The risk of malignancy index (RMI) scoring system is used to predict whether a pelvic mass is malignant (Box 13.1). Women with an RMI of >200 should be referred to a specialist centre for further management and surgery. An RMI of >200 has a positive predictive value of 87% and a sensitivity of 88% for diagnosing malignant disease.

Box 13.1
Risk of malignancy index (RMI)

Feature	RMI score
Ultrasound features: multilocular cyst solid areas bilateral lesions ascites intra-abdominal metastases

0 = none

1 = one abnormality

3 = two or more abnormalities

Premenopausal

Postmenopausal

CA-125 U/ml

RMI score = ultrasound score × menopausal score × CA-125 level in U/ml.

To assess operability patients should have a CT of the abdomen and pelvis (Figure 13.1), and a CXR. In patients with a pleural effusion, cytological diagnosis is required to determine if the effusion is malignant.

Figure 13.1 A&B, CT scan in ovarian cancer. Contrast enhanced CT in a patient with advanced ovarian cancer demonstrates bilateral solid (black arrows) and cystic (white arrows) adnexal masses and omental cake (white arrow heads).

Courtesy of Dr. E Sala, University of Cambridge.

Patients with ascites without a mass on CT, should have cytological and immunohistochemical analysis, in addition to CA-125, CEA and CA19-9 (p. 287). The immunohistochemical profile of an ovarian tumour is typically CK 7 positive and CK 20 negative. A serum CA125:CEA ratio >25 is strongly suggestive of an ovarian rather than a GI primary.

Box 13.2
FIGO staging of ovarian cancer

Stage I – limited to one or both ovaries

IA – involves one ovary; capsule intact; no tumour on ovarian surface; no malignant cells in ascites or peritoneal washings

IB – involves both ovaries; capsule intact; no tumour on ovarian surface; negative washings

IC – tumour limited to ovaries with any of the following: capsule ruptured, tumour on ovarian surface, positive washings

Stage II – pelvic extension or implants

IIA – extension or implants onto uterus or fallopian tube; negative washings

IIB – extension or implants onto other pelvic structures; negative washings

IIC – pelvic extension or implants with positive peritoneal washings

Stage III – microscopic peritoneal implants outside of the pelvis; or limited to the pelvis with extension to the small bowel or omentum

IIIA – microscopic peritoneal metastases beyond pelvis

IIIB – macroscopic peritoneal metastases beyond pelvis less than 2 cm in size

IIIC – peritoneal metastases beyond pelvis >2 cm or lymph node metastases including para-aortic nodes

Stage IV – distant metastases to the liver or outside the peritoneal cavity

Management (Figure 13.2)

Primary surgery

Surgery involves total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO), infra-colic omentectomy, peritoneal washings, biopsy of any lesions or adhesions, blind peritoneal biopsies of the bladder, cul de sac, paracolic gutter, hemidiaphragm and pelvic sidewall and pelvic and para-aortic node sampling. Surgical staging is important to guide treatment with chemotherapy and estimate prognosis.

Figure 13.2 Management of ovarian cancer.

Early stage disease (stage I and II)

Surgery

Initial management in early stage disease is maximal cytoreductive surgery and surgical staging. Around one-third of patients with apparent stage I–IIA disease will have a higher stage of disease after full staging, mostly stage III (77%). The frequency of lymph node involvement for apparent stage I disease is 20%. There is no evidence that total lymphadenectomy improves survival. Patients with mucinous tumours should have an appendicectomy, as this may be the site of the primary.

Fertility preserving surgery

In younger patients with stage IA tumours and favourable histology, unilateral salpingo-oophorectomy and staging may be carried out, although data on fertility preserving surgery is limited. Endometrial biopsy should be carried out as a synchronous primary is present in 10% of patients. Wedge biopsy of the contralateral ovary should only be taken if it appears abnormal, as the probability of involvement of a macroscopically normal ovary is low (2.5%).

Chemotherapy

For patients with stage IA/B G1 non-clear cell cancer (low risk) 5-year disease free survival is >90% without chemotherapy if optimal surgery has been performed. For patients with high risk features (G3, clear cell, stage IIA disease), 5-year recurrence rates are 25–40% and adjuvant chemotherapy is recommended. In these patients, chemotherapy improves 5-year disease free survival (DFS) by 11% (from 65% to 76%), and 5-year overall survival (OS) by 8% (75% to 82%). Chemotherapy with 6 cycles of carboplatin and paclitaxel is recommended, although 6 cycles of carboplatin is also acceptable (Box 13.3). For stage I G2 tumours the role of chemotherapy is not clear but 6 cycles of carboplatin may be offered.

Advanced stage disease (stage III and IV)

Patients with advanced disease may develop medical complications as a result of their cancer, notably thrombosis which has consequences for further management (Box 13.4).

Box 13.4
Thrombosis in ovarian cancer

Patients with ovarian cancer have a relatively high risk of venous thromboembolism. Approximately 5% of ovarian cancer will have either a DVT or PE within in the first 2 years after diagnosis, with 30% of these occurring within the first 3 months. Rates of thrombosis are highest in those with metastatic disease, medical co-morbidities and clear cell histology. Management is with low molecular weight heparin. Vena-caval filters may be considered prior to surgery to prevent pulmonary emboli if the clot extends proximally, is non-resolving, or if the patient develops further emboli despite optimal anticoagulation.

Surgery

The extent of cytoreductive surgery is the most important prognostic factor after stage. The aim of surgery is to achieve a complete macroscopic debulking, or failing this, an ‘optimal debulking’. The definition of ‘optimal debulking’ is visible residual tumour of <1 cm. Studies have shown that patients with residual >2 cm show no improvement in survival over patients without debulking, and are considered incurable. Outcomes according to cytoreductive surgery are shown in Box 13.5. However, even after a complete response 25–50% will recur later.

Box 13.5
Stage-wise survival according to surgical cytoreduction at primary surgery

Meta-analyses suggest that patients with stage IV disease obtain a survival benefit after optimal debulking surgery. Even in patients with liver metastases, studies indicate an improved survival for those in whom optimal extra-hepatic cytoreduction is achieved (27 vs. 8 months). However, more extensive surgery such as hepatic metastatectomies does not appear to improve the survival of patients. Patients with chemotherapy resistant disease have a poor prognosis, even if optimal extra-hepatic cytoreduction is achieved.

Assessment of operability

Surgery is the primary treatment of choice where a complete debulking is considered possible. Patients with bulky disease or a poor performance status (25%) are treated with neo-adjuvant chemotherapy then reassessed for interval debulking surgery (IDS). Surgery should only be attempted where optimal debulking is possible. In general, debulking is less likely to be successful in patients with bulky upper abdominal disease or fixed tumour. Even if debulking surgery is not possible, palliative bowel surgery may be appropriate to relieve impending or actual bowel obstruction.

Neoadjuvant chemotherapy

A randomized trial (EORTC 55971) has shown that neo-adjuvant chemotherapy has equivalent efficacy with lower morbidity than primary debulking surgery in patients with stage bulky III/IV disease. Neo-adjuvant chemotherapy usually comprises 3 cycles of carboplatin and paclitaxel (or carboplatin alone) followed by interval debulking surgery for patients responding to chemotherapy, then a further three cycles of adjuvant carboplatin and paclitaxel. Approximately 10% of patients will progress on chemotherapy (platinum refractory) and the prognosis for these patients is poor and not improved by surgery. For this group further treatment is with a change of chemotherapy or best supportive care.

Adjuvant chemotherapy

Adjuvant chemotherapy is aimed at improving overall survival. There are no studies comparing best supportive care with chemotherapy. Meta-analyses suggest that adjuvant treatment with platinum compared with non-platinum monotherapy achieves a 30% relative risk reduction in mortality implying some benefit from platinum based chemotherapy. Four phase III trials have investigated the benefit of adding taxanes to platinum. Two trials (GOG111 and OV10) showed a mean survival benefit of 10–14 months whist other two (ICON3 and GOG132) did not. A meta-analysis of the four trials demonstrates a small survival advantage with the addition of paclitaxel to platinum. Many expert consider the combination of carboplatin and paclitaxel as the standard adjuvant chemotherapy.

The choice between single agent carboplatin and carboplatin with paclitaxel as first line treatment should be made after discussion of the risks and benefits with the patient. Since platinum exerts the major effect, and paclitaxel increases toxicity, single agent carboplatin will be the treatment of choice for patients with poor performance status or co-morbidities.

Intraperitoneal (IP) chemotherapy

A number of studies have investigated intraperitoneal chemotherapy. Although some have shown a small improvement in PFS and OS (GOG-172), the toxicities were high (p. 38). In the UK, IP chemotherapy is not currently offered outside a clinical trial.

Prognosis

Prognosis according to stage is shown in Table 13.1. The most important prognostic variables after stage are in order; degree of differentiation, cyst rupture, substage of disease and age.

Table 13.1 Prognosis of ovarian cancer

FIGO stage	5-year survival (%)	5-year disease-free survival
I	80–90	70–85
II	65–80	55–65
IIIa	50	45
IIIb	40	25
IIIc	30	20
IV	15	10

Relapse

Despite 70% of patients with advanced disease having a complete clinical response at the end of surgery and chemotherapy (no detectable disease on CT scan and/or normal CA-125), 70% of these will relapse, with a median progression free survival from diagnosis of 16 months. The time from first relapse to death is now around 2 years. There are no studies comparing best supportive care with chemotherapy in relapsed patients, but the recent studies suggest that chemotherapy improves survival.

