不明原发灶肿瘤的诊断

Metastatic CancerUnknown Primary Site,中国医学院肿瘤医院内科王宏羽,Metastatic CancerUnknown Primary Site,Synonyms and related keywords tumor of unknown primary cancer of unknown origin carcinoma of unknown origin unknown primary cancer,Metastatic CancerUnknown Primary Site, unknown primary carcinoma carcinoma of unknown primary origin,Metastatic CancerUnknown Primary Site, cancer of unknown primary site (cups) carcinoma of unknown primary origin (CUP),Metastatic CancerUnknown Primary Site, metastatic cancer metastatic carcinoma metastatic tumor metastases occult primary malignancy,CUP,Background(in the United States) 32,100 pats with CUPS in 2007 (15,720 males; 16,380 females) About 2% of all cancers,CUP, Deaths due to CUPS :45,230 (24,440 males; 20,790 females),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,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,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,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,CUP,Frequency United States:2-6% International:2-9%,CUP,Mortality/Morbidity Median survivalranges from 11 weeks to 11 months The 5-year overall survival rate is about 11%,CUP,Sex An approximate equal incidence for men and women,CUP,Age The median age on presentation for both men and women ranges from 59- 66 years,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,CUP,CLINICAL(Physical) The clinical presentation of cup is extremely variable Depends on the extent and type of organ involvement,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,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,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,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,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),CUP,CLINICAL(Physical) The most common sites of involvement being lung, bone, lymph nodes, and liver,CUP,CLINICAL(Physical) Including head and neck, rectal, testicular, pelvic, and breast examinations,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),CUP,CLINICAL(Physical, Lab and radiological studies )urinalysis (microscopic hematuria may be a sign of occult genitourinary malignancy),CUP,CLINICAL(Physical, Lab and radiological studies ) liver and renal function tests stool for occult blood chest radiograph,CUP,CLINICAL(Physical, Lab and radiological studies ) abdomen and pelvis CT mammography in women measurement of PSA in men,CUP,PhysicalAscites should lead one to evaluate for a GI or an ovarian primaryAn axillary mass in a female should make the clinician check for breast cancerA cervical node should lead to a thorough ENT examination,CUP,PhysicalA brain metastasis should lead to a search for a lung, breast, or kidney primaryBone metastasis should lead to evaluation for prostate, breast, lung, renal, or thyroid primary,CUP,PhysicalA testicular mass should lead to measurement of tumor markers such as beta-HCG and AFP,CUP,PhysicalDepending on the clinical situation, these may include chest CT, breast MRI, upper or lower endoscopy,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,CUP,CLINICAL(Physical) Diagnostic tonsillectomy may be warranted,CUP,CLINICAL(Physical)Intensive testing also adds to the morbidity for the weak and frail patient,CUP,CLINICAL(Physical) A large negative cost-to-benefit ratio exists for an extensive unguided clinical evaluation,CUP,CLINICAL(Physical) One study quoting a 9.5% increase in 1-year survival at a cost of 2-8 million dollars,CUP,CLINICAL(Physical)When these investigations fail to reveal a potential primary lesion, a cancer of unknown primary origin is assumed,CUP,WORKUP(Imaging Studies) 18F-FDG-PET is increasingly being used in the evaluation of metastatic malignancies,CUP,WORKUP(Imaging Studies) This may be especiallythe case in suspected head and neck malignancies,CUP,WORKUP(Imaging Studies) This testing lacks specificity and may only be useful to identify promising sites for biopsy,CUP,WORKUP(Imaging Studies)18氟-脱氧葡萄糖(18F-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,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,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,CUP,Other Tests Most tumor markers are nonspecific It may not be used to establish definitive diagnoses,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HCCB-HCG和AFP水平并不能预测化疗效果或生存期,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,CUP,Procedures A biopsy of the metastatic site A careful evaluation of the pathology,CUP,Histologic Findings The pathologist has an indispensable role in the evaluation of CUP,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,CUP,Histologic Findings Various immunoperoxidase(免疫过氧化物酶) stains are available for providing a differential diagnosisfor CUP,CUP,Histologic Findings Appropriate DNA microarray(微阵列) techniques and proteonomic(蛋白质组学 ) studies to establish a definitive diagnosis,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,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,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,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,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,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,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,CUP,Histologic Findings Puts the tissue specimen through 1-4 steps, depending on the need,CUP,Histologic Findings light microscopy Immunohistochemical stains Electron microscopy Chromosomal analysis including cytogenetics,CUP,Histologic Findings Light microscopy: epithelial cancers, lymphomas, sarcomas, melanomas, or germ cell tumors,CUP,Histologic Findings When cytologic distinguishing features are limited, the tumor may be classified as undifferentiated or poorly differentiated carcinoma,CUP,Histologic Findings Immunohistochemistry: These tests help define tumor lineage by using peroxidase-labeled antibody against specific tumor antigens,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),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。7595 的结肠肿瘤呈现此染色模式 肺癌仅有915 CK20呈阳性，这有助于 肺内转移性腺癌原发灶的鉴别,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,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,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,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,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,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,CUP, The majority of CUP are adenocarcinomas or undifferentiated tumors (up to 58% in some studies),CUP, Less commonly, squamous cell carcinoma, melanoma, sarcoma, and neuroendocrine tumors can also present as metastasis with an unknown primary site of origin,CUP, Most studies exclude sarcomas and melanomas from their analysis,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%),CUP, Sarcomas, melanomas, and lymphomas each contribute 6-8%,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%),CUP, Staging Patients with cancer of unknown primary origin are presumed to all have stage IV disease at the time of initial presentation,CUP,CUP表现为转移性疾病但未找到原发灶,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,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,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,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,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,Thanks for your attention!,CUP,TREATMENT(Medical Care) Multiple organ involvement and poor performance statusis grave,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%,CUP,Poor prognostic markers male sex multiple brain metastases pleural/lung involvement liver involvement adrenal involvement adenocarcinoma histology,CUP,Favorable prognostic markers lymph node involvement neuroendocrine histology,CUP,TREATMENT( cervical lymph nodes) Upper aerodigestive tract, including direct visualization of the hypopharynx, nasopharynx, larynx, and upper esophagus,CUP,TREATMENT Squamous Adenocarcinoma Melanoma Anaplastic tumors(间变性肿瘤),CUP,TREATMENTSquamous or undifferentiated carcinoma, tonsillectomies should be considered,CUP,TREATMENTCervical adenopathy can be the primary disease manifestation in 2-5% of patients with primary squamous cell carcinoma of the head and neck region,CUP,TREATMENTIn the absence of localization of a primary site, aggressive local therapy is indicated. This may involve any of the following:,CUP,TREATMENT Radical radiation therapy with curative intent to the neck and possible site of origin,CUP,TREATMENT Preoperative radiation therapy followed by radical neck dissection Radical neck dissection Radical neck dissection followed by radiation to possible sites of origin,CUP,TREATMENT Five-year survival rates as high as 30-50% have been achieved with this approach,CUP,TREATMENT Role of chemotherapy is debated,CUP,TREATMENTOne randomized study showed improved response rate and median survival with cisplatin and 5-fluorouracilbased chemotherapy when compared to radiation alone,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,CUP,TREATMENT Radiation therapy to the involved and local fields may be provided as well,CUP,TREATMENT Combination therapy may be superior to monotherapy with 5-year survival rates of 35% reported,CUP,TREATMENT Metastatic adenocarcinoma presenting as isolated axillary lymphadenopathy in women is usually a manifestation of an occult breast primary cancer,CUP,TREATMENT Mastectomy specimens in this subset of patients have shown a previously undiagnosed breast primary tumor in 40-70% cases,CUP,TREATMENT Immunohistochemical stains with ER and PR should be performed in this setting, as they may aid in diagnosis,CUP,TREATMENT Modified radical mastectomy with axillary node dissection has been advocated,CUP,TREATMENT A study with 42 patients, however, showed improved survival with systemic chemotherapy and improved local control with breast and axillary radiation,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,CUP,TREATMENT Women with peritoneal carcinomatosis with adenocarcinoma have similarities with patients with ovarian cancer,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,CUP,TREATMENTMetastatic melanoma to a single nodal site5% of patients with malignant melanoma may present with nodal metastasis in the absence of a documented primary site,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,CUP,TREATMENTPoorly differentiated and undifferentiated carcinoma1/3 CUP Can be potentially curable Includes lymphomas, germ cell tumors, or neuroendocrine tumors,CUP,TREATMENTThe features that point toward a treatment-responsive tumor include the following:Patient younger than 50 years Midline distribution, with elevated levels of beta-HCG or AFP,CUP,TREATMENT Beta-HCG/AFP positive on immunohistochemistry Neuroendocrine granules Rapid tumor growth Iso-chromosome 12p in midline tumors,CUP,TREATMENTPlatinum-based combination CT regimens specific for germ cell tumorsRR 63%, CR 26%10-year survival rates 16%,CUP,TREATMENT (Poorly differentiated neuroendocrine carcinomas)Positive histochemical stains for chromogranin(嗜铬铁蛋白) or NSEOften present with extensive liver or bone metastases,CUP,TREATMENT 29 patients,19 were treated with intensive cisplatin-based CT 6 others received doxorubicin-based combinations CR in 6 patients 4 of these patients were alive 19-100 months after diagnosis,CUP,TREATMENT(Inguinal node metastasis) 1-3.5% Squamous cell histology in this area is usually metastatic from the genital/anorectal area The anorectal area should be carefully inspected in both sexes,CUP,TREATMENT Inguinal node metastasisVulvar, vaginal, and cervical examination in women and penile examination in men is warranted,CUP,TREATMENT Treatment can involve groin dissection alone o