Definition
Cervical cancer is one of the most common gynecologic malignancies worldwide. Cervical carcinoma ranks third among gynecologic cancers in the female population and is one of the leading causes of cancer-related death in women, with higher incidence and mortality rates in countries with limited access to prevention programs and healthcare.
The primary etiologic factor is infection with human papillomavirus (HPV), a very common infection in the sexually active population. It is estimated that approximately 80% of sexually active individuals come into contact with the virus at least once during their lifetime. In most cases the infection resolves spontaneously, while in a minority it may persist over time and promote the development of precancerous lesions and, subsequently, cervical carcinoma.
Risk Factors
Among the main risk factors for the development of cervical lesions and cervical carcinoma are sexual behaviors associated with a higher likelihood of exposure to sexually transmitted infections. The use of oral contraceptives, when associated with reduced use of barrier methods such as condoms, may indirectly facilitate transmission of HPV and other pathogens.
An additional relevant risk factor is cigarette smoking, which interferes with local and systemic immune responses, reducing the body's ability to clear the viral infection. Similarly, immunosuppressive conditions, such as HIV infection, other malignancies, or immunosuppressive therapies, increase susceptibility to persistent infections and progression of cervical lesions.
- Vaginal bleeding after intercourse or between menstrual periods
- Profuse, abnormal, or malodorous vaginal discharge
- Persistent pelvic pain or lower-extremity edema
- Failure to undergo screening at recommended intervals
Symptoms
Precancerous lesions of the uterine cervix, in most cases, do not produce evident symptoms. Even cervical carcinoma in its early stages may be clinically silent and identified only through screening programs, which is why early detection plays a decisive role.
When the disease becomes clinically manifest, particularly at more advanced stages, symptoms may include abnormal vaginal bleeding, a sensation of pelvic heaviness, lower-extremity edema, lumbosciatalgia, and pain involving the bladder or rectum.
Prevention
Over time, effective preventive strategies against cervical cancer have been developed, based on organized screening, HPV infection identification, and vaccination. HPV prevention is structured into primary, secondary, and tertiary prevention.
Primary prevention is based on the adoption of healthy lifestyle behaviors, including smoking cessation, and HPV vaccination. Currently the most widely used vaccine is Gardasil 9, which provides coverage against 9 viral genotypes, including those with the highest oncogenic potential. In Italy, vaccination is provided free of charge for women up to 26 years of age and, in specific clinical contexts, also for women with a prior diagnosis of cervical lesions.
Secondary prevention aims to detect cervical abnormalities early through screening tests: Pap test and HPV DNA test. The Pap test is generally performed starting at age 21 in sexually active women, at three-year intervals. In women aged 30 to 65, the HPV DNA test assumes a central role, performed alone or in combination with the Pap test; if negative, the repeat interval may be 5 years. After age 65, when prior screening results have been adequately negative, the risk of new persistent infection is significantly reduced.
Tertiary prevention consists of limiting the extent of already-diagnosed disease, promptly treating lesions, and establishing rehabilitative pathways for patients with delayed diagnosis or treatment sequelae.
Diagnosis
In patients with a positive HPV DNA test for high-risk oncogenic genotypes, particularly 16 and 18, direct referral to colposcopy is indicated. For other genotypes, the diagnostic pathway initially involves a Pap test and, in the presence of cytologic abnormalities, subsequent colposcopic evaluation. Colposcopy is a second-level examination during which specific reagents are applied to highlight any suspicious areas; if present, such areas may undergo targeted biopsy.
Histologic examination of the biopsy may document precancerous lesions, classified as CIN1, CIN2, or CIN3, or confirm invasive carcinoma. In cases of invasive cancer, clinical staging must be performed, with the aid of ancillary investigations such as cystoscopy, rectoscopy, CT, and PET-CT, to assess potential extension of the disease to adjacent or distant structures. The staging system used is the FIGO classification, from stage I to stage IVB, and it directly determines treatment and prognosis. In early stages, survival rates may approach 90%.
Treatment
Treatment of cervical cancer must be defined according to disease stage, histologic characteristics, pathologic risk factors, the patient's general condition, and the potential desire for fertility preservation. In pre-invasive stages and early-stage disease, treatment is primarily surgical, while in locally advanced forms, concurrent chemoradiation represents the standard of care. In metastatic or recurrent disease, treatment is mainly systemic and requires multidisciplinary planning.
