{"id":420,"date":"2020-08-13T20:35:42","date_gmt":"2020-08-13T20:35:42","guid":{"rendered":"https:\/\/brooksidepress.org\/basic_obgyn\/?page_id=420"},"modified":"2022-09-08T17:09:58","modified_gmt":"2022-09-08T17:09:58","slug":"cervical-disease","status":"publish","type":"page","link":"https:\/\/brooksidepress.org\/basic_obgyn\/advanced-training\/cervical-disease\/","title":{"rendered":"Cervical Disease"},"content":{"rendered":"<p><iframe loading=\"lazy\" src=\"https:\/\/www.youtube.com\/embed\/lMdINPOrttE\" width=\"560\" height=\"315\" frameborder=\"0\" allowfullscreen=\"allowfullscreen\"><span data-mce-type=\"bookmark\" style=\"display: inline-block; width: 0px; overflow: hidden; line-height: 0;\" class=\"mce_SELRES_start\">\ufeff<\/span><\/iframe><\/p>\n<p>Duration 10:14<\/p>\n<input type='hidden' bg_collapse_expand='69e9c84ca29e09031208158' value='69e9c84ca29e09031208158'><input type='hidden' id='bg-show-more-text-69e9c84ca29e09031208158' value='Show Teaching Script'><input type='hidden' id='bg-show-less-text-69e9c84ca29e09031208158' value='Hide Teaching Script'><button id='bg-showmore-action-69e9c84ca29e09031208158' class='bg-showmore-plg-button bg-blue-button  '   style=\" color:#ffffff;\">Show Teaching Script<\/button><div id='bg-showmore-hidden-69e9c84ca29e09031208158' ><\/p>\n<p class=\"p2\">Cervical Intraepithelial Neoplasia<\/p>\n<p class=\"p2\">Liang A<\/p>\n<p class=\"p3\"><b>Clinical case applicability<\/b>: Abnormal pap smear, HPV, genital warts, CIN, cervical cancer<\/p>\n<p class=\"p3\"><b>Learning Objectives: <\/b><\/p>\n<p class=\"p4\">1) Understand the role of HPV in causing cervical intraepithelial neoplasia and cancer<\/p>\n<p class=\"p5\"><span class=\"s3\">2) <\/span>Describe the histopathology of cervical intraepithelial neoplasia<\/p>\n<p class=\"p3\"><b>What is human papilloma virus (HPV)? <\/b><\/p>\n<p class=\"p3\">Double-stranded circular DNA virus with 7 early genes E1-E7 (proteins involved in viral gene regulation and cell transformation) &amp; 2 late genes L1-L2 (proteins that form the shell)<\/p>\n<p class=\"p3\"><b>What is HPV\u2019s role in CIN? <\/b>HPV necessary for CIN but HPV alone NOT sufficient to cause CIN. Depends on:<\/p>\n<p class=\"p3\"><b>1) Subtype: <\/b>Determines the oncogenic potential of the virus.<\/p>\n<p class=\"p3\">&#8211; Low risk types (HPV 6, 11) don\u2019t integrate into host genome (6 &amp; 11 account for 90% of warts)<\/p>\n<p class=\"p3\">&#8211; High risk types (HPV 16, 18, 31, 33, 35, 39, 45, 51, etc) \u2191 persistence &amp; progression to cancer (16 &amp; 18 account for 70% of cervical cancers)<\/p>\n<p class=\"p3\"><b>2) Persistence <\/b>\u2013 &gt;50% new HPV infections are cleared in 6-18 months, 80-90% resolve within 2-5 years; Risks for persistence: 1) <b><i>Older age <\/i><\/b>&#8211; 50% persist in women age &gt;55 versus 20% in women &lt;25 (co-testing for screening only in women &gt; 30), 2) <b><i>High risk subtypes<\/i><\/b>, 3) <b><i>Duration <\/i><\/b>of infection<\/p>\n<p class=\"p3\"><b>What causes neoplastic