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Title: Aetiology, epidemiology, presentation, detection, clinical course and pathophysiology of:


1
Aetiology, epidemiology, presentation, detection,
clinical course and pathophysiology of
  • Cervical Cancer

2
Aetiology- Cervical CA
  • Same as for Cervical Intraepithelial Neoplasia
    (CIN)
  • A sexually transmitted agent has long been
    implicated- now known to be HPV
  • HPV DNA is found in 99.7 of all cervical
    carcinomas. HPV 16 accounts for almost 60 of
    cervical cancer cases, and HPV 18 accounts for
    another 10 of cases other HPV types contribute
    to less than 5 of cases, individually.
  • The risk factors for cervical cancer are related
    to both host and viral characteristics such as
    HPV exposure, viral oncogenicity, inefficiency of
    immune response, and presence of co-carcinogens.
    These include
  • Multiple sexual partners
  • A male partner with multiple previous or current
    sexual partners
  • Young age at first intercourse
  • Hx of STI
  • High parity
  • Persistent infection with a high oncogenic risk
    HPV, e.g., HPV 16 or HPV18
  • Immunosuppression eg. HIV
  • Certain HLA subtypes
  • Use of oral contraceptives
  • Use of nicotine

3
Epidemiology- Cervical CA
  • Fifty years ago, carcinoma of the cervix was the
    leading cause of cancer deaths in women in the
    United States, but the death rate has declined by
    two thirds to its present rank as the eighth
    leading cause of cancer mortality. In sharp
    contrast to this reduced mortality, the detection
    frequency of early cancers and precancerous
    lesions is high. (Robbin Cotrans)
  • Similar trend has been seen in Australia (AIHW,
    2008)
  • In 2007 the National Cervical Screening Program
    detected 14,466 women in the target age group
    with high-grade abnormalities.
  • The number of new cases of cervical cancer in
    Australia has continued to decline. There were
    734 new cases in Australia in 2005 compared with
    1,092 detected in 1991, at the start of the
    organised screening program.
  • The age-standardised mortality rate from cervical
    cancer has more than halved since the start of
    the Program, from 4.0 deaths per 100,000 women in
    1991 to 1.9 deaths per 100,000 women in 2006.
  • The incidence of cervical cancer rises most
    significantly after the age of 40 years. The
    average age at diagnosis of patients with
    cervical cancer is 51 years. However, the disease
    can occur in the second decade of life and during
    pregnancy, with cervical cancer the most common
    malignancy of pregnancy, with an incidence of
    1.24.5 cases per 10,000 pregnancies
    (Holschneider)

4
Presentation- Cervical CA
  • Early disease is frequently asymptomatic,
    underscoring the importance of cervical cytology
    screening
  • Abnormal uterine bleeding and vaginal discharge
    are the most common symptoms
  • A cervical lesion may be visible on inspection as
    a tumour or ulceration cancer within the
    cervical canal may be occult.
  • A history of postcoital bleeding may be elicited
    on specific questioning
  • Pelvic pain, often unilateral and radiating to
    the hip or thigh, is a manifestation of advanced
    disease, as is the involuntary loss of urine or
    faeces through the vagina, a sign of fistula
    formation.
  • Weakness, weight loss, and anaemia are
    characteristic of the late stages of the disease

5
Detection
  • The National Cervical Screening Program was
    introduced in Australia in 1991 and recommends
    and encourages women to have Pap smears every two
    years.
  • Cervical screening services are provided by
    general practitioners, community or womens
    health centres, family planning clinics or sexual
    health clinics and funded through Medicare
  • Pap tests are cytologic preparations of
    exfoliated cells from the cervical transformation
    zone that are stained with the Papanicolaou
    method. Using a spatula or brush, the
    transformation zone of the cervix is
    circumferentially scraped and the cells are
    smeared or spun down onto a slide. Following
    fixation and staining, the cytotechnologist, a
    person specifically trained to identify cytologic
    abnormalities, screens the smears.
  • HPV DNA testing may be added to cervical
    cytology. With women who are high-risk HPV
    DNA-positive, having pap smears every6 to 12
    months (?not routine in Aus though?)
  • Management of Pap smear abnormalities- Any
    abnormal paps smears or any suspicious lesion of
    the cervix regardless of cytologic examination
    result should be further investigated with
    colposcopy (visual examination of the cervix with
    a magnifying glass) and biopsy
  • When the Pap test is abnormal, a colposcopic
    examination of the cervix and vagina is performed
    to delineate the extent of the lesion and to
    target the areas to be biopsied. Application of
    acetic acid to the cervix highlights abnormal
    areas.
  • Further management- While early invasive cancers
    of the cervix (microinvasive carcinomas) may be
    treated by cone biopsy alone, most invasive
    cancers are managed by hysterectomy with lymph
    node dissection and, for advanced lesions,
    irradiation and chemotherapy.

