Management of Hodgkin lymphoma

Approximately 7350 new cases of Hodgkin lymphoma (HL) are diagnosed annually in the United States. The Incidence of HL has a bimodal pattern, with the highest incidence seen in young adults and in elderly patients. The disease is composed of 2 distinct entities: the more commonly diagnosed classical HL and the rare nodular lymphocyte-predominant HL. Classical HL includes the subgroups nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte rich. Selection of the appropriate therapy Is based on accurately assessing the stage of disease. Patients with early-stage disease are treated with combined modality strategies using abbreviated courses of combination chemotherapy followed by Involved-field radiation therapy, whereas those with advanced-stage disease receive a longer course of chemotherapy without radiation therapy. Currently, more than 80% of all patients with newly diagnosed HL are expected to be long-term survivors. Although many patients respond well to initial therapies and have durable long-term remissions, a subset of patients has resistant disease and experiences relapse even after subsequent high-dose chemotherapy and autologous stem cell transplantation. New therapies are clearly needed for these patients.     

Role of the primary care physician in Hodgkin lymphoma

Approximately 8,200 new cases of Hodgkin lymphoma are diagnosed annually in the United States. Common presenting features include painless lymphadenopathy (usually above the diaphragm), cough, fever, night sweats, and weight loss. To decrease late complications, treatment has gradually evolved toward shorter-duration chemotherapy with use of lower-dose, shorter-duration radiation therapy. ABVD (a chemotherapy regimen consisting of doxorubicin, bleomycin, vinblastine, and dacarbazine) is now more commonly used than MOPP (a regimen consisting of mechlorethamine, vincristine, procarbazine, and prednisone) in patients with Hodgkin lymphoma. Many significant complications of therapy (e.g., cardiovascular conditions, infertility, premature menopause, secondary neoplasms) directly reflect the choice of primary treatment and may be reduced by more current treatment strategies. Recurrences of Hodgkin lymphoma are most common in the first few years after diagnosis and treatment. Prognosis is related to the stage of lymphoma, disease bulk, and age of the patient. Currently, more than 80 percent of patients with newly diagnosed Hodgkin lymphoma are expected to be long-term survivors.     

Detection of T-regulatory cells has a potential role in the diagnosis of classical Hodgkin lymphoma

Previous studies have demonstrated an increase in T-regulatory cells in the involved lymph nodes and peripheral blood of patients with Hodgkin lymphoma. Our study examined whether the detection of T-regulatory cells by flow cytometry could distinguish classical Hodgkin lymphoma (CHL) from benign cases and B-cell non-Hodgkin lymphomas (B-NHL). We measured CD4, CD25, and CD152 in 14 CHLs, 2 nodular lymphocyte-predominant Hodgkin lymphomas, 31 B-NHLs, and 54 benign cases. All T-regulatory cell parameters, including percent lymphocytes CD4+/CD152+ and CD4+/CD25+/CD152+, and mean and median CD152 expression in CD4+/CD25+ lymphocytes, were higher in CHL than in B-NHL and benign. Mean CD152 in CD4+/CD25+ lymphocytes distinguished CHL from benign with 79% sensitivity and 100% specificity, and from B-NHL with 71% sensitivity and 90% specificity. Overall, our results show that T-regulatory cells are increased in CHL and their detection may be a useful tool in differentiating CHL from other entities.     

~(18)F-FDG PET-CT显像对恶性淋巴瘤诊断和分期中的临床应用价值

目的探讨18F-FDG PET-CT显像在恶性淋巴瘤诊断、疗效评价及临床分期中的应用价值。方法对30例疑诊为淋巴瘤并进行18F-FDG PET-CT显像28例经病理证实为淋巴瘤,其中HD6例,NHL22例。图像分析采用视图分析及测量病灶平均标准摄取值方法相结合。结果 30例疑诊淋巴瘤患者中,14例治疗前行PET-CT检查,11例确诊为淋巴瘤,2例假阳性,1例假阴性;5例手术治疗后,2例术后复发及转移;11例放疗/化疗的患者,4例复发,4例见局部有病灶残存,3例未见异常;5例患者于治疗前及放化疗后检查,4例肿瘤明显受抑制1。8F-FDG PET-CT诊断符合率为93.3%。检测淋巴瘤病灶敏感性为89.4%。特异性为95.5%。结论 18F-FDG PET-CT显像对淋巴瘤病灶有较高的敏感性、特异性,有助于临床更准确的分期从而指导治疗。     

Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma

Using current diagnostic criteria, primary mediastinal B cell lymphoma (PMBL) cannot be distinguished from other types of diffuse large B cell lymphoma (DLBCL) reliably. We used gene expression profiling to develop a more precise molecular diagnosis of PMBL. PMBL patients were considerably younger than other DLBCL patients, and their lymphomas frequently involved other thoracic structures but not extrathoracic sites typical of other DLBCLs. PMBL patients had a relatively favorable clinical outcome, with a 5-yr survival rate of 64% compared with 46% for other DLBCL patients. Gene expression profiling strongly supported a relationship between PMBL and Hodgkin lymphoma: over one third of the genes that were more highly expressed in PMBL than in other DLBCLs were also characteristically expressed in Hodgkin lymphoma cells. PDL2, which encodes a regulator of T cell activation, was the gene that best discriminated PMBL from other DLBCLs and was also highly expressed in Hodgkin lymphoma cells. The genomic loci for PDL2 and several neighboring genes were amplified in over half of the PMBLs and in Hodgkin lymphoma cell lines. The molecular diagnosis of PMBL should significantly aid in the development of therapies tailored to this clinically and pathogenetically distinctive subgroup of DLBCL.     

灰区淋巴瘤2例临床病理分析

目的:探讨灰区淋巴瘤(grey zone lymphoma,GZL)的临床和病理组织学特征。方法:应用光镜观察及免疫组化染色对2例GZL患者的病理标本进行分析,同时复习相关文献。结果:例1患者经右锁骨上淋巴结活检,其肿瘤病理组织学形态类似经典型霍奇金淋巴瘤(classic Hodgkin's lymphoma,CHL),但肿瘤细胞免疫表型为CD30+、CD15-、CD20+。例2患者为纵隔肿瘤,肿块主要表现为弥漫性大B细胞淋巴瘤(diffuse large B cell lymphoma,DLB-CL),肿块边缘灶区分布霍奇金细胞和RS(Hodgkin's and Reed-Sternberg,HRS)样细胞,这些细胞呈CD30+、CD15+、部分CD20+、CD79α+、BOB.1+、OCT2-,同时部分HRS样细胞呈EBV+。结论:本研究的2例GZL患者在组织学形态和免疫学表型上同时具有CHL和DLBCL的共同特点,预后较差。     

Risk of breast cancer and breast cancer characteristics in women treated with supradiaphragmatic radiation for Hodgkin lymphoma: Mayo Clinic experience

OBJECTIVE: To evaluate the overall risk of breast cancer and breast cancer characteristics in women given supradiaphragmatic radiation therapy for Hodgkin lymphoma. PATIENTS AND METHODS: Medical records of 653 female patients who received supradiaphragmatic radiation therapy for Hodgkin lymphoma at the Mayo Clinic in Rochester, Minn, between 1950 and 1993 were abstracted, and follow-up questionnaires were mailed. In 4 patients, breast cancer was diagnosed before Hodgkin lymphoma was discovered. RESULTS: The median age of 649 patients at supradiaphragmatic radiation therapy was 31.8 years (range, 2.6-86.5 years). The median duration of follow-up was 8.7 years (range, < 1-47.9 years). In 30 patients, breast cancer developed (bilaterally in 4 patients) after supradiaphragmatic radiation therapy; the median interval was 19.9 years (range, 0.7-423 years). The median age at breast cancer diagnosis was 44.4 years (range, 27.5-70.8 years). The standardized morbidity ratio for breast cancer after supradiaphragmatic radiation therapy was 2.9 (95 % confidence interval [CI], 2.0-4.2) (P < .001). Breast cancer risk significantly increased 15 to 30 years after patients received supradiaphragmatic radiation therapy, and risk was inversely related to age at supradiaphragmatic radiation therapy until age 30 years. The standardized morbidity ratio for patients younger than 30 years at supradiaphragmatic radiation was 8.5 (95% CI, 53-13.1) vs 1.2 (95% CI, 0.5-2.2) for those aged 30 years or older (P < .001). Splenectomy increased breast cancer risk (P = .01). Breast cancer detection was by self-examination in 15 cancers, by mammography in 13, and by clinical examination in 4; in 2 cancers, the mode of detection was unknown. Modified radical mastectomy was used to treat breast cancer. CONCLUSION: The increased risk of breast cancer in survivors of Hodgkin lymphoma given supradiaphragmatic radiation therapy appears to be limited to patients who are younger than 30 years at radiation therapy or to those who have undergone splenectomy.     

