不明原发灶肿瘤的诊断.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,大家好,*,Metastatic Cancer,Unknown Primary,Site,1,大家好,Metastatic CancerUnknown Primary,Site,Synonyms and related keywords,tumor of unknown primary,cancer of unknown origin,carcinoma of unknown origin,unknown primary cancer,2,大家好,Metastatic CancerUnknown PrimarySite,unknown primary carcinoma,carcinoma of unknown primary,origin,3,大家好,Metastatic CancerUnknown Primary,Site,cancer of unknown primary site,(cups),carcinoma of unknown primary,origin(CUP),4,大家好,Metastatic CancerUnknown Primary,Site,metastatic cancer,metastatic carcinoma,metastatic tumor,metastases,occult primary malignancy,5,大家好,CUP,Background(in the United States),32,100 pats with CUPS in 2007,(15,720 males;16,380 females),About 2%of all cancers,6,大家好,CUP,Deaths due to CUPS:45,230(24,440 males;20,790 females),7,大家好,CUP,This discrepancy between incidence and mortality is believed to be due to a lack of specificity in the listing ofcause of death on death certificates,8,大家好,CUP,Its true incidence is most probably,between 2%and 6%,In 15-25%of cases,the primary site,cannot be identified even on,postmortem,9,大家好,CUP,Pathophysiology,Cancers are thought to arise from a single cell that escapes the controls of normal cell replication,Forms a tumor at the site of origin,Ultimately metastasizes to other,organs,10,大家好,CUP,Pathophysiology,In some cases the original tumor may remain small or undetectable at the time of metastasis,Leading to the clinical presentation of CUP,11,大家好,CUP,Frequency,United States,:,2-6%,International,:,2-9%,12,大家好,CUP,Mortality/Morbidity,Median survivalranges from 11,weeks to 11 months,The 5-year overall survival rate is,about 11%,13,大家好,CUP,Sex,An approximate equal incidence for men and women,14,大家好,CUP,Age,The median age on presentation for,both men and women ranges from,59-66 years,15,大家好,CUP,CLINICAL(History),Because most patients with cup have fairly advanced-staged cancers,The constitutional symptoms of,malaise,weakness,fatigue,and,weight loss,are present in nearly all patients,16,大家好,CUP,CLINICAL(Physical),The clinical presentation of cup is,extremely variable,Depends on the extent and type of,organ involvement,17,大家好,CUP,一群异源发生的肿瘤,除外淋巴瘤、转移性黑色素瘤和转移,性肉瘤,集中于上皮细胞组织，包括腺癌、鳞,状上皮细胞癌、分化不良上皮癌和神,经内分泌癌,18,大家好,CUP,CUP,的诊断标准,组织活检证实为恶性肿瘤,(,活检部位不能检出原发灶,),经过彻底地收集病史或物理检查,(,包括女性盆腔检查和男性睾丸及前列腺触诊,),未发现原发性肿瘤,19,大家好,CUP,CUP,实验室检查结果正常，包括完整的血细胞计数、血液生化、胸部,X,线、腹部和盆腔,CT,、乳房影像学检查或前列腺特异性抗原,(PSA),检查等等,20,大家好,CUP,CLINICAL,完整的病史和彻底的体格检查是诊断,CUP,的基本前提，尤其是既往组织活检结果,家族史很可能提示遗传性非息肉病性结肠癌或乳腺癌易感性,21,大家好,CUP,彻底的体检可能会发现特异性原发肿瘤,左侧锁骨上淋巴结肿大,(VirehowS,结节,)(,胃,Ca?),脐周淋巴结肿大或包块,(Sister Mary JosphS,结节,-,由恶性腹水造成的腹胀以及脐周肿块,脐孔肿大变硬,产生冰山样脐部肿块,)(,低分化癌,-,胃肠道,),腹股沟淋巴结肿大、肛周包块,(,肛门肿瘤,),22,大家好,CUP,CLINICAL(Physical),The most common sites of,involvement being,lung,bone,lymph,nodes,and liver,23,大家好,CUP,CLINICAL(Physical),Including,head and neck,rectal,testicular,pelvic,and breast,examinations,24,大家好,CUP,CLINICAL(,Physical,Lab and radiological studies,),A complete blood cell