Invasive cervical cancer is generally a disease of low socioeconomic groups, with a mean age at diagnosis of 52 years. Many epidemiological risk factors have been implicated in its development and these include early age at coitarche, multiple sexual partners and smoking. Infection with human papilloma virus (HPV) has been strongly implicated as a causative agent.
Squamous cell carcinomas account for about 80% of all invasive cervical cancers and adenocarcinomas and mixed tumours (adenosquamous) the bulk of the rest. Less frequently encountered cell types include small cell (neuroendocrine), adenoid basal, adenoid cystic, primary melanoma, sarcoma and primary lymphoma. Squamous and adenocarcinomas should be treated in a similar fashion.
Early lesions may be asymptomatic and are usually detected on routine Pap testing. Common symptoms include post coital, intermenstrual or post-menopausal bleeding. Offensive vaginal discharge may also be present. Pain, bladder and bowel symptoms, weight loss and bone pain may occur in advanced disease.
Confirmation of suspected cervical cancer is by way of cervical biopsy. For a small or occult lesion cone biopsy will be needed whereas for an obvious lesion a cone biopsy should be avoided, rather an incisional wedge biopsy should be performed.
Staging is by the clinically based FIGO system. A stage is assigned after a vaginal pelvic examination, cystoscopy, sigmoidoscopy and biopsy have been performed. Limited radiological examinations are allowed in the determination of the stage. The findings derived from a CT scan are not allowed to influence the assignment of stage. The value of the FIGO system is to compare results between institutions using either radiotherapy, radical surgery or a combination of both as primary therapy. The limitations of this system are obvious to those whose therapy is predominantly surgical.
The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded)
IA Invasive carcinoma which can be diagnosed only by microscopy, with deepest invasion < 5mm and largest extension < 7mm
IA1 Measured stromal invasion < 3.0mm in depth and extension of < 7.0mm
IA2 Measured stromal invasion of > 3.0mm and not > 5.0mm with an extension of not > 7.0mm IB Clinically visible lesions limited to the cervix uteri or pre-clinical cancers greater than stage IA*
IB1 Clinically visible lesions < 4.0 cm in greatest dimension
IB2 Clinically visible lesion > 4.0 cm in greatest dimension
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 lesions < 4.0 cm in greatest dimension IIA2 Clinically visible lesion > 4.0 cm in greatest dimension IIB With obvious parametrial invasion
The tumour extends to the pelvic wall and/or involves lower third of the vagina and/or causes hydronephrosis or non-functioning kidney**
IIIA Tumour 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
The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. Bullous oedema does not permit a case to be allotted to stage IV
IVA Spread of the growth to adjacent organs
IVB Spread to distant organs
*All macroscopically visible lesions-even with superficial invasion-are allotted to stage IB carcinomas. Invasion is limited to a measured stromal invasion with a maximal depth of 5 mm and a horizontal extension of not > 7mm. Depth of invasion should not be > 5mm taken from the base of the epithelium of the original tissue-superficial or glandular. The depth of invasion should always be reported in mm, even in those cases with “early (minimal) stromal invasion” (~1 mm)
The involvement of vascular/lymphatic spaces should not change the stage allotment
**On rectal examination, there is no cancer-free space between the tumour and the pelvic wall. All cases with hydronephrosis or non-functioning kidney are included unless they are know to be due to another cause
Spread patterns include initial local spread, followed by lymphatic spread to regional pelvic nodes. Haematogenous and peritoneal spread occurs but is uncommon, particularly in early stage disease. Historically lymphangiograms were used to assess regional nodal spread. They have been found to have a false negative rate of 10-20%. In more recent times CT scans have been used to radiologically assess disease spread. Their limitations include missing small positive lymph nodes and overcalling nodes enlarged by inflammation. CT scans are more useful in evaluating paraaortic nodes (sensitivity 67%) than pelvic nodes (sensitivity 25%).
A variety of clinical and histopathologic variables have been reported in cervical cancer. Some of these include: age, stage, tumour size, grade, lymph vascular invasion, depth of invasion, tumour volume, endometrial extension and regional node spread.
Survival has been found to be affected by (i) increasing number of positive nodes (ii) size of the node (microscopic vs. macroscopic) and (iii) unresected positive nodes.
The term “microinvasive” is commonly used but should be disregarded as it gives little treatment or prognostic information. The risk of lymph node metastasis is uncommon with less than 3mm of cervical stromal invasion and where there is no lymph vascular invasion. All other patients have a significant risk of lymphatic spread and formal surgical assessment of the pelvic nodes should be a part of the surgical management.
