Cervical Carcinoma Presentation (PATH 752)


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PATH 752 Presentation on Cervical Carcinoma, including 10 summary questions and answers

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  • Cervical Cancer: Can be invasive or in situ Etiology: almost always related to HPV infection Pap smears: cells are scraped from the cervix and examined with a microscope to be diagnosed are used to identify pre-cancerous/cancerous/dysplastic cells of the cervix http://www.cap.org/apps/microsites/MyBiopsy/cervical_dysplasia.html http://www.cancer.gov/cancertopics/factsheet/Risk/HPV
  • Koilocytic atypia : is Commonly seen in dysplastic cells infected with HPV Microinvasive carcinoma – cancer cells have just (barely) breached the basement membrane Colposcopy : is typically performed after a positive Pap test Robbins pg 1019-1020, 1022 Pathology secrets CAP
  • http://screening.iarc.fr/atlasglossdef.php
  • Figure 22-16 Cervical squamocolumnar junction showing mature, glycogenized (pale) squamous epithelium, immature (dark pink) squamous metaplastic cells, and columnar endocervical glandular epithelium. Robbins pg 1019
  • SCJ Location changes w/ age and hormonal influences: Pre-puberty = endocervical During reproductive years = ectocervical Post-menopausal = endocervical
  • Notice that the T zone is an area of Squamous Metaplasia (columnar cells  squamous cells), and that it contains both cell types
  • The Pap smear has significantly reduced mortality rates by early detection of preinvasive stages of carcinomas EARLY DETECTION IS KEY Worldwide - There are ~493,000 new cases each year, +50% of which are fatal In 2007 (in the U.S.), 11,150 women were diagnosed with cervical cancer and 3,670 women died from the disease Robbins pg 1017
  • Most HPV infections are eliminated by our immune system ~50% w/in 8 months ~90% w/in 2 years Robbins pg 1019 Rb and p53 are 2 important tumor suppressor genes Viral E6 & E7 proteins are critical for the oncogenic effects of HPV
  • HPV accesses cervical epithelium via micro-abrasions  infection  squamous epithelium proliferation  interference of E2  increased regulation of E6 & E7 oncogene expression 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 Figure caption: Basal cells in the cervical epithelium rest on the basement membrane, which is supported by the dermis. Human papillomavirus (HPV) is thought to access the basal cells through micro-abrasions in the cervical epithelium. Following infection, the early HPV genes E1, E2, E4, E5, E6 and E7 are expressed and the viral DNA replicates from episomal DNA (purple nuclei). In the upper layers of epithelium (the midzone and superficial zone) the viral genome is replicated further, and the late genes L1 and L2 , and E4 are expressed. L1 and L2 encapsidate the viral genomes to form progeny virions in the nucleus. The shed virus can then initiate a new infection. Low-grade intraepithelial lesions support productive viral replication. An unknown number of high-risk HPV infections progress to high-grade cervical intraepithelial neoplasia (HGCIN). The progression of untreated lesions to microinvasive and invasive cancer is associated with the integration of the HPV genome into the host chromosomes (red nuclei), with associated loss or disruption of E2 , and subsequent upregulation of E6 and E7 oncogene expression. LCR, long control region.
