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Cervical Metaplasia

The cervix is composed of columnar epitheJfum which lines the endocervix and squamous epithelium which covers the ectocervix. The point at which they meet is known as squamocolumnar junction (Transformation zone).

 

The squamocolumnar junction lies at the level of external os.?

 

Under the influence of hormones the subcolumnar cells transform into squamous cells. This changing of one type of epithelium into the other is called as metaplasia.
 

Metaplastic cells are:

  • Normal cells.
  • No Nuclear atypia.
  • Do not transform into malignant cells.
  • Squamous metaplasia is a normal process and occurs in all young females.

Factors predisposing to CIN / CA cervix

  • Human Pappiloma virus infection (most important)
  • Sexually transmitted infections-
    • Coitus before 18 years of age
    • Multiple sex partnersv
    • Multiparity
    • Poor personal hygiene
    • Poor socioeconomic status
  • Smoking?
  • "Immunosuppressed individuals
  • Women on ocp, progesterone therapy for long time are predisposed to adenocarcinoma of endocervix
  • In utero exposure to diethylstilbestrol (DES)

Dysplasia:

 

Represents a change in which there is alteration in cell morphology and disorderly arrangemen of the cells of the stratified squamous epithelium. It is a premalignant lesion.

 

Characteristics of Dysplastic Cell

  • Vary in size, shape and polarity.
  • Have altered nucleo-cytoplasmic ratio (N/C ratio is increased)
  • Have large, irregular hyperchromatic nuclei with marginal condensation of
  • chromatin material.?
  • Have several mitotic figures.
  • The basement membrane, however, is intact and there is no stromal infiltration.

CIN

 

Term CIN (Cervical Intraepithelial Neoplasia) It has almost universally replaced WHO classification of dysplasia. It is a term used to describe the condition of cervix when a part or the full thickness of startified squamous epithelial cells is replaced by dysplastic cells
 

WHO

CIN

Description

Bethesda classification cotton

Mild dysplasia

CIN I

Dysplastic cells seen in lower

1/3 of epithelial lining of cervix

LSIL

Moderate

dysplasia

CIN II

Dysplastic cells seen in 2/3 of

epithelial lining of cervix

HSIL

Severe dysplasia

CIN III

Dysplastic cells seen in more

than 2/3 of epithelial lining of cervix

HSIL

 

Carcinoma

insitu

Dyplastic cells seen full thickness but basement menturane is intact

HSIL

 

In Invasive carcinoma: Breach of basement membrane seen.

 

Note: LSIL = Low squamous intraepithelial lesion.

 

HSIL = High squamous intraepithelial lesion,

 

Rate of progression of CIN

 

 

CIN I

CIN II

CIN III

Regression to normal

60%

40%

30%

Persistence

30%

35%

50%

Progression to CIN III

10%

20%

-

Progression to cancer

<1%

5%

20%

 

Epidemiology of CIN- Age

 

CIN

M/c in 20-30 years

Ca in situ

30-35 years.

Ca in cervix

Bimodal peak

 

1 st peak seen at 35-39 years.

 

2nd peak seen at 55-60 years.

Diagnosis of CIN

 

Pap Smear (Exfoliative Cytology)

  • Time for initiating pap smear: 21 years of age regardless of the age of first sexual intercourse.
    • Instrument used: Ayres spatula and endocervical brush
    • Method: Ayres spatula is rotated through 3600 over portio vaginalis of cervix and 1st slide is prepared
  • With Cytobrush, 2nd slide is prepared from endocervix
  • Control slide prepared from posterior wall/ posterior fornix of vagina
    • Fixative used: 95% ethyl alcohol and ether

Note: Liquid base cytology is being used nowadays.

 

Preservative used in liquid based cytology is Methanol.

 

If liquid based cytology is being done it should be repeated every 2 years till female is 30 years of age then 3 yearly.

 

Screening guidelines for cancer cervix are formulated by American Society for Colposcopy and Cervical Pathology (ASCCP) and have been revised by the American College of Obs and Gynae in 2009.

