Cervical Carcinoma Presentation (PATH 752)

transcript

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:

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?

Squamocolumnar Junction (SCJ)

Question #3: Worldwide, how does cervical carcinoma

rank compared to other cancers in women?

2nd most common

Question #4:

What is said to be the MOST significant risk factor in cervical oncogenesis?

High oncogenic risk HPV infections

Question # 5:

What does CIN stand for, what are the subtypes, and what is the clinical significance?

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?

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)?

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?

Pap smear

Question # 9:

What is the percent of decrease in incidence and mortality rate, in women that get regular Pap smears?

~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?

Cervarix protects against:HPV 16 & 18 (High oncogenic risk HPVs

Gardasil protects against: HPV 16 & 18 (High oncogenic risk HPVs

~70%)HPV 6 & 11 (Low oncogenic risk HPVs

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.

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

Cervical Carcinoma Presentation (PATH 752)

Health & Medicine