  • Basically the same thing as the previous slide; just another way to look at it This diagram includes: treatment methods, prophylactic vaccine influences How will HPV vaccines affect cervical cancer? Richard Roden & T.-C. Wu Nature Reviews Cancer 6 , 753-763 (October 2006) doi:10.1038/nrc1973 http://www.nature.com/nrc/journal/v6/n10/fig_tab/nrc1973_F2.html Figure caption: a | The cervical squamocolumnar junction. The basal cells rest on the basement membrane, which is supported by the dermis. Normal squamous epithelium differentiates as shown. The transformation zone is the most common site for the development of cervical cancer. Prophylactic vaccines induce L1- or L2-specific antibodies that neutralize the virus. b | After the human papillomavirus (HPV) infection of basal keratinocytes, the early HPV genes E1 , E2 , E5 , E6 and E7 are expressed (red nuclei) and the viral DNA replicates. Low-grade squamous intraepithelial lesions (LSILs) support productive viral replication. In the upper layers of epithelium the viral genome is replicated further, and E4 (green cytoplasm), L1 and L2 (orange nuclei) are expressed. L1 and L2 encapsidate the viral genomes to form progeny virions in the nucleus. The shed virus then re-initiates infection. c | A significant fraction of high-risk HPV infections progress to high-grade squamous intraepithelial lesions (HSILs), which show a lesser degree of differentiation. HSILs are effectively treated by loop electrosurgical excision (LEEP). Pap screening and HPV tests can be used to detect SILs (Box2). d The progression of untreated lesions to microinvasive and frankly invasive cancer is associated with the integration of the HPV genome into the host chromosomes, loss of E2 and upregulation of viral oncogene expression and genomic instability. These cancers are treated with surgery, chemotherapy or radiotherapy with limited success. Therapeutic vaccines and immune stimulants such as imiquimod can potentially induce an infiltration of T cells specific for the early viral antigens and clearance. Patients with immune suppression due to HIV infection or organ transplantation suffer more frequent and severe HPV-related disease.
  • Robbins pg 1018
  • HPV is spread by skin-to-skin contact Harald zur Hausen - Received the 2008 Nobel Prize Award Robbins pg 1018 http://www.cancer.gov/cancertopics/factsheet/Risk/HPV
  • Shows the classification systems for pre-malignant squamous epithelial cervical lesions Former = CIN Current = SIL
  • Neoplastic changes of the ectocervical squamous epithelium CIN I & CIN II: Peak presentation ~25 y/o CIN III: Peak presentation ~35-40 y/o Robbins pg 1019-1021 Pathology secrets pg 343
  • Normal squamous epithelium LSIL (CIN I) with koilocytic atypia HSIL (CIN II) the atypia is expanding w/ immature basal cells growing toward the surface epithelium HSIL (CIN III) shows diffuse atypia; loss of squamous cell maturation; the immature basal cells have grown to the surface Figure 22-17 Spectrum of cervical intraepithelial neoplasia: normal squamous epithelium for comparison; LSIL (CIN I) with koilocytic atypia; HSIL (CIN II) with progressive atypia and expansion of the immature basal cells above the lower third of the epithelial thickness; HSIL (CIN III) with diffuse atypia, loss of maturation, and expansion of the immature basal cells to the epithelial surface. Robbins pg 1020
  • Normal shows koilocytes of an LSIL (CIN I) HSIL (CIN II) HSIL (CIN III) - Decreasing cytoplasm  changing the nucleus:cytoplasm (ratio) Figure 22-21 The cytology of cervical intraepithelial neoplasia as seen on the Papanicolaou smear. Normal cytoplasmic staining in superficial cells ( A and B ) may be either red or blue. A, Normal exfoliated superficial squamous cells. B, LSIL-koilocytes. C, HSIL (CIN II). D, HSIL (CIN III). Note the reduction in cytoplasm and the increase in the nucleus-to-cytoplasm ratio, which occurs as the grade of the lesion increases. This reflects the progressive loss of cellular differentiation on the surface of the lesions from which these cells are exfoliated. (Courtesy of Dr. Edmund S. Cibas, Brigham and Women's Hospital, Boston, MA.) Robbins pg 1023
  • Early changes in cell shape and size HPV 16 is the most common type of HPV that is associated with both LSILs and HSILs Lower risk of cancer progression Risk of progression to HSIL  cancer is related to: - HPV type - Immune status - Environmental factors http://www.cancer.gov/cancertopics/factsheet/Risk/HPV Robbins pg1020 - Based on severity
  • Higher chance of progressing into cancer More severe changes in cell shape and size Unlike LSILs, HSILs = an immediate precursor to cervical SCC Robbins pg 1020-1021
  • Table showing most common HPV types and their associated risk