Presentation of relapse

55–70% of patients present with an asymptomatic rise in CA-125. The median time from this to onset of symptoms is 3 months. 30–45% of patients present with symptoms, of whom 30% relapse in the abdomen, 36% in the pelvis, 14% in abdomen and pelvis, and the remainder have distant metastases (frequently liver metastases).

Relapse may be defined by conventional RECIST criteria (p. 44) or by the gynaecological cancer inter-group (GCIG) CA-125 criteria. CA-125 relapse for those who had elevated pre-treatment value which normalized after first line treatment (60% of all new patients) is defined as ≥2× upper limit of normal on two occasions not less than 1 week apart. Patients in whom CA-125 was elevated but never normalized (30% of all new patients): relapse is defined as a CA-125 value ≥2× nadir value on two occasions. The definition of relapse in patients with normal CA-125 prior to initial treatment (10% of all new patients) is similar to that of patients with elevated CA-125 which normalized after first line treatment.

Treatment (Figure 13.3)

Chemotherapy for relapsed disease is palliative and aims to prevent or treat symptoms in order to improve quality of life and possibly extend survival. In selected cases with a long disease free interval (exceeding 12 or 18 months) and localized relapse, surgery may be an option and long term disease free survival may be possible.

Figure 13.3 Treatment of relapsed ovarian cancer.

The probability of response to re-treatment with platinum chemotherapy depends upon the interval between the completion of platinum-based first line therapy to the time of relapse, known as the platinum free interval (PFI). A longer PFI is associated with a higher response rate, longer PFS and improved survival.

Disease relapsing >6 months after platinum treatment is considered ‘platinum sensitive’, however this group is subdivided into ‘relatively’ platinum sensitive (PFI 6–12 months) and fully platinum sensitive (PFI >12 months).

Although most of the data about the PFI and its relation to response is taken from first relapse studies, this finding has been extended to second and subsequent relapses. Standard practice is continue re-treating with platinum (or platinum combination) until the patient becomes platinum resistant, regardless of the line of treatment. It has been suggested that the response rate to platinum can be improved by ‘artificially’ extending the platinum free interval by using non-platinum agents, but this has not been proven.

Platinum sensitive disease

Patients with a PFI of >18 months show response rates of 60–95% to second line therapy, with a median time to progression of 10–12 months. Those with a PFI of 12–18 months show response rates of 50–60%, and a time to progression of approximately 9 months. Patients with a PFI of 6–12 months show response rates of 25–35% to platinum chemotherapy and a median time to progression of <6 months.

ICON4 showed an improvement in response rate for carboplatin and paclitaxel compared with carboplatin alone (57% vs. 50%), progression free survival (12 months vs. 9 months), and 2-year survival (57% vs. 50%) and median survival (29 vs. 24 months). In relapsed platinum sensitive disease, combination treatment is therefore recommended unless there is significant residual neuropathy. Gemcitabine and carboplatin is sometimes used as combination therapy, as phase III trial results show similar improvements in response rates and progression free survival to carboplatin and paclitaxel.

In patients with a PFI of 6–12 months, the benefits of combination chemotherapy are reduced. Single agent carboplatin is more commonly offered in this group. An alternative that may be considered in this group is peglyated doxorubicin (caelyx), since response rates from non-comparative phase III trials are similar.

Platinum resistant disease

Approximately 25% of patients will progress during, or within 6 months of completion of first line treatment. These patients have a low probability of response to any chemotherapy and should be considered for clinical trials if possible. The response to platinum agents is <10%. The overall median time-to-progression (TTP) is 2–3 months from starting second line treatment. The median OS from time of relapse is 8–10 months, and 2-year survival is 17–21%.

Caelyx, paclitaxel and topotecan are useful; all with response rates are around 6–13%. Rates of stable disease 28–43%, PFS is 2–3 months and OS is 8–10 months. Caelyx is most commonly chosen as the initial treatment because of its favourable toxicity profile. Paclitaxel tends to be used only when patients have not received paclitaxel with 1st line therapy. Recently some centres in the UK have used a weekly carboplatin and paclitaxel regime which has shown favourable response rates. However this regime awaits validation in a prospective RCT. Other agents with activity are oral etoposide, gemcitabine, vinorelbine, ifosfamide and tamoxifen. In this group of patients there is no evidence that combination treatment is superior to single agent.

Hormonal treatment

A proportion of ovarian cancers express the oestrogen receptor (ER) in a percentage of the tumour population. After the use of tamoxifen and aromatase inhibitors in breast cancers, several groups have used these agents in relapsed ER positive ovarian cancers. Compared with breast cancer a lower proportion of tumour cells express ER but the response to aromatase inhibitors has been shown to reflect the percentage of ER positivity. In a phase II study 17% had a response and 26% had stable disease by CA-125 criteria when letrozole was used in patients with significant ER positivity in their tumour at the time of relapse. By RECIST criteria 9% had a PR and 42% achieved stable disease. The responses were greatest amongst those with the highest ER scores.

Future directions

Examples of agents under investigation include anti-angiogenics such as VEGF inhibition with bevacizumab, and PARP inhibitors. Poly (ADP-ribose) polymerase (PARP) is an enzyme involved in the repair of single strand DNA breaks. The involvement of the PARP pathway in ovarian cancer was suggested by the relationship of BRCA positive patients who have an increased incidence of ovarian cancer and a deficiency in homologous repair. In addition 50% of sporadic serous papillary ovarian cancers also have impaired PARP expression. PARP inhibitors have shown some benefit in the prevention of further relapse when used in a maintenance setting after response to chemotherapy.

Palliative care

The most common palliative symptoms in advanced ovarian cancer are ascites, pleural effusion and small bowel obstruction. Permanent ascitic drains can be placed for those with frequent recurrent ascites. The most debilitating symptom is of small bowel obstruction which is frequently recurrent. Treatment of small bowel obstruction consists of minimal oral intake and symptomatic control with anti-emetics (haloperidol or cyclizine), antispasmodics (e.g. buscopan) and steroids (dexamethasone) if not responding to the initial treatment. Pain relief should be added to the syringe driver (e.g. diamorphine). If there is colicky abdominal pain metoclopramide should be avoided as this will exacerbate the symptoms. If secretions remain high, octreotide given via a separate syringe driver can be useful. Intravenous fluids should be given but the use of parenteral nutrition should be reserved for patients with a meaningful chance of treatment to remission, e.g. with bowel obstruction at presentation or at first relapse after a long disease free interval.

Follow-up

Most (approximately 95%) recurrences will occur in the first 3 years and relapse after 5 years is rare. Follow-up is directed at detecting localized relapse which is potentially curable with surgery or radiotherapy, e.g. local vaginal vault relapse. Follow-up should include clinical examination, CA-125 (if elevated at presentation) and intermittent imaging if CA-125 was not informative or with symptoms. A typical follow-up would be 3-monthly for 2–3 years then 6-monthly up to 5 years. Patients with an informative CA-125 can become very focused on their blood result at each appointment so a clear plan of action with a raised CA-125 is recommended as there is no evidence that treatment with an asymptomatic elevated CA-125 improves outcome.

Endometrial cancer

Introduction

Endometrial cancer is the fifth most common female cancer in developed countries. In the UK 6800 new patients are diagnosed every year. The incidence rises steeply to a peak at 64–74, with 75% of cases diagnosed in post-menopausal women. In the UK, women have a lifetime risk of 0.9% of developing endometrial cancer. Endometrial cancer is responsible for 2% of all cancer deaths in women in the UK. Most cases are diagnosed at an early stage and overall 5-year survival is 75%.

Aetiology

Table 13.2 shows the risk factors for endometrial cancer. Less than 5% of endometrial cancers are hereditary, and most of these arise in women with hereditary non-polyposis coli (HNPCC) or Lynch syndrome II (p. 51).

Table 13.2 Risk factors for endometrial cancer

Risk factor	Relative risk
Increased age	–
Unopposed oestrogen	2–10
Late menopause (after age 55)	2
Nulliparity	2
Polycystic ovary syndrome	3
Obesity	2–4
Diabetes mellitus	2
Hereditary non-polyposis colorectal cancer	22 to 50% lifetime risk
Tamoxifen	2/1000

Pathogenesis and pathology

Generally there are two types (type I and II) of endometrial cancer and the characteristics these differ.

• Type I (80%) – related to oestrogen stimulation and associated with obesity, nulliparity, and insulin resistance. Median age at presentation is 59 years. The precursor lesion of endometrioid carcinoma is atypical hyperplasia. These tumours are typically low grade (grade 1/2) endometrioid tumours presenting in early stage and express oestrogen (ER) and progesterone receptors (PR) in 92% of cases. It has an overall survival of 80%.

• Type II (20%) – unrelated to oestrogen stimulation and often occur in elderly thin women. Median age at presentation is 68 years. These tend to be high grade tumours of non-endometrioid histology (including serous, clear cell and high grade endometrial), usually present at a later stage and have a poorer prognosis, with recurrence in 50% of patients. Endometrial intraepithelial carcinoma is proposed as a precursor of serous carcinomas which express ER in 31% of cases and PR in 12%. Clear cell carcinomas do not have a proven precursor lesion and rarely express ER or PR.

