Abstract
A classification system for invasive endocervical adenocarcinoma (ECA) focusing on high-risk human papillomavirus (HPV) detection has been recently developed. However, precursor lesions of each ECA subtype and immunohistochemical markers that effectively subcategorize ECAs with gastric and intestinal differentiation have not been fully described. Here, we aimed to subcategorize endocervical adenocarcinoma in situ (AIS) by immunophenotype and to characterize the histopathology of each AIS subtype. We immunohistochemically analyzed 36 AIS and 25 lobular endocervical glandular hyperplasia (LEGH) samples using three cell lineage–specific markers (CLDN18, gastric epithelial cells; CDH17, intestinal epithelial cells; and PAX8, Müllerian epithelial cells). The AISs were immunophenotypically classified as gastric-type (G-AIS; n = 2), intestinal-type (I-AIS; n = 10), gastrointestinal-type (GI-AIS; n = 3), Müllerian-type (M-AIS; n = 18), and AIS, not otherwise specified (AIS-NOS; n = 3). All 25 LEGHs were categorized as gastric-type. G-AIS had pale eosinophilic or clear cytoplasm with a small amount of apical mucin and fewer mitotic bodies. I-AIS comprised various numbers of goblet cell-type tumor cells. GI-AIS showed intermediate or mixed features of G-AIS and I-AIS. M-AIS, as with the usual-type ECA, was typically characterized by mucin depletion; however, several lesions had abundant cytoplasmic mucin. High-risk HPV was detected in most AISs but was negative in 100% (2/2) of G-AIS, 10% (1/10) of I-AIS, and 6% (1/18) of M-AIS lesions. In summary, the AIS subtypes defined by immunophenotype had distinct histopathological and etiological characteristics. Thus, immunophenotyping with CLDN18, CDH17, and PAX8 might improve the diagnostic accuracy of histopathological classifications of ECAs.
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References
Smith HO, Tiffany MF, Qualls CR, Key CR (2000) The rising incidence of adenocarcinoma relative to squamous cell carcinoma of the uterine cervix in the United States—a 24-year population-based study. Gynecol Oncol 78(2):97–105. https://doi.org/10.1006/gyno.2000.5826
Adegoke O, Kulasingam S, Virnig B (2012) Cervical cancer trends in the United States: a 35-year population-based analysis. J Women's Health 21(10):1031–1037. https://doi.org/10.1089/jwh.2011.3385
Bray F, Carstensen B, Moller H, Zappa M, Zakelj MP, Lawrence G, Hakama M, Weiderpass E (2005) Incidence trends of adenocarcinoma of the cervix in 13 European countries. Cancer Epidemiol Biomark Prev 14(9):2191–2199. https://doi.org/10.1158/1055-9965.Epi-05-0231
Pirog EC, Lloveras B, Molijn A, Tous S, Guimera N, Alejo M, Clavero O, Klaustermeier J, Jenkins D, Quint WG, Xavier Bosch F, Alemany L, de Sanjose S (2014) HPV prevalence and genotypes in different histological subtypes of cervical adenocarcinoma, a worldwide analysis of 760 cases. Mod Pathol 27(12):1559–1567. https://doi.org/10.1038/modpathol.2014.55
Castellsague X, Diaz M, de Sanjose S, Munoz N, Herrero R, Franceschi S, Peeling RW, Ashley R, Smith JS, Snijders PJ, Meijer CJ, Bosch FX (2006) Worldwide human papillomavirus etiology of cervical adenocarcinoma and its cofactors: implications for screening and prevention. J Natl Cancer Inst 98(5):303–315. https://doi.org/10.1093/jnci/djj067
Karamurzin YS, Kiyokawa T, Parkash V, Jotwani AR, Patel P, Pike MC, Soslow RA, Park KJ (2015) Gastric-type endocervical adenocarcinoma an aggressive tumor with unusual metastatic patterns and poor prognosis. Am J Surg Pathol 39(11):1449–1457. https://doi.org/10.1097/pas.0000000000000532
Kusanagi Y, Kojima A, Mikami Y, Kiyokawa T, Sudo T, Yamaguchi S, Nishimura R (2010) Absence of high-risk human papillomavirus (HPV) detection in endocervical adenocarcinoma with gastric morphology and phenotype. Am J Pathol 177(5):2169–2175. https://doi.org/10.2353/ajpath.2010.100323
