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Ovarian cancer

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Ovarian cancer is the second most common gynaecological cancer (after endometrial), but the most common cause of gynaecological cancer death due to its poor prognosis. It has no early symptoms, it has potential to grow very large, and it has aggressive behaviour. There is no effective screening for it in the general population. The most common type is the epithelial type (90% of cases), which has the worst prognosis. It is mostly a disease of postmenopausal women in the 55 – 65 age group. The 5-year survival is 30 – 35%. 70% of cases are stage III or IV at the time of diagnosis. The only real opportunity for survival is early diagnosis with complete surgical excision.

Ovarian germ cell tumours (like teratoma) account for < 3% of ovarian cancers. They mostly affect younger women, rarely affecting those over 30. They’re most commonly benign. Most are diagnosed at an early stage and are highly curable (5-year survival > 95%).

Etiology

Risk factors include any which increase oestrogen exposure:

  • Old age
  • BRCA1/BRCA2 mutation
  • Family history
  • Early menarche
  • Late menopause
  • Lynch syndrome

Protective factors include:

  • Oral contraceptive pills
  • Multiparity
  • Breastfeeding

High oestrogen exposure is involved in the pathogenesis, which explains many of the risk and protective factors.

Pathology

We can distinguish multiple histological types of ovarian cancer:

  • Epithelial ovarian carcinoma – arise from ovarian surface epithelium
    • Serous type
    • Endometrioid type
    • Clear cell type
    • Mucinous type
    • Brenner tumour
  • Germ cell tumours
    • Dysgerminoma
    • Teratoma
  • Sex cord-stromal tumours
  • Krukenberg tumour
    • Bilateral ovarian metastatic spread from gastric cancer

The epithelial type is the most common, accounting for 90%.

The FIGO classification is used for staging.

Borderline ovarian tumour

Borderline ovarian tumours are epithelial ovarian tumours of low-grade malignant potential. They are characterised by atypical growth but no stromal invasion. They sometimes have intraperitoneal spread. Borderline tumours account for 15% of epithelial tumours. They mostly affect postmenopausal women. Borderline tumours have an excellent prognosis (5-year survival > 90%).

There’s nothing in particular which can distinguish borderline tumours from other tumours clinically. The diagnosis is made pathologically, after surgery.

Ovarian germ cell tumours

Ovarian germ cell tumours are those ovarian tumour which originate from primordial germ cells in the ovary. These can develop into foetus-like structures, placenta-like structures, extraembryonal structures, or grow completely undifferentially. It’s a heterogenous group of tumours with many different types with different characteristics.

Germ cell tumours have a much better prognosis than epithelial tumours, are more commonly benign, and they affect younger women. Germ cell tumours are relatively frequently bilateral, especially dysgerminoma.

Classification

  • Teratoma
    • Dermoid cyst (mature teratoma)
    • Immature teratoma
    • Struma ovarii
  • Dysgerminoma
  • Yolk sac tumour
  • Embryonal carcinoma

A teratoma is a germ cell tumour which grows into somatic structures originating from ectoderm, endoderm, and mesoderm. They may contain structures like hair and teeth. The benign mature teratoma (dermoid cyst) is more common than the malignant immature teratoma. Struma ovarii is a rare type of teratomy which consists of thyroid tissue and produces thyroid hormones. Anti-NMDA receptor encephalitis is associated with teratomas.

A dysgerminoma is a germ cell tumour which has grown into an undifferentiated structure. It’s more frequent in those with streak gonads. It’s the most common malignant ovarian germ cell tumour.

A yolk sac tumour is a germ cell tumour which has grown into a yolk sac-like structure. They characteristically produce AFP.

Embryonal carcinoma of the ovary is one of the most aggressive ovarian tumours. It’s very rare.

Ovarian sex cord-stromal tumours

Ovarian sex cord-stromal tumours (SCSTs) are a group of ovarian tumours. Some of them are benign, some of them are malignant. These tumours arise from sex cord cells, like Sertoli or granulosa cells, or from stromal cells, like fibroblasts and gonadal stroma. In contrast to epithelial ovarian cancers, malignant SCSTs are often diagnosed at an early stage, and so the prognosis is good. SCSTs account for < 5% of all ovarian tumours. Most types are most prevalent in postmenopausal women. The only exception is Sertoli-Leydig cell tumour, which primarily affects 30 – 40 year old women. There are many types:

  • Pure stromal tumours
    • Fibroma
    • Thecoma
    • Fibrosarcoma
    • Leydig cell tumour
  • Pure sex cord tumours
    • Granulosa cell tumour
    • Sertoli cell tumour
  • Mixed sex cord-stromal tumours
    • Sertoli-Leydig cell tumour

Fibroma is the most common benign SCST, while granulosa cell tumour is the most common malignant SCST.