Epstein-Barr virus and malignant lymphoma

Association between Epstein-Barr virus and malignant lymphomas such as Burkitt's lymphoma, Hodgkin's disease(HD), nasal T/NK cell lymphoma(NTL), immunodefficiency-associated lymphoma, and pyothorax associated lymphoma (PAL) has been suggested. Among these, HD, SNL, PAL are relatively common in Japan. For HD, EBV association was found in the disease peak incidences; those are peak in older adults in Japan, older peak of the bimodal peaks in Western countries, and unimodal peak in the childhood in the developing countries. For NTL, EBV was associated with almost all cases with CD56+ phenotype and cases with polymorphic reticulosis morphology with CD56- phenotype. For PAL, most cases are EBV-associated, about 40% of these show Type B subtype, the ratio of type A EBV to type B EBV in PAL was similar to those in immunodeficiency-associated lymphomas.     

Incidental discovery of a Hodgkin lymphoma synchronous to a papillary thyroid carcinoma

Papillary thyroid carcinoma is the most common type of thyroid cancer and accounts for almost 89.4% of all thyroid carcinomas. Hodgkin lymphoma is a heterogeneous group of neoplasms and represents 10% of lymphomas. These two cancers do not share the same risk factors. Some studies have reported the association of thyroid papillary carcinoma with lymphomas, mainly Hodgkin''s lymphoma, treated with radiotherapy. However, to our knowledge less than 10 cases have illustrated synchronous papillary thyroid carcinoma and Hodgkin lymphoma with no history of radiotherapy. We present the case of a 49‐year‐old female patient, with no history of past exposure to radiation, who was incidentally diagnosed with Hodgkin lymphoma during the work up for papillary thyroid carcinoma. Our patient had total thyroïdectomy with cervical lymphadenectomy. The histopathologic examination concluded to a papillary thyroid carcinoma of classical variant. And the lymph node dissection enabled us to diagnose not only papillary thyroid carcinoma''s lymph node metastasis, but also Hodgkin Lymphoma. This discovery of the Hodgkin lymphoma was totally incidental. The discovery of synchronous tumors in patients with papillary thyroid carcinoma has been reported in the literature. However, the diagnosis of Hodgkin through lymph node dissection for papillary thyroid carcinoma is extremely rare. This underlines the singularity and the importance of our case. The synchronous papillary thyroid carcinoma and Hodgkin lymphoma is a rare condition, which may pose significant diagnostic and treatment dilemmas. To date, there is no standardized approach due to lack of experience. The molecular mechanisms of this link are poorly understood and yet remain to be elucidated.     

Cutaneous lymphoma associated with Epstein-Barr virus infection in 2 patients treated with methotrexate

Whether patients with rheumatoid arthritis (RA) have an increased risk of developing non-Hodgkin lymphoma is controversial, and opinions differ on the possible role of methotrexate in the occurrence of lymphomas in patients with RA. We report 1 T-cell lymphoma and 1 B-cell lymphoma restricted to the skin associated with Epstein-Barr virus infection that healed completely and spontaneously after discontinuation of methotrexate in a man with RA and a woman with dermatomyositis. Cutaneous infiltrating cells were infected by a replicative form of Epstein-Barr virus. After discontinuation of methotrexate, the cutaneous lesions disappeared completely in 15 days without recurrence. Discontinuation of methotrexate is necessary in patients with RA or dermatomyositis who have a lymphoproliferative disorder, and a follow-up period of several weeks should be observed before specific therapy is initiated.     