An argument exists for pre-treatment surgical staging and debulking enlarged positive lymph nodes. Such an approach may afford a survival benefit without affecting treatment related morbidity or mortality. An extraperitoneal rather than transperitoneal approach will significantly reduce treatment related morbidity.
Cervical cancer is primarily staged clinically. However there is a more recent tendency to improve the accuracy of pre-surgical staging using advanced imaging modalities including MRI and PET-CT. In the pre-operative evaluation of cervical cancer staging for MRI is most accurately staged by MRI and preferentially before cone biopsy is performed (Thomeer et al., 2012; Shepherd, 2011).
PET-CT has also emerged as a useful adjunct in the evaluation of cervical cancer both in the primary setting and in recurrent disease. It has a higher negative predictive value for the assessment of para-aortic nodal disease compared to MRI and the two are comparable for pelvic nodal assessment (Monteil et al., 2011). It is therefore reasonable to include PET-CT in the preoperative workup of cervical cancers deemed to be suitable for surgery.
If there are colposcopic or cytologic indicators of invasion, cone biopsy is the treatment of choice. A single specimen gives the pathologist the best tissue from which to make the diagnosis of histological tumour type, assess depth of invasion, lymphatic space involvement and resection margins. Loop excision is not considered appropriate in these cases where there is a greater chance of piecemeal removal. Where loop excision is performed it should aim to comprise a single specimen and reach a depth of greater than 10mm. LEEP biopsies may be suitable when assessing clinically obvious lesions where there is doubt about the extent or nature of the lesion. Where disease invades less than 3mm, cone biopsy may be adequate treatment depending on the factors mentioned above. Lymph node involvement is rare. With disease invading more than 3 mm, further treatment is usually recommended as for Stage Ib disease. This would usually involve either a simple or modified radical hysterectomy and lymph node dissection (Biliatis et al., 2012). In the unusual instance of lymph-vascular space involvement in stage 1A1 tumours, pelvic lymphadenectomy may be offered (Yeasmin et al., 2008).
Incidence of lymph node metastases in early stage squamous cervical cancer
Stage 1A1 <1mm invasion 0.1%
Stage 1A1 <3mm invasion <1%
Stage 1A2 <5mm invasion <1%* – 7% *the higher figure may include clinical lesions (i.e. stage 1B (Rogers and Luesley, 2009)
Primary treatment can be either surgery or combination radiotherapy/chemotherapy. The results of treatment appear to be equivalent though this is an area of continuing debate (Yeo et al., 2011). Factors to be considered when deciding upon treatment include the patient’s general health, her informed decision about treatment options and her age. We preferentially treat all stage 1B1 and selected stage 1B2 with radical surgery, except those associated with significant co-morbidities or obesity. Surgery allows for the preservation of coital and ovarian function, tends to have lower morbidity than associated with radiation therapy, with fewer long term bladder and bowel complications. Surgery will also allow the debulking of enlarged lymph nodes, and allow full pathological staging.
Standard surgery consists of a radical hysterectomy and pelvic lymph node dissection. The extent of parametrial dissection is generally a type II or III procedure with dissection of the ureteric tunnel. The pelvic lymph nodes from the crossing of the circumflex iliac vein to the common iliac vessels are removed. There is some evidence that removing lymphatic tissue lateral to the vessels is not necessary and its conservation may reduce lymphoedema. Resection of any enlarged common iliac or para-aortic lymph nodes should be performed for “debulking”. There is mounting evidence of the safety of a sentinel node approach to lymphadenectomy in early stage cervical cancer. This is particularly true for small tumours (<2cm) and could be considered in selected patients who decline full lymphadenectomy following adequate counselling of the limitations and false negative rate of the procedure.
With squamous disease in younger patients, the ovaries may be conserved and transposed out of the pelvis. For postmenopausal patients with glandular tumours they should be removed. There are few reports of ovarian metastases in younger patients with glandular tumours and it is possible to conserve them in this group after discussion with the patient about possible risks. There does not appear to be any contraindication to the use of hormone treatment when they are removed.
Definitive radiotherapy and chemotherapy is a treatment option for stage 1B/2A patients. Reported results of surgery and radiation therapy are comparable with 70-80% survival. Potential toxicities of radiation generally favour surgery for younger patients with less bulky tumours.
Patients receiving radical surgery followed by radiotherapy +/- chemotherapy have greater late toxicity. If patients are strongly predicted to have positive pelvic lymph nodes (bulky IB2, extensive lymph vascular invasion on biopsy and/or deep stromal invasion on MRI), then definitive chemoradiation should be considered.
