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3. Mitra Mohit Gyn. Oncologist
Management of High Grade Cervical Intraepithelial Neoplasia Role of Colposcopy
Mitra Mohit
Gyn. Oncologist

4. Cervical Cancer
Throughout the world: The second most frequent malignancy in women on global scale, approximately yearly 500,000 new cases
The third most frequent cause of women cancer death; about 300,000 deaths
NCI.cancer advances in focus: cervical cancer. At: advances-in-focus/cervical.

5. ACS cervical cancer 2019 Estimates

6. US incidence: 7.2/100,000
Death rate: 2.4/100,000
5 y survival overall: 62.2%
Fatality/case ratio: at least 50%
Disease of relatively young women
Majority: y/o

7. In recent decades public health measures and mass screening programs clearly decrease cervical cancer incidence and mortality in developed countries
Widespread adoption of pap screening with established guidelines for management of abnormal P/S are already inroad against cervical cancer
Despite development and continued improvement of screening tools the dream of “detecting precursor lesions and eliminating all cervical cancer deaths” has not been realized and cervical cancer remains a significant women's health problem worldwide

8. Preinvasive cervical lesions
Cervical intraepithelial neoplasia is a biological spectrum of disease that antedate invasive SCC
Histopathologic diagnosis is based on disordered pattern of squamous cell maturation and nuclear atypia
Changing terminology and management strategy can be often “confusing to the practitioners strategy for treatment and post treatment surveillance” of pre invasive lesions of cervix

9. Preinvasive cervical lesions
Mean age : Carcinoma in situ 15.6 years younger than invasive cancer
Almost always asymptomatic
Usually normal cervix in physical examination
Diagnosis of CIN is based on screening modality

10. Incidence:
million annual case of CIN in US( about case/ 1 case of cervical cancer)
- Annual incidence in screened women: 2.7/1000 screen ( 1.2/ CIN I + 1.5/1000 for CIN II, III ). AJOG :
Diagnosis of CIN:
Is based on evaluation of women with positive screening by confirmatory tests ; colposcopy punch biopsy/ excisional diagnostic procedures
Goal of evaluation of abnormal P/S & colposcopy:
Most important: rule out invasive carcinoma
Next focus is: defining severity & extent of preinvasive lesion

11. classification
Introduction of CIN classification:1960 by Richart was an attempt to clarify that dysplasia and C insitu were one disease process
Now it is suspected that HPV changes and mild dysplasia are biologically and histologically indistinguishable
Bethesda in 1988 an then 1991, 2001 take this into account by cytologic grouping of HPV and CIN I as LSIL and CIN II, III, C insitu in HSIL group
For practical treatment planning histologically preinvasive cervical lesions are best divided into two subgroup:
low grade (HPV & CIN I) & high grade (CIN II, II, C insitu)

12. HGCIN in women with abnormal cytology:
Goal of evaluation of an abnormal pap smear:
find high grade lesion & cancer
Risk of high grade lesion with single abnormal pap:
- ASC: % Cancer
- ASC-US: 5-17% CIN II,III
- ASC-H: % CIN II,III
- LSIL:15- 30% CIN II,III
- HSIL:1- 2% Cancer, % CIN II,III
- AGC- NOS: 7- 41% CIN II,III
- Favor neoplasia: % CIN II,III

13. CERVICAL PREINVASIVE DISEASE TERMINOLOGY
DYSPLASIA SYSTEM
CIN SYSTEM
WHO CLASSIFICATION SYSTEM
LAST
CAP/ASCCP “-IN” OR “SIL” TERMINOLOGY
MILD
CIN 1
GRADE 1
C-IN 1
LOW GRADE LESIONS OR LGCIN
MODERATE
CIN 2
GRADE 2
C-IN 2
P16 -
P16 ?/+
HIGH GRADE LESIONS
OR HGCIN
SEVERE
CIN 3
GRADE 3
C-IN 3
C insitu

