Many systems have been developed for classifying cervical cytologic findings. Although criteria for the diagnosis of CIN and degree of neoplasia vary somewhat between pathologists, the important features of CIN are cellular immaturity, cellular disorganization, nuclear abnormalities, and increased mitotic activity. The term cervical intraepithelial neoplasia, as proposed by Richart [37] refers to a lesion that may progress to invasive carcinoma:

Following a 1988 National Cancer Institute Consensus Conference, the Bethesda system of classification was developed in an effort to further standardize reporting [38]. This system defines squamous intraepithelial lesions (SILs) as including all squamous alterations in the cervical transformation zone that are induced by HPV; SILs include all lesions that were classified in previous systems as condyloma, dysplasia, or CIN. The Bethesda system divides SILs into two groups: low grade and high grade. Low-grade SILs (LSILs) have nuclear crowding or atypia without frequent mitoses, parabasal cell anisokaryosis, or coarse chromatin; these lesions are usually associated with low-risk HPV types and have a low likelihood of progressing to invasive cancers. High-grade SILs (HSILs) have nuclear atypia in lower and upper epithelial layers, abnormal mitoses, coarse chromatin, and loss of polarity. HSILs are usually associated with high-risk HPV types and have a higher likelihood of progressing to invasive cancer. The Bethesda system was meant to replace the Papanicolaou system and is now widely used in the United States. However, its use is still controversial. Some groups [39, 40] argue that the new nomenclature has failed to improve diagnostic accuracy and believe that with dichotomization of the spectrum of atypical lesions, lesions that were formerly classified as CIN 2 (now HSIL) may be overtreated despite their relatively low risk of progression.

The term atypical squamous cells of undetermined significance (ASCUS) was introduced by Bethesda system. This uncertain diagnosis is now the most common abnormal Pap smear result in United States laboratories [41], with 1.6–9 % of Pap smears reported as having ASCUS. Although most cases of ASCUS reflect a benign process, about 5–10 % are associated with an underlying HSIL, and one-third or more of HSILs are heralded by a finding of ASCUS on a Pap smear.

Histopathologic types of cervical cancer are [42]: squamous cell carcinoma (69 %), adenocarcinoma (including adenosquamous – 25 %) and other histologies (6 %). The incidence of invasive cervical adenocarcinoma and its variants has increased dramatically over the past few decades, particularly in younger women [43, 44]. Several causative factors have been proposed to explain this trend, including increased prevalence of specific HPV-16 and 18 variants that are associated more with adenocarcinoma than with squamous cell carcinoma as well as exposure to estrogens, both endogenous (e.g., obesity) and exogenous (e.g., hormonal contraception, postmenopausal estrogen therapy).

Adenosquamous tumors exhibit both glandular and squamous differentiation. They may be associated with a poorer outcome than squamous cell cancers or adenocarcinomas [15].

Neuroendocrine or small cell carcinomas can originate in the cervix in women, but are infrequent [45]. Rhabdomyosarcoma of the cervix is rare; it typically occurs in adolescents and young women [46]. Primary cervical lymphoma and cervical sarcoma are also rare [47, 48].

Adenocarcinoma in situ (AIS) is diagnosed when normal endocervical gland cells are replaced by tall, irregular columnar cells with stratified, hyperchromatic nuclei and increased mitotic activity but the normal branching pattern of the endocervical glands is maintained and there is no obvious stromal invasion. About 20–50 % of women with cervical AIS also have squamous CIN [49]. Because AIS is frequently multifocal, cone biopsy margins are unreliable. AIS is a precursor of invasive adenocarcinoma. It is found adjacent to many invasive adenocarcinomas, often accompanied by squamous dysplasia. Both AIS and invasive adenocarcinoma of the cervix are associated with HPV (usually type 18, but sometimes type 16). AIS is characterized by preservation of the overall endocervical gland architecture. However, endocervical glands and surface epithelium are replaced to varying degrees by cells displaying atypia, including nuclear enlargement and stratification, nuclear hyperchromasia, and mitotic figures. Most adenocarcinomas in situ occur near the transformation zone, and skip lesions are unusual [49].