Histologic types of endometrial malignancies are as follows:

• Endometrioid carcinomas (75%) – usually low-grade and confined to uterus.

• Uterine serous papillary carcinoma (UPSC – 5–10%) – high-grade, high-risk of metastasis and often presents with extra-uterine disease.

• Clear cell carcinoma (1–5%) – high-grade and high-risk of metastasis.

• Mixed adenocarcinomas (5%) – usually composed of endometrioid and serous papillary carcinoma.

• Mesenchymal tumours include stromal sarcomas, leiomyosarcoma and other types of sarcoma (p. 260, uterine sarcomas). Mixed non-epithelial tumours include carcinosarcomas (previously termed malignant mixed Müllerian tumours).

Presentation

Abnormal vaginal bleeding is the usual presentation. Other presentations include vaginal discharge, pain in advanced disease and symptoms of metastatic disease. Less than 5% are diagnosed incidentally (abnormal smear test).

Diagnosis and staging

Initial investigations

• Trans-vaginal ultrasound scan (TVUSS) is the initial investigation of choice. In the UK, a threshold of 5 mm has been adopted to determine if it is required. Women with an endometrial thickness >5 mm (7–8% probability of endometrial cancer) need further investigation by hysteroscopy.

• Endometrial sampling/hysteroscopy is useful in obtaining histologic confirmation. Pre-menopausal women with significant menstrual abnormality should be investigated by endometrial biopsy with or without hysteroscopy.

Further investigations

Once a diagnosis of endometrial cancer is made, further investigations are indicated to stage and assess fitness for definitive treatment.

• Blood – full blood count, biochemistry and serum CA-125 (raised in extrauterine spread especially in USPC).

• Chest X-ray.

• Magnetic resonance imaging (MRI) (Figure 13.4) – is the imaging of choice to assess the depth of myometrial invasion, and lymph node metastasis.

• CT scan of abdomen and chest is indicated for patients with high risk of distant metastasis such as stages II–IV and histologic types of clear cell, UPSC, and carcinosarcomas.

• PET scan – is not sufficiently sensitive to assess lymph node involvement (60–69%) and therefore at present has no role in the staging of endometrial cancer.

• Examination under anaesthesia (EUA) – when locally advanced tumour is suspected following clinical or radiological examination, EUA is indicated to determine operability.

Figure 13.4 MRI in endometrial cancer. Sagittal T2-weighted (A) and sagittal dynamic contrast enhanced T1-weighted (B) images in a patient with stage 1B endometrial carcinoma demonstrate a large endometrial tumour (E) which is invading the outer myometrium (black arrows). The tumour is extending to the endocervix, but the cervical stroma (white arrows) is intact.

Courtesy of Dr. E Sala, University of Cambridge.

Staging

The FIGO postoperative surgico-pathological staging system is given in Box 13.6.

Box 13.6
FIGO staging of endometrial cancer

Stage I * Tumour confined to the corpus uteri (includes endocervical gland involvement)

IA No or less than half myometrial invasion

IB Invasion equal to or more than half of the myometrium

Stage II Tumour invades cervical stroma, but does not extend beyond the uterus

Stage III Local and/or regional spread of the tumour

IIIA Tumour invades the serosa of the corpus uteri and/or adnexae **

IIIB Vaginal and/or parametrial involvement **

IIIC Metastases to pelvic and/or para-aortic lymph nodes **

IIIC1 Positive pelvic nodes

IIIC2 Positive para-aortic lymph nodes with or without positive pelvic lymph nodes

Stage IV Tumour invades bladder and/or bowel mucosa, and/or distant metastases

IVA Tumour invasion of bladder and/or bowel mucosa

IVB Distant metastases, including intra-abdominal metastases and/or inguinal lymph nodes

^* Grade 1–3.

^** Positive cytology does not change stage, but reported separately.

Prognostic factors

The most important prognostic factors are stage, age, depth of myometrial invasion >50%, grade 3, serous or clear cell histology and lymphovascular invasion (LVI). Table 13.3 shows the 5-year survival rate according to stage and grade.

Table 13.3 5-year survival rate by stage and grade

Endometrioid cancer presents more commonly with stage I and II (86%) than serous papillary (57%) or clear cell (70%). However, serous papillary and clear cell carcinomas have a poorer prognosis even after their stage at presentation is taken into account (see Table 13.4).

Table 13.4 5-year relative survival rates for endometrial carcinoma according to histology

Treatment (Figure 13.5)

Stage I disease

Surgery

Total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH-BSO) and peritoneal washings for cytology is the treatment of choice. Vaginal hysterectomy (LAVH) can be considered in some patients.

Figure 13.5 Management of endometrial cancer.

Controversy exists over the role of staging lymphadenectomy for stage I endometrial cancer. Grade and myometrial invasion are important determinants of lymph node involvement in stage I cancer. For grade 3 tumours, the risk of lymph node involvement is 15%, and for those with more than invasion of the myometrium, the risk is approximately 25%. With both these factors, there is a 34% risk of pelvic node involvement, and a 24% risk of aortic node involvement. North American practice is to perform routine bilateral pelvic lymph node dissection (BPLND) with or without para-aortic lymphadenectomy but there is no clear evidence that lymphadenectomy improves survival. The initial results of the ASTEC trial comparing pelvic lymphadenectomy with no lymphadenectomy in mostly stage I disease showed similar survival and progression free survival with both approach and hence the UK practice is to perform lymph node sampling of clinically suspicious nodes only. The rationale being patients with micrometastases will be identifiable as having a high risk of locoregional relapse and these patients can be stratified to receive radiotherapy. Some UK centres perform lymphadenectomy in stage I patients with a high risk of locoregional relapse, and omitting External beam radiotherapy (EBRT) to those with uninvolved nodes.

Staging lymphadenectomy is useful for better risk stratification of stage I patients with high-risk disease and significant co-morbidity, e.g. inflammatory bowel disease which would increase the risk of radiation related morbidity.

Adjuvant radiotherapy (Box 13.7)

Meta-analyses show that EBRT reduces locoregional recurrence in stage I endometrial cancer by 72% but does not have any benefit on survival. Three quarters of locoregional recurrences are restricted to the vagina, and most of these are curable with vaginal radiotherapy. However, it is important to define the risk of loco-regional recurrence to choose patients for adjuvant pelvic radiotherapy is to prevent uncontrolled pelvic disease and to prevent stress and morbidity associated with a diagnosis and treatment of a relapse. A general consensus is that radiotherapy is considered only if the risk of relapse is >15% (see Box 13.8). Role of adjuvant radiotherapy in patients with intermediate risk remains controversial. In this group, PORTEC-1 identified a subgroup of patients (those aged more than 60 years with 1C or G3 disease) who have an 18% risk of locoregional relapse. The GOG 33 study identified lymphovascular invasion (LVI) as a significant poor prognostic factor for locoregional relapse (HR = 2.4, p = 0.005) Most centres in the UK include LVI as a high risk factor, and would offer patients adjuvant EBRT +/− brachytherapy to patients with 1C or G3 disease if they were either >60 or had LVI, sometimes described as high-intermediate risk. Early results of PORTEC-2 trial suggest that vaginal brachytherapy (BT) alone may be sufficient for this group of patients.

Box 13.7
Radiotherapy for endometrial cancer

Side effects

EBRT

• Bowel symptoms (22%) – abdominal cramps, urgency and frequency of stool, and diarrhoea

• Bladder toxicity: reduced capacity, urgency, recurrent infections and minor incontinence

• Vaginal narrowing (4%)

• Bone toxicity (1%)

Brachytherapy

Temporary diarrhoea and urinary irritation (9% each), transient vaginal mucositis (17%), vaginal cuff telangiectasia (14%), vaginal atrophy, stricture or adhesions (16%), and dyspareunia (5%).

Box 13.8
Risk of locoregional relapse

A recent meta-analysis found a 10% statistically significant difference in disease free survival for high risk patients treated with EBRT vs. no treatment (80% vs. 69%). Hence all patients with 1CG3 disease should be offered adjuvant EBRT +/− vaginal brachytherapy.

In the UK, most patients will not have had a staging lymphadenectomy. For those with negative nodes but high risk disease the role of radiotherapy is uncertain. Many would treat patients with 1CG3 disease and >50% myometrial invasion with BT, while some would treat with EBRT +/− BT.

Adjuvant chemotherapy

The high risk of distant relapse for patients with 1CG3 disease suggests a possible role of adjuvant chemotherapy but the evidence is not clear. The incidence of distant metastases is reduced in women receiving chemotherapy compared with pelvic radiotherapy but chemotherapy does not prevent pelvic recurrence. The ongoing PORTEC-3 study randomizes between pelvic radiotherapy or pelvic radiotherapy with concurrent cisplatin followed by carboplatin/paclitaxel chemotherapy.

Stage II

For patients with cervical involvement (clinically or on MRI prior to surgery), a modified radical hysterectomy with bilateral lymph node dissection is indicated. This involves resection of a parametrial and paracervical tissue, and a cuff of 2 cm of upper vagina. Evidence show that radical hysterectomy results in an improved survival in stage II patients compared to standard hysterectomy (93% vs. 89% at 5 years). For patients with adequate tumour free margins and negative nodes there is no evidence that the addition of radiotherapy improved survival. Those with positive margins or involved nodes should receive adjuvant EBRT and BT.