 

Screening Guidelines

 

Regular screening should begin at 21 years regardless of the age of first sexual intercourse

 

Screening should be done annually till 30 years of age and then every 3 yearly provided there is no H/O HIV infection, CIN 213, in utero DES exposure.

Women donot meet the criteria for less frequent screening or those who have important risk factors present should continue to be screened annually

Screening can be stopped by the age of 65-70 years if there are no risk factors and they have 10 years legative screen result

Women who have had a total hysterectomy done for benign indications do not require further screening unless they have a H/O CIN 2,3

In HIV positive patients, screening is done at 6 months for 1 year after the diagnosis and then annually.

 

 

Pap Spear Results

 

The pap smear report can have the following terminologies as per the bethesda system:

  • Atypical squamous cells of undetermined significance (ASC-US)
  • Cannot exclude high grade (ASC-H)
  • Cow-grade squamous intraepitheliallesion (LSIL)
  • High-grade squamous intraepitheliallesion (HSIL)
  • Atypical glandular cells (AGC)
  • Not otherwise specified (AGC-NOS)
  • Favor neoplasia (AGC - favor neoplasia)
  • Adenocarcinoma in situ (AIS)

In bethesda system: The most common cytological abnormality encountered is atypical squamous cells (ASC).

 

The category ASC is further divided into ASCUS (atypical squamous cells of unknown significance), and ASC-H (atypical squamous cells where HSIL cannot be ruled out) which indicates cells that are suggestive of, but do not fulfill the criteria for squamous intraepitheliallesion.

The Bethesda Classificaiton System is based on cytological results of a pap test that permits the examination of cells but not tissue structure. The diagnosis of cervical intraepithelial neoplasia (ClN) or cervical carcinoma requires a tissue sample, obtained by biopsy of suspicious lesions (done during colposcopy), to make a histologic diagnosis That is why pap smear should always be followed by colposcopy or punch biopsy.

 

Note: Females with ASCUS can be followed by any of the following three methods

  • HPV DNA testing (best method)
  • Immediate colposcopy
  • Repeat cytology after 6 months

CIN

 

Correlation of Dysplasia, (In (Who) And Bethesda System Textbook of Gynecology

Dysplasia

CIN

Limit of histologic changes

Bethesda (see p. 113)

Mild

CIN I

Basal one-third

LSIL

Moderate

CIN II

Basal half to two – third

HSIL

Severe

CIN III

Whole thickness except one or two superficial layers

CIS

 

Whole thickness

 

Scheme-2: Life Cycle Of Unstable Cervical Epithelium

Cervical epithelium

CIN I

CIN II

CIN III/CIS

Regression to normal (%)

60

40

30

Persistence (%)

30

35

50

Progression to CIN III/CIS (%)

10

20

-

Progression to invasion (%)

< 1

5

20

Duration of disease progression (years)

Normal

CIN I, II

CIN III / CIS

Invasion

 

0

5

10

20

Age of the patient (year)

 

25-30

30-35

40-45


Indications of Diagnostic Conization

 

Colposcopy available

  1. Entire limits of the lesion not seen.
  2. Transformation zone not seen.
  3. Evidences of microinvasion on biopsy, colposcopy or cytology.
  4. Significant CIN on endocervical curettage.
  5. Normal colposcopic findings with abnormal cytology/biopsy.
  6. High grade CGIN lesion.

Colposcopy not available

  1. Abnormal smear with healthy cervix.
  2. Positive diagnosis of CIS to exclude invasive carcinoma.
  3. Biopsy report is inconsistent with cytologic findings.

Histologic Picture of Cis

  1. The entire epithelial layer is affected.
  2. There is loss of stratification and polarity.
  3. The cells vary in size and shape.
  4. The nuclei stain deeply with presence of frequent mitosis and abnormal chromatin pattern.
  5. The nuclei are larger and hyperchromatic with scanty cytoplasm.
  6. The basement membrane remains intact

Features of a Dyskaryotic Cell

  1. Increased cell size.
  2. Pleomorphism-different staining appearance.
  3. Cells vary in their size and shape.
  4. Multinucleation.
  5. Clumping of chromatin-varying degree.
  6. Aneuploidy.
  7. Alteration in nuclear membrane.
  8. Perinuclear halo.

