This chapter should be cited as follows:
Lazzeri L, Centini G, et al, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.420263

The Continuous Textbook of Women’s Medicine Series – Gynecology Module

Volume 8

Gynecological endoscopy

Volume Editors: Professor Alberto Mattei, Director Maternal and Child Department, USL Toscana Centro,Italy
Federica Perelli, Obstetrics and Gynecology Unit, Ospedale Santa Maria Annunziata, USL Toscana Centro, Firenze, Italy

Chapter

Treatment Options for Early-Stage Endometrial and Cervical Cancer

First published: January 2024

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ENDOMETRIAL CANCER

Introduction

Endometrial cancer (EC) is a malignancy of the inner epithelial lining of the uterus. With an increasing incidence and disease-associated mortality, it is the most common gynecological cancer in the developed world.¹ It occurs typically in postmenopausal and nulliparous (70%) women, indeed only 4% of patients with endometrial carcinoma are <40 years of age.²

Risk factors

The main risk factors for endometrial cancer are conditions involving an excessive estrogenic stimulus to the endometrium. Different reproductive factors such as young age at menarche, late age at menopause, infertility, nulliparity, age of birth of the first child, and long-term use of unopposed estrogens during hormone replacement therapy have been associated with an increased risk of endometrial cancer.³ Patients undergoing tamoxifen therapy, due to its antiestrogenic effect in the breast and proestrogenic effect in the uterus, have a double risk of developing endometrial cancer, which increases fourfold if tamoxifen is taken for more than 5 years. One of the most common and important risk factors is obesity, which is often associated with diabetes, metabolic syndrome, and polycystic ovary syndrome.⁴ On the other hand, multiparity and the use of combined oral contraceptives have been shown to reduce the risk of endometrial cancer.³ In addition to a genetical predisposition to endometrial cancer, it is possible to find a familial predisposition to developing malignant tumors in various organs like in Lynch syndrome type II. Women with Lynch syndrome type II have the risk related to the onset of malignancies of 40–80% for colon cancer, 40–60% for endometrial cancer, and 10–12% for ovarian cancer.⁵

Classification

Endometrial carcinoma can be classified into two main clinic-pathological and molecular types: type I and type II. These two types differ in epidemiology, histopathology, prognosis, and treatment.

Type I endometrial cancers (85% of diagnosis) typically have a good prognosis because of the low-grade histology and are often confined to the uterus at the time of diagnosis; indeed, they present an overall 5-year survival rate of 85%, with a low recurrence rate (20%). These types of tumors are strongly associated with conditions that induce excessive estrogen exposure and are commonly seen in younger, obese, and perimenopausal women.

Type II cancers are considered high grade by definition and include mainly serous carcinomas (10%) and clear cell carcinomas (<5%); approximately 20% of endometrioid tumors present as high grade (FIGO grade 3) and may be classified as type II. Mixed cell, undifferentiated, dedifferentiated, neuroendocrine, and carcinosarcomas also fall into this category. These types of tumors are generally aggressive and often present themselves at an advanced stage, with higher rates of recurrence (near 50%) and lower 5-year overall survival (55%).⁶

Histological types

Endometrioid adenocarcinoma (more than 83%): it is the most frequent histological type, estrogen related. It is usually pure, in rare cases, however, it may be associated with the presence of non-endometrioid cancer (less than 10% by definition) and the proportion of these two components influences the prognosis. The level of differentiation can be classified by percentage of solid areas:^7,8

• G1 <5%
• G2 6–50%
• G3 >50%

Serous-papillary adenocarcinoma: it is the prototype of non-endometrioid adenocarcinoma (5–10% of EC). Typically, it is more invasive, and affects older women with a history of pelvic irradiation, prolonged tamoxifen therapy, and breast cancer.⁹

Clear cell adenocarcinoma: it is a rare histological type of adenocarcinoma (1% of EC) that affects usually elderly women. The architectural histological features are the same of clear cell carcinoma of other genital sites. Clear cell adenocarcinoma, serous-papillary adenocarcinoma and grade 3 endometrioid adenocarcinoma are predictors of poor survival (high-grade carcinoma).¹⁰

Mucinous adenocarcinoma: similar but different from primitive endocervical adenocarcinoma (worst prognosis) from which it differs due to the low presence of mucin.

