不明原发灶肿瘤的诊断2-ed课件.ppt

1、精选1Metastatic CancerUnknown Primary Site中国医学院肿瘤医院内科中国医学院肿瘤医院内科王宏羽王宏羽精选2Metastatic CancerUnknown Primary Site Synonyms and related keywords tumor of unknown primary cancer of unknown origin carcinoma of unknown origin unknown primary cancer 精选3Metastatic CancerUnknown Primary Site unknown primary car

2、cinoma carcinoma of unknown primary origin 精选4Metastatic CancerUnknown Primary Site cancer of unknown primary site (cups)carcinoma of unknown primary origin(CUP)精选5Metastatic CancerUnknown Primary Site metastatic cancer metastatic carcinoma metastatic tumor metastases occult primary malignancy 精选6CU

3、P Background(in the United States)32,100 pats with CUPS in 2007 (15,720 males;16,380 females)About 2%of all cancers精选7CUP Deaths due to CUPS:45,230(24,440 males;20,790 females)精选8CUP This discrepancy between incidence and mortality is believed to be due to a lack of specificity in the listing of cau

4、se of death on death certificates精选9CUP Its true incidence is most probably between 2%and 6%In 15-25%of cases,the primary site cannot be identified even on postmortem精选10CUPPathophysiology Cancers are thought to arise from a single cell that escapes the controls of normal cell replication Forms a tu

5、mor at the site of origin Ultimately metastasizes to other organs精选11CUP Pathophysiology In some cases the original tumor may remain small or undetectable at the time of metastasis Leading to the clinical presentation of CUP精选12CUPFrequency United States:2-6%International:2-9%精选13CUPMortality/Morbid

6、ity Median survival ranges from 11 weeks to 11 months The 5-year overall survival rate is about 11%精选14CUPSex An approximate equal incidence for men and women精选15CUP Age The median age on presentation for both men and women ranges from 59-66 years精选16CUP CLINICAL(History)Because most patients with c

7、up have fairly advanced-staged cancers The constitutional symptoms of malaise,weakness,fatigue,and weight loss are present in nearly all patients 精选17 CUPCLINICAL(Physical)The clinical presentation of cup is extremely variable Depends on the extent and type of organ involvement精选18CUP 一群异源发生的肿瘤一群异源发

8、生的肿瘤除外淋巴瘤、转移性黑色素瘤和转移除外淋巴瘤、转移性黑色素瘤和转移 性肉瘤性肉瘤 集中于上皮细胞组织，包括腺癌、鳞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状上皮细胞癌、分化不良上皮癌和神 经内分泌癌经内分泌癌精选19CUP CUPCUP的诊断标准的诊断标准组织活检证实为恶性肿瘤组织活检证实为恶性肿瘤(活检部位不能活检部位不能检出原发灶检出原发灶)经过彻底地收集病史或物理检查经过彻底地收集病史或物理检查(包括女包括女性盆腔检查和男性睾丸及前列腺触诊性盆腔检查和男性睾丸及前列腺触诊)未未发现原发性肿瘤发现原发性肿瘤精选20CUP CUPCUP实验室检查结果正常，包括

9、完整的实验室检查结果正常，包括完整的血细胞计数、血液生化、胸部血细胞计数、血液生化、胸部X X线、腹部线、腹部和盆腔和盆腔CTCT、乳房影像学检查或前列腺特、乳房影像学检查或前列腺特异性抗原异性抗原(PSA)(PSA)检查等等检查等等精选21CUPCLINICAL完整的病史和彻底的体格检查是诊断完整的病史和彻底的体格检查是诊断CUPCUP的基本前提，尤其是既往组织活检结果的基本前提，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肠癌或乳腺癌易感性精选22CUP彻底的体检可能会发现特异性原发肿瘤彻底的体检可能会发现特异性原发肿瘤左侧锁

10、骨上淋巴结肿大左侧锁骨上淋巴结肿大(VirehowS(VirehowS结节结节)()(胃胃Ca?)Ca?)脐周淋巴结肿大或包块脐周淋巴结肿大或包块(Sister Mary(Sister Mary JosphSJosphS结节结节-由恶性腹水造成的腹胀以及脐由恶性腹水造成的腹胀以及脐周肿块周肿块 脐孔肿大变硬脐孔肿大变硬,产生冰山样脐部肿产生冰山样脐部肿块块)()(低分化癌低分化癌-胃肠道胃肠道)腹股沟淋巴结肿大、肛周包块腹股沟淋巴结肿大、肛周包块(肛门肿瘤肛门肿瘤)精选23 CUPCLINICAL(Physical)The most common sites of involvement be

