胃MALT淋巴瘤的临床病理研究和PTEN、PI3K、pAkt的表达及意义
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摘要
目的总结32例胃黏膜相关淋巴组织淋巴瘤患者的临床、内镜和病理表现特征,探讨胃黏膜相关淋巴组织淋巴瘤的治疗策略。研究第10号染色体同源性磷酸酶-张力蛋白基因表达产物、磷脂酰肌醇3激酶、丝氨酸/苏氨酸蛋白激酶等蛋白在胃黏膜相关淋巴组织淋巴瘤中的表达、意义及相关性。
方法回顾性分析经病理证实的32例胃黏膜相关淋巴组织淋巴瘤患者临床相关资料。采用免疫组织化学法对其病理切片中PTEN、PI3K、Akt蛋白的表达进行检测。
结果
1.32例患者的平均发病年龄为63.0岁,男女比例为1:1.13。常见症状为上腹痛、腹胀、反酸、呕吐等,也有以消化道出血入院者。
2.内镜下病变主要分布在胃窦部,约占40.63%;形态多样,以隆起型和溃疡型表现为主。诊断较为困难,首次胃镜检查约25.00%获正确诊断。
3.胃MALT淋巴瘤全部起源于B淋巴细胞,CD45RO、CD20、EMA、LCA等为常用的病理诊断标志物。根据Ann Arbor分期,正期4例,ⅡE9例,Ⅲ期14例,Ⅳ期5例。
4.本组病例幽门螺杆菌感染率约为88.00%,15例(46.88%)进行了幽门螺杆菌根除治疗。本组病例中,20例(62.50%)接受了手术治疗,手术切除辅以化疗13例,单纯化疗2例。3例获得组织学完全缓解。
5.PTEN蛋白在胃黏膜相关淋巴组织淋巴瘤中的阳性率为31.25%,PI3K和pAkt两蛋白在胃黏膜相关淋巴组织淋巴瘤中的阳性率则分别为75.00%和71.88%。
6.胃MALT淋巴瘤中PTEN和PI3K阳性表达率呈负相关,相关系数r_s=-0.896,P＜0.001;PTEN和pAkt阳性表达率呈负相关,相关系数r_s=-0.840,P＜0.001;PI3K和pAkt阳性表达率呈正相关,相关系数r_s=0.975,P＜0.001。
结论
1.胃黏膜相关淋巴组织淋巴瘤的临床表现、内镜下特征和病理特点的认识有待进一步提高。该病临床表现无特异性,对长期上腹痛及有消化道出血表现者应考虑到本病可能。
2.病变好发于胃窦,胃镜检查中多处、多次活检有助于早期病例的发现。
3.对于诊断困难者,可选用B、T细胞标志物进行免疫组织化学检测。
4.幽门螺杆菌在胃黏膜相关淋巴组织淋巴瘤的发病中起着重要作用,对早期阶段患者幽门螺杆菌治疗当属首选。过去,治疗该病以手术为主;目前,根除幽门螺杆菌显示出较好疗效。适宜方案的选择应结合幽门螺杆菌感染情况、病情分期等多种因素而定。
5.胃黏膜相关淋巴组织淋巴瘤发生过程中存在着抑癌基因PTEN编码蛋白表达下调,PI3K和Akt蛋白的表达上调,而且PTEN表达的下调和后两者之间存在着负相关。
6.本实验结果提示PTEN基因在胃黏膜相关淋巴组织淋巴瘤的发病中起着重要作用,PI3K/Akt通路的异常激活参与了胃黏膜相关淋巴组织淋巴瘤的发生、发展过程,为该病晚期阶段的治疗提供了潜在的靶点。
Objective To summarize the clinical,endoscopic and pathologic characteristics of 32 patients with gastric mucosa-associated lymphoid tissue(MALT)lymphoma.To investigate the treatment strategies of the gastric MALT lymphoma.To study the expression and significance of phosphatase and tension homology deleted on chromosome ten(PTEN),phosphatidylinositol-3-kinase(PI3K),serine/threonine protein kinase B(Akt)in gastric MALT lymphoma and analyze their relationship.
