23. Gynaecologic tumors

Overian cancer

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.

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.

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.

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.

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.

Cervical cancer

Cervical cancer is the cancer of the uterine cervix. It's the 4th most common cancer in females, but the 6th most common cause of cancer death. It mostly affects women 35 - 50 years old. It progresses from cervical intraepithelial neoplasia (CIN), which is the precancerous lesion of cervical cancer. Human papilloma virus (HPV) infection is the cause in virtually all cases.

Cervical carcinoma is a “controllable”, highly preventable cancer for three reasons:

• The precursor lesion (CIN) progresses slowly to cancer
• There is an inexpensive and non-invasive screening test for CIN (Pap smear)
• The precursor lesion can be treated simply and effectively to prevent progression to cancer

Additionally, HPV vaccines are available which effectively prevent HPV-related cervical cancer. For these reasons, cervical cancer is a preventable disease which, according to the WHO, no person should die from. Deaths from cervical cancer mainly occurs in countries without access to screening and vaccines. The 5-year survival is approximately 60%.

Etiology

Cervical cancer, and by extension CIN, requires infection by high-risk HPV serotypes (16, 18, 31, 33, +++). HPV 16 is the most carcinogenic and accounts for 50%+ of cases. For this reason, the risk factors for cervical cancer are related to the risk factors for HPV infection:

• Multiple sex partners
• Early sexual debut
• Early childbearing
• Multiparity

There are also some risk factors which are unrelated to HPV infection (although infection is still required):

• Cigarette smoking
• In-utero exposure to DES
• Low socioeconomic status
• Immunosuppression

Pathology

Cervical cancer originates in the squamocolumnar junction of the cervix as cervical intraepithelial neoplasia, and takes years or even decades to develop into invasive cancer. The squamocolumnar junction of the cervix is where the squamous epithelium of the ectocervix meets the columnar epithelium of the endocervix. The location of the squamocolumnar junction depends on age and parity, so that young, nulliparous women has it around the external os, while older, multiparous women have it more internally.

There are two major types of cervical carcinoma, squamous carcinoma and adenocarcinoma. Squamous cell carcinoma accounts for 80-90% of cases, while adenocarcinoma accounts for the remaining cases. Other types, including neuroendocrine type, are very rare. Adenocarcinoma has a worse prognosis.

Cervical intraepithelial neoplasia

CIN is the precancerous lesion of cervical cancer. According to severity, CIN is classified as CIN 1 to CIN 3, where CIN3 has the highest risk of malignancy. A significant number (possibly up to 70%) of CIN 2+ lesions regress over time rather than progress to cancer, and this number is even higher for CIN 1 lesions. However, as of yet we have no way of distinguishing lesions which will progress from those who will regress. As such, all CIN II+ lesions must be treated.

Clinical features

Early cervical cancer is frequently asymptomatic. The most common symptoms are:

• Abnormal vaginal bleeding (metrorrhagia, hypermenorrhoea)
  • Especially postcoital bleeding
• Vaginal discharge
• Dyspareunia
• Pelvic pain

Diagnosis and evaluation

Cervical examination may reveal ulceration, induration, or an exophytic tumor. Biopsy is required for diagnosis. Cervical cytology (Pap smear) should always be performed in case of symptoms, and involves scraping of ectocervix and endocervix with spatula or brush. Cervical cytology has a high specificity but moderate sensitivity.

If physical examination shows a suspicious lesion, a punch biopsy should be taken directly from it. If no tumour is visible, colposcopy with acetic acid or Schiller test (applying iodine solution) should be used to look for suspicious areas to biopsy.

If no suspicious lesions are found or biopsy is negative but malignancy is still suspected, cervical conization can be performed and examined histologically.

If cancer is suspected, we should look for involvement of the parametrium by rectovaginal examination. Further evaluation of the parametrium can be accomplished with PET/CT or MRI.

Cervical cytology

The Pap smear is the investigation used for screening for CIN and cervical cancer. It’s named after Greek physician George Papanicolaou. It is performed with the patient in the lithotomy position. A speculum is used to open the posterior and anterior vaginal wall to visualise the cervix. A brush is used to collect cells from the cervix and the posterior vaginal fornix. This cytologic specimen is then examined by a cytopathologist, who will examine and describe the squamous cells and the glandular cells of the specimen.

Colposcopy

Colposcopy uses a special equipment called the colposcope to magnify and visualise the cervix directly. It can be used to guide sampling for the Pap smear or punch biopsy. It is indicated if the Pap smear showed ASC-US, ASC-H, LSIL, or HSIL.

By applying dilute acetic acid to the surface, we can differentiate between atypical and normal cells, which gives an indication of where to take the sample/biopsy. Atypical cells will be stained white.