  • For LSIL: H & E stained Testing for HPV DNA contained in the koilocytes (dark = HPV positive) Immunostained for Ki-67 marker (normally basally located, but as you can see they are rising toward the surface) The brown signifies the up-regulation of p16INK4 = High oncogenic HPV infection Ki-67 & p16 are used to confirm SIL diagnosis Both are highly correlated with HPV infection Figure 22-18 A, LSIL-routine H&E staining. B, In situ hybridization test for HPV DNA. The dark granular staining denotes HPV DNA, which is typically most abundant in the koilocytes. C, Diffuse immunostaining for the proliferation marker Ki-67, illustrating abnormal expansion of the proliferating cells from the normal basal location to the superficial layers of the epithelium. D, Up-regulation of p16INK4 (seen as intense brown immunostaining) characterizes high oncogenic risk HPV infections. Figure 22-18A illustrates the histologic features of LSIL. Figure 22-18B, shows detection of HPV DNA using an in situ hybridization test. The staining is most intense in the superficial layers of the epithelium, which contain the highest viral load. Figures 22-18C and D show immunostaining for Ki-67 and p16. Ki-67 is a marker of cellular proliferation, and in normal squamous mucosa is confined to the basal layer of the epithelium. In contrast, in SILs, Ki-67 positivity is seen throughout the entire thickness of epithelium, indicating abnormal expansion of the epithelial proliferative zone (see Fig. 22-18C). p16, a cyclin kinase inhibitor, is a cell cycle-regulatory protein, which inhibits the cell cycle by preventing the phosphorylation of RB. It has been shown that in cells infected with oncogenic HPVs, there is overexpression of p16 (see Fig. 22-18D). Despite high levels of p16, however, the HPV-infected cells continue to proliferate because RB, the target of p16 inhibitory activity, is inactivated by the E7 HPV oncoprotein. Robbins pg 1020-1021
  • This table shows the different classification schemes for HPV related dysplasia/in situ carcinoma/invasive carcinoma of the cervix - This table is a really good summary of how all of the different classification systems are tied together http://www.prn.org/index.php/coinfections/article/anogenital_hpv_neoplasia_hiv_positive_502 Figure Caption: The progression of HPV-related cervical disease is well characterized and proceeds through distinct phases. The Bethesda System Classification, which categorizes cervical cytology, organizes HPV-associated lesions into low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL) and invasive cancer (Figure 1). LSIL corresponds to the histologic diagnoses of flat condylomas and CIN 1, whereas HSIL corresponds to the histologic diagnoses of CIN 2 and 3. As the degree of severity increases, the more oncogenic HPV types become increasingly predominant. In most cases, the time from development of initial HPV infection to CIN 2-3 is believed to be less than five years, whereas the progression of CIN 2-3 to invasive cancer may take several decades. Kurman R, Solomon D. The Bethesda system for reporting cervical/vaginal cytologic diagnoses: definitions, criteria and explanatory notes for terminology and specimen adequacy . New York: Springer-Verlag;1994. Bonnez W. Papilloma Virus. In: Richman D, Whitley R, and Hayden F, eds. Clinical Virology , 2nd ed. Washington DC: American Society for Microbiology; 2002:557-596.
  • Table 22-2: Progression of SILs LSIL is significantly more common than HSIL Only ~10% of LSILs  HSILs Only ~10% of HSILs  carcinoma Notice progression is slow and over an extended period of time (years)
  • Peak presentation ~45-50 y/o Robbins pg 1022
  • Squamous cell carcinoma (SCC) accounts for ~80 - 90% of cervical cancers ( most common ) Adenocarcinoma accounts for ~10 – 15% of cervical cancers ( 2 nd most common ) Less common varients: account for ~5% Adenosquamous carcinoma (or Mixed Cell Carcinomas) Neuroendocrine (oat cell) carcinoma (NEC) Small cell NEC (SCNEC) & Large Cell NEC (LCNEC) are all caused by high oncogenic risk HPVs Primary sarcomas and primary/secondary malignant lymphomas of the cervix have been very rarely noted, in addition Kumar, V., Abbas, A.K., Fausto, N., and Aster, J. C. Robbins and Cotran Pathologic Basis of Disease. 8 TH ed. Philadelphia: Saunders Elsevier, 2010. Print. http://www.cancer.gov/cancertopics/pdq/treatment/cervical/HealthProfessional/page1/AllPages#2 Pathology Secrets pg 344 #29
  • Develop in the squamous epithelium of the ectocervix “ Barrel-shaped cervix” Robbins pg 1021 Pathology Secrets pg. 344
  • This is the gross appearance of a cervical squamous cell carcinoma that is still limited to the cervix (stage I). The tumor is a fungating red-tan to yellow mass.
