遗传性肾癌综合征培训讲义课件.ppt

1、遗传性肾癌综合征（优选）遗传性肾癌综合征意义意义早期筛查早期筛查仔细随访相应患者及其家属仔细随访相应患者及其家属降低疾病相关死亡率并改善预后降低疾病相关死亡率并改善预后发现遗传性肾癌的相关基因发现遗传性肾癌的相关基因进行肿瘤形成机制相关的细胞分子通路研究进行肿瘤形成机制相关的细胞分子通路研究进行肿瘤治疗的分子靶点的研究进行肿瘤治疗的分子靶点的研究种类种类 VHLVHL综合征综合征遗传性乳头状肾细胞癌遗传性乳头状肾细胞癌(HPRC)(HPRC)遗传性平滑肌瘤病及肾细胞癌综合征遗传性平滑肌瘤病及肾细胞癌综合征(HLRCC)(HLRCC)BirtBirtHoggHoggDube Dube 综合征综合

2、征结节性硬化病结节性硬化病(TS)(TS)？2023-1-165Von HippleVon HippleLindau Lindau 综合征综合征 1895 1895 年由德国眼科教授年由德国眼科教授Eugen von HippleEugen von Hipple首先发现首先发现19261926年由瑞典病理学家年由瑞典病理学家Avid LindauAvid Lindau再次确认再次确认19361936年由年由DavisonDavison教授总结相关临床表现并命名为教授总结相关临床表现并命名为von von Hippel Lindau syndromeHippel Lindau syndrome

3、是一种相对罕见的常染色体显性遗传病，发病率是一种相对罕见的常染色体显性遗传病，发病率1/360001/36000主要表现包括肾透明细胞癌，嗜铬细胞瘤，视网膜成血管主要表现包括肾透明细胞癌，嗜铬细胞瘤，视网膜成血管母细胞瘤，中枢神经系统成血管细胞瘤等母细胞瘤，中枢神经系统成血管细胞瘤等基因学研究基因学研究 VHL 基因定位在常染色体基因定位在常染色体3p2625目前已被完全测序，并确认是存在于散发性和家目前已被完全测序，并确认是存在于散发性和家族性肾透明细胞癌中的抑癌基因族性肾透明细胞癌中的抑癌基因该基因的丢失、突变和甲基化失活导致正常的该基因的丢失、突变和甲基化失活导致正常的VHL蛋白合成障碍

4、，是导致蛋白合成障碍，是导致VHL综合征的重要分综合征的重要分子学基础子学基础 2023-1-168头颅MRI显示左侧延髓见类圆形混杂信号灶，大小约1.Isolated cases of uterine leiomyosarcomasPreoperative PET scans may prove beneficial in cases in which lymph node or nonlocalized disease is suspectedIsolated cases of uterine leiomyosarcomasMean age at diagnosis is older,ne

5、ar age 50 yearsaggressive tumor features in young patientsBe mapped to a region on chromosome 1(1q42.发病隐匿，多无明显临床表现其他病变如胰腺囊肿、附睾或阔韧带乳头状囊腺瘤、肾囊肿,多无明显症状，一般预后良好肾癌占VHL综合征患者死亡原因的50%，发生率为2470%BirtHoggDube syndromeIsolated cases of uterine leiomyosarcomas仔细随访相应患者及其家属仔细随访相应患者及其家属仔细随访相应患者及其家属既往体健，否认高血压病史，否认家族史，

6、体格检查血压轻度升高150/78mmHg仔细随访相应患者及其家属More recently,detailed histologic description has led to more refined characterization of the pathologic features now termed HLRCC renal tumorsBirtHoggDube syndrome该基因在该基因在VHLVHL病家族成员中突变率几乎达病家族成员中突变率几乎达100%100%散发的肾透明细胞癌患者中，散发的肾透明细胞癌患者中，VHLVHL基因突变率为基因突变率为46%46%70%70%肾脏

7、其他病理类型肿瘤未发现肾脏其他病理类型肿瘤未发现VHLVHL基因突变基因突变 2023-1-1610chromophobe嫌色细胞,oncocytoma,clear cell and hybrid oncocytic tumors composed of elements of oncocytoma and chromophobeBirtHoggDube syndrome一项研究对肾脏肿瘤小于3cm的108例VHL综合征患者与肿瘤大于3cm的73例患者做比较该基因的丢失、突变和甲基化失活导致正常的VHL蛋白合成障碍，是导致VHL综合征的重要分子学基础pulmonary metastases f

