子宮頸鱗狀上皮癌為女性癌症的第五位，因子宮頸抹片篩檢的推行，子宮頸侵襲性鱗狀上皮癌發生率已逐年下降，相對子宮頸腺癌發生率則在上昇，同時子宮內膜腺癌發生率也有上昇的趨勢。大多數子宮頸腺癌及子宮內膜腺癌的個案，可以做出明確的診斷，但在檢體較少的切片或腫瘤位於子宫下段與子宮內頸交界時，區別是子宮頸或子宮內膜腺癌則有其困難性，但兩者開刀治療方式卻絕然不同，所以正確的診斷及區分此兩種腺癌有其臨床重要性。
傳統的子宮頸抹片主要用來偵測子宮頸上皮病變，包括鱗狀上皮及腺體細胞病變。但在子宮頸抹片中單用細胞形態學不足以區分腺體細胞病變是來自子宮頸或子宮內膜。我們進一步用五種免疫染色來幫忙鑑別診斷子宮頸或子宮內膜腺癌。
本研究收集了37例病理切片証實為子宮頸腺癌或子宮內膜癌的子宮頸抹片，發現當細胞呈聚合型排列且核大小差異有三倍大時，較偏向子宮頸腺體細胞病變。
使用的五個免疫染色標記包括CK-2，p16，CK34ßE12，bcl-2 及Ki-67。子宫頸腺癌p16核染色陽性率及Ki-67核染色陽性率較子宮內膜癌高 (p=0.02 及 p<0.0001)。p16及Ki-67核染色陽性，其陽性概似比分別為7.4及2.8。CK-2 ，CK34ßE12，bcl-2的表現在這兩種腺癌皆無明顯差異。
此研究顯示子宮頸抹片的細胞形態學及在小檢體中利用p16及Ki-67免疫染色對鑑別診斷子宮頸腺癌及子宮內膜癌有幫忙。

Cervical squamous cell carcinoma is the fifth cause of death in female cancers in Taiwan. The incidence and mortality of cervical cancer are decreased in the last decades in most developed countries, including Taiwan, because of the effectiveness of the cytology screening programs. By contrast, the incidence and mortality of cancers of uterine corpus are slowly increasing. In most situation, the diagnosis for endometrial or endocervical adenocarcinoma is straightforward. However, the diagnosis of adenocarcinoma from endometrial or endocercival origin sometimes is difficult, when few tissue fragments are obtained from endocervical curreting or biopsy specimens, and from the tumor located at the interface between endocervical canal and lower uterine segment.The surgical protocol for endometrial adenocarcinoma or endocervical adenocarcinoma is different. Therefore, the correct diagnosis is important in clinical practice.
Conventional Pap smear is developed for detecting the cervical abnormalities including squamous and glandular lesions. However, only use of the cytomorphology of the glandular lesions in Pap smears is not sufficient to differentiate the cell origin of endocervix form endometrium. We further use five immunostain markers to help the differential diagnosis between endocervical adenocarcinoma and endometrial adenocarcinoma.
In this study, we collected and reviewed 37 Pap smears which are diagnosed as endometrial or endocervical adenocarcinomas in surgical specimens. The results showed the syncytial arragement and the nuclear size variation with three fold difference are more common in endocervical glandular lesions.
The pannel of five immunostain markers includes CK-2, p16, 34ßE12, bcl-2 and Ki-67.The positive rates of nuclear staining of p16 and Ki-67 are higher in endocervical adenocarcinomas than endometrial adenocarcinomas (p=0.02 and p&lt;0.0001, respectively). The positive likelihood ratio of nuclear p16 and Ki-67staining are 7.4 and 2.8 respectively. The CK-2, 34ßE12 and bcl-2 expression showed no significant difference in both cancers. Taken together, data suggests that use of cytomorphology in Pap smear combined with p16 and Ki-67 imunohistochemistry in small surgical specimens are helpful for the differential diagnosis of endocervical and endometrial adenocarcinoma.