For some patients, endocervical stromal involvement (stage II) will have been an incidental finding following simple hysterectomy for presumed stage I. These patients would normally receive adjuvant EBRT and BT. In practice, many patients are not fit enough for modified radical hysterectomy and these patients are treated with standard hysterectomy with adjuvant EBRT and BT. There is no proven role for adjuvant chemotherapy for stage II disease yet.

Stage III–IV

The optimal management of patients with advanced stage endometrial cancer is not well defined. Advanced stage endometrial cancers are a heterogeneous group and treatment needs to be individualized.

Surgery

Primary surgery should be considered for all fit patients with stage III disease in whom an optimal cytoreduction appears to be feasible. Several retrospective studies suggest that optimal tumour cytoreduction may improve survival. The definition of optimal cytoreduction varies in different studies from no macroscopic disease to <2 cm. One study found a 5-year survival of 41% in patients with stage III disease had a complete resection of macroscopic tumour compared with 16% for those without. In cases of suspicious operability, a diagnostic laparoscopy should be carried out. In patients with borderline operability, primary radiotherapy may be used to improve chances of subsequent surgery.

Most stage IV tumours will not be considered operable. However, in a subgroup of stage IV patients where complete resection is feasible, a 25% long-term survival can be achieved.

Palliative hysterectomy is useful in controlling local symptoms such as bleeding or pain. Occasionally bowel or urinary diversion may be appropriate, although radiotherapy and/or platinum based chemotherapy may also offer useful palliation.

Radiotherapy (Box 13.7)

Postoperative EBRT and BT should be carried out for patients with a complete macroscopic resection of stage III disease. Patients with stage IIIC disease involving the para-aortic or pelvic nodes may have extended field radiotherapy covering the para-aortic region. The likelihood of local control is related to disease volume. Although radiotherapy reduces the local recurrence rates, there are no data showing improved survival.

Patients with optimal debulking should also be considered for adjuvant chemotherapy based on the results of GOG 122 (see below) followed by radiotherapy for those with a complete clinical response.

For patients with inoperable stage III and IV disease, palliative radiotherapy is an option for local and distant symptom control.

Chemotherapy for Stage III–IV (Box 13.9)

Adjuvant chemotherapy

Adjuvant chemotherapy should be offered to patients with stage III/IV who have had a complete debulking, and may be considered for those with residual tumour <2 cm based on the GOG 122 trial. This phase III trial randomized patients with stage III/IV endometrial cancer, with less than 2 cm of residual disease (87% with no macroscopic disease) to whole abdominal radiation or doxorubicin and cisplatin chemotherapy. Chemotherapy significantly improved progression-free and overall survival compared with WAI. Progression free survival at 5 – years was 50% for those in the chemotherapy arm compared with 38% in the radiotherapy arm, and OS survival was 55% compared with 42% respectively (p < 0.01). Other studies have reported higher pelvic failure rate (40%) in patients with high-risk endometrial cancer treated with adjuvant chemotherapy alone. Hence current practice is to offer adjuvant pelvic radiotherapy in addition to chemotherapy.

Box 13.9
Chemotherapy regimes in endometrial cancer

• Carboplatin (AUC 5–7) IV d1 repeated 3-weekly

• Paclitaxel (Taxol) 175 mg/m² IV repeated 3-weekly

• Doxorubicin (Adriamycin) 60 mg/m² IV for 7 cycles + cisplatin (CDDP) 50 mg/m² IV repeated 3-weekly

• Carboplatin (AUC 5–7) IV d1 + paclitaxel 175 mg/m² IV d1 repeated 3-weekly

Palliative chemotherapy

Patients with unresectable disease may be treated with palliative chemotherapy or hormonal treatment. Generally patients with rapidly progressive or symptomatic disease are treated with chemotherapy, while those with slowly progressing or asymptomatic disease are treated with hormones. There is limited information available on quality of life or survival data.

The median overall survival for patients with metastatic endometrial cancer following chemotherapy is 6–12 months. The time to progression is generally 4–6 months. The most active single agents in advanced or recurrent endometrial cancer are anthracyclines, platinum and paclitaxel which have similar response rates of 20–35%. The most commonly used combination regimes are carboplatin and paclitaxel and (60–70% response from phase II studies), and cisplatin and Adriamycin (34% response).

Hormonal therapy

It is particularly useful for patients with slowly progressing or asymptomatic disease, and for those unfit for chemotherapy.

Progestogen

Oral progestogen treatment has a response rate of 15–20%. The median duration of response is four months, and survival is approximately 8 to 11 months. Patients with low-grade histology (37% response for G1 compared with 9% for G3), expression of oestrogen (ER) (29% response) and/or progesterone receptors (PR) (39% response) and a long treatment-free interval between initial diagnosis and recurrence have the highest probability of responding. Megestrol acetate is usually given initially at 160 mg daily. Medroxyprogesterone acetate 200–400 mg daily is an alternative. Side effects include weight gain and increased risk of thrombosis. There is no known benefit from using progestogens for adjuvant treatment.

Tamoxifen

Tamoxifen has an overall response rate of 10% and is not generally used as a single agent.

Gonadotrophin-releasing hormone (GnRH) analogues

GnRH analogues may provide benefit in progestogen-refractory advanced or metastatic disease. The response rate is up to 28%. Complete and partial responses to treatment are seen with monthly injections of goserelin acetate 3.6 mg giving a progression free-survival of several months.

Aromatase inhibitors

Reported response rates are approximately 10%. One phase II study reported a disease stabilization rate of 39% for a median of 6.7 months with 2.5 mg letrozole in patients with metastatic or recurrent endometrial cancer.

Recurrent disease

Approximately two-thirds of relapses will either be distant, or locoregional and distant. However the other third will be a pelvic recurrence, of which 75% will be the upper vagina, or ‘vaginal vault’.

For patients with a vault recurrence who have not previously received radiotherapy, radical radiotherapy is the treatment of choice (Box 13.8). Those patients who had previously received only BT can have EBRT with a boost if tumour is <0.5 cm. In the PORTEC-1 study 75% of patients with pelvic recurrence could be treated with curative intent and 85% achieved complete remission. The survival rate after relapse was 69% at 3 years in the control group compared with 13% in patients who had received EBRT up-front.

In single recurrence at the vaginal vault, or localized pelvic disease not extending to the sidewall after previous pelvic radiotherapy, surgery may offer a chance of cure. If the bladder and bowels are involved, then a large exenterative procedure may be required for complete resection. The surgical morbidity of exenteration is significant and is suitable only for selected patients, after metastatic disease has been carefully ruled out. Reported 5-year survival is up to of 50% with a complete cytoreduction.

Patients not suitable for salvage surgery or radiotherapy may be treated with systemic therapy.

Special situations

Serous papillary and clear cell carcinoma

Patterns of spread for uterine serous papillary carcinoma (USPC) are similar to epithelial ovarian carcinoma and 50% of recurrences occur in the abdomen alone. Clear cell carcinoma relapses occur more commonly in the pelvis and para-aortic nodes and less commonly in the abdomen than UPSC.

The principles of surgery for both these tumours parallel those for ovarian cancer (p. 198). Optimal therapy of early-stage papillary serous and clear cell carcinomas remains undefined. However the high relapse rates indicate that surgery alone is inadequate. Hence, all women with resected stage IB, IC, and II USPC or clear cell cancers may be offered platinum based chemotherapy (usually with carboplatin and taxol) with postoperative radiotherapy (EBRT+VBT, VBT or EBRT alone) in those with a complete clinical response. Most centres would also offer adjuvant chemotherapy and radiotherapy for stage IA serous papillary carcinoma in which there was any residual disease at hysterectomy following biopsy. Some centres consider whole abdominal radiation for UPSC because of the high rate of abdominal relapse, though the benefit has not been established.

Surgery and chemotherapy for stage III and IV UPSC and clear cell carcinoma is as for ovarian cancer. Radiotherapy is offered to those who have had a complete clinical response.

Synchronous cancers

Synchronous primary cancers of the ovary are found in 5% of patients with endometrial cancer. Management is the combined treatment for each separate cancer. Metastatic disease should be considered where the disease on the ovary is small volume, surface deposits, bilateral with multinodular implants and with lymphovascular invasion of the ovarian cortex.

Follow-up

There is no evidence for best follow-up. The majority of recurrences (80%) occur in the first 18 months to two years. A typical follow up schedule would be outpatient appointments three-monthly for two years, followed by six-monthly to 5-years with full history and physical examination (including pelvic) examination.

Cervical cancer

Introduction and aetiology

Cervical cancer affects 520,000 women each year worldwide. In the UK around 2900 women are diagnosed with cervical cancer per year which represents 2% of female cancer. It is the second most common cancer in women under 35 (after breast cancer). In the UK, the life time risk of developing risk of cervical cancer is 1 in 116.

There are a number of risk factors implicated in the development of cervical cancer such as sexual activity under the age of 20, smoking, immunosuppression, and infection with sexually transmitted diseases. Human papilloma virus (HPV) has emerged as the principal causative agent in the majority of cases of cervical cancer. The most frequent subtypes are 16 or 18.

