Ovarian neoplasms

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Chapter 21 Ovarian neoplasms

Amy Tang

Risk of Malignancy Index (RMI)

RMI is useful to help determine those women with a pelvic ovarian mass who would benefit from direct referral to a tertiary gynaecological oncology unit.

• menopausal status: premenopausal = 1; postmenopausal = 3

• ultrasound features (multiloculated, solid areas, bilateral pathology, ascites, metastases): no features = 0; one feature = 1; more than one feature = 3

If RMI >=200, there is a high risk of malignancy and the woman should be referred to a gynaecological oncologist.

Screening for ovarian cancer

Screening for ovarian cancer has not been proven to reduce ovarian cancer deaths in the general population. It may have a role in high-risk patients (e.g. a strong family history).

• Bimanual pelvic examination: low-cost, requires no special equipment but not specific or sensitive in the detection of ovarian cancer.

• Ultrasound scan: malignant features include semisolid or cystic areas, thick septa, surface papillary growths, neovascularisation, bilateral masses and/or ascites.

• Cytology: routine cervical cytological tests give abnormal results in 10%–30% of advanced ovarian cancer cases. Peritoneal cytology is not specific or sensitive, and is time-consuming and painful to perform.

• Prophylactic salpingo-oophorectomy: this should be considered in women with a strong family history of ovarian cancer or women who are BRCA carriers; 7% of women with ovarian cancer have had a previous laparotomy; 0.2% of women who have had their ovaries conserved during operations for benign gynaecological disorders develop ovarian cancer.

Tumour markers for ovarian cancer

• Markers are used in diagnosis, prognosis and to detect subclinical disease.

• The four types of potential markers for ovarian cancer are oncodevelopmental markers, carcinoplacental, metabolic and tumour-specific/tumour-associated antigens. None has sufficiently high specificity for screening.

• CA125 tumour-associated antigen is a high molecular weight glycoprotein expressed in coelomic epithelium during embryogenic development; 80% of patients with ovarian carcinoma have levels >35 IU/mL. It is elevated in about 1% of healthy women and also in non-malignant conditions such as endometriosis, inflammation, benign tumours and pregnancy. CA125 levels fall with age. It is a good marker for epithelial carcinoma, except mucinous tumours, but has poor specificity (not useful for screening).

• CA19.9 is usually elevated in mucinous tumours and pancreatic cancers.

• CEA is useful to exclude metastatic bowel primary if patient complains of bowel symptoms.

• The markers may be used in combination to improve specificity and sensitivity.

• False-negative results can occur in early-stage disease.

Ovarian cancer

Epidemiology

There are geographical variations in the incidences of ovarian cancer. The peak incidence by age group occurs in the seventh to eighth decade. Ovarian cancer accounts for up to 35% of all gynaecological cancers.

Risk factors

• nulliparity, infertility

• family history: a woman with a mother or sister with ovarian cancer has a twenty-fold increased risk; increased risk is associated with inherited mutations in the BRCA1 and BRCA2 genes

• previous other cancers: breast, endometrial

• oral contraceptive pill affords protection

• other risk factors: blood group A, Peutz-Jeghers syndrome

Pathology of ovarian cancer

• epithelial tumours: make up 90% of ovarian malignancies

• types of epithelial ovarian cancer: serous, mucinous, endometroid, Brenner, clear-cell

• sex cord stromal tumours: granulosa cell, Sertoli-Leydig cell (androblastoma, arrhenoblastoma), fibroma, sex cord tumours with annular tubules

• germ cell tumours: dysgerminoma, non-dysgerminoma (endodermal sinus tumour, embryonal carcinoma, choriocarcinoma, mature and immature teratomas)

• secondary tumours: Krukenberg (gastrointestinal, especially stomach), breast

Presentation

• Ovarian cancer is often asymptomatic in early disease.

