Screening and diagnostic modalities in carcinoma cervix: A Pathologist's perspective.

  • Harsh Mohan Professor and Head, Department of Pathology, Government Medical College and Hospital, Chandigarh
  • Reetu Kundu
Keywords: Carcinoma cervix, Pap smear, Liquid based cytology, Human papilloma virus, Screening,


Carcinoma cervix is the second most common cancer among women worldwide with majority of cases in the developing nations. It develops over a considerable period of time through precursor lesions that are amenable to detection when properly screened. A sea change has occurred in the detection and further the management of cervical cancer with the advances in the field of diagnostics. The orchestra ranges from the conventional Papanicolaou (Pap) test to high throughout expression profiling. The discovery of human papilloma virus (HPV) as the etiologic agent with recognition of various high risk types prompted the development of techniques for HPV detection. Several biomarkers have been recognized although many of them still require validation before they can be put to use at a large scale. Efforts directed at early detection of carcinoma cervix are desired for reducing incidence rates for carcinoma cervix. This review highlights the screening guidelines and the entire available armamentarium which can be applied to screen and diagnose cervical cancer at an early stage. However it can be foreseen that the etiology based testing is unlikely to replace cytology as a screening modality although it will remain a useful adjunct. This is especially true for the developing countries which are resource poor where cost-effective Pap test continues to be main method. 

Author Biography

Harsh Mohan, Professor and Head, Department of Pathology, Government Medical College and Hospital, Chandigarh
Professor and Head, Department of Pathology,Government Medical College and Hospital, Chandigarh