Patterns of spread

From the cervix, the tumour may extend locally to the lower uterine segment, vagina, or into the paracervical spaces. It may become fixed to the pelvic wall by direct extension or due to regional adenopathy.

Cervical cancer follows a pattern of metastatic progression, initially to nodes in the pelvis and then para aortic nodes and distant sites. The most frequent sites of distant recurrence are lung, extra pelvic nodes, liver, and bone.

Presentation

Early invasive disease may be asymptomatic. The earliest symptom of invasive cervical cancer is usually abnormal vaginal bleeding, often post-coital. Pelvic pain may result from loco-regionally invasive disease. The triad of sciatic pain, leg oedema, and hydronephrosis is associated with extensive pelvic wall involvement. Patients with advanced disease may present with haematuria or symptoms of a vesicovaginal fistula. Cachexia, cough, jaundice, and a left supraclavicular nodal mass may occur with distant metastases.

Evaluation and staging

Pretreatment evaluation

• Examination under anaesthesia (EUA).

• FBC, and biochemistry to exclude anaemia and renal impairment.

• Biopsy for histological diagnosis.

• Chest X-ray.

• MRI pelvis (Figure 13.6) is useful in assessing tumour extent and nodal status.

• Cystoscopy/sigmoidoscopy/barium enema/IVU – if there is clinical suspicion of bladder, rectal or ureteric involvement.

• PET/CT has a role in accurate selection of patients for surgery as well as for treatment planning.

• CT scan chest, abdomen and pelvis are indicated in patient with clinically apparent stage IV disease.

Figure 13.6 MRI scan in cervical cancer. Sagittal (A) and axial (B&C) T2-weighed MRI in a patient with stage 2B squamous cervical cancer demonstrate a large cervical tumour (C) with bilateral parametrial invasion (black arrows) and bilateral enlarged external iliac lymph nodes (white arrows). Note the presence of cystic/necrotic changes within the right external iliac node (white arrow head) which is a common feature of squamous cell cervical cancer.

Courtesy of Dr. E Sala, University of Cambridge.

Staging

The FIGO staging is given in Table 13.5 which does not take into consideration the findings on imaging.

Table 13.5 FIGO cervical cancer staging

Stage I confined to the cervix (extension to the corpus disregarded)

IA Invasive carcinoma diagnosed only by microscopy

IA1 Stromal invasion of ≤3.0 mm in depth and extension of ≤7.0 mm

IA2 stromal invasion of >3.0 mm and not >5.0 mm with an extension of not >7.0 mm

IB Clinically visible lesions limited to the cervix uteri or pre-clinical cancers greater than stage IA

IB1 Clinically visible lesion ≤4.0 cm in greatest dimension

IB2 Clinically visible lesion >4.0 cm in greatest dimension

Stage II Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or to the lower third of the vagina

IIA Without parametrial invasion

IIA1 Clinically visible lesion ≤4.0 cm in greatest dimension

IIA2 Clinically visible lesion >4 cm in greatest dimension

IIB Parametrial invasion

Stage III

IIIA Tumor involves lower third of the vagina, with no extension to the pelvic wall

IIIB Extension to the pelvic wall and/or hydronephrosis or non-functioning kidney

Stage IV extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum

IVA Spread of the growth to adjacent organs

IVB Spread to distant organs

Management (Figure 13.7)

Choice of treatment is based on tumour size, stage, histology, evidence of lymph node involvement, risk factors for complications of surgery or radiotherapy, and patient preference.

Figure 13.7 Management of cervical cancer.

In situ disease (CIN III) can be treated by a number of methods (such as cone biopsy, laser therapy etc.) depending on the extent of disease, age of the patient, and requirement for fertility preservation.

Stage IA disease

Stage IA1

IA1 without lymphovascular invasion (LVI) the treatment options are:

• Cone biopsy or large loop excision of the transformation zone (LLETZ) if patient wishes to preserve fertility.

• Simple hysterectomy.

IA1 with LVI is managed with:

• Modified radical hysterectomy with pelvic node dissection or

• Radical trachelectomy with laparoscopic pelvic node dissection if fertility is desired.

Stage IA2

The treatment options are:

• Radical hysterectomy (type II) with pelvic node dissection (3–10% risk of node involvement).

• Radical trachelectomy with laparoscopic pelvic node dissection (if tumour <2 cm and no LVI) if fertility preservation is intended. The 5-year cumulative pregnancy rate was 52.8% with low cancer recurrence rate with this approach.

• Radiotherapy – brachytherapy alone (75–80 Gy equivalent to point A – Box 13.11) or with external beam pelvic in women who are not fit for surgery.

Box 13.11
Radiotherapy in cervical cancer

Principles of cervical cancer radiotherapy

Radical radiotherapy is aimed to delivery 80–90 Gy to point A and 50–60 Gy to point B using a combination of external beam radiotherapy (EBRT) and brachytherapy. Point A in anatomical terms is the point of crossing of uterine artery and ureters and for dosimetry, it is a point 2 cm from central line and 2 cm above ovoids. Point B is 3 cm lateral to point A and receives 20% dose of point A dose from intracavitary radiotherapy.

The maximum tolerated dose of pelvic EBRT is 50 Gy in 1.8–2 Gy per fraction. The rest of radiotherapy is delivered using brachytherapy. The total dose is based on conventional radium treatment over using a dose rate of 0.5 Gy/hour. When medium dose rate (MDR) of >1.5 Gy/hour is used, a 10% reduction of conventional dose is made to account for the reduced treatment time. With high dose rate (1.5 Gy/minute), this reduction is 40–45% from conventional dose.

Dose

When brachytherapy is not possible, additional EBRT (16–20 Gy in 8–10#) may be considered.

Parametrial boost – may be considered in patients with distal parametrial disease at the time of brachytherapy and some centres routines consider this for bulky parametrial disease. A parallel opposed field is used to deliver 6–10 Gy in 3–5 fractions. The medial edge of the half-beam blocked parametrial boost field is placed at the 70–80% brachytherapy isodose.

Figure 13.8 A,B – Treatment volumes for external beam radiotherapy in cervical cancer C,D – Brachytherapy dose distribution and dosimetric points (AR – right side point A, AL – left side point A, BR – right side point B, BL – left side point B, ICRU bladder – bladder point and ICRU rectum – rectal point).

Stage IB and IIA

Stage IB1 and IIA1 (<4 cm tumour)

The treatment options are between radical hysterectomy with bilateral pelvic node dissection or radical radiotherapy.

Surgery involves removal of the uterus, upper third of vagina, bilateral parametria, uterosacral, utero-vesical ligaments and bilateral pelvic lymph nodes. Para-aortic lymph node sampling is indicated if there is clinical suspicion of nodal involvement to plan radiotherapy fields. Radiotherapy is with external beam pelvic irradiation combined with intracavitary applications, which deliver a dose of equivalent to 80–85 Gy to point A (Box 13.11).

Patients with more than two involved pelvic nodes are usually offered postoperative radiotherapy.

Stage IB2 and IIA2 (>4 cm tumour)

The treatment options include:

• Radical hysterectomy and bilateral pelvic lymphadenectomy +/− adjuvant therapy as indicated.

• Concurrent chemoradiation (weekly cisplatin) – deliver 85–90 Gy to point A.

• Radical radiation therapy (when cisplatin is not suitable PS >2 and GFR <50 ml/min) (Box 13.11).

Adjuvant treatment

Adjuvant chemoradiation (EBRT with concurrent weekly cisplatin) is recommended after radical surgery if there are any risk factors such as positive nodes, positive parametria, or close (≤5 mm) or positive surgical margins. Adjuvant concurrent chemoradiation (using 5FU + cisplatin or cisplatin alone) improves survival compared with pelvic irradiation alone in these patients.

Patients with any two of the three factors of deep invasion of cervical stroma, lympho-vascular space invasion, or tumour size >4 cm are classified as intermediate risk. In these patients, adjuvant whole pelvic irradiation reduces the local failure rate and improves progression-free survival.

Concurrent chemoradiation

A recent meta-analysis of 2491 patients in 24 trials suggests that addition of concurrent chemotherapy to radical radiotherapy improves disease-free survival by an absolute 10% and overall survival by 13%. Hence concurrent chemoradiotherapy is the standard of care in patients who have no contraindications for cisplatin.

Stage IIB–IIIB

Concurrent chemoradiotherapy (weekly cisplatin during EBRT) is the treatment of choice. Using a combination of EBRT and brachytherapy a dose of 85–90 Gy to point A and 55–60 Gy to point B is given. Patients with common iliac nodes and para-aortic nodes are treated with extended field radiotherapy.

Stage IV

Stage IVA

The management of patients with stage IVA disease (invasion of bladder and/or rectum) has to be individualized. The treatment options include:

1 Neo-adjuvant chemotherapy or concurrent chemoradiotherapy.

2 Pelvic exenteration.

3 Palliative radiotherapy or chemotherapy.

4 Best supportive care.

A radical approach with neo-adjuvant chemotherapy or concurrent chemoradiotherapy is suitable for selected patients with good general and renal status and not suitable for surgical exenteration. Surgical exenteration is suitable for selected stage IV patients.

