most Common NHLs T-LL, 2% Other, 9% MZL, nodal, 2% 这张饼图显示了疾病发生频率的分布 如前所述 最 常见的恶性淋巴细胞增生疾病 非霍奇金淋巴瘤 是 大 B 细胞淋巴瘤和滤泡性淋巴瘤 DLBCL 31% BL 2% ALCL 2% This pie chart gives you an idea of the frequency of distribution. Like I said before, the most common lymphoproliferative malignancies, non-hodgkin s lymphomas are the large B-cell lymphomas and the follicular lymphomas. PMLBCL 2% MCL 6% SLL/CLL 7% PTCL 7% FL, 22% MALTL 8% Armitage JO, Weisenburger DD. J Clin Oncol (8):2780 Follicular Lymphoma This is an example of how a researcher would evaluate and what he would see under regular electron --- [I m sorry] --- under regular microscopy on low-power field. This would be a follicular lymphoma, so-called follicular because it respects the follicular active texture of the lymph nodes. The areas that are less dense are the areas that are involved by the lymphoma: and that is the center of the follicle, so-called germinal center of the follicle. The areas in between the follicles are not involved by lymphoma. 这张照片显示了研究人员在普通显微镜低倍视野会看 到的表现 这是滤泡性淋巴瘤 之所以称为滤泡性是 因为它与淋巴结活性滤泡的构造一致 致密性较低的 区域是淋巴瘤累及的区域 即滤泡中央区域 也就是 所谓的滤泡生长中心 滤泡之间的区域未被淋巴瘤累 及 6

7 Diffuse Large B-cell Lymphoma Morphologic Variants This is how a diffuse large B-cell lymphoma would present. As the name states, it s a diffuse effacement of the architecture of the lymph node. And it is mostly composed of large cells whether they are centroblastic or whether they are the immunoblastic cytologic variants, which in some papers is reportedly more aggressive behaving. 这是弥漫性大 B 细胞淋巴瘤的表现 名符其实, 弥漫性大 B 细胞淋巴瘤是淋巴结结构弥漫性分布的一种疾病 弥漫性大 B 细胞淋巴瘤主要由大细胞组成, 可以是中心母细胞型, 或者是免疫母细胞型, 而一些文献认为后者进展更快速 Centroblastic Variant Immunoblastic Variant Clinical Staging of Lymphomas Stage I Single lymph node region Single organ outside the lymph nodes Stage II Two or more lymph node regions near to each other Stage III Two or more lymph node regions above and below the diaphragm Stage IV Widespread disease Multiple organs involved One organ with lymph node involvement You will also want to stage the disease. You will want to know if this is an early presentation or a more advanced presentation. We still use the Ann Arbor Classification devised for Hodgkin s lymphoma decades ago, but it is now not the only way to predict prognosis of the disease. 还需要对疾病进行分期 需要知道这是早期表现, 还是较为晚期的表现 我们仍在使用几十年前制定的霍奇金淋巴瘤 Ann Arbor 分类, 但这一方法不再是预测疾病预后的唯一方式 7

