DR OMOLO THE CLINIC GROUP NCD Report May 2015 A total of 183 cancer related deaths occurred in Swaziland as reported by t he national prevention and control of noncommunicable diseases programme annual report 2014 ID: 910439
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Slide1
MANAGEMENT OF CERVICAL INTRAEPITHELIAL NEOPLASIA
.
DR OMOLO
THE CLINIC GROUP
Slide2NCD Report May 2015
A total of 183 cancer related deaths occurred in Swaziland as reported by
t
he national prevention and control of non-communicable diseases programme annual report 2014
Slide3I screened a total of 75 ladies who presented in my practice, the youngest being
20
years and oldest 76 years. 54 ladies had normal results and 21 abnormal results, thus 22.6% of ladies required additional evaluation.
Slide4The results were categorized as: 54 normal;1 ASCUS;1 AGCUS; 2 LSIL; 2 LSIL-HSIL;13 HSIL; 2 carcinoma
Slide574 ladies accepted to be tested for HIV;52 ladies were HIV negative(69.3%);22 ladies tested HIV positive(29.3%) and 1 lady declined to be tested(0.01%)
Slide6Lesions in the background of HIV
: 1 lady with normal findings declined screening; among 52 who were HIV negative 8(15.3%) had abnormal smear results; among 22 who were HIV positive 13 (59%) had abnormal results. Being HIV makes the lady 4 times likely to have abnormal CIN.
Slide7CIN
CIN
₌ Cervical
intraepithelial neoplasia, is the term now used to encompass all epithelial abnormalities of the cervix. These abnormalities are confined to the epithelium and are regarded as preinvasive lesions. In average cervical
preinvasive
lesions
precedes
cervical cancer by 15.6 years (range 3-20 years).
CIN is asymptomatic.
Slide8Screening
Being asymptomatic, CIN are identified through screening. The standard
screening test
is cervical cytology. Eitheri) Papanicolaou (Pap) smear Ii) Liquid based cytology,(thin layer preparation of cervical specimen) is a modification of pap smear.Cervical cytology selects
those women who should have further
evaluation
and ≈
7-10% of women who are screened require additional evaluation.
Terminology
for reporting cervical cytology
is
standardized by the Bathesda
system.
Lesions are broadly divided
into two subgroups:
1)Mild
atypical cellular changes in the lower third of the epithelium
referred to as
l
ow-grade
cervical intraepithelial
neoplasia(CIN1= ASCUS
, Atypical squamous cell cannot exclude high grade squamous intraepithelial lesion, LSIL)
2)Moderate
and
severe
atypical cellular changes confined to the basal two thirds and full thickness of the
epithelium referred to as
h
igh-grade
cervical intraepithelial neoplasia (CIN II–III/CIS)
Slide9Diagrammatic illustration of CIN
Slide10Screening guidelines
a)With cytology (Pap smear or LBC) every 2 years between ages 21-29 years, then cytology every 3 years between ages 30-65 years provided that the last 3 reports are normal.
b) With cytology & HPV-DNA typing every 3 years after 30 years, discontinue between 65-70 years in negative screened women in the last 10 years.
c) More frequent screening is advised in high risk group e.g. those with HIV; those who are immunosuppressed-transplant patients or those on prolonged steroids and those who have been treated for CIN II, CIN III, or cervical cancer.
Slide11Role of human papillomavirus
Sexual activity has been consistently implicated as the dominant risk factor for occurrence of cervical cancer. These lesions are almost non-existent in women who have not had any sexual relationships.
And t
he major factor causing these lesions is the infection with the human papilloma virus .HPVI association is so strong that most other behavioural, sexual and socioeconomic co-variables are all dependent upon HPV infection and do not hold up as independent risk factors
.
Slide1212
Normal
epithelium
Basement membrane
Basal (stem)
cells
Parabasal
cells
Squamous
layer
Mature
squamous
layer
Infected
epithelium
Cervical canal
HPV infects basal layer of cervical epithelium
HPV lifecycle in the cervix is confined to the epithelium
Adapted from Frazer IH.
Nat Rev Immunol
2004;
4:
46–54.
Virus particles are assembled and virus released
Virus uses host cell to replicate viral DNA and express virally encoded proteins
Note that this diagram depicts infection of the squamous epithelium not columnar epithelium.
Slide13Sequelae of acute infection
Once
the epithelium is
infected. 3 clinical scenarios may result :1) Latent infection without any manifestations, what is seen in over 90% of infected women
2) Active
infection where HPV undergoes vegetative replication, but is
not
integrated into the host cell genome (will results in
low grade lesions)
3) Neoplastic
transformation in which HPV integrates into the human
genome (results in HSIL
and cancer). 2 major factors
i)
Infection with
high
risk HPV subtypes(16,18,31,33,35,45,59)
and ii)
Persistence
factors
such as
smoking, sexual exposure and immunosuppression as predisposing factors to neoplastic transformation.
