Session 12: Tumours of the Female Repro Tract

Question 1

Describe the epidemiology, aetiology and types of Vulval tumours

Answer 1

• Uncommon (approximately 3% of female genital cancers)
• Approximately 2/3rds occur in women over 60 years of age
• Types:

[*] Squamous cell carcinoma – most common type

[*] Extramammary Paget’s disease

[*] Basal cell carcinoma

[*] Malignant melanoma

• In pre-menopausal women, the main causative factor appears to be human papilloma virus with invasion developing in a field of intraepithelial neoplasia (vulval intraepithelial neoplasia – VIN).

[*] The tumour spreads locally and metastasises to the inguinal lymph nodes.

[*] Definitive surgery would include removing the primary tumour and nodes.

• Areas of intraepithelial neoplasia may be detected by the patient herself or during the cause of gynaecological examination. Under these circumstances excision affects cure.
• In older women, the causative agents of vulval carcinoma are unknown but are probably related to chronic irritation and longstanding dermatoses such as lichen sclerosus (inflammatory condition of the vulva, suspected autoimmune cause) and squamous hyperplasia

Question 2

Describe Squamous Neoplastic Lesions of the Vulva

Answer 2

[*] Approximately 30% are related to HPV infection

• Usually HPV 16
• Peak age: 6th decade
• Risk factors the same as for cervical carcinoma

[*] Approximately 70% are unrelated to HPV infection:

• Peak age: 8th decade
• Often occur in longstanding inflammatory and hyperplastic conditions of the vulva e.g. lichen sclerosis

[*] They arise from vulvar intraepithelial neoplasia (VIN):

• In situ precursor
• Atypical squamous cells within the epidermis (no invasion)

[*] Vulva Squamous Cell Carcinoma

• Spreads initially to inguinal, pelvic, iliac and para-aortic lymph nodes
• Also to lungs and liver
• Lesions less than 2cm (if detected early) – 90& five year survival following vulvectomy and lymphadenectomy

Question 3

Describe the aims and principles of Cervical Screening

Answer 3

• The aim of the cervical screening programme is to detect the pre-invasive lesion and to excise the involved area completely before a tumour can develop.

Worldwide, cervical carcinoma is the third most common cancer in women. Rate has decreased significantly since introduction of screening.

[*] Cervix accessible to visual examination (colposcopy) and sampling

[*] Slow progression from precursor lesions to invasive cancers (years) (time to treat)

[*] Papanicolaou (Pap) test detects precursor lesions and low stage cancers

[*] Allows early diagnosis and curative therapy

[*] The process involves scraping off cells from the transformation zone, stained with papanicolaou stain and examined microscopically.

• Cervical screening detects cells with abnormally enlarged nuclei possessing abnormal chromatin (dyskaryotic cells).
• This is an indication for referral for colposcopy where abnormal areas can be highlighted by the application of diluted acetic acid (lesions stain white).
• Most commonly these areas are excised by diathermy (loop biopsy).
• Follow up is by cytology

Question 4

What can Cervical Cancer Screening also detect these days?

Answer 4

Cervical screening can also test for HPV DNA in cervical cells

[*] Molecular method of screening

[*] Vaccine against high risk HPVs given to girls:

Protects for up to 10 years
Doesn’t protect against all high risk types – therefore screening is being continued

Question 5

Describe the pathogenesis for CIN and Cervical Carcinoma

Answer 5

[*] HPV - DNA - viruses, 15 high risk types known

[*] Most important in pathogenesis of cervical carcinoma:

HPV 16 – 80% of causes
HPV 18 – 10% of cases

[*] Infect immature metaplastic squamous cells in transformation zone

[*] Produce viral proteins E6 and E7 – interfere with activity of tumour suppressor proteins to cause inability to repair damaged DNA and increased proliferation of cells

[*] Most genital HPV infections are transient and eliminated by immune response in months

Question 6

What are the risk factors for CIN and Cervical Carcinoma?

