lecture cervical ca note for year three medicine students

1. Premalignant and malignant
condition of the cervix

2. Anatomy and Physiology of the Cervix:
Important Terms
 Cervix is lower part of uterus that connects to vagina
Exocervix: connects to vagina
 The opening in the exocervix(external os) marks the transition from
the ectocervix to the endocervical canal
 Covered with squamous epithelium
Endocervix: inner region of the cervix
 Covered with glandular columnar epithelium
Squamocolumnar junction (SCJ)
 Place where squamous cells meet columnar cells
 Is usually visible on cervix as a line

5.  The SCJ is dynamic and moves during early adolescence
and during first pregnancy
 The original SCJ originates in the endocervical canal but as
the cervix everts during adolescence or pregnancy the SCJ
comes to lie on the ecto cervix and becomes the new SCJ.
 The epithelium between these two SCJ is the transition
zone ,its position also is variable and is the site where
malignant transformation occurs.
 TZ is more ectocervical during women's reproductive year
and return to endocervix during menopause

7. Nulliparous
Smooth round opening (os) of the cervix
SCJ is a faint, thin white line just at the entrance of the
cervical canal
Columnar epithelium is red due to blood vessels beneath
the single layer of cells
Squamous epithelium is less red because it is several
layers thick

8. Multi parous
Uneven cervical os with a worn appearance
“Fish mouth” appearance
The cervix may need to be manipulated to view the SCJ
Nulliparous

9. Function of the cervix
Produce cervical mucus which block ascent of
pathogens
Facilitate passage of sperm in to uterine cavity
Canal for passage of menstrual flow
Canal for fetal passage to vagina during labor
by dilatation

10. CIN
 the term intraepithelial neoplasia refers to epithelial
lesions that are potential precursors of invasive cancer.
 These lesions demonstrate a range of histologic
abnormality from mild to severe based on cytoplasm,
nuclear, and histologic changes.
 The severity of squamous intraepithelial lesions is
graded by the proportion of epithelium with abnormal
cells.
 These alterations begin at the basement membrane
and continue upward toward the epithelium surface.

11. With cervical intraepithelial neoplasia (CIN), abnormal
cells solely confined to the lower third of the squamous
epithelium are referred to as mild dysplasia or CIN 1.
 Those that extend into the middle third are moderate
dysplasia or CIN 2,· into the upper third, severe
dysplasia or CIN 3; and
full-thickness involvement, carcinoma in situ (CIS).
 Preinvasive squamous lesions of the vagina, vulva,
perianal, and anal squamous epithelia are graded
similarly to CIN.

12. Precancerous changes almost always develop
in the T-zone and specifically on or near SCJ
Screening for precancerous lesions should
focus on the T-zone and SCJ because that is
where a dangerous lesion will develop

14. Squamous metaplasia
Physiologic process through which the glandular cells
lining the cervical canal near the SCJ are replaced with
squamous cells
Due to cervix’s exposure to noxious agents in the
environment such as bacteria, viruses, and unclean
foreign bodies
Has a thin white, veil appearance that will not wipe
away

15. Ectropion
 also called Ectropy /cervical erosion
 Condition where cell lining the inside of the cervix evert on to the
outside of the cervix
 glandular cells mixed into the squamous cells, can extend onto vagina
continuously
 normal, may reflect microglandular hyperplasia (benign, OCP)due to high
estrogen exposure

17. Risk factors
Risk factors for CIN are similar to cervical cancer and
include the following
Demographic risk factors
Ethnicity (Latin American countries, U.S. minorities)
Low socioeconomic status
Increasing age
Behavioral risk factors
Early coitarche
Multiple sexual partners
Male partner with multiple prior sexual partners

18. Tobacco smoking
Medical risk factors
Cervical high-risk human papillomavirus infection
Exogenous hormones (combination hormonal
contraceptives)
Parity
lmmunosuppression
Inadequate screening

19. Natural History
The natural history of HPV infection include
Regression
Persistent infection
Progression to preinvasive lesion
Progression to invasive carcinoma from high grade
lesion
The risk of progression to invasive cancer rises with
CIN severity.

20. Low grade lesions are thought to be
manifestations of acute HPV infection, and
approximately 90 percent regress within a few
years.
High-grade lesions are less likely to regress.
 Approximately 40% CIN 2 cases show
spontaneous regression within 2 years.
This is even more frequent (>60 percent) in
young, healthy women.