Squamous cell carcinoma: it must be distinguished from adenocarcinoma with squamous differentiation by the absence of glandular differentiation and from squamous cell carcinomas of the uterine cervix diffused at the endometrial level.

Mixed tumors: the different components exceed 10% for each.

Undifferentiated carcinoma: tumor composed of solid masses of undifferentiated cells, it can be associated with endometrioid adenocarcinoma, or it can represent the only documented component in the tumor. Other entities are undifferentiated small cell carcinoma, which shows neuroendocrine differentiation with positivity for chromogranin, synaptophysin and other typical markers and dedifferentiated carcinoma, which is characterized by the association of a grade 1 or 2 adenocarcinoma and an undifferentiated carcinoma composed of uniform, ovoid or rounded cells with large cores and prominent nucleoli, typically associated with Lynch syndrome.¹¹

The degree of differentiation is closely related to the disease’s diffusion. G1 tumors tend to be confined to the endometrium, while G3 tumors have a higher percentage of myometrial involvement.

Histopathology and molecular biology

The main molecular alterations of type I carcinoma are represented by the PTEN gene silencing, by defects in DNA repair genes, microsatellite instability and mutations in the KRAS and/or β-catenin and/or PIK3 genes, whereas serous carcinomas often present p53 gene mutations, p16 gene inactivation, E-cadherin low expression and HER-2 overexpression.¹²

Extensive studies have led to a molecular classification that identifies four subgroups:

• POLE ultramutated, characterized by high mutagenicity and favorable patient outcome (the exonuclease domain of POLE 58 mutations, mutations of PTEN, PIK3R1, PIK3CA, FBXW7, e KRAS).
• MSI hypermutated, characterized by microsatellite instability secondary to MLH1 promoter methylation, high mutagenicity, infrequent gene copy number aberrations, recurrent frameshift deletions of RPL22, and mutations of KRAS and PTEN.
• Copy number low (generally G1-G2 endometrioids), characterized by microsatellite stability, low mutagenicity, frequent CTNNB1 mutations.
• Copy number high (serous-like), characterized by frequent gene copy number aberrations, low mutagenicity, frequent mutations of TP53, FBXW7, and PPP2R1A, rare mutations of PTEN and KRAS, poor outcome.

The clinical importance of this new classification is linked to the peculiar characteristics of MSI tumors associated with hereditary endometrial cancer (Lynch syndrome). Immunohistochemical determination of MSI on tumor specimen has been identified as a potential predictor of response to new generation immunotherapies.^13,14

Diagnosis

In most cases the clinical onset of endometrial cancer is represented by abnormal vaginal bleeding, whether it is vaginal bleeding in menopause or unexpected bleeding compared to the normal menstrual flow in women of childbearing age. For that reason, patients presenting these types of bleeding should be subjected to clinical examination. Abdominal, pelvic and lumbosacral pain, subocclusive syndromes, bone pain and dyspnea are generally late signs of metastatic spread of the disease.

Diagnostic steps:

• Trans-vaginal ultrasound, with color Doppler/power Doppler study of endometrial vascularization.^15,16
• Hysteroscopy (assessment of endometrial tissue with targeted biopsies).¹⁷
• MRI, which can detect gross myometrial invasion or extension of tumor to the cervical stroma and the presence of lymphnodal involvement, local and distant metastatic disease at diagnosis.¹⁸
• CT has poor diagnostic accuracy compared to MRI in the evaluation of the uterus but it is useful in the evaluation of any extra-uterine involvement of disease.

Staging

The staging of endometrial cancer is based on anatomopathological evaluation. There are two classification systems: FIGO (International Federation of Gynecology and Obstetrics) classification and AJCC (American Joint Committee on Cancer) classification.

Treatment

Presurgical prognostic factors

Before surgery, it is important to collect the presence of the history of cancer in the family (colorectal, endometrial, and ovarian cancers) to identify possible risk factors associated with Lynch syndrome. An evaluation of general conditions is necessary in patients with comorbidities to choose the correct type of surgical procedure.

