摘要
目的分析原发性干燥综合征合(pSS)合并非霍奇金淋巴瘤(NHL)患者的临床表现、实验室血清学检查以及淋巴瘤组织学的特征。方法检索1982年10月至2008年10月我院住院患者数据库中pSS合并NHL的病例。分别记录pSS合并NHL主要的临床和实验室特点。结果共9例患者入组,其中女性8例(8/9,89%),男性1例(1/9,11%)。pSS和NHL诊断时平均年龄分别为50.6岁和55.6岁。8例(8/9,89%)符合美欧合议的干燥综合征分类标准(AECC)。患者主要的SS临床表现是无痛性腮腺肿大(7/9,78%),其中6例(6/9,67%)为单侧肿大;血清免疫学主要表现为类风湿因子(7/7,100%)阳性,滴度平均增高14.4倍(8.0倍～22.7倍),以及高免疫球蛋白血症(7/9,78%),其中IgG均增高(7/9,78%),平均增高69.4%(5.6%～215.6%),IgA增高3例(3/9,33%),平均增高95.5%(52.2%～176.3%),IgM增高2例(2/9,22%),平均增高221.8%(112.5%～331.0%);5例(5/9,56%)接受过糖皮质激素治疗,其中的4例(4/5,80%)还接受过至少一种免疫抑制剂(甲氨蝶呤、雷公藤多甙、环磷酰胺和依木兰)治疗。NHL主要临床表现包括脾脏肿大(7/9,78%)和淋巴结肿大(5/9,56%)。其主要病理组织亚型是黏膜相关淋巴组织(MALT)B细胞淋巴瘤(4/9,44%)和弥漫大B细胞淋巴瘤(2/9,22%)。MALT患者均无结区受累。8例(8/9,89%)患者出现结外受累,其中以累及涎腺(4/9,44%)和肺脏(4/9,44%)为最多。结论pSS合并NHL患者临床上以单侧腮腺(无痛性)、淋巴结和脾脏肿大,血清免疫学检查RF高滴度阳性和高球蛋白血症,MALT为主的NHL病理分型和高发结外受累为主要特征。
Objective To characterize clinical patterns of expression, laboratory serologics, and lymphomatous histologics in patients with primary sj(o|¨)gren's syndrome(pSS) who subsequently developed non-Hodgkin's lymphoma(NHL).
Metholds Searching in hospitalized patients database of our hospital admitted from October 1982 to October 2008. Identifying patients with pSS who developed NHL. A protocol form was used to record the main characteristics of pSS and NHL. Results Nine patients with pSS and NHL were included in the study. There were 8 (8/9, 89%) women and 1 (1/9, 11%) man (mean age 50.6 and 55.6 years at pSS and lymphoma diagnosis, respectively). Eight patients (8/9, 89%)fulfilled the American-European Consensus Criteria (AECC). The main SS manifestations were painless parotid enlargement (7/9, 78%), of whom six patients (6/9,67%) were unilateral; the main immunologic features were positive rheumatoid factor (RF) in all examined patients (7/7, 100%) with an average 14.4-fold (range 8.0-22.7) increased titre and hyperimmunoglobulinemia (7/9, 78%) with an average 69.4% (range 5.6%-215.6%) and 95.5% (range 52.2%-176.3%) and 221.8% (range 112.5%-331.0%) increased value of IgG (7/9, 78%) and IgA(3/9,33%) and IgM (2/9,22%) respectively; Five patients (5/9, 56%) had received glucocorticoids, of whom four patients (4/5,80%) had received at least one immunosuppressive drugs(methotrexate, glucosidorum tripterygll totorum, cyclophosphamide, and imuran). The main NHL manifestations were splenomegaly (7/9, 78%) and lymphadenopathy (5/9, 56%). The main histologic subtypes were mucosa-associated lymphoid tissue (MALT) lymphoma (4/9, 44%) and diffuse large B cell lymphoma (2/9, 22%). None of the patients with MALT lymphoma had a nodal primary location. Eight patients (8/9, 89%) had an extranodal primary location, most frequently in the salivary gland (4/9, 44%) and lung (4/9, 44%). Conclusion Patients with pSS and NHL are clinically characterized by a high frequency of painless unilateral parotid enlargement and splenomegaly and lymphadenopathy, an immunologic pattern dominated by the presence of high-titre RF and hyperimmunoglobulinemia, a predominance of MALT lymphomas, and an elevated frequency of primary extranodal involvement.