• The woman may present with:

• abdominal pain, pelvic pressure, frequency of urine

• abdominal swelling, dyspepsia, back pain

• constipation, deep venous thrombosis

Examination

• general examination

• assess for lymphadenopathy

• examination of breasts, thyroid, abdomen/liver, ascites

• pelvic and rectal examination

Investigations for ovarian masses

• tumour markers: CA125, CA19.9, CEA

• consider human chorionic gonadotrophin (hCG), alpha-fetoprotein, inhibin, lactate dehydrogenase (LDH) if suspect non-epithelial ovarian tumours

• full blood count, electrolytes, liver biochemistry

• radiology: abdominopelvic ultrasound and/or computed tomography (CT) scan, chest X-ray, colonoscopy

FIGO staging for ovarian cancer

Staging is based on clinical examination, laparotomy, histology and cytology findings.

• stage 1: growth limited to ovaries

• 1A: growth limited to one ovary, capsule intact, no ascites, negative peritoneal cytology

• 1B: growth limited to both ovaries, no ascites, no tumour on the external surfaces, capsule intact

• 1C: tumour either stage 1A or 1B, but with tumour on surface of one or both ovaries; or capsule ruptured; or with ascites present containing malignant cells or with positive peritoneal washings

• stage 2: growth involving one or both ovaries with pelvic extension

• 2A: extension and/or metastases to the uterus and/or tubes

• 2B: extension to other pelvic tissues

• 2C: tumour either stage 2A or 2B, but with tumour on surface of one or both ovaries; or with capsule(s) ruptured; or with ascites present containing malignant cells or with positive peritoneal washings

• stage 3: tumour involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes; superficial liver metastasis equals stage 3; tumour is limited to the true pelvis but with histologically proven malignant extension to the small bowel or omentum

• 3A: tumour grossly limited to the true pelvis with negative nodes, but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces

• 3B: tumour involving one or both ovaries with histologically confirmed implants of abdominal peritoneal surfaces; none >2 cm in diameter

• 3C: abdominal implants >2 cm in diameter and/or positive retroperitoneal or inguinal nodes

• stage 4: growth involving one or both ovaries with distant metastases; if pleural effusion present, there must be positive cytology to allot a case to stage 4; parenchymal liver metastasis equals stage 4

Epithelial ovarian tumours

These account for 90% of ovarian cancer.

Management

Preoperative preparation

• Optimise health if other medical problems are present.

• Admit for bowel preparation and anaesthetic review.

• Employ prophylactic antibiotics and anticoagulation therapy.

Chemotherapy

• used for adjuvant treatment and palliation

• most commonly used agents are combination carboplatin and paclitaxel

• can be given intravenously or intraperitoneally

• used at an earlier stage in cases with poorer prognostic factors, such as poorly differentiated tumours, cyst rupture or ascites

• can be used as neoadjuvant treatment in stage 4 disease or in those patients who are not fit for initial upfront surgery (e.g. recent pulmonary embolism)

Aims of surgery

• to improve tumour response to further therapy

• to delay/prevent inevitable complications, such as gastrointestinal obstruction

• to alter immunological state and immunosuppresion

• to relieve symptoms and to achieve psychological benefit from the removal of a large mass

Sex cord stromal tumours

Stromal cells retain the potential for differentiation into any of the cells/tissues from mesenchymal gonad (i.e. granulosa, theca, Leydig and Sertoli cells).

• Some tumours produce sex steroid hormones:

• feminising: granulosa and theca cell tumours

• masculinising: Sertoli-Leydig (androblastoma).

Granulosa cell tumours

• These account for 2% of ovarian tumours and occur at any age.

• These solid tumours are usually unilateral (bilateral in 2%–5%).

• They vary in size, with an average of 10 cm in diameter.

• Rupture or haemorrhage into the tumour may occur.

• They can produce oestrogen and inhibin.

• Histopathology: Call-Exner bodies are granulosa cells arranged around small spaces containing nuclear fragments.

• They are associated with endometrial hyperplasia and even endometrial cancer in 5%–6% of cases.

• They are mostly diagnosed at stage 1 disease, are usually a slow-growing tumour, and late recurrences are not uncommon.