8、rom a case of locally advanced clear cell carcinoma in a 20yearold patientIsolated cases of uterine leiomyosarcomasNephronsparing surgery is less well established in this setting6cm，增强后边缘较前清晰。aggressive tumor features in young patientsVHL 基因定位在常染色体3p2625发现遗传性肾癌的相关基因Lung cysts were common and seen in

9、 83%VHL基因抑癌机制清楚，抑癌作用明显，而且VHL基因只有3个外显子，是基因治疗十分理想的目的基因intervention for tumors,which grow to reach 3cm in size and include the use of nephronsparing procedures when possiblePathologic analysis of 130 tumors obtained from 30 surgically managed cases identified proportional differences including hybrid o

10、nco/chromo 50%,chromophobe 34%,conventional clear cell 9%,oncocytoma 5%and papillary 2%chromophobe嫌色细胞,oncocytoma,clear cell and hybrid oncocytic tumors composed of elements of oncocytoma and chromophobe与cMet原癌基因的突变有关，定位于染色体7q31pulmonary cysts阴囊B超提示双侧附睾头囊肿，左侧0.既往体健，否认高血压病史，否认家族史，体格检查血压轻度升高150/78mmHg

11、44%before the age of 30Preoperative PET scans may prove beneficial in cases in which lymph node or nonlocalized disease is suspectedrenal cell carcinoma仔细随访相应患者及其家属Classic triad of skin fibrofolliculomasBe mapped to a region on chromosome 1(1q42.renal tumors were discovered in 14 34%.仔细随访相应患者及其家属One

12、 39year old patient with BHD and mixed renal tumor,including clear cell components developed distant progression and deathBirtHoggDube syndrome结节性硬化病(TS)？Be mapped to a region on chromosome 1(1q42.chromophobe嫌色细胞,oncocytoma,clear cell and hybrid oncocytic tumors composed of elements of oncocytoma an

13、d chromophobe对最大径超过3cm的肿瘤行肾部分切除术，这样可以减低肿瘤的转移的风险而且保留肾脏的功能指的是病人易于罹患肾乳头状细胞癌的状态the relative heterogeneity of tumor subtypesCutaneous leiomyomas are common among affected individuals,though may be difficult to identifyrenal tumorsVHLVHL综合征临床表现综合征临床表现VHLVHL综合征诊断标准综合征诊断标准 （1 1）中枢神经系统或视网膜成血管细胞瘤家族病史，）中枢神经系统或

14、视网膜成血管细胞瘤家族病史，有一种成血管细胞瘤或内脏病变（如肾肿瘤、胰腺肿有一种成血管细胞瘤或内脏病变（如肾肿瘤、胰腺肿瘤或囊肿、嗜铬细胞瘤、附睾乳头状囊腺瘤等）瘤或囊肿、嗜铬细胞瘤、附睾乳头状囊腺瘤等）（2 2）对于无明确家族遗传史的孤立病例，若患有两）对于无明确家族遗传史的孤立病例，若患有两种或两种以上成血管母细胞瘤种或两种以上成血管母细胞瘤,或一种成血管母细胞或一种成血管母细胞瘤和一种内脏病变瘤和一种内脏病变 类型类型 I I型不表现为肾上腺嗜铬细胞瘤，病变可累及中枢神经型不表现为肾上腺嗜铬细胞瘤，病变可累及中枢神经系统、肾脏、胰腺等系统、肾脏、胰腺等型伴发肾上腺嗜铬细胞瘤型伴发肾上腺嗜

15、铬细胞瘤AA型，不伴有肾癌型，不伴有肾癌BB型，伴有肾癌型，伴有肾癌CC型，仅有肾上腺嗜铬细胞瘤表现型，仅有肾上腺嗜铬细胞瘤表现 chromophobe嫌色细胞,oncocytoma,clear cell and hybrid oncocytic tumors composed of elements of oncocytoma and chromophobeMean age at diagnosis is older,near age 50 years但是复杂的囊肿有可能包含肿瘤组织而逐渐生长，需要定期监测renal tumors were discovered in 14 34%.目前已被