Methods Clinical and other related materials of 32 patients with gastric MALT lymphoma diagnosed pathologically were retrospectively analyzed.Their pathologic sections were detected for PTEN,PI3K and Akt proteins by immunohistochemical staining.
Results
1.32 patients with gastric MALT lymphoma had a median age of 63.0 years.The male to female ratio was about 1:1.13.The common symptoms were upper abdominal pain,abdominal distension,acid regurgitation,vomiting and so on. Some of them were admitted for gastrointestinal hemorrhage.
2.Under endoscopy,about 40.63%lesions were observed in gastric antrum,which was the most common site.The appearances of gastric MALT lymphoma were manifold,and the main pathological changes were upheaval type and ulcer type. The lymphoma was made definite so difficult that 25.00%cases could be diagnosed by endoscopy correctly at the first time.
3.All the gastric MALT lymphoma stemmed from B lymphocyte.Markers such as CD45RO,CD20,EMA,LCA and so on were detected for pathologic diagnosis frequently.According to Ann Arbor staging system,4 cases belonged to stageⅠE, 9 cases belonged to stageⅡE,14 cases and 5 cases were at stageⅢand stageⅣrespectively.
4.Helicobacter pylori infection was detected in 22 cases(88.00%),15 cases (46.88%)received H.pylori eradication therapy.Among 32 cases,20(62.50%) accepted surgery,surgery combined with chemotherapy were exerted on 13 patients,2 cases were treated with chemotherapy solely.3 patients achieved histological complete remission.
5.The expression rate of PTEN in gastric MALT lymphoma was 31.25%,while the expression rate of PI3K and pAkt was 75.00%and 71.88%respectively.
6.In gastric MALT lymphoma,the expression of PTEN was negatively correlated with that of PI3K(r_s=-0.896,P＜0.001).The expression of PTEN was also negatively correlated with that of pAkt(r_s=-0.840,P＜0.001).The expression of PI3K was positively correlated with that of pAkt(r_s=0.975,P＜0.001).
Conclusions
1.We should attach importance to the clinical,endoscopic and pathologic features of gastric MALT lymphoma.The clinical manifestations showed nonspecific. Patients who suffered from upper abdominal pain and gastrointestinal hemorrhage might be diagnosed as gastric lymphoma.
2.Gastric MALT lymphoma was often detected at gastric antrum.Endoscopy could help find out the early focus,multiple biopsies could raise the rate of diagnosis.
3.As for those hard to be diagnosed definitely,B and T cellular markers could be detected by immunohistochemical assay.
4.H.pylori played an important role in pathogenesis of gastric MALT lymphoma. H.pylori eradication should be the first choice to treat gastric MALT lymphoma at early stage.In the past,surgery was the major strategy in treating gastric MALT lymphoma.However,H.pylori eradication has shown a good curative effect nowadays.As for the adaptive schemes,H.pylori infection,pathologic conditions and many other factors should be concerned.
5.In gastric MALT lymphoma,expression of the encoding products of anti-oncogene PTEN was down-regulation,while the expressions of PI3K and pAkt were up-regulation.Moreover,the expression of PTEN was negatively correlated with that of PI3K and pAkt.
6.These data suggest that PTEN may play an important role in pathogenesis of gastric MALT lymphoma.The abnormal activation of gastric MALT lymphoma correlated with its occurrence and development and it provided a potential therapeutic target.