Around 80–90 % of cervical carcinomas are squamous cell carcinomas. Squamous carcinoma of the cervix includes both microinvasive squamous carcinoma and more deeply invasive carcinoma. Small cell squamous carcinomas have small to medium-sized nuclei, open chromatin, small or large nucleoli, and abundant cytoplasm [50]. Sarcomatoid squamous carcinoma is very rare variant, demonstrating areas of spindle-cell carcinomatous tumor confluent with poorly differentiated squamous cell carcinoma; immunohistochemistry demonstrates expression of cytokeratin and vimentin.

While the incidence of squamous carcinoma of the cervix has decreased in past decades owing to cytologic screening, the number of cases of cervical adenocarcinoma has increased [53, 54]. Adenocarcinoma of various types accounts for 20–25 % of cervical carcinomas [53].

About 80 % of cervical adenocarcinomas are endocervical-type adenocarcinomas, which are composed predominantly of cells with eosinophilic cytoplasm, frequent apoptotic bodies, although many other patterns and cell types have also been observed.

There are several variants of mucinous adenocarcinoma of the cervix, including endocervical, intestinal, signet ring cell, minimal deviation, and villoglandular variants. HPV DNA has been detected in more than 90 % of mucinous adenocarcinomas of the cervix, including endocervical, intestinal, and endometrial subtypes [55]. Endocervical-type adenocarcinomas are frequently referred to as mucinous; however, although some have abundant intracytoplasmic mucin, most have little or none [53].

Endometrioid carcinomas of the uterine cervix are rare (about 7 % of all cervical adenocarcinomas). These neoplasms display histologic features identical to endometrial carcinoma. Therefore, the possibility of a primary endometrial adenocarcinoma with endocervical extension or drop metastasis must be excluded before establish the diagnosis of primary endocervical endometrioid adenocarcinoma. Immunohistochemistry may help in difficult cases: combination of CEA positivity, ER and vimentin negativity is most often seen in endocervical primary tumors, while the reverse is more often characteristic of endometrial primary tumors. Evidence of association with HPV also supports an endocervical primary neoplasm [56].

Quadrivalent vaccine (Gardasil): administered in three doses at time zero, 2 and 6 months of follow-up.

Bivalent vaccine (Cervarix): administered in three doses at time zero, 1 and 6 months of follow-up.

The ACIP recommends that if the vaccination series is interrupted for any length of time, it can be resumed without restarting the series.

HPV vaccines have shown excellent duration of protection for the time periods through which they have been studied. However, the duration of protection after immunization is unknown; to date, women have been protected during a mean follow-up time of 42 months after the first dose of quadrivalent HPV vaccine [74]. The precise level of antibody needed for protection against infection is also unknown.

Challenges for HPV vaccination include older age for vaccination, a three-dose regimen at a high cost relative to other childhood vaccines, and potential socio-cultural concerns about HPV being a sexually transmitted disease [56]. The majority of cervical cancer cases occur in the developing world [56, 75] and patients in these nations are less likely to receive HPV vaccination. Despite its high cost relative to other childhood vaccines, in nations with high incidence, emerging models suggest that vaccination is cost-effective [56, 76].

Stage IA involves microscopic lesions with horizontal or superficial extension and limited vertical invasion with low risk for lymphatic dissemination (less than 1 %) [78]. Lesions classified as stage IA1 by the FIGO system and without angiolymphatic invasion are considered low risk lesions and eligible for a conservative surgical treatment [79]. The indicated surgical treatment in this scenario for women with no desire for future pregnancies is the extrafascial simple hysterectomy, which could be performed through the access that best suits the patient and surgeon’s experience.

A wide cone biopsy (cold knife or LLETZ) could be performed in patients who desire fertility preservation as long as negative margins are obtained.

Treatment for tumors stage IA2 remains controversial. According to literature, up to 13 % of patients in this group may have positive lymph nodes. This relatively high incidence generally contributes to the indication of a more radical approach [80]. On the other hand, a recent literary review [81] suggests an incidence lower than 1 % for lymph node positivity in stage IA2 patients. Historically, there has been a tendency to attribute an unfavorable prognosis to adenocarcinomas, contraindicating any attempt to a non-radical approach. However, recent case studies including one literary review [82], support that micro invasive cervical adenocarcinomas may be treated in the same manner as squamous cell carcinomas when in equivalent stages. The presence of angiolymphatic invasion in pathology reports, regardless of tumor histology or degree of invasion, considerably increases the risk for lymph node metastasis [83] and determines the necessity for a radical approach (refer to stages IB1 and IIA1 below).