8 Clinical Staging of Lymphoma Stage I Stage II Stage III Stage IV In this staging system, which I will show in a more illustrative fashion, we have four stages depending upon the areas involved. Stage I is a region of nodes involved either above or below the diaphragm. Stage II are two regional areas both either above or below. Stage III has regions involved below and above the diaphragm. And Stage IV is when there is an extranodal presentation along with a region of lymph nodes or two extranodal presentations. In this illustration, the extranodal sites are the bone marrow and the liver, but there could be other extranodal sites. 我会用图示更为详细地介绍此分期系统 根据累及部位的不同, 此分期系统将疾病分为四期 I 期累及横膈膜上侧或下侧的淋巴结区域 II 期累及的淋巴结区域均在横膈膜上侧或下侧 III 期累及横膈膜下侧和上侧的淋巴结区域 而 IV 期有一处淋巴结外表现伴累及一个淋巴结区域, 或者有两处淋巴结外表现 在这张图示中, 累及的淋巴结外部位是骨髓和肝脏, 但也可能是其他的淋巴结外部位 International Prognostic Index (IPI) for Diffuse Large B-cell Lymphoma Factor Age PS 2 LDH Extranodal sites 2 Stage Factor Adverse > 60 years > Normal III-IV PS 2 LDH Stage Adverse > Normal III-IV Age-Adjusted The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med (14):987 As I have mentioned before, we have included in the most recent models of prognosis, not only the stage, which you see in the lower part of the graph - -- of the table but other factors such as age, performance status, the level of the lactate dehydrogenase in the serum, and the number of extranodal sites. You can see that, according to the number of factors that you have, you will decrease your chances of being alive at five years, going from 73% chance if you have none or one of these five variables in the adverse category, all the way to 26% only if you have four to five of these variables on the adverse area. There is an age-adjusted model that also helps in specific groups of patients by age --- less or equal to 60 versus more than 60. 正像我之前所述, 最新的预后模型不仅纳入了分期因素, 如这张表格的下部所示, 还包括了其他因素, 例如年龄 身体功能状态 血清乳酸脱氢酶的水平以及累及的淋巴结外部位数量 可以看见, 随着风险因素数量的增加, 五年存活率会下降 没有不良可变因素或有五项不良可变因素中的一项时, 五年存活的几率为 73% 之后存活率一直下降, 等到有五项不良可变因素的四或五项时, 五年存活率降为 26% 还有一项经过年龄调整的模型, 可以帮助按年龄区分的特定患者组别,60 岁及 60 岁以下对于 60 岁以上的患者 8

9 International Prognostic Index for Follicular Lymphomas (FLIPI) Factor Nodal Sites 5 LDH Adverse Age 60 Stage Hemoglobin > Normal III-IV < 12 g/dl Prognosis Number of Factors Patients (%) 5-year OS (%) 10-year OS (%) Good Intermediate Poor This previous staging model was for the diffuse large-cell lymphomas. We have since modified it also to be applicable for the follicular lymphomas. This model has five variables also, although two variables have been removed and two new ones have been added, mainly the number of nodal sites and the level of hemoglobin. And, as you can see, this model predicts, for better or worse, 10 year overall survival. 前面的分期模型适用于弥漫性大细胞淋巴瘤 我们对 该模型进行了修订, 以适用于滤泡性淋巴瘤 这一模型也有五个可变因素, 但是去掉了两个可变因素, 然后加入了两个新的可变因素 主要是淋巴部位的数量 和血红蛋白水平 可以看到, 这一模型用于预测 10 年总体生存率是较好还是较差 Solal-Celigny P et al. Blood (5):1258 Mantle Cell International Prognostic Index (MIPI) Points Age, y ECOG LDHULN WBC, 10 9 /L 0 < < 0.67 < Another example where a recently introduced model is being applied is the mantle cell lymphoma. There is a Mantle Cell International Prognostic Index. And these are four variables that have been included in the model. Two of them are familiar because they have been included in the previous models, the age and the serum level of LDH, and the other two are particular to this lymphoma. 另一个例子是最近开始使用的套细胞淋巴瘤模型 有套细胞国际预后指数 这个模型包括了四个可变因素 其中两个较为熟悉, 在之前的模型已经得到使用, 即年龄和血清 LDH 水平 ; 另外两个是这种淋巴瘤特有的可变因素 U/dL /mm 3 For each prognostic factor, 0 to 3 points were given to each patient and points were summed up to a maximum of 11. Patients with 0 to 3 points in summary were classified as low risk, patients with 4 to 5 points as intermediate risk, and patients with 6 to 11 points as high risk. ECOG performance status was weighted with 2 points if patients were unable to work or bedridden (ECOG 2-4). LDH was weighted according to the ratio to the ULN. Thus, for an ULN of 240 U/L, the cutpoints were 180 U/L, 240 U/L, and 360 U/L, for example. 9

