Presented By: L. Luketic
Definitions: Cervical Dysplasia: is abnormal cell growth
on the surface lining of the cervix, which may progress to cervical cancer
Cervical Cancer: cancer that arises in the tissues of the uterine cervix
Pap (Papanicolaou) Smear/Test: is a cytologic exfoliative screening test
Intraepithelial: is the layer of cells that forms the surface of the cervix
Definitions Continued: Koilocytic atypia: are nuclear alterations and is a
cytoplasmic perinuclear halo
Microinvasive Carcinoma: stromal invasion of the cervical epithelium does not extend deeper than 3mm and is not wider than 7mm
Carcinoma in situ: a group of abnormal cells that have not spread, but may progress to invasive cancer
Colposcopy: a procedure that uses a lighted magnifying tool (colposcope), allowing the doctor to take a closer look at the cervix and vagina
Cervical SCJ & T zone: Squamocolumnar Junction (SCJ):
Non-keratinized stratified Squamous epithelium (ectocervix) Non-ciliated simple columnar epithelium (endocervix)
Transformation Zone (T zone):Original SCJ New SCJ
Clinical significance of the SCJ:Almost ALL primary cervical carcinomas arise
in this region of the cervix
Cervical Squamocolumar Junction: (Robbins Fig. 22-16)
Cervical SCJ & T zone Grossly:
Merck & Co., Inc. Human Papillomavirus, Monographs in Medicine. Whitehouse Station, NJ: Merck and Co; 2008.
SCJ & T zone Histologically:
http://1.bp.blogspot.com/_OwoEg7Db_AE/TQTYcJz2cTI/AAAAAAAAA9o/Q5neoLm6-CQ/s1600/CTZ%2Bb.png
Incidence & Mortality Rate of Cervical Carcinomas: According to the National Cancer
Institute, estimated new cases and deaths from cervical (uterine cervix) cancer in the U.S. in 2013 are:New cases: 12,340Deaths: 4,030
Worldwide, cervical carcinoma is the second most common cancer in women
Pathogenesis of Cervical Neoplasia: Most HPV infections are eliminated by our
immune system
HPV infects immature squamous epithelial cells
HPV replicates in maturing squamous cells koilocytic atypia
HPV activates the cell cycle by interfering with the function of Rb and p53
Pathogenesis of Cervical Neoplasia Continued: E6 HPV oncoprotein binds to p53 interrupted
apoptosis of genetically altered cell
E7 HPV oncoprotein binds to RB promotes cell growth and up regulation of cyclin E (E7)
Together E6 & E7 induce centrosome duplication and genomic instability
Factors other than HPV also play a role in cervical carcinoma
http://www.nature.com/nrc/journal/v7/n1/fig_tab/nrc2050_F1.html
Roden and Wu Nature Reviews Cancer 6, 753–763 (October 2006) | doi:10.1038/nrc1973
Risk Factors for Cervical Cancer: Persistent infection with a high oncogenic
risk HPV, e.g., HPV 16 or HPV 18 Multiple sexual partners A male partner with multiple previous or
current sexual partners Young age at first intercourse High parity Immunosuppression Age Use of oral contraceptives Use of nicotine/smoking
Human Papillomavirus (HPV): “HPV is the most common viral STI in the U.S.”