Gynecological examination and pelvic ultrasound are essential for presurgical evaluation; these allow the study of tumor volume, myometrial infiltration, cervical involvement and exclusion of the presence of ovarian disease.

The preoperative histological examination (histological grade and histotype) is essential to establish the surgical plan, although differences may exist between the preoperative and definitive histological examination.

Stage I

The standard surgical approach for the treatment of EC stage I hysterectomy, bilateral adnexectomy with or without lymphadenectomy; when possible, with laparoscopic surgery.²¹ In this stage, the role of lymphadenectomy is still debated but sentinel lymph node biopsy has shown a good diagnostic performance and could represent a right compromise between performing a complete surgical staging and omitting a systematic lymphadenectomy.²²

In patients with low/intermediate risk, sentinel lymph node biopsy is an alternative to lymphadenectomy and its histological negativity is accepted as node-negative for staging. On the other hand, in a patient with upper-intermediate/upper risk a systematic lymphadenectomy should be performed.²³

“Fertility sparing”

Standard treatment for endometrial cancer precludes fertility and it may be rejected by young women eager to preserve their reproductive potential. In these patients, endometrial cancer generally occurs with favorable prognostic characteristics: endometrioid histotype, well-differentiated, minimal/absent myometrial invasion. Considering the excellent oncological outcomes (overall 5-year survival rate of 99.2% and overall 10-year survival rate of 98%) a conservative treatment involving oral (medroxyprogesterone or megestrol acetate) or intrauterine (levonorgestrel intrauterine system) progestin administration can be hypothesized. The pharmacological therapy may be preceded by resectoscopic surgery.²⁴

This conservative treatment must be considered temporary and aimed at obtaining pregnancy starting from the detection of a complete tumor response.

Standard surgical treatment is recommended in the case of disease progression, non-response to therapy after 12 months and after obtaining pregnancy; ovarian preservation may be considered, except for special histotype (serous-papillary adenocarcinoma) or genetical predisposition to gynecological cancers.²⁵

Stage II

The surgical approach in this group of patients consists of radical hysterectomy. Surgical treatment’s choice should follow the recent classification of radical hysterectomy to obtain tumor-free margins. In selected cases, simple hysterectomy with adnexectomy can be considered. In regard to lymphadenectomy, the same considerations previously reported for stage I apply.

PRACTICE RECOMMENDATIONS

CERVICAL CANCER

Introduction

In 2020, 604,000 new cases and 342,000 deaths for cervical cancer were recorded worldwide,²⁶ therefore representing the fourth tumor by incidence in women. Additionally, an estimated 84% of cervical cancer cases currently occur in developing countries.²⁷ The global incidence and mortality rates strictly depend on the presence of screening programs for precancerous lesions and vaccination against human papillomavirus (HPV), both more available in industrialized countries. Thanks to these interventions, a reduction in the incidence (about 75%) and mortality from cervical cancer has been recorded in industrialized countries in the last 50 years²⁸ although there are some exceptions.²⁹ According to some models, if vaccination rates of 70% were achieved worldwide, there would be a decrease of 344,520 new cases each year and 178,182 deaths caused by cervical cancer would be avoided.³⁰

Surprisingly, in countries that have achieved immunization rates >70%, including Australia, there have already been a 38% reduction in high-grade dysplasia.³¹

Data suggest that PAP smear screening combined with HPV vaccination can significantly reduce the incidence of cervical cancer in developing countries.

Carcinoma in situ has a maximum incidence around 25–35 years of age, progressively decreasing in the following age groups until it is absent over 65 years. In contrast, invasive carcinoma has a variable incidence in the various age groups: under 20 years it is practically absent with an incidence of 0.1 per 100,000 women, between 20 and 30 years the incidence rises to 4.5 per 100,000 women but however, it remains extremely low, between 30 and 40 years of age it is 14 per 100,000 women, between 40 and 65 it reaches its peak incidence with 16 cases per 100,000 women and above 65 the incidence starts to fall again with 14 cases per 100,000 women.