count(iron deficiency may point toward an occult gastrointestinal malignancy leading to chronic blood loss),25,大家好,CUP,CLINICAL(,Physical,Lab and radiological studies,),urinalysis(microscopic hematuria may be a sign of occult genitourinary malignancy),26,大家好,CUP,CLINICAL(,Physical,Lab and radiological studies,),liver and renal function tests,stool for occult blood,chest radiograph,27,大家好,CUP,CLINICAL(,Physical,Lab and radiological studies,),abdomen and pelvis CT,mammography in women,measurement of PSA in men,28,大家好,CUP,Physical,Ascites,should lead one to evaluate for a GI or an ovarian primary,An axillary massin a female should make the clinician check for breast cancer,A cervical node,should lead to a thorough ENT examination,29,大家好,CUP,Physical,A brain metastasis,should lead to a search for a,lung,breast,or kidney,primary,Bone metastasis,should lead to evaluation for,prostate,breast,lung,renal,or thyroid,primary,30,大家好,CUP,Physical,A testicular mass,should lead to measurement of tumor markers such as beta-HCG and AFP,31,大家好,CUP,Physical,Depending on the clinical situation,these may include chest CT,breast,MRI,upper or lower endoscopy,32,大家好,CUP,CLINICAL(Physical),In suspected head and neck malignancies,panendoscopy of the upper aerodigestive pathways should be performed with even as indicated blind biopsies of the lymphoid tissue in these areas,33,大家好,CUP,CLINICAL(Physical),Diagnostic tonsillectomy may be,warranted,34,大家好,CUP,CLINICAL(Physical),Intensive testing also adds to the morbidity for the weak and frail patient,35,大家好,CUP,CLINICAL(Physical),A large negative cost-to-benefit ratio exists for an extensive unguided clinical evaluation,36,大家好,CUP,CLINICAL(Physical),One study quoting a 9.5%increase in 1-year survival at a cost of 2-8 million dollars,37,大家好,CUP,CLINICAL(Physical),When these investigations fail to reveal a potential primary lesion,a cancer of unknown primary origin is assumed,38,大家好,CUP,WORKUP(Imaging Studies),18F-FDG-PET is increasingly being used in the evaluation of metastatic malignancies,39,大家好,CUP,WORKUP(Imaging Studies),This may be especiallythe case in,suspected head and neck,malignancies,40,大家好,CUP,WORKUP(Imaging Studies),This testing lacks specificity and may only be useful to identify promising sites for biopsy,41,大家好,CUP,WORKUP(Imaging Studies),18,氟,-,脱氧葡萄糖,(,18,F-FDG)-PET,可辅助指导活组织检查，确定疾病程度和辅助选择恰当的治疗,42,大家好,CUP,WORKUP(Imaging Studies),Although promising,high cost and false positive rates of 20%limit its utility in cases of CUP,The combination of PET/CT may reduce the false-positive rate,43,大家好,CUP,Other Tests,The role of tumor markers like AFP,beta-HCG,CA125,CA 27.29,CA 19.9,and CEA to establish a specific primary site,44,大家好,CUP,Other Tests,Most tumor markers are nonspecific,It may not be used to establish,definitive diagnoses,45,大家好,CUP,Other Tests,男性腺癌和骨转移，常规检查血清,PSA,男性未分化癌和低分化癌，检测,B-HCG,和,AFP,AFP,也用于诊断,HCC,B-HCG,和,AFP,水平并不能预测化疗效果或生存期,46,大家好,CUP,Other Tests,CEA,、,CA125,、,CA19-9,和,CA15-3,对于确定原发灶没有帮助,大多数血清肿瘤标记物是非特异性的，可判断预后,47,大家好,CUP,Procedures,A