15. Natural history of CIN
Inevitably management of each disease is directly related to natural history
CIN is linked closely to the presence of HR HPV
Persistent HPV infection is necessary for development of almost all invasive cancers
Risk of cervical ca. in HR HPV negative: extremely rare
HR HPV infection:1/10-1/30 is abnormal cervical cytology
HR HPV test for women >30 can help to predict whether CIN II,III will be diagnosed in next few years in those with normal cytology: 15% (~ 1/7) will develop abnormal cytology in next 5 y

16. Natural history of CIN and HR HPV
Persistent (& no proliferative HPV infections) HR HPV infection imparts risk for developing “true precancerous lesions”
True Cancer Precursors: CIN III, AIS, to a lesser extent CIN II
Generally results are similar between hybridization techniques and PCR if cutoff and viral types are similar
Note: for HPV test Clinical sensitivity of the test is important not analytical sensitivity; From a clinical perspective it is important to determine which intraepithelial neoplasia will progress to cancer if left untreated

17. Natural history of HG CIN?
Natural history of CIN III: controversially discussed over the last few decades
Overall progression to cancer: 12% -< 50 %
Regression rate: reported 4% - 38%
Rate of spontaneous natural regression is controversial: little date, excisional treatment change the natural behavior and monitoring, no treatment would be unethical
Now we know: majority CIN III will not develop cancer. So raising the concern that >50% over-treatment
Identification of such regressing CIN III lesions will have clear benefit: abrogate the need for conization
Example: Higher CIN III regression in young could offer chance to avoid conization & ↓ preterm labor danger

18. What about CIN 2 ?
Three-tiered intraepithelial neoplasia (-IN) classification used is problematic for several reasons. Both -IN 2 and -IN 3 are considered high-grade lesions
CAP/ASCCP : recommend uniform, two-tiered terminology histology of HPV-associated squamous disease of all ano- genital tract: vulva, vagina, cervix, penis, perianal, and anus (LAST project)
Two tiered terminology of “low-grade” & “high-grade” squamous intraepithelial lesion (infection vs precancer)
But diagnosis of intermediate category of -IN 2 has much poorer reproducibility by pathologists; % agreement
Agreement for CIN III: 81-85% agreement

20. Natural history of CIN II
It remains unclear whether “- IN 2” is a distinct biological entity with specific clinical meaning…??
Observational studies show CIN 2 has an intermediate risk of progression, behaviour between CIN 1 and CIN 3
CIN regress: CIN I 70% regress in 1y & 90% in 2y
CIN II % regress in 2y
CIN III Controversial (Bosch et al. Vaccine 2008;26:K1-16)
Progression to C insitu: CIN I 11% , CIN II 22%
Progression to invasive cancer: CIN I 1%
CIN II 5%
CIN III at least 12%

23. So: CIN II is a poorly reproduced diagnosis, many are caused by by HPV types not found to cause cancer and associated with significant spontaneous regression: % in two years
Many believe that this intermediate risk reflects averaging of the individual CIN 1 and CIN 3 risks rather than a true risk related to a CIN 2 diagnosis
It seems that diagnosis of CIN 2 cannot be reliably differentiated by histopathologic criteria alone

24. Histologically CIN II,III both are known as cancer precursor
Recent studies show that adding P-16 immunostaining significantly improves reliability of diagnosing high-grade CIN compared with H&E morphology alone, especially when P-16 is used as an adjunct to a diagnosis of CIN 2
Low grade CIN (LGCIN): CIN I + P-16 negative CIN II
High grade CIN(HGCIN): P-16 positive CIN II + CIN III
Role of P-16 IHC in natural history of CIN I, III (regression or progression): unclear

25. What is P-16? LAST project:
HPV E7: PRb (tumor suppressor protein) deactivated and P-16 overexpressed
Positive P-16 ; Diffuse strong p-16 (block positivity) has accuracy similar to histopathology of high grade precancerous disease
Use of P-16 IHC increase accuracy of single pathologist interpretation to accuracy of diagnosis by a panel of experts

27. When do we use P16? LAST recommendation:
HSIL vs mimic; immature metaplasia, atypical reparative changer, tanjunctional cuttings, severe thin atrophied endometrium
Category -IN2
Difference in opinion
No histologic HSIL in biopsy of high risk situations with prior high grade PAP
Not for: obvious –IN 1,-IN 3 or normal epithelium