1. Treatment of pre-invasive lesions (CIN / SIL)
Pre-invasive lesions of the uterine cervix include low-grade and high-grade squamous intraepithelial abnormalities, the management of which depends on the grade of the lesion, patient age, extent of the squamocolumnar junction, colposcopic visibility of the lesion, and reproductive desire.
Excisional procedures represent the reference treatment for high-grade lesions and include LEEP/LLETZ, cold-knife conization, and laser excision in selected cases. These techniques allow not only removal of the lesion but also complete histologic evaluation of the specimen, including resection margins — an aspect particularly relevant when there is suspicion of microinvasion, glandular involvement, or discrepancy between cytology, colposcopy, and biopsy.
Ablative procedures, such as cryotherapy and laser vaporization, may be considered only in carefully selected patients when colposcopy is satisfactory, the lesion is entirely visible, there are no signs of invasion, and the endocervical canal shows no suspicious findings. In the presence of diagnostic uncertainty, the excisional procedure should be preferred. In some situations, a conservative approach with observation and cytologic-colposcopic follow-up is appropriate, particularly for low-grade lesions and, in selected cases, CIN2 in young patients who wish to preserve the cervix, provided strict adherence to follow-up is ensured.
2. Treatment of early-stage invasive disease (IA–IB2)
In early stages of cervical carcinoma, the standard treatment is primarily surgical. The extent of the procedure depends on the depth of stromal invasion, tumor size, the presence of lymphovascular space invasion, lymph node involvement, and the desire for fertility preservation.
In selected patients who wish to preserve fertility, fertility-sparing surgery may be considered. Radical trachelectomy is the most established option for small-volume early-stage tumors, in the absence of lymph node spread, and after thorough clinical-radiological and pathologic selection. This approach allows maintenance of the possibility of pregnancy, albeit with an increased obstetric risk, particularly of preterm delivery.
Selection criteria for fertility-sparing surgery (NCCN v2.2026)
NCCN guidelines recommend fertility-sparing surgery for early-stage cervical carcinoma (IA1–IB1 and selected IB2 cases) provided specific clinicopathologic criteria are met. The choice of procedure depends on the FIGO stage and the presence or absence of lymphovascular space invasion (LVSI).
- Absence of LVSI (preferred)
- Negative conization margins for carcinoma
- Histology: squamous cell carcinoma (any grade) or usual-type adenocarcinoma G1–G2 (preferred)
- Tumor size ≤ 2 cm
- Depth of invasion ≤ 10 mm on LEEP/conization
- Negative imaging for locoregional disease (MRI recommended)
Algorithm by stage (NCCN CERV-2, v2.2026)
- Stage IA1 without LVSI: conization with negative margins (non-fragmented specimen, margins ≥ 1 mm). Lymph node assessment is not required.
- Stage IA1 with LVSI: conization with negative margins + SLN mapping or pelvic lymphadenectomy.
- Stage IA2–IB1 (conservative criteria met): conization with negative margins + SLN mapping or pelvic lymphadenectomy.
- Stage IB1 non-conservative / selected IB2: radical trachelectomy + SLN mapping or pelvic lymphadenectomy ± para-aortic lymphadenectomy.
Small-cell neuroendocrine histology and gastric-type adenocarcinoma are not considered eligible for radical trachelectomy. Abdominal radical trachelectomy may be used for selected IB1–IB2 lesions between 2 and 4 cm in diameter.
Oncologic outcomes
A systematic review of 65 studies involving 3,044 patients reported reassuring oncologic outcomes for fertility-sparing surgery. The multicenter FERTIlity Sparing Surgery study (733 patients) confirmed that non-radical procedures are not associated with an increased risk of recurrence compared with radical procedures for tumors ≤ 2 cm, while tumors > 2 cm carry an approximately 3-fold higher risk of recurrence.
Reproductive outcomes and perioperative considerations
The live-birth rate after fertility-sparing surgery is approximately 68%, with the highest rate following vaginal radical trachelectomy (67.5% clinical pregnancies). Approximately 20% of pregnancies require assisted reproductive techniques. The main obstetric complication is preterm delivery, due to reduction of postoperative cervical length. ASCO 2025 guidelines confirm the adequacy of fertility-sparing options for patients with early-stage disease, favorable histology, and negative lymph nodes.
Pelvic MRI is recommended for preoperative assessment. A consultation with a reproductive endocrinology and infertility (REI) specialist is indicated. Neoadjuvant chemotherapy followed by conservative surgery for tumors > 2 cm is under investigation and is not yet recommended as standard treatment.