中文摘要..................................................1
英文摘要..................................................3
第一章 文獻回顧...........................................5
第一節 子宮頸癌與子宮內膜癌的盛行率............................5
第二節 子宮頸癌的組織形態及分化............................... 5
第三節 子宮內膜癌的組織形態及分化..............................6
第四節 子宮頸抹片篩檢..........................................6
第五節 子宮頸抹片的判讀........................................8
第六節 傳統子宮頸抹片(conventional cytology)及薄層子宮頸抹片(liquid base cervical cytology)的比較..........................8
第七節 子宮頸癌的危險因子......................................9
第八節 台灣人類乳突病毒在子宮頸癌及子宮頸癌前病變的盛行率.....10
第九節 子宮內膜癌的危險因子...................................11
第十節 人類乳突病毒與子宮內膜癌...............................11
第十一節 子宮頸抹片的限制及人類乳突病毒DNA檢測在篩檢上的應用.12
第十二節 子宮頸抹片的腺體細胞病變.............................13
第十三節 子宮頸腺癌及子宮內膜癌在子宮頸抹片的鑑別診斷.........14
13.1.子宮頸抹片中的子宮內膜細胞......................14
13.1.1 盛行率........................................14
13.1.2 形態學........................................14
13.1.2.1正常子宮內膜細胞.............................14
13.1.2.2 非典型子宮內膜細胞..........................15
13.1.2.3 背景細胞…..................................16
13.1.3子宫內膜腺癌在子宮頸抹片的診斷條件.........................16
13.2 子宮頸抹片中的子宮頸腺體細胞 ...................17
13.2.1非典型子宮頸腺體細胞...........................17
13.2.2子宮頸腺癌.....................................17
13.3 子宮頸腺癌與子宮內癌在細胞學的鑑別診斷……………18
第十四節 子宮頸腺癌與子宮內膜癌在病理切片下的鑑別診斷.........18
第十五節 蛋白激酶CK-2(protein kinase CK-2)與子宮內膜癌及人類乳突病毒………………………………………………………………………………19
第二章 研究動機及目的....................................20
第三章 研究材料與方法 ................................. 21
第一節 子宮頸抹片的收集及細胞形態學的紀錄.....................21
第二節 子宮頸抹片的判讀.......................................21
第三節 組織晶片的製作及檢體的收集.............................21
3.1 免疫染色..........................................22
3.2 免疫染色的判讀....................................23
第四節 統計分析...............................................23
第四章 結果..............................................24
第一節子宮頸抹片中，子宮頸癌與子宮內膜癌細胞形態學的比較......24
1.1子宮頸癌與子宮內膜癌細胞形態學的比較................24
1.2複閱後的子宮頸抹片診斷..............................25
第二節 正常子宮頸、正常子宮內膜癌、子宮頸腺癌與子宮內膜癌病理切片免疫染色結果................................................26
2.1 CK-2及p16在正常子宮頸、正常子宮內膜癌、子宮頸腺癌與子宮內膜癌免疫染色結果..........................................26
2.2 34βE12,bcl-2及Ki-67在正常子宮頸、正常子宮內膜癌、子宮頸腺癌與子宮內膜癌免疫染色結果................................27
第三節 p16及Ki-67診斷子宮頸腺癌的敏感度，特異度及概似比.....28
第五章 討論.............................................30
第六章 結論..............................................40
第七章 參考文獻..........................................41
第八章 圖表..............................................46
第九章 附錄..............................................69

1.Arrossi S, Sankaranarayanan R, and Parkin DM. Incidence and mortality of cervical cancer in Latin America. Salud Publica Mex 2003; 45 Suppl 3:S306-14.
2.國民健康局. 衛生署資訊網
3.F.A Tavassoli, Peter Devilee, WHO classification of tumor:Tumours of the breast and female genital organs
4.Herzog TJ, Monk BJ. Reducing the burden of glandular carcinomas of the uterine cervix. Am J Obstet Gynecol 2007; 197:566-71
5.Solomon D, Nayar R, The Bethesda System for reporting cervical cytology. 2004, New York: Springer-Verlag.
6.Soost HJ, Lange HJ, Lehmacher W, et al. The validation of cervical cytology. Sensitivity, specificity and predictive values. Acta Cytol 1991; 35:8-14.
7.Davey E, Barratt A, Irwig L, et al. Effect of study design and quality on unsatisfactory rates, cytology classifications, and accuracy in liquid-based versus conventional cervical cytology: a systematic review. Lancet 2006; 367:122-32.
8.Ronco G, Cuzick J, Pierotti P, et al. Accuracy of liquid based versus conventional cytology: overall results of new technologies for cervical cancer screening: randomised controlled trial. BMJ 2007; 335:28.
9.Ogura K, Ishi K, Matsumoto T, et al. Human papillomavirus localization in cervical adenocarcinoma and adenosquamous carcinoma using in situ polymerase chain reaction: review of the literature of human papillomavirus detection in these carcinomas. Pathol Int 2006; 56:301-8.
10.Chen CA, Liu CY, Chou HH, et al. The distribution and differential risks of human papillomavirus genotypes in cervical preinvasive lesions: A Taiwan Cooperative Oncologic Group Study. Int J Gynecol Cancer 2006; 16:1801-8.