11、ing lung,bone,lymph nodes,and liver精选24CUPCLINICAL(Physical)Including head and neck,rectal,testicular,pelvic,and breast examinations精选25CUPCLINICAL(Physical,Lab and radiological studies)A complete blood cell count(iron deficiency may point toward an occult gastrointestinal malignancy leading to chro

12、nic blood loss)精选26CUPCLINICAL(Physical,Lab and radiological studies)urinalysis(microscopic hematuria may be a sign of occult genitourinary malignancy)精选27CUPCLINICAL(Physical,Lab and radiological studies)liver and renal function tests stool for occult blood chest radiograph精选28CUPCLINICAL(Physical,

13、Lab and radiological studies)abdomen and pelvis CT mammography in women measurement of PSA in men精选29CUP Physical Ascites should lead one to evaluate for a GI or an ovarian primary An axillary mass in a female should make the clinician check for breast cancer A cervical node should lead to a thoroug

14、h ENT examination精选30CUP 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精选31CUP Physical A testicular mass should lead to measurement of tumor markers such as beta-HCG

15、and AFP精选32CUPPhysicalDepending on the clinical situation,these may include chest CT,breast MRI,upper or lower endoscopy精选33CUPCLINICAL(Physical)In suspected head and neck malignancies,panendoscopy of the upper aerodigestive pathways should be performed with even as indicated blind biopsies of the l

16、ymphoid tissue in these areas精选34CUPCLINICAL(Physical)Diagnostic tonsillectomy may be warranted精选35CUPCLINICAL(Physical)Intensive testing also adds to the morbidity for the weak and frail patient精选36CUPCLINICAL(Physical)A large negative cost-to-benefit ratio exists for an extensive unguided clinical

17、 evaluation精选37CUPCLINICAL(Physical)One study quoting a 9.5%increase in 1-year survival at a cost of 2-8 million dollars精选38CUPCLINICAL(Physical)When these investigations fail to reveal a potential primary lesion,a cancer of unknown primary origin is assumed精选39CUPWORKUP(Imaging Studies)18F-FDG-PET

18、is increasingly being used in the evaluation of metastatic malignancies精选40CUPWORKUP(Imaging Studies)This may be especially the case in suspected head and neck malignancies精选41CUPWORKUP(Imaging Studies)This testing lacks specificity and may only be useful to identify promising sites for biopsy精选42CU

19、PWORKUP(Imaging Studies)1818氟氟-脱氧葡萄糖脱氧葡萄糖(1818F-FDG)-PETF-FDG)-PET可辅助可辅助指导活组织检查，确定疾病程度和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选择恰当的治疗精选43CUPWORKUP(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

20、rate精选44CUPOther 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精选45CUPOther Tests Most tumor markers are nonspecific It may not be used to establish definitive diagnoses精选46CUPOther Tests男性腺癌和骨转移，常规检查血清男性腺癌和骨转移，常规检查血清PSAPSA男性未分化癌

21、和低分化癌，检测男性未分化癌和低分化癌，检测B-HCGB-HCG和和AFP,AFPAFP,AFP也用于诊断也用于诊断HCCHCCB-HCGB-HCG和和AFPAFP水平并不能预测化疗效果或水平并不能预测化疗效果或生存期生存期精选47CUPOther Tests CEACEA、CA125CA125、CA19-9CA19-9和和CA15-3CA15-3对于确定对于确定原发灶没有帮助原发灶没有帮助大多数血清肿瘤标记物是非特异性的，大多数血清肿瘤标记物是非特异性的，可判断预后可判断预后 精选48CUPProcedures A biopsy of the metastatic site A carefu

22、l evaluation of the pathology精选49CUPHistologic Findings The pathologist has an indispensable role in the evaluation of CUP精选50CUPHistologic Findings Needle biopsy specimens may provide insufficient tissue for diagnosis or provide tissue that has been too damaged or distorted by the biopsy procedure

23、for accurate diagnosis精选51CUPHistologic Findings Various immunoperoxidase(免疫过氧化物酶)stains are available for providing a differential diagnosis for CUP精选52CUPHistologic Findings Appropriate DNA microarray(微阵列)techniques and proteonomic(蛋白质组学)studies to establish a definitive diagnosis精选53CUPHistologic

24、 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精选54CUPHistologic 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的诊断极有帮助精选55CUPHistologic 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精选56CUPHistologic 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

25、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个被正确分类精选57CUPHistologic 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精选58CUPHistologic 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精选59CUPHistologic Findings引用一系列基因表达库的