  • This is a larger cervical squamous cell carcinoma which spread to the vagina. A total abdominal hysterectomy with bilateral salpingo-oopherectomy (TAH-BSO) was performed.
  • Figure 22-19 Squamous cell carcinoma of the cervix. A, Microinvasive squamous cell carcinoma with invasive nest breaking through the basement membrane of HSIL. B, Invasive squamous cell carcinoma. Robbins pg 1022
  • http://www.cancer.org/cancer/cervicalcancer/detailedguide/cervical-cancer-what-is-cervical-cancer?sitearea=cri Robbins pg 1021
  • Cervical adenocarcinoma – a multilobular fleshy mass at the external cervical os near the cervico-vaginal junction.
  • Figure 22-20 Adenocarcinoma of the cervix. A, Adenocarcinoma in situ (arrow) showing dark glands adjacent to normal, pale endocervcial glands. B, Invasive adenocarcinoma. Robbins pg 1022
  • Top Left: Transformation Zone Normal squamous epithelium Normal glandular epithelium Mid Left: CIN 1 w/ HPV features Mid Right: High-grade CIN (CIN 2-3) Top Right: SCC Bottom Left: Adenocarcinoma in situ Bottom Right: Invasive adenocarcinoma Notice the nests of squamous cells in the squamous cell carcinoma Human Papillomavirus E6/E7 mRNA Testing as a Predictive Marker for Cervical Carcinoma Agnes Kathrine Lie, MD, PhD, Gunnar Kristensen, MD, PhD Expert Rev Mol Diagn. 2008;8(4):405-415. 
  • Robbins pg 1022 (morphology)
  • Depends on the grade, stage, and cell type at the time of diagnosis Robbins pg 1023
  • Localized (Stage I) has a high survival rate, but distant (Stage IV) has a very poor prognosis
  • Most medical guidelines suggest women get a Pap test beginning at age 21 or after starting to have sexual intercourse (which ever comes 1 st ) Pap screening is LOW SENSATIVITY/HIGH SPECIFICITY HPV DNA Testing is HIGH SENATIVITY/LOW SPECIFICITY Cervical SCC vs. Adenocarcinoma SCC is more easily detected with Pap smears (compared to adenocarcinomas) b/c squamous cells make up the ectocervix (superficial & more accessible) Adenocarcinoma is more difficult to detect b/c the glandular cells make up the endocervix (more proximal & cells can be below the surface  not as easily accessed) HPV DNA Testing - Used for women 30+ y/o www.cancer.gov http://www.mayoclinic.com/print/cervical-cancer/DS00167/DSECTION=all&METHOD=print Pathology Secrets pg 343 www.cap.org
  • Both vaccines are highly effective in preventing infections with HPV types 16 and 18, two high-risk HPVs that cause about 70 percent of cervical and anal cancers Gardasil also protects against HPV 6 & 11, which cause 90% of genital warts www.cancer.gov http://www.mayoclinic.com/print/cervical-cancer/DS00167/DSECTION=all&METHOD=print Pathology Secrets pg 343
  • Type of treatment depends on the grade and stage at the time of diagnosis surgical conization (surgery with a scalpel, a laser, or both to remove a cone-shaped piece of tissue from the cervix and cervical canal) cryosurgery (freezing that destroys tissue) laser vaporization conization (use of a laser to destroy cervical tissue). LEEP (using a hot wire loop to remove cervical tissue) Hysterectomy (includes removal of uterus and cervix) TAHBSO: Total Abdominal Hysterectomy Bilateral Salpingo Oophorectomy (= uterus, cervix, both fallopian tubes, and both ovaries) Radiation Therapy (uses “pin-pointed high energy beams” to destroy cancer cells/shrink tumors) External (uses a big machine) Internal (uses implants/seeds) Chemotherapy (uses drugs to slow cancer progression/reduce pain, used when cancer METs) www.cap.org www.cancer.gov
  • HPV 16 & 18: Account for ~70% of cancer causing HPV infections HPV 16: Is associated with LSILs and HSILs
  • Cervical Carcinoma Presentation (PATH 752)

    1. 1. Presented By: L. Luketic
    2. 2. 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
    3. 3. 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
    4. 4. 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
    5. 5. Cervical Squamocolumar Junction: (Robbins Fig. 22-16)
    6. 6. Cervical SCJ & T zone Grossly: Merck & Co., Inc. Human Papillomavirus, Monographs in Medicine. Whitehouse Station, NJ: Merck and Co; 2008.