16、完全测序，并确认是存在于散发性和家族性肾透明细胞癌中的抑癌基因与散发的肾癌相比并无特异性遗传性平滑肌瘤病及肾细胞癌Spontaneous pneumothoraces occurred in 23%:most common in younger family members(40 years)renal tumors were discovered in 14 34%.其他病变如胰腺囊肿、附睾或阔韧带乳头状囊腺瘤、肾囊肿,多无明显症状，一般预后良好降低疾病相关死亡率并改善预后44%before the age of 30Pathologic analysis of 130 tumors obt

17、ained from 30 surgically managed cases identified proportional differences including hybrid onco/chromo 50%,chromophobe 34%,conventional clear cell 9%,oncocytoma 5%and papillary 2%对最大径超过3cm的肿瘤行肾部分切除术，这样可以减低肿瘤的转移的风险而且保留肾脏的功能1895 年由德国眼科教授Eugen von Hipple首先发现Lung cysts were common and seen in 83%仔细随访相应

18、患者及其家属Isolated cases of uterine leiomyosarcomasPreoperative PET scans may prove beneficial in cases in which lymph node or nonlocalized disease is suspectedintervention for tumors,which grow to reach 3cm in size and include the use of nephronsparing procedures when possible影像学表现为乏血供的肿瘤，CT增强仅表现为轻度强化（

19、增加1030HU），MRI增强仅15%影像学表现为乏血供的肿瘤，CT增强仅表现为轻度强化（增加1030HU），MRI增强仅15%6cm，增强后边缘较前清晰。临床特点临床特点一般情况下，病变是视网膜成血管母细胞瘤最早出一般情况下，病变是视网膜成血管母细胞瘤最早出现，然后是中枢神经系统血管母细胞瘤，而肾癌出现，然后是中枢神经系统血管母细胞瘤，而肾癌出现较晚现较晚中枢神经系统血管母细胞瘤和肾脏透明细胞癌为该中枢神经系统血管母细胞瘤和肾脏透明细胞癌为该病最常见的致死原因病最常见的致死原因嗜铬细胞瘤，临床上多因出现高血压症状而发现嗜铬细胞瘤，临床上多因出现高血压症状而发现其他病变如胰腺囊肿、附睾或阔韧带

20、乳头状囊腺瘤、其他病变如胰腺囊肿、附睾或阔韧带乳头状囊腺瘤、肾囊肿肾囊肿,多无明显症状，一般预后良好多无明显症状，一般预后良好 VHLVHL综合征是遗传性肾癌最常见的原因综合征是遗传性肾癌最常见的原因肾癌也是肾癌也是VHLVHL综合征主要的恶性肿瘤综合征主要的恶性肿瘤与散发的肾癌相比并无特异性与散发的肾癌相比并无特异性 肾癌占肾癌占VHLVHL综合征患者死亡原因的综合征患者死亡原因的50%50%，发生率为，发生率为24247 70%0%加上肾囊肿，加上肾囊肿，VHLVHL综合征患者中肾脏病变的发生率可达到综合征患者中肾脏病变的发生率可达到60%60%肾脏病变的平均年龄为肾脏病变的平均年龄为39

21、39岁岁(16(1667)67)体积较小的肾脏肿瘤（体积较小的肾脏肿瘤（3cm3cm）恶性度低）恶性度低VHLVHL综合征肾脏病变为多灶性综合征肾脏病变为多灶性 WaltherWalther等对等对VHLVHL综合征患者的肾脏标本进行研究，综合征患者的肾脏标本进行研究，显微镜下观察，发现有的标本中存在显微镜下观察，发现有的标本中存在600600个肿瘤病个肿瘤病灶和灶和11001100个囊肿病灶个囊肿病灶随访研究表明由单纯囊肿变为肾癌的可能性很小随访研究表明由单纯囊肿变为肾癌的可能性很小所以所以VHLVHL综合征的单纯肾囊肿若没有症状一般无综合征的单纯肾囊肿若没有症状一般无需特殊治疗需特殊治疗