Clinical features

Ovarian cancer is characteristically asymptomatic until the late stages, which is part of the reason for the poor prognosis.

When symptoms do appear, these are the most common:

  • Abdominal enlargement (due to ascites)
  • Symptoms of pressure on surrounding organs
    • Dysuria
    • Constipation
    • UTI
  • Symptoms relating to complications of the tumour (usually acute)
    • Torsion – acute pain and vomiting
    • Rupture – generalised abdominal pain
    • Haemorrhage – abdominal pain and haemorrhagic shock

Some present with an asymptomatic adnexal mass which is discovered on bimanual examination or on ultrasound. Germ cell tumours grow quickly and therefore often cause pelvic pain or symptoms of bladder or bowel compression.

Features of SCSTs

Fibromas may present as Meigs syndrome, which is the presence of ascites and/or hydrothorax simultaneously as a fibroma.

Granuloma cell tumour produce oestrogens. Thecomas are often mixed with granulosa cells and can therefore also be oestrogen-secreting. The symptoms of this depends on the age of the patient:

  • Before puberty – causes precocious puberty
  • Reproductive age – causes bleeding disorder (metrorrhagia, hypermenorrhoea)
  • After menopause – causes postmenopausal bleeding

Sertoli-Leydig cell tumours produce androgens, which may cause virilisation, hirsutism, acne, etc.

Diagnosis and evaluation

Physical examination should be performed for an adnexal mass as well as inguinal and cervical lymphadenopathy. Ultrasound (usually transvaginal) of the adnexal mass can reveal features suspicious for malignancy (solid mass, irregularity, papillary structures, etc.) and ascites. Chest, abdominal, and pelvic CT or MRI are used to look for ascites and disease spread. FNAB is never performed as it may cause spreading.

The definite diagnosis of ovarian cancer, as well as determination of its histological type, requires histology. Biopsy causes tumour seeding and is not performed. All cases of suspected ovarian cancer undergo complete surgical staging, involving total hysterectomy with bilateral salpingo-oophorectomy with pelvic and paraaortic lymph node dissection and omentectomy. Peritoneal cytology is also acquired by peritoneal washing. Only after histological evaluation of these samples can the diagnosis be made.

It’s important to distinguish germ cell tumours from other ovarian tumours during the diagnostic evaluation, as the treatment is different. Germ cell tumours are more often solid on ultrasound than epithelial tumours. Because germ cell tumours frequently are bilateral, both sides must be examined (bilateral examination is performed routinely in all cases anyway). If germ cell tumour is suspected in a young girl, we may perform karyotyping (as the probability of intersex disorder is high). Ovarian germ cell tumours often produce tumour markers, especially hCG, AFP, and lactate dehydrogenase (LDH).

Tumour markers of malignant ovarian cancer

Tumour markers in ovarian cancer are not used for diagnosis but rather for preoperative evaluation and follow-up. They’re not appropriate for screening of the general population.

Several biomarkers are available for ovarian cancer:

  • Typical for epithelial tumours
    • CA 125
    • CEA
    • HE4 (human epididymis protein 4)
  • Typical for germ cell tumours
    • β-hCG
    • AFP
  • Typical for granulosa cell tumours
    • Inhibin B
    • Anti-Müllerian hormone

Of these, CA 125 is the most widely used. Up to 80% of endothelial ovarian cancers will have elevated CA 125. It’s elevated if > 35 units/mL. It’s specificity for ovarian cancer is high in postmenopausal women but low in premenopausal. It should be routinely measured in postmenopausal women with adnexal masses, and, if elevated, should raise suspicion of malignancy.

CEA can be elevated in many conditions other than ovarian cancer, benign and malignant, including GI tract cancer, smoking, liver disease, gallbladder disease, IBD, etc.

β-hCG and AFP are mostly elevated in germ cell tumours and choriocarcinoma.

Inhibin is only elevated in sex cord-stromal tumours. Oestrogens and androgens could be elevated in these tumours as well.