21. CIN 2 is thought to be a mixture of low- and
high-grade lesions that are difficult to
distinguish histologically, rather than an
intermediate step in the progression from CIN
1 to CIN 3.
The risk of progression of biopsied but
untreated CIN 3 to invasive cancer
approximates 30 percent over 30 years.

22. Prevention of cervical cancer
1)Primary prevention
Involve primary prevention of HPV infection like
A)behavioral changes abstinence from sexual intercourse, being
mutually faithful in relation and consistent use of condoms
B) HPV vaccination which are found as
 Cervarix (bivalent vaccine )that targets HPV 16&18
 HPV Quadrivalent ( gardasil 4)that targets HPV 16,18 and low
risk serotypes HPV 6&11
 HPV Nonavalent ( gardasil 9)that targets HPV
16,18,6,11,31,33,45,52 and 58

23. HPV is recommended to be give for all male and
female age 9-13 years old
For adolescents and adults aged13-26 who have not
been previously vaccinated or who have not
completed the vaccine series , catch-up vaccination
is recommended
For those above 27 years , catch-up vaccination is
not recommended but studies have shown that HPV
is safe and effective in those above 27 and in USA it
is give up to 45 years of age.

24. Prior history of sexual contact , abnormal pap status ,
genital wart or prior HPV infection is not
contraindication for vaccination.
Immunization schedule
For individual starting the vaccine at 9-14 years of
age, two dose of HPV should be give at 0&6 to 12
month interval
For individual starting the vaccine at 15 years or
older ,three doses given at 0,2 months and 6 months

25.  Minimum interval between the doses is at least 4 weeks between the first
two doses and 12 weeks between the second and third dose and 5
months between the first and third dose.
 If a dose was administered at a shorter interval ,it should be repeated
once the minimum recommended interval since the most recent dose has
passed

26. Immunocompromised patients - three doses of HPV
vaccine should be given at 0,2month and 6 month
interval regardless of age.
Missed doses-the ACIP recommends that if the
vaccination series is interrupted for any length of time ,
it can be resumed without restarting the series.
HPV vaccination is not recommended during pregnancy
because of limited information on its safety during
pregnancy but can be given for lactating women

27. Efficacy varies for the vaccine types and generally
range from 99%in HPV naïve to 44-61% in overall
population in preventing CIN -2 and above and
CIS.
2)Secondary prevention
halts the progression of the diseases once it has
started.
Includes screening and treatment of
precancerous cervical lesion

28. CERVICAL INTRAEPITHELIAL NEOPLASIA DIAGNOSIS
 Cytology(Pap smear)
 HPV DNA test
 Co-test
 Resource limited set up
 VIA
 VILI
NB:Read on how each tests are done and interpretation

29. Current Cervical Cancer Screening Guideline
Screening Initiation
 Cervical cancer screening begins at age 21 in average-risk women.
 This is true regardless of sexual history, sexual orientation, or other
risk factors.
Screening Strategies and Intervals
 For women aged 21 to 29 years, all current guidelines recommend
screening with cytology alone at 3-year intervals.
 Women aged 30 to 65 years can continue screening with cytology
alone at 3-year intervals or can begin co-testing at 5-year intervals
 HPV DNA is incorporated by the WHO as primary screening
modality

30. Screening Discontinuation
Screening may be stopped at age 65 years in those at
average risk for cervical cancer and who have
undergone adequate screening, regardless of past or
current sexual history.
 Adequate screening is defined as three consecutive,
negative cytology results or two consecutive,
negative co-test results in the prior 10 years, with
the most recent result occurring within the past 5
years.

31.  Women with prior treatment for CIN 2, CIN 3, AIS, or
cervical cancer should continue screening for at least 20
years past their diagnosis and treatment, even if this
extends screening beyond age 65.
Post hysterectomy
 Primary vaginal carcinoma is rare and makes up < 5
percent of all gynecologic malignancies .
 All guidelines recommend against Pap test screening for
women who have undergone total hysterectomy (cervix
removed) for a benign disease indication and who lack a
prior high-grade CIN or cervical cancer diagnosis

32. lmmunocompromised Patients
 With HIV infection, screening should commence within 1 year of
sexual activity onset and no later than age 21 years.
 Women aged 21 to 29 years should receive Pap testing at the time
of HIV diagnosis.
 If an initial Pap test result is negative, testing should be repeated
6 or 12 months later and then continued every 12 months.
 After three consecutive, negative Pap test results, the interval of
Pap testing can be extended to 3 years.
 Cervical cancer screening is continued indefinitely even in those
aged 65 years or older who have been adequately screened.