1. Sepúlveda C, Prado R. Effective cervical cytology screening programmes in middle-income countries: the Chilean experience. Cancer Detect Prev. 2005;29:405-11.
2. Petignat P, Roy M. Diagnosis and management of cervical cancer. BMJ. 2007;335:765-8.
3. Hassumi-Fukasawa MK, Miranda-Camargo FA, Zanetti BR, Galano DF, Ribeiro-Silva A, Soares EG. Expression of BAG-1 and PARP-1 in precursor lesions and invasive cervical cancer associated with human papillomavirus (HPV). Pathol Oncol Res. 2012;18:929-37.
4. Pirog EC, Lloveras B, Molijn A, Tous S, Guimerà N, Alejo M, et al. HPV prevalence and genotypes in different histological subtypes of cervical adenocarcinoma, a worldwide analysis of 760 cases. Mod Pathol. In press.
5. Carmichael JA, Jeffrey JF, Steele HD, Ohlke ID. The cytologic history of 245 patients developing invasive cervical carcinoma. Am J Obstet Gynecol. 1984;148:685-90.
6. Janerich DT, Hadjimichael O, Schwartz PE, Lowell DM, Meigs JW, Merino MJ, et al. The screening histories of women with invasive cervical cancer, Connecticut. Am J Public Health. 1995;85:791-4.
7. Diamantis A, Beloukas AI, Kalogeraki AM, Magiorkinis E. A brief chronicle of cytology: from Janssen to Papanicolaou and beyond. Diagn Cytopathol. 2013;41:555-64.
8. Stoler M. Advances in cervical screening technology. Mod Pathol. 2000;13:275-84.
9. Krane JF, Granter SR, Trask CE, Hogan CL, Lee KR. Papanicolaou smear sensitivity for the detection of adenocarcinoma of the cervix: a study of 49 cases. Cancer. 2001;93:8-15.
10. Boddington MM, Spriggs AI, Cowdell RH. Adenocarcinoma of the uterine cervix: Cytological evidence of a long preclinical evolution. Br J Obstet Gynecol. 1976;83:900-3.
11. Costa MJ, Kenny MB, Naib ZM. Cervicovaginal cytology in uterine adenocarcinoma and adenosquamous carcinoma. Comparison of cytologic and histologic findings. Acta Cytol. 1991;35:127-34.
12. Hurt WG, Silverberg SG, Frable WJ, Belgrad R, Crooks LD. Adenocarcinoma of the cervix: histopathologic and clinical features. Am J Obstet Gynecol. 1977;129:304-15.
13. Saigo PE, Wolinska WH, Kim WS, Hajdu SI. The role of cytology in the diagnosis and follow-up of patients with cervical adenocarcinoma. Acta Cytol. 1985;29:785-94.
14. Lee KR, Minter LJ, Granter SR. Papanicolaou smear sensitivity for adenocarcinoma in situ of the cervix. A study of 34 cases. Am J Clin Pathol. 1997;107:30-5.
15. Janicek MF, Averette HE. Cervical cancer: prevention, diagnosis, and therapeutics. CA Cancer J Clin. 2001;51:92-114.
16. Klinkhamer PJ, Meerding WJ, Rosier PF, Hanselaar AG. Liquid-based cervical cytology. Cancer. 2003;99:263-71.
17. Hoda RS, Loukeris K, Abdul-Karim FW. Gynecologic cytology on conventional and liquid-based preparations: a comprehensive review of similarities and differences. Diagn Cytopathol. 2013;41:257-78.
18. Bernstein SJ, Sanchez-Ramos L, Ndubisi B. Liquid-based cervical cytologic smear study and conventional Papanicolaou smears: A metaanalysis of prospective studies comparing cytologic diagnosis and sample adequacy. Am J Obstet Gynecol 2001;185:308-17.
19. Bentz JS. Liquid-based cytology for cervical cancer screening. Expert Rev Mol Diagn 2005;5:857-71.
20. Rinas AC, Mittman BW Jr, Le LV, Hartmann K, Cayless J, Singh HK. Split-sample analysis of discarded cells from liquid-based Pap smear sampling devices. Acta Cytol. 2006;50:55-62.
21. Hoda RS. Non-gynecologic cytology on liquid-based preparations: a morphologic review of facts and artifacts. Diagn Cytopathol 2007;35:621-34.
22. Yeong ML, Pringle E, Stewart J, Retter E. A comparison of ThinPrep Imager-assisted with manual screening, and its place in the New Zealand cervical cancer screening program. Pathology. 2013;45:474-7.
23. Böcking A, Nguyen VQ. Diagnostic and prognostic use of DNA image cytometry in cervical squamous intraepithelial lesions and invasive carcinoma. Cancer. 2004;102:41-54.
24. Chatelain R, Schunck T, Schindler EM, Schindler AE, Böcking A. Diagnosis of prospective malignancy in koilocytic dysplasias of the cervix with DNA cytometry. J Reprod Med. 1989;34:505-10.
25. Böcking A, Hilgarth M, Auffermann W, Hack-Werdier C, Fischer-Becker D, von Kalkreuth G. DNA-cytometric diagnosis of prospective malignancy in borderline lesions of the uterine cervix. Acta Cytol. 1986;30:608-15.
26. Kashyap V, Das DK, Luthra UK. Microphotometric nuclear DNA analysis in cervical dysplasia of the uterine cervix: its relation to the progression to malignancy and regression to normalcy. Neoplasma. 1990;37:487-500.