The place of central cleansing hysterectomy after definitive chemoradiation is unclear but may be considered if there is any doubt about response to treatment. Prospective data would suggest a lower incidence of local relapse and progression free survival.
Adverse features that prompt consideration for adjuvant therapy after performing a radical hysterectomy include: nodal metastases, small cell histology and close surgical margins. Post-operative radiotherapy (+/- chemotherapy) may be considered in the node negative setting with close or positive margins or at least two risk factors including: deep cervical invasion, tumour size >4cm or lymph-vascular space invasion.
Chemotherapy and radiotherapy are commenced concurrently. Cisplatin is given at a dose of 40mg/m2 weekly for 5 weeks. Radiation therapy utilises a 4 field technique, with a dose of 50.4Gy in 28 treatments. This is supplemented with high dose rate (HDR) brachytherapy 18Gy in 3 weekly treatments to Pt A, with the rectal dose <70% of Pt A dose. We try to limit the overall treatment time to less than 55 days and maintain Hb > 10g/dl.
Acceptable variations include giving the brachytherapy at a dose of 17Gy in 2 fractions in very elderly, or those with a high anaesthetic risk. Alternatively the NCIC protocol can be used, with 45Gy delivered in 25 fractions external beam + 24Gy in 3 fractions brachytherapy.
Small Field Radiotherapy
Standard adjuvant radiotherapy includes treatment to the whole pelvis with a boost to the vaginal vault and can cause significant additional morbidity in node-negative patients. For high-risk node-negative patients therefore (as identified by Sedlis criteria or GOG score) small-field radiotherapy may be a suitable adjuvant option where the radiotherapy fields are confined to the central pelvis. The available small-scale studies show a lower risk of radiation-related morbidity without compromising recurrence rates however this has not yet been established as a standard treatment (Yeo et al., 2011). Dosage is 45-50.4 Gy in 1.8-2.0Gy fractions delivered by four-field technique.
There is an emerging role for neoadjuvant chemotherapy followed by surgery in patients with early or local-advanced cervical cancer to prevent the addition of radiotherapy for bulky tumours or to maintain fertility options including delay to treatment during pregnancy. This approach may be considered in special circumstances on the understanding that it is currently not considered a standard treatment (Rydzewska et al., 2012).
Where disease involves the parametrium but not the pelvic side wall (stage 2B), lower third of vagina (stage 3A); pelvic side wall and ureteric obstruction (stage 3B); mucosa of bladder or bowel (stage 4A) or distant metastases (stage 4B). Treatment of stage 2B-3B disease is by chemoradiation, usually with curative intent(12-14). Chemotherapy and radiotherapy are commenced concurrently. Cisplatin is given at a dose of 40mg/m2 weekly for 5 weeks. Radiation therapy utilises a 4 field technique, with a dose of 50.4Gy in 28 treatments. This is supplemented with high dose rate (HDR) brachytherapy, 18Gy in 3 weekly treatments to Pt A, with the rectal dose <70% of Pt A dose. We try to limit the overall treatment time to less than 55 days and maintain Hb > 10g/dl. Acceptable variations include giving the brachytherapy at a dose of 17Gy in 2 fractions in very elderly, or those with a high anaesthetic risk. Alternatively the NCIC protocol can be used, with 45Gy delivered in 25 fractions external beam + 24Gy in 3 fractions brachytherapy.
Adjuvant chemotherapy is not currently regarded as part of standard care. One trial has demonstrated a benefit with the addition of gemcitabine to cisplatin during radiotherapy and for a further 2 adjuvant cycles at the expense of considerable toxicity (Dueñas-González et al., 2011). Trials are ongoing.
Treatment of stage IVa disease may be curative or palliative. Treatment of distant disease is usually palliative aimed at symptom control. Platinum combinations have improved response rates and progression free survival compared to cisplatin alone and are most commonly used (Moore et al., 2004; Long et al., 2005). One trial has demonstrated a survival benefit with cisplatin combination therapy, although the cisplatin only arm may have underperformed due to prior therapy (Long et al., 2005). Targeted radiotherapy may be useful for control of local symptoms
Recurrent cervical carcinoma has very low overall survival and this is usually in patients with localised pelvic disease. Early involvement of Palliative Care services to assist symptom control is recommended.
Disease that is apparently confined to the pelvis may be managed surgically or by radiotherapy. Surgery usually requires an exenteration procedure with appropriate reconstruction. It is indicated for an isolated central cervical recurrence. Radical hysterectomy may be considered in patients with a small central recurrence if they have not had previous surgery. It is not indicated for patients with any spread beyond central mobile disease. Radiotherapy is more commonly used unless previous radiotherapy has been given. Advantage of treating both central and lateral pelvis and curative doses may be given.