Answer 6

[*] Sexual intercourse

[*] Early first marriage

[*] Early first pregnancy

[*] Multiple births

[*] Many partners

[*] Promiscuous partner

[*] Long term use of OCP

[*] Partner with carcinoma of the penis (which is also related to HPV infection)

[*] Low socio-economic class

[*]
[*]

Question 7

What are the types of carcinomas of the cervix? Describe the presentation of cervical carcinoma and the common aetiology of both

Answer 7

Most carcinomas of the cervix are squamous carcinomas although the incidence of adenocarcinoma is increasing and in some populations may represent up to 25-30%.

[*] Average age = 45 years

[*] 80% - squamous cell carcinomas

[*] 15% - adenocarcinomas (also caused by high risk HPVs)

[*] May be exophytic (sticking out) or infiltrative

• Locally to para-cervical soft tissues, bladder, ureters, rectum and vagina
• Lymph nodes – para-cervical, pelvic, para-aortic
• Distally

Cervical carcinoma – presentation

[*] Screening abnormality

[*] Postcoital, intermenstrual or postmenopausal vaginal bleeding.

Both lesions appear to have a common aetiology of human papilloma virus and arise on the basis of (squamous) cervical intraepithelial neoplasia – or cervical glandular intraepithelial neoplasia – CIN or CGIN, respectively.

Question 8

Describe CIN including treatment

Answer 8

[*] Dysplasia of squamous cells within the cervical epithelium, induced by infection with high risk HPVs

[*] CIN I – least abnormal, most regresses spontaneously, only a small percentage progresses to –

[*] CIN II

[*] CIN III (carcinoma in situ) – 10% progresses to invasive carcinoma in 2-10 years, 30% regresses

[*] From CIN I to CIN III takes approximately 7 years

Question 9

Describe the factors which influence prognosis of carcinoma of the cervix

Answer 9

• The prognosis of carcinoma of the cervix relates to the depth of invasion and the size of the tumour.
• Spread is initially to the iliac and then aortic lymph nodes before wider systematic dissemination.
• Local spread involves the ureters, bladder and rectum and is extremely distressing with pain and fistula formation.

Treatment for Cervical Carcinoma

[*] Microinvasive carcinomas:

• Treated with cervical cone excision
• 5 year survival = 100%

[*] Invasive carcinomas (larger)

• Treated with hysterectomy, lymph node dissection and, if advanced, radiation and chemotherapy
• Overall, 62% ten year survival

Question 10

Describe Endometrial Hyperplasia

Answer 10

[*] Endometrium

Lines internal cavity of uterus
Glands within a cellular stroma

[*] Endometrial hyperplasia:

• Frequent precursor to endometrial carcinoma
• Increased gland to stroma ratio (increased glands, decreased stroma)
• Associated with prolonged oestrogenic stimulation:
  
  • Anovulation
  • Increased oestrogen from endogenous sources (e.g. adipose tissue)
  • Exogenous oestrogen (e.g. Tamoxifen)

If complex and atypical, treated by hysterectomy.

Question 11

Describe Endometrial Carcinoma

Answer 11

• This is a tumour of perimenopausal and older women. In the perimenopausal age group the most probable aetiology relates to unopposed oestrogen from obesity, exogenous oestrogen administration or a hormone-secreting tumour. Tamoxifen (oestrogen agonist – it is an antagonist of the oestrogen receptor) may be implicated. It is the most common invasive cancer of the female genital tract

[*] Usual age: 55-75 years, unusual before 40 years

[*] Usual presentation – irregular or postmenopausal vaginal bleeding

[*] Early detection and cure often possible

[*] Overall, 75% 10 year survival.

• In older women a hormonal aetiology is less common
• The tumours are usually adenocarcinomas although a minority may be adenosquamous or may possess a malignant stroma (malignant mixed Mullerian tumour).

Question 12

Describe the 2 main types of Endometrial Adenocarcinoma

Answer 12

Endometrial Adenocarcinoma – Two main Types

[*] Endometrioid Endometrial Carcinoma

• More common
• Mimics proliferative glands
• Typically arises in setting of endometrial hyperplasia
• Associated with unopposed oestrogen and obesity
• Spreads by myometrial invasion and direct extension to adjacent structures, to local lymph nodes and distant sites.