33. Colposcopy -is a magnified view of the
cervix , vaginal and vulva .
 Indications
Unexplained lower genital tract bleeding
Abnormal cytology on pap
smear(LSIL,HSIL,ASC-H,AGC..)
Abnormal vaginal discharge
Grossly visible cervical lesion

34. Management of CIN
1)Ablation
 This involves physical destruction of tissue and is generally
effective for noninvasive ectocervical disease.
 Commonly indicated for persistent CIN I and CIN 2
 The most commonly used ablative treatment modalities are
cryosurgery , thermal ablation and carbon dioxide (CO2)
laser ablation
 Ablation should not be used after previous therapy, after
glandular cytologic abnormalities, or for AIS and high grade
lesions.

35. 2) Excisional therapy
 commonly used for high grade lesion(CIN-III, glandular
cytologic abnormalities, or for AIS and repeat therapy)
 Includes LEEP(loop electrosurgical excision procedure)
and clod knife conization(CKC).
3) Hysterectomy is unacceptable as primary therapy for CIN
 However, it may be considered when treating recurrent
high-grade cervical disease if childbearing has been
completed or if a repeat cervical excision is strongly
indicated but not technically feasible.

36. 3) Tertiary care for cervical cancer
Care give once a women is diagnosed with
invasive cervical cancer
include surgery,radiotheraphy,chemotheraphy
and palliative care

37. Cervical cancer
Cervical cancer is the most common
gynecologic cancer in women worldwide.
 Most of these cancers (99.7%) stem from
infection with the human papillomavirus (HPV)
Most early cancers are asymptomatic.
Thus, diagnosis usually follows histologic
evaluation of biopsies taken during colposcopic
examination or from a grossly abnormal cervix

38. Fourth most common cancer among women
world wide
569,847 new case and 311,000 death annually
In LMIC including Ethiopia commonest
reproductive organ cancer and leading cause of
death from cancer
In Ethipian,second most common cancer with
6200 new cases yearly with mortality close to
5000

39. Cervical cancer is potentially preventable diseases as
effective screening program led to significant
decrement in mortality and morbidity from cervical
cancer in developed countries.
Ethiopia launched the first ever national guideline on
cervical cancer screening and treatment in 2015
which served for 5 years
During the past 5 years, the national coverage of
cervical cancer screening and treatment for women
age 30-49 is only 5%.

40. Human Papillomavirus Infection
 This virus is the primary etiologic infectious agent associated
with cervical cancer.
 Although other sexually transmitted factors, including herpes
simplex virus 2, may play a concurrent causative role,
 99.7 percent of cervical cancers are associated with an oncogenic
HPV subtype.
 Low risk HPV Types 6 & 11 associated with development of
genital warts
 High risk types -16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59,
66 associated with development of dysplasia/cancer

41. Each of these serotypes can lead to either
squamous cell carcinoma or adenocarcinoma
of the cervix.
However, HPV 16 is more commonly
associated with squamous cell carcinoma of
the cervix, whereas HPV 18 is a risk factor for
adenocarcinoma of the cervix.

42. PATHOPHYSIOLOGY
 Tumorigenesis
 Squamous cell carcinoma of the cervix typically arises at the
squamocolumnar junction from a preexisting dysplastic lesion, which
in most cases follows infection with HPV.
 Although most women readily clear HPV, those with persistent infection
may develop preinvasive dysplastic cervical disease.
 In general, progression from dysplasia to invasive cancer requires
several years, but wide variation exists.
 The molecular alterations involved with cervical carcinogenesis are
complex and not fully understood.
 Accordingly, carcinogenesis is suspected to result from the interactive
effects between environmental insults, host immunity, and somatic-cell
genomic variations.

43.  HPV plays a major role in the development of cervical cancers.
 Increasing evidence also suggests that HPV oncoproteins may be
a critical component of continued cancer cell proliferation.
 Unlike low-risk sero-types, oncogenic HPV serotypes can integrate
into the human genome.
 As a result, with infection, oncogenic HPV’s early replication
proteins E1 and E2 enable the virus to replicate within cervical
cells.
 These proteins are expressed at high levels early in HPV
infection.
 They can lead to cytologic changes detected as low-grade
squamous intraepithelial (LSIL) cytologic findings on Pap smears.

45.  Amplification of viral replication and subsequent
transformation of normal cells into tumor cells may follow.
 Specifically, viral gene products E6 and E7 oncoproteins
are implicated in this transformation.
 E7 protein binds to the retinoblastoma (Rb) tumor
suppressor protein, whereas E6 binds to the p53 tumor
suppressor protein.
 In both instances, binding leads to degradation of these
suppressor proteins.
 The E6 effect of p53 degradation is well studied and linked
with the proliferation and immortalization of cervical cells.