Distant recurrent cervical carcinoma is rarely curable. Palliative treatment is aimed at symptom control and maintaining quality of life. Radiotherapy and chemotherapy can be used depending on what the patient wishes to achieve.
Adenocarcinoma of the cervix
Adenocarcinoma of the cervix is generally treated as squamous and adensquamous tumours. However there is reported to be a higher incidence of ovarian metastases for adenocarcinomas (Shimada et al., 2005). Therefore it is reasonable to consider bilateral salpingoophorectomy in those patients suitable for surgery. Furthermore there is controversy over whether the prognosis for adenocarcinoma treated by radiotherapy alone is worse than for squamous carcinoma and surgery is encouraged for carefully selected early stage tumours, albeit with a higher incidence of adjuvant treatment (Baalbergen et al., 2013)
Occult disease found on loop excision
An assessment of the resected tissue should be made by a Gynaecological Pathologist examining depth of invasion, lymphatic vascular involvement and resection margins. In cases that have been removed in a single pass with clear and wide resection margins and invasion less than 3 mm, selected patients can be managed conservatively with regular assessment as for invasive disease. The majority of patients in this category should have invasion less than 1mm. With disease resected piecemeal, adequate assessment of resection margins is not possible and cone biopsy to assess the lower cervix/treatment bed is recommended. Invasion greater than 3mm should go on to have treatment as for stage 1a2 or 1b. This would involve further resection of the cervical disease and lymph node dissection.
Conservative management in the young patient
Patients wishing to retain fertility with stage Ia2 disease may be treated with cone biopsy and pelvic lymphadenectomy. The risk of lymphatic metastases is low but the patient needs to be aware of this risk and that it is not considered standard therapy for this stage of disease. This approach is not recommended for clinical disease (stage 1B1 or above) but some patients may refuse standard therapy. They need to be aware of the risks to their long term survival but in these circumstances wide excision (radical trachelectomy, see below) and pelvic lymphadenectomy may be performed.
Radical trachelectomy and fertility-sparing surgery
Radical trachelectomy is now established as a viable treatment option for those patients with disease which would otherwise be treated by radical surgery or radical chemoradiotherapy who wish to preserve fertility (Shepherd, 2011). The procedure is considered to be oncologically sound with approximately a 5% recurrence rate. The largest series reports relate to vaginal trachelectomy but the abdominal approach is becoming more popular due to being possible to perform without significant additional training. Vaginal trachelectomy is associated with a higher pregnancy rate but poorer oncological outcomes than abdominal trachelectomy although there is as yet insufficient evidence to recommend one approach over the other (Cao et al., 2013). Experience in this unit is limited but it is possible to offer abdominal (open or laparoscopic) trachelectomy to carefully selected patients. Patients requesting vaginal trachelectomy would need onward referral. Ideal selection criteria for radical trachelectomy include: squamous tumours <2cm, absence of LVSI and disease clear of the isthmus on MRI evaluation although non-squamous tumours and those with focal LVSI may be considered. Patients should also require future fertility with a reasonable prospect of pregnancy. Pre-operative assessment requires MRI and PET-CT.
Although the bulk of experience relates to radical trachelectomy there is now a growing body of evidence supporting extremely conservative treatment of selected stage 1A2 and 1B1 tumours for the purpose of fertility preservation (Ramirez et al., 2013). It may therefore be reasonable to offer conization or simple trachelectomy with pelvic lymphadenectomy to patients who desire fertility and decline more radical treatment with the following criteria: tumour <2cm, absence of LVSI and absence of high grade morphology. The pregnancy rates achievable with this approach appear to be higher than those seen with trachelectomy without additional oncological risk.
Cervical Cancer diagnosed during pregnancy
The progress of invasive cervical carcinoma is not altered by pregnancy. The management of cervical cancer during pregnancy must be individualised as there are no large trials available to guide treatment. Depending on the stage of pregnancy and after discussion with the patient about risks, such disease may be managed conservatively with observation or a limited excision performed. Definitive treatment can be undertaken at delivery or postpartum. If surgical treatment is planned at delivery this should be by elective caesarean radical hysterectomy with pelvic lymphadenectomy provided that the expertise and facilities are available. If postnatal treatment is planned or the diagnosis is in doubt a vaginal delivery might be preferable to avoid repeat surgery. If the diagnosis is made prior to fetal maturity (34-36 weeks’ gestation) neoadjuvant chemotherapy may allow temporization until that time without a significant risk of worsening outcome. For low volume tumours diagnosed before 18 weeks, pelvic lymphadenectomy may be considered to stratify those patients who can be safely observed (Morice et al., 2009).
