Premalignant disease of the cervix

Dr.Miami Abdul Hassan 2016

F.I.C.O.G.

Objective:

The aim of this lecture is to:

1.Understand the normal cervical changes and distinguish it from premalignant conditions

2.Be able to manage cases with cervical intraepithelial neoplasia

3.Get knowledge about the screening methods of cervical intraepithelial neoplasia

Cervical cancer is the second most common canceramong women worldwide, with only breast cancer occurringmorecommonly.It has long natural history, and intervention and treatment in the premalignant phase is highly effective. The accessibility of the cervix and the availability of a simple test for the presence of pre-malignancy make it suitable for mass screening.

Cervical cancer screening is effective and has contributed to the fall in the developed world of cervical cancer deaths.

Definitions:

Metaplasia:is a physiological change from columnar epithelium lining the endocervix to squamous epitheliumcovering the ectocervixinresponse to acid environment of the vagina.

Neoplasia: demonstrates a disease spectrum ranging from mildly dysplastic cytoplasmic and nuclear changes to those of severe dysplasia. With these changes, there is no invasion through the basement membrane, which defines invasive cancer.

Squamocolumnar junction (SCJ): the point where these two epithelia met, the position of the SCJ varies throughout thereproductive years. It everts outward onto the ectocervix during adolescence, pregnancy, and with use of combined hormonal contraceptions. It regresses into the endocervical canal with menopause and other low-estrogen states such as prolonged lactation and use of progestin-only contraceptives

Transformation Zone:the area on the cervix that has undergone metaplasia, it is bounded by the original SCJ and the present SCJ.It is the site of malignancy in > 90% of cases.

Dysplasia or cervical intra-epethial neoplasia(CIN)

CIN is a premalignant condition of the cervix characterized by specific cytology (dyskaryosis) and histological (dysplasia) features, etiological factors are similar to those of cervical carcinoma.

Clinically:It is usually asymptomatic with normal looking cervix; peak age is late thirties diagnosis requires cytology, colposcopy and histology.

Causes:The process of the metaplasia can be disrupted by external influences and lead to disordered squamous epithelial called dysplastic epithelial.

  1. HPV is now implicated in more than 90% of cases
  2. Smoking
  3. Immune suppression
  4. Sexual behavior such as early coitarche, multiple sexual partners and high parity

appear to be additional factors which may act as co- agent.

The nuclei tend to be larger, more variable in the size and shape more actively dividing than in healthy squamous epithelium.

The severity of a lesion is graded according to the proportion of epithelium affected from the basement membrane upwards. In the case of CIN, abnormal cells confined to the lower third of the squamous epithelium are referred to as mild dysplasia or CIN 1; extending into the middle third as moderate dysplasia or CIN 2; and into the upper third as severe dysplasia or CIN 3, with full-thickness involvement called carcinoma in situ (CIS). Once there is invasion of the basement membrane then cervical cancer is diagnosed

Bethesda classification

In North America and many other countries, the Bethesda reporting system has been adopted. The classification uses the term squamous intraepitheliallesion (SIL) to encompass all grades of CIN. SIL is further subdivided into two categories :

(LSIL) low grade which includes cellular changes associated with human papillomavirus (HPV) infection and CIN 1.low progressive potential.

(HSIL)high-grade SIL which includes CIN 2 and 3.are likely to behave as cancer precursors.

Most CIN are reversible lesions (i.e. curable lesions) and directed more to malignancy with increase the degree of dysplasia.

The progressive potential of high-grade lesions or CIN 3has been calculated to be 18% at 10 years and 36% at 20 years.

Screening methods for CIN:

1.Conventional cervical cytology (pap smear) is prepared by smearing collected cells from transformation zone directly onto a glass slide with the collection device followed by immediate fixation (left)

2.Thin-layer liquid-based cytology involves transfer of collected cells from the collection device into a liquid transport medium with subsequent processing and transfer onto a glass slide. Cells are distributed over a smaller area and debris, mucus, blood, and cell overlap are largely eliminated with the result of one cell layer (right)

Sampling tools

The spatula and the endocervical brush .A spatula predominantly samples the transformation zone as more than 90% of malignancy arise there. An endocervical brush samples the endocervical canal and is used in combination with a spatula.

