Pathology and Molecular Diagnosis of Cervical Cancer and Precursor Lesions

  • Mariana CanepaEmail author
  • Nimesh R. Patel
  • Maria Luisa Garcia-Moliner


Pathologic diagnosis of cervical neoplasia incorporates the practice of cytopathology, molecular pathology, and surgical pathology. Cervical pathology includes preinvasive squamous lesions (squamous intraepithelial lesions/SIL), invasive squamous cell carcinoma, adenocarcinoma in situ, invasive adenocarcinoma, as well as other less common primary epithelial and mesenchymal tumors. The most common cervical lesions are human papillomavirus (HPV)-associated squamous lesions. A two-tiered diagnostic approach classifying preinvasive lesions into low-grade and high-grade squamous intraepithelial lesions is used in cytopathology and surgical pathology. Low-grade squamous intraepithelial lesions (LSIL), which include condylomata, are the result of productive HPV infection that may be transient and regress. High-grade squamous intraepithelial lesions (HSIL) have a greater risk of progression to invasive carcinoma and require further treatment. Adenocarcinoma in situ, a precursor to invasive adenocarcinoma, is also HPV-associated and may coexist with squamous lesions. HPV testing/genotyping has been incorporated into the Papanicolaou cytology screening and helps stratify patients into those needing further evaluation. The incidence of invasive carcinoma has decreased with the widespread use of cytology testing. A subset of tumors not associated with HPV infection, while rare, may present diagnostic challenges, especially in cytology and small biopsies.


Classification of cervical tumors Cervical tumor classification HPV and cervical dysplasia/neoplasia Squamous lesions of the cervix Glandular lesions of the cervix Unusual neoplasias of the cervix 


  1. 1.
    Kurman RJ, Carcangiu ML, Herrington CS, Young RH, editors. WHO classification of tumours of female reproductive organs. 4th ed. Lyon: IARC; 2014.Google Scholar
  2. 2.
    Haghshenas MR, Mousavi T, Kheradmand M, Afshari M, Moosazadeh M. Efficacy of human papillomavirus L1 protein vaccines (Cervarix and Gardasil) in reducing the risk of cervical intraepithelial neoplasia: a meta-analysis. Int J Prev Med. 2017;8:44.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Krishnamurti U, Unger ER. Pathobiology of human papillomaviruses in human immunodeficiency virus – infected persons. Semin Diagn Pathol. 2017;34(4):364–70.PubMedCrossRefGoogle Scholar
  4. 4.
    Thomison J, Thomas LK, Shroyer KR. Human papillomavirus: molecular and cytologic/histologic aspects related to cervical intraepithelial neoplasia and carcinoma. Hum Pathol. 2008;39(2):154–66.PubMedCrossRefGoogle Scholar
  5. 5.
    Baseman JG, Koutsky LA. The epidemiology of human papillomavirus infections. J Clin Virol. 2017;32:16–24.CrossRefGoogle Scholar
  6. 6.
    Lee L-Y, Garland SM. Human papillomavirus vaccination: the population impact. F1000Res. 2017;6:866.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Doorbar J. Host control of human papillomavirus infection and disease. Best Pract Res Clin Obstet Gynaecol. 2017;47:27–41.PubMedCrossRefGoogle Scholar
  8. 8.
    Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer. Lancet. 2007;370(9590):890–907.PubMedCrossRefGoogle Scholar
  9. 9.
    Doorbar J, Quint W, Banks L, Bravo IG, Stoler M, Broker TR, et al. The biology and life-cycle of human papillomaviruses. Vaccine. 2012;30(Suppl 5):F55–70.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Mirkovic J, Howitt BE, Roncarati P, Demoulin S, Suarez-Carmona M, Hubert P, et al. Carcinogenic HPV infection in the cervical squamo-columnar junction. J Pathol. 2015;236(3):265–71.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Burd EM. Human papillomavirus and cervical cancer. Clin Microbiol Rev. 2003;16(1):1–17.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Huh WK, Ault KA, Chelmow D, Davey DD, Goulart RA, Garcia FAR, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance. Obstet Gynecol. 2015;125(2):330–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Committee on Practice Bulletins—Gynecology. Practice Bulletin No. 168: cervical cancer screening and prevention. Obstet Gynecol. 2016;128(4):e111–30.CrossRefGoogle Scholar
  14. 14.