Cervical Cancer and Cin

Carcinoma cervix is the MC cancer affecting women in India today, followed by breast cancer

  • Risk factors for CA cervix/CIN:
    1. Young age at first intercourse (<16 years) •
    2. Multiple sexual partners
    3. Cigarette smoking
    4. Race
    5. High parity
    6. Low socioeconomic status
    7. Human papilloma virus (HPV) infection
    8. HIV
    9. Immunosuppression
  • The cervix is composed of the columnar epithelium, which lines the endocervical canal, and squamous epithelium, which covers the exocervix. The point at which they meet is called as squamocolumnar junction (SCJ).
  • The SCJ rarely remains restricted to external os. Instead, it is a dynamic point that changes in response to puberty, pregnancy, menopause, and hormonal stimulation. In neonates, SCJ is located on the exocervix, At menarche, the production of estrogen causes the vaginal epithelium to fill with glycogen. Lactobacilli act on the glycogen and lower the pH, stimulating the sub columnar reserve cells to undergo metaplasia.
  • Metaplasia advances from the original sq inward, toward the internal os and over the columnar villi. This process establishes an area called the transformation zone (TZ). The TZ extends from the original sq to the physiologically active SCJ.

Human Papilloma Virus and Cin

  •  HPV produces CIN in 90% cases

HPVType

Oncogenic Potential

Comment

6,11

Low

• Anogenital warts

31,33,35,51,52

Intermediate

• CIN 1, 2, 3

16,18,45,56

High

• CIN 2,3

 

 

• Invasive CA

  • HPV-16 is the most common HPV seen in invasive CA and CIN 2/3 and is found in 50% cases.
  • HPV-16 is not very specific and is also the most common HPV type in women with normal cytology.
  • HPV-18 is more specific than HPV-16 for invasive tumors.

Life Cycle of Unstable Cervical Epithelium

Cervical Epithelium

CINI

CIN II

CIN III/CIS

Regression to normal (%)

60

40

30

Persistence (%)

30

35

50

Progression to CIN III/CIS (%)

10

20

-

Progression to invasion (%)

<1

5

20

 

Pathogenesis of CIN and Invasive Carcinoma

 

The initial event in cervical dysplasia and carcinogenesis is likely to be infection with HPY. The mechanism by which HPV affects cellular growth and differentiation is, by interactions of viral E6 and E7 proteins with p53 and Rb resulting in gene activation.

 

 

  • As per ACOG guidelines the first PAP smear should be done at 21 years of age or 3 years after vaginal sex.
  • If first PAP smear is normal then it should be repeated after 1 year and then again after a year. If three annual
     
    PAP smears are normal, then PAP smear should be done every three years.

 

ASCUS = atypical squamous cell of unknown significance


Fixative for PAP smear is 95% ethyl alcohol and ether.

  • PAP smear is cytology, whereas CIN is a histological diagnosis after cervical biopsy.
  • As per Bethesda system:
  • Low-grade squamous intraepitheliallesion (L-SIL) = CIN I
  • High-grade squamous intraepitheliallesion (H-SIL) = CIN II/CIN III/CIS

NOTE: If a patient presents with obvious fungating growth on lips of cervix, next step to be done is punch biopsy.

 

Abnormal Patterns at Colposcopy

  • Acetowhite epithelium (due to charring/ denaturation of proteins)
  • Puncta tion
  • Mosaicism
  • Atypical vessels

Management of CIN

  • CIN I = Wait and watch/ follow up
  • CIN II = Cryosurgery
  • CIN III
    1. If patient wants to conserve the uterus/ desirous of further child bearing == loop electro-excision procedure/ large loop excision of transformation zone (LEEP/LLETZ).
    2. If the family is complete or if the patient is not ready for regular follow-ups or has associated features such as prolapse or fibroids, then the treatment includes simple hysterectomy (abdominal/vaginal)