Stage 1B2 Disease
There is debate about primary treatment for disease greater than 4 cm confined to the cervix. While these are frequently operable, there is a higher rate of involved pelvic and para-aortic lymph nodes necessitating adjuvant radiotherapy giving higher complication rates. Neoadjuvant chemotherapy is an option but not commonly utilized by our Group. A higher relapse rate has also been reported when these tumours are treated by radiotherapy alone compared to surgery and radiotherapy. Our policy is to offer patients with stage Ib2 disease chemo-irradiation, with or without subsequent hysterectomy.
Diagnosis after hysterectomy
Cervical carcinoma may be found incidentally after hysterectomy for benign disease. Management choices include further surgery with excision of the parametrium and lymphadenectomy or chemoradiation. The decision will depend on the condition of the patient and her preference after explanation of the risks involved.
Small cell neuroendocrine tumours
These are rare tumours but clinically very aggressive. A significant proportion of tumours have metastases, frequently to brain. Surgery, radiotherapy and chemotherapy have all been used. No modality has demonstrated any survival advantage.
Adenoid Basal Carcinoma
This is a rare tumour type that may clinically present in a similar manner to the more typical carcinoma of the cervix but generally follows a more indolent course. Hysterectomy (simple or radical) without pelvic lymphadenectomy are reasonable treatment options for these tumours.
- Baalbergen A, Veenstra Y, Stalpers L. Primary surgery versus primary radiotherapy with or without chemotherapy for early adenocarcinoma of the uterine cervix. 2013. Cochrane Database Syst Rev. 1:CD006248.
- Biliatis I, Kucukmetin A, et al. Small volume stage 1B1 cervical cancer: Is radical surgery still necessary? 2012. Gynecol Oncol. 126:73-7.
- Cao DY, Yang JX, et al. Comparisons of vaginal and abdominal radical trachelectomy for early-stage cervical cancer: preliminary results of a multi-center research in China. 2014. Br J Cancer. 109:2778-82.
- Dueñas-González A, Zarbá JJ, et al. Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix. 2011. J Clin Oncol. 29:1678-85.
- Long HJ, Bundy BN, et al. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. 2005. J Clin Oncol. 23:4626-33.
- Monteil J, Maubon A, et al. Lymph node assessment with (18)F-FDG-PET and MRI in uterine cervical cancer. 2012. Anticancer Res. 31:3865-71.
- Moore DH, Blessing JA, et al. Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a gynecologic oncology group study. 2004. J Clin Oncol. 22:3113-9.
- Morice P, Narducci F, et al. French recommendations on the management of invasive cervical cancer during pregnancy. 2010. Int J Gynecol Cancer. 19:1638-41.
- Ramirez PT, Pareja R, et al. Management of low-risk early-stage cervical cancer: should conization, simple trachelectomy, or simple hysterectomy replace radical surgery as the new standard of care? 2014. Gynecol Oncol. 132:254-9.
- Rogers LJ, Luesley DM. Stage IA2 cervical carcinoma: how much treatment is enough? 2010. Int J Gynecol Cancer. 19:1620-4.
- Rydzewska L, Tierney J, et al. Neoadjuvant chemotherapy plus surgery versus surgery for cervical cancer. 2013. Cochrane Database Syst Rev. 12:CD007406.
- Shepherd JH. Cervical cancer. 2012. Best Pract Res Clin Obstet Gynaecol. 26:293-309.
- Shimada M, Kigawa J, et al. Ovarian metastasis in carcinoma of the uterine cervix. 2005. Gynecol Oncol. 101:234-7.
- Thomeer MG, Gerestein C, et al. Clinical examination versus magnetic resonance imaging in the pretreatment staging of cervical carcinoma: systematic review and meta-analysis. 2014. Eur Radiol. 23:2005-18.
- Yeasmin S, Nakayama K, et al. A case of bilateral pelvic lymph node involvement in stage 1a1 squamous cell carcinoma of cervix and a review of the literature. 2010. Int J Clin Oncol. 14:564
- Yeo RM, Chia YN, et al. Tailoring adjuvant radiotherapy for stage IB-IIA node negative cervical carcinoma after radical hysterectomy and pelvic lymph node dissection using the GOG score. 2011. Gynecol Oncol. 123:225-9.