    Khan MJ, Castle PE, Lorincz AT, Wacholder S, Sherman M, Scott DR, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst. 2005;97(14):1072–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Schiffman M, Burk RD, Boyle S, Raine-Bennett T, Katki HA, Gage JC, et al. A study of genotyping for management of human papillomavirus-positive, cytology-negative cervical screening results. J Clin Microbiol. 2015;53(1):52–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Arbyn M, Snijders PJF, Meijer CJLM, Berkhof J, Cuschieri K, Kocjan BJ, et al. Which high-risk HPV assays fulfil criteria for use in primary cervical cancer screening? Clin Microbiol Infect. 2015;21(9):817–26.PubMedCrossRefGoogle Scholar
  17. 17.
    Zhao C, Moriarty AT, Ghofrani M, Husain M, Tambouret RH, Laucirica R, et al. Human papillomavirus testing and reporting rates in 2012: results of a College of American Pathologists national survey. Arch Pathol Lab Med. 2014;139(6):757–61.PubMedCrossRefGoogle Scholar
  18. 18.
    de Thurah L, Bonde J, Lam JUH, Rebolj M. Concordant testing results between various human papillomavirus assays in primary cervical cancer screening: systematic review. Clin Microbiol Infect. 2017;24:29–36.PubMedCrossRefGoogle Scholar
  19. 19.
    Mills AM, Dirks DC, Poulter MD, Mills SE, Stoler MH. HR-HPV E6/E7 mRNA in situ hybridization: validation against PCR, DNA in situ hybridization, and p16 immunohistochemistry in 102 samples of cervical, vulvar, anal, and head and neck neoplasia. Am J Surg Pathol. 2017;41(5):607–15.PubMedCrossRefGoogle Scholar
  20. 20.
    Nayar R, Wilbur DC, editors. The Bethesda system for reporting cervical cytology: definitions, criteria, and explanatory notes. 3rd ed. Cham: Springer; 2015.Google Scholar
  21. 21.
    Darragh TM, Colgan TJ, Cox JT, Heller DS, Henry MR, Luff RD, McCalmont T, Nayar R, Palefsky JM, Stoler MH, Wilkinson EJ. The lower anogenital squamous terminology standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Arch Pathol Lab Med. 2012;136(10):1266–97.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Massad LS, Einstein MH, Huh WK, Katki HA, Kinney WK, Schiffman M, Solomon D, Wentzensen N, Lawson HW. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol. 2013;121(4):829–46.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Doorbar J. Model systems of human papillomavirus-associated disease. J Pathol. 2016;238(2):166–79.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    McCluggage WG, Walsh MY, Thornton CM, Hamilton PW, Caughley LM, Bharucha H. Inter-and intra-observer variation in the histopathological reporting of cervical squamous in intraepithelial lesion using a modified Bethesda grading system. BJOG. 1998;105(2):206–10.CrossRefGoogle Scholar
  25. 25.
    Carreon JD, Sherman ME, Guillén D, Solomon D, Herrero R, Jerónimo J, Wacholder S, Rodríguez AC, Morales J, Hutchinson M, Burk RD. CIN2 is a much less reproducible and less valid diagnosis than CIN3: results from a histological review of population-based cervical samples. Int J Gynecol Pathol. 2007;26(4):441–6.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Castle PE, Stoler MH, Solomon D, Schiffmanx M, for the ALTS Group. The relationship of community biopsy-diagnosed cervical intraepithelial neoplasia grade 2 to the quality control pathology-reviewed diagnoses: an ALTS report. Am J Clin Pathol. 2007;127(5):805–15.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Stoler MH, Schiffman M, for the Atypical Squamous Cells of Undetermined Significance-Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS) Group. Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL triage study. JAMA. 2001;285(11):1500–5.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Galgano MT, Castle PE, Atkins KA, Brix WK, Nassau SR, Stoler MH. Using biomarkers as objective standards in the diagnosis of cervical biopsies. Am J Surg Pathol. 2010;34(8):1077–87.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Group TA. A randomized trial on the management of low-grade squamous intraepithelial lesion cytology interpretations. Am J Obstet Gynecol. 2003;188(6):1393–400.CrossRefGoogle Scholar
  30. 30.