transformation? HPV integrates into the genome <\/b>(see figure 1)<\/p>\n<p class=\"p3\">Viral integration <span class=\"s4\">\uf0e0<\/span>disrupts E1\/E2 open reading frames <span class=\"s4\">\uf0e0<\/span>loss of transcriptional regulation of E6\/E7 <span class=\"s4\">\uf0e0<\/span>immortalization of infected cell lines<\/p>\n<p class=\"p3\">1) <b>E6 <\/b><span class=\"s4\">\uf0e0<\/span>binds p53 protein (negative regulator of cell growth, tumor suppressor protein) <span class=\"s4\">\uf0e0 <\/span>cellular degradation of p53 <span class=\"s4\">\uf0e0 <\/span>unchecked cellular cycling, accumulation of mutations w\/o repair<\/p>\n<p class=\"p3\">2) <b>E7 <\/b><span class=\"s4\">\uf0e0<\/span>binds Rb protein (halts cell growth &amp; induces cell apoptosis, binds E2F transcription factor to make it inactive) <span class=\"s4\">\uf0e0 <\/span>release of transcription factor E2F<span class=\"s4\">\uf0e0<\/span>promotes cell cycle progression<\/p>\n<p class=\"p3\"><b>What changes are noted histologically? What is the risk of progression to cancer? <\/b>(for classification systems, see figure 2)<\/p>\n<p class=\"p3\">Occurs at the transformation zone of the cervix<\/p>\n<p class=\"p3\"><b>CIN-1\/LSIL<\/b>: Regress in most women; low grade, mild, atypical cellular changes in lower 1\/3 of the epithelium, HPV persists in cytoplasm (no integration)<span class=\"s5\">\uf0e0 <\/span>+koilocytes (nuclear enlargement, halo)<\/p>\n<p class=\"p3\"><b>CIN-2\/LSIL vs. HSIL<\/b>: 22% progress to CIN 3, 5% progress to cancer; High grade, atypical cellular changes confined to lower 2\/3 of the epithelium; CIN-2\/3 often classified together secondary to poor reproducibility of CIN-2; if p16 staining done<span class=\"s5\">\uf0e0 <\/span>negative p16 = LSIL, positive p16 = HSIL<\/p>\n<p class=\"p3\"><b>CIN-3\/HSIL<\/b>: 12-40% progress to cancer; High grade, atypical cellular changes &gt;2\/3 to full thickness<\/p>\n<p class=\"p3\"><b>What are cofactors in pathogenesis? <\/b><\/p>\n<p class=\"p3\">1) Immunosuppression (HIV, immunosuppressive therapies)<\/p>\n<p class=\"p3\">2) Cigarette smoking: synergistic effects with HPV on development of CIN; breakdown products of cigarette smoke are concentrated in cervical mucus <span class=\"s4\">\uf0e0 <\/span>induce cellular abnormalities and \u2193local immunity<\/p>\n<p class=\"p3\">3) HSV, chlamydia, OCPS: likely surrogate markers of exposure to HPV rather than causal factor<\/p>\n<p class=\"p3\"><b>What is Gardasil? How does it work? <\/b><\/p>\n<p class=\"p7\"><span class=\"s6\">&#8211; <\/span>Gardasil quadrivalent targets 6, 11, 16, 18; 9-valent ALSO covers 31, 33, 45, 52, 58<\/p>\n<p class=\"p3\"><span class=\"s6\">&#8211; <\/span>Contains inactive HPV capsid proteins (L1) which produce neutralizing antibodies<\/p>\n<p class=\"p3\">Cervical Intraepithelial Neoplasia<\/p>\n<p class=\"p2\">Liang A<\/p>\n<p class=\"p8\">HPV<\/p>\n<p class=\"p9\">E6<\/p>\n<p class=\"p9\">E7<\/p>\n<p class=\"p9\">E6<\/p>\n<p class=\"p9\">p53<\/p>\n<p class=\"p8\"><i>Degradation of p53 <\/i><\/p>\n<p