11.Clifford GM, Smith JS, Plummer M, et al. Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer 2003; 88:63-73.
12.Moberg M, Gustavsson I, and Gyllensten U. Type-specific associations of human papillomavirus load with risk of developing cervical carcinoma in situ. Int J Cancer 2004; 112:854-9.
13.Munoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003; 348:518-27.
14.Giatromanolaki A, Sivridis E, Papazoglou D, et al. Human papillomavirus in endometrial adenocarcinomas: infectious agent or a mere "passenger"? Infect Dis Obstet Gynecol 2007; 2007:60549.
15.Brewster WR, Monk BJ, Burger RA, et al. Does human papillomavirus have a role in cancers of the uterine corpus? Gynecol Oncol 1999; 75:51-4.
16.Lai CH, Wang CY, Lin CY, et al. Detection of human papillomavirus RNA in ovarian and endometrial carcinomas by reverse transcription/polymerase chain reaction. Gynecol Obstet Invest 1994; 38:276-80.
17.Cecchini S, Palli D, and Casini A. Cervical intraepithelial neoplasia III. An estimate of screening error rates and optimal screening interval. Acta Cytol 1985; 29:329-33.
18.Coppleson LW, Brown B. Estimation of the screening error rate from the observed detection rates in repeated cercival cytology. Am J Obstet Gynecol 1974; 119:953-8.
19.May D. Error rates in cervical cytological screening tests. Br J Cancer 1974; 29:106-13.
20.van der Graaf Y, Vooijs GP, Gaillard HL, et al. Screening errors in cervical cytologic screening. Acta Cytol 1987; 31:434-8.
21.Lonky NM, Felix JC, Naidu YM, et al. Triage of atypical squamous cells of undetermined significance with hybrid capture II: colposcopy and histologic human papillomavirus correlation. Obstet Gynecol 2003; 101:481-9.
22.Ronco G, Giorgi-Rossi P, Carozzi F, et al. Results at recruitment from a randomized controlled trial comparing human papillomavirus testing alone with conventional cytology as the primary cervical cancer screening test. J Natl Cancer Inst 2008; 100:492-501.
23.Meijer CJ, Berkhof J, Castle PE, et al. Guidelines for human papillomavirus DNA test requirements for primary cervical cancer screening in women 30 years and older. Int J Cancer 2009; 124:516-20.
24.Behtash N, Nazari Z, Fakhrejahani F, et al. Clinical and histological significance of atypical glandular cell on Pap smear. Aust N Z J Obstet Gynaecol 2007; 47:46-9.
25.Lai CR, Hsu CY, Tsay SH, et al. Clinical significance of atypical glandular cells by the 2001 Bethesda System in cytohistologic correlation. Acta Cytol 2008; 52:563-7.
26.Thrall MJ, Kjeidahl KS, Savik K, Gulbahce HE, Pambuccian SE. Significance of benign endometrial cells in Papanicolaou Tests from women aged 940 years. Cancer Cytopathol 2005;105:207-16.
27.Chhieng DC, Elgert P, Cohen JM, Cangiarella JF. Clinical implications of atypical glandular cells of undetermined significance, favor endometrial origin. Cancer (Cancer Cytopathol) 2001;93:351-6.
28.DeMay RM. The Pap Smear. In: The Art and Science of Cytopathology. Chicago: ASCP Press, 1996:120-9
29.Raab SS, Snider TE, Potts SA, McDaniel HL, Robinson RA, Nelson DL, et al. Atypical glandular cells of undetermined significance: diagnostic accuracy and interobserver variability using select cytologic criteria. Am J Clin Pathol 1997;107:299-307.
30.Simsir A, Hwang S, Cangiarella J, Elgert P, Levine P, Sheffield MV, et al. Glandular cells atypical atypical on Papanicoloau smears: interobserver variabilitiy in the diagnosis and prediction of the cell of origin. Cancer (Cancer Cytopathol) 2003;99:323-30.
31.Cangiarella JF, Chhieng DC. Atypical glandular cells Van update. Diagn Cytopathol 2003;29:271-9
32.David L. Greenspan, Marina Cardillo, Diane D. Davey et al. Endometrial Cells in Cervical Cytology: Review of Cytological Features and Clinical Assessment .Journal of Lower Genital Tract Disease,2006;10(2): 111- 122
33.Zucker PK, Kasdon EJ, Feldstein ML. The validity of pap smear parameters as predictors of endometrial pathology in menopausal women. Cancer 1985;56:2256-63.