In some African states, the disease still affects more than 40 cases per 100,000 inhabitants compared to Western Europe and the United States where the average incidence is less than 10 cases per 100,000 inhabitants.²⁷

Risk factors

The two main histological types of cervical cancer (adenocarcinoma and squamous cell carcinoma) share many of the same risk factors.^27,32,33

HPV-related cervical cancer – in the majority of diagnosed cases, cervical cancer is caused by human

papillomavirus (HPV) infection.

Risk factors associated with HPV-related cancers include the following:

• Early onset of sexual activity – compared to women 21 years of age or older at the time of first intercourse, the risk is approximately 1.5 times for women 18–20 years of age at the time of first intercourse and 2 times higher for young people under the age of 18.
• High number of partners – the risk of developing cervical cancer is doubled in women with two partners and triple in those with six or more partners than in women with a single partner – high-risk sexual partner (e.g., partners with multiple sexual partners or with a known HPV infection).
• History of sexually transmitted infections (e.g., Chlamydia trachomatis, genital herpes).
• Young age at first pregnancy (less than 20 years) and multiple pregnancies (three or more full-term births); these are probably related to HPV exposure through sexual intercourse.
• History of vulvar or vaginal squamous intraepithelial neoplasia or cancer (HPV infection is also the etiology of most cases of such neoplasms).
• Immunosuppression (e.g., HIV infection).

Non-HPV-related cervical cancer

• Low socioeconomic status – the incidence and mortality of cervical cancer is higher in women who live in communities with higher levels of poverty. This is probably related to the limited access to healthcare and screening programs for these categories.
• Use of oral contraceptives.
• Cigarette smoking – smoking is associated with increased risk of squamous cell carcinoma but not of adenocarcinoma.
• Genetics – although there is no definite genetic theory for cervical cancer, population studies have shown an increased incidence of cervical cancer within members of the same family. Studies are currently underway to identify genetic alterations that may make patients less able to fight persistent HPV infections and more susceptible to develop cervical cancer. The results obtained to date show an association of cervical cancer with a large variety of polymorphisms in a wide variety of genes, including those that regulate immunity and susceptibility, cytokine production, angiogenesis, of tumor suppression.

Histology and diagnosis

In the initial cases, the diagnostic suspicion of cervical neoplasia arises based on a doubtful or positive report on the Pap test, which represents the first-level exam. Colposcopy follows an abnormal cytology: as a II level examination, it allows performing a targeted biopsy and an accurate histological examination. In some cases, a conization may be required if the biopsy is inadequate to define invasiveness or to characterize microinvasive carcinoma. In more advanced cases, the suspicion of neoplasia can also arise on the clinical basis alone, however the diagnosis still requires histological confirmation.

The most frequent histological forms are those of an epithelial nature, which include the following histological types:³²

• Squamous (85%): keratinizing, non-keratinizing, with a special histotype (verrucous, spindle).
• Adenocarcinoma (10–12%): endometrioid, a clear cell, serous, intestinal type.
• Adenosquamous (3–5%).
• Adenocystic (3–5%).
• Undifferentiated.

The human papillomavirus (HPV) subtypes associated with squamous cell carcinoma are different from those

associated with adenocarcinoma. In an international study of over 3000 women diagnosed with cervical cancer, the distribution of histological types was as follows:

• Squamous cell carcinoma – HPV 16 (59% of cases), 18 (13%), 58 (5%), 33 (5%), 45 (4%).
• Adenocarcinoma – HPV 16 (36%), 18 (37%), 45 (5%), 31 (2%), 33 (2%).

Squamous adenocarcinomas exhibit both glandular and squamous differentiation. They may be associated with a worse prognosis than squamous cell carcinomas and adenocarcinomas.

Neuroendocrine or small cell tumors can originate in the cervix but are uncommon. Rhabdomyosarcoma of the cervix is rare; typically develops in young patients. Primary lymphoma of the cervix and cervical sarcomas are also rare histological types. After the histological confirmation of cervical neoplasia, a complex process of clinical and instrumental investigations begins. This diagnostic process must ensure a correct evaluation of the extent of the disease. Some of the procedures indicated are a prerequisite or an integral part of the FIGO staging system (see below), mostly used in gynecological oncology.