    7. 7. SCJ & T zone Histologically: http://1.bp.blogspot.com/_OwoEg7Db_AE/TQTYcJz2cTI/AAAAAAAAA9o/Q5neoLm6-CQ/s1600/CTZ%2Bb.png
    8. 8. 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: 12,340 Deaths: 4,030  Worldwide, cervical carcinoma is the second most common cancer in women
    9. 9. 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
    10. 10. 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
    11. 11. http://www.nature.com/nrc/journal/v7/n1/fig_tab/nrc2050_F1.html
    12. 12. Roden and Wu Nature Reviews Cancer 6, 753–763 (October 2006) | doi:10.1038/nrc1973
    13. 13. 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
    14. 14. 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”
    15. 15. ROBBINS TABLE 22-1 Dysplasia/ Carcinoma in Situ Cervical Intraepithelial Neoplasia (CIN) SquamousIntraepithelial Lesion (SIL) [Current Classification] Mild Dysplasia CIN I Low-grade SIL(LSIL) Moderate Dysplasia CIN II High-grade SIL(HSIL) Severe Dysplasia CIN III High-grade SIL(HSIL) Carcinoma inSitu CIN III High-grade SIL(HSIL) ROBBINSTABLE22-1 CLASSIFICATION SYSTEMSFORPREMALIGNANTSQUAMOUSCERVICALLESIONS
    16. 16. Cervical Intraepithelial Neoplasia (CIN):  Precursor to Cervical SCC Neoplastic changes of the ectocervical squamous epithelium  CIN I: caused by low oncogenic risk HPVs Mild koilocytic atypia  CIN II: caused by high oncogenic risk HPVs Moderate koilocytic atypia of the squamous cells  CIN III: caused by high oncogenic risk HPVs Severe koilocytic atypia of immature squamous cells
    17. 17. Cervical Cancer Histology: Robbins Fig. 22-17 Normal  CIN I  CIN II  CIN III
    18. 18. The cytology of a CIN seen on a Pap smear (Robbins Fig. 22-21)
    19. 19. 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
    20. 20. 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
    21. 21. HPV Groups/Types: Expert Rev Mol Diagn. 2008;8(4):405-415. © 2008 Expert Reviews Ltd. http://www.medscape.com/viewarticle/585223
    22. 22. Cervical Cancer Histology: (Robbins Fig. 22-18) LSIL – stained with multiple techniques  Ki-67 & p16 are used to confirm SIL diagnosis
    23. 23. ROBBINS TABLE 22-2
    24. 24. Normal Cervix (Gross): http://library.med.utah.edu/WebPath/jpeg4/FEM002.jpg
    25. 25. Invasive Carcinoma of the Cervix  Tumor extension is by direct MET, involving adjacent tissues which can include: Paracervical tissues Urinary bladder Ureters Rectum Vagina  Local and distant lymph node METs  Distant METs (liver, lungs, bone marrow, other)
    26. 26. 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)
    27. 27. SCC of the Uterine Cervix:  SCCs most often arise at the SCJ  Grossly: (3 forms) Fungating (exophytic) or infiltrative Ulcerated Invasive lesion that causes induration or other deformities of the cervix  Histologically: Nests and tongues of malignant cells Keratinizing or Non-keratinizing  Clinical Symptoms: Early-stage: may be asymptomatic Later-stage: abnormal vaginal bleeding, increased vaginal discharge, pelvic pain, or pain during intercourse
    28. 28. Gross Cervical SCC: (Stage 1) http://library.med.utah.edu/WebPath/FEMHTML/FEMIDX.html#2
    29. 29. Cervical SCC (Gross) Extensive: http://library.med.utah.edu/WebPath/FEMHTML/FEMIDX.html
    30. 30. SCC of the Cervix (Robbins Fig. 22-19)