方法回顾性分析经病理证实的32例胃黏膜相关淋巴组织淋巴瘤患者临床相关资料。采用免疫组织化学法对其病理切片中PTEN、PI3K、Akt蛋白的表达进行检测。
结果
1.32例患者的平均发病年龄为63.0岁,男女比例为1:1.13。常见症状为上腹痛、腹胀、反酸、呕吐等,也有以消化道出血入院者。
2.内镜下病变主要分布在胃窦部,约占40.63%;形态多样,以隆起型和溃疡型表现为主。诊断较为困难,首次胃镜检查约25.00%获正确诊断。
3.胃MALT淋巴瘤全部起源于B淋巴细胞,CD45RO、CD20、EMA、LCA等为常用的病理诊断标志物。根据Ann Arbor分期,正期4例,ⅡE9例,Ⅲ期14例,Ⅳ期5例。
4.本组病例幽门螺杆菌感染率约为88.00%,15例(46.88%)进行了幽门螺杆菌根除治疗。本组病例中,20例(62.50%)接受了手术治疗,手术切除辅以化疗13例,单纯化疗2例。3例获得组织学完全缓解。
5.PTEN蛋白在胃黏膜相关淋巴组织淋巴瘤中的阳性率为31.25%,PI3K和pAkt两蛋白在胃黏膜相关淋巴组织淋巴瘤中的阳性率则分别为75.00%和71.88%。
6.胃MALT淋巴瘤中PTEN和PI3K阳性表达率呈负相关,相关系数r_s=-0.896,P＜0.001;PTEN和pAkt阳性表达率呈负相关,相关系数r_s=-0.840,P＜0.001;PI3K和pAkt阳性表达率呈正相关,相关系数r_s=0.975,P＜0.001。
结论
1.胃黏膜相关淋巴组织淋巴瘤的临床表现、内镜下特征和病理特点的认识有待进一步提高。该病临床表现无特异性,对长期上腹痛及有消化道出血表现者应考虑到本病可能。
2.病变好发于胃窦,胃镜检查中多处、多次活检有助于早期病例的发现。
3.对于诊断困难者,可选用B、T细胞标志物进行免疫组织化学检测。
4.幽门螺杆菌在胃黏膜相关淋巴组织淋巴瘤的发病中起着重要作用,对早期阶段患者幽门螺杆菌治疗当属首选。过去,治疗该病以手术为主;目前,根除幽门螺杆菌显示出较好疗效。适宜方案的选择应结合幽门螺杆菌感染情况、病情分期等多种因素而定。
5.胃黏膜相关淋巴组织淋巴瘤发生过程中存在着抑癌基因PTEN编码蛋白表达下调,PI3K和Akt蛋白的表达上调,而且PTEN表达的下调和后两者之间存在着负相关。
6.本实验结果提示PTEN基因在胃黏膜相关淋巴组织淋巴瘤的发病中起着重要作用,PI3K/Akt通路的异常激活参与了胃黏膜相关淋巴组织淋巴瘤的发生、发展过程,为该病晚期阶段的治疗提供了潜在的靶点。
Objective To summarize the clinical,endoscopic and pathologic characteristics of 32 patients with gastric mucosa-associated lymphoid tissue(MALT)lymphoma.To investigate the treatment strategies of the gastric MALT lymphoma.To study the expression and significance of phosphatase and tension homology deleted on chromosome ten(PTEN),phosphatidylinositol-3-kinase(PI3K),serine/threonine protein kinase B(Akt)in gastric MALT lymphoma and analyze their relationship.
Methods Clinical and other related materials of 32 patients with gastric MALT lymphoma diagnosed pathologically were retrospectively analyzed.Their pathologic sections were detected for PTEN,PI3K and Akt proteins by immunohistochemical staining.
Results
1.32 patients with gastric MALT lymphoma had a median age of 63.0 years.The male to female ratio was about 1:1.13.The common symptoms were upper abdominal pain,abdominal distension,acid regurgitation,vomiting and so on. Some of them were admitted for gastrointestinal hemorrhage.
2.Under endoscopy,about 40.63%lesions were observed in gastric antrum,which was the most common site.The appearances of gastric MALT lymphoma were manifold,and the main pathological changes were upheaval type and ulcer type. The lymphoma was made definite so difficult that 25.00%cases could be diagnosed by endoscopy correctly at the first time.
3.All the gastric MALT lymphoma stemmed from B lymphocyte.Markers such as CD45RO,CD20,EMA,LCA and so on were detected for pathologic diagnosis frequently.According to Ann Arbor staging system,4 cases belonged to stageⅠE, 9 cases belonged to stageⅡE,14 cases and 5 cases were at stageⅢand stageⅣrespectively.
