Transcript Cancer - Ipswich-Year2-Med-PBL-Gp-2

Aetiology, epidemiology,
presentation, detection,
clinical course and
pathophysiology of:
Cervical Cancer
Aetiology- Cervical CA
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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:
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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
Epidemiology- Cervical CA
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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
1.2–4.5 cases per 10,000 pregnancies (Holschneider)
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
Detection
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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 women’s
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.
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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?)
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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.
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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.
Pathophysiology/ Clinical course
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HPV is epitheliotropic. Once the epithelium is acutely infected with HPV, one of three
clinical scenarios ensues:
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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, 9–16% of patients with untreated CIN I are diagnosed with CIN II/III over a 2year follow-up. And a percentage of all dysplasias, especially high-grade lesions, will
progress to an invasive cancer if left untreated
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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
Aetiology, epidemiology,
presentation, detection, clinical
course and pathophysiology of:
Endometrial Cancer
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.
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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)
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
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
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
Pathophysiology
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Type I and II which have distinct
pathogenesis
Type I are the most common type,
accounting >80%. 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.
Characteristics
Type I
Type II
Age
55-65 yr
65-75 yr
Clinical setting
Unopposed
oestrogen
Atrophy
Thin 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*
β-catenin
p53
Behaviour
Indolent
Aggressive
Spreads via
lymphatics
Intraperitoneal and
lymphatic
spread
Pathophysiology Cont:
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P53 is altered in both tumour types of endometrial CA.
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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)
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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.
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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.
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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
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.
Aetiology, epidemiology,
presentation, detection, clinical
course and pathophysiology of:
Ovarian Cancer
Aetiology
• Risk factors for Ovarian cancers are much less clear than for other
gynaecological cancer, the following things may play a role
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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
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
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…
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, noninvasive approach to ovarian cancer screening.
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. It’s 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.
Pathogenesis- Epithelial Ovarian
Cancers:
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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 β-catenin
oncogenes. Similar to endometrioid carcinomas of the endometrium, p53 mutations are
common in the poorly differentiated tumours
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
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
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/statistics
• http://www.anecs.org.au/
• http://www.nbocc.org.au/ovarian-cancer/about/5-thingswomen-should-know-about-ovarian-cancer