The majority of stage IVA patients are of poor performance status or with many co-morbidities and extensive local disease, and are best treated with palliative treatment (radiotherapy or chemotherapy). Patients with poor general health, or extensive local disease can be offered best supportive care.

Relapse in the pelvis following primary surgery may be treated by radiotherapy or pelvic exenteration. Radical radiotherapy (+/− concurrent chemotherapy) may cure a substantial proportion of those with isolated pelvic failure after primary surgery. Radiation dose and volume should be tailored to the extent of disease. Where disease is metastatic or recurrent in the pelvis after failure of primary therapy and not curable, a trial of cisplatin chemotherapy with palliative intent or symptomatic care may be considered. The expected median time to progression or death is three to seven months.

Recurrence after primary radiotherapy

Selected patients may be considered for pelvic exenteration, which is the only potentially curative treatment after primary irradiation. Those with resectable central recurrences that involve the bladder and/or rectum without evidence of intraperitoneal or extra pelvic spread and who have a dissectable tumour-free plane along the pelvic sidewall are potentially suitable. Surgery should be undertaken only in centres with appropriate facilities and expertise. The prognosis is better for patients with a disease-free interval greater than six months, a recurrence 3 cm or less in diameter, and no sidewall fixation. The 5-year survival for patients selected for treatment with pelvic exenteration is between 30–60% and the operative mortality should be <10%.

Role of chemotherapy in distant metastasis and recurrent metastatic disease

Chemotherapy has a palliative role after failure of surgery or radiotherapy. There are a number of agents with activity in metastatic or recurrent cervical cancer. Cisplatin is the most active agent, with a response rate of 20–30% and a median survival of 7 months. Recent studies suggest that cisplatin in combination with paclitaxel or topotecan is superior than cisplatin alone.

Treatment toxicities

Significant surgical complications are uretero-vaginal fistula (<2%) and vesicovaginal fistula (<1%). The risk of complications increases with addition of radiotherapy. Extensive pelvic fibrosis can lead to ureteric obstruction and small bowel obstruction.

The late sequelae following radiation therapy commonly affect the rectum, bladder and small bowel. These depend on the duration of follow-up, type of treatment modalities and estimated radiation doses to these organs. The reported grade III/IV late sequelae range from 5–15%.

Palliative care

Palliative care issues include pelvic pain, bleeding, bone pain from metastases and systemic symptoms for advanced cancer.

Follow-up

Optimal follow-up strategy has not been established. A general guideline is for clinical evaluation three monthly for one year, four-monthly for one year, 6-monthly for three years and then annually. Patients are advised to have annual chest X-ray. Other investigations are dictated by clinical indications.

Screening

The main goal of screening is to reduce the incidence and mortality. Screening has been shown to be an effective method of identifying pre-neoplastic disease and reducing mortality. Cervical Cytology (Pap Smear) Screening programs have been found to be successful in reducing cervical cancer incidence. In the UK, women aged 25 years receive the first invitation for screening, those aged 25–49 years have 3 yearly screening, those aged 50–64 years have 5-yearly and those above 65 years have screening test only if they have not had screening since 50 years or have had a recent abnormal test.

Prevention

HPV vaccines have been shown to reduce the number of further pre-invasive lesions and invasive disease in young women with pre-invasive lesions. In the UK, there is a national programme to vaccinate girls aged 12–13 against HPV.

Ovarian germ cell tumours

Introduction and aetiology

Ovarian germ cell tumours (GCTs) have a peak incidence at 15–19 years, due equally to dysgerminoma and teratoma, and a second at age 65–69 mainly due to teratoma. They account for less than 5% of all ovarian malignancies in Western countries, and up to 15% of ovarian cancers in Asian and black patients.

The cause is unknown. Less than 5% are associated with dysgenetic ovaries (unlike their testicular counterparts). The oral contraceptive pill does not confer a protective effect in germ cell tumours as it does in the epithelial ovarian cancers.

Pathology

GCTs are classified as dysgerminomas or non-dysgerminomas based on their origin in primordial germ cells and their ability to differentiate in vivo. Dysgerminomas are the ovarian counterpart of seminomas, whereas the non-dysgerminomatous tumours include all other germ cell tumours and encompass a wide range of differentiated cell types.

• Dysgerminoma – is the most common (30–40%) malignant germ cell tumour. It has the highest rate of bilaterality (10–15%) and is the commonest (20–30%) malignant GCT associated with pregnancy.

• Non-dysgerminoma – composed of immature teratoma, endodermal sinus tumours (yolk sac carcinoma), embryonal carcinoma, non-gestational choriocarcinoma, polyembryoma and mixed germ cell tumour.

• Immature teratoma (20%) – is sometimes associated with miliary peritoneal implants composed exclusively of mature glial tissue (called gliomatosis peritonei).

• Endodermal sinus tumour or EST (also called yolk sac tumour – YST) (20%). It usually presents as stage I disease, but rapidly growing with more than 50% of the patients reporting symptoms of less than one-week duration. These tumours invariably express alpha-fetoprotein (AFP). Intraperitoneal spread predominates in this tumour.

• Embryonal carcinoma (3%) – is often associated (60%) with abnormal hormonal manifestations of precocious puberty, irregular bleeding, amenorrhea, or hirsutism due to β-hCG stimulation. It can produce both AFP and β-hCG.

• Mixed germ cell tumours (7%) are composed of at least two different germ cell elements of which at least one is primitive. The most frequent combination is dysgerminoma and EST followed by dysgerminoma and immature teratoma.

Clinical features

Abdominal pain (87%) is the most frequent symptom followed by abdominal mass (85%), but 10% may present with acute abdomen due to torsion, haemorrhage or rupture of the ovarian tumour. Abdominal distension, fever and vaginal bleeding each occur in 10%. Ascites is present in 20% of cases.

The two specific markers for GCTs are beta-human chorionic gonadotrophin (β-hCG) and alpha-feto protein (AFP). Up to five percent patients with dysgerminoma can have an elevated β-hCG, which gives rise to a positive pregnancy test in 3% of patients. An elevated AFP or a β-hCG level of >100 IU/L indicates the presence of nondysgerminomatous elements.

Most endodermal sinus tumours secrete AFP. Embryonal carcinomas can secrete both AFP and β-hCG whereas tumour markers are negative in pure immature teratomas.

Other markers include lactate dehydrogenase (LDH) levels in dysgerminomas (88% have raised serum LDH isoenzyme-10) and placental alkaline phosphatase (PLAP) – raised in >95% of dysgerminomas. More than 50% of GCTs express CA-125 but its role in clinical management not known.

Imaging

Dysgerminomas and non-dysgerminomas exhibit different radiological features. On CT (Figure 13.9) and MRI dysgerminoma shows multiloculated solid mass divided by fibrovascular septa. There can be associated abdominal lymphadenopathy. Calcification is rare in dysgerminoma but when present it appears as a speckled pattern.

Figure 13.9 Dysgerminoma of the ovary. Contrast-enhanced CT scan shows a large, multilobulated solid mass with highly enhancing fibrovascular septa (arrows) and cystic change (arrowheads).

Non-dysgerminomas are usually unilateral mixed solid and cystic mass. On CT and MRI, there may be a heterogeneous enhancement due to haemorrhage or necrosis. Calcification occurs in up to 40% of the cases.

There are so far no studies examining the role of PET scans in ovarian GCTs, however, in future, it may have the similar clinical application as that of testicular germ cell tumours.

Principles of surgery follow that of the epithelial ovarian cancer. However, since this disease predominantly affects the young females, conservative surgery to preserve fertility is preferred and the minimal surgery is unilateral oophorectomy. Even in advanced stage (20–30%), the contralateral ovary, fallopian tube and uterus may be left in situ to preserve fertility, and postoperative chemotherapy is given. Although the role of maximal cytoreduction is less defined than for epithelial ovarian cancer, all obvious metastases should be debulked or removed if possible. Even if BSO is necessary, the uterus can be left behind for future assisted reproduction. Routine biopsy of a normal looking contralateral ovary is not advised due to the risk of infertility from peritoneal adhesion or ovarian failure. The role of routine lymphadenectomy is yet to be established.

Secondary cytoreduction and second look laparotomy

A small study suggests that there may be a possible role for secondary debulking in chemo-refractory patients with immature teratoma. Routine second-look surgery is not recommended because of the low incidence of positivity after combination chemotherapy. However, a second-look procedure may be recommended for the subset of patients with a teratoma component in the primary tumour and persistent radiologic abnormalities along with normal serum tumour markers at the end of chemotherapy.

Postoperative management

Dysgerminoma

Adequately staged FIGO IA dysgerminoma has long-term survival of more than 90%, and these patients are observed without any postoperative treatment. The recurrences (rate of 15–25%) in these patients can be effectively salvaged with chemotherapy. All other patients need adjuvant treatment after maximal debulking with or without fertility preservation.

Completely resected stage IB–III and those without staging laparotomy are treated with three courses of standard chemotherapy with BEP regime (Box 13.12). Disease-free survival of completely resected dysgerminoma is very high, approaching 100% and that of advanced disease is in the range of 60–80%. Incompletely resected stage II–IV are treated with 3–4 courses of BEP.

Rarely, radiotherapy may be an option for women with other co-morbid conditions preventing chemotherapy administration or those who decline chemotherapy. Whole abdominal radiotherapy is used which leads to loss of fertility.