    Van Baars R, Griffin H, Wu Z, Soneji YJ, Van de Sandt M, Arora R, et al. Investigating diagnostic problems of CIN 1 and 2 associated with high-risk HPV by combining the novel molecular biomarker PanHPV E4 with P16(ink4a). Am J Surg Pathol. 2015;39(11):1518–28.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Tsoumpou I, Arbyn M, Kyrgiou M, Wentzensen N, Koliopoulos G, Martin-Hirsch P, et al. p16(INK4a) immunostaining in cytological and histological specimens from the uterine cervix: a systematic review and meta-analysis. Cancer Treat Rev. 2009;35(3):210–20.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Conesa-Zamora P, Domenech-Peris A, Orantes-Casado FJ, Ortiz-Reina S, Sahuquillo-Frias L, Acosta-Ortega J, et al. Effect of human papillomavirus on cell cycle-related proteins p16, Ki-67, cyclin D1, p53, and ProEx C in precursor lesions of cervical carcinoma: a tissue microarray study. Am J Clin Pathol. 2009;132(3):378–90.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Bergeron C, Ordi J, Schmidt D, Trunk MJ, Keller T, Ridder R. Conjunctive p16INK4a testing significantly increases accuracy in diagnosing high-grade cervical intraepithelial neoplasia. Am J Clin Pathol. 2010;133(3):395–406.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Pinto AP, Schlecht NF, Woo TYC, Crum CP, Cibas ES. Biomarker (ProEx C, p16(INK4A), and MiB-1) distinction of high-grade squamous intraepithelial lesion from its mimics. Mod Pathol. 2008;21(9):1067–74.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Dijkstra MG, Heideman DAM, de Roy SC, Rozendaal L, Berkhof J, Van Krimpen K, et al. p16(INK4a) immunostaining as an alternative to histology review for reliable grading of cervical intraepithelial lesions. J Clin Pathol. 2010;63(11):972–7.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Pinto AP, Crum CP, Hirsch MS. Molecular markers of early cervical neoplasia. Diagn Histopathol (Oxf). 2010;16(10):445–54.CrossRefGoogle Scholar
  37. 37.
    Maniar KP, Sanchez B, Paintal A, Gursel DB, Nayar R. Role of the biomarker p16 in downgrading -IN 2 diagnoses and predicting higher-grade lesions. Am J Surg Pathol. 2015;39(12):1708–18.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    del Pino M, Garcia S, Fuste V, Alonso I, Fuste P, Torne A, et al. Value of p16(INK4a) as a marker of progression/regression in cervical intraepithelial neoplasia grade 1. Am J Obstet Gynecol. 2009;201(5):488.e1-7.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Quint KD, de Koning MNC, Quint WGV, Pirog EC. Progression of cervical low grade squamous intraepithelial lesions: in search of prognostic biomarkers. Eur J Obstet Gynecol Reprod Biol. 2013;170(2):501–6.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Wang SS, Trunk M, Schiffman M, Herrero R, Sherman ME, Burk RD, Hildesheim A, Bratti MC, Wright T, Rodriguez AC, Chen S. Validation of p16INK4a as a marker of oncogenic human papillomavirus infection in cervical biopsies from a population-based cohort in Costa Rica. Cancer Epidemiol Biomarkers Prev. 2004;13(8):1355–60.PubMedGoogle Scholar
  41. 41.
    Sagasta A, Castillo P, Saco A, Torne A, Esteve R, Marimon L, et al. p16 staining has limited value in predicting the outcome of histological low-grade squamous intraepithelial lesions of the cervix. Mod Pathol. 2016;29(1):51–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Moyer VA. Screening for cervical cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;156(12):880–91.PubMedCrossRefGoogle Scholar
  43. 43.
    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(3):147–72.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    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(2):308–17.PubMedCrossRefGoogle Scholar
  45. 45.