    31. 31. Cervical Adenocarcinomas:  Arise in the columnar epithelium (glandular cells that produce mucus) of the endocervix  Grossly: Fungating (exophytic) Infiltrative Abnormal mass/growth visible during colposcopy  Histologically: Glandular epithelium proliferation of malignant endocervical cells Large hyperchromatic nuclei Cytoplasm is mostly depleted of mucin  Clinical Symptoms: Abnormal vaginal bleeding/discharge, pelvic pain, or asymptomatic
    32. 32. Cervical Adenocarcinoma (Gross): http://www.askjpc.org/wsco/wsc_showconference.php?id=294
    33. 33. Adenocarcinoma of the Cervix (Robbins Fig. 22-20)
    34. 34. Staging of Cervical Carcinoma (Robbins) http://www.studentconsult.com/content/default.cfm?ISBN=9781416031215
    35. 35. 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
    36. 36. Cervical Screening:  Pap smears are the most efficient way to test for/diagnose pre-invasive and invasive cervical carcinomas Studies 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 testing Determines positive/negative infection for HPV strands most likely to cause cervical carcinoma  Sensitivity vs. Specificity
    37. 37. 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
    38. 38. Treatment Options:  Pre-malignant Lesions: Surgical Conization Cryosurgery Laser surgery LEEP (Loop Electrosurgical Excision Procedure)  Malignant Lesions: Surgery (i.e., hysterectomy/TAHBSO) Radiation Therapy Chemotherapy
    39. 39. Review
    40. 40. Question # 1:  What is KOILOCYTIC ATYPIA?
    41. 41. Answer to Question #1  Nuclear alterations and a cytoplasmic perinuclear halo Commonly seen in dysplastic cells infected with HPV
    42. 42. Question #2:  What region of the cervix do almost ALL cervical carcinomas arise?
    43. 43. Answer to Question #2  Squamocolumnar Junction (SCJ)
    44. 44. Question #3:  Worldwide, how does cervical carcinoma rank compared to other cancers in women?
    45. 45. Answer to Question #3  2nd most common
    46. 46. Question #4:  What is said to be the MOST significant risk factor in cervical oncogenesis?
    47. 47. Answer to Question #4  High oncogenic risk HPV infections
    48. 48. Question # 5:  What does CIN stand for, what are the subtypes, and what is the clinical significance?
    49. 49. Answer to Question #5  Cervical Intraepithelial Neoplasia (CIN) I: Mild dysplasia II: Moderate dysplasia III: Severe dysplasia III: Carcinoma in situ  Precursor to cervical cancer
    50. 50. Question # 6:  What do LSIL and HSIL stand for and which main virus strands cause them?
    51. 51. Answer to Question #6  Low-grade Squamous Intraepithelial Lesion HPV 6 & 11  High-grade Squamous Intraepithelial Lesion HPV 16 & 18
    52. 52. Question # 7:  What are the 4 main types of primary cervical carcinoma (most common  least common)?
    53. 53. Answer to Question #7  Squamous Cell Carcinoma  Adenocarcinoma  Adenosquamous Carcinoma  Neuroendocrine Carcinoma
    54. 54. Question # 8:  What is the most efficient way to test for/diagnose pre-invasive/invasive cervical carcinoma?
    55. 55. Answer to Question #8  Pap smear
    56. 56. Question # 9:  What is the percent of decrease in incidence and mortality rate, in women that get regular Pap smears?
    57. 57. Answer to Question #9  ~80% decrease in cervical cancer (incidence & mortality rate) for women that get regular Pap smears
    58. 58. Question # 10:  What are the 2 vaccines that prevent HPV, and what are the main strands they prevent?
    59. 59. 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%)
    60. 60. 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
    61. 61. 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