biopsy of the metastatic site,A careful evaluation of the pathology,48,大家好,CUP,Histologic Findings,The pathologist has an indispensable role in the evaluation of CUP,49,大家好,CUP,Histologic Findings,Needle biopsy specimens may provide insufficient tissue for diagnosis or provide tissue that has been toodamagedor distorted by the biopsy procedure for accurate diagnosis,50,大家好,CUP,Histologic Findings,Various immunoperoxidase(,免疫过氧化物酶,)stains are available for providing a differential diagnosisfor CUP,51,大家好,CUP,Histologic Findings,Appropriate DNA microarray(,微阵列,),techniques and proteonomic(,蛋白质组学,),studies to establish a definitive diagnosis,52,大家好,CUP,Histologic Findings,如果查不到原发肿瘤，要想确定各种,CUP,患者的治疗策略和判断预后是非常困难的,53,大家好,CUP,Histologic Findings,免疫组化和影像学联合检查的诊断率约为,20,-30,目前认为,最有前途的可提高诊断率的方法是肿瘤的分子诊断。现有的基因表达数据库对于,CUP,的诊断极有帮助,54,大家好,CUP,Histologic Findings,预警基因分为两类，一类是在某些起源组织中特异性表达的基因，另一类是在各种肿瘤中均有异常表达的基因,55,大家好,CUP,Histologic Findings,一批源于,l0,种普通肿瘤的,100,个原发癌样品，用,110,个在这些肿瘤中表达最低的基因开发了一个预警芯片。对另外,75,个盲样,(,包括,l2,个转移癌样品,),进行检验，预测肿瘤原发灶的正确率大于,90,，,12,个转移癌中有,l1,个被正确分类,56,大家好,CUP,Histologic Findin,对,218,个肿瘤,(14,个普通类型,),组织和,90,个正常组织样品的寡核苷酸微阵列基因表达进行分析，用,16 063,个基因表达的相对水平和表达基因的序列标签开发了一个基因预警芯片,57,大家好,CUP,Histologic Findin,对,54,个肿瘤样品,(,其中,8,例转移性肿瘤,),检测，总的预测正确率是,78,，转移性肿瘤中有,6,例被正确识别出原发部位,提示肿瘤保留其组织起源标记物是贯穿于转移过程的始终,58,大家好,CUP,Histologic Findings,引用一系列基因表达库的分析数据和相关肿瘤标记物的文献资料确定了,61,个基因为候选肿瘤基因，以其表达模式预测起源位置。用反转录,PCR,对原发性腺癌样品,(,包括乳腺、卵巢、胃、胰腺和肺,),检测了其中,11,个基因，,7,个,(64,),基因存在组织特异性,这些组织限制性肿瘤标志物能够用于,CUP,原发性肿瘤可能位点的预测,59,大家好,CUP,Histologic Findings,Puts the tissue specimen through 1-4 steps,depending on the need,60,大家好,CUP,Histologic Findings,light microscopy,Immunohistochemical stains,Electron microscopy,Chromosomal analysis including,cytogenetics,61,大家好,CUP,Histologic Findings,Light microscopy:epithelial cancers,lymphomas,sarcomas,melanomas,or germ cell tumors,62,大家好,CUP,Histologic Findings,When cytologic distinguishing features are limited,the tumor may be classified as undifferentiated or poorly differentiated carcinoma,63,大家好,CUP,Histologic Findings,Immunohistochemistry:These tests help define tumor lineage by using peroxidase-labeled antibody against specific tumor antigens,64,大家好,CUP,Histologic Findings,These include stains for keratin,LCA and S-100(expressed in melanomas),TTF-1(for lung and thyroid cancer),PSA,HCG(for germ cell tumors),AFP(for germ-cell tumors and hepatomas),ER,PR,and Her-2(for breast cancer),65,大家好,CUP,Histologic Findings,CK20,在胃肠道上皮、泌尿道上皮和,Merkel,细胞中表达,CK7,在肺癌、卵巢癌、子宫内膜癌和乳腺癌中有表达；而在低位胃肠道肿瘤未发现表达,CK20,阳性和,CK7,阴性强烈支持结肠原发肿瘤。