27. Bollmann R, Bollmann M, Henson DE, Bodo M. DNA cytometry confirms the utility of the Bethesda system for the classification of Papanicolaou smears. Cancer. 2001;93:222-8.
28. Kashyap V, Bhambhani S. DNA aneuploidy in invasive carcinoma of the uterine cervix. Indian J Pathol Microbiol. 2000;43:265-9.
29. Biesterfeld S, Reus K, Bayer-Pietsch E, Mihalcea AM, Böcking A. DNA image cytometry in the differential diagnosis of endocervical adenocarcinoma. Cancer. 2001;93:160-4.
30. Nguyen VQ, Grote HJ, Pomjanski N, Knops K, Böcking A. Interobserver reproducibility of DNA-image-cytometry in ASCUS or higher cervical cytology. Cell Oncol. 2004;26:143-50.
31. Umayahara K, Numa F, Suehiro Y, Sakata A, Nawata S, Ogata H, et al. Comparative genomic hybridization detects genetic alterations during early stages of cervical cancer progression. Genes Chromosomes Cancer. 2002;33:98-102.
32. Heselmeyer-Haddad K, Janz V, Castle PE, Chaudhri N, White N, Wilber K, et al. Detection of genomic amplification of the human telomerase gene (TERC) in cytologic specimens as a genetic test for the diagnosis of cervical dysplasia. Am J Pathol. 2003;163:1405-16.
33. Xiang L, Yang H, Li J, Wu X, Zhou X. Different amplification patterns of the human telomerase RNA gene in invasive cervical carcinomas and cervical intraepithelial neoplasia grade III. Diagn Cytopathol. 2012;40:849-55.
34. Gupta N, Srinivasan R, Rajwanshi A. Functional biomarkers in cervical precancer: an overview. Diagn Cytopathol. 2010;38:618-23.
35. Baak JPA, Kruse AJ, Robboy SJ, Janssen EAM, van Diermen B, Skaland I. Dynamic behavioural interpretation of cervical intraepithelial neoplasia with molecular markers. J Clin Pathol 2006;59:1017-28.
36. Grapsa D, Frangou-Plemenou M, Kondi-Pafiti A, Stergiou E, Nicolopoulou-Stamati P, Patsouris E, et al. "Immunocytochemical expression of P53, PTEN, FAS (CD95), P16INK4A and HPV L1 major capsid proteins in ThinPrep cervical samples with squamous intraepithelial lesions". Diagn Cytopathol. 2014;42:465-75.
37. Cheung AN, Tsun KL, Ng KM, Szeto E, Siu MK, Wong ES, et al. P634A4 and TAp73 immunocytochemistry in liquid-based cervical cytology--potential biomarkers for diagnosis and progress prediction of cervical neoplasia. Mod Pathol. 2010;23:559-66.
38. Wang JL, Zheng BY, Li XD, Nokelainen K, Angström T, Lindström MS, et al. p16INK4A and p14ARF expression pattern by immunohistochemistry in human papillomavirus-related cervical neoplasia. Mod Pathol. 2005;18:629-37.
39. von Keyserling H, Kühn W, Schneider A, Bergmann T, Kaufmann AM. p16INK4a and p14ARF mRNA expression in Pap smears is age-related. Mod Pathol. 2012;25:465-70.
40. Roelens J, Reuschenbach M, von Knebel Doeberitz M, Wentzensen N, Bergeron C, Arbyn M. p16INK4a immunocytochemistry versus human papillomavirus testing for triage of women with minor cytologic abnormalities: a systematic review and meta-analysis. Cancer Cytopathol. 2012;120:294-307.
41. Cheung AN. Molecular targets in gynaecological cancers. Pathology. 2007;39:26-45.
42. Nishino HT, Tambouret RH, Wilbur DC. Testing for human papillomavirus in cervical cancer screening: a review of indications and methodology. Cancer Cytopathol. 2011;119:219-27.
43. Dehn D, Torkko KC, Shroyer KR. Human papillomavirus testing and molecular markers of cervical dysplasia and carcinoma. Cancer. 2007;111:1-14.
44. Saslow D, Solomon D, Lawson HW, Killackey M, Kulasingam SL, Cain J, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin. 2012;62:147-72.
45. Li R, Zhou Q, Li M, Tong SM, He M, Qiu H, et al. Evaluation of visual inspection as the primary screening method in a four-year cervical (pre-) cancer screening program in rural China. Trop Doct. 2013;43:96-9.
46. Sankaranarayanan R, Wesley R, Thara S, Dhakad N, Chandralekha B, Sebastian P, et al. Test characteristics of visual inspection with 4% acetic acid (VIA) and Lugol's iodine (VILI) in cervical cancer screening in Kerala, India. Int J Cancer. 2003;106:404-8.
47. Schiller W. Leucoplakia, leucokeratosis, and carcinoma of the cervix. Am J Obstet Gynecol. 1938;35:17.
48. Ghosh P, Gandhi G, Kochhar PK, Zutshi V, Batra S. Visual inspection of cervix with Lugol's iodine for early detection of premalignant & malignant lesions of cervix. Indian J Med Res. 2012;136:265-71.
49. Sarian LO, Derchain SF, Naud P, Roteli-Martins C, Longatto-Filho A, Tatti S, et al. Evaluation of visual inspection with acetic acid (VIA), Lugol's iodine (VILI), cervical cytology and HPV testing as cervical screening tools in Latin America. This report refers to partial results from the LAMS (Latin AMerican Screening) study. J Med Screen. 2005;12:142-9.
Review Article