Screening intervals for national screening programme:

Age (years) / Frequency of screening
25 / First invitation
25-49 / Three yearly
50-64 / Five yearly
65 and more / Screen those who had no test since 50 years or had abnormal test

Result: divided into 5 groups: (first 2 negative, last 3 positive):

  1. Normal.
  2. Negative but with (inflammation, atrophic changes).
  3. CIN I
  4. CIN II
  5. CIN III

HPV vaccines

The introduction of vaccines against human papillomavirus (HPV), the causal agent in cervical cancer, has been a major advance in cervical cancer prevention.

Cervical cancer and CIN are caused by HPV infection and in recent times HPV vaccines have been developed to prevent the primary infection withcertain oncogenic HPV types. The quadravalent vaccine (gardasil) against HPV serotypes (6, 11, 16 and 18) and bivalent vaccine(cervarix) against serotypes ( 16 and 18). All girls between the age of 12-17 years should be offered the vaccine with the sole aim of reducing death rates from cervical cancer through a prevention of HPV-related high-grade CIN in addition to the reduction in genital warts. The diagnosis of HPV infection is by PCR for viral DNA and smear which reveals koilocytes.

koilocytes(HPV)Large squamous cell with enlarged hyperchromatic nucleus & large sharply demarcated perinuclear clear zone

Management of abnormal cervical smear:

1.Ideally all women with abnormal cervical cytology should have a colposcopic assessment except patients withCIN1, PAP smear could be repeated after 6 months,if still positive refer for colposcopy.

Three normal smears are required before a woman can be returned to routine screening in case of mild dysplasia.

2.Women with CIN II &CIN III should be referred for colposcopy.

3.Smears show abnormal glandular cell should always be referred for colposcopy because of increased risk of invasive cancer.

Colposcopic examination with directed biopsyand endocervical curettage to confirm the diagnosis or cone biopsy (when indicated).

The aim ofcolposcopy is first to exclude an invasive process and secondarily to identify the extent of the abnormality and its likely grade which may allow a more conservative approach in the management. For adequate colposcopy, the whole of the transformation zone(TZ) needs to be visualized. If the TZ is not fully visualized, then colposcopyis deemed unsatisfactory. This inability to visualize the squamo-columnar junction (SCJ) may be an indication for excisional biopsy of the cervical transformation zone (cone biopsy).

Colposcopy:

Colposcopy is an outpatient examination of the cervix using a binocular microscope. It is used for both diagnosis and treatment of CINwith amagnification of 4-25 times.

Method:

1.The cervix is examined at low magnification (4-6X), then a saline soaked cotton ball helps to remove cervical mucus and allows vascular and surface features of lesions to be initially assessed under higher magnification (16-25X).

2.Abnormal vessels are better viewed with green filtered light.

3. Acetic Acid 3-5% causes nucleoproteins within cells to coagulatetemporarily, therefore areas of increased cell turnover,for example in CIN will appear white at colposcopy .

4. Lugol's iodine Solution.Schiller test: a test used to identify normal squamous epithelium which contains glycogen that stains dark brown with iodine, while abnormal squamous cells lacks glycogen and fails to stain

5. Abnormal subepithelial capillary pattern may be revealed as punctuation or mosaicim . Abnormal vessels suggestive of micro invasive carcinoma .

6. Colposcopic –directed biopsy: from acetowhite or schiller's positive areas and those with abnormal vessels.

Colposcopic findings:

Normal colposcopic findings:

  1. Original squamous epithelium.
  2. Columnar epithelium.
  3. Normal transformation zone.

Abnormal colposcopic findings (atypical transformation zone )which could be one of the following :

  1. Acetowhite epithelium.
  1. Punctation (dilated elongated vessels).
  2. Mosaic (crazy paving appearance).
  3. Abnormal blood vessels (coma –shape, wires) in invasive cancer.

Unsatisfactory finding, where the squamo-columnar junction cannot be visualized as in postmenopausal women (located distally in the cervix canal).