22、但是复杂的囊肿有可能包含肿瘤组织而逐渐生长，但是复杂的囊肿有可能包含肿瘤组织而逐渐生长，需要定期监测需要定期监测 散发的肾癌一样，散发的肾癌一样，VHLVHL综合征肾癌缺乏早期临床综合征肾癌缺乏早期临床症状，通常在很长时间内都没有任何表现症状，通常在很长时间内都没有任何表现 肾癌进展的病例可以表现为血尿，疼痛或肿块肾癌进展的病例可以表现为血尿，疼痛或肿块 肾癌病理类型基本是透明细胞癌亚型，肿瘤体积肾癌病理类型基本是透明细胞癌亚型，肿瘤体积越小倾向恶性程度越低越小倾向恶性程度越低与非与非VHLVHL综合征肾癌相比，综合征肾癌相比，VHLVHL综合征肾癌的发综合征肾癌的发病年龄较早，通常表现为双侧

23、多中心的实性和囊病年龄较早，通常表现为双侧多中心的实性和囊性的病变性的病变 治疗治疗VHLVHL综合征患者肾癌的预后与肿瘤的大小密切相关综合征患者肾癌的预后与肿瘤的大小密切相关 对最大径超过对最大径超过3cm3cm的肿瘤行肾部分切除术，这样可以的肿瘤行肾部分切除术，这样可以减低肿瘤的转移的风险而且保留肾脏的功能减低肿瘤的转移的风险而且保留肾脏的功能对于直径较小的肿瘤（对于直径较小的肿瘤（3cm3cm）可以选择密切观察）可以选择密切观察 一项研究对肾脏肿瘤小于一项研究对肾脏肿瘤小于3cm3cm的的108108例例VHLVHL综合征患者与肿综合征患者与肿瘤大于瘤大于3cm3cm的的7373例患者做

24、比较例患者做比较中位时间超过中位时间超过5 5年随访结果显示肿瘤小于年随访结果显示肿瘤小于3cm3cm患者中无病例患者中无病例发生转移，而肿瘤大于发生转移，而肿瘤大于3cm3cm组组7373例患者中有例患者中有2020例发生转移例发生转移（27%27%）VHLVHL综合征肾癌常为双侧多发，肿瘤生长较慢，转移较晚，综合征肾癌常为双侧多发，肿瘤生长较慢，转移较晚，肾脏肿瘤平均每年增长肾脏肿瘤平均每年增长0.5cm0.5cm一般不建议对一般不建议对VHLVHL综合征行肾根治性切除术，即使为单侧综合征行肾根治性切除术，即使为单侧肾癌，也应尽量行保留肾单位的肿瘤切除手术，因为对侧肾癌，也应尽量行保留肾单

25、位的肿瘤切除手术，因为对侧肾脏也有再发生肾癌的可能肾脏也有再发生肾癌的可能 如果无法保留肾脏，可选择进行双侧肾根治性切除术，如果无法保留肾脏，可选择进行双侧肾根治性切除术，再透析或行肾移植术加服免疫抑制剂再透析或行肾移植术加服免疫抑制剂当当VHLVHL患者接受肾移植以后，移植肾无发展为肾囊肿患者接受肾移植以后，移植肾无发展为肾囊肿或肾癌的倾向或肾癌的倾向但长期服用免疫抑制剂是否增加但长期服用免疫抑制剂是否增加VHLVHL综合征其他系统综合征其他系统肿瘤的发病率？肿瘤的发病率？VHLVHL基因抑癌机制清楚，抑癌作用明显，而且基因抑癌机制清楚，抑癌作用明显，而且VHLVHL基基因只有因只有3 3个

26、外显子，是基因治疗十分理想的目的基因个外显子，是基因治疗十分理想的目的基因目前目前VHLVHL基因治疗还处在体外研究动物实验阶段基因治疗还处在体外研究动物实验阶段VHLVHL基因治疗将为基因治疗将为VHLVHL综合征治疗开辟一个新的方向综合征治疗开辟一个新的方向 随访随访VHLVHL综合征合并肾癌的患者应每年复查一次综合征合并肾癌的患者应每年复查一次CTCT或或MRIMRI如果最大肿瘤直径超过如果最大肿瘤直径超过3cm3cm，就应对所有肿瘤行，就应对所有肿瘤行肿瘤剜除术或肾部分切除术肿瘤剜除术或肾部分切除术有有VHLVHL家族病史的人，也应该每年复查一次家族病史的人，也应该每年复查一次CTCT