10 Overall Survival According to MIPI And based on the number of variables, you will have low, intermediate, and high risk of death from disease. 根据可变因素的数目, 死于疾病的风险分为低 中 高 Probability of overall survival LR, median not reached IR, median = 51 HR, median = Months since registration Numbers of patients at risk LR IR HR Hoster E et al. Blood (2):558 Hodgkin s Lymphoma: The WHO Classification Nodular lymphocyte predominant with or without diffuse areas Classic types: Nodular sclerosing Mixed cellularity Lymphocyte depleted Lymphocyte rich, nodular or diffuse There are other models for T-cell lymphomas, but the T-cell lymphomas are not being discussed in this talk. Going into the Hodgkin s lymphoma, the World Health Organization Classification divides them into two major types: nodular lymphocyte predominant with or without diffuse areas. This is the least common and the classical types, which are by far the most common: predominantly nodular sclerosing but also mixed cellularity as well, and the lesser common lymphocyte-depleted and lymphocyte-rich subcategories. 还有其他的 T 细胞淋巴瘤模型, 但本次讲座并不讨论 T 细胞淋巴瘤 现在让我们来谈谈霍奇金淋巴瘤 世界卫生组织分类将霍奇金淋巴瘤分为两大类 : 有或无弥漫性区域的结节性淋巴细胞为主型的霍奇金淋巴瘤, 这是最不常见的类型 ; 以及目前最为常见的经典类型 : 结节硬化为主分型和混合细胞分型, 以及较不常见的淋巴细胞缺乏分型和富于淋巴细胞分型 10

11 Hodgkin s Lymphoma: Reed-Sternberg Cell This is an example of the Reed-Sternberg cell, which is a pathognomonic cell or used to be called pathognomonic for Hodgkin s. It is still [a] very reliable parameter to diagnosis Hodgkin s. As you can see in the center of the slide, there is a cell that has two nuclei. And this is a very typical cell that is present in Hodgkin s lymphomas. 这一例是 Reed-Sternberg 细胞 这是具有诊断价值的细胞, 一度被称为霍奇金淋巴瘤的诊断性细胞, 目 前仍然是诊断霍奇金淋巴瘤非常可靠的指标 在幻灯片的中间可以看到有个双核细胞 这是霍奇金淋巴瘤出现的非常典型的细胞 Courtesy of Jeffrey L. Medeiros, M.D. Early Stage (Stage I and II) Unfavorable HL General risk factors for unfavorable group: Large mediastinal mass Extranodal disease Elevated erythrocyte sedimentation rate (ESR) 3 involved areas The classification, as I stated earlier, is the Ann Arbor Classification. And it is still in use. We broadly divide them into the early stages, stage 1 and II. But even among the stage ones and twos, we further divide them into favorable and unfavorable. And any of these factors that you see here will make that person unfavorable and will have implications in terms of treatment: either a large mediastinal mass, or extranodal disease, or three or more involved areas of disease, or an elevated sedimentation rate. 这一分类就是我之前曾提及的 Ann Arbor 分类 目前仍在使用这一分类方法 我们粗略分为早期 I 期和 II 期 但是我们又把 I 期和 II 期进一步分为良好型和不良型 这里可以看到, 如果有这些因素中的任何一种, 就会造成患者情况不良, 影响治疗情况 : 有一个 纵膈大肿块, 或者累及淋巴结外, 或者累及三处或更多处, 或者沉积率升高 As defined by German Hodgkin Lymphoma Study Group (GHSG) 11

12 International Prognostic Score for Advanced Hodgkin s Lymphoma Analysis of 5,141 patients treated with chemotherapy +/- radiation 7 factors emerged: 1. Albumin < 4 g/dl 2. Hemoglobin < 10.5 g/dl 3. Male gender 4. Age > Stage IV 6. WBC count 15, Lymphocyte count < 600/µL or 8% of WBC Those with 5 or more factor theoretically would benefit from alternative treatments, but small group (7% of population) Hasenclever D, Diehl V. N Engl J Med (21):1506 Multiple Myeloma Disseminated malignancy of monoclonal plasma cells Second most common hematologic malignancy Findings Lytic bone lesions Anemia Renal failure or azotemia Hypercalcemia Recurrent infections For the Hodgkin s lymphomas that are advanced stage at presentation, this model has been devised with seven variables. And, as you can see, as the variable number increases, your chance of being alive without recurrence or any events will decrease in this case from 84% to 42%. Again, this is for patients with advanced stage Hodgkin s lymphoma, stages III and IV. The last topic that I want to discuss is multiple myeloma. This is a malignancy of plasma cells which are mature B-cells. It is a very common hematologic malignancy. The main findings are lytic bone lesions, which could cause pain in the patient; anemia, which would give symptoms of fatigue; kidney failure due to precipitation of a protein produced by the myeloma into the kidney; elevated calcium because of destruction of bone and re --- re --- demineralization of the bone; and hypercalcemia would give symptoms of increasing urination; as well as somnolence and could be fatal if not treated soon. You could also present with recurrent infections, mostly urinary. 针对有晚期表现的霍奇金淋巴瘤, 制定了这一具有七个可变因素的模型 可以看到, 随着可变因素数目的增加, 没有疾病复发或没有任何事件的存活几率会下 降, 这里是从 84% 降至 42% 如前所述, 此模型适用于 III 期和 IV 期晚期霍奇金淋巴瘤患者 我要讨论的最后一个主题是多发性骨髓瘤 多发性骨髓瘤是成熟 B 细胞的恶性浆细胞瘤 这是非常常见的恶性血液疾病 主要检查结果包括溶骨性病变, 可引起疼痛 ; 贫血, 可产生疲劳症状 ; 骨髓瘤产生的蛋 白质在肾内沉积, 造成的肾脏衰竭 ; 骨破坏和去矿物质引起的钙水平升高 ; 以及高钙血症, 可引起排尿增加的症状 ; 以及嗜睡, 如果不加治疗可能会致命 还可能出现反复感染, 主要是泌尿系统感染 12