47. Tumor Spread
Following tumorigenesis, the pattern of local growth may
be exophytic if a cancer arises from the ectocervix, or may
be endophytic if it arises from the endocervical canal.
Mode of spread include direct extension , lymphatic
spread and hematogenous spread.
Histologic types are SCC(70%), adenocarcinoma (25%)
and other rare histologic types like mixed
adenosquamous , large cell neuroendocrine and small cell
neuroendocrine

48. Diagnosis
 In early stage women diagnosed with this cancer are
asymptomatic.
 In others, early-stage cervical cancer may create a watery
blood-tinged vaginal discharge.
 Intermittent vaginal bleeding that follows coitus or douching
also can be noted.
 occasionally, a woman presents with uncontrolled
hemorrhage from a tumor bed.
 Other symptoms include chronic pelvic pain , loss of appetite
, weight loss and bowel and bladder symptoms

49. Physical Examination
 Most women with this cancer have normal general physical
examination findings.
 In those with suspected cervical cancer, a thorough external
genital and vagina examination is performed.
 With speculum examination, the cervix can appear grossly
normal if cancer is micro invasive.
 Visible disease displays varied appearances.
 Lesions may be exophytic or endophytic growth; a polypoid
mass, or barrel-shaped cervix; a cervical ulceration or
granular mass; or necrotic tissue.

50.  During bimanual examination, a clinician may palpate an
enlarged uterus resulting from tumor invasion and
growth , hematometra or pyometra.
 With posterior spread. palpation of the rectovaginal
septum between the index and middle finger of an
examiner's hand reveals a thick, hard, irregular septum.
 The proximal posterior vaginal wall is most commonly
invaded.
 In addition, during digital rectal examination, parametrial,
uterosacral, and pelvic sidewall involvement can be
appreciated

51. DDX
cervical leiomyoma,
cervical polyp
 vaginitis
 cervical eversion, cervicitis,
condyloma acuminata
 prolapsing uterine leiomyoma, polyp or
sarcoma.

52. Diagnostic workup
Biopsy preferably by CKC or if not punch
biopsy
CBC,OFT,PICT
CXR
 Abdominopelvic MRI
Cystescopy / proctoscopy /IVP based on
indication

53. Staging
 Historically, cervical cancer has been staged clinically.
 The current FIGO (2018)staging system now incorporates
radiologic and pathologic evaluation
Allowable components of clinical staging are
 Cold-knife conization
 Pelvic examination under anesthesia,
 Cystoscopy, Proctoscopy,
 Chest radiograph, and Intravenous Pyelogram (or this portion of
the computed tomography [CT] scan can be used).
 See FIGO 2018 staging

54. Management of cervical cancer
1)Micro invasive diseases- option of treatment include
 Cold knife conization(CKC)
 Radical trachelectomy for those who want to preserve fertility
 Simple extra facial hysterectomy
2)Early stage disease(IB-IIA)
 One option for those with early stage diseases is RH+BPLND
 For those who decline surgery or not fit for surgery ,primary chemo
radiation is other treatment option
3) Advanced stage diseases(stage IIB-IVA)
 Primary chemo radiation is preferred treatment for this group of
patients

55. 4) Stage IVB
Patients with stage IVB disease have a poor prognosis
and are treated with a goal of palliation.
Pelvic radiation is administered to control vaginal
bleeding and pain.
 Systemic chemotherapy is offered to palliate
symptoms and prolong overall survival.
The chemotherapy regimens used in this group of
women are similar to those used in the setting of
recurrent cancer

56. Surveillance
In general, patients are seen at 3-month intervals for 2
years .
 Then every 6 months until 5 years have passed from
treatment and then annually.
 At each visit, in addition to pelvic examination, a
thorough manual nodal survey includes neck,
supraclavicular, axillary, and inguinal lymph nodes.
 A cervical or vaginal cuff Pap test also is collected
annually for 20 years after treatment completion.

57. Prognosis
 FIGO stage is the most significant prognostic factor.
 Lymph node involvement is an important prognostic feature,
and modified prognosis before it was formally incorporated
into the staging system.
 For example, in early-stage cervical cancer (stages I through
IIA), nodal metastases are an independent predictor of survival.
 In advanced- stage (stage IIB through IV) cervical cancer, lymph
node metastases also worsen prognosis.
 In general, microscopic nodal involvement has a better
prognosis than macroscopic nodal disease.