Non-dysgerminoma

Surgery alone is adequate for properly staged FIGO Stage IA grade I immature teratoma, which has 80–85% long-term disease-free-survival. All other groups of patients with non-dysgerminoma should receive postoperative chemotherapy.

The optimal number of courses of chemotherapy for GCT is unclear, unlike testicular tumours. One GOG study had shown that three courses of BEP will nearly always prevent recurrence in well-staged patients with completely resected ovarian germ cell tumours. However, those with a raised tumour marker but with no measurable disease should receive two more courses of chemotherapy after normalization of serum markers and those with bulky residual tumour may need 5–6 courses.

The role of carboplatin in place of cisplatin is undergoing clinical trials.

Recurrence

The role of surgery in the management of recurrence has yet to be established. One study reported better survival for patients with immature teratoma who underwent salvage surgery than of those with other tumour cell types.

There is no clear standard for treatment of relapsed ovarian germ cell tumour. Based on experience of testicular tumours, ovarian GCTs can also be divided into those which are platinum resistant and those which are platinum sensitive. Platinum resistant tumours are defined as progressive disease during treatment or during 6–8 weeks of stopping treatment. Prognosis in these cases is dismal and high dose chemotherapy or experimental drugs are advocated. Platinum sensitive tumours are defined as relapses occurring after 6–8 weeks of discontinuation of treatment. Prognosis in these cases is good. They are treated with platinum containing salvage chemotherapy regimens such as VeIP or TIP (Box 13.12).

Prognosis and survival

In spite of high cure rates, 12–20% of patients still die of this disease. Poor prognostic factors include advanced stage, bulky residual disease after surgery, age >22 years, endodermal sinus tumour and AFP of >1000 ng/ml at diagnosis.

In stage I dysgerminoma the long term survival approaches 100%. The stage-wise overall survival long-term survival is stage I 100%, stage II 85%, stage III 79% and stage IV 71%.

Follow-up and survivorship

The majority of case relapses occur within the first two years after completion of treatment, although dysgerminoma can relapse late. Initial follow up should be every 2–3 months for 1–2 years then 3–4 months up to 3 years after which 6-monthly to 5 years. Dysgerminomas should be followed up to 10 years. For those who had raised markers at the time of presentation, these should be followed every 2 months for the first year and 3-monthly for the second year, preferably alongside clinical follow-up. Regular imaging depends upon the nature of the previous tumour. With the risk of radiation from regular CT scanning, USS or MRI is advocated in most cases. Patients without raised markers should be scanned alongside their clinical follow-up.

Limited experience suggests that future fertility is not significantly affected by previous treatment for GCTs and there are no reports of adverse outcome or increased malformations in the fetus.

Future directions

Due to the success of treating most cases, current developments are in optimizing treatment for relapsed disease. This includes high dose chemotherapy.

Sex cord stromal tumours

Ovarian sex cord stromal tumours comprise 5–8% of all primary ovarian tumours. These tumours are generally low grade with no associated BRCA mutations. Many tumours produce steroid hormones and present with features of oestrogen or androgen hypersecretion. These are classified as granulosa cell tumours, thecoma-fibroma, Sertoli–Leydig cell tumours and gynandroblastoma. Inhibin, a protein secreted by these tumours, can be used as a diagnostic marker, particularly for granulosa cell tumour. These tumours are staged similar to epithelial ovarian cancers.

Granulosa cell tumour

There are two subtypes:

• Adult type – 95% of tumours occur in 5th decade of life.

• Juvenile type – 5% of tumours occur in children and young women.

These tumours usually present with large masses with features of increased oestrogen production. These can be associated with endometrial hyperplasia and adenocarcinoma. TAH-BSO is the treatment of choice in those who have completed their family. Unilateral salpingo-oophorectomy is an option for young women with stage I disease. Role of adjuvant chemotherapy after surgery is unknown. The approaches vary from routine chemotherapy for stage II–IV to no treatment until recurrence. Retrospective data suggests that adults with stage III–IV disease have a better progression free survival with adjuvant chemotherapy. The most commonly used chemotherapy is BEP (p. 223). Alternative options include combinations of carboplatin with paclitaxel and cisplatin with etoposide.

Patients with recurrent localized disease may undergo salvage surgery if feasible; otherwise treated with chemotherapy. Radiotherapy may have a role in patients with isolated inoperable pelvic recurrence.

5-year survival of completely resected stage I disease is >90% and advanced stage is 30%. Late relapses are not unusual.

Fibroma/thecoma

Fibromas are treated with oophorectomy, while thecomas are treated with either conservative surgery or TAH-BSO.

Sertoli–Leydig cell tumours

The majority of these tumours (75%) occur in women aged less than 40 years. These can be either benign or malignant (<20%) and only 2–3% have extra-ovarian disease at presentation. The presentation is with abdominal pain or distension or with features of virilization. TAH-BSO is the treatment of choice and conservative surgery is attempted when fertility preservation is intended. The benefit of adjuvant chemotherapy is not known. 5-year survival is 70–90%. Patients with recurrent and metastatic disease are treated with platinum based chemotherapy (usual regime is BEP).

Gynandroblastomas

These are very rare benign mixed tumours with elements of Sertoli–Leydig or granulosa cell elements. Presentation can be either with features of virilization or increased oestrogen production. Unilateral oophorectomy is the treatment of choice.

Gestational trophoblastic disease

Introduction

Gestational trophoblastic disease (GTD) is a rare complication of pregnancy. The gestational trophoblastic tumours include invasive mole, choriocarcinoma and placental site trophoblastic tumour (PSTT). 15% of complete moles develop into an invasive mole and around 3% of complete moles may develop into choriocarcinomas. Risk factors include age (<16 and >40 years), previous molar pregnancy and Asian origin.

Pathology

Persistent GTD can occur after any pregnancy. Invasive mole is composed of diffuse trophoblastic hyperplasia invading underlying tissues. Choriocarcinoma is characterized by absence of chorionic villi with sheets of anaplastic cyto- and syncytiotrophoblasts. PSTT is composed mainly of intermediate trophoblasts.

Clinical features

Up to 20% of patients present with persistent trophoblastic disease after surgical evacuation. The usual presentation is irregular vaginal bleeding and/or persistently elevated serum beta-hCG. Metastatic disease can occur in 4% of patients. The commonest site of metastasis is lung followed by vagina, CNS, liver and pelvis and presentation depends on the site of disease.

All women are followed up with serum beta-hCG estimation after evacuation of a molar pregnancy to identify persistent disease. 5–10% women may need chemotherapy for persistent GTD. The indications for chemotherapy are shown in Box 13.13.

Box 13.13
Indications for chemotherapy in persistent trophoblastic disease

• Serum hCG >20,000 iu/l after one or two uterine evacuations

• Static or rising hCG levels after one or two uterine evacuations

• Persistent hCG elevation six months post-uterine evacuation

• Persistent vaginal bleeding with raised hCG levels

• Pulmonary metastasis with static or rising hCG levels

• Metastasis in liver, brain, or GI tract

• Histological diagnosis of choriocarcinoma

Assessment prior to chemotherapy

Investigations

Patients need further investigations with FBC, biochemistry, serum beta hCG, chest X-ray and CT scan of thorax and CNS staging in high risk patients (WHO score of ≥7, high risk score, multiple lung metastases and hCG >50,000 iu/l). CNS staging consists of imaging the craniospinal axis and CSF examination (ratio of CSF: serum hCG > greater than 1 in 60 suggests involvement).

Staging and prognostic scoring

FIGO staging (Box 13.14) is mainly used to compare outcome data and the scoring system (Table 13.6) guides treatment. Low risk disease is defined by a total score of ≤6 and high risk score ≥7.

Box 13.14
FIGO staging of GTD

• Stage I – Disease confined to uterus

• Stage II – disease beyond uterus but confined to genital structures

• Stage III – lung metastasis with or without genital tract involvement

• Stage IV – distant metastasis other than lung

Table 13.6 FIGO-WHO prognostic scoring

Treatment

Low-risk disease (score ≤6)

Single agent chemotherapy is the treatment of choice and the commonly used agents are methotrexate and dactinomycin (Box 13.15). Methotrexate does not cause alopecia. Around 10–20% patients do not respond to methotrexate, and salvage treatment options are single agent D-actinomycin (if hCG level is low) or combination chemotherapy (if hCG level is high) (Box 13.15). Selected patients are salvaged with hysterectomy.

Patients with CNS disease are treated with chemotherapy with or without surgery or radiotherapy. Modifying EMA/CO chemotherapy with an increased dose of systemic methotrexate and with the addition of intrathecal methotrexate may improve the dose of methotrexate in CNS.

Placental site trophoblastic tumour (PSTT)

PSTT is less chemosensitive than other GTDs and hence hysterectomy is the treatment of choice for disease limited to uterus. Metastatic PSTT is treated like high risk GTD.

Assessing response to treatment and number of courses of chemotherapy

In patients receiving chemotherapy for low-risk disease, patients are closely monitored after one course of chemotherapy with weekly hCG. Further treatment is withheld as long as serum hCG is falling. A second course of treatment is indicated if the hCG levels are stationary for three consecutive weeks, re-elevates or does not decline by one logarithmic fall within 18 days of completion of the first treatment. If a second course of chemotherapy is necessary, the same treatment is given if there was an adequate response to previous treatment. An adequate response is defined as at least a logarithmic fall in hCG after a course of chemotherapy. If the response is not adequate, another single agent chemotherapy or combination chemotherapy is given. There is no consensus on when to stop chemotherapy after biochemical remission. Many patients receive 1–3 cycles of chemotherapy after biochemical remission, depending on the risk category and the rate of reduction of hCG.