Slide14Natural history of CIN(cervical carcinogenesis
)
REGRESS
HSIL/CIS
CA
ASCUS IN 24 MONTHS
68%
7.3%
0.25%
LOSIL IN 24 MONTHS
47%
21%
0.15%
HSIL IN 24 MONTHS
35%
1.44%
LOSIL IN 20 YEARS
60%
10%
1%
HSIL IN 20 YEARS
33%
12%
Slide15Burd EM.
Clin Microbiol Rev
2003;
16:
1
–
17;
Solomon D,
et al. JAMA
2002;
287:
2114
–
2119.
Low-grade squamous intraepithelial lesion (ASCUS/LSIL)
High-grade squamous intraepithelial lesion (HSIL)
Invasive
carcinoma
Time
Years
Months
Normal
epithelium
HPV infection
koilocytosis
CIN1
CIN2
CIN3
Regression
* With increasing probability of viral DNA integration.
CIN = cervical intraepithelial neoplasia; ASCUS = atypical squamous cells of undetermined significance.
Progression*
HPV cervical disease: cervical carcinogenesis
(Progression
&
regression)
Slide16II Treatment
Given the natural history of CIN, the goal of treatment is to
prevent possible progression to invasive cancer while
avoiding overtreatment of lesions that are likely to regress
Slide17Diagnosis
Being asymptomatic,
screening
is our only option of making a diagnosis .Cytology(pap smear & LBC) (remains an art - as many as 30% of new cases of cervical cancer each year are the result of false-negative test results).To improve accuracy of screening ,it is best, where available to combine HPV DNA testing with cytology for ladies above 30 years
Slide18Colposcopy
As
an adjunctive technique to cytology
Colposcope is designed to study the genital epithelium. It allows the entire cervix to be carefully examined at low power, with emphasis on the details of the transformation zone. Findings sought for include:-Keratosis(represents HPV infection, chronic trauma or scarring)-Acetowhite (represent higher nuclear/cytoplasm ratio-more distinct in CIN)-Borders(sharper & smoother of Acetowhite lesions are seen in HSIL)
-Surface contour(uneven contours seen with warts,cauliflower,nodular or ulcer with cancer)
-Color
-Lugol’s
uptake(neoplastic
cells lack glycogen hence do not turn brown
)
-Vascular
pattern(neoplastic
epithelium produces angiogenic factors VEGF which results in neovascularisation).
-inflammation (when present make exam difficult and must be treated before colposcopy)
Slide19CIN1
Cytology
Mild dysplasia
Changes to shape and size of cells
Changes to size and appearance of cell nuclei
Koilocytosis
Appearance on colposcopy
Acetowhite reaction
More transient
Mild translucent acetowhite
Margins
Feathered, flocculated and geographic
Indistinct
Irregular
Surface contours flat
No abnormal vessels
Reduced iodine uptake, light yellow
Normal, healthy cervix
1
1. Image used with permission from Professor Achim Schneider.
2. Image used with permission from
Dr Alejandro Ortiz de la Peña
.
Cervix with CIN1
Mild aceto-white epithelium
2
Slide20CIN2
Cytology
Moderate dysplasia
More abnormal nuclei, especially in immature cells
Appearance on colposcopy
Acetowhite reaction
Dull, oyster-white colour
Surface contour
Flat or raised
Margins
Straight
Vascular pattern
Mosaic
Punctation
Iodine uptake
Reduced, bright yellow
Cervix with CIN2
Image used with permission from Professor Muhieddine Seoud.
Moderate aceto-
white epithelium
Slide21CIN3
Cytology
Severe dysplasia
Severe nuclear abnormality in immature basal cells
Keratinization or cornification may be present at surface or in isolated cells inside epithelium
Appearance on colposcopy
Acetowhite reaction
Dull, denser white, not shiny
Remains for longer time
Surface contour
Flat or raised
Margins
Sharp and distinct
Internal margins possibly present with LSIL
Vascular pattern
Coarse punctation and or mosaic
Wide intercapillary distance
Iodine uptake
Rejects iodine
Cervix with CIN3
Image used with permission from
Dr Alejandro Ortiz de la Peña
.
A dense opaque acetowhite area with coarse mosaics
Slide22Treatment overview techniques
Treatment
decisions are
based upon diagnostic results from histologic examination, preferably colposcopically directed biopsies where available.
Slide23Low grade lesions(HPV &CIN 1)
These have
a high spontaneous remission rate and that most lesions will regress within a 2-year follow-up period.
Options for the management include Conservative treatment by ablation or Close follow-up without treatment (observation,
expectant management
) by
surveillance Pap smears every 4–6
months
or HPV testing at 12 months
for 2 years then every 6 months if low-grade changes persist.