26、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精选60CUPHistologic Findings Puts the tissue specimen through 1-4 steps,depending on the need精选61CUPHistologic Findings light microscopy Immunohistochemical stains Elec

27、tron microscopy Chromosomal analysis including cytogenetics精选62CUPHistologic Findings Light microscopy:epithelial cancers,lymphomas,sarcomas,melanomas,or germ cell tumors精选63CUPHistologic Findings When cytologic distinguishing features are limited,the tumor may be classified as undifferentiated or p

28、oorly differentiated carcinoma精选64 CUPHistologic Findings Immunohistochemistry:These tests help define tumor lineage by using peroxidase-labeled antibody against specific tumor antigens精选65CUPHistologic Findings These include stains for keratin,LCA and S-100(expressed in melanomas),TTF-1(for lung an

29、d thyroid cancer),PSA,HCG(for germ cell tumors),AFP(for germ-cell tumors and hepatomas),ER,PR,and Her-2(for breast cancer)精选66CUPHistologic Findings CK20CK20在胃肠道上皮、泌尿道上皮和在胃肠道上皮、泌尿道上皮和MerkelMerkel细细胞中表达胞中表达 CK7 CK7在肺癌、卵巢癌、子宫内膜癌和乳腺癌在肺癌、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中有表达；而在低位胃肠道肿瘤未发现表达 CK20 CK20阳性和阳性

30、和CK7CK7阴性强烈支持结肠原发肿瘤。阴性强烈支持结肠原发肿瘤。75759595 的结肠肿瘤呈现此染色模式的结肠肿瘤呈现此染色模式 肺癌仅有肺癌仅有9 91515 CK20CK20呈阳性，这有助于呈阳性，这有助于 肺内转移性腺癌原发灶的鉴别肺内转移性腺癌原发灶的鉴别精选67CUPHistologic Findings CK20CK20阴性和阴性和CK7CK7阳性将鉴别诊断缩小至肺癌、阳性将鉴别诊断缩小至肺癌、乳腺癌、胆管癌、胰腺癌、卵巢癌和子宫内膜乳腺癌、胆管癌、胰腺癌、卵巢癌和子宫内膜癌癌应用应用TTF-1TTF-1和表面活性物质脱辅基蛋白和表面活性物质脱辅基蛋白(surfactant a

31、poprotein)(surfactant apoprotein)可将原发性肺癌从可将原发性肺癌从其他其他CK7CK7阳性肿瘤中区分出来阳性肿瘤中区分出来精选68CUPHistologic Findings TTF-1TTF-1是一种是一种38kD38kD的含有同源结构域的核蛋白，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转录活化中起作用 TTF-1 TTF-1在肺癌和甲状腺癌呈典型阳性染色在肺癌和甲状腺癌呈典型阳性染色 有利于有利于对转移性颈部淋巴结肿大和转移性胸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

32、诊断腔积液的原发肿瘤的诊断精选69CUPHistologic 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 精选70CUPHistologic Findings Chromosomal studies:In cases of CUP with suspected oc

33、cult NPC,DNA amplification of Epstein Barr virus(EBV)in tissue may clinch the diagnosis精选71CUPHistologic 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精选72CUPHist

34、ologic 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精选73CUP The majority of CUP are adenocarcinomas or undifferentiated tumors(up to 58%in some studies)精选74CUP Less commonly,squamous cell carcinoma,melanoma,sarcoma,and neuroendocrine tumors can a

35、lso present as metastasis with an unknown primary site of origin精选75CUP Most studies exclude sarcomas and melanomas from their analysis精选76CUP In the approximately 30%of CUP,the most common epithelial malignancies are lung(15%),pancreas(13%),colon/rectum(6%),kidney(5%),and breast(4%)精选77CUP Sarcomas

36、,melanomas,and lymphomas each contribute 6-8%精选78CUP The remaining primary tumors are those of stomach(4%),ovary(3%),liver(3%),esophagus(3%),prostate(2%),and a variety of other malignancies(22%)精选79CUP Staging Patients with cancer of unknown primary origin are presumed to all have stage IV disease a

37、t the time of initial presentation精选80CUPCUPCUP表现为转移性疾病但未找到原发灶表现为转移性疾病但未找到原发灶精选81CUP原发灶隐匿的原因可能与以下因素有关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，于转移机体的免疫机制控制了原发灶，于转移后消失后消失 原发灶太小，不能被目前的检查方法所原发灶太小，不能被目前的检查方法所发现发现精选82CUPNaresh19假设认为假设认为原发灶血供改变使其生长受抑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