Follow-up and survivorship

Patients need regular follow-up after completion of treatment. Women are advised not to conceive for at least 12 months after completion of their treatment. Women are advised not to take the oral contraceptive pill until hCG is normal.

There is no evidence that treatment for a previous GTD affects future pregnancy and its outcome. Chemotherapy generally results in an early menopause such that patients are advised to complete their families before the age of 35. There is also a risk of second tumours such as AML.

Vulval cancer

Introduction

Vulval cancer is rare, with 1022 new cases being diagnosed in the UK each year. It predominantly affects older women, with 80% of cases occurring in those over 60. HPV (mainly 16, 18 and 31) has been found to be responsible for approximately 30–50% of vulval cancers and up to 80% of vulval intraepithelial neoplasias (VIN). There is also an increased risk in those with HIV as well as those on immunosuppressions. Other risk factors include smoking and chronic skin conditions such as lichen sclerosus (a 4–7% risk of malignancy), lichen planus and Paget’s disease.

Pathology

There are two varieties of intraepithelial neoplasia: squamous cell carcinoma-in-situ (Bowen’s disease) or vulvar intraepithelial neoplasia III and Paget’s disease.

The majority (90%) of vulval cancers are squamous cell (SCC) in origin, however, melanomas (4%), basal cell carcinomas, adenocarcinomas (1–2%), undifferentiated carcinomas, sarcomas (<2%) and metastatic tumours from a variety of primary sites also occur. Verrucous SCC carcinomas are a slow growing type of squamous cell carcinoma.

Patterns of spread

Vulval cancer spreads by direct extension to involve adjacent structures such as the vagina, urethra and anus, by lymphatic channels to the inguinal and femoral groin nodes, and haematogenously to distant sites including the lungs, liver and bone. The overall incidence of lymph node metastases is approximately 30%. Haematogenous spread tends to occur late, and is rare in the absence of nodal metastases.

Clinical features

The most common symptoms include itch or irritation, pain and soreness, a thickened, raised area of discolouration, ulcer, vaginal discharge or bleeding, or lump.

Diagnosis and staging

The size and location of the lesion should be documented, and any involvement of adjacent structures such as vagina, urethra, base of bladder or anus, should be noted. The diagnosis of vulval cancer is made after biopsy. Vulval cancer is staged using the FIGO classification (Box 13.16).

Box 13.16
FIGO staging of vulval cancer

Stage I – Tumour confined to the vulva

• IA – Lesions ≤2 cm in size, confined to the vulva or perineum and with stromal invasion ≤1.0 mm, no nodal metastasis

• IB Lesions >2 cm in size or with stromal invasion >1.0 mm

Stage II – Tumour of any size with extension to adjacent perineal structures (

lower urethra,

lower vagina, anus) with negative nodes.

Stage IV – Tumour invades other regional (

upper urethra,

upper vagina), or distant structures.

• IVA Tumour invades any of the following:

(i) upper urethral and/or vaginal mucosa, bladder mucosa, rectal mucosa, or fixed to pelvic bone, or

(ii) fixed or ulcerated inguino-femoral lymph nodes

• IVB – Any distant metastasis including pelvic lymph nodes

Management (Figure 13.11)

Early-stage disease (Stages I and II)

Surgery is the treatment of choice which involves a wide and deep resection (radical local excision) to obtain surgical margins of at least 1 cm. All patients except stage Ia (depth of penetration <1 mm when the risk of node metastasis is <1%) need an ipsilateral inguinofemoral lymphadenectomy to reduce the risk of recurrence. Bilateral lymphadenectomy is indicated if the tumour is within 1 cm of midline or involving labia minor. Postoperative bilateral pelvic and groin irradiation is indicated in the following setting:

• One macrometastases (>5 mm in diameter).

• Two or more micrometastases (≤5 mm).

• Extracapsular spread.

Figure 13.11 Management of vulval cancer.

Radiotherapy field should include inguino-femoral nodes and at least pelvic nodes below the SI joints. Microscopic disease needs 50 Gy in 1.8–2 Gy per fraction, 60 Gy for extracapsular spread or multiple nodes and 60–70 Gy for macroscopic disease.

Advanced disease

If it is possible to resect the primary lesion with clear margins and without the need for a bowel or urinary stoma, primary surgery is desirable. Surgery involves radical vulvectomy, bilateral groin node dissection and pelvic exenteration, or ano-vulvectomy with formation of end colostomy. The overall 5-year survival rate in women with locally advanced disease treated by radical ano-vulvectomy has been reported to be 62%. Postoperative radiotherapy is indicated if the margin is <5 mm and re-excision is not feasible.

Primary radiotherapy is the treatment of choice in those women with larger, more advanced lesions involving bladder or rectum, or who are considered unsuitable for surgery. Nodal disease may be dissected prior to management of primary tumour. Initial treatment involves 50 Gy at 1.7–1.8 Gy per fraction to include pelvis, inguinal nodes and primary tumour. The second phase of treatment is to the gross disease to deliver a total dose of 60–70 Gy. The exact role of the combination of chemotherapy (cisplatin alone or in combination with 5-FU) with radiotherapy is not fully explored.

Prognosis

Prognosis depends on nodal status and the size of the primary lesion. In the absence of lymph node involvement, the 5-year survival is >80%. This decreases to approximately 50% with inguinal node involvement, and to 10–15% with pelvic node metastases.

Post-treatment issues

Lymphoedema is a late complication, with an incidence of 62–69% following groin node dissection. When it occurs, the onset of lymphoedema is apparent within three months in 50% of women, and within 12 months in 85% of women.

Complications following radiotherapy include vulval soreness, skin blistering, diarrhoea, urinary frequency, and the formation of fistulae (recto-vaginal, vesico-vaginal and entero-vaginal). The incidence of developing lower limb lymphoedema is also greater in those women who have been treated by surgery including lymphadenectomy, and adjuvant radiotherapy (groin and pelvis).

Recurrence and management

15 and 33% of vulval cancers recur and the most common sites of recurrence are the vulva (69.5%), groin nodes (24.3%), the pelvis in 15.6% and distant metastases in 18.5%.

Local vulval recurrences are treated by surgery when possible. Groin recurrences are more difficult to manage. Radiotherapy is the preferred treatment, but surgery should be considered in patients who have already received groin irradiation.

Cancer of the vagina

Introduction

Primary vaginal cancer constitutes 2% of female genital tract cancers, and 240 new cases are diagnosed annually in the UK. It causes approximately 100 deaths in the UK each year.

Aetiology

The incidence of vaginal cancer is greatest in women between the ages of 60–70 years, with more than 70% of cases occurring in this group. Risk factors include fetal exposure of diethylstilboestrol (vaginal clear cell carcinoma), persistent HPV infection especially 16, a history (in up to 30%) of in-situ or invasive cervical cancer treated in the preceding 5-years, and a previous history of chronic vaginal irritation, use of ring pessaries, and previous treatment with radiotherapy. Vaginal cancer is also common in less well educated women, those with lower income, with five or more lifetime sexual partners, an early age at first intercourse, and smokers.

Pathology

The common histologic types are:

• Squamous cell carcinoma – 80% of vaginal cancers are due to direct extension of adjacent tumours (e.g. cervical) or metastases (e.g. endometrial) and 20% originate in the vagina, the most common histological type is squamous cell (over 90% of cases).

• Adenocarcinoma – tends to occur in women over the age of 50, with the exception of clear cell carcinoma. Clear cell adenocarcinoma is rare, almost always associated with an exposure to diethylstilboestrol in utero, and most commonly presents between 17 and 22 years of age.

• Papillary adenocarcinoma tends to arise from the connective tissue surrounding the vagina, and is less likely to spread via the lymphatics.

• Adenosquamous carcinomas (2%) tend to be more aggressive.

• Malignant melanomas of the vagina (2%) – develop in women in the 5th decade of life, and in the lower third of the vagina.

Presentation

Patients generally remain asymptomatic (20%) in both the pre-invasive and early stages of vaginal cancer, and early lesions are most commonly detected during routine cervical screening. 80–90% of women will present with bleeding, discharge, dyspareunia, vaginal irritation, or a vaginal mass. In more advanced disease, women may also complain of pelvic pain, constipation, difficulty in micturition and lower limb oedema.

Diagnosis and staging

The diagnosis of primary vaginal cancer is made by histology and clinical examination. Tumours extending to the external cervical os are classified as cervical cancers, while tumours involving the vulva as vulval cancers. MRI scan is useful in assessing local extension of tumour. FIGO staging for vagina is given in Box 13.17.

Box 13.17
FIGO staging of vaginal cancer

Stage I	Tumour limited to vaginal wall
Stage II	Tumour involving the subvaginal tissue but not extending to pelvic side wall
Stage III	Tumour extending up to pelvic side wall
Stage IVa	Spread to adjacent organs and/or direct extension beyond true pelvis
Stage IVb	Distant