引文
1 Smedby KE,Hjalgrim H,Askling J,et al.Autoimmune and chronic inflammatory disorders and risk of non-Hodgkin lymphoma by subtype.J Natl Cancer Inst,2006,98:51-60.
2 Kauppi M,Pukkala E,Isomaki H.Elevated incidence of hematologic malignancies in patients with Sj(o|¨)gren's syndrome compared with patients with rheumatoid arthritis(Finland).Cancer Causes Control,1997,8:201-204.
3 Theander E,Henriksson G,Ljungberg O,et al.Lymphoma and other malignancies in primary Sj(o|¨)gren's syndrome A cohort study on cancer incidence and lymphoma predictors.Ann Rheum Dis,2006,65:796-803.
4 Engels EA,Cerhan JR,Linet MS,et al.Immune-related conditions and immune-modulating medications as risk factors for non-Hodgkin's lymphoma:a case-control study.Am J Epidemiol,2005,162:1153-1161.
5 Ekstr(o|¨)m Smedby K,Vajdic CM,Falster M,et al.Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes:a pooled analysis within the Inter Lymph Consortium.Blood,2008,111:4029-4038.
6 Mackay F,Sierro F,Grey ST,et al.The BAFF/APRIL system:an important player in systemic rheumatic diseases.Curr Dir Autoimmun,2005,8:243-265.
7 Szodoray P,Jonsson R.The BAFF/APRIL system in systemic autoimmune diseases with a special emphasis on Sj(o|¨)gren's syndrome.Scand J Immunol,2005,62:421-428.
8 Fox RI.Sj(o|¨)gren's syndrome.Lancet,2005,366:321-331.
9 Voulgarelis M,Skopouli FN.Clinical,Immunologic,and Molecular Factors Predicting Lymphoma Development in Sj(o|¨)gren's Syndrome Patients.Clinic Rev Allerg Immunol,2007,32:265-274.
10 Ramos-Casals M,Brito-Zeron P,Yague J,et al.Hypocomplementaemia as an immunological marker of morbidity and mortality in patients with primary Sjogren's syndrome. Rheumatology (Oxford),2005,44:89 - 94.
11 Tzioufas AG, Voulgarelis M.Update on Sjogren's syndrome autoimmune epithelitis: from classification to increased neoplasias. Best Pract Res Clin Rheumatol,2007,21:989-1010.
12 Kato I, Tajima K, Suchi T, et al. Chronic thyroiditis as a risk factor of B-cell lymphoma in the thyroid gland. Jpn J Cancer Res,1985,76:1085-1090.
13 Derringer GA, Thompson LD, Frommelt RA, et al.Malignant lymphoma of the thyroid gland: a clinicopathologic study of 108 cases. Am J Surg Pathol,2000,24:623 -39.
14 Troch M,Woehrer S,Streubel B,et al.Chronic autoimmune thyroiditis (Hashimoto's thyroiditis) in patients with MALT lymphoma.Annals of Oncology,2008,19:1336-1339.
1 Zintzaras E,Voulgarelis M,Moutsopoulos HM.The risk of lymphoma development in autoimmune diseases:a meta-analysis.ArchIntern Med,2005,165:2337-2344.