• Abdominopelvic MRI with contrast medium: this exam with high levels of sensitivity (93%) and diagnostic accuracy (86%) allows evaluation of the tumor volume, the preservation of the cervical stromal ring, the vaginal extension, the invasion of adjacent structures and organs, the presence of pelvic and retroperitoneal adenopathies, hydronephrosis. Together with pelvic Doppler echoflowmetry, it also represents a fundamental examination for the evaluation of tumor volume, the distance of the tumor from the internal uterine orifice and the length of the cervical canal, which are essential for any conservative surgery in young women.
• Gynecological examination under narcosis when deemed necessary by the gynecological oncologist for the evaluation of parametrial involvement, with biopsy of cervical and vaginal mappings. In the case of suspected infiltration, it is necessary to perform cystoscopy and/or rectoscopy with biopsies of the mucous membranes.
• Total body CT or chest CT with contrast medium, in locally advanced lesions, for the study of distant disease.
• 18 FDG PET-CT. As an alternative to the CT scan, this exam improves the definition of equivocal lesions, lymph node involvement and distant metastases.

Clinical staging

For the staging of cervical cancer, two classifications have been drawn up: the FIGO staging (International Federation of Gynecology and Obstetrics) and the American Joint Committee on Cancer (AJCC) staging, updated 2018 and 2010, which is not generally used in cervical cancer.^34,35

FIGO staging (2018)

The FIGO staging is the one most widely used in the gynecological–oncological field. The following prognostic factors are not included in staging: histological type, grading, oncogenic viruses, mode of infiltration, spread in lymphovascular spaces.

• Stage I: the cancer is strictly confined to the cervix
  • IA: invasive carcinoma that can only be diagnosed microscopically with deep invasion <5 mm
    • IA1: stromal invasion <3 mm in depth
    • IA2: stromal invasion >3 mm but <5 mm deep
  • IB: invasive carcinoma with stromal invasion >5 mm deep (greater than stage IA), lesion limited to the cervix
    • IB1: invasive carcinoma with stromal invasion >5 mm in depth, and <2 cm in greatest diameter.
    • IB2: invasive carcinoma >2 cm and <4 cm maximum diameter
    • IB3: invasive carcinoma >4 cm maximum diameter
• Stage II: cervical cancer extending beyond the uterus without reaching the pelvic wall or III bottom of the vagina
  • IIA: involvement of the upper 2/3 of the vagina without invasion of parameters
    • IIA1: invasive carcinoma <4 cm in greatest dimension
    • IIA2: invasive carcinoma >4 cm in greatest dimension
  • IIB: with invasion of the parameters without reaching the pelvic wall
• Stage III: the carcinoma extends to the pelvic wall and/or involves the lower third of the vagina and/or causes hydronephrosis and/or non-functioning kidney and/or pelvic and/or aortic lymph nodes
  • IIIA: carcinoma involves the lower third of the vagina, without extension to the pelvic wall
  • IIIB: pelvic wall extension and/or hydronephrosis or nonfunctioning kidney (with no other known cause
  • IIIC: involvement of pelvic and/or aortic lymph nodes (r: radiologically; p: pathologically assessed):
    • IIIC1: involvement of pelvic lymph nodes only
    • IIIC2: aortic lymph node involvement
• Stage IV: carcinoma extends beyond the lesser pelvis or has involved the lining of the bladder or rectum (with histological confirmation on biopsy). Bullous edema, as such, does not allow assigning stage IV
  • IVA: infiltration of adjacent organs
  • IVB: distant organ metastasis

Prognostic factors and risk categories

The clinical, instrumental and anatomopathological evaluation of risk factors is necessary not only to formulate a prognostic judgement, but also plays a central role in treatment planning. Evaluation of risk factors includes cervical neoplasm size, stage, depth of invasion, lymph node involvement, presence of lymphovascular space infiltration (LVSI), and histotype.