4.Helicobacter pylori infection was detected in 22 cases(88.00%),15 cases (46.88%)received H.pylori eradication therapy.Among 32 cases,20(62.50%) accepted surgery,surgery combined with chemotherapy were exerted on 13 patients,2 cases were treated with chemotherapy solely.3 patients achieved histological complete remission.
5.The expression rate of PTEN in gastric MALT lymphoma was 31.25%,while the expression rate of PI3K and pAkt was 75.00%and 71.88%respectively.
6.In gastric MALT lymphoma,the expression of PTEN was negatively correlated with that of PI3K(r_s=-0.896,P＜0.001).The expression of PTEN was also negatively correlated with that of pAkt(r_s=-0.840,P＜0.001).The expression of PI3K was positively correlated with that of pAkt(r_s=0.975,P＜0.001).
Conclusions
1.We should attach importance to the clinical,endoscopic and pathologic features of gastric MALT lymphoma.The clinical manifestations showed nonspecific. Patients who suffered from upper abdominal pain and gastrointestinal hemorrhage might be diagnosed as gastric lymphoma.
2.Gastric MALT lymphoma was often detected at gastric antrum.Endoscopy could help find out the early focus,multiple biopsies could raise the rate of diagnosis.
3.As for those hard to be diagnosed definitely,B and T cellular markers could be detected by immunohistochemical assay.
4.H.pylori played an important role in pathogenesis of gastric MALT lymphoma. H.pylori eradication should be the first choice to treat gastric MALT lymphoma at early stage.In the past,surgery was the major strategy in treating gastric MALT lymphoma.However,H.pylori eradication has shown a good curative effect nowadays.As for the adaptive schemes,H.pylori infection,pathologic conditions and many other factors should be concerned.
5.In gastric MALT lymphoma,expression of the encoding products of anti-oncogene PTEN was down-regulation,while the expressions of PI3K and pAkt were up-regulation.Moreover,the expression of PTEN was negatively correlated with that of PI3K and pAkt.
6.These data suggest that PTEN may play an important role in pathogenesis of gastric MALT lymphoma.The abnormal activation of gastric MALT lymphoma correlated with its occurrence and development and it provided a potential therapeutic target.
引文
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57. Park GS, Joo YE, Kim HS, et al. Expression of PTEN and its correlation with angiogenesis in gastric carcinoma[J]. Korean J Gastroenterol, 2005, 46(3): 196-203.
58. Huang J, Kotons CD. PTEN modulates vascular endothelial growth factor-mediated signaling and angiogenic effects [J]. J Biol Chem, 2002, 277(13):10760-10766.
59. Fang J, Ding M, Yang L, et al. PI3K/PTEN/AKT signaling regulates prostate rumor angioenesis [J]. Cell Signal, 2007,19(12):2187-2497.
60. Sun H, Zheng H, Yang X, et al. Expression of PTEN and Caspase-3 and their clinicopathological significance in primary gastric malignant lymphoma[J]. Chin Med Sci J, 2004,19(1): 19-24.
61. Reichert M, Saur D, Hamacher R, et al. Phosphoinositide-3-kinase signaling controls S-phase kinase-associated protein 2 transcription via E2F1 in pancreatic ductal adenocarcinoma cells[J]. Cancer Res, 2007, 67(9):4149-4156.
62. Liang J, Pan Y, Zhang D, et al. Cellular prion protein promotes proliferation and G1/S transition of human gastric cancer cells SGC7901 and AGS[J]. FASEB J, 2007, 21(9):2247-2256.
63. Gao N, Flynn DC, Zhang Z, et al. G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells [J]. Am J Physiol Cell Physiol, 2004, 287(2):C281-291.
64. Zhao Y, Chen X, Cai L, et al. Angiotensin II suppresses adriamycin-induced apoptosis through activation of phosphatidylinositol 3-kinase/Akt signaling in human breast cancer cells [J]. Acta Biochim Biophys Sin, 2008, 40(4):304-310.
