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病理-IHC免疫組織染色

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病理-IHC免疫組織染色

  1. 1. Gem Wu 吳懷玨 整理 2017/11/3 【病理】 免疫組織化學染色 Immunohistochemistry (IHC)
  2. 2. 看病理報告,完全不知道在說什麼,怎麼辦? “CK7-/CK20+, TTF1-, CK17+…”
  3. 3. Pathologist’s H&E is like the clinician’s H&P Special studies like IHC could be performed
  4. 4. Purpose of IHC Purpose 目的 Example Classification of tumors 區分腫瘤 carcinoma vs. lymphoma B cell vs. T cell lymphoma in situ lesions vs. invasive carcinomas 原位癌 或 侵襲癌 myoepithelial markers in breast cancers basal cell markers in prostate Prognostic factors 預後因子 Ki-67 in glioblastomas (GBM) Predictive factors for specific therapy 標靶治療效果預測 c-KIT ER, PR, HER2/neu Identification of extracellular material 胞外物質 β-2 microglobulin amyloid Identification of infectious agents 傳染性物質 CMV or HSV [整理自: Susan Lester, Manual of Surgical Pathology 3e]
  5. 5. IHC applications -1 Application Tumor markers Histological typing Carcinoma Cytokeratin Sarcoma Vimentin Glial tumor GFAP Melanoma HMB-45, Melan-A Lymphoma LCA Differentiation Sarcoma Liposarcoma S-100 Angiosarcoma CD31 factor VIII Leiomyo- sarcoma SMA Rhabdomyo- sarcoma Desmin [Note from Ming-Yuan Lee, M.D.’s Lecture] Application Tumor/site Markers Organ specific Thyroid Thyroglobulin prostate PSA Lung, thyroid TTF-1 Sub- classification B-cell CD20, CD79a T-cell CD3, CD5, CD43 NK cell CD56 Myeloid series MPO Infectious disease - CMV Lung PJP
  6. 6. IHC applications -2 Application Tumor markers Secretion or tumor products Adenocarcinoma CEA Neuroendocrine tumor Synaptophysin, insulin, gastrin Breast tumor BRST-2 HCC α-fetoprotein, Hepar-1 Choriocarcinoma β-HCG Yolk sac tumor or embryonal carcinoma α-fetoprotein Biological factors for prognostic values (Proliferation index) Ki-67 (anti-apoptotic factor) Bcl-2 (Poor prognosis) Her2 [Note from Ming-Yuan Lee, M.D.’s Lecture] Application Treatment marker s Therapy Tamoxifen ER/PR Herceptin HER2 Gleevec CD117 Erlotinib (Tarceva®) EGFR Pem- brolizumab PD-L1 不同的organ, standard不同 Lymphoma 50% Ki-67+可能只是moderate, 但breast可能就是high
  7. 7. Tumor sites 各別來看看不同地方的carcinoma可能會有哪些IHC
  8. 8. Carcinoma: CK7, CK20 CK7+ CK20+ Lung adenoCA Breast ductal, lobular CA Ovary, uterus, cervix colorectal adenoCA CK7+/CK20+ Transitional cell CA Pancreatic cancer cholangiocarcinoma CK7-/CK20- SqCC (lung, HEENT), lung Small cell CA, HCC, RCC, prostate, adrenal cortical CA thyroid Ligament of Treitz
  9. 9. Organ specific markers of carcinoma Breast Cancer – IHC有助規劃Treatment IHC result ER/PR HER2/neu Positive 70-80% 15-20% Borderline 5-10% 25-35% Negative 20-30% 70% [來自: Susan Lester, Manual of Surgical Pathology 3e] HER2/neu+ → 可用Herceptin治療 ↓ HER2/neu+用IHC(左)與ISH(右) Other markers: (如果不確定可以三個一起染) GCDFP-15, mammaglobin, GATA3… [Arch Pathol Lab Med. 2016;140:508–523; doi: 10.5858/arpa.2015-0173-CP)]