[*] Serous Carcinoma:

• Poorly differentiated, aggressive, worse prognosis
• Exofoliates, travels through Fallopian tubes, implants on peritoneal surfaces

The prognosis depends on grade and spread into the myometrium with involvement of more than half the myometrial depth requiring adjuvant therapy.
Advanced disease spreads to cervix, bladder and rectum, through the peritoneal cavity and to the regional lymph nodes.

Question 13

What are meant by Fibroids?

Answer 13

Fibroids are benign tumours of uterine smooth muscle called leiomyomas.

[*] Probably most common tumour in women

[*] Symptoms include heavy menstrual loss and intermenstrual bleeding, pain, discharge, urinary frequency (due to bladder compression) and infertility. But they may be asymptomatic.

[*] Single or more commonly multiple leiomyomas can cause massive uterine enlargement and can cause pressure symptoms in the pelvis. They range from tiny to massive, filling the pelvis.

[*] Their growth is oestrogen dependent and they usually regress after the menopause.

[*] Malignant transformation probably doesn’t occur.

[*] They are well-circumscribed, round, firm and whitish in colour. Bundles of smooth muscle – resembling normal myometrium can be seen.

Question 14

Describe Leiomyosarcomas

Answer 14

[*] Uncommon

[*] Peak incidence 40-60 years

[*] Highly malignant

[*] Doesn’t arise from leiomyomas

[*] Metastasizes to lungs.

[*] They present with similar symptoms but are usually single. The aetiology is not known.

[*] Histologically they may display massively increased mitotic activity, cellular atypia and an infiltrative growth pattern.

[*] Like other sarcomas they infiltrate locally with metastasis by the blood stream to the lungs and then systematically

Question 15

Describe the epidemiology and presentation of Ovarian tumours

Answer 15

Tumours of the ovary may arise from the surface epithelium, stroma, germ cells or sex cord elements.

[*] Approximately 80% are benign – generally occur at 20-45 years

[*] Malignant tumours generally occur at 45-65 years

[*] Ovarian cancer accounts for3% of all cancers in women

[*] Ovarian cancers have often spread beyond the ovary by the time of presentation and therefore the prognosis is often poor

[*] Many are bilateral

[*] Ovarian cancer:

• 70% 1 year survival
• 41% 5 year survival
• 38% 10 year survival

Ovarian Tumours – Presentation

[*] Most non-functional – produce symptoms when they become large, invade adjacent structures or metastasize

• Mass effects: abdominal pain, abdominal distension, urinary and gastrointestinal symptoms
• Ascites

[*] Hormonal problems

• Menstrual disturbances
• Inappropriate sex hormones

Question 16

How can Ovarian tumours arise (4 categories)?

Answer 16

There is a vast list of subtypes but the majority of tumours are epithelial. Ovarian tumours can arise from:

[*] Mullerian epithelium (including endometriosis)

[*] Germ cells (pluripotent)

[*] Sex cord-stromal cells (from the endocrine apparatus of the ovary)

[*] Metastases

Question 17

Why is there no screening programme for ovarian cancer? What are useful biological markers?

Answer 17

• Ovarian carcinoma does not present until the late stage and there is no accepted pre-invasive pre-cursor lesion.
• Consequently there is no screening programme although the role of CA125 and ultrasonography is currently being investigated.
• Ovarian tumours spread within the abdomen where they cause ascites, intestinal obstruction, perforation and death.

[*] They spread to regional nodes and elsewhere e.g. liver, lungs

[*] Approximately 50% spread to other ovary

[*] Serum CA125 is used in diagnosis and to monitor disease recurrence and progression

[*] Known BRCA mutation carriers can be treated with prophylactic salpingo-oophrectomy.

Recently BRCA1 and BRCA2 genes have been identified as markers for familial ovarian epithelial carcinoma but this represents less than 1% of cases.