65. Gibson E M, Henson E S, Haney N, et al. Epidemal growth foctor-related apptosis-inducing ligand-induced apoptosis by inhibiting cytochrome c release [J]. Cancer Res, 2002,62(2):488-496.
66. Coffey JC, Wang JH, Smith MJ, et al. Phosphoinositide 3-kinase accelerates postoperative tumor growth by inhibiting apoptosis and enhancing resistance to chemotherapy-induced apoptosis. Novel role for an old enemy [J]. J Biol Chem, 2005,280(22):20968-20977.
67. Baohua Y, Xiaoyan Z, Tiecheng Z,et al. Mutations of PIK3CA Gene in Diffuse Large B-Cell Lymphoma[J]. Diagn Mol Pathol, 2008 Mar 28 [Epub ahead of print].
68. Maier D, Jones G, Li X, et al. The PTEN lipid phosphatase domain is not required to inhibit invasion of glioma cells [J]. Cancer Res, 1999, 59(21):5479-5482.
69. Zhong H, Chiles K, Feldser D, et al. Modulation of hypoxia-inducible factor lalpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics [J]. Cancer Res, 2000, 60(6): 1541 -1545.
1. Solit DB, Basso AD, Olshen AB, et al. Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol[J]. Cancer Res, 2003, 63(9):2139-2144.
2. Reichert M, Saur D, Hamacher R, et al. Phosphoinositide-3-kinase signaling controls S-phase kinase-associated protein 2 transcription via E2F1 in pancreatic ductal adenocarcinoma cells[J]. Cancer Res, 2007,67(9):4149-4156.
3. Liang J, Pan Y, Zhang D, et al. Cellular prion protein promotes proliferation and G1/S transition of human gastric cancer cells SGC7901 and AGS [J]. FASEB J, 2007,21(9):2247-2256.
4. Gao N, Flynn DC, Zhang Z, et al. G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells [J]. Am J Physiol Cell Physiol, 2004,287(2):C281-291.
5. Zhao Y, Chen X, Cai L, et al. Angiotensin II suppresses adriamycin-induced apoptosis through activation of phosphatidylinositol 3-kinase/Akt signaling in human breast cancer cells [J]. Acta Biochim Biophys Sin, 2008,40(4):304-310.
6. Gibson E M, Henson E S, Haney N, et al. Epidemal growth foctor-related apptosis-inducing ligand-induced apoptosis by inhibiting cytochrome c release [J]. Cancer Res, 2002,62(2):488-496.
7. Coffey JC, Wang JH, Smith MJ, et al. Phosphoinositide 3-kinase accelerates postoperative tumor growth by inhibiting apoptosis and enhancing resistance to chemotherapy-induced apoptosis. Novel role for an old enemy [J]. J Biol Chem, 2005, 280(22):20968-20977.
8. Qian Y, Corum L, Meng Q, et al. PI3K induced actin filament remodeling through Akt and p70S6K1: implication of essential role in cell migration[J]. Am J Physiol Cell Physiol, 2004,286(1):C153-163.
9. Maier D, Jones G, Li X, et al. The PTEN lipid phosphatase domain is not required to inhibit invasion of glioma cells [J]. Cancer Res, 1999, 59(21):5479-5482.
10. Zhong H, Chiles K, Feldser D, et al. Modulation of hypoxia-inducible factor lalpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics [J]. Cancer Res, 2000, 60(6): 1541 -1545.
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13. Urbano A, Gorgun G, Foss F. Mechanisms of apoptosis by the tyrphostin AG957 in hematopoietic cells [J]. Biochem Pharmacol, 2002, 63(4):689-692.
14. Mandal M, Kim S, Younes MN, et al. The Akt inhibitor KP372-1 suppresses Akt activity and cell proliferation and induces apoptosis in thyroid cancer cells. Br J Cancer, 2005, 92(10): 1899-905.
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69. Zhong H, Chiles K, Feldser D, et al. Modulation of hypoxia-inducible factor lalpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics [J]. Cancer Res, 2000, 60(6): 1541 -1545.
1. Solit DB, Basso AD, Olshen AB, et al. Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol[J]. Cancer Res, 2003, 63(9):2139-2144.