Punctation Mosaicappearance

Results of colposcopic directed biopsy or cone biopsy if revealed invasive cervical cancer then treatment(radical surgery , radiotherapy, chemotherapy ) ,but if the results revealed CIN, the treatment will be as following:

Methods for the treatment of CIN:

CIN 1 may regress spontaneously in up to 60 per cent of cases, therefore close follow up with colposcopy and cytologysix months after initial diagnosis is favored as this avoids overtreating lesions which might regress,treatment is indicated if it persists for at least 2 years.

CIN 2 and CIN 3 are treated by excision orablation (destroying the abnormal epithelium).

The aim of treatment is to effectively eradicate CIN and ensuring that post-treatment smears are negative

Excisional methods Ablative methods

1-Loop TZ excision (LLETZ/LEEP) 1-Cryocautery

2-Laser TZ excision 2-Electrodiathermy

3-Knifeconebiopsy 3- Cold coagulation

4-Laser conebiopsy 4-Carbondioxid Laser

5-Loop conebiopsy

6- Hysterectomy

Cure rates for both ablative and excisional techniques are in excessof 90%. Recently there has been a tendency towardsusing excisional methods. This allows better histopathological interpretation of the excised specimen and incertain circumstances allows a ‘see and treat’ strategyif the colposcopic assessment is consistent with a lesionrequiring local treatment and the patient is agreeable to treatment under local anaesthetic at the initial visit. This policy can lead to overtreatment of insignificant lesions and with this realization a ‘select and treat’ strategy is employed in most colposcopy units.

Ablative techniques: can be done under general, regional or local anaesthesia,but does not providea specimen for histopathology.

Types:

1-Cryocautery destroys tissue by freezing using probes of various shapes and sizes.It is sufficient treatmentfor low-grade CIN, but not effective enough forhigh-grade disease.

2- Electrodiathermy destroys tissue more effectively than cryocautery.

3-Cold coagulation is a misnomer as the treatment involves placing ahot probe on the cervix in outpatients under localanaesthetic. It is a destructive treatment, is effective for

both high- and low-grade CIN.

4-Laser technique is precise, it allows good control of the depth of destruction,good haemostasis and excellent healing as there is minimalthermal damage to the adjacent tissue. The techniqueis particularly useful for treating premalignant disease with vaginal involvement.

Excisional methods:

Transformation zone excision has been developed as aconservative excisional technique. Both the laser anddiathermy loop have been used for this purpose.

The favored method of treatment is loop diathermy (large loop excision of transformation zone, LLETZ). Under local anaesthesia, a diathermy wire loop is used to remove a portion of the cervix which includes the transformation zone with the area of CIN.

The technique isreferred to as large loop excision of transformation zone(LLETZ) in Europe and as loop electrosurgical excision procedure (LEEP) in North America

Cone biopsy and hysterectomy still retain a place in the management of CIN.

LLETZ CONIZATION

Conization

Conization of the cervix plays an important role in the management of CIN. Before the availabilityof colposcopy, conization was the standard method of evaluating an abnormal Pap testresult. Conization is both a diagnostic and therapeutic procedure and has theadvantage over ablative therapies of providing tissue for further evaluation to ruleout invasive cancer

Conization is indicated for diagnosis in women with HSIL based on a Pap test underthe following conditions:

  1. Limits of the lesion cannot be visualized with colposcopy.
  2. The SCJ is not seen at colposcopy.
  3. Endocervical curettage (ECC) histologic findings are positive for CIN II or CIN III.
  4. There is a substantial lack of correlation between cytology, biopsy, and colposcopy results.
  5. Microinvasion is suspected based on biopsy, colposcopy, or cytology results.
  6. The colposcopist is unable to rule out invasive cancer.
  7. When colposcopy is not available.

Complication:

1.Immediate (infection and haemorrhage).

2.Late (cervical stenosis, cervical incompetence and infertility).

Patients who have undergone treatment requireclose follow up with regular cervical smears sixmonthly after treatment and then yearly for ten years,as they remain as a group at elevated risk of recurrentCIN and cervical cancer

Hysterectomy

There are some situations inwhich hysterectomy remains a valid and appropriate method of treatment of CIN:

  1. Microinvasion, CIN 3 at limits of conization specimen in selected patients
  2. Poor compliance with follow-up
  3. Other gynecologic problems requiring hysterectomy, such as fibroids, prolapse, endometriosis,and pelvic inflammatory disease

Thank you

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