Question 18

What are the 3 main types of Ovarian Epithelial Tumours? What are the risk factors?

Answer 18

[*] Three main histological types:

Serous
Mucinous
Endometrioid

[*] All can be classified as:

Benign
Borderline
Malignant

[*] Many are cystic

[*] Risk factors

• Nulliparity or low parity (continuous ovulation)
• OCP is protective!
• Heritable mutations e.g. BRCA1 and BRCA2
• Smoking
• Endometrisosis

Question 19

Describe Serous and Mucinous Ovarian Epithelial Tumours

Answer 19

[*] Serous Ovarian Tumours often spread to peritoneal surfaces and omentum, therefore commonly associated with ascites

[*] Mucinous Ovarian Tumours

• Often large, cystic masses – can be >25kg
• Filled with sticky, thick fluid
• Usually benign or borderline but can be malignant
• Pesudomyxoma peritonei
  
  • Extensive mucinous ascites
  • Epithelial implants on peritoneal surfaces
  • Frequent involvement of ovaries
  • Can cause intestinal obstruction
  • Most likely primary is extra-ovarian, usually appendix

Question 20

Describe Endometrioid Ovarian Epithelial Tumours

Answer 20

• Contain tubular glands resembling endometrial glands
• Can arise in endometriosis (15-20% of cases)
• 15-30% have associated endometrial endometrioid adenocarcinoma, probably arising separately

Question 21

Describe Germ Cell Tumours. What are 3 types of ovarian teratomas?

Answer 21

Germ cell tumours may be benign or malignant, the most common being mature (benign) cytic teratoma that contains skin, hair, teeth, bone and other tissues.

[*] The presence of immature tissue such as primitive neuroepithelium indicates a risk for intra-abdominal spread and a potential to cause cancer

[*] Malignant germ cell tumours include dysgerminoma (resembles seminoma of the testis), yolk sac tumour (produces alpha-fetoprotein), non-gestational choriocarcinoma (produces human chorionic gonadotrophin, unlike gestational type they are aggressive and often fatal) or embryonal carcinomas. Useful tumour markers in this group are alpha-feto-protein and beta human chorionic gonadotrophin (Beta-hCG).

[*] There are 3 groups of Ovarian Teratomas

• Mature (benign) – most common
• Immature (malignant) – rare, composed of tissues that resemble immature foetal tissue
• Monodermal (highly specialised)

Question 22

Describe Mature Ovarian Teratomas

Answer 22

• Most are cystic
• Also called dermoid cysts as they almost always contain skin-like structures
• Usually occur in young women
• Bilateral in 10-15% of cases
• Usually contain hair and sebaceous material, can contain tooth structures
• Often tissue from other germ layers also present e.g. cartilage, bone, thyroid, neural tissue
• Have been blamed on witches, nightmares or sex with the devil.

Question 23

Describe Monodermal Ovarian Teratomas

Answer 23

Most common are:

• Struma ovarii: benign, composed entirely of mature thyroid tissue, may be functional and cause hyperthyroidism
• Carcinoid: malignant, may be functional producing 5HT and can cause carcinoid syndrome (even without hepatic metastases)

Question 24

Describe Ovarian Sex-Cord Stromal Tumours

Answer 24

[*] Derived from ovarian stroma (which is derived from sex cords of the embryonic gonad)

[*] Sex cord produces Sertoli and Leydig cels in testes and granuloma and theca cells in ovaries.

[*] Tumours resembling all of these four cell types can be found in the ovary

[*] These tumours can be feminising (granulosa/theca cell tumours) or masculinising (Leydig cell tumours).

[*] Rare sex-cord stromal tumours may produce androgens and cause defeminisation, masculinisation, amenorrhoea and infertility

Question 25

Describe Granulosa Cell and Ovarian Sertoli-Leydig Cell Tumours

Answer 25

[*] Granulosa cell tumours resemble the cells lining the ovarian follicle and are thus sex cord tumours.