    Stein SR. ThinPrep versus the conventional Papanicolaou test: a review of specimen adequacy, sensitivity, and cost-effectiveness. Prim Care Update OB Gyns. 2003;10(6):310–3.CrossRefGoogle Scholar
  46. 46.
    Schiffman M, Solomon D. Screening and prevention methods for cervical cancer. JAMA. 2009;302(16):1809–10.PubMedCrossRefGoogle Scholar
  47. 47.
  48. 48.
    Cibas ES, Ducatman BS. Cervical and vaginal cytology. In: Cytology. Diagnostic principles and clinical correlates. 4th ed. Philadelphia: Saunders; 2014. p. 7–8.Google Scholar
  49. 49.
    Jones BA, Novis DA. Cervical biopsy-cytology correlation. A College of American Pathologists Q-Probes study of 22,439 correlations in 348 laboratories. Arch Pathol Lab Med. 1996;120:523–31.PubMedGoogle Scholar
  50. 50.
    Eversole GM, Moriarty AT, Schwartz MR, Clayton AC, Souers R, Fatheree LA, et al. Practices of participants in the College of American Pathologists interlaboratory comparison program in cervicovaginal cytology, 2006. Arch Pathol Lab Med. 2010;134(3):331–5.PubMedGoogle Scholar
  51. 51.
    Sherman ME, Castle PE, Solomon D. Cervical cytology of atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion (ASC-H): characteristics and histologic outcomes. Cancer. 2006;108(5):298–305.PubMedCrossRefGoogle Scholar
  52. 52.
    Thomas C, Wright J, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ. Conference for the 2001 A-SC. 2001 Consensus Guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002;287(16):2120–9.CrossRefGoogle Scholar
  53. 53.
    Vizcaino AP, Moreno V, Bosch FX, Munoz N, Barros-Dios XM, Borras J, et al. International trends in incidence of cervical cancer: II. Squamous-cell carcinoma. Int J Cancer. 2000;86(3):429–35.PubMedCrossRefGoogle Scholar
  54. 54.
    Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189(1):12–9.PubMedCrossRefGoogle Scholar
  55. 55.
    De Sanjose S, Quint WG, Alemany L, Geraets DT, Klaustermeier JE, Lloveras B, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol. 2010;11(11):1048–56.PubMedCrossRefGoogle Scholar
  56. 56.
    Brinck U, Jakob C, Bau O, Fuzesi L. Papillary squamous cell carcinoma of the uterine cervix: report of three cases and a review of its classification. Int J Gynecol Pathol. 2000;19(3):231–5.PubMedCrossRefGoogle Scholar
  57. 57.
    Koenig C, Turnicky RP, Kankam CF, Tavassoli FA. Papillary squamotransitional cell carcinoma of the cervix: a report of 32 cases. Am J Surg Pathol. 1997;21(8):915–21.PubMedCrossRefGoogle Scholar
  58. 58.
    Randall ME, Andersen WA, Mills SE, Kim JA. Papillary squamous cell carcinoma of the uterine cervix: a clinicopathologic study of nine cases. Int J Gynecol Pathol. 1986;5(1):1–10.PubMedCrossRefGoogle Scholar
  59. 59.
    Zbroch T, Grzegorz Knapp P, Knapp PA. Verrucous carcinoma of the cervix – diagnostic and therapeutic difficulties with regards to HPV status. Case report. Eur J Gynaecol Oncol. 2005;26(2):227–30.PubMedGoogle Scholar
  60. 60.
    Grayson W, Cooper K. A reappraisal of “basaloid carcinoma” of the cervix, and the differential diagnosis of basaloid cervical neoplasms. Adv Anat Pathol. 2002;9(5):290–300.PubMedCrossRefGoogle Scholar
  61. 61.
    Martorell MA, Julian JM, Calabuig C, Garcia-Garcia JA, Perez-Valles A. Lymphoepithelioma-like carcinoma of the uterine cervix. Arch Pathol Lab Med. 2002;126(12):1501–5.PubMedGoogle Scholar
  62. 62.