Women
can return to regular screening only if consecutive normal Pap smear results are obtained.
If
the lesion progresses during the surveillance period it should be treated.
Treatment
is only recommended:
If
CIN 1 persists for >24 months
For
an occasional anxious patient who may elect to be treated to relieve her anxiety.
In
a patient at very high risk for loss to follow-up.
Slide24High grade lesions /(CIN 2, 3; CIS)
These patients require
treatment.
Ablative techniques are only appropriate when invasive cancer has been excluded .1. If the lesion is small, the entire lesion is well-visualized, and there is no endocervical disease, then cryotherapy can be used for the management of high-grade lesions. Cryotherapy is not recommended for large, complex high-grade lesions. 2.Large lesions are treated with:i) The LEEP procedure (
widely
available and
easy).
The main advantage of the LEEP is that there is a histologic specimen for evaluation. Two
disadvantages
for
it’s use,
include the removal of excessive amounts of tissue and the danger of overtreatment.
ii) CO
2
laser
vaporization(if available) allows
greater precision in the destruction of abnormal tissues.
It’s
main advantage
is
in the treatment of lesions wide on the transformation zone and in situations in which the treatment of cervical dysplasia is concurrent with laser treatment of dysplastic lesions of the vagina and vulva.
Slide25High grade lesions /(CIN 2, 3; CIS)
Excisional therapy(cervical conization)
:
is recommended for women with cytological findings potentially associated with high-grade lesions. These allow further histologic study. Cervical conization (also known as cone biopsy) refers to the excision of a cone shaped portion of the cervix surrounding the endocervical canal and including the entire transformation zone.Techniques for cervical conization include cold-knife conization, laser conization, and the use of the LEEP as cone. In general, either ablative or excisional treatments of CIN are successful.
Slide26Hysterectomy
Hysterectomy is not the treatment of choice
But valid
indications include:1. When conization specimen margins are positive for HSIL,(completed childbearing and expected poor compliance with follow-up). Though, the treatment of choice is close clinical follow-up or, in select cases, reexcision to exclude an invasive cancer instead of hysterectomy. Hysterectomy should generally be reserved for those in whom a repeat excisional procedure is not technically feasible or where the cervix and vagina are scarred in a way that severely compromises the reliability of cervical cytology and close clinical follow-up.
2. Presence
of coexistent gynaecologic conditions requiring hysterectomy such as symptomatic uterine fibroids
3. Patient
request and persistent or recurrent HSIL.
Slide27III Preinvasive cervical lesions in HIV -setting
In 1993, the CDC designated high grade lesions as conditions defining a stage of early symptomatic HIV infection and invasive cervical carcinoma as an AIDS defining condition.
The
incidence of CIN is 4-5 times higher among HIV-infected compared to HIV-negative women. And the risk of cervical cancer among HIV-infected women is 5-7 fold the risk in the HIV-negative women.HIV infected women especially those with low CD4 counts have the highest prevalence of HPV infection,habor high risk HPV types and are at high risk for persistence of cervical HPV infection
Slide28How then do one manage CIN in these setting:
The appropriate management of CIN, timing and method of follow up is still unfortunately largely unknown.
Guiding data is not available and therefore
close follow up is essential.This is study item for one to look into in order to design treatment of CIN for this category.
Slide29Low grade lesions
U
nderstanding
the natural history of such lesions in HIV infected women is necessary in order to determine the treatment approach. No satisfactory data exist and therefore same recommendation of expectant management of women with biopsy confirmed CIN1 and satisfactory colposcopy. The use of HAART has been associated with increased rates of regression and decreased rates of recurrence in HIV infected women. Based on this, HIV infected women using HAART with low viral loads and stable CD4 levels may be managed similar to non-HIV infected women.
Slide30High grade lesions
Excision and ablation
are both accepted treatment modalities for HIV infected women with satisfactory colposcopic examinations.
If colposcopy is not available or not satisfactory, then ablative treatment is unacceptable because histopathological examination of the nonvisualized tissue is required to exclude the presence of occult cancer. A diagnostic and therapeutic excisional procedure is performed in these cases. Excision is also recommended for patients with recurrent disease after ablation.The success rate of these modalities in HIV-negative women is over 90% but is lower in HIV-infected women. Persistence and recurrent disease is also more common. One factor that contributes to the poorer treatment outcome is incomplete excision or ablation of CIN. The margin status of the tissue specimens is critical.
Slide31Medical therapy
Because of the results of standard excisional therapy are not better as compared to those in HIV-negative women, use of primary or adjuvant medical therapy to improve treatment outcomes has been investigated.