Management

• surgery: if childbearing complete, total abdominal hysterectomy and bilateral salpingo-oophorectomy; if early-stage and the patient still requires fertility, uterine curettage and removal of the affected ovary and fallopian tube

• chemotherapy: for disease beyond the ovary or for late recurrences

Androblastoma

• These are solid tumours with low malignant potential, composed of Sertoli and/or Leydig cells (pure Sertoli cell tumours are rare; Leydig cell tumours are hilus or lipoid cell tumour).

• They present with masculinisation, abdominal pain and menstrual dysfunction.

Fibroma

• This large, firm and lobulated mass consists of fibroblast-like cells.

• It is usually benign; bilateral in 10% of cases.

• It is associated with Meigs’ syndrome (ascites and right hydrothorax), which resolves with removal of the tumour.

• If marked atypia and mitosis, it is termed fibrosarcoma; this tumour is very aggressive.

Germ cell tumours

Germ cell tumours are the second largest group of ovarian neoplasms. They occur predominantly in childhood and adolescence. The commonest germ cell tumour in all ages is the mature cystic teratoma/benign dermoid. This is derived from multipotent germ cells (i.e. from primitive germ cells before sexual differentiation occurs).

• Treatment intent is curative with conservation of ovarian function and fertility.

• Tumour markers: alpha-fetoprotein is produced by yolk sac cells; hCG is produced by syncytiotrophoblast.

Dysgerminoma

• This is the commonest malignant germ cell tumour.

• Peak age incidence is 10–30 years, especially in patients with developmentally abnormal gonads.

• It is hormonally inert.

• It is associated with elevated lactate dehydrogenase.

• Rapid growth can occur; most tumours are over 10 cm in diameter at time of diagnosis.

• It is solid, rubbery and bilateral in 15% of cases; most (75%) present in stage 1.

Management

• The tumour is very radiosensitive and chemosensitive.

• Stage 1A: unilateral salpingo-oophorectomy, peritoneal cytology, exploration of abdomen and removal of retroperitoneal lymph nodes, biopsy of contralateral ovary if suspicious. No adjuvant chemotherapy is required.

• All other stages: conservative surgery can be offered, but will need chemotherapy. BEP (bleomycin, etoposide and cisplatin) is recommended.

• Overall 5-year survival rate is over 90%, but prognosis is worse if the tumour is at an advanced stage and other germ cell elements are present.

• Careful follow-up is required, as 15%–20% of tumours recur.

• Consider karyotyping the patient.

Choriocarcinoma

• This is the rarest of the germ cell group. It can be mixed with other germ cell elements.

• It secretes hCG.

• It may present with precocious puberty.

• Choriocarcinoma in the ovary can occur as metastasis from gestational trophoblast disease in the uterus, malignant change in an ovarian ectopic pregnancy or as a primary ovarian germ cell tumour.

• It is highly malignant, with early local and lymphatic spread compared with gestational trophoblast.

• Management comprises combination chemotherapy.

Embryonal carcinoma

• This is the least well-differentiated of the germ cell tumours.

• It can differentiate along somatic line to produce teratoma, or extraembryonal to endodermal sinus or choriocarcinoma.

• It can produce tumour markers such as hCG, alpha-fetoprotein.

• It is highly malignant with early metastasis.

• Management: remove ovary for tissue diagnosis. These tumours are not radio-resistant, but treatment is usually with combination chemotherapy.

Intersex

• Dysgenetic gonad has high malignant potential.

• The commonest tumours are dysgerminoma and gonadoblastoma.

• The greatest risk occurs when associated with the Y chromosome.

Endodermal sinus tumour

• This is a yolk sac tumour with alpha-fetoprotein as the tumour marker.

• The median age at presentation is 18 years.

• It is the most aggressive of germ cell group tumours, with rapid growth.

• Presentation: acute abdomen, a large mass with haemorrhage and necrosis; 50% of patients complain of symptoms for <24 hours, and rarely symptoms are present for >2 weeks.