27、对于无肿瘤的单纯囊肿，不推荐手术切除对于无肿瘤的单纯囊肿，不推荐手术切除 遗传性乳头状肾细胞癌遗传性乳头状肾细胞癌指的是病人易于罹患肾乳头状细胞癌的状态指的是病人易于罹患肾乳头状细胞癌的状态与与cMetcMet原癌基因的突变有关，定位于染色体原癌基因的突变有关，定位于染色体7q317q31常染色体显性遗传常染色体显性遗传临床表现临床表现发病隐匿，多无明显临床表现发病隐匿，多无明显临床表现多为多灶性，双侧发病多为多灶性，双侧发病影像学表现为乏血供的肿瘤，影像学表现为乏血供的肿瘤，CTCT增强仅表现为轻度强增强仅表现为轻度强化（增加化（增加1030HU1030HU），），MRIMRI增强仅增强仅1

28、5%15%2023-1-1625治疗治疗通常选择肾部分切除术通常选择肾部分切除术术中仔细检查，防止遗漏病灶术中仔细检查，防止遗漏病灶遗传性平滑肌瘤病及肾细胞癌A relatively new,rare and aggressive form of HRC A relatively new,rare and aggressive form of HRC syndromesyndromecutaneous leiomyomascutaneous leiomyomas uterine leiomyomas uterine leiomyomas renal cell carcinoma renal c

29、ell carcinomafumarate hydratase,a Krebs cycle enzymefumarate hydratase,a Krebs cycle enzymeGeneticsGeneticsBe mapped to a region on chromosome 1 Be mapped to a region on chromosome 1(1q42.343)(1q42.343)encodes for the HLRCC gene product,fumarate encodes for the HLRCC gene product,fumarate hydrataseh

30、ydratasean autosomal dominant patternan autosomal dominant patternthe tumor suppressor function of the genethe tumor suppressor function of the geneClinical featuresClinical featuresthe finding of severely symptomatic uterine the finding of severely symptomatic uterine fibroids among affected women

31、within familiesfibroids among affected women within familiesoften requiring early hysterectomy due to often requiring early hysterectomy due to difficulties from menometrorrhagiadifficulties from menometrorrhagia89%of affected women underwent hysterectomy89%of affected women underwent hysterectomy44

32、%before the age of 3044%before the age of 30Clinical features89%of affected women underwent hysterectomypotentially misclassified as collecting duct tumors1926年由瑞典病理学家Avid Lindau再次确认Lung cysts were common and seen in 83%遗传性乳头状肾细胞癌(HPRC)Pathologic analysis of 130 tumors obtained from 30 surgically ma

33、naged cases identified proportional differences including hybrid onco/chromo 50%,chromophobe 34%,conventional clear cell 9%,oncocytoma 5%and papillary 2%the finding of severely symptomatic uterine fibroids among affected women within familiesIsolated cases of uterine leiomyosarcomasBirtHoggDube synd

34、romepotentially misclassified as collecting duct tumors散发的肾透明细胞癌患者中，VHL基因突变率为46%70%但长期服用免疫抑制剂是否增加VHL综合征其他系统肿瘤的发病率？cutaneous leiomyomasthe tumor suppressor function of the gene6cm，增强后边缘较前清晰。头颅MRI显示左侧延髓见类圆形混杂信号灶，大小约1.肾癌占VHL综合征患者死亡原因的50%，发生率为2470%Isolated cases of uterine leiomyosarcomasIsolated cases

35、of uterine leiomyosarcomasCutaneous leiomyomas are common among affected Cutaneous leiomyomas are common among affected individuals,though may be difficult to identifyindividuals,though may be difficult to identifyRenal cancers with a prevalence estimated Renal cancers with a prevalence estimated be

36、tween 2 and 21%between 2 and 21%papillary type 2 tumors papillary type 2 tumors potentially misclassified as collecting duct tumors potentially misclassified as collecting duct tumorsMore recently,detailed histologic description has More recently,detailed histologic description has led to more refin