38、致转移性肿瘤迅血管表型的亚克隆出现，才导致转移性肿瘤迅速生长速生长在肿瘤发生过程中，转移灶发生于晚期的传统在肿瘤发生过程中，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新的数据提示，肿瘤发生早期即有转移倾向精选83CUPCUPCUP的原发性肿瘤极有可能从一开始就有的原发性肿瘤极有可能从一开始就有“预后不良预后不良”的特征的特征分子靶点和分子靶点和DNADNA微阵列在微阵列在CUPCUP诊断中的应诊断中的应用正在开展用正在开展揭示转移癌的发病机制揭示转移癌的发病机制促进新的治疗药物的开发促进新的治疗药物的开发精选84CUP代表肿瘤类型的、已知的原发性肿

39、瘤基代表肿瘤类型的、已知的原发性肿瘤基因引入诊断因引入诊断CUPCUP无足够的源于原发性肿瘤转移灶样品的无足够的源于原发性肿瘤转移灶样品的基因表达数据，尤其是低分化肿瘤基因表达数据，尤其是低分化肿瘤精选85CUPDNADNA微阵列与更大规模的免疫组化标记物微阵列与更大规模的免疫组化标记物和转移模式相结合和转移模式相结合提高预测提高预测CUPCUP起源位置的正确率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原发灶与其转移灶的基因转录谱的对比性研究性研究 精选86Thanks for your attention!精选87CUPTREATMENT(Medical Care)Multiple

40、organ involvement and poor performance status is grave 精选88CUPTREATMENT(Medical Care)The median survival is only 3-4 months The 1-year survival rate is less than 15%The 5-year survival of 5-10%精选89CUP Poor prognostic markers male sex multiple brain metastases pleural/lung involvement liver involveme

41、nt adrenal involvement adenocarcinoma histology 精选90CUP Favorable prognostic markers lymph node involvement neuroendocrine histology 精选91CUPTREATMENT(cervical lymph nodes)Upper aerodigestive tract,including direct visualization of the hypopharynx,nasopharynx,larynx,and upper esophagus精选92CUPTREATMEN

42、T Squamous Adenocarcinoma Melanoma Anaplastic tumors(间变性肿瘤)精选93CUPTREATMENTSquamous or undifferentiated carcinoma,tonsillectomies should be considered 精选94CUPTREATMENTCervical adenopathy can be the primary disease manifestation in 2-5%of patients with primary squamous cell carcinoma of the head and

43、neck region精选95CUPTREATMENTIn the absence of localization of a primary site,aggressive local therapy is indicated.This may involve any of the following:精选96CUPTREATMENT Radical radiation therapy with curative intent to the neck and possible site of origin 精选97CUPTREATMENT Preoperative radiation ther

44、apy followed by radical neck dissection Radical neck dissection Radical neck dissection followed by radiation to possible sites of origin精选98CUPTREATMENT Five-year survival rates as high as 30-50%have been achieved with this approach精选99CUPTREATMENT Role of chemotherapy is debated精选100CUPTREATMENTOn

45、e randomized study showed improved response rate and median survival with cisplatin and 5-fluorouracilbased chemotherapy when compared to radiation alone精选101CUPTREATMENT A single adenocarcinoma-involved lymph node in either the cervical or inguinal areas with no evidence of disease elsewhere may be

46、 managed with surgical excision alone and watchful expectation精选102CUPTREATMENT Radiation therapy to the involved and local fields may be provided as well精选103CUPTREATMENT Combination therapy may be superior to monotherapy with 5-year survival rates of 35%reported精选104CUPTREATMENT Metastatic adenoca

47、rcinoma presenting as isolated axillary lymphadenopathy in women is usually a manifestation of an occult breast primary cancer精选105CUPTREATMENT Mastectomy specimens in this subset of patients have shown a previously undiagnosed breast primary tumor in 40-70%cases精选106CUPTREATMENT Immunohistochemical

48、 stains with ER and PR should be performed in this setting,as they may aid in diagnosis精选107CUPTREATMENT Modified radical mastectomy with axillary node dissection has been advocated精选108CUPTREATMENT A study with 42 patients,however,showed improved survival with systemic chemotherapy and improved loc

49、al control with breast and axillary radiation精选109CUPTREATMENT 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精选110CUPTREATMENT Women with peritoneal carcinomatosis with adenocarcinoma

50、 have similarities with patients with ovarian cancer精选111CUPTREATMENT Papillary histology Elevation of CA 125 A good response to platinum-based chemotherapy But a primary tumor is not revealed on exploratory laparotomy精选112CUPTREATMENTMetastatic melanoma to a single nodal site5%of patients with mali