Lymph node staging is an integral part of surgical treatment. In early stages, the sentinel lymph node procedure has assumed an increasing role in reducing the morbidity of complete lymphadenectomy, while maintaining good diagnostic accuracy in centers with adequate experience. Pelvic lymphadenectomy remains indicated when the sentinel lymph node is not identified or when the risk of lymph node metastases is considered higher.
In patients with early-stage low-risk disease, the most recent data suggest that less radical surgery may be oncologically appropriate in well-selected subgroups. Specifically, in patients with small tumors, absence of high-risk parameters, and confined disease, simple hysterectomy may be considered as an alternative to radical hysterectomy, according to rigorous selection criteria. In cases with greater local or parametrial risk, radical hysterectomy remains the reference treatment.
Querleu-Morrow Classification — Types of radical hysterectomy
The Querleu-Morrow classification defines the degree of radicality of hysterectomy based on the extent of resection of the lateral, ventral, and dorsal parametria, and the extent of vaginectomy. The choice of type depends on the FIGO stage, the intent to preserve pelvic nerves, and the individual oncologic risk.
| Type | Lateral Parametrium | Ventral Parametrium | Dorsal Parametrium | Vaginectomy |
|---|---|---|---|---|
| A | Midway between cervix and ureter | Minimal excision | Minimal excision | Less than 1 cm |
| B1 | At the level of the ureter | Partial excision of vesicouterine ligament | Partial resection of rectouterine-rectovaginal ligament | Excision of 1 cm |
| B2 | Same as B1 + paracervical lymphadenectomy without vascular structure resection | Same as B1 | Same as B1 | Same as B1 |
| C1 | At the level of the iliac vessels transversely; caudal portion preserved | Excision of vesicouterine ligament at bladder level (bladder nerves dissected and preserved) | At the level of the rectum (hypogastric nerve dissected and preserved) | Excision of 2 cm or as needed |
| C2 | At the medial surface of the iliac vessels completely (including caudal portion) | At bladder level (bladder nerves sacrificed) | At the level of the sacrum (hypogastric nerve sacrificed) | Same as C1 |
| D1 | At the pelvic sidewall, with resection of internal iliac vessels | At bladder level | At the level of the sacrum | As needed |
| D2 | Same as D1, with resection of lateral pelvic wall | As needed | As needed | As needed |
Pivotal clinical trials: LACC and SHAPE
Primary outcome: disease-free survival at 4.5 years was significantly lower in the laparoscopic arm (91.2% vs 97.1%). Overall survival was also reduced with the minimally invasive approach.
Clinical impact: NCCN and ESGO guidelines recommend laparotomy as the standard approach for radical hysterectomy in invasive cervical carcinoma.
Primary outcome: equivalent 3-year disease-free survival in both arms (97.1% vs 96.7%). Lower urinary morbidity in the simple hysterectomy arm.
Lymph node staging and sentinel lymph node (SLN)
Lymph node assessment is an essential component of surgical staging. Sentinel lymph node biopsy using a combined technique (blue dye + radioisotope tracer or indocyanine green fluorescence) has demonstrated high sensitivity and specificity in tumors ≤ 2 cm. In low-risk patients, omission of systematic lymphadenectomy in the presence of a negative SLN is a validated option; in tumors > 2 cm, bilateral systematic lymphadenectomy remains indicated.
The minimally invasive surgical approach in radical surgery for early cervical carcinoma is not considered equivalent to open laparotomy. Therefore, the laparotomic approach represents the preferred route for candidates for radical surgery. After surgical treatment, adjuvant therapy is determined based on pathologic risk factors: in patients with intermediate risk (Sedlis criteria), pelvic radiotherapy reduces the risk of recurrence; in patients with high-risk factors — positive lymph nodes, positive margins, or parametrial infiltration (Peters criteria) — postoperative concurrent chemoradiation improves disease control and survival.
3. Treatment of locally advanced disease (IB3–IVA)
In locally advanced disease, the reference treatment is concurrent cisplatin-based chemoradiation, combined with external-beam radiotherapy and completed by brachytherapy. This approach constitutes the international standard of care, as it is associated with better local control and superior oncologic outcomes compared with radiotherapy alone. External-beam radiotherapy is delivered using three-dimensional conformal techniques or IMRT. Image-guided brachytherapy is an essential component of treatment with curative intent and should not be omitted.