Biomarker panels

Several biomarker panels, which measures multiple biomarkers, are available. These use multiple biomarkers to assess the likelihood of malignancy in patients with adnexal mass. Combining biomarkers makes them more sensitive and more specific.

  • ROMA index is the most important and uses two biomarkers
    • CA 125 and HE4
  • OVA1 uses five biomarkers
  • Overa uses five different biomarkers

The RMI (Risk of Malignancy Index) can be calculated to predict the risk that an adnexal mass is malignant. This calculation requires ultrasound features and the CA125 level.

Screening

As already stated, there is no screening for it in the general population. However, we do screen people who have hereditary ovarian cancer or hereditary breast cancer. In these people, we can use serum markers, ultrasound, and frequent pelvic examination to screen them.

In high-risk patients (BRCA, Lynch syndrome), we can do prophylactic bilateral salpingo-oophorectomy after the age of 35.

Management

Most patients with epithelial ovarian carcinoma are treated by surgical removal or cytoreduction followed by adjuvant chemotherapy. Borderline tumours are managed like malignant epithelial tumours.

Surgical treatment

The treatment, diagnosis, and staging of ovarian cancer is surgical, either by laparotomy or in some cases, laparoscopy. Frozen section is performed during the operation, and the information is used to help determine the diagnosis and stage of the tumour, and therefore the extent of the surgical procedure.

The standard staging procedure is total hysterectomy with bilateral salpingo-oophorectomy with pelvic and paraaortic lymph node dissection and omentectomy. Peritoneal cytology is also acquired by peritoneal washing.

The upper abdomen, peritoneal surfaces, mesenteries, and other abdominal organs are inspected visually. If metastases are evident during surgery, they’re removed as much as possible.

In cases of mucinous epithelial ovarian cancer, some experts advocate removal of the appendix, even though it appears normal visually. This is because mucinous ovarian cancer is associated with appendiceal metastasis.

In young patients with stage Ia disease or non-epithelial ovarian cancers who desire it, fertility-preserving surgery may be performed instead. This includes unilateral salpingo-oophorectomy, peritoneal washing, omentectomy, and pelvic and paraaortic lymphadenectomy.

Cytoreduction (removing as much as possible of visible lesions) may be performed in stage III and IV when complete resection is impossible.

Chemotherapy

Epithelial ovarian cancer is chemosensitive. Neoadjuvant and/or adjuvant chemotherapy is therefore widely used. Chemotherapy is mostly platinum-based, for example carboplatin + paclitaxel. It may sometimes be administered intraperitoneally.

Targeted molecular therapy

All patients with epithelial ovarian cancer should be tested for familial cancer syndromes which may cause ovarian cancer, especially familial BRCA1 and BRCA2 mutations. In cases of epithelial ovarian cancers in people with positive familial BRCA mutations, PARP inhibitors may be used as adjuvant therapy in addition to chemotherapy.

Bevacizumab (anti-VEGF) may also be used.

Radiotherapy

Radiotherapy is not part of the standard management of ovarian cancer, but it may be used on a palliative indication for recurrent or metastatic ovarian cancer.

Germ cell tumours

Ovarian germ cell tumours often occur in fertile women, and as such special measures should be taken to preserve fertility if possible, if the patient wants to. If a germ cell tumour is highly suspected, bilateral oophoerctomy may not be required, and we may opt for fertility-sparing surgery instead (unilateral salpingo-oophorectomy with preservation of the uterus).

If the contralateral ovary appears to also be affected by the tumour at the time of surgery, we may resect this tumour affection while preserving the rest of the contralateral ovary to preserve fertility. Even if the whole tumour can’t be removed during surgery, cure is likely with adjuvant chemotherapy.

Adjuvant chemotherapy cures most patients with germ cell tumours as they’re highly chemosensitive. The standard chemotherapy regimen consists of bleomycin, etoposide, and carboplatin/cisplatin (BEP).

Sex cord-stromal tumours

The treatment of malignant SCSTs is generally the same as for other ovarian cancers and includes bilateral salpingo-oophorectomy (adnexectomy) and total hysterectomy. Adjuvant chemotherapy may be used in some cases. Surgical removal of the tumour generally causes resolution of the tumours effects. In patients with Meigs syndrome, surgical removal of the fibroma leads to complete resolution of the symptoms. In patient with hormonal changes, these changes are reversed after surgery.