6
Pathophysiology/ Clinical course
  • HPV is epitheliotropic. Once the epithelium is
    acutely infected with HPV, one of three clinical
    scenarios ensues
  • Asymptomatic latent infection
  • Active infection in which HPV undergoes
    vegetative replication but not integration into
    the genome (eg, leading to condyloma or CIN I)
  • Neoplastic transformation following integration
    of oncogenic HPV DNA into the human genome.
  • Integration of HPV into the human genome ?
    upregulation of the viral oncogenes E6 and E7 ?
    E6 and E7 interfere with cell-cycle control in
    the human host cell, disabling tumour suppressor
    genes p53 and Rb, respectively ? host cell
    immortalization and transformation ? Cervical
    intraepithelial neoplasia (CIN), formerly called
    dysplasia
  • ? Spontaneous regression, especially of CIN I,
    occurs in a significant number of patients
  • ? However, 916 of patients with untreated CIN
    I are diagnosed with CIN II/III over a 2-year
    follow-up. And a percentage of all dysplasias,
    especially high-grade lesions, will progress to
    an invasive cancer if left untreated
  • However, as cancer of the cervix is generally a
    slowly developing process, pap smears and easy
    access of the cervix via colopscopy at allowing
    eradication of preinvasive lesions, and early
    diagnosis with more than 95 of patients with
    early cancer of the cervix cured

7
Aetiology, epidemiology, presentation, detection,
clinical course and pathophysiology of
  • Endometrial Cancer

8
Aetiology- Endometrial CA
  • Same as for endometrial hyperplasia prolonged
    oestrogen stimulation of the endometrium, which
    can be due to anovulation, increased oestrogen
    production from endogenous sources, or exogenous
    oestrogen.
  • Obesity
  • diabetes (abnormal glucose tolerance is found in
    more than 60)
  • hypertension
  • Menopause
  • polycystic ovarian disease (PCOS)
  • infertility (women who develop cancer of the
    endometrium tend to be nulliparous and have a
    history of functional menstrual irregularities
    consistent with anovulatory cycles)
  • functioning granulosa cell tumours of the ovary
  • excessive cortical function (cortical stromal
    hyperplasia)
  • prolonged administration of estrogenic substances
    (HRT therapy)

9
Epidemiology- Endometrial CA
  • the most common invasive gynaecological cancer in
    Australia
  • At one time, it was far less common than cancer
    of the cervix, but ratio has reversed
  • It affects approximately 1/75 Australian women by
    the age of 75 years, and there are about 1700 new
    cases and 230 deaths from the disease every year.
  • total number of cases is increasing each year,
    due to increasing population age. The problem may
    be further magnified in the future, with
    increasing rates of obesity, a known risk factor
    for the disease.
  • Carcinoma of the endometrium is uncommon in women
    younger than 40 years of age. Most affected women
    are aged between 50 and 70 years

10
Presentation- Endometrial CA
  • May be asymptomatic for a period of time
  • Usually produces irregular or postmenopausal
    vaginal bleeding with excessive leukorrhea
    (vaginal discharge)
  • Uterine enlargement may be present in the later
    stages

11
Detection Endometrial CA
  • There is currently no effective screening
    procedure for early detection
  • However the occurrence of postmenopausal bleeding
    often makes early detection and cure possible
  • diagnosis established by biopsy or curettage and
    histologic examination of the tissue

12
Pathophysiology
Characteristics Type I Type II
Age 55-65 yr 65-75 yr
Clinical setting Unopposed oestrogen AtrophyThin physique
  Obesity  
  Hypertension  
  Diabetes  
Morphology Endometrioid Serous
    Clear cell
    Mixed müllerian tumour
Precursor Hyperplasia Endometrial intraepithelial carcinoma
Molecular genetics PTEN p53
  PIK3CA Aneuploidy
  KRAS PIK3CA
  MSI  
  ß-catenin  
  p53  
Behaviour Indolent Aggressive
  Spreads via lymphatics Intraperitoneal and lymphatic spread
  • Type I and II which have distinct pathogenesis
  • Type I are the most common type, accounting gt80.
    They are well differentiated and mimic
    proliferative endometrial glands and, as such,
    are referred to as endometrioid carcinoma.
    Recent studies show that endometrial hyperplasia
    is a precursor to endometrioid carcinoma
  • Type 2 account for approximately 15 of
    endometrial carcinoma. Generally occur in women
    a decade later and usually arise in the setting
    of endometrial atrophy. They are poorly
    differentiated tumours and are more aggressive.
    The most common subtype is serous carcinoma,
    referred to as such because of morphologic and
    biologic overlap with ovarian serous carcinoma.