  10. 10. Organ specific markers of carcinoma Lung Cancer – IHC分辨不同類型 tumor CK7 CK20 TTF-1 P63 Chromogranin Adenocarcinoma 90+% 10-40% 60-90% 10-40% <10% Bronchioloalveolar carcinoma — nonmucinous 90+% 10-40% 60-90% 60-90% <10% Bronchioloalveolar carcinoma — mucinous 60-90% 60-90% 10-40% <10% Squamous cell carcinoma 10-40% <10% <10% 90+% <10% Large cell carcinoma 60-90% 10-40% 40-60% 40-60% <10% Small cell carcinoma 10-40% <10% 90+% <10% 40-60% Carcinoid tumor 40-60% <10% 10-40% <10% 90+% Metastatic colon carcinoma 90+% 10-40% <10% <10% <10% Metastatic breast carcinoma 90+% <10% <10% <10% <10% 通常會染TTF-1來確認lung origin,但總有些例外… [整理自: Susan Lester, Manual of Surgical Pathology 3e] Neuroendocrine tumor marker
  11. 11. Organ specific markers of carcinoma GI tract Cancer v. GYN cancer – 確認origin CDX2 is expressed in virtually 100% of colorectal adenocarcinomas. (除了MSI – microsatellite unstable genotype外) tumor CK7 CK20 MUC2 CDX2 WT-1 Stomach 60-90% 40-60% 40-60% 40-60% 40-60% pancreas 90+% 60-90% 90+% 40-60% 40-60% appendix 10-40% 90+% 90+% 90+% - Colon <10% 90+% 60-90% 90+% 60-90% Uterus 90+% 10-40% <10% 10-40% 40-60% Ovary, serous 90+% 10-40% 10-40% 40-60% 60-90% Ovary, mucinous 90+% 60-90% 10-40% 40-60% 10-40% Breast, no special type (NST) 90+% <10% 10-40% <10% 10-40% Breast, mucinous 90+% 10-40% 90+% - 60-90% [整理自: Susan Lester, Manual of Surgical Pathology 3e] 1 2 3 4 5 6 PAX-8是Müllerian duct轉錄因子,因此許多GYN tumor會表現,也可以此區別mets的breast CA v. primary
  12. 12. Organ specific markers of carcinoma Liver Cancer – 區分primary或metastasis Hep-Par 1 Ab, arginase-1 比傳統的 α-FP更sensitive與specific for HCC [圖來自: Susan Lester, Manual of Surgical Pathology 3e] Hepatoplastoma Cholangiocarcinoma ? ?CK7+, AE1/AE3+, keratin HMW+ 一般來說,liver primary cancer會有CAM5.2+, CK20-, CEA+ CD10+ cirrhosis (65-90%) ↓ HBV+ (50%) α-FP+, HEP+ CDX2+ HEP+ [Arch Pathol Lab Med. 2016;140:508–523; doi: 10.5858/arpa.2015-0173-CP)]
  13. 13. Other markers for carcinomas Prostate CA (NKX3.1) (PSA) TCC (GATA3) (Uroplakin) (p63, p40) RCC (PAX2) (PAX8) Thyroid papillary, follicular CA (Thyroglobulin) (PAX8) Most thyroid CA (TTF-1) adrenal CA (inhibin-α) (Melan-A) (Steroidogenic factor 1) SqCC (not organ specific) (p63+, p40+) (CK5)[Arch Pathol Lab Med. 2016;140:508–523; doi: 10.5858/arpa.2015-0173-CP)]
  14. 14. 一些小練習 要開始囉
  15. 15. Case 1 • Ex-smoker • Biopsy from left lower lobe of lung • w/ Hx of biopsy proven colon CA • Dx? CK20+++H&E CDX2+++ TTF1- (CK7-) [Arch Pathol Lab Med. 2016;140:508–523; doi: 10.5858/arpa.2015-0173-CP)]
  16. 16. [CASE2] 63M, no known primary carcinoma, CCx cervical lymphadenopathy, this is the result of FNA of the node: CK7-, CK20-, TTF1-, CDX2-, PSA+++, Villin-. Dx? [CASE3] 73F, hx hysterectomy for unknown reason, CCx retroperitoneal lymphadenopathy, image showed left pelvic sidewall mass probably residual ovary. this is the FNA result: ER++, WT++, PAX+++, CK7+++, CK20-, GATA3-, CDX2-, p63-. Dx? [Arch Pathol Lab Med. 2016;140:508–523; doi: 10.5858/arpa.2015-0173-CP)]
  17. 17. Lymphoma太難QAQ 請更專業的來吧…
  18. 18. 最後幾點原則 1. 看不懂報告,自己查資料也不懂的話,還是要請教病理專業! 2. IHC不是絕對,positive與negative的出現也有其機率,不能妄 下診斷。 3. 遇到奇怪的marker表現,或異常不表現,還是可以去survey一 下其他器官。小心駛得萬年船。