,75,95,的结肠肿瘤呈现此染色模式,肺癌仅有,9,15,CK20,呈阳性，这有助于,肺内转移性腺癌原发灶的鉴别,66,大家好,CUP,Histologic Findings,CK20,阴性和,CK7,阳性将鉴别诊断缩小至肺癌、乳腺癌、胆管癌、胰腺癌、卵巢癌和子宫内膜癌,应用,TTF-1,和表面活性物质脱辅基蛋白,(surfactant apoprotein),可将原发性肺癌从其他,CK7,阳性肿瘤中区分出来,67,大家好,CUP,Histologic Findings,TTF-1,是一种,38kD,的含有同源结构域的核蛋白，在甲状腺、中脑和呼吸道上皮胚胎发生过程的转录活化中起作用,TTF-1,在肺癌和甲状腺癌呈典型阳性染色,有利于,对转移性颈部淋巴结肿大和转移性胸腔积液的原发肿瘤的诊断,68,大家好,CUP,Histologic Findings,Electron microscopy:This study has limited utility in identification of the primary site of cancer of unknown primary origin but may rarely be used in poorly differentiated tumors,69,大家好,CUP,Histologic Findings,Chromosomal studies:In cases of CUP with suspected occult NPC,DNA amplification of Epstein Barr virus(EBV)in tissue may clinch the diagnosis,70,大家好,CUP,Histologic Findings,The presence of iso-chromosome 12p,i(12p),a specific chromosomal marker characteristic of germ cell tumors can help diagnose extragonadal germ cell tumors in patients with CUP,71,大家好,CUP,Histologic Findings,生殖细胞肿瘤有特征性的细胞遗传学改变,(,等臂染色体,12p-i12p,拷贝数增加或,12,号染色体长臂缺如,与无染色体异常的患者相比，生殖细胞肿瘤有染色体异常的患者对顺铂为主的化疗有更好的反应,72,大家好,CUP,The majority of CUP are,adenocarcinomas or undifferentiated tumors(up to 58%in some studies),73,大家好,CUP,Less commonly,squamous cell carcinoma,melanoma,sarcoma,and neuroendocrine tumors can also present as metastasis with an unknown primary site of origin,74,大家好,CUP,Most studies exclude sarcomas and melanomas from their analysis,75,大家好,CUP,In the approximately 30%of CUP,the most common epithelial malignancies are,lung(15%),pancreas(13%),colon/rectum(6%),kidney(5%),and breast(4%),76,大家好,CUP,Sarcomas,melanomas,and lymphomas each contribute 6-8%,77,大家好,CUP,The remaining primary tumors are those of,stomach(4%),ovary(3%),liver(3%),esophagus(3%),prostate(2%),and a variety of other malignancies(22%),78,大家好,CUP,Staging,Patients with cancer of unknown primary origin are presumed to all have stage IV disease at the time of initial presentation,79,大家好CUP,CUP,表现为转移性疾病但未找到原发灶,80,大家好,CUP,原发灶隐匿的原因可能与以下因素有关,机体的免疫机制控制了原发灶，于转移后消失,原发灶太小，不能被目前的检查方法所发现,81,大家好,CUP,Naresh19,假设认为,原发灶血供改变使其生长受抑,在内脏，转移灶可能处于静止期，直到有生成血管表型的亚克隆出现，才导致转移性肿瘤迅速生长,在肿瘤发生过程中，转移灶发生于晚期的传统理论正受到质疑,新的数据提示，肿瘤发生早期即有转移倾向,82,大家好,CUP,CUP,的原发性肿瘤极有可能从一开始就有“预后不良”的特征,分子靶点和,DNA,微阵列在,CUP,诊断中的应用正在开展,揭示转移癌的发病机制,促进新的治疗药物的开发,83,大家好,CUP,代表肿瘤类型的、已知的原发性肿瘤基因引入诊断,CUP,无足够的源于原发性肿瘤转移灶样品的基因表达数据，尤其是低分化肿瘤,84,大家好,CUP,DNA,微阵列与更大规模的免疫组化标记物和转移模式相结合,提高预测,CUP,起源位置的正确率,原发灶与其转移灶的基因转录谱的对比性研究,85,大家好,Thanks for your attention!,86,大家好,CUP,TREATMENT(Medical Care),Multiple organ involvement and poor performance statusis grave,87,大家好,CUP,TREATMENT(Medical Care),The median survival is only 3-4 months,The 1-year survival rate is less than15%,The 5-year survival of5-10%,88,大家好,CUP,Poor prognostic markers,male sex,multiple brain metastases,pleural/lung involvement,liver involvement,adrenal involvement,adenocarcinoma histology,89,大家好,CUP,Favorable prognostic markers,lymph node involvement,neuroendocrine histology,90,大家好,CUP,TREATMENT(cervical lymph nodes),Upper aerodigestive tract,including direct visualization of the hypopharynx,nasopharynx,larynx,and upper esophagus,91,大家好,CUP,TREATMENT,Squamous,Adenocarcinoma,Melanoma,Anaplastic tumors,(,间变性肿瘤,),92,大家好,CUP,TREATMENT,Squamous or undifferentiated carcinoma,tonsillectomies should be considered,93,大家好,CUP,TREATMENT,Cervical adenopathy can be the primary disease manifestation in 2-5%of patients with primary squamous cell carcinoma of the head and neck