13
Pathophysiology Cont
  • P53 is altered in both tumour types of
    endometrial CA.
  • However P53 mutations are not evident in
    endometrial hyperplasias, the precursor of Type
    I. Thus, it is thought that p53 mutations are a
    late-occurring event in endometrioid carcinoma
    (type I)
  • The precursor of serous carcinoma, endometrial
    intraepithelial carcinoma (EIC), consists of
    cells identical to those of serous carcinoma but
    lacks identifiable stromal invasion. Mutations in
    p53 are found in approximately 75 of these
    lesions, suggesting that mutation of p53 is an
    early event in serous endometrial carcinoma.
    Thus, serous carcinoma presumably begins as a
    surface epithelial neoplasm that extends into
    adjacent gland structures and later invades
    endometrial stroma. Their generally poorer
    prognosis is thought to be a consequence of this
    and they have often spread outside of the uterus
    by the time of diagnosis.
  • Another common genetic alteration is inactivation
    of the PTEN tumour suppressor gene ? AKT
    phosphorylation is enhanced ? stimulation of
    protein synthesis and cell proliferation and
    inhibition of apoptosis.
  • Mutations in PTEN have been found in more than
    20 of hyperplasias,, and in 30 to 80 of
    endometrial carcinomas, suggesting that
    alterations in PTEN occur at a relatively early
    stage in endometrial tumorigenesis

14
Clinical Course- Endometrial CA
  • Surgery, alone or in combination with
    irradiation, gives about 90 5-year survival in
    stage I (grade 1 or 2) disease. This rate drops
    to approximately 75 for grade 3/stage I and to
    50 or less for stage II and III endometrial
    carcinomas
  • As mentioned, serous carcinoma has a propensity
    for extrauterine (lymphatic or transtubal)
    spread, even when apparently confined to the
    endometrium or its surface epithelium. Overall,
    fewer than 50 of patients with these tumours are
    alive 3 years after diagnosis and 35 after 5
    years.

15
Aetiology, epidemiology, presentation, detection,
clinical course and pathophysiology of
  • Ovarian Cancer

16
Aetiology
  • Risk factors for Ovarian cancers are much less
    clear than for other gynaecological cancer, the
    following things may play a role
  • Nulliparity or lower parity
  • family history, and heritable mutations play a
    role in tumour
  • Gonadal dysgenesis in children
  • Women 40 to 59 years of age who have taken oral
    contraceptives or undergone tubal ligation have a
    reduced risk of developing ovarian cancer.
  • mutations in both BRCA1 and BRCA2 increase
    susceptibility to ovarian cancer. The estimated
    risk of ovarian cancer in women bearing BRCA1 or
    BRCA2 mutations is 20 to 60 by the age of 70
    years
  • Risk of ovarian cancer is slightly higher for
    women who
  • have medical conditions such as endometriosis
  • use long-term hormone replacement therapy (HRT)
  • smoke cigarettes
  • are obese

17
Epidemiology- Ovarian CA
  • Ovarian cancer is the 9th most common cancer
    diagnosed in Australian women, and the second
    most commonly diagnosed gynaecological cancer
  • As most ovarian cancers are detected when they
    have spread beyond the ovary, they account for a
    disproportionate number of deaths. It is
    the sixth cause of cancer death for Australian
    women
  • Malignant tumours are more common in older women,
    between the ages of 45 and 65 years.
  • The median age for first diagnosis is 64

18
Presentation
  • Most are nonfunctional (not hormonally active)
    and tend to produce relatively mild, if any
    symptoms until they reach a large size
  • most common complaints are lower abdominal pain
    and abdominal enlargement
  • Gastrointestinal complaints, urinary frequency,
    dysuria, pelvic pressure, vaginal bleeding and
    many other symptoms may appear
  • progressive weakness, weight loss, and cachexia
    appear, characteristic of all malignant
    neoplasms
  • if the carcinomas extend through the capsule of
    the tumour to seed the peritoneal cavity, massive
    ascites is common.
  • Many patients are first seen with lesions that
    are no longer confined to the ovary, with liver,
    lungs or gastrointestinal tract metastasis found
    first