Editor's Notes

  • 最重要的就這句:Pathologist’s H&E is like the clinician’s H&P
  • 更詳細的DDx有時需要區分不同的immuno-markers,以sarcoma為例:
    Liposarcoma易local recurrence,是否要有adjuvant RT要再評估
    Angiosarcoma易distant metastasis,要追蹤其他organ system的狀況
    Leiomyosarcoma在子宮的預後不錯,但其他soft tissue就不然
    Rhabdomyosarcoma就需要Chemotherapy
    有時得到一個更詳細的診斷,有助於治療的規劃
  • 記marker很易忘,但大原則是:
    不應一股腦兒全部都染,成本太高,也影響解讀。如果臨床H&P詳細,病理也不會太辛苦。
    不同的tumor可能會表現不同種的tumor marker,像是同樣是lung cancer,adenoma和small cell lung CA的表現就不同
    不同的tumor也可能會有同種tumor marker,像colon CA和pancreatic cancer (colon subtype)
    基於上述三原則,應該要視每個site的可能tumor來解讀IHC,也會因著H&E的形狀而多做些染色,像是針對 gastrin, insulin等secretion product

    至於應用在therapy的IHC,有些target therapy極貴,做了test得到positive result的後續治療花費動輒十萬百萬;有些人很可能因為target therapy可多延幾個月就傾家盪產地去接受治療。也因此,臨床醫師與病理醫師也需要考量Social economic factors。
  • 就算大概念是這樣,但總是有例外! 不是所有的TCC都是double CK positive!!
    Colorectal adenocarcinoma也有5%的不是CK7-/CK20+!
  • Breast CA主要是因為有target therapy,除了分invasive還是CIS以外 (for surgical purpose),可配搭tumor marker specific的用藥,像是tamoxifen (for ER+/PR+)與Herceptin (Her2/neu)。
  • 基本上除了SqCC以外的primary lung cancer會表現TTF-1,因此可以大致上區分metastasis與primary
    常見的adenocarcinoma就看CK7+/CK20-, TTF1+
    SqCC可以看p63
    Carcinoid tumor可以看chromogranin和synaptophysin
    有些metastasis的tumor會帶有原本cancer的一些marker,此時需要review clinical Hx,再來看要染什麼IHC
  • Ligament of Treitz以上的GI organ (stomach, pancreas)基本上是CK7+, 以下 (colon, appendix)的偏CK7-/CK20+
    Stomach有CK7+-/CK20+-的各種組合,比較不定
    Pancreas大多是CK7+/CK20+
    GYN organ大部份是CK7+/CK20-, 除了ovary, mucinous比較多CK20+外
    Colon CA的CDX2是個重要的參考指標
    WT-1在某些GYN tumor非常sensitive
  • aFP除了HCC以外,還有可能出現在germ cell tumor與一些aFP producing的tumor,因此會說它不是那麼地specific。Hep-Par 1在應用上會更為準確,只是poorly differentiated 的HCC可能就沒有辦法。
  • 這只是個大略的圖,有些marker的specificity不好,有些sensitivity不好,出現positive的佔比也不同,應該還是要參考研究資料,或直接詢問專家。
    以病理的角度來看,如果IHC還是有疑慮,其實還是要再回來看H&E (pathologist的H&P),甚至是clinical profile (就是H&P啦)。
  • Colorectal adenocarcinoma metastasis to lung, 如果是lung adenocarcinoma enteric subtype的話,的確會有CK20+, CDX2+, 但它的CK7也會是+。
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