    Chao A, Tsai CN, Hsueh S, Lee LY, Chen TC, Huang SL, Chao FY, Lai CH. Does Epstein-Barr virus play a role in lymphoepithelioma-like carcinoma of the uterine cervix? Int J Gynecol Pathol. 2009;28(3):279–85.PubMedCrossRefGoogle Scholar
  63. 63.
    Noel J, Lespagnard L, Fayt I, Verhest A, Dargent J. Evidence of human papilloma virus infection but lack of Epstein-Barr virus in lymphoepithelioma-like carcinoma of uterine cervix: report of two cases and review of the literature. Hum Pathol. 2001;32(1):135–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Zaino RJ, Ward S, Delgado G, Bundy B, Gore H, Fetter G, et al. Histopathologic predictors of the behavior of surgically treated stage IB squamous cell carcinoma of the cervix. A Gynecologic Oncology Group study. Cancer. 1992;69(7):1750–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Amin MB. Cervix uteri. In: AJCC cancer staging manual. 8th ed. New York: Springer; 2017. p. 649–59.CrossRefGoogle Scholar
  66. 66.
    Rushing L, Cibas ES. The frequency of tumor diathesis in smears from women with squamous cell carcinoma of the cervix. Acta Cytol. 1997;41:781–5.PubMedCrossRefGoogle Scholar
  67. 67.
    Levine PH, Elgert PA, Mittal K. False-positive squamous cell carcinoma in cervical smears: cytologic-histologic correlation in 19 cases. Diagn Cytopathol. 2003;28(1):23–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Bibbo M, Wilbur D. Comprehensive cytopathology. 4th ed. Philadelphia: Saunders; 2014. p. 161.Google Scholar
  69. 69.
    Joshi D, Shivkumar VB, Sharma SM, Gangane N. Cytomorphologic diagnosis of basaloid squamous cell carcinoma: a case report. Acta Cytol. 2009;53(1):89–92.PubMedCrossRefGoogle Scholar
  70. 70.
    Frega A, Lukic A, Nobili F, Palazzo A, Iacovelli R, French D, et al. Verrucous carcinoma of the cervix: detection of carcinogenetic human papillomavirus types and their role during follow-up. Anticancer Res. 2007;27(6C):4491–4.PubMedGoogle Scholar
  71. 71.
    Martínez-Girón R, Martínez-Torre S, Mosquera-Martínez AJ. Basaloid squamous cell carcinoma of the uterine cervix: cytological and histological features. Diagn Cytopathol. 2015;43:993–5.PubMedCrossRefGoogle Scholar
  72. 72.
    Ng W-K, Cheung LKN, Li ASM. Warty (condylomatous) carcinoma of the cervix. A review of 3 cases with emphasis on thin-layer cytology and molecular analysis for HPV. Acta Cytol. 2003;47(2):159–66.PubMedCrossRefGoogle Scholar
  73. 73.
    Andersson S, Rylander E, Larsson B, Strand A, Silfversvard C, Wilander E. The role of human papillomavirus in cervical adenocarcinoma carcinogenesis. Eur J Cancer. 2001;37(2):246–50.PubMedCrossRefGoogle Scholar
  74. 74.
    Iwasawa A, Nieminen P, Lehtinen M, Paavonen J. Human papillomavirus DNA in uterine cervix squamous cell carcinoma and adenocarcinoma detected by polymerase chain reaction. Cancer. 1996;77(11):2275–9.PubMedCrossRefGoogle Scholar
  75. 75.
    An HJ, Kim KR, Kim IS, Kim DW, Park MH, Park IA, et al. Prevalence of human papillomavirus DNA in various histological subtypes of cervical adenocarcinoma: a population-based study. Mod Pathol. 2005;18(4):528–34.PubMedCrossRefGoogle Scholar
  76. 76.
    Holl K, Nowakowski AM, Powell N, McCluggage WG, Pirog EC, Collas De Souza S, et al. Human papillomavirus prevalence and type-distribution in cervical glandular neoplasias: results from a European multinational epidemiological study. Int J Cancer. 2015;137(12):2858–68.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    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. 2014;27(12):1559.PubMedCrossRefGoogle Scholar
  78. 78.