37、ed characterization of the led to more refined characterization of the pathologic features now termed HLRCC renal pathologic features now termed HLRCC renal tumorstumorsManagementManagementRadiographic appearance of HLRCC tumors may appear Radiographic appearance of HLRCC tumors may appear partly cy

38、stic and poorly definedpartly cystic and poorly definedNephronsparing surgery is less well established in this Nephronsparing surgery is less well established in this setting setting Surgical intervention must be performed with care to Surgical intervention must be performed with care to ensure mini

39、mal handling of the tumor and complete wide ensure minimal handling of the tumor and complete wide resection,including lymph node dissectionresection,including lymph node dissectionPreoperative PET scans may prove beneficial in cases in Preoperative PET scans may prove beneficial in cases in which l

40、ymph node or nonlocalized disease is suspectedwhich lymph node or nonlocalized disease is suspectedBirtBirtHoggHoggDube syndromeDube syndromeThe familial association of perifollicular dermatosis The familial association of perifollicular dermatosis involving the face and trunk among three firstdegre

41、e involving the face and trunk among three firstdegree relatives was first described by Hornstein and Knickenberg relatives was first described by Hornstein and Knickenberg in 1975in 1975Two years later,Drs Birt,Hogg and Dube described clinical Two years later,Drs Birt,Hogg and Dube described clinic

42、al dermatologic findings involving 15 family members with dermatologic findings involving 15 family members with similar skin nodules described as fibrofolliculomassimilar skin nodules described as fibrofolliculomas纤维毛囊纤维毛囊瘤瘤,trichodiscomas,trichodiscomas毛盘状瘤毛盘状瘤 acrochordons acrochordons软垂疣软垂疣Genet

43、icsGeneticsautosomal dominant patterns of inheritance autosomal dominant patterns of inheritance chromosomechromosomeThe gene product,folliculin,is thought to be involved The gene product,folliculin,is thought to be involved in regulation of the mammalian target of rapamycin in regulation of the mam

44、malian target of rapamycin(mTOR)pathway by acting through(mTOR)pathway by acting through folliculininteracting protein(FNIP1)and folliculininteracting protein(FNIP1)and 50AMPactivated protein kinase50AMPactivated protein kinaseClinical featuresClinical featuresClassic triad of skin fibrofolliculomas

45、Classic triad of skin fibrofolliculomas pulmonary cysts pulmonary cysts renal tumors renal tumorsrenal tumors were discovered in 14 34%.renal tumors were discovered in 14 34%.Spontaneous pneumothoraces occurred in Spontaneous pneumothoraces occurred in 23%:most common in younger family members 23%:m

46、ost common in younger family members(40 years)(40 years)Lung cysts were common and seen in 83%Lung cysts were common and seen in 83%Skin lesions in 90%Skin lesions in 90%the relative heterogeneity of tumor subtypes the relative heterogeneity of tumor subtypes indolent forms of diseaseindolent forms

47、of diseasechromophobechromophobe嫌色细胞嫌色细胞,oncocytoma,clear cell,oncocytoma,clear cell and hybrid oncocytic tumors composed of and hybrid oncocytic tumors composed of elements of oncocytoma and chromophobeelements of oncocytoma and chromophobeMean age at diagnosis is older,near age 50 yearsMean age at

48、 diagnosis is older,near age 50 yearsPathologic analysis of 130 tumors obtained from 30 Pathologic analysis of 130 tumors obtained from 30 surgically managed cases identified proportional surgically managed cases identified proportional differences including hybrid onco/chromo 50%,differences includ

49、ing hybrid onco/chromo 50%,chromophobe 34%,conventional clear cell 9%,chromophobe 34%,conventional clear cell 9%,oncocytoma 5%and papillary 2%oncocytoma 5%and papillary 2%less aggressive tumor histologiesless aggressive tumor histologiesnot be considered an indolent disease processnot be considered

50、an indolent disease processaggressive tumor features in young patientsaggressive tumor features in young patients pulmonary metastases from a case of locally advanced pulmonary metastases from a case of locally advanced clear cell carcinoma in a 20yearold patientclear cell carcinoma in a 20yearold p