Harald zur Hausen: discovered that HPV is a major cause of cervical carcinoma
2 Classifications of HPV Infection:Low oncogenic risk HPVs: (6, 11, …)High oncogenic risk HPVs: (16, 18, 31, 33, …)
The most significant factor in cervical oncogenesis is said to be “High Oncogenic risk HPVs”
ROBBINS TABLE 22-1
Cervical Intraepithelial Neoplasia (CIN): Precursor to Cervical SCC
Neoplastic changes of the ectocervical squamous epithelium
CIN I: caused by low oncogenic risk HPVsMild koilocytic atypia
CIN II: caused by high oncogenic risk HPVsModerate koilocytic atypia of the squamous cells
CIN III: caused by high oncogenic risk HPVsSevere koilocytic atypia of immature squamous cells
Cervical Cancer Histology: Robbins Fig. 22-17Normal CIN I CIN II CIN III
The cytology of a CIN seen on a Pap smear (Robbins Fig. 22-21)
The Bethesda System: (LSIL) Low-grade Intraepithelial Lesions (LSIL):
Mild dysplasia
Do NOT directly progress to invasive carcinoma
HPV 6 & 11 cause ~90% of all condylomata acuminata
Koilocytic atypia of immature squamous cells = remains in the lower 1/3rd of epithelium
The Bethesda System: (HSIL) High-grade Intraepithelial Lesions (HSIL):
Moderate to severe dysplasia
Pre-cancerous lesions
HPV types 16 & 18 have the highest correlation of causing cervical cancer○ HPV types 31 & 33 also have a high correlation of
causing cervical cancer
Koilocytic atypia of immature squamous cells = extends to 2/3rds of epithelial thickness
HPV Groups/Types:
Expert Rev Mol Diagn. 2008;8(4):405-415. © 2008 Expert Reviews Ltd. http://www.medscape.com/viewarticle/585223
Cervical Cancer Histology: (Robbins Fig. 22-18) LSIL – stained with multiple techniques
Ki-67 & p16 are used to confirm SIL diagnosis
ROBBINS TABLE 22-2
Normal Cervix (Gross):
http://library.med.utah.edu/WebPath/jpeg4/FEM002.jpg
Invasive Carcinoma of the Cervix Tumor extension is by direct MET,
involving adjacent tissues which can include:Paracervical tissuesUrinary bladderUretersRectumVagina
Local and distant lymph node METs Distant METs (liver, lungs, bone marrow,
other)
4 Main Types of Primary Cervical Cancer: Squamous cell carcinoma (SCC) = most
common
Adenocarcinoma = 2nd most common
Adenosquamous carcinoma (or Mixed Cell Carcinomas)
Neuroendocrine (oat cell) carcinoma (NEC)
SCC of the Uterine Cervix: SCCs most often arise at the SCJ Grossly: (3 forms)
Fungating (exophytic) or infiltrativeUlceratedInvasive lesion that causes induration or other
deformities of the cervix Histologically:
Nests and tongues of malignant cellsKeratinizing or Non-keratinizing
Clinical Symptoms:Early-stage: may be asymptomaticLater-stage: abnormal vaginal bleeding, increased
vaginal discharge, pelvic pain, or pain during intercourse
Gross Cervical SCC: (Stage 1)
http://library.med.utah.edu/WebPath/FEMHTML/FEMIDX.html#2
Cervical SCC (Gross) Extensive:
http://library.med.utah.edu/WebPath/FEMHTML/FEMIDX.html
SCC of the Cervix (Robbins Fig. 22-19)
Cervical Adenocarcinomas: Arise in the columnar epithelium (glandular cells that
produce mucus) of the endocervix Grossly:
Fungating (exophytic)InfiltrativeAbnormal mass/growth visible during colposcopy
Histologically: Glandular epithelium proliferation of malignant endocervical
cellsLarge hyperchromatic nucleiCytoplasm is mostly depleted of mucin
Clinical Symptoms: Abnormal vaginal bleeding/discharge, pelvic pain, or
asymptomatic
Cervical Adenocarcinoma (Gross):
http://www.askjpc.org/wsco/wsc_showconference.php?id=294
Adenocarcinoma of the Cervix (Robbins Fig. 22-20)
Staging of Cervical Carcinoma (Robbins)
http://www.studentconsult.com/content/default.cfm?ISBN=9781416031215
Prognosis:
5-year survival rates:Stage Ia = ~95%Stage Ib = ~80-90%Stage II = ~75%Stage III+ = <50%
Stage IV most common cause of death is local extension
The prognosis of adenosquamous and neuroendocrine carcinomas are worse than adenocarcinomas and SCCs
Cervical Screening: Pap smears are the most efficient way to
test for/diagnose pre-invasive and invasive cervical carcinomasStudies show that there is an ~80% decrease in
cervical cancer (incidence & mortality rate) for women that get regular Pap smears○ Cervical SCC vs. Adenocarcinoma Pap smear accuracy
HPV DNA Testing: Similar to the Pap test, HPV DNA testing uses
cervical cells for lab testingDetermines positive/negative infection for HPV
strands most likely to cause cervical carcinoma Sensitivity vs. Specificity
Prevention: Vaccines: Gardasil and Cervarix
Cervarix protects against HPV 16 & 18 (High oncogenic risk HPVs ~70%)
Gardasil protects against HPV 16 & 18 (High oncogenic risk HPVs ~70%) and HPV 6 & 11 (Low oncogenic risk HPVs ~90%)
Avoid smoking Remain abstinent Delay first intercourse Use a condom during intercourse Have fewer sexual partners
Treatment Options:
Pre-malignant Lesions:Surgical ConizationCryosurgeryLaser surgeryLEEP (Loop Electrosurgical Excision Procedure)
Malignant Lesions:Surgery (i.e., hysterectomy/TAHBSO)Radiation TherapyChemotherapy
Review
Question # 1:
What is KOILOCYTIC ATYPIA?