Stage of disease remains the most important prognostic factor for cervical cancer, as reported in the 26th FIGO Annual Report. The subdivision of the stages into IB1 (<4 cm) and IB2 (>4 cm) stratifies the prognosis in terms of survival and the possibility of local disease control. Bilateral parametrial infiltration and disease

extending into the pelvic wall correlate with lower survival rates and poorer disease control.³⁶

The incidence of lymph node metastases increases with the increase in the stage of the disease and is considered one of the factors with the greatest prognostic impact. According to the literature data, the pelvic lymph node involvement is reported between 12–22%, 10–27%, and 34–43% in stages IB, IIA, and IIB, respectively.^37,38 The presence of LVSI (neoplastic infiltration of lymphovascular spaces) is considered a negative prognostic element and it is correlated to a greater risk of lymph node metastases even in the early stages and a reduction in disease-free survival.^37,39 Survival also appears to be correlated with the depth of stromal invasion; a relative risk of 3 and 4 times higher was recorded in the groups with stromal invasion >10 and 20 mm, respectively; during anatomopathological analysis, the ratio between tumor infiltration and total thickness is to be evaluated, in order to determine the disease-free space.³⁸

As far as the histotype is concerned, to date there is no consensus data in the literature regarding the impact on the prognosis. According to one study, adenocarcinoma histology is an independent negative prognostic factor.³⁹ The degree of differentiation of the tumor cells would seem to be a less important factor in terms of prognosis.

Other negative prognostic factors reported in the literature are high SCC values and low hemoglobin levels at diagnosis.³⁷

Treatment according to stage

Pre-invasive cancers

The aim of the treatment of pre-invasive tumors of the uterine cervix is the elimination of potentially progressive lesions and the recognition of possibly already invasive lesions. The excisional treatment must in any case be conservative, above all in consideration of the average age of onset and the reproductive desire;⁴⁰ in particular, less extensive treatments are to be preferred under the age of 25 and for minor lesions.⁴⁰ The excisional treatment can be performed with a cold blade, diathermic loop, CO₂ laser, radiofrequency needle.^41,42

In any case, in excisional treatments the cone must be obtained with margins in healthy tissue (possibly in a single piece)⁴¹ and the treatment must allow the restoration of a new squamo-columnar junction (SCG) accessible to cytological and colposcopic follow-up.⁴²

HPV-related CIN1, both at high and low risk, regresses spontaneously in most cases, especially in young women, with no increase in invasive cancers at follow-up.⁴³ The risk of occult CIN3+ is low and mainly depends on the previous cytology: 3.8% after LSIL or HPV+ ASC-US, 15% after HSIL.⁴⁴ Therefore, only follow-up after adequate colposcopy is preferentially indicated, differentiating on the basis of previous cytology and age group:

• 12-month follow-up based on cotesting (Pap test + HPV test), except in women <25 years in which only cytology is allowed;
• in case of persistence at 12 months, excisional treatment recommended particularly after HSIL or ASC-H;
• colposcopy suggested at 12 months, regardless of cytology/HPV-test result, in CIN1 cases after HSIL or ASC-H, regardless of age.

The distinction between CIN2 and CIN3 can be difficult in individual cases, but the rates of regression and progression are significantly different between the two grades, obviously to the detriment of CIN3, which, therefore, represents the immediate precursor of invasive cancer and requires treatment excisional/ablative.⁴⁵

However, the histological diagnosis of CIN2 (or CIN2–3 unspecified) equally requires excisional treatment except in young women in whom six-monthly follow-up (colposcopy and cytology) for 12 months is acceptable, followed by excisional treatment if of persistence.

The risk of progression from CIN 2, CIN2–3, and CIN3 to microinvasive or overtly invasive carcinoma during pregnancy is minimal, therefore excisional treatment of high-grade lesions is avoided during pregnancy and excision by conization is recommended only in the case of suspected invasive disease;⁴⁶ resection with diathermic snare performed in pregnancy is associated with a greater risk of hemorrhage, while the association with pre-term delivery, low birth weight newborn, or cesarean section is not confirmed; there is also a high percentage of incomplete excisions, with significant persistence or recurrence of CIN.

In pregnant women, a quarterly follow-up (colposcopy and cytology) with re-evaluation not earlier than 4–6 weeks after delivery is therefore acceptable.