We also apply 2% iodine to the surface. Healthy cells pick up the iodine and change colour to mahogany brown, while atypical cells will remain white or yellowish. This is also called Schiller’s test.

With colposcopy we can also see other features which are suspicious of malignancy, like exophytic lesions and hypervascularisation.

FIGO classification

Alternative name for stage	Stage	Description
Early cervical disease	0	Carcinoma in situ
	I	Tumour strictly confined to the cervix
	Ia1	Stromal invasion < 3 mm in depth
	Ia2	Stromal invasion 3 – 5 mm in depth
	Ib	Stromal invasion > 5 mm in depth
	II	Tumour invades beyond the uterus, but not into the pelvic wall or lower third of the vagina
	IIa	Tumour does not invade parametrium, invades upper 2/3 part of vagina
Locally advanced disease	IIb	Tumour invades the parametrium, but not the pelvic wall
	III	Tumour invades pelvic wall or lower third of the vagina or causes hydronephrosis or pelvic lymph nodes or paraaortic lymph nodes
Metastatic disease	IVa	Tumour invades adjacent organs in the pelvis
	IVb	Distant metastasis

(I’ve excluded some of the substages for simplicity)

Management

Surgery is the mainstay of treatment of cervical cancer.

• Conisation or total/simple hysterectomy for stage Ia1
• Radical (Wertheim) hysterectomy up until and including stage IIa

Surgical treatment

Wertheim hysterectomy involves modified radical hysterectomy + pelvic lymphadenectomy, total removal of uterus and its ligaments, and removal of pelvic lymph nodes on both sides.

Hysterectomy obviously takes away the woman’s fertility, but cervical cancer often affects women in their fertile age. A fertility-preserving surgical alternative to hysterectomy for cervical cancer is trachelectomy.

Surgery is not the main treatment in locally advances disease, stage IIb and beyond (i.e., when the parametrium is involved). However, it may be part of the adjuvant treatment.

Chemotherapy and radiotherapy

Radiation is effective in all stages of cervical cancer. External beam radiation therapy (EBRT) may be used, but the bladder is sensitive to radiation, so external radiation for cervical cancer should be limited to 50 Gy. After 50 Gy has been delivered by ERBT, we switch to brachytherapy, usually HDR brachytherapy with afterloading.

For stages IIb to IVa radiochemotherapy is the main treatment. Treatment for stage IVb is palliative and is mostly chemotherapy. Radiochemotherapy may be used as adjuvant treatment after surgery.

The standard chemotherapy regimen is cisplatin-based. Chemotherapy is rarely used alone in the treatment of cervical cancer; it’s almost always combined with radiotherapy.

Radiotherapy may be used as primary therapy in early stages (I – IIa) in cases where surgery is not an option.

Management of CIN

CIN I is not an indication for treatment, but rather for regular follow-up until it progresses or regresses. Treatment of CIN II+ premalignant lesions is conisation, the excision of a triangular part of cervical tissue containing the lesion + a safety margin. This may be performed with a scalpel, an electrical knife, or with a laser.

In premenopausal women, the squamocolumnar junction lies externally. It is this junction which is essential to remove, so a flatter cone can be cut out. In postmenopausal women, the junction lies more internally, and so a deeper cone must be cut out to ensure that the junction is cut out.

Conisation is often followed by dilation and curettage. This involves obtaining cytological specimens by abrasion of the remnants of the cervix, after which the cervix is dilated, and samples are obtained from the uterine cavity as well. These samples are then examined by a pathologist.

Prevention

Regular screening with cervical cytology (Pap smear) is recommended for females in sexually active ages. HPV vaccination before sexual debut also decreases the risk.

In Norway, this includes women at the age of 25 - 69, and involves screening every 5 years. The cytology specimen is first analysed for HPV. If there is no HPV, the cytology specimen is not examined. If there is HPV, the specimen is examined for CIN. If there are signs of CIN or HPV positivity, more frequent screenings or colposcopy and biopsy are recommended, depending on the type of CIN and HPV.

In Hungary, screening with Pap smear is recommended once a year in sexually active women of all ages. If older than 65, screening is recommended every two years.

Endometrial cancer

Endometrial cancer is the cancer of the endometrial lining of the uterine corpus. There are multiple histological types, but the most common is the endometroid carcinoma. It’s mostly a disease of postmenopausal women.

It’s the most common form of gynaecological cancer (but not the most deadly, ovarian cancer is). It causes symptoms early, enabling diagnosis at a stage where there is a high likelihood of cure. The mortality is relatively low.

