Keywords

7.1 Cytology and Cervical Cancer

Cervico-vaginal cytology is an accessible, simple, sensitive, and specific test. In Mexico, the cervical cancer detection program was implemented in 1974, with the aim of detecting precursor lesions, as well as decreasing the number of invasive carcinomas [1].

The sensitivity of this test is very high (90–95%), although its specificity is low (50–75%) given the great percentage of false-negative results. Such results are caused by inadequate sampling, processing and interpretation. Poor-quality sample acquisition is due to the lack of sample transformation area, poor extension technique, and improper sample fixation or processing. Errors in interpretation are due to deficