不明原發(fā)灶腫瘤的診斷

1、Metastatic CancerUnknown Primary Site,中國(guó)醫(yī)學(xué)院腫瘤醫(yī)院內(nèi)科王宏羽,,Metastatic CancerUnknown Primary Site,Synonyms and related keywords ◆ tumor of unknown primary ◆ cancer of unknown origin ◆ carcinoma of unknown origin ◆ u

2、nknown primary cancer,,Metastatic CancerUnknown Primary Site,◆ unknown primary carcinoma ◆ carcinoma of unknown primary origin,,Metastatic CancerUnknown Primary Site,◆ cancer of unknown primary site

3、 (cups) ◆ carcinoma of unknown primary origin (CUP),,Metastatic CancerUnknown Primary Site,◆ metastatic cancer ◆ metastatic carcinoma ◆ metastatic tumor ◆ metastases ◆ occult primary malignancy,

4、,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 di

5、screpancy between incidence and mortality is believed to be due to a lack of specificity in the listing of cause of death on death certificates,,CUP,◆ Its true incidence is most probably between 2% and 6% ◆

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 ◆For

7、ms 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

8、 presentation of CUP,,CUP,Frequency◆ United States:2-6% ◆ International:2-9%,,CUP,Mortality/Morbidity◆ Median survival ranges from 11 weeks to 11 months◆ The 5-year overall survival rate is ab

9、out 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 wi

10、th 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

11、is extremely variable◆ Depends on the extent and type of organ involvement,,CUP,◆ 一群異源發(fā)生的腫瘤◆除外淋巴瘤、轉(zhuǎn)移性黑色素瘤和轉(zhuǎn)移 性肉瘤 ◆集中于上皮細(xì)胞組織，包括腺癌、鱗 狀上皮細(xì)胞癌、分化不良上皮癌和神 經(jīng)內(nèi)分泌癌,,CUP,CUP的診斷標(biāo)準(zhǔn)◆組織活檢證實(shí)為惡性腫瘤(活檢部位不能檢出原發(fā)灶)◆經(jīng)過(guò)

12、徹底地收集病史或物理檢查(包括女性盆腔檢查和男性睪丸及前列腺觸診)未發(fā)現(xiàn)原發(fā)性腫瘤,,CUP,◆ CUP實(shí)驗(yàn)室檢查結(jié)果正常，包括完整的血細(xì)胞計(jì)數(shù)、血液生化、胸部X線、腹部和盆腔CT、乳房影像學(xué)檢查或前列腺特異性抗原(PSA)檢查等等,,CUP,CLINICAL◆完整的病史和徹底的體格檢查是診斷CUP的基本前提，尤其是既往組織活檢結(jié)果◆家族史很可能提示遺傳性非息肉病性結(jié)腸癌或乳腺癌易感性,,CUP,◆徹底的體檢可能會(huì)發(fā)現(xiàn)特異性原發(fā)腫瘤

13、◆左側(cè)鎖骨上淋巴結(jié)腫大(Virehow’S結(jié)節(jié))(胃Ca?)◆臍周淋巴結(jié)腫大或包塊(Sister Mary Josph’S結(jié)節(jié)-由惡性腹水造成的腹脹以及臍周腫塊{臍孔腫大變硬,產(chǎn)生冰山樣臍部腫塊})(低分化癌-胃腸道)◆腹股溝淋巴結(jié)腫大、肛周包塊(肛門腫瘤),,CUP,CLINICAL(Physical)◆ The most common sites of involvement being lung, bone, lymph

14、 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 deficie

15、ncy 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 ma

16、lignancy),,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 C

17、T◆ 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 cervi

18、cal 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, rena

19、l, 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, up

20、per 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 i

21、n 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 ne

22、gative 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)◆W

23、hen 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 mali

24、gnancies,,CUP,WORKUP(Imaging Studies)◆ This may be especially the case in suspected head and neck malignancies,,CUP,WORKUP(Imaging Studies)◆ This testing lacks specificity and may only be useful to i

25、dentify promising sites for biopsy,,CUP,WORKUP(Imaging Studies)◆18氟-脫氧葡萄糖(18F-FDG)-PET可輔助指導(dǎo)活組織檢查，確定疾病程度和輔助選擇恰當(dāng)?shù)闹委?,CUP,WORKUP(Imaging Studies)◆ Although promising, high cost and false positive rates of 20% limit its ut

26、ility 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

27、,,CUP,Other Tests◆ Most tumor markers are nonspecific ◆ It may not be used to establish definitive diagnoses,,CUP,Other Tests◆男性腺癌和骨轉(zhuǎn)移，常規(guī)檢查血清PSA◆男性未分化癌和低分化癌，檢測(cè)B-HCG和AFP,AFP也用于診斷HCC◆B-HCG和AFP水平并不能預(yù)測(cè)化療效果或生存期,,CU

28、P,Other Tests◆ CEA、CA125、CA19-9和CA15-3對(duì)于確定原發(fā)灶沒(méi)有幫助◆大多數(shù)血清腫瘤標(biāo)記物是非特異性的，可判斷預(yù)后,,CUP,Procedures◆ A biopsy of the metastatic site ◆ A careful evaluation of the pathology,,CUP,Histologic Findings◆ The pathologist has an ind

29、ispensable role in the evaluation of CUP,,CUP,Histologic Findings◆ Needle biopsy specimens may provide insufficient tissue for diagnosis or provide tissue that has been too damaged or distorted by the biopsy p

30、rocedure for accurate diagnosis,,CUP,Histologic Findings◆ Various immunoperoxidase(免疫過(guò)氧化物酶) stains are available for providing a differential diagnosis for CUP,,CUP,Histologic Findings◆  Appropriate DNA micro

31、array(微陣列) techniques and proteonomic(蛋白質(zhì)組學(xué) ) studies to establish a definitive diagnosis,,CUP,Histologic Findings◆  如果查不到原發(fā)腫瘤，要想確定各種CUP患者的治療策略和判斷預(yù)后是非常困難的,,CUP,Histologic Findings◆免疫組化和影像學(xué)聯(lián)合檢查的診斷率約為20％-30％◆目前認(rèn)為

32、,最有前途的可提高診斷率的方法是腫瘤的分子診斷?，F(xiàn)有的基因表達(dá)數(shù)據(jù)庫(kù)對(duì)于CUP的診斷極有幫助,,CUP,Histologic Findings◆預(yù)警基因分為兩類，一類是在某些起源組織中特異性表達(dá)的基因，另一類是在各種腫瘤中均有異常表達(dá)的基因,,CUP,Histologic Findings◆ 一批源于l0種普通腫瘤的100個(gè)原發(fā)癌樣品，用110個(gè)在這些腫瘤中表達(dá)最低的基因開(kāi)發(fā)了一個(gè)預(yù)警芯片。對(duì)另外75個(gè)盲樣(包括l2個(gè)轉(zhuǎn)移癌樣品)進(jìn)

33、行檢驗(yàn)，預(yù)測(cè)腫瘤原發(fā)灶的正確率大于90％，12個(gè)轉(zhuǎn)移癌中有l(wèi)1個(gè)被正確分類,,CUP,Histologic Findin◆對(duì)218個(gè)腫瘤(14個(gè)普通類型)組織和90個(gè)正常組織樣品的寡核苷酸微陣列基因表達(dá)進(jìn)行分析，用16 063個(gè)基因表達(dá)的相對(duì)水平和表達(dá)基因的序列標(biāo)簽開(kāi)發(fā)了一個(gè)基因預(yù)警芯片,,CUP,Histologic Findin◆ 對(duì)54個(gè)腫瘤樣品(其中8例轉(zhuǎn)移性腫瘤)檢測(cè)，總的預(yù)測(cè)正確率是78％ ，轉(zhuǎn)移性腫瘤中有6例被正確識(shí)別

34、出原發(fā)部位◆提示腫瘤保留其組織起源標(biāo)記物是貫穿于轉(zhuǎn)移過(guò)程的始終,,CUP,Histologic Findings◆引用一系列基因表達(dá)庫(kù)的分析數(shù)據(jù)和相關(guān)腫瘤標(biāo)記物的文獻(xiàn)資料確定了61個(gè)基因?yàn)楹蜻x腫瘤基因，以其表達(dá)模式預(yù)測(cè)起源位置。用反轉(zhuǎn)錄PCR對(duì)原發(fā)性腺癌樣品(包括乳腺、卵巢、胃、胰腺和肺)檢測(cè)了其中11個(gè)基因，7個(gè)(64％)基因存在組織特異性◆這些組織限制性腫瘤標(biāo)志物能夠用于CUP原發(fā)性腫瘤可能位點(diǎn)的預(yù)測(cè),,CUP,Histolo

35、gic 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 cyt

36、ogenetics,,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

37、 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 tum

38、or 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 hepato

39、mas), ER, PR, and Her-2 (for breast cancer),,CUP,Histologic Findings ◆ CK20在胃腸道上皮、泌尿道上皮和Merkel細(xì)胞中表達(dá) ◆ CK7在肺癌、卵巢癌、子宮內(nèi)膜癌和乳腺癌中有表達(dá)；而在低位胃腸道腫瘤未發(fā)現(xiàn)表達(dá) ◆ CK20陽(yáng)性和CK7陰性強(qiáng)烈支持結(jié)腸原發(fā)腫瘤。75％～95％ 的結(jié)腸腫瘤呈現(xiàn)此染色模式 ◆ 肺癌僅有9％～15％ CK20呈陽(yáng)性，這有助于

40、 肺內(nèi)轉(zhuǎn)移性腺癌原發(fā)灶的鑒別,,CUP,Histologic Findings ◆CK20陰性和CK7陽(yáng)性將鑒別診斷縮小至肺癌、乳腺癌、膽管癌、胰腺癌、卵巢癌和子宮內(nèi)膜癌◆應(yīng)用TTF-1和表面活性物質(zhì)脫輔基蛋白(surfactant apoprotein)可將原發(fā)性肺癌從其他CK7陽(yáng)性腫瘤中區(qū)分出來(lái),,CUP,Histologic Findings◆ TTF-1是一種38kD的含有同源結(jié)構(gòu)域的核蛋白，在甲狀腺、中腦和呼吸道

41、上皮胚胎發(fā)生過(guò)程的轉(zhuǎn)錄活化中起作用◆ TTF-1在肺癌和甲狀腺癌呈典型陽(yáng)性染色◆ 有利于對(duì)轉(zhuǎn)移性頸部淋巴結(jié)腫大和轉(zhuǎn)移性胸腔積液的原發(fā)腫瘤的診斷,,CUP,Histologic Findings ◆ Electron microscopy: This study has limited utility in identification of the primary site of cancer of unknown p

42、rimary 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

43、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 wit

44、h CUP,,CUP,Histologic Findings◆生殖細(xì)胞腫瘤有特征性的細(xì)胞遺傳學(xué)改變(等臂染色體12p-i[12p] ◆拷貝數(shù)增加或12號(hào)染色體長(zhǎng)臂缺如◆與無(wú)染色體異常的患者相比，生殖細(xì)胞腫瘤有染色體異常的患者對(duì)順鉑為主的化療有更好的反應(yīng),,CUP,◆ The majority of CUP are adenocarcinomas or undifferentiated tumors (up to 58% in so

45、me 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 melan

46、omas 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

47、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 wi

48、th cancer of unknown primary origin are presumed to all have stage IV disease at the time of initial presentation,,CUP,◆CUP表現(xiàn)為轉(zhuǎn)移性疾病但未找到原發(fā)灶,,CUP,◆原發(fā)灶隱匿的原因可能與以下因素有關(guān)機(jī)體的免疫機(jī)制控制了原發(fā)灶，于轉(zhuǎn)移后消失原發(fā)灶太小，不能被目前的檢查方法所發(fā)現(xiàn),,CUP,Naresh[19]假

49、設(shè)認(rèn)為◆原發(fā)灶血供改變使其生長(zhǎng)受抑◆在內(nèi)臟，轉(zhuǎn)移灶可能處于靜止期，直到有生成血管表型的亞克隆出現(xiàn)，才導(dǎo)致轉(zhuǎn)移性腫瘤迅速生長(zhǎng)◆在腫瘤發(fā)生過(guò)程中，轉(zhuǎn)移灶發(fā)生于晚期的傳統(tǒng)理論正受到質(zhì)疑◆新的數(shù)據(jù)提示，腫瘤發(fā)生早期即有轉(zhuǎn)移傾向,,CUP,◆CUP的原發(fā)性腫瘤極有可能從一開(kāi)始就有“預(yù)后不良”的特征◆分子靶點(diǎn)和DNA微陣列在CUP診斷中的應(yīng)用正在開(kāi)展◆揭示轉(zhuǎn)移癌的發(fā)病機(jī)制◆促進(jìn)新的治療藥物的開(kāi)發(fā),,CUP,◆代表腫瘤類型的、已知的原發(fā)

50、性腫瘤基因引入診斷CUP◆無(wú)足夠的源于原發(fā)性腫瘤轉(zhuǎn)移灶樣品的基因表達(dá)數(shù)據(jù)，尤其是低分化腫瘤,,CUP,◆DNA微陣列與更大規(guī)模的免疫組化標(biāo)記物和轉(zhuǎn)移模式相結(jié)合◆提高預(yù)測(cè)CUP起源位置的正確率◆原發(fā)灶與其轉(zhuǎn)移灶的基因轉(zhuǎn)錄譜的對(duì)比性研究,Thanks for your attention!,,CUP,TREATMENT(Medical Care) ◆ Multiple organ involvement and poor perfo

51、rmance status is grave,,CUP,TREATMENT(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%,,CUP,Poor prognostic markers

52、◆ male sex ◆ multiple brain metastases ◆ pleural/lung involvement ◆ liver involvement ◆ adrenal involvement ◆ adenocarcinoma histology,,CUP,Favorable prognostic markers ◆lymph node involvement ◆neuroendocrine his

53、tology,,CUP,TREATMENT( cervical lymph nodes) ◆ Upper aerodigestive tract, including direct visualization of the hypopharynx, nasopharynx, larynx, and upper esophagus,,CUP,TREATMENT◆ Squamous◆ Adenocarcinoma◆ Melanoma

54、◆ Anaplastic tumors(間變性腫瘤),,CUP,TREATMENT◆Squamous or undifferentiated carcinoma, tonsillectomies should be considered,,CUP,TREATMENT◆Cervical adenopathy can be the primary disease manifestation in 2-5% of patients w

55、ith primary squamous cell carcinoma of the head and neck region,,CUP,TREATMENT◆In the absence of localization of a primary site, aggressive local therapy is indicated. This may involve any of the following:,,CUP,TREATME

56、NT◆ 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

57、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,,

58、CUP,TREATMENT◆One randomized study showed improved response rate and median survival with cisplatin and 5-fluorouracil—based chemotherapy when compared to radiation alone,,CUP,TREATMENT◆ A single adenocarcinoma-involve

59、d  lymph 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

60、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 is

61、olated 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 t

62、umor 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

63、 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

64、◆ 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 carc

65、inomatosis 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

66、tumor is not revealed on exploratory laparotomy,,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 documen

67、ted 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,TREATMEN

68、T◆Poorly differentiated and undifferentiated carcinoma◆1/3 CUP ◆ Can be potentially curable◆ Includes lymphomas, germ cell tumors, or neuroendocrine tumors,,CUP,TREATMENT◆The features that point toward