• Most occur in post-menopausal women
• May produce large amounts of oestrogen:
  
  • In pre-pubertal girls may produce precocious puberty (therefore need to exclude this diagnosis)
  • In adult women may be associated with endometrial hyperplasia, endometrial carcinoma and breast disease
• They may spread and recur many years after surgery

[*] Ovarian Sertoli-Leydig Cell Tumours

Often functional:

• In children may block normal female sexual development
• In women can cause defeminisation and masculinisation: breast atrophy, amenorrhoea, sterility, hair loss, hirsuitism with male hair distribution, clitoral hypertrophy and voice changes
• Peak incidence in teens or twenties

Question 26

Describe Metastases to the Ovaries

Answer 26

[*] Most commonly Mullerian tumours:

• Uterus
• Fallopian tubes
• Contralateral ovary
• Pelvic peritoneum

[*] Also gastrointestinal tumours (colon, stomach, biliary tract, pancreas, appendix) and breast

[*] Krukernberg tumour = metastatic gastrointestinal tumour within the ovaries:

• Often bilateral
• Usually from stomach (transcoelomic spread)

Question 27

Describe Thecomas and Fibromas

Answer 27

• Thecomas are benign tumours derived from the ovarian stroma. They may also produce oestrogen and give rise to similar conditions.
• Fibromas are stromal tumours that cause pressure symptoms and sometimes cause ascites.

Question 28

What are the major types of Gestational Tumours

Answer 28

Gestational Trophoblastic Disease:

[*] Tumours and tumour-like conditions which show proliferation of placental tissue = villous and/or trophoblastic

[*] Major types:

Hydatidiform mole (complete and partial)

• Complete: caused by a single or two sperm combining with an egg which has lost its DNA => forming 46 chromosome set
• Partial: occurs when an egg is fertilised by two sperm or by one sperm which replicates itself yielding the genotypes 69,XXY or 69,XXXY
• Complete hydatidiform moles have a higher risk of developing into choriocarcinoma than partial moles.

Invasive mole
Choriocarcinoma

Question 29

Describe a Hydatidiform Mole

Answer 29

Hydatidiform mole results from a chromosomal defect in the conceptus causing oedema of the placental chorionic villi. There is associated atypical trophoblastic hyperplasia and cystic swelling of chorionic villi. These tumours have the propensity for myometrial penetration.

[*] They may persist, invade, metastasize and kill.

[*] There is a significant risk of development of choriocarcinoma.

[*] 1-3/1000 pregnancies

[*] Associated with invasive mole and choriocarcinoma

[*] Usually diagnosed in early pregnancy by USS, can present with miscarriage

[*] Highest risk age groups are teenagers and 40-50 years (extreme of reproductive life)

[*] Appearance

• Friable mass of thin-walled translucent, grape-like (nodule-like) structures = swollen oedematous villi
• Treated with curettage followed by HCG monitoring
• If HCG levels don’t fall, may indicate invasive mole

Question 30

Describe an Invasive Mole

Answer 30

[*] Not very common

[*] Mole that penetrates or perforates uterine wall

[*] Locally destructive – can cause uterine rupture requiring hysterectomy

[*] Produces vaginal bleeding and uterine enlargement

[*] Persistently elevated HCG

[*] Treated with chemotherapy

Question 31

Describe a Choriocarcinoma

Answer 31

Choriocarcinoma is a malignant tumour of placenta composed of syncytio and cytotrophoblast without villi. Placental site trophoblastic tumour is a rare variant of trophoblastic malignancy resembling intermediate trophoblast.

[*] Malignant neoplasm of trophoblastic cells derived from previously normal or abnormal pregnancy, no villi present

[*] Rapidly invasive, metastasises widely but responds well to chemotherapy

[*] Incidence:

• 50% occur in association with complete moles
• 25% following abortion
• 22% following a normal pregnancy
• 3% in ectopic pregnancies

[*] NB: non-gestational choriocarcinomas arise from germ cells in the ovary or in the mediastinum

[*] Usually presents with vaginal spotting

[*] HCG levels are high

[*] Treated with uterine evacuation and chemotherapy – very high cure rate (compared with non-gestational choriocarcinomas)