Answer to Question #1
Nuclear alterations and a cytoplasmic perinuclear halo
Commonly seen in dysplastic cells infected with HPV
Question #2:
What region of the cervix do almost ALL cervical carcinomas arise?
Answer to Question #2
Squamocolumnar Junction (SCJ)
Question #3: Worldwide, how does cervical carcinoma
rank compared to other cancers in women?
Answer to Question #3
2nd most common
Question #4:
What is said to be the MOST significant risk factor in cervical oncogenesis?
Answer to Question #4
High oncogenic risk HPV infections
Question # 5:
What does CIN stand for, what are the subtypes, and what is the clinical significance?
Answer to Question #5
Cervical Intraepithelial Neoplasia (CIN)I: Mild dysplasiaII: Moderate dysplasiaIII: Severe dysplasiaIII: Carcinoma in situ
Precursor to cervical cancer
Question # 6:
What do LSIL and HSIL stand for and which main virus strands cause them?
Answer to Question #6
Low-grade Squamous Intraepithelial LesionHPV 6 & 11
High-grade Squamous Intraepithelial LesionHPV 16 & 18
Question # 7:
What are the 4 main types of primary cervical carcinoma (most common least common)?
Answer to Question #7
Squamous Cell Carcinoma Adenocarcinoma Adenosquamous Carcinoma Neuroendocrine Carcinoma
Question # 8:
What is the most efficient way to test for/diagnose pre-invasive/invasive cervical carcinoma?
Answer to Question #8
Pap smear
Question # 9:
What is the percent of decrease in incidence and mortality rate, in women that get regular Pap smears?
Answer to Question #9
~80% decrease in cervical cancer (incidence & mortality rate) for women that get regular Pap smears
Question # 10:
What are the 2 vaccines that prevent HPV, and what are the main strands they prevent?
Answer to Question #10
Cervarix protects against:HPV 16 & 18 (High oncogenic risk HPVs
~70%)
Gardasil protects against: HPV 16 & 18 (High oncogenic risk HPVs
~70%)HPV 6 & 11 (Low oncogenic risk HPVs
~90%)
References: Agnes Kathrine Lie, MD, PhD, Gunnar Kristensen, MD, PhD. Human Papillomavirus
E6/E7 mRNA Testing as a Predictive Marker for Cervical Carcinoma. Expert Rev Mol Diagn. 2008;8(4):405-415. Accessed <07/06/2013>.
"Cervical Cancer." American Cancer Society. American Cancer Society, 11 Apr. 2013. Web. 6 July 2013. <http://www.cancer.org/cancer/cervicalcancer/detailedguide/cervical-cancer-what-is-cervical-cancer?sitearea=cri>.
Ciaran B. J. Woodman, Stuart I. Collins & Lawrence S. Young. The natural history of cervical HPV infection: unresolved issues. Nature Reviews Cancer 7, 11-
22 (January 2007). doi:10.1038/nrc2050
Damjanov, Ivan. Pathology Secrets. 3rd ed. Philadelphia: Saunders Elsevier, 2009. 342-44. Print.
Expert Rev Mol Diagn. 2008;8(4):405-415. © 2008 Expert Reviews Ltd. http://www.medscape.com/viewarticle/585223
http://screening.iarc.fr/atlasglossdef.php
http://www.askjpc.org/wsco/wsc_showconference.php?id=294
References Continued: http://www.cap.org
http://www.mayoclinic.com/print/cervical-cancer/DS00167/DSECTION=all&METHOD=print
http://www.prn.org/index.php/coinfections/articleanogenital_hpv_neoplasia_hiv_positive_502
Kumar, Vinay, Abul Abbas, Nelson Fausto, and Jon Aster. Robbins and Cotran: Pathologic Basis of Disease. 8th ed. Philadelphia: Saunders Elsevier, 2010. 1017-24. Print.
National Cancer Institute: PDQ® Cervical Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified <05/15/2013>. Available at: http://cancer.gov/cancertopics/pdq/treatment/cervical/HealthProfessional. Accessed <07/06/2013>.
Richard Roden & T.-C. Wu. How will HPV vaccines affect cervical cancer? Nature Reviews Cancer. 6, 753-763 (October 2006). doi:10.1038/nrc1973