29. Management of High Grade Abnormal Cervical Histology HGCIN

30. LAST 2013 terminology

31. Choice of therapy depends on :
Histologic degree of high grade CIN: II or III X
Antecedent cytology result: low or high grade abnormality X
Colposcopic finding (adequacy, Location & size of the lesion, endocervical extension & ECC result, suspicious microinvasion or invasion): the most important determinant
Primary or recurrent lesion
Physician experience
Setting and facilities
Patient’s compliance to exact follow up
Patient’s age, fertility desire and choice

32. HGCIN(HSIL)

33. Colposcopic fingings: The most important determinant
1- Adequacy of colposcopy
2- Endocervical sampling result
3- Primary or recurrent lesion
Ablative treatment is acceptable only in: Primary lesion with adequate colposcopy and no endocervical involvement
Exception: special population (adolescence, pregnant)

34. WHO guideline for Histologically confirmed CIN 2+:
2014
To guide policy makers, managers and program planners and also clinicians
Systematic review to answer the questions comparing cryotherapy, LEEP, CKC outcome for the treatment of histologically confirmed CIN 2+
Panel developed recommendations (strong/conditional) for patients, clinicians and policy makers
Panel include consideration of eligibility criteria for treatment modality and also resources and feasibility

35. WHO guideline for Histologically confirmed CIN 2+:
Recommendation 1: strongly recommend cryotherapy over no treatment
Recommendation 2: strongly recommend LEEP over no treatment
Recommendation 3: strongly recommend cold knife over no treatment
Recommendation 4: suggest cryotherapy or LEEP for CIN 2+
Recommendation 5: strongly recommend cryotherapy over CKC for whom both are appropriate
Recommendation 6: strongly recommend LEEP over CKC for whom both are appropriate
Recommendation 7: Suggest CKC over LEEP for AIS

36. Recommendation 1: strongly recommend cryotherapy over no treatment
Non randomized studies: over 12 m recurrence of CIN 2+ with cryo: 4% , 647/1000 lesser than natural history without treatment
May be 55/1000 more preterm delivery after cryotherapy
No more abortion or infertility
Role on HPV clearance: not measured

37. Recommendation 2: strongly recommend LEEP over no treatment
Non randomized studies(Low quality evidences) but strong recommendation
647/1000 fewer recurrence than no treatment at 12 m
Premature delivery with LEEP: increased (R.R: 1.85)
Role of LEEP on infertility and spontaneous abortion and HPV clearance : not clear
Little/no major organ damage, major infection/ bleeding
Minor bleeding: 200/1000
Generally: Benefit outweigh any uncertainty about harm and resource use

38. Recommendation 3: strongly recommend cold knife over no treatment
Note: This recommendation considers that no other treatment may be available, CKC benefit outweigh harms
11 non randomized studies: 677/1000 fewer recurrence of CIN 2+ compared to no treatment
More harm: major bleeding and major infection both 9/1000), organ damage(3/1000), minor bleeding (24/1000), premature delivery (RR: 3.4), spont aborton all increased

39. Recommendation 4: suggest cryotherapy or LEEP for CIN 2+
Non randomized studies: 12 m recurrence rate is greater with cryotherapy (RR: 3, 95% CI )
Little or no difference in major infection or bleeding , fewer minor bleeding with cryotherapy (108/1000)
Unclear effect of cryotherapy on preterm delivery; low quality evidenced indicated about 18/1000 more prrterm delivery with cryotherapy
Unclear difference in the effect of on spont abortion, infertility, HPV clearance

40. Recommendation 5: strongly recommend cryotherapy over CKC for whom both could be appropriate
Although there may be fewer recurrence with CKC than cryotherapy, the harm may be greater
CKC: greater resource required, need for OR, anesthesia, highly trained provider
Six non-randomized study: greater recurrence rate with cryo: RR 3.29(95% CI 2.7-4)
with cryo: Lesser risk of premature delivery, lesser major bleeding and major infection, other organ damage and minor bleeding
Unclear effect on maternal mortality, infertility, spont abortion and HPV clearance