Indications for Cone Biopsy

 

 

Preinvasive Carcinoma

Stage 0

Invasive

Carcinoma

Carcinoma in situ, intraepithelial carcinoma (cases of stage 0 hould not be included in any

therapeutic statistics)

Stage I Stage Ia

Carcinoma strictly confined to the cervix (extension to the corpus should be disregarded)

Preclinical carcinomas of the cervix i.e., those diagnosed only by microscopy

Stage lal: lesion with <3 mm invasion

Stage la2: lesions detected microscopically and can be measured

The upper limit of the measurement should show a depth of invasion of >3-5 mm taken from the base of the epithelium, either surface or glandular, from which it originates, and a second dimension, the horizontal spread, must not exceed 7 mm. Larger lesions should be staged as Ib

Stage Ib

Lesions invasive >5 mm

Stage Ibl: lesions less than or equal to 4 cm

Stage Ib2: lesions larger than 4 cm

The carcinoma extends beyond the cervix but has not extended onto the wall

 Stage II

 

The carcinoma involves the vagina, but not the lower one-third

Stage IIa: No obvious parametrial involvement

Stage lIb: obvious parametrial involvement

Stage III

 

The carcinoma has extended onto the pelvic wall. On rectal examination, there is no CA-free space between the tumor and the pelvic wall. l1'te-tumor involves the lower one-third of the vagina. All cases with hydronephrosis or nouwnctioning kidney

Stage IIIa: no extension to the pelvic wall Stage IIIb: extension onto the pelvic wall and I or hydronephrosis or nonfunctioning kidney

Stage IV

The carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the bladder or rectum. A bullous edema, as such, does not permit a case to be allotted to stage IV

Stage IVa: spread of the growth to adjacent organs

Stage IVb: spread to distant organs

 

Recent Advances : FIGO (2009) Staging for Ca Cervix

IA1

 

IA1

 

IB1

IB2

IIA1

 

IIA2

IIB

IIIA/B

IVAIB

Confined to the cervix, diagnosed only by microscopy with invasion of <3 mm in depth and lateral

spread <7mm

Confined to the cervix, diagnosed with microscopy with invasion of >3 mm and <5 mm with lateral spread <7mm

Clinically visible lesion or greater than A2, <4 cm in greatest dimension

Clinically visible lesion, >4 cm in greatest dimension

Involvement of the upper two-thirds of the vagina, without parametrial invasion, <4 ecm in greatest dimension

>4 cm in greatest dimension

With parametrial involvement

Unchanged

Unchanged

 

Staging Procedures

 

Physical examination

 

 

 

Radiologic studies (allowed by FIGO)

 

 

 

 

 

 

 

 

 

 

Optional studies (not allowed by FIGO)

 

 Palpate lymph nodes

 Examine vagina

 Bimanual rectovaginal examination (under anesthesia recommended)

 Intravenous pyelogram

 Barium enema

 Chest X-ray

 Skeletal X-ray

 Biopsy

 Conization

 Hysteroscopy

 Colposcopy

 Endocervical curettage

 Cystoscopy

 Proctoscopy

 Computerized axial tomography

 Lymphangiography

 Ultrasonography

 Magnetic resonance imaging

 Radionucleotide scanning

 Laparoscopy

 

Management of Cancer of Cervix Stage-wise

 

Stage 1A1

  • Young patient/family not complete (to retain uterus) = therapeutic conization
  • Old patient/ family complete = simple extrafascial hysterectomy

Stage 1A2

 

Radical/Wertheim's hysterectomy

Concurrent chemoradiation (CTRT)

Only for stages: lA2, 18, IIA

I-IV

 

lib-IV

  • Cisplatin is given before RT as a radiosensitizer.
  • All stages (I-IV) are radiosensitive.
  • Stages of Ca cervix that are operable (radical/Wertheim's hysterectomy) are lAII, 18, and lIA.
  • Stages lIB-IV are not operable and have to be treated with CTRT only.
  • lA2, 18, IIA are radiosensitive and surgically operable, but surgery IS preferred over CTRT for these stages for the following reasons:
    • Preservation of ovarian function
    • Preservation of vagina for coital function
    • Psychological benefit to the patient
  • Ca cervix almost never spreads to ovary and so when radical hysterectomy is done, oophorectomy is not required.