Topical –fluorouracil (5-FU) is an effective prophylactic agent for immunosuppressed women with CIN
. 6 months of topical application of 2g of 5% cream biweekly is recommended as adjunctive therapy to excision/ ablation procedures for high grade lesionsHAART- is associated with regression of CIN. It lends support to the recommendation that CIN is a relative indication for HAART.
Slide32Follow-up
HIV-infected women with CIN should be advised that recurrence is more frequent than in the general
population.
Cancer can also develop rapidly in HIV infected women (3.2 vs. 15.7 years). Therefore, these women require close monitoring after treatment. Hysterectomy is an option for recurrent CIN in women not desirous of fertility.The recommendation is monitor with both cervical cytology, colposcopy, with liberal use of biopsy, at least 3 month intervals for an indefinite period of time.
Slide33Surveillance
Surveillance after treatment should be designed to identify women with treatment failures as well as those in whom recurrent CIN develops.
Persistence
of a lesion (incomplete treatment or recurrent CIN)seen in 1–20% of cases). Factors associated with persistent or recurrent disease include age older than 40 years, glandular involvement, large lesions, and positive treatment margins, HIV coinfection
.
Serial
repeat Pap smears performed at
3–6month
intervals for several years
will identify
persistent or recurrent CIN.
The use of HPV testing is particularly
attractive in post treatment follow up. The
majority of women with recurrent CIN have persistent positive high-risk HPV tests while recurrence is rare in the face of negative follow-up HPV testing.
Slide34Surveillance
When several consecutive smears are within normal limits and/or a repeat high-risk HPV test is negative for persistent infection, the patient can return to regular screening.
If
recurrent dysplasia is noted on follow-up Pap, the patient should undergo repeat colposcopy. Recurrent dysplasia documented by directed biopsy should be treated with cold-knife conization or LEEP conization. In cases in which invasive carcinoma has been excluded and fertility is not desired, hysterectomy can be considered.
Care
should be taken to evaluate for vaginal involvement in these recurrent cases, because failure to treat concomitant vaginal dysplasia may result in persistently abnormal smears.
Slide35Treatment
complications
Cryotherapy
, CO2 laser therapy, and LEEP excision all have excellent success rates, each is associated with some risk of complication.Cryotherapy has the lowest rates of bleeding and infection but has higher failure rates when treating large lesionsBoth laser and LEEP
may be associated with bleeding, but complication rates are low. Post treatment bleeding occurs in 2–7% of LEEP procedures, with bleeding significant enough to result in hospitalization in only 1–2
%.
Long-term morbidity of these procedures is minimal
.
i)
Scarring severe enough to result in unsatisfactory colposcopic examination occurs in 1.3% to 9% of patients undergoing LEEP and 1.3–3.8% have cervical stenosis after the procedure. The risk of cervical stenosis and its resulting hydro-hematometra is much higher in women who have a LEEP that extends 1.5 cm or more into the endocervical canal and in women who have had previous ablative therapy.
Slide36Treatment
complications
Ablative techniques such as cryotherapy or CO
2 laser for treatment of dysplasia have less impact on future fertility than surgical conization. Several studies have addressed the impact of LEEP procedures on subsequent pregnancy outcome with favourable results. Two case–control studies showed that compared with controls, patients with a history of a cervical LEEP procedure had no higher rate of prematurity or cesarean delivery. Impact on fertility is more difficult to obtain, but no clear association between decreased fertility and LEEP procedures has been demonstrated. In general, excision depth should be limited to less than 7–10 mm in patients desiring to preserve fertility, and repeat excisions should be performed with caution, and for good reason, in young patients.
Slide37Our duty/ role
Sex the all important risk factor is rampant in the human race.
And
CIN exists, more so amongst the HIV positive population. CIN is asymptomatic and therefore we should look for it when an opportunity presents itself, remember the screening guidelines and enquire with your client and recommend screening if it is due.The burden for us in the fight against cervical cancer mainly is in prevention. We are completely helpless when it comes to treating cervical cancer. We should advocate for
screening
a
s a secondary preventive method and
HPV vaccination to prevent HPVI and with it, the development of CIN and
attempt to instill good morals amongst the at risk groups.
Vaccination have almost eradicated over 27 infections.
I leave you with the disease human race have benefited from vaccines.
Slide38To date, vaccines have been used very successfully to prevent 27 major diseases
Anthrax
Cholera
Diphtheria
Haemophilus influenzae type b
Hepatitis A
Hepatitis B
Influenza
Japanese
encephalitis
Measles
Meningococcal
Mumps
Pertussis
Pneumococcal
Polio
Rabies
Rubella
Smallpox and vaccinia
Tetanus
Tick-borne encephalitis
Tuberculosis
Typhoid
Varicella
Yellow fever
Human papillomavirus
B
enefits of vaccination
Slide39END
THANK YOU.