2. Reichert M, Saur D, Hamacher R, et al. Phosphoinositide-3-kinase signaling controls S-phase kinase-associated protein 2 transcription via E2F1 in pancreatic ductal adenocarcinoma cells[J]. Cancer Res, 2007,67(9):4149-4156.
3. Liang J, Pan Y, Zhang D, et al. Cellular prion protein promotes proliferation and G1/S transition of human gastric cancer cells SGC7901 and AGS [J]. FASEB J, 2007,21(9):2247-2256.
4. Gao N, Flynn DC, Zhang Z, et al. G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells [J]. Am J Physiol Cell Physiol, 2004,287(2):C281-291.
5. Zhao Y, Chen X, Cai L, et al. Angiotensin II suppresses adriamycin-induced apoptosis through activation of phosphatidylinositol 3-kinase/Akt signaling in human breast cancer cells [J]. Acta Biochim Biophys Sin, 2008,40(4):304-310.
6. Gibson E M, Henson E S, Haney N, et al. Epidemal growth foctor-related apptosis-inducing ligand-induced apoptosis by inhibiting cytochrome c release [J]. Cancer Res, 2002,62(2):488-496.
7. Coffey JC, Wang JH, Smith MJ, et al. Phosphoinositide 3-kinase accelerates postoperative tumor growth by inhibiting apoptosis and enhancing resistance to chemotherapy-induced apoptosis. Novel role for an old enemy [J]. J Biol Chem, 2005, 280(22):20968-20977.
8. Qian Y, Corum L, Meng Q, et al. PI3K induced actin filament remodeling through Akt and p70S6K1: implication of essential role in cell migration[J]. Am J Physiol Cell Physiol, 2004,286(1):C153-163.
9. Maier D, Jones G, Li X, et al. The PTEN lipid phosphatase domain is not required to inhibit invasion of glioma cells [J]. Cancer Res, 1999, 59(21):5479-5482.
10. Zhong H, Chiles K, Feldser D, et al. Modulation of hypoxia-inducible factor lalpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics [J]. Cancer Res, 2000, 60(6): 1541 -1545.
11. Okada T, Sawada T, Kubota K. Rapamycin enhances the anti-tumor effect of gemcitabine in pancreatic cancer cells [J]. Hepatogastroenterology, 2007, 54(79):2129-2133.
12. Takeuchi H, Kondo Y, Fujiwara K, et al. Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors[J]. Cancer Res, 2005,65(8):3336-3346.
13. Urbano A, Gorgun G, Foss F. Mechanisms of apoptosis by the tyrphostin AG957 in hematopoietic cells [J]. Biochem Pharmacol, 2002, 63(4):689-692.
14. Mandal M, Kim S, Younes MN, et al. The Akt inhibitor KP372-1 suppresses Akt activity and cell proliferation and induces apoptosis in thyroid cancer cells. Br J Cancer, 2005, 92(10): 1899-905.
15. Koul D, Shen R, Bergh S, et al. Inhibition of Akt survival pathway by a small-molecule inhibitor in human glioblastoma[J]. Mol Cancer Ther, 2006, 5(3):637-644.
16. Zeng Z, Samudio IJ, Zhang W, et al. Simultaneous inhibition of PDK1/AKT and Fms-like tyrosine kinase 3 signaling by a small-molecule KP372-1 induces mitochondrial dysfunction and apoptosis in acute myelogenous leukemia[J]. Cancer Res, 2006, 66(7):3737-3746.
17. Sonoyama J, Matsumura I, Ezoe S, et al. Functional cooperation among Ras, STAT5, and phosphatidylinositol 3-kinase is required for full oncogenic activities of BCR/ABL in K562 cells [J]. J Biol Chem, 2002, 277(10):8076-8082.
18. Okudela K, Hayashi H, Ito T, et al. K-ras gene mutation enhances motility of immortalized airway cells and lung adenocarcinoma cells via Akt activation: possible contribution to non-invasive expansion of lung adenocarcinoma [J]. Am J Pathol, 2004, 164(1): 91-100.