    Biscotti CV, Hart WR. Apoptotic bodies: a consistent morphologic feature of endocervical adenocarcinoma in situ. Am J Surg Pathol. 1998;22(4):434–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Park JJ, Sun D, Quade BJ, Flynn C, Sheets EE, Yang A, et al. Stratified mucin-producing intraepithelial lesions of the cervix: adenosquamous or columnar cell neoplasia? Am J Surg Pathol. 2000;24(10):1414–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Lastra RR, Park KJ, Schoolmeester JK. Invasive stratified mucin-producing carcinoma and stratified mucin-producing intraepithelial lesion (SMILE): 15 cases presenting a Spectrum of cervical neoplasia with description of a distinctive variant of invasive adenocarcinoma. Am J Surg Pathol. 2016;40(2):262–9.PubMedGoogle Scholar
  81. 81.
    Mikami Y, Kiyokawa T, Hata S, Fujiwara K, Moriya T, Sasano H, et al. Gastrointestinal immunophenotype in adenocarcinomas of the uterine cervix and related glandular lesions: a possible link between lobular endocervical glandular hyperplasia/pyloric gland metaplasia and “adenoma malignum”. Mod Pathol. 2004;17(8):962–72.PubMedCrossRefGoogle Scholar
  82. 82.
    Kawauchi S, Kusuda T, Liu X-P, Suehiro Y, Kaku T, Mikami Y, et al. Is lobular endocervical glandular hyperplasia a cancerous precursor of minimal deviation adenocarcinoma?: a comparative molecular-genetic and immunohistochemical study. Am J Surg Pathol. 2008;32(12):1807–15.PubMedCrossRefGoogle Scholar
  83. 83.
    Talia KL, Stewart CJ, Howitt BE, Nucci MR, McCluggage WG. HPV-negative gastric type adenocarcinoma in situ of the cervix: a Spectrum of rare lesions exhibiting gastric and intestinal differentiation. Am J Surg Pathol. 2017;41(8):1023–33.PubMedCrossRefGoogle Scholar
  84. 84.
    Negri G, Egarter-Vigl E, Kasal A, Romano F, Haitel A, Mian C. p16INK4a is a useful marker for the diagnosis of adenocarcinoma of the cervix uteri and its precursors: an immunohistochemical study with immunocytochemical correlations. Am J Surg Pathol. 2003;27(2):187–93.PubMedCrossRefGoogle Scholar
  85. 85.
    Cameron RI, Maxwell P, Jenkins D, McCluggage WG. Immunohistochemical staining with MIB1, bcl2 and p16 assists in the distinction of cervical glandular intraepithelial neoplasia from tubo-endometrial metaplasia, endometriosis and microglandular hyperplasia. Histopathology. 2002;41(4):313–21.PubMedCrossRefGoogle Scholar
  86. 86.
    Biscotti CV, Gero MA, Toddy SM, Fischler DF, Easley KA. Endocervical adenocarcinoma in situ: an analysis of cellular features. Diagn Cytopathol. 1997;17(5):326–32.PubMedCrossRefGoogle Scholar
  87. 87.
    Lee KR, Manna EA, Jones MA. Comparative cytologic features of adenocarcinoma in situ of the uterine cervix. Acta Cytol. 1991;35:117–26.PubMedGoogle Scholar
  88. 88.
    Lee KR, Darragh TM, Joste NE, Krane JF, Sherman ME, Hurley LB, et al. Atypical glandular cells of undetermined significance (AGUS) Interobserver reproducibility in cervical smears and corresponding thin-layer preparations. Am J Clin Pathol. 2002;117(1):96–102.PubMedCrossRefGoogle Scholar
  89. 89.
    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.PubMedCrossRefGoogle Scholar
  90. 90.