13 Diagnosis of Myeloma This is a smear of a --- it could be a bone marrow or peripheral blood, where you see the plasma cells which are the cells that have a basophilic cytoplasm with an eccentric nucleus. 这张涂片可能来自骨髓或外周血 可以看见有嗜碱性胞浆, 而且核偏在一边的浆细胞 Diagnosis of Myeloma Serum Protein electrophoresis Immunofixation Free light chains 24 hrs urine Total protein Electrophoresis Immunofixation to define protein types Quantitative immunoglobulin And, in addition, you would want to know what --- how much serum protein, which is abnormal protein produced by T-cells, is present. For that you would test in the serum for protein electrophoresis and do immunofixation in these proteins. You would also do the same in the 24-hour collection of the urine. 此外还应了解有多少 T 细胞产生的异常血清蛋白 可以进行血清蛋白电泳, 并对得到的蛋白进行免疫固定检测 还可以对采集的 24 小时尿液进行同样的检测 13

14 Further Evaluation If you do an x-ray of your skull, you will see the areas that are lucent. It means that there is less mineralization and these areas are devoid of bone. 如果对颅骨进行 X 光检查, 可以看到一些透光区域 这表示这些区域矿物质化的程度较低, 并且有骨缺失 Further Evaluation Routine laboratory studies CBC Chemistries including calcium, BUN and creatinine, LDH Skeletal survey Bone marrow biopsy Cytogenetics Serum β2m You will do a complete blood count to see if your hemoglobin and platelets are adequate. You will test for the calcium and the kidney function tests in the blood. You will do a skeletal survey to see if you find any other areas in the body that have lytic lesions in your skull --- in your skeleton. You will do the bone narrow biopsy to document involvement by the increased amount of plasma cells. More recently, cytogenetics are becoming important in being able to predict how the patient will respond to therapy as well as survival. And also a blood test for the serum beta-2- microglobulin is becoming important in predicting outcome. 需要做全血计数, 查看血红蛋白和血小板是否正常 需要用血液检测钙水平并做肾功能检测 需要检查骨骼, 了解骨骼的其他任何部位是否有溶骨性病变 做骨髓活检, 记录浆细胞数量增加的累及情况 最近, 细胞遗传学的作用变得越来越重要, 可以预测患者的治疗效果以及存活时间 同时, 检测血液中的血清 β- 2 微球蛋白对于预测转归正变得日益重要 14