In the context of locally advanced disease, the rationale for induction prior to chemoradiation must be distinguished from that of neoadjuvant chemotherapy followed by surgery. The INTERLACE trial, a phase III randomized study, showed that a short course of induction chemotherapy with carboplatin and paclitaxel before concurrent chemoradiation improves progression-free survival and overall survival compared with chemoradiation alone. However, this is a strategy distinct from neoadjuvant chemotherapy aimed at surgery and must not be conflated with the latter. Intensification with induction is associated with increased acute adverse events, although without apparent worsening of quality of life in published data.
Neoadjuvant chemotherapy followed by surgery requires cautious interpretation. The available major randomized trials have not demonstrated superiority in overall survival compared with concurrent chemoradiation, and this represents the most clinically relevant finding. A modest advantage in progression-free survival observed in favor of chemoradiation should be interpreted with caution, as it may reflect delayed identification of persistence or recurrence after radiation treatment. In randomized trials, a higher frequency of severe late sequelae was observed in the concurrent chemoradiation arm; however, these data do not alter the fact that concurrent chemoradiation remains the standard. Neoadjuvant chemotherapy cannot be considered superior to the standard, but it cannot be absolutely excluded as an option in selected settings. Some subgroup analyses suggest that younger patients and those with stages IB3–IIA2 may be the most suitable candidates, but these findings remain exploratory and inconclusive.
Para-aortic lymph node staging may be achieved through advanced imaging and, in selected cases, through surgical staging, especially when the result is likely to modify the radiation treatment volumes. Therapeutic choice must be individualized, taking into account the biological and staging characteristics of the disease, local resource availability, quality of brachytherapy, the center's surgical expertise, and effective access to multimodal treatments.
Conceptual distinction: induction pre-CRT vs neoadjuvant pre-surgery
It is essential to distinguish two strategies with different rationales and objectives: induction chemotherapy prior to chemoradiation (CRT), which aims to intensify the radiation treatment without modifying its completion, and neoadjuvant chemotherapy aimed at surgery, which targets preoperative downstaging. The two strategies are not interchangeable and their results must not be conflated in clinical assessment.
Outcome: significant improvement in PFS and OS in the induction arm.
Note: intensification is associated with greater acute toxicity, without apparent worsening of quality of life in published data. A distinct approach from neoadjuvant chemotherapy aimed at surgery.
Outcome: promising antitumor activity and manageable toxicity profile.
Limitation: the absence of randomization precludes comparative conclusions versus the standard. Data remain preliminary.
Status: a line of clinical research of interest under development.
Note: available data remain preliminary. The lack of a randomized control arm currently limits conclusions.
4. Treatment of metastatic or recurrent disease (IVB)
In metastatic, persistent, or recurrent disease, treatment is predominantly systemic and is modulated according to performance status, site of metastases, prior treatments, residual toxicities, and biomolecular profile. Platinum-taxane doublets remain the cornerstone of first-line therapy in many patients.
The addition of bevacizumab to chemotherapy demonstrated an overall survival benefit in the GOG-240 study and is therefore a relevant therapeutic option in eligible patients, in the absence of specific clinical contraindications. In patients with PD-L1-positive disease, the addition of pembrolizumab to chemotherapy, with or without bevacizumab, showed a significant improvement in overall survival and progression-free survival in the KEYNOTE-826 study, changing the first-line standard of care for eligible cases.
In later lines, the therapeutic choice depends on prior exposure to immunotherapy, antiangiogenics, and radiotherapy, as well as general clinical conditions. In this setting, symptom control, prevention of urologic, intestinal, and hemorrhagic complications, and early integration of palliative care represent integral components of oncologic treatment.
In its early stages, cervical cancer is frequently asymptomatic and is identified through screening via Pap test or HPV test. When clinical signs appear, the most common manifestations are abnormal vaginal bleeding — particularly after intercourse, between menstrual periods, or after menopause — and profuse or malodorous vaginal discharge.
At more advanced stages, pelvic pain, flank pain secondary to hydronephrosis, lower-extremity edema, and deep vein thrombosis may occur.
Ref.: [1, 2, 3, 4]
The HPV vaccine is a prophylactic vaccine, with efficacy exceeding 99% when administered before exposure to the virus. It does not have a therapeutic effect on an existing infection, does not accelerate viral clearance, and does not halt the progression of a pre-existing infection.