Kojima A, Mikami Y, Sudo T, Yamaguchi S, Kusanagi Y, Ito M, Nishimura R (2007) Gastric morphology and immunophenotype predict poor outcome in mucinous adenocarcinoma of the uterine cervix. Am J Surg Pathol 31(5):664–672. https://doi.org/10.1097/01.pas.0000213434.91868.b0
Mikami Y, Kyokawa T, Hata S, Fujiwara K, Moriya T, Sasano H, Manabe T, Akahira JI, Ito K, Tase T, Yaegashi N, Sato I, Tateno H, Naganuma H (2004) 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 17(8):962–972. https://doi.org/10.1038/modpathol.3800148
Nucci MR, Clement PB, Young RH (1999) Lobular endocervical glandular hyperplasia, not otherwise specified: a clinicopathologic analysis of thirteen cases of a distinctive pseudoneoplastic lesion and comparison with fourteen cases of adenoma malignum. Am J Surg Pathol 23(8):886–891
Kawauchi S, Kusuda T, Liu XP, Suehiro Y, Kaku T, Mikami Y, Takeshita M, Nakao M, Chochi Y, Sasaki K (2008) Is lobular endocervical glandular hyperplasia a cancerous precursor of minimal deviation adenocarcinoma? A comparative molecular-genetic and immunohistochemical study. Am J Surg Pathol 32(12):1807–1815. https://doi.org/10.1097/PAS.0b013e3181883722
Wilbur DC, Mikami Y, Colgan TJ, Park KJ, Ferenczy AS, Ronnett BM, Hirschowitz L, Schneider A, Loening T, Soslow R, McCluggage WG, Wells M, Wright T (2014) Glandular tumours and precursors. In: Kurman RJ, Carcangiu ML, Herrington CS, Young RH (eds) WHO classification of tumours of female reproductive organs, 4th edn. International Agency for Research on Cancer, Lyon, pp 183–189
Stolnicu S, Barsan I, Hoang L, Patel P, Terinte C, Pesci A, Aviel-Ronen S, Kiyokawa T, Alvarado-Cabrero I, Pike MC, Oliva E, Park KJ, Soslow RA (2018) International endocervical adenocarcinoma criteria and classification (IECC): a new pathogenetic classification for invasive adenocarcinomas of the endocervix. Am J Surg Pathol 42(2):214–226. https://doi.org/10.1097/pas.0000000000000986
Hodgson A, Park KJ, Djordjevic B, B EH, Nucci MR, Oliva E, Stolnicu S, Xu B, Soslow RA, Parra-Herran C (2018) International endocervical adenocarcinoma criteria and classification: validation and interobserver reproducibility. Am J Surg Pathol 43(1):75–83. https://doi.org/10.1097/pas.0000000000001095
Stolnicu S, Barsan I, Hoang L, Patel P, Chiriboga L, Terinte C, Pesci A, Aviel-Ronen S, Kiyokawa T, Alvarado-Cabrero I, Pike MC, Oliva E, Park KJ, Soslow RA (2018) Diagnostic algorithmic proposal based on comprehensive immunohistochemical evaluation of 297 invasive endocervical adenocarcinomas. Am J Surg Pathol 42(8):989–1000. https://doi.org/10.1097/pas.0000000000001090
Stolnicu S, Hoang L, Chiu D, Hanko-Bauer O, Terinte C, Pesci A, Aviel-Ronen S, Kiyokawa T, Alvarado-Cabrero I, Oliva E, Park KJ, Abu-Rustum NR, Soslow RA (2019) Clinical outcomes of HPV-associated and unassociated endocervical adenocarcinomas categorized by the international endocervical adenocarcinoma criteria and classification (IECC). Am J Surg Pathol 43(4):466–474. https://doi.org/10.1097/pas.0000000000001224
Hodgson A, Olkhov-Mitsel E, Howitt BE, Nucci MR, Parra-Herran C (2019) International endocervical adenocarcinoma criteria and classification (IECC): correlation with adverse clinicopathological features and patient outcome. J Clin Pathol 72(5):347–353. https://doi.org/10.1136/jclinpath-2018-205632
Asaka S, Nakajima T, Momose M, Miyamoto T, Uehara T, Ota H (2019) Trefoil factor family 2 protein: a potential immunohistochemical marker for aiding diagnosis of lobular endocervical glandular hyperplasia and gastric-type adenocarcinoma of the uterine cervix. Virchows Arch 474(1):79–86. https://doi.org/10.1007/s00428-018-2469-z
Ota H, Hayama M, Nakayama J, Hidaka H, Honda T, Ishii K, Fukushima M, Uehara T, Kurihara M, Ishihara K, Hotta K, Katsuyama T (2001) Cell lineage specificity of newly raised monoclonal antibodies against gastric mucins in normal, metaplastic, and neoplastic human tissues and their application to pathology diagnosis. Am J Clin Pathol 115(1):69–79