19
Detection- Ovarian CA
  • No current effective screening programs
  • If the disease is detected and treated at an
    early stage it is expected that an 80 rate of
    recovery can be achieved, thus specific
    biochemical markers for tumour antigens or tumour
    products in the plasma of these patients are
    being sought vigorously
  • One such marker, known as CA-125, present in the
    serum of more than 80 of patients with serous
    and endometrioid carcinomas. However it cannot be
    used as a screening or diagnostic test alone
    because elevations in CA-125 can occur with
    nonspecific irritation of the peritoneum (e.g.,
    endometriosis, inflammation, menstruation).
  • Newly identified biomarkers such as osteopontin,
    which is expressed at significantly higher levels
    in ovarian cancer patients, may improve early and
    give hope to a future cost-effective,
    non-invasive approach to ovarian cancer
    screening.

20
Pathogenesis- Ovarian Ca
  • Epithelial ovarian cancer starts on the outer
    covering of the ovary (the epithelium). Nine out
    of ten women with ovarian cancer have epithelial
    ovarian cancer. Epithelial tumours, tend to be
    bilateral.
  • Germ cell ovarian cancer starts in the egg cells
    within ovaries. Its relatively uncommon and
    usually affects younger women or teenage girls
  • Sex-cord stromal cancer is a relatively rare
    ovarian cancer, starting in the cells that
    produce female hormones.

21
Pathogenesis- Epithelial Ovarian Cancers
  • Serous carcinomas account for approximately 40
    of all cancers of the ovary, Mucinous tumours
    accounting for about 30 and Endometrioid
    carcinomas account for approximately 20 .
    Little is known about the pathogenesis of serous
    or mucinous ovarian tumours.
  • The low-grade serous tumours have mutations in
    the KRAS or BRAF oncogenes, with only rare
    mutations in p53.
  • The high-grade serous tumours have a high
    frequency of mutations in the p53 gene but lack
    mutations in either KRAS or BRAF.
  • Almost all reported cases of ovarian carcinomas
    arising in women with BRCA1 or BRCA2 mutations
    are high-grade serous carcinoma and commonly have
    p53 mutations.
  • The one consistent alteration that has been
    identified in Mucinous tumours is mutation of the
    KRAS proto-oncogene.
  • Endometrioid tumours are distinguished from
    serous and mucinous tumours by the presence of
    tubular glands bearing a close resemblance to
    benign or malignant endometrium. About 15 to 20
    of cases with endometrioid carcinoma coexist with
    endometriosis, although an origin directly from
    ovarian surface epithelium is also possible.
    Molecular studies have found relatively frequent
    mutations in the PTEN tumour suppressor gene and
    in the KRAS and ß-catenin oncogenes. Similar to
    endometrioid carcinomas of the endometrium, p53
    mutations are common in the poorly differentiated
    tumours

22
Clinical Course
  • Ovarian carcinomas readily spread to the pelvis
  • Approximately 75 of women are diagnosed with
    ovarian cancer at an advanced stage when the
    cancer is difficult to treat successfully
  • The 5-year survival rate for malignant tumours
    confined within the ovarian mass is, 70, whereas
    the 5-year survival rate for the same tumours
    involving the peritoneum is about 25.
  • This prognosis is significantly poorer that
    endometrial and cervical CA

23
Note
  • OCP decrease the risk of endometrial and ovarian
    carcinomas, but increase risk of cervical CA
  • More babies your have, the greater your risk
    cervical Ca, lower your risk of Endometrial and
    Ovarian CA
  • HRT increases your risk of Endometrial and
    ovarian

24
References
  • Robbins SL, Kumar V. Robbins and Cotran
    pathologic basis of disease. 8th ed.
    Philadelphia, PA Saunders/Elsevier 2010.
  • CURRENT Obstetric Gynecological Diagnosis
    Treatment www.accessmedicine.com
  • http//www.ovariancancer.net.au/awareness/statisti
    cs
  • http//www.anecs.org.au/
  • http//www.nbocc.org.au/ovarian-cancer/about/5-thi
    ngs-women-should-know-about-ovarian-cancer
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