2 Fisher SG,Fisher RI.The epidemiology of non-Hodgkin's lymphoma.Oncogene 2004,23:6524-6534.
3 Herve M,Xu K,Ng YS,et al.Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity.J Clin Invest,2005,115:1636-1643.
4 Weyand CM,Seyler TM,Goronzy JJ.B cells in rheumatoid synovitis.Arthritis Res Ther,2005,7 Suppl 3:S9-12.
5 Mackay F,Sierro F,Grey ST,et al.The BAFF/APRIL system:an important player in systemic rheumatic diseases.Curr Dir Autoimmun,2005,8:243-265.
6 Szodoray P,Jonsson R.The BAFF/APRIL system in systemic autoimmune diseases with a special emphasis on Sj(o|¨)gren's syndrome.Scand J Immunol,2005,62:421- 428.
7 Rothman N, Skibola CF, Wang SS, et al. Genetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the Inter Lymph Consortium. Lancet Oncol,2006,7:27 - 38.
8 Lan Q, Zheng T, Rothman N, et al.Cytokine polymorphisms in the Th1/Th2 pathway and susceptibility to non-Hodgkin lymphoma. Blood,2006;107:4101-4108.
9 Kalsi JK, Grossman J, Kim J, et al.Peptides from antibodies to DNA elicit cytokine release from peripheral blood mononuclear cells of patients with systemic lupus erythematosus: relation of cytokine pattern to disease duration. Lupus,2004,13:490-500.
10 Garcic-Carrasco M, Font J, Filella X, et al. Circulating levels of Th1/Th2 cytokines in patients with primary Sjogren's syndrome: correlation with clinical and immunological features. Clin Exp Rheumatol,2001,19:411-415.
11 Askling J, Fored CM, Baecklund E, et al. Haematopoietic malignancies in rheumatoid arthritis: lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists. Ann Rheum Dis,2005,64:1414-1420.
12 Franklin J, Lunt M, Bunn D, et al. Incidence of lymphoma in a large primary-care derived cohort of inflammatory polyarthritis. Ann Rheum Dis, 2006,65:617-622.
13 Kaiser R. Incidence of lymphoma in patients with rheumatoid arthritis: a systematic review of the literature. Clin Lymphoma Myeloma,2008,8:87-93.
14 Ekstrom K, Hjalgrim H, Brandt L, et al. Risk of malignant lymphomas in patients with rheumatoid arthritis and in their first-degree relatives.Arthritis Rheum, 2003,48:963-970.
15 Baecklund E, Iliadou A, Askling J, et al. Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis.Arthritis Rheum,2006,54:692-701.
16 Smedby KE, Hjalgrim H, Askling J, et al. Autoimmune and chronic inflammatory disorders and risk of non-Hodgkin lymphoma by subtype.J Natl Cancer Inst,2006,98:51-60.
17 Wolfe F, Michaud K. Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients.Arthritis Rheum,2004,50:1740-1751.
18 Jaffe ES, Harris NL, Stein H, et al. Pathology and genetics of tumours of hematopoietic and lymphoid tissues. Lyon:IARC Press,2001.
19 Salloum E, Cooper DL, Howe G, et al. Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases. J Clin Oncol,1996,14:1943-1949.
20 Mariette X, Cazals-Hatem D, Warszawki J, et al.Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France. Blood,2002,99:3909-3915.
21 Zhang Y, Holford TR, Leaderer B, et al. Prior medical conditions and medication use and risk of non-Hodgkin lymphoma in Connecticut United States women. Cancer Causes Control,2004,15:419-428.
22 Kato I, Koenig KL, Shore RE, et al. Use of anti-inflammatory and nonnarcotic analgesic drugs and risk of non-Hodgkin's lymphoma (NHL) (United States). Cancer Causes Control,2002,13:965-974.
23 Cerhan JR, Anderson KE, Janney CA, et al. Association of aspirin and other non-steroidal anti-inflammatory drug use with incidence of non-Hodgkin lymphoma. Int J Cancer,2003,106:784-788.