We can distinguish type I and type II endometrial cancer. Compared to type II tumours, type I tumours have a favourable prognosis, are oestrogen-induced, responsive to progestins, and may be preceded by an intraepithelial neoplasm.

Risk factors

The risk factors for type I and type II are different. Type I is generally related to increased unopposed oestrogen exposure, while type II is unrelated to oestrogen:

• Type I tumours
  • Obesity
  • Unopposed oestrogen therapy
  • Tamoxifen
  • PCOS
  • Early menarche
  • Late menopause
• Type II tumours
  • Old age
  • Low BMI
  • Non-white ethnicity

Pathology

These are most common histological types:

• Endometrioid type (80%)
• Non-endometrioid type
  • Serous adenocarcinoma
  • Clear cell carcinoma
  • Mucinous adenocarcinoma
  • +++

However, we can also distinguish two types based on the incidence, responsiveness to hormones, and clinical behaviour:

• Type I tumours – 80% of cases
  • Endometrioid carcinoma grade 1
  • Endometrioid carcinoma grade 2
• Type II tumours
  • Endometrioid carcinoma grade 3
  • Non-endometrioid carcinomas

Compared to type II tumours, type I tumours have a favourable prognosis, are oestrogen-induced, responsive to progestins, and may be preceded by an intraepithelial neoplasm.

Clinical features

The characteristic symptom is abnormal uterine bleeding, which is the presenting complaint in almost all cases. There is often metrorrhagia or hypermenorrhoea.

Diagnosis and evaluation

As always, history and physical examination is important. History should evaluate if the patient has received unopposed oestrogen therapy, if there is family history of gynaecological cancer, etc. Physical examination should include a conventional gynaecological exam, as well as a rectovaginal examination, to assess the rectovaginal septum. This can give information on whether the cancer has spread regionally.

Imaging is important. Transvaginal ultrasound can be used to evaluate the endometrial thickness. A thickness of ≤4 mm in postmenopausal women means a very low risk for endometrial cancer.

The gold standard for abnormal postmenopausal bleeding is fractional dilatation and curretage, which allows for histological examination. One may also perform an endometrial biopsy, or hysterectomy specimen. The endometrial biopsy may be blind or guided by hysteroscopy.

Staging

MRi or CT is important in staging the tumour, to evaluate the local and distant spread. The complete staging can only be performed after total hysterectomy, bilateral salpingo-oophorectomy, and lymphadenectomy.

FIGO classification

The International Federation of Gynaecology and Obstetrics (FIGO) classifications are similar to the TNM, but slightly different. FIGO classifications are preferred in gynaecology.

Stage	Description
0	Carcinoma in situ
I	Tumour is localised to the corpus
II	Tumour reaches the cervix
III	Tumour infiltrates the neighbouring tissues (adnexa, vagina, lymph nodes)
IVa	Tumour infiltrates the bladder or rectum
IVb	Distant metastasis

(There are substages of I, II, and III, but I’ve excluded them for simplicity)

Management

Unless contraindicated, surgical therapy should always be part of the therapy of endometrial cancer. If surgery is contraindicated, primary combined irradiation, brachytherapy, and teletherapy are necessary. Preoperative and/or postoperative irradiation may be performed as well.

Surgical therapy

Total laparoscopic hysterectomy with bilateral salpingo-oophorectomy (BSO) is the mainstay of surgical treatment. It is curative in early stages and improves prognosis in later stages. It also allows the proper surgical staging. Laparoscopy is preferred over laparotomy.

Pelvic and para-aortic lymph nodes are removed in case of middle risk and high risk stages, generally IIIc and above.

If presurgical evaluation shows possible spreading to the cervix (stage II), a radical hysterectomy is performed instead. Radical hysterectomy means the en bloc removal of the uterus, cervix, upper vagina, and parametrium.

Hormonal therapy

It was theorised that because Type I endometrial cancer is hormone sensitive that progestins may reduce tumour growth, but a large meta-analysis found no survival benefit for progestins. Hormonal therapy is therefore not routinely recommended but is an option for those with low-risk endometrial cancer who wish to preserve fertility.

Radiotherapy

Endometrial cancer is not particularly radiosensitive (especially compared with cervical cancer). Radiotherapy may be used for inoperable patients or for palliation. Both external beam radiotherapy and intravaginal brachytherapy may be used.

Chemotherapy

Chemotherapy is not frequently used in endometrial cancer. It may be used in recurring cancer or as adjuvant therapy. Paclitaxel + carboplatin is used.

Follow-up after treatment

• Physical examination
  • Every 3 months in the first year
  • Every 4 months in the second year
  • Then less and less frequently until 1 time per year
• Imaging
  • Chest x-ray
  • MRI/CT/transvaginal ultrasound
• CA-125 detection