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 1.2–4.5 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 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. • 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, 9–16% 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 • 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.

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 ovariancancer 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.

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 β-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 & Treatmentwww.accessmedicine.com • http://www.ovariancancer.net.au/awareness/statistics • http://www.anecs.org.au/ • http://www.nbocc.org.au/ovarian-cancer/about/5-things-women-should-know-about-ovarian-cancer