Nakajima K, Ota H, Zhang MX, Sano K, Honda T, Ishii K, Nakayama J (2003) Expression of gastric gland mucous cell-type mucin in normal and neoplastic human tissues. J Histochem Cytochem 51(12):1689–1698. https://doi.org/10.1177/002215540305101213
Shinozaki A, Ushiku T, Morikawa T, Hino R, Sakatani T, Uozaki H, Fukayama M (2009) Epstein-Barr virus-associated gastric carcinoma: a distinct carcinoma of gastric phenotype by claudin expression profiling. J Histochem Cytochem 57(8):775–785. https://doi.org/10.1369/jhc.2009.953810
Tamura A, Yamazaki Y, Hayashi D, Suzuki K, Sentani K, Yasui W, Tsukita S (2012) Claudin-based paracellular proton barrier in the stomach. Ann N Y Acad Sci 1258:108–114. https://doi.org/10.1111/j.1749-6632.2012.06570.x
Shinozaki A, Shibahara J, Noda N, Tanaka M, Aoki T, Kokudo N, Fukayama M (2011) Claudin-18 in biliary neoplasms. Its significance in the classification of intrahepatic cholangiocarcinoma. Virchows Arch 459(1):73–80. https://doi.org/10.1007/s00428-011-1092-z
Tanaka M, Shibahara J, Fukushima N, Shinozaki A, Umeda M, Ishikawa S, Kokudo N, Fukayama M (2011) Claudin-18 is an early-stage marker of pancreatic carcinogenesis. J Histochem Cytochem 59(10):942–952. https://doi.org/10.1369/0022155411420569
Halimi SA, Maeda D, Shinozaki-Ushiku A, Koso T, Matsusaka K, Tanaka M, Arimoto T, Oda K, Kawana K, Yano T, Fujii T, Fukayama M (2013) Claudin-18 overexpression in intestinal-type mucinous borderline tumour of the ovary. Histopathology 63(4):534–544. https://doi.org/10.1111/his.12182
Maeda D (2015) Utility of claudin-18 and p16 immunohistochemistry for distinguishing gastric-type adenocarcinoma from other subtypes of cervical adenocarcinoma. Mod Pathol 28:296A–297A
Ordonez NG (2014) Cadherin 17 is a novel diagnostic marker for adenocarcinomas of the digestive system. Adv Anat Pathol 21(2):131–137. https://doi.org/10.1097/pap.0000000000000008
Su MC, Yuan RH, Lin CY, Jeng YM (2008) Cadherin-17 is a useful diagnostic marker for adenocarcinomas of the digestive system. Mod Pathol 21(11):1379–1386. https://doi.org/10.1038/modpathol.2008.107
Hinoi T, Lucas PC, Kuick R, Hanash S, Cho KR, Fearon ER (2002) CDX2 regulates liver intestine-cadherin expression in normal and malignant colon epithelium and intestinal metaplasia. Gastroenterology 123(5):1565–1577
Berndorff D, Gessner R, Kreft B, Schnoy N, Lajous-Petter AM, Loch N, Reutter W, Hortsch M, Tauber R (1994) Liver-intestine cadherin: molecular cloning and characterization of a novel Ca(2+)-dependent cell adhesion molecule expressed in liver and intestine. J Cell Biol 125(6):1353–1369
Panarelli NC, Yantiss RK, Yeh MM, Liu Y, Chen YT (2012) Tissue-specific cadherin CDH17 is a useful marker of gastrointestinal adenocarcinomas with higher sensitivity than CDX2. Am J Clin Pathol 138(2):211–222. https://doi.org/10.1309/ajcpkshxi3xehw1j
Matsusaka K, Ushiku T, Urabe M, Fukuyo M, Abe H, Ishikawa S, Seto Y, Aburatani H, Hamakubo T, Kaneda A, Fukayama M (2016) Coupling CDH17 and CLDN18 markers for comprehensive membrane-targeted detection of human gastric cancer. Oncotarget 7(39):64168–64181. https://doi.org/10.18632/oncotarget.11638
Talia KL, Stewart CJ, Howitt BE, Nucci MR, McCluggage WG (2017) HPV-negative gastric type adenocarcinoma in situ of the cervix: a spectrum of rare lesions exhibiting gastric and intestinal differentiation. Am J Surg Pathol 41(8):1023–1033. https://doi.org/10.1097/pas.0000000000000855
Park KJ, Kiyokawa T, Soslow RA, Lamb CA, Oliva E, Zivanovic O, Juretzka MM, Pirog EC (2011) Unusual endocervical adenocarcinomas: an immunohistochemical analysis with molecular detection of human papillomavirus. Am J Surg Pathol 35(5):633–646. https://doi.org/10.1097/PAS.0b013e31821534b9
An HJ, Kim KR, Kim IS, Kim DW, Park MH, Park IA, Suh KS, Seo EJ, Sung SH, Sohn JH, Yoon HK, Chang ED, Cho HI, Han JY, Hong SR, Ahn GH (2005) Prevalence of human papillomavirus DNA in various histological subtypes of cervical adenocarcinoma: a population-based study. Mod Pathol 18(4):528–534. https://doi.org/10.1038/modpathol.3800316