Cervical adenocarcinoma in situ (AIS) is an infrequent but increasing clinical entity; presents management difficulties related to the often absence of colposcopic anomalies, the frequent extension in the cervical canal and multifocality.⁴⁷

Total hysterectomy is, therefore, the recommended therapeutic choice in women who have completed the reproductive cycle; in childbearing age with desire for offspring, conization/cylindrization alone may be considered an option in the presence of negative margins of the cervical conus/cylindrum, even in the presence of a slightly less than 10% risk of persistent AIS and much less of covert invasive carcinoma.^40,47

Early invasive cancers

Early invasive cancer of the uterine cervix is represented by the disease strictly confined to the cervix and corresponds to the so-called “microinvasive” cancer (IA1-IA2) and to the clinically visible ≤4 cm (IB1-IB2) and IIA1.

Surgery

Current guidelines envisage radical hysterectomy with pelvic lymphadenectomy as the standard treatment of early cervical cancer,^34,48 with the sole exception of stage IA1 squamous cell tumors without invasion of lymphovascular spaces, which can be treated with conization or extra hysterectomy fascial.⁴⁹

The surgical treatment of invasive cervical cancer represents an elective field of modulation of surgical radicality, which can range (depending on the stage of the disease and the pathological risk factors) from conservative treatments of conization and trachelectomy, to classic radical hysterectomy and modified, and up to demolition interventions of pelvic evisceration.

The cornerstone of primary surgical treatment of early-stage cervical cancer remains radical hysterectomy (with varying degrees of parametrectomy); pelvic lymphadenectomy is indicated in all patients with tumors at stage IA1 and invasion of lympho-vascular spaces and from stage IA2 onwards.⁵⁰

Adnexectomy is a procedure usually performed in postmenopausal patients and in advanced stages, while in young patients with early stage squamous cell carcinoma, in selected cases, it may not be performed.⁵¹

The new classification of radical hysterectomy by Querleu-Morrow, compared to the previous one by Piver Rutldege, replaces the term "parametrium" with "paracervix", revises a series of anatomical landmarks and classifies the increasingly widespread "nerve-sparing" techniques of preservation of the main visceral nerve pathways.⁵² In the table below, the types of radical hysterectomy according to the latest review of 2017.⁵³

Radical hysterectomy that is oncologically adequate for the treatment of early cervical cancer can unanimously be defined as type B,^38,48,49,54 which, although not free from peri-operative complications and deferred morbidity, is associated with a significantly lower incidence of hemorrhages, bladder/ureteral and urinary/defecation dysfunctions from denervation compared to classic non-nerve-sparing hysterectomy (similar to type C2 according to the new classification).⁵⁵ In our opinion, type C hysterectomy remains advisable in stage IB2 disease due to the known correlation between tumor size and risk of invasion of the paracervix. In the table below, in detail, the type of radical hysterectomy suggested based on the prognostic risk.⁴⁹

In early cervical cancer, paracervical involvement ranges from 6 to 24%, drastically decreasing below 1% in low-risk groups of patients (tumor size <2 cm, stromal invasion <10 mm, absence of lymphatic space invasion, vascular disease, non-neuroendocrine/undifferentiated histology, lymph node negativity)⁵⁶ making parametrectomy a superfluous procedure in over 75% of cases. Paracervical involvement is closely related to lymph node status. Pelvic lymph node metastases had been observed in 4–31%, progressively decreasing with decreasing stage.⁵⁷ Paracervical involvement without pelvic lymph node metastasis is rare (0–6%), so pelvic lymph node status is an effective predictor of paracervical status.^37,58

With these premises, radical trachelectomy (vaginal or abdominal) has been widely practiced in selected groups of patients: age <40–45 years, desire for fertility, stage IA1 (with invasion of lympho-vascular spaces), stage IA2, stage IB1 "not unfavorable" histotype, absence of lymph node and/or distant metastases.⁵⁹ However, even radical trachelectomy presupposes parametrectomy (and relative morbidity), for which simple hysterectomy has also recently been proposed for low-risk patients,⁵⁵ if they wish to have offspring, simple trachelectomy or, better, for gestational purposes, the large conization^60,61,62,63 always associated with pelvic lymphadenectomy (laparoscopic). Neoadjuvant chemotherapy followed by extensive conization was performed in this subset of patients for tumors larger than 2 cm in reference centers.

PRACTICE RECOMMENDATIONS

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