24 Sorensen HT, Mellemkjaer L, Nielsen GL, et al.Skin cancers and non-hodgkin lymphoma among users of systemic glucocorticoids: a population-based cohort study. J Natl Cancer Inst,2004,96:709-711.
25 Sorensen HT, Friis S, Norgard B, et al. Risk of cancer in a large cohort of nonaspirin NSAID users: a population-based study. Br J Cancer,2003,88:1687-1692.
26 Beiderbeck AB, Holly EA, Sturkenboom MC, et al. Prescription medications associated with a decreased risk of non-Hodgkin's lymphoma. Am J Epidemiol,2003,157:510-516.
27 Chang ET, Smedby KE, Hjalgrim H, et al. Medication use and risk of non- Hodgkin's lymphoma. Am J Epidemiol,2005,162:965-974.
28 Brown SL, Greene MH, Gershon SK, et al. Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum,2002,46:3151-3158.
29 Bongartz T, Sutton AJ, Sweeting MJ, et al.Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA,2006,295:2275-2285.
30 Kauppi M, Pukkala E, Isomaki H. Elevated incidence of hematologic malignancies in patients with Sjogren's syndrome compared with patients with rheumatoid arthritis (Finland). Cancer Causes Control, 1997,8:201-204.
31 Theander E, Henriksson G, Ljungberg O, et al. Lymphoma and other malignancies in primary Sjogren's syndrome A cohort study on cancer incidence and lymphoma predictors. Ann Rheum Dis,2006,65:796 - 803.
32 Engels EA, Cerhan JR, Linet MS, et al. Immune-related conditions and immune-modulating medications as risk factors for non-Hodgkin's lymphoma: a case-control study. Am J Epidemiol,2005,162:1153-1161.
33 Ekstrom Smedby K, Vajdic CM, Falster M, et al. Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the Inter Lymph Consortium. Blood,2008,111:4029-4038.
34 Ramos-Casals M, Brito-Zeron P, Yague J, et al. Hypocomplementaemia as an immunological marker of morbidity and mortality in patients with primary Sjogren's syndrome. Rheumatology (Oxford),2005,44:89 - 94.
35 Voulgarelis M, Skopouli FN.Clinical,Immunologic,and Molecular Factors Predicting Lymphoma Development in Sjogren's Syndrome Patients.Clinic Rev Allerg Immunol,2007,32:265-274.
36 Royer B, Cazals-Hatem D, Sibilia J, et al. Lymphomas in patients with Sjogren's syndrome are marginal zone B-cell neoplasms, arise in diverse extranodal and nodal sites, and are not associated with viruses. Blood,1997,90:766-775.
37 Voulgarelis M, Dafni UG, Isenberg DA, et al. Malignant lymphoma in primary Sjogren's syndrome: a multicenter, retrospective, clinical study by the European Concerted Action on Sjogren's Syndrome. Arthritis Rheum,1999,42:1765-1772.
38 Tzioufas AG, Voulgarelis M.Update on Sjogren's syndrome autoimmune epithelitis: from classification to increased neoplasias. Best Pract Res Clin Rheumatol,2007,21:989-1010.
39 Tonami H, Matoba M, Kuginuki Y, et al. Clinical and imaging findings of lymphoma in patients with Sjogren syndrome. J Comput Assist Tomogr,2003,27:517 -524.
40 Ambrosetti A, Zanotti R, Pattaro C, et al. Most cases of primary salivary mucosa-associated lymphoid tissue lymphoma are associated either with Sjogren syndrome or hepatitis C virus infection. Br J Haematol,2004,126: 43 - 49.
41 Bjornadal L, Lofstrom B, Yin L, et al. Increased cancer incidence in a Swedish cohort of patients with systemic lupus erythematosus. Scand J Rheumatol,2002,31:66-71.