Pirog EC, Kleter B, Olgac S, Bobkiewicz P, Lindeman J, Quint WG, Richart RM, Isacson C (2000) Prevalence of human papillomavirus DNA in different histological subtypes of cervical adenocarcinoma. Am J Pathol 157(4):1055–1062. https://doi.org/10.1016/s0002-9440(10)64619-6
Carleton C, Hoang L, Sah S, Kiyokawa T, Karamurzin YS, Talia KL, Park KJ, McCluggage WG (2016) A detailed immunohistochemical analysis of a large series of cervical and vaginal gastric-type adenocarcinomas. Am J Surg Pathol 40(5):636–644. https://doi.org/10.1097/pas.0000000000000578
Talia KL, Cretney A, McCluggage WG (2014) A case of HPV-negative intestinal-type endocervical adenocarcinoma in situ with coexisting multifocal intestinal and gastric metaplasia. Am J Surg Pathol 38(2):289–291. https://doi.org/10.1097/pas.0000000000000139
Kushima R, Hattori T (1993) Histogenesis and characteristics of gastric-type adenocarcinomas in the stomach. J Cancer Res Clin Oncol 120(1–2):103–111
Fujimori Y, Akamatsu T, Ota H, Katsuyama T (1995) Proliferative markers in gastric carcinoma and organoid differentiation. Hum Pathol 26(7):725–734
Kobayashi M, Fujinaga Y, Ota H (2014) Reappraisal of the immunophenotype of pancreatic intraductal papillary mucinous neoplasms (IPMNs)-gastric pyloric and small intestinal immunophenotype expression in gastric and intestinal type IPMNs. Acta Histochem Cytochem 47(2):45–57. https://doi.org/10.1267/ahc.13027
Howitt BE, Herfs M, Brister K, Oliva E, Longtine J, Hecht JL, Nucci MR (2013) Intestinal-type endocervical adenocarcinoma in situ: an immunophenotypically distinct subset of AIS affecting older women. Am J Surg Pathol 37(5):625–633. https://doi.org/10.1097/PAS.0b013e318285be00
Mikami Y, Hata S, Melamed J, Fujiwara K, Manabe T (2001) Lobular endocervical glandular hyperplasia is a metaplastic process with a pyloric gland phenotype. Histopathology 39(4):364–372. https://doi.org/10.1046/j.1365-2559.2001.01239.x
Nara M, Hashi A, Murata S-I, Kondo T, Yuminamochi T, Nakazawa K, Katoh R, Hoshi K (2007) Lobular endocervical glandular hyperplasia as a presumed precursor of cervical adenocarcinoma independent of human papillomavirus infection. Gynecol Oncol 106(2):289–298. https://doi.org/10.1016/j.ygyno.2007.03.044
Acknowledgments
We thank Kayo Suzuki and Misako Yamada (Research Center for Supports to Advanced Science, Shinshu University) and Chinatsu Kobayashi and Masayuki Ito (Department of Clinical Laboratory Sciences, Shinshu University School of Medicine) for providing expert technical assistance. We also thank Editage (www.editage.jp) for English language editing.
Contributions
Conceptualization: Shiho Asaka and Hiroyoshi Ota; Methodology: Shiho Asaka, Tomoyuki Nakajima, Takeshi Uehara, and Hiroyoshi Ota; Formal analysis and investigation: Shiho Asaka, Tomoyuki Nakajima, Kaori Kugo, Risako Kashiwagi, Nozomi Yazaki, and Hiroyoshi Ota; Writing—original draft preparation: Shiho Asaka; Writing—review and editing: Hiroyoshi Ota; Funding acquisition: Shiho Asaka and Hiroyoshi Ota; Resources: Tsutomu Miyamoto and Takeshi Uehara; Supervision: Hiroyoshi Ota. All authors gave final approval for publication. Shiho Asaka takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript.
Funding
This work was funded by the Japan Society for the Promotion of Science (JSPS), Grants-in-Aid for Scientific Research (KAKENHI) to Shiho Asaka (17K15641) and Hiroyoshi Ota (17K09010).
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Asaka, S., Nakajima, T., Kugo, K. et al. Immunophenotype analysis using CLDN18, CDH17, and PAX8 for the subcategorization of endocervical adenocarcinomas in situ: gastric-type, intestinal-type, gastrointestinal-type, and Müllerian-type. Virchows Arch 476, 499–510 (2020). https://doi.org/10.1007/s00428-019-02739-x
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DOI: https://doi.org/10.1007/s00428-019-02739-x