41. Recommendation 6: strongly recommend LEEP over CKC for whom both could be appropriate
Inconsistent results of non randomized studies
12 m Recurrence rate of CIN2+ is lower with CKC: RR 0.52: 2 randomized study RR 0,64 in 7 nonrandomized study
Major bleeding, major infection, preterm delivery: more with CKC
Spont abortion, infertility, HPV clearance: uncertain

42. Recommendation 7: Suggest CKC over LEEP for AIS
No randomized study, imprecise results of small Non randomized studies:
Greater recurrence with LEEP 31/1000 more AIS recurrences
49/1000 more invasive adenocarcinoma ( not all studies)
Very low quality studies: Fewer preterm delivery with LEEP, more spontaneous abortion with LEEP
Panel generally felt benefits outweigh the additional resources required for CKC

43. Note: Much of the data came from non-randomized or single arm studies and the results were therefore assessed as inconsistent and/or indirect. It is leading to low quality evidences
Note: Appropriate use of treatments should be determined by the eligibility criteria.
Eligibility for cryotherapy: entire lesion is visible, visible SCJ, lesion cover < 75% of ectocervix

44. Ablative treatments:
Electrocautery: More popular in Europe, Total failure with deep destruction : about 3% , no failure in CIN I & II ,13 % in CIN III( most failure rate)
Deep destruction is painful & needs anesthesia
Laser ablation/vaporization: Under guide of colposcpopy, CO2 laser vaporization of lesion or entire T-zone with controlled depth of 5-7 mm
Disadvantage : more painful than cryo, more time required, more experience, bleeding with deep destructions, more cost
Cryotherapy: Pain free, Depth of destruction : 4mm
Not used in USA, Failure rate : 6.8 %, Success rate : in CIN III patients : 95 % in 1year , 92 % in 5 years

45. Excisional treatments of HGCIN
Diagnostic and therapeutic procedures:
Knife Conization(CKC)
Laser Conization/excision
LEEP
Hysterectomy

46. Cervical Conization Old diagnostic and therapeutic procedure
It could be done by cold- knife(CKC) or Laser excision
Advantage of CKC: providing good tissue for further evaluation to rule out invasive cancer
good specimen
Disadvantages:
- needs anesthesia
- cervical stenosis
- cervical incompetence in future pregnancies

47. Limits of the lesion cannot be visualized with colposcopy ▀
Diagnostic conization is indicated for women with HSIL P/S after colposcopy and biopsy if:
Limits of the lesion cannot be visualized with colposcopy ▀
SCJ is not seen at colposcopy ▀
Endocervical curettage (ECC) histologic findings are positive for CIN 2 or CIN 3.
There is a substantial lack of correlation between cytology, biopsy, and a satisfactory colposcopy results.
Microinvasion is suspected based on biopsy, colposcopy, or cytology results ▀
The colposcopist is unable to rule out invasive cancer ▀
Note : ▀ are dependent on colposcopist experience

50. Knife cone versus laser excision cone:
Laser conization: can be done outpatient
Similar blood loss (OR), infection, stenosis in knife & laser
Some suggests less dysmenorrhea after laser cone
Coagulation artifact in laser cone:13% ( importance of experience, cooked specimens) , Laser artifact made margin assess impossible: 14 %
Cure rate: 100% if margin free,95 % positive margin
Recurrence : 3.3%
Cinsitu after therapeutic cone : 2.3% recurrence of Cinsitu ,0.9% invasive cancer

51. Loop Electrosurgical Excision: LEEP
Instrument popular since 1990s
Low voltage diathermy loop
Local anesthesia
Under colposcopy or logol guide
Depth : 5-8 mm

53. LEEP

54. Loop Electrosurgical Excision
Is a valuable tool for diagnosis and treatment of CIN
It offers the advantage of: diagnostic and therapeutic during one out patient visit
The tissue effect of electricity depends on: concentration of electrons (size of the wire), power (watts) & water content of the tissue.
If low power or a large-diameter wire is used, effect will be electrocautery, with extensive tissue thermal damage
With high power (35–55 watts) + small wire loop (0.5 mm): the effect will be electrosurgical, and the tissue will have little thermal damage