42 Bernatsky S, Boivin JF, JosephL, et al. An international cohort study of cancer in systemic lupus erythematosus. Arthritis Rheum,2005,52:1481-1490.
43 King JK,Costenbader KH.Characteristics of patients with systemic lupus erythematosus (SLE) and non-Hodgkin's lymphoma (NHL).Clin Rheumatol,2007,26:1491-1494.
44 Bernatsky S,Ramsey-Goldman R,Isenberg D,et al.Hodgkin's lymphoma in systemic lupus erythematosus.Rheumatology,2007,46:830-832.
45 Kato I, Tajima K, Suchi T, et al. Chronic thyroiditis as a risk factor of B-cell lymphoma in the thyroid gland. Jpn J Cancer Res, 1985,76:1085-1090.
46 Thieblemont C, Mayer A, Dumontet C, et al. Primary thyroid lymphoma is a heterogeneous disease. J Clin Endocrinol Metab,2002,87:105 -111.
47 Derringer GA, Thompson LD, Frommelt RA, et al. Malignant lymphoma of the thyroid gland: a clinicopathologic study of 108 cases. Am J Surg Pathol,2000,24:623-39.
48 Intidhar Labidi S, Chaabouni AM, Kraiem T,et al.Thyroid carcinoma and Hashimoto thyroiditis. Ann Otolaryngol Chir Cervicofac,2006,123:175-178.
49 Troch M,Woehrer S,Streubel B,et al.Chronic autoimmune thyroiditis (Hashimoto's thyroiditis) in patients with MALT lymphoma.Annals of Oncology,2008,19:1336-1339.
50 Hill CL, Zhang Y, Sigurgeirsson B, et al. Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study. Lancet,2001,357:96-100.
51 Lewis JD, Bilker WB, Brensinger C, et al.Inflammatory bowel disease is not associated with an increased risk of lymphoma. Gastroenterology,2001,121:1080-1087.
52 Askling J, Brandt L, Lapidus A, et al. Risk of haematopoietic cancer in patients with inflammatory bowel disease.Gut,2005,54:617-622.
53 Bernstein CN,Blanchard JF,Kliewer E, et al.Cancer risk in patients with inflammatory bowel disease: a population-based study.Cancer,2001,91:854-862.
54 von Roon AC, Reese G, Teare J,et al.The risk of cancer in patients with Crohn's disease.Dis Colon Rectum,2007,50:839-855.
55 Gelfand JM, Shin DB, Neimann AL, et al. The risk of lymphoma in patients with psoriasis. J Invest Dermatol,2006,126:2194 -2201.
56 Shibata A, Zhao S, MakuchRW , et al.Lymphoma risk in ankylosing spondylitis patients is greater than that observed in the general population. Ann Rheum Dis,2004,63Suppl 1:98.
57 Askling J, Klareskog L, Fored M, et al. Risk for malignant lymphoma in ankylosing spondylitis. a nationwide Swedish case control study. Ann Rheum Dis,2006,65:1184-1187.
58 Szekanecz E, Szamosi S, Gergely L,et al. Incidence of lymphoma in systemic sclerosis: a retrospective analysis of 218 Hungarian patients with systemic sclerosis. Clin Rheumatol,2008,27:1163-6.
59 Hill CL,Nguyen AM,Roder D, et al.Risk of cancer in patients with scleroderma: a population based cohort study. Ann Rheum Dis,2003,62:728-731.
60 Chatterjee S,Dombi GW,Severson RK, et al.Risk of malignancy in scleroderma: a population-based cohort study. Arthritis Rheum,2005,52:2415-2424.
61 Knight A, Askling J, Ekbom A. Cancer incidence in a population based cohort of patients with Wegener's granulomatosis. Int J Cancer,2002,100:82-85.
62 Askling J, Grunewald J, Eklund A, et al. Increased risk for cancer following sarcoidosis. Am J Respir Crit Care Med,1999,160:1668-1672.