However, in women already positive for a given genotype, vaccination may provide protection against other viral types not yet contracted. In one study, efficacy against CIN2+ related to HPV-16/18 in women already infected with other types was 82.7%. A recent systematic review also showed that vaccination after conization may reduce the risk of CIN2+ recurrence by up to 87%.
Ref.: [5, 6, 7, 8, 9, 10]
According to the Bethesda system, ASC-US (Atypical Squamous Cells of Undetermined Significance) indicates the presence of squamous cells with mild changes of undetermined significance, insufficient for a diagnosis of intraepithelial lesion. It is an indeterminate cytologic category that requires further stratification, usually by HPV testing.
L-SIL (Low-grade Squamous Intraepithelial Lesion) indicates a low-grade squamous intraepithelial lesion, generally corresponding to CIN1 on histologic examination and often representing an active HPV infection. In the majority of cases it regresses spontaneously, but in a limited proportion it may be associated with higher-grade lesions. Management depends on the concurrent HPV test result and the patient's clinical history, according to the 2019 ASCCP guidelines.
Ref.: [4, 11, 12, 13, 14, 15]
In average-risk women aged 30 to 65, major guidelines recommend primary HPV testing every 5 years; alternatively, co-testing with HPV and Pap test every 5 years, or Pap test alone every 3 years if HPV testing is unavailable.
The American Cancer Society has updated its recommendations to include the possibility of self-collected vaginal samples for HPV, with a repeat interval of every 3 years for self-collected samples and every 5 years for clinician-collected samples. Screening may be discontinued after age 65 when prior results have been adequately negative.
Ref.: [15, 17, 18, 19, 20, 21]
HPV is considered a necessary but not always sufficient cause in the development of cervical cancer. Over 90% of squamous cell carcinomas and the majority of cervical adenocarcinomas are associated with HPV. However, HPV-independent cervical tumors do exist, accounting for approximately 5–7% of squamous cell carcinomas and some adenocarcinoma subtypes (gastric-type, clear cell, mesonephric); these tend to present at an older age and often at more advanced stages.
Among the cofactors that increase risk in the presence of persistent HPV infection are cigarette smoking, prolonged use of oral contraceptives, high parity, immunosuppression, co-infection with Chlamydia trachomatis, and HSV-2 infection.
Ref.: [1, 23, 24, 25, 26]
Colposcopy is an outpatient examination performed by an experienced clinician using a colposcope, an instrument that allows magnified observation of the cervix after application of 3–5% acetic acid. Areas with altered cells may appear as acetowhite plaques; during the examination, vascular patterns such as mosaicism, punctation, and atypical vessels are also assessed.
Biopsies are performed in a targeted manner on suspicious areas, usually with 2–4 samples, as increasing the number of biopsies improves diagnostic sensitivity for CIN3+. In higher-risk patients, endocervical curettage may also be performed. According to the 2019 ASCCP guidelines, colposcopy is recommended when the immediate risk of CIN3+ is 4% or higher.
Ref.: [3, 15]
The chances of cure for cervical cancer diagnosed at an early stage are high. Stage IA2 achieves a 5-year survival rate of 95–98% with standard surgical treatment. In stage IB1 with negative lymph nodes, 5-year survival reaches up to 87%, dropping to 73% in cases of positive lymph nodes. In stages IB1–IIA, 5-year survival is 87–92% with either radical surgery or radiotherapy.
The SHAPE trial demonstrated that, in patients with low-risk disease at stage IA2–IB1, tumor ≤ 2 cm and absence of LVSI, simple hysterectomy is non-inferior to radical hysterectomy in terms of survival, allowing a less demolitive surgical approach.
Ref.: [1, 23, 27, 28, 29]
Conization does not preclude the possibility of conception but is associated with an increased risk of adverse obstetric outcomes in subsequent pregnancies, particularly preterm delivery with risk proportional to the depth of the cone: excisions of 20 mm carry a risk of 18%. Cervical incompetence, premature rupture of membranes, and second-trimester miscarriage are also more frequent.
More conservative techniques, such as LEEP/LLETZ with smaller cone dimensions, carry a lower risk compared with cold-knife conization. Simple hysterectomy is indicated in stage IA1 without LVSI when there is no desire for fertility; radical hysterectomy in stages IA2–IB2 that do not meet conservative criteria; for advanced stages ≥ IIB, the standard treatment is definitive chemoradiation.
Ref.: [15, 23, 29, 30, 31, 32]
For information on gynecologic examination, HPV screening, and the initial diagnostic pathway, visit the portal dedicated to clinical gynecology.
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