    Zhao C, Florea A, Onisko A, Austin RM. Histologic follow-up results in 662 patients with Pap test findings of atypical glandular cells: results from a large academic womens hospital laboratory employing sensitive screening methods. Gynecol Oncol. 2009;114(3):383–9.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Baalbergen A, Ewing-Graham PC, Hop WCJ, Struijk P, Helmerhorst TJM. Prognostic factors in adenocarcinoma of the uterine cervix. Gynecol Oncol. 2004;92(1):262–7.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    McCluggage WG, Shah R, Connolly LE, McBride HA. Intestinal-type cervical adenocarcinoma in situ and adenocarcinoma exhibit a partial enteric immunophenotype with consistent expression of CDX2. Int J Gynecol Pathol. 2008;27(1):92–100.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Balci S, Saglam A, Usubutun A. Primary signet-ring cell carcinoma of the cervix: case report and review of the literature. Int J Gynecol Pathol. 2010;29(2):181–4.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    McCluggage WG. Recent developments in non-HPV-related adenocarcinomas of the lower female genital tract and their precursors. Adv Anat Pathol. 2016;23(1):58–69.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Gilks CB, Young RH, Aguirre P, DeLellis RA, Scully RE. Adenoma malignum (minimal deviation adenocarcinoma) of the uterine cervix. A clinicopathological and immunohistochemical analysis of 26 cases. Am J Surg Pathol. 1989;13(9):717–29.PubMedCrossRefGoogle Scholar
  96. 96.
    Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R, et al. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet. 1998;18(1):38–43.PubMedCrossRefGoogle Scholar
  97. 97.
    Kuragaki C, Enomoto T, Ueno Y, Sun H, Fujita M, Nakashima R, et al. Mutations in the STK11 gene characterize minimal deviation adenocarcinoma of the uterine cervix. Lab Investig. 2003;83(1):35–45.PubMedCrossRefGoogle Scholar
  98. 98.
    Jones MW, Silverberg SG, Kurman RJ. Well-differentiated villoglandular adenocarcinoma of the uterine cervix: a clinicopathological study of 24 cases. Int J Gynecol Pathol. 1993;12(1):1–7.PubMedCrossRefGoogle Scholar
  99. 99.
    Hanselaar A, Van Loosbroek M, Schuurbiers O, Helmerhorst T, Bulten J, Bernhelm J. Clear cell adenocarcinoma of the vagina and cervix. An update of the Central Netherlands registry showing twin age incidence peaks. Cancer. 1997;79(11):2229–36.PubMedCrossRefGoogle Scholar
  100. 100.
    Kaminski PF, Maier RC. Clear cell adenocarcinoma of the cervix unrelated to diethylstilbestrol exposure. Obstet Gynecol. 1983;62(6):720–7.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Zhou C, Gilks CB, Hayes M, Clement PB. Papillary serous carcinoma of the uterine cervix: a clinicopathologic study of 17 cases. Am J Surg Pathol. 1998;22(1):113–20.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Ferry JA, Scully RE. Mesonephric remnants, hyperplasia, and neoplasia in the uterine cervix. A study of 49 cases. Am J Surg Pathol. 1990;14(12):1100–11.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Ayer B, Pacey F, Greenberg M. The cytologic diagnosis of adenocarcinoma in situ of the cervix uteri and related lesions. II. Microinvasive adenocarcinoma. Acta Cytol. 1988;32(3):318–24.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Granter SR, Lee KL. Cytologic findings in minimal deviation adenocarcinoma (adenoma malignum) of the cervix: a report of seven cases. Am J Clin Pathol. 1996;105:327–33.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Khalbuss W, Monaco S, Pantanowitz L. Cytomorphology of unusual primary tumors in the Pap test. CytoJournal. 2013;10:17.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Choi Y, Kim H, Choi H, Hwang D, Choe G, Chung J-H, et al. Liquid-based cytology of villoglandular adenocarcinoma of the cervix: a report of 3 cases. Korean J Pathol. 2012;46(2):215–20.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Hanselaar AGJM, Boss EA, Massuger LFAG, Bernheim JL. Cytologic examination to detect clear cell adenocarcinoma of the vagina or cervix. Gynecol Oncol. 1999;75:338–44.PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Mannion C, Park WS, Man YG, Zhuang Z, Albores-Saavedra J, Tavassoli FA. Endocrine tumors of the cervix: morphologic assessment, expression of human papillomavirus and evaluation for loss of heterozygosity on 1p,3p, 11q, and 17p. Cancer. 1998;83(7):1391–400.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Bosman FT, Carneiro F, Hruban RH, Theise ND, editors. WHO classification of tumours of the digestive system. 4th ed. Lyon: IARC; 2014.Google Scholar
  110. 110.