region,94,大家好CUP,TREATMENT,In the absence of localization of a primary site,aggressive local therapy is indicated.This may involve any of the following:,95,大家好,CUP,TREATMENT,Radical radiation therapy with curative intent to the neck and possible site of origin,96,大家好,CUP,TREATMENT,Preoperative radiation therapy followed,by radical neck dissection,Radical neck dissection,Radical neck dissection followed by,radiation to possible sites of origin,97,大家好,CUP,TREATMENT,Five-year survival rates as high as 30-50%have been achieved with this approach,98,大家好,CUP,TREATMENT,Role of chemotherapy is debated,99,大家好,CUP,TREATMENT,One randomized study showed improved response rate and median survival with cisplatin and 5-fluorouracilbased chemotherapy when compared to radiation alone,100,大家好,CUP,TREATMENT,A single adenocarcinoma-involvedlymph node in either the cervical or inguinal areas with no evidence of disease elsewhere may be managed with surgical excision alone and watchful expectation,101,大家好,CUP,TREATMENT,Radiation therapy to the involved and local fields may be provided as well,102,大家好,CUP,TREATMENT,Combination therapy may be superior to monotherapy with 5-year survival rates of 35%reported,103,大家好,CUP,TREATMENT,Metastatic adenocarcinoma presenting as isolated axillary lymphadenopathy in women is usually a manifestation of an occult breast primary cancer,104,大家好,CUP,TREATMENT,Mastectomy specimens in this subset of patients have shown a previously undiagnosed breast primary tumor in 40-70%cases,105,大家好,CUP,TREATMENT,Immunohistochemical stains with ER and PR should be performed in this setting,as they may aid in diagnosis,106,大家好,CUP,TREATMENT,Modified radical mastectomy with axillary node dissection has been advocated,107,大家好,CUP,TREATMENT,A study with 42 patients,however,showed improved survival with systemic chemotherapy and improved local control with breast and axillary radiation,108,大家好,CUP,TREATMENT,Local excision,As having primary breast cancer,50%of patients achieve 2-10 year,survival,Currently,management is based on,the guidelines for stage II breast,cancer,109,大家好,CUP,TREATMENT,Women with peritoneal carcinomatosis with adenocarcinoma have similarities with patients with ovarian cancer,110,大家好,CUP,TREATMENT,Papillary histology,Elevation of CA 125,A good response to platinum-based,chemotherapy,But a primary tumor is not revealed on,exploratory laparotomy,111,大家好,CUP,TREATMENT,Metastatic melanoma to a single nodal,site,5%of patients with malignant melanoma may present with nodal metastasis in the absence of a documented primary site,112,大家好,CUP,TREATMENT,They should be treated with radical lymph node dissection,Survival,surprisingly,is slightly better than that for stage II melanoma in patients with a known primary site,113,大家好,CUP,TREATMENT,Poorly differentiated,and undifferentiated carcinoma,1/3 CUP,Can be potentially curable,Includes lymphomas,germ cell tumors,or neuroendocrine tumors,114,大家好,CUP,TREATMENT,The features that point toward a treatment-respons