• Management: radical surgery produces no better results than local tumour removal. Irradiation is not helpful. Combination chemotherapy may be curative. The ideal management is conservative surgery and combination chemotherapy. Alpha-fetoprotein is the marker to gauge the woman’s response to treatment and is also used as a marker for recurrence.

Teratoma

All but 1% are cystic, mature teratomas or benign dermoid cysts. Cells are derived from all three germ cell layers of the embryo: the ectoderm, mesoderm and endoderm. Teratomas are often asymptomatic, unilateral, and large at time of diagnosis.

Malignancy

• occurs in solid immature teratomas

• occurs in the first two decades of life

• very rarely found in the postmenopausal woman

• immature teratomas with neurogenic elements have better prognosis

• stage 1A grade 1 immature teratoma can be managed by surgery alone without BEP

Mature cystic teratoma/dermoid cyst

• accounts for 20%–40% of ovarian tumours in pregnancy

• presentation: asymptomatic; torsion in pregnancy or puerperium; rupture, especially with torsion; infection is uncommon; malignant change is found in up to 3% of cases, most commonly squamous cell carcinoma, to be managed by surgery (prognosis depends on the presence of extraovarian disease)

Struma ovarii

• a monodermal teratoma which is usually benign

• usually involves non-functioning thyroid tissue

• treatment: surgery

Carcinoid tumour of the ovary

• a rare monodermal teratoma, usually occurring in older women

• one-third present with the carcinoid syndrome of flushes due to histamine release, diarrhoea, tachycardia, hypertension

• slow-growing and rarely metastasises

• investigation: raised urinary 5-hydroxyindole acetic acid

• treatment: surgical excision.

Borderline (low malignant potential) tumours

Low malignant potential tumours account for 15% of all epithelial ovarian cancers. Up to 20% occur with metastases. Metastases may represent disease of multifocal origin, rather than spread from a single site. The average age at time of diagnosis is the late 40s. About 30% of women are nulliparous.

FIGO and World Health Organization criteria for diagnosis of low malignant potential tumour are the presence of epithelial stratification, cellular atypia, mitotic activity with multilayering and nuclear pleomorphism, but with absence of ovarian stromal invasion.

Pathology

• 80%–95% are serous or mucinous

• 50%–80% are stage 1 at diagnosis

• 8%–35% are stage 3 at diagnosis

Management

• Initial management is similar to that for any patient with a pelvic mass.

• Perform a thorough physical examination.

• Test for tumour markers, renal and liver biochemistry.

• Ultrasound scan and/or CT scan of the pelvis.

• Laparotomy/laparoscopy: staging and debulking as indicated.

• Management of early-stage disease: when fertility is desired and disease is localised, conservative surgery is indicated. This includes unilateral salpingo-oophorectomy and biopsy of the contralateral ovary if suspicious and omental biopsy. In older patients, or if fertility is not required, treatment is with total abdominal hysterectomy/bilateral salpingo-oophorectomy.

• Recurrence in stage 1 disease: if managed by cystectomy alone, this is associated with a 25% recurrence rate; with oophorectomy of the affected ovary alone, a 10% recurrence rate. If total pelvic clearance, the recurrence rate is <5%.

• Management of advanced disease: treatment is similar to that for invasive ovarian cancer (total abdominal hysterectomy, bilateral salpingo-oophorectomy, debulking of tumour deposits, omentectomy, lymphadenectomy and appendicectomy).

• Chemotherapy is not indicated for stage 1. In advanced stages, chemotherapy does not appear to be as effective as in invasive ovarian cancer because the tumour is slow-growing with poor clinical response to chemotherapy or radiotherapy.

Prognostic features

• Pseudomyxoma peritonei with mucinous tumours is associated with a poor prognosis.

• Ploidy (DNA analysis by flow cytometry): most tumours are diploid and follow an indolent course. Two-thirds of ovarian cancer are aneuploid, compared with 5%–12% in low malignant potential tumours.

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