15 Durie-Salmon Staging System Stage Characteristic MM Cell Mass 1 Hgb > 10 g/dl Ca ++ < 12 mg/dl Bone survey nl or 1 lesion IgG < 5 g/dl IgA < 3 g/dl Urine BJP < 4 g/day Low 2 Fits neither stage 1 or 3 Int. 3 Hgb < 8.5 g/dl Ca ++ > 12 mg/dl Advanced bone lesions IgG > 7 g/dl IgA > 5 g/dl Urine BJP > 12 g/day High International Staging System Stage Characteristic Risk 1 β 2 M < 3.5 mg/l Albumin > 3.5 g/dl OS (med. Mos) Low 62 The Durie-Salmon staging system is an old system that is still --- can be applicable to a patient in order to predict how he will do and it is basically a tumor load system. As you can see between cycles --- stages I and III, the difference is that the hemoglobin is lower, the calcium is higher, the bone lesions are more, the amount of protein deposition is more, and this is the high tumoral mass stage. An international system has been devised, which is easy to do. It involves doing two blood tests. It includes a beta-2-microglobulin and a serum albumin. And, as you can see, the survival will range anywhere from 62 to 29% depending upon how many of these two variables are in the poor risk category. Durie-Salmon 分期系统是较为陈旧的系统, 目前仍然适用于预测患者的身体机能状况 这基本上是肿瘤负荷系统 可以看见 I 期和 III 期之间的差异在于, 血红蛋白的水平较低, 钙水平较高, 更多的骨病变, 沉积的蛋白量更多, 所以这是高肿瘤质量期 已经制定了一套国际分期系统 这套系统简单易行, 需要进行两项血液检测, 包括 β-2 微球蛋白和血清白蛋白 可以看到, 生存率的范围在 62% 至 29% 之间, 具体取决于这两个可变因素中有几个属于不良风险 2 β 2 M mg/l Albumin < 3.5 g/dl Int β 2 M > 5.5 mg/l High 29 15

16 MM: Common Cytogenetics Poor prognosis features Deletion 13 (cytogenetics >>>> FISH) t(4;14) t(14;16) Deletion 17q13 (p53 mutation) Gain of 1q21 Non-hyperdiploid 22q deletions Cytogenetics, as I mentioned before, is important. The lesion 13, the lesion 17 among these that you see are important prognostic features 如同我前面介绍的一样, 细胞遗传学检查很重要 13 缺失 17 缺失以及这里的其他突变都是重要的预后特征 Combining ISS Stage and Chromosomal Abnormalities on Survival Outcomes in Multiple Myeloma IMWG Analysis Genetic Abnormalities 4-Year Estimated OS Minus vs. Plus Abnormality Log Rank P Value Any 73% vs. 57% <.0001 t(4;14) ISS I ISS2 ISS3 Del 17 ISS I ISS2 ISS3 64% vs. 36% 81% vs. 52% 63% vs. 30% 44% vs. 22% 68% vs. 44% 81% vs. 64% 68% vs. 42% 48% vs. 28% a. ISS I or ISS2, normal FISH 193/610 deaths (76%) b. ISS I + abnormal FISH / ISS III + normal FISH 140/252 deaths (52%) c. ISS II or ISS III + abnormal FISH 146/196 deaths (32%) <.0001 <.0001 <.0001 <.007 <.0001 <.020 <.0001 <.020 a vs. b <.0001 a vs. c <.0001 b vs. c <.0001 Adapted from: Avet-Loiseau H et al. Blood (ASH Annual Meeting Abstracts) : Abstract 743and Avet-Loiseau H. et al. Blood :3489.such that they have been combined with the international staging system. And this is a recent presentation with a combination of these two models that is a better predictor of how the patients will do at four years in terms of survival. 因此将这些特征与国际分期系统相结合 这是最近演示的将两个模型相结合, 可以更好预测患者的四年生存情况 16

17 Summary Hematologic malignancies are quite diverse in their presentation and diagnosis Tools are available to assist in diagnosis, staging and determining prognosis for each hematologic malignancy So, in summary, I have described the principle hematologic malignancies. As you see, they are quite diverse in their presentation and diagnosis. We have available ever-increasing tools to assist in diagnosis and staging. And we have developed newer models to try to help determine prognosis and arrange --- and decide what therapy is best according to the different subgroups. I hope this will help you evaluate patients who present in any of these presentations. And this concludes my talk. I hope that you have enjoyed the lecture and we welcome your feedback. Thank you. 综上所述, 我介绍了主要的恶性血液疾病 正如大家知道的一样, 恶性血液疾病表现和诊断千差万别 目前正不断涌现出各种工具帮助我们进行诊断和分期 而且我们还制定了更新的模型, 帮助判断预后, 并根据不同的亚组确定最佳治疗方法 我希望本次讲座会帮助各位评估出现上述任何表现的患者 我的讲座到此结束 希望大家喜欢本次讲座, 敬请提出反馈意见 谢谢 17