Tumors up to 4 cm in diameter, limited to the cervix or compromising the upper third of the vagina, defines the patient population that most benefits from a radical surgical approach (radical hysterectomy combined with bilateral pelvic lymphadenectomy). Radical hysterectomy is not defined by a single technique but rather by a group of techniques united by a common denominator – removal of the uterus en bloc with the upper third of the vagina. The Rutledge, Piver and Smith classification [84] or even more recent, the Querleu and Morrow classification [85] define different classes of hysterectomies based on the extension of vaginal and parametrial resection with or without preservation of the hypogastric nerve plexus. The purpose of this discussion is not to provide a detailed description of each individual technique due to the variety and complexity of possible procedures and anatomical considerations. The table below summarizes the different classes of hysterectomies and each indication. Refer to the bibliographic references and surgical textbooks for further information. Note that none of the radical hysterectomy techniques described below include oophorectomy as a mandatory procedure. Given the rarity of occult metastatic involvement of the ovaries (<1 %) in initial stages and the benefits of hormone function preservation in young women, ovarian-sparing hysterectomy could be a feasible option. The most frequently adopted procedures are the type II Piver radical hysterectomy (Querleu-Morrow B) and type III (Querleu-Morrow C-1 or C-2), the tumor size generally orienting the most indicated technique (2 cm cut-off). The most significant difference between these procedures, besides operative time, is hypogastric nerve plexus injury clinically manifested as bladder dysfunction, necessity for intermittent or permanent bladder catheterization, recurrent urinary tract infections and diminished quality of life. Less extensive procedures (type II or B) reduce manipulation of the hypogastric nerves, minimizing bladder function disruption. Furthermore, since the original prospective study [86], increasing evidence supports that type II or B radical hysterectomy could be sufficient treatment for lesions limited to the cervix up to 4 cm in diameter (refer to stages IB2 and IIA2 below). Recent studies have questioned the necessity for any degree of parametrial resection, suggesting the permanent substitution of the radical hysterectomy for the simple hysterectomy [87]. However, there is still no consensus that defines the ideal extent of resection, leading many centers to continue indicating type III or C hysterectomies. This practice increases the interest in nerve sparing surgery (type C1) intended to successfully combine surgical radicalness with decreased neurological morbidity [88].

The concept of fertility preservation originally described by Daniel Dargent in 1987 [89], consists of the resection of the cervix, proximal parametria and upper third of the vagina, conserving the uterine body which is anastomosed to the remaining vaginal wall. This procedure, also known as radical vaginal trachelectomy, could be performed via abdominal incision or transvaginal as long as adequately complemented by pelvic lymphadenectomy, preferably through video laparoscopy. Subsequent studies [90] support that this feasible technique respects fundamental oncological principles present in traditional radical hysterectomy while successfully maintaining fertility, occasionally affected by cervical insufficiency or stenosis. The literature is limited regarding the use of this technique for gestation preservation in pregnant women [91]. The success rate for radical vaginal trachelectomy depends on adequate patient selection. Patients who require adjuvant radiotherapy (refer to adjuvant radiotherapy for indications) will experience endometrial and ovarian dysfunction, impairing the possibility for future pregnancies. As in Dargent’s original series, current recommendation for this procedure is limited to patients with tumors up to 2 cm, yet a few studies have questioned this limit and even considered the possibility of neoadjuvant chemotherapy [92].

The amount of prospective and randomized evidence available comparing video laparoscopic versus conventional hysterectomy is still surprisingly scarce despite the existence of reports on laparoscopy dating back over 20 years [93] and the widespread practice of this procedure amongst the gynecologic oncology community [94]. Yet sufficient retrospective data [95] consistently support the advantages of a minimally invasive access such as blood loss reduction, faster reestablishment of intestinal function, less painkiller use and hospitalization period. Robotic video laparoscopic surgery is a recent technique apparently safe in experienced hands. Success rates are similar to those of conventional surgery [96] yet with improved practical conditions to perform nerve sparing surgery [97]. Other advantages include a smaller learning curve and inferior conversion rate when compared to regular video laparoscopy [98]. Its major limitation is the excessive financial cost, considerably reducing acceptance [99].