Epstein-Barr virus-associated lymphomas

Following Epstein and colleagues' ground-breaking discovery of Epstein-Barr virus by electron microscopy of Burkitt's lymphoma cell lines, there came the observation that Epstein-Barr virus induces immortalization of B cells in vitro. Thus, initial hopes were of a virus confined to equatorial Africa with a causal link to a particular subtype of childhood lymphoma. Over the past 40 years there has been great progress towards understanding the biology and epidemiology of Epstein-Barr virus, which conclusively show that these early ideas were overly simplistic. It is now known that Epstein-Barr virus has a seroprevalence of approximately 95% worldwide, and persists for life within host B lymphocytes. Infection in New World primates leads to lymphoma and inoculation of peripheral blood mononuclear cells from Epstein-Barr virus-seropositive subjects into severe combined immunodeficiency mice results in B-cell lymphoproliferative disorders. Epstein-Barr virus is now known to be implicated in a range of lymphoid and other malignancies, and this association will be the subject of this review.     

The frequency of immunoglobulin heavy chain gene and T-cell receptor gamma-chain gene rearrangements and Epstein-Barr virus in ALK+ and ALK- anaplastic large cell lymphoma and other peripheral T-cell lymphomas

We previously identified a relatively high frequency of B-cell proliferations along with simultaneous T-cell receptor gamma-chain gene (TRG) and immunoglobulin heavy chain gene (IGH) rearrangements in a series of angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified. Here, we report on a series of 74 peripheral T-cell lymphoma (PTCL) cases composed entirely of specific PTCL subtypes, including 28 cases of ALK+ anaplastic large-cell lymphoma (ALCL), 35 cases of ALK- ALCL, and 11 cases that represent other specific PTCL subtypes. We performed IGH and TRG gene rearrangement studies and in situ hybridization for Epstein-Barr virus (EBV) to determine the frequency of IGH clonality and to investigate the relationship between EBV, clonality, and associated B-cell proliferations. Using BIOMED-2 PCR assays, we detected TRG clones in 64 of 74 (86%) cases and IGH clones in 6 of 74 (8%) cases, with all IGH-positive cases exhibiting a concurrent TRG clone. Despite the detection of occasional IGH clones, there was no correlation between IGH clonality and EBV, and B-cell proliferations were not identified in any of the cases. These findings suggest that other factors contribute to IGH clonality and demonstrate that, in the absence of an associated B-cell proliferation, IGH clonality occurs infrequently (8%) in specific PTCL subtypes.     

RON基因在淋巴瘤的表达及与EB病毒感染相关性研究

目的 研究RON基因在不同淋巴瘤组织及其细胞株中的表达情况及与EB病毒感染的相关性. 方法 通过免疫组织化学染色法检测淋巴瘤患者以及正常和炎性淋巴组织RON的表达,计算RON阳性组织的比例及RON蛋白表达阳性标记强度特征;蛋白免疫印迹法检测淋巴瘤细胞株RON的表达情况;并且用原位杂交的方法检测EBV编码的小RNA （EBER）在伯基特淋巴瘤和霍奇金淋巴瘤组织的表达情况.结果 RON在霍奇金淋巴瘤和伯基特淋巴瘤组织中阳性率分别为55.0％ （11/20）、66.7％（8/12）,高于其在良性淋巴组织（正常淋巴组织及炎性淋巴组织）中的表达（P均＜0.05）.进一步发现霍奇金淋巴瘤和伯基特淋巴瘤组织芯片及其细胞株L428和Raji细胞株中RON表达水平远高于其他淋巴瘤.霍奇金淋巴瘤和伯基特淋巴瘤中EB病毒的阳性和RON过表达相关性密切.结论 RON在淋巴瘤中表达呈异质性,其中伯基特淋巴瘤和霍奇金淋巴瘤中高表达,而且两者的RON过表达和EB病毒感染密切相关.     

霍奇金淋巴瘤治疗的研究进展

霍奇金淋巴瘤(HL)是一种治愈率较高的恶性淋巴瘤,目前的常规治疗手段可使90％早期HL患者及80％晚期患者获得长期无病生存(DFS),但治疗相关的远期并发症也日益显现.探索更为精准的HL风险分层方法,以及在保证疗效的基础上减少化疗周期、减低放射剂量的治疗方案一直为HL相关研究的重点.笔者拟就近年来HL治疗方案的相关研究进展进行综述.     