class=\"p8\">Loss of<\/p>\n<p class=\"p8\">tumor<\/p>\n<p class=\"p8\">suppression<\/p>\n<p class=\"p8\">Cervical squamous cell<\/p>\n<p class=\"p8\">Nucleus<\/p>\n<p class=\"p9\">E7<\/p>\n<p class=\"p10\">Rb<\/p>\n<p class=\"p11\">E2F<\/p>\n<p class=\"p8\">Cell<\/p>\n<p class=\"p8\">cycle<\/p>\n<p class=\"p8\">progression<\/p>\n<p class=\"p9\">E7<\/p>\n<p class=\"p10\">Rb<\/p>\n<p class=\"p11\">E2F<\/p>\n<p class=\"p9\">+<\/p>\n<p class=\"p8\"><i>Release of E2F <\/i><\/p>\n<p class=\"p12\"><b>Figure 1 <\/b><\/p>\n<p class=\"p13\">p53<\/p>\n<table class=\"t1\" cellspacing=\"0\" cellpadding=\"0\">\n<tbody>\n<tr>\n<td class=\"td1\" valign=\"top\">\n<p class=\"p2\"><b>Figure 2 Bethesda <\/b><\/p>\n<\/td>\n<td class=\"td1\" valign=\"top\">\n<p class=\"p2\"><b>CIN 1 <\/b><\/p>\n<\/td>\n<td class=\"td1\" valign=\"top\">\n<p class=\"p2\"><b>CIN 2 <\/b><\/p>\n<\/td>\n<td class=\"td1\" valign=\"top\">\n<p class=\"p2\"><b>CIN 3 <\/b><\/p>\n<\/td>\n<\/tr>\n<tr>\n<td class=\"td1\" valign=\"top\">\n<p class=\"p2\"><b>LAST <\/b><\/p>\n<\/td>\n<td class=\"td1\" valign=\"top\">\n<p class=\"p2\"><b>LSIL <\/b><\/p>\n<\/td>\n<td class=\"td1\" valign=\"top\">\n<p class=\"p2\"><b>LSIL <\/b><\/p>\n<p class=\"p2\">(p16 negative)<\/p>\n<\/td>\n<td class=\"td1\" valign=\"top\">\n<p class=\"p2\"><b>HSIL <\/b><\/p>\n<p class=\"p2\">(p16 positive)<\/p>\n<\/td>\n<td class=\"td1\" valign=\"top\">\n<p class=\"p2\"><b>HSIL <\/b><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<p><\/div>\n<hr \/>\n<p><iframe loading=\"lazy\" src=\"https:\/\/player.vimeo.com\/video\/112182019\" width=\"640\" height=\"360\" frameborder=\"0\" allowfullscreen=\"allowfullscreen\"><\/iframe><\/p>\n<p>Duration = 7:42<\/p>\n<hr \/>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>\ufeff Duration 10:14 Duration = 7:42 &nbsp;<\/p>\n","protected":false},"author":2,"featured_media":0,"parent":160,"menu_order":4,"comment_status":"closed","ping_status":"closed","template":"","meta":{"footnotes":""},"class_list":["post-420","page","type-page","status-publish","hentry"],"_links":{"self":[{"href":"https:\/\/brooksidepress.org\/basic_obgyn\/wp-json\/wp\/v2\/pages\/420","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/brooksidepress.org\/basic_obgyn\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/brooksidepress.org\/basic_obgyn\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/brooksidepress.org\/basic_obgyn\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/brooksidepress.org\/basic_obgyn\/wp-json\/wp\/v2\/comments?post=420"}],"version-history":[{"count":3,"href":"https:\/\/brooksidepress.org\/basic_obgyn\/wp-json\/wp\/v2\/pages\/420\/revisions"}],"predecessor-version":[{"id":1231,"href":"https:\/\/brooksidepress.org\/basic_obgyn\/wp-json\/wp\/v2\/pages\/420\/revisions\/1231"}],"up":[{"embeddable":true,"href":"https:\/\/brooksidepress.org\/basic_obgyn\/wp-json\/wp\/v2\/pages\/160"}],"wp:attachment":[{"href":"https:\/\/brooksidepress.org\/basic_obgyn\/wp-json\/wp\/v2\/media?parent=420"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}