Comparison between the two modalities of treatment for Ca cervix

 

 

Surgery

Radiation

Survival

Serious complications

85%

Urologic fistulas 1-2%

85%

Intestinal and urinary strictures and fistulas

1.4-5.3%

Ovaries

Can be conserved

Destroyed

Chronic effects

Bladder atony in 3%

Radiation fibrosis of bowel and bladder in 6-8%

Surgical mortality

1%

1 % (from pulmonary embolism during intracavita- tory therapy)

  • Point A and Point B are in relation to radiotherapy for Ca Cervix

 

Point A

Point B

Location

2 em above and 2 em lateral to external os

2 cm above and 5 em lateral to external os

Structure present

Paracervical/parametriallymph node

Obturator lymph node

Dose of radiation

7000-8000 cGy

6000 cGy

  • Uremia/renal failure is the MC cause of death in patient of Ca cervix.
  • Hemorrhage is the second MC cause of death.
  • Vaginal bleeding (most often postcoital) is the MC symptom occurring in patients with Ca Cervix
  • MC cause of postmenopausal bleeding in India is Ca cervix
  • Causes 01 pyometra:
    1. Cervical cancer (MC)
    2. Uterine cancer
    3. Cervical atresia
    4. Cervical stenosis
    5. Genital TB

Piver-Rutledge Classification Types of Hysterectomies

 

Type

Comments

I

Extrafascial hysterectomy

II (Wertheim's/modified radical

Medial half of uterosacral & cardinal ligaments are also removed. Uterine

hysterectomy)

vessels divided medial to ureter

III (Meigs/radical hysterectomy)

Uterosacrals are divided at their origin & cardinal ligaments removed from

 

the lateral pelvic wall

IV

Type III + upper 75% of vagina also removed

V

Complete pelvic exenteration

 

Carcinoma Cervix in Pregnancy

  • PAP smear should be performed ideally on all pregnant women at the first antenatal visit and if required colposcopy and biopsy should be done
  • If there is a need to perform a diagnostic cone biopsy, it should be done in second trimester
  • CIN 1, 2 & 3 can be managed after pregnancy, vaginal delivery is possible
  • Treatment modalities for Ca cervix are the same as in nonpregnant women
  • Stage 1Al: vaginal delivery and then simple extrafascial hysterectomy or therapeutic conization after 6 weeks postpartum
  • Stage 1A2, 1B, 2A:
     
    If detected in first trimester = immediate Wertheim's hysterectomy on pregnant uterus
     
    If detected in late second or third trimester: wait (treatment can be delayed up to 4-6 weeks) for fetal lung maturity and then classical caesarean section followed immediately by Wertheim's hysterectomy
  • Stage 2B-4:
     
    If detected in first trimester: immediate radiotherapy
     
    If detected in late second or third trimester: wait for fetal maturity, classical caesarean section and then radio-therapy after 4 weeks.

Vaccines for Prevention of Cervical Cancer

 

 

Gardasil

Cervirax

Type

Quadrivalent

Bivalent

Effective against HPV strains

6,11,16,18

16,18

Schedule

0,2,6 months

0,1,6 months

Route

Intramuscular

Intramuscular

Protects against

Carcinoma cervix & genital warts

Carcinoma cervix

 

Contraindications:

  1. Pregnancy
  2. Hypersensitivity

Recent Advances

 

Radical trachelectomy: This involves removal of cervix, parametrium, vaginal cuff and pelvic lymphadenectomy.
The uterus is preserved for further fertility.

The eligibility criteria include:

  1. Desire to preserve fertility /young patients
  2. Lesion size of 2 em or smaller
  3. FICO stage lA2 and 181
  4. No lymph node metastasis.

However, it is not yet considered the standard of care, Wertheim's hysterectomy is the standard care for stages 1A2 and IB1.





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