Salvage regimens for Hodgkin lymphoma

There are many effective salvage chemotherapy regimens for the treatment of patients with Hodgkin lymphoma (HL) who relapse after or are refractory to primary therapy. All eligible patients with relapsed or refractory HL should be considered for high-dose chemotherapy with autologous stem cell transplantation. This type of therapy has become the standard of care for patients with chemosensitive disease, based on numerous phase II and two phase III clinical trials. The major considerations in the choice of salvage therapy are response rate, toxicity, and effect on subsequent stem cell collection. For patients who do not respond to salvage therapy or who relapse after autologous transplantation, available treatment options include additional salvage regimens, reduced-intensity allogeneic stem cell transplantation, and investigational agents. This review summarizes the results of various salvage chemotherapy regimens, including newer regimens that incorporate gemcitabine, in addition to novel therapies that are currently being studied in patients with relapsed or refractory HL.     

成人霍奇金淋巴瘤69例临床预后分析

目的 探讨霍奇金淋巴瘤(HL)的临床特点与预后的关系。方法 回顾2004年1~12月在我院初治的69例成人HL患者的临床资料,分析各临床特征与预后的关系。结果 ①50例(72.5%)患者以颈部淋巴结肿大起病,病理以混合细胞型最多见。②治疗有效率达76.8％(53/69)。5年总生存率及无失败生存率分别为80.0%和72.0%。③单因素分析显示年龄、分期、结外器官侵犯、脾大、淋巴瘤国际预后指数(International Prognostic Index,IPI)分组、血红蛋白、一线化疗方案、化疗疗程、缓解情况是影响生存的主要因素(P＜0.05)。④多因素分析显示缓解情况是影响HL患者生存的主要因素(P＜0.05)。结论 HL患者以颈部淋巴结肿大起病最常见,治疗后缓解情况是HL独立预后危险因素。     

AIDS-related malignant lymphoma

Patients with HIV-1 infection have high risk for malignant lymphoma(AIDS lymphoma). In Japanese patients, more than 90% of AIDS lymphoma are related to EBV. All 22 cases which we have experienced are non-Hodgkin's lymphoma and their histological classification is either diffuse large or diffuse immunoblastic. Their mean CD4 count is 13.6/mm3. The reports from United States and Europe show that a half of AIDS lymphoma cases are small noncleaved type and the mean CD4 count is approximately 200/mm3. This difference between Japan and other countries may be caused by difference of EBV prevalence, but precise reason is not clear.     

自身造血干细胞移植术后复发的霍奇金淋巴瘤患者的治疗

自身造血干细胞移植术后霍奇金淋巴瘤的复发率约为50%。复发通常发生在手术一年后,而且治疗起来并不容易。复发霍奇金淋巴瘤的自然病程可从刚开始的快速发展逐渐过渡到一个相对顽固且不活跃的缓解期。如果患者年轻,无伴发疾病且肿瘤对化疗敏感,则仍然有希望治愈。治疗方案的选择取决于一系列临床因素(如复发时间,对细胞毒疗法的敏感性以及疾病所处的阶段等)。放疗前对病史的要求:通过临床试验发现有HLA相合供体和新的因子。虽然很少有病例能获得治愈,但一系列研究结果表明,放疗、单药或联合化疗和强度减低的同种移植对病情的控制具有极好的效果。本文针对这些方法的治疗效果进行分析,并对病例收治标准、试验药以及治疗方案进行了讨论。     

Lymphatic diseases specific to the tropics (Burkitt's lymphoma, tropical splenomegaly and Mediterranean lymphoma)

Certain lymphoproliferative disorders (Burkitt's lymphoma, tropical splenomegaly, and Mediterranean lymphoma) are more frequently observed in the tropical or subtropical areas than in other parts of the world. The polymicrobial exposure of human beings in those areas to viral, bacterial and protozoal infections led to the assumption of a specific connection between these conditions and the lymphoproliferative disease. Some evidence has accumulated that the Epstein-Barr virus might be an oncogenic virus connected with the development of Burkitt's lymphoma. Repeated plasmodial infections were more tenuously thought to be associated with tropical splenomegaly and, similarly, Giardia lamblia or Vibrio cholerae infections with immunoproliferative small-intestinal disease. However, those connections are only speculative and by no means proven. Small-intestinal lymphoma represents an example of a wide spectrum of manifestations covering autonomous pre-malignant immunoproliferative stages, als well as the full-blown malignant stages. Polyclonal activation and proliferation of B-lymphocytes, as well as concomitant immunosuppression are the characteristic features of the pre-malignant situation and may be the basis for the malignant transformation of single cells. Thus, the final clinical picture resembles that of a malignant non-Hodgkin lymphoma.