    McCusker ME, Cote TR, Clegg LX, Tavassoli FJ. Endocrine tumors of the uterine cervix: incidence, demographics, and survival with comparison to squamous cell carcinoma. Gynecol Oncol. 2003;88(3):333–9.PubMedCrossRefGoogle Scholar
  111. 111.
    Zaino RJ, Nahhas WA, Mortel R. Glassy cell carcinoma of the uterine cervix. An ultrastructural study and review. Arch Pathol Lab Med. 1982;106(5):250–4.PubMedGoogle Scholar
  112. 112.
    Guitarte C, Alagkiozidis I, Mize B, Stevens E, Salame G, Lee Y-C. Glassy cell carcinoma of the cervix: a systematic review and meta-analysis. Gynecol Oncol. 2014;133(2):186–91.PubMedCrossRefGoogle Scholar
  113. 113.
    Chen T-D, Chuang H-C, Lee L. Adenoid basal carcinoma of the uterine cervix: clinicopathologic features of 12 cases with reference to CD117 expression. Int J Gynecol Pathol. 2012;31(1):25–32.PubMedCrossRefGoogle Scholar
  114. 114.
    Ferry JA, Scully RE. “Adenoid cystic” carcinoma and adenoid basal carcinoma of the uterine cervix: a study of 28 cases. J Surg Pathol. 1988;12(2):134–44.CrossRefGoogle Scholar
  115. 115.
    Abell MR, Ramirez GJA. Sarcomas and carcinosarcomas of the uterine cervix. Cancer. 1973;31(5):1176–92.PubMedCrossRefGoogle Scholar
  116. 116.
    Kim M, Lee C, Choi H, Ko J-K, Kang G, Chun K. Carcinosarcoma of the uterine cervix arising from Müllerian ducts. Obstet Gynecol Sci. 2015;58(3):251.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Singh N, Tripathi R, Mala YM. Primary malignant melanoma of uterine cervix with probable origin from benign cervical melanosis. BMJ Case Rep [Internet] 2013 is repeated.
  118. 118.
    Myriokefalitaki E, Babbel B, Smith M, Ahmed AS. Primary malignant melanoma of uterine cervix FIGO IIa1: a case report with 40 months ongoing survival and literature review. Gynecol Oncol Case Rep. 2013;5:52–4.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Mardi K, Gupta N, Bindra R. Primary yolk sac tumor of cervix and vagina in an adult female: a rare case report. Indian J Cancer. 2011;48(4):515.PubMedCrossRefGoogle Scholar
  120. 120.
    Bellevicine C, Zabatta A, Malapelle U, Vetrani A, Troncone G. Diffuse large B-cell extranodal lymphoma of the uterine cervix. Diagn Cytopathol. 2014;42(7):644–6.PubMedCrossRefGoogle Scholar
  121. 121.
    Giorgadze T, Kanhere R, Pang C, Ganote C, Miller LE, Tabaczka P, Brown E, Husain M. Small cell carcinoma of the cervix in liquid-based Pap test: utilization of split-sample immunocytochemical and molecular analysis. Diagn Cytopathol. 2012;40:214–9.PubMedCrossRefGoogle Scholar
  122. 122.
    Li S, Zhu H. Twelve cases of neuroendocrine carcinomas of the uterine cervix: cytology, histopathology and discussion of their histogenesis. Acta Cytol. 2013;57(1):54–60.PubMedCrossRefGoogle Scholar
  123. 123.
    Sasagawa M, Nishino K, Honma S, Kodama S, Takahashi T. Origin of adenocarcinoma cells observed on cervical cytology. Acta Cytol. 2003;47:410–4.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Mariana Canepa
    • 1
    Email author
  • Nimesh R. Patel
    • 1
  • Maria Luisa Garcia-Moliner
    • 1
  1. 1.Department of Pathology and Laboratory MedicineBrown University Warren Alpert Medical SchoolProvidenceUSA

Personalised recommendations