34.Nguyen TN, Bourdeau J, Ferenczy A, Franco EL. Clinical significance of histiocytes in the detection detection of endometrial adenocarcinoma and hyperplasia. Diagn Cytopathol 1998;19:89-93.
35.Paulette Mhawech-Fauceglia, Francois Herrmann, Wiam Bshara et al. Intraobserver and Interobserver Variability in Distinguishing Between Endocervical and Endometrial Adenocarcinoma on Problematic Cases of Cervical Curettings. International Journal of Gynecological Pathology 27:431–436
36.Han CP et al. Scoring of p16(INK4a) immunohistochemistry based on independent nuclear staining alone can sufficiently distinguish between endocervical and endometrial adenocarcinomas in a tissue microarray study. modern pathology. 2009 Jun;22(6):797-806.
37.Judit Pallares et al.CK2 Is Expressed in Endometrial Carcinoma and Has a Role in Apoptosis Resistance and Cell Proliferation.Am J Pathol 2009, 174:287–296
38.Wei-Ming Chien, Jacqueline N. Parker, Delf-Christian Schmidt-Grimminger et al. Casein Kinase II Phosphorylation of the Human Papillomavirus-18 E7 Protein Is Critical for Promoting S-Phase Entry. Cell Growth & Differentiation. 2000, August , Vol. 11, 425–435.
39.Paul K. S. Chan, Ching-Wan Lam, Tak-Hong Cheung et al. Association of Human Papillomavirus Type 58 Variant With the Risk of Cervical Cancer. J Natl Cancer Inst 2002;94:1249– 53
40.Aylin Simsir, Sonya Hwang, Joan Cangiarella et al .Glandular cell atypia on Papanicolaou smears: interobserver variability in the diagnosis and prediction of cell of origin. Cancer cytopathology, 2003 Dec 25;99(6):323-30
41.Charles J. Dunton, Management of Atypial glandular cell and adenocarcinoma in situ. Obstet Gynecol Clin N Am 35 (2008) 623–63
42.Schnatz PF, Guile M, O''Sullivan DM, Sorosky JI. Clinical significance of atypical glandular cells on cervical cytology. Obstet Gynecol 2006;107(3):701–8.
43. Salomão DR, Hughes JH, Raab SS. Atypical glandular cells of undetermined significance favor endometrial origin. Criteria for separating low grade endometrial adenocarcinoma from benign endometrial lesions. Acta Cytol,
2002 May-Jun;46(3):458-64. 44. Zhou J, Tomashefski J Jr, Khiyami A .Diagnostic value of the thin-layer,
liquid-based Pap test in endometrial cancer: a retrospective study with emphasis on cytomorphologic features. Acta Cytol, 2007 Sep-Oct;51(5):735-41
45.國家衛生研究院，TCOG 子宮頸癌臨床治療指引
46.國家衛生研究院，TCOG 子宮內膜癌臨床治療指引
47. Kong CS, Balzer BL, Troxell ML, Patterson BK, Longaxre TA. p16INK4A immunohistochemistry is superior to HPV in situ hybridization for the detection of high-risk HPV in atypical squamous metaplasia. Am J Sur Pathol,2007 Jan;31(1):33-43.
48. Stanley J. Robboy,George L. Mutter,Jaime Prat,Rex Bentley,Peter Russell. Robboy''s pathology of female reproductive tract.2009, Elsevier health sciences.
49. Anna Yemelyanova,MD,* Russell Vang,MD,*w Jeffrey D. Seidman,MD et al. Endocervical Adenocarcinomas With Prominent Endometrial or Endomyometrial Involvement Simulating Primary Endometrial Carcinomas. Am J Surg Pathol Volume 33, Number 6, June 2009.
50. Chiew-Loon Koo, Lai-Fong Kok, Ming-Yung Lee Han CP et al. Scoring mechanisms of p16INK4A immunohistochemistry based on either independent nucleic stain or mixed cytoplasmic with nucleic expression can significantly signal to distinguish between endocervical and endometrial adenocarcinomas in a tissue microarray study. Journal of Translational medicine, 2009, 7:25.
51. David W. LITCHFIELD.Protein kinase CK2: structure, regulation and role in cellular decisions of life and death.Biochem. J. (2003) 369, 1-15 52. A. M. Gown and A. M. Vogel.Monoclonal antibodies to human intermediate
filament proteins. II. Distribution of filament proteins in normal human tissues.Am J Pathol. 1984 February; 114(2): 309–321
53. Ebell MH. Evidence-based diagnosis: a handbook of clinical prediction rules. Berlin, New York, Vienna: Springer, 2001.