55. Loop Electrosurgical Excision
After the excision, a 5-mm diameter ball electrode is used, and power is set at 50 watts. The ball is placed near the surface so that a spark occurs between the ball and tissue. This process is called electrofulguration, and it results in some thermal damage that leads to hemostasis.
Experience is too important to:
Excise all lesion
Minimize thermal injury to specimen
If too much fulguration occurs: the patient will develop an scar with more discharge, and the risk for infection and late bleeding will be higher.

60. Advantages of LEEP
LEEP is relatively easy to learn, easy to teach, and easy to apply
Used for high-grade CIN without the disadvantages and great cost of cold-knife conization
For LEEP to be used effectively, extent of excision and choice of electrodes must be tailored to size and distribution of lesion
Shape of excision is tailored for each patient based on lesion shape, age and fertility desire

61. Complications of LEEP
Complications following LEEP are fairly minimal, compare favorably with laser ablation & cone (acceptably low rates)
Significant intraoperative bleeding: uncommon, can occur. The surgical team & clinic need to be prepared 5%
Hemorrhage requiring special techniques to control: more common if larger loop is used, no local injection of epinephrine /vasoconstrictive agents, vagina is accidentally lacerated with the electrode
Invisible SCJ: The SCJ is visible in more than 90% of patients after this procedure.
Cervical stenosis: can uncommonly occur, 4%

62. Disadvantages of LEEP
Anecdotal reports of infertility & preterm labor (9.4% versus 5% )
Thermal artifact 10% unreadable ,20-40% significant coagulation artifact !!
Higher frequency of tissue fragmentation
Not suitable for lesions high in endocervical canal
Failure : 4.3 %
Recurrence : reported up to 40 %

66. Recurrence of dysplasia
More recurrences if :
Lesions with positive margins are more likely to recur after conization
Endocervical gland involvement also is predictive of recurrence (23.6% versus 11.3%)
In a prospective study examining long-term effects of LEEP, conization & laser excision: no difference in recurrence of dysplasia or in pregnancy outcomes
Choice is guided by:
Size of the lesions
Desire for future pregnancy
Training of the surgeon
Availability of the equipment

67. knife cone is better than LEEP
If colposcopy suspicious to cancer
For documentation of microinvasion in biopsy report of microinvasion or
Biopsy report of AIS

68. Excisional treatments of HGCIN
Hysterectomy:
May be appropriate if high grade CIN in patient with:
- Poor follow up, Completed childbearing, Other indication for hysterectomy (CIN is not appropriate as sole indication)
Essential point: Only after complete assessment of abnormal P/S as guidelines
A major fault Hysterectomy for any degree of cytology abnormality
Removal of upper vagina is not recommended , indicated if involved in colposcopy
Recurrence: is possible ,3%
follow indefinitely

69. Follow up after HGCIN treatment
A- ADEQUATE COLPOSCPY→ EXCISION OF T-ZONE/ ABLATION
F.U. AFTER ABLATION: REPEAT COTEST 2 TIMES YEARLY:
BOTH NEGATIVE→COTEST AT 3 Y THEN RETURN TO ROUTINE
POSITIVE CYTOLOGY OR HR HPV: COLPOSCOPY+ ECC
B- INADEQUATE COLPOSCOPY/POSITIVE ECC/RECURRENCE →
DIAGNOSTIC EXCISIONAL PROCEDURE
F.U. AFTER EXCISIONAL TREATMENT:
MARGIN POSITIVE: - REPEAT CYTOLOGY /ECC 6M VS
REPEAT CONE/ HYSTERECTOMY
MARGIN NEGATIVE: REPEAT COTEST 2 TIMES YEARLY IF
BOTH NEGATIVE→ COTEST AT 3 Y THEN RETURN TO ROUTINE
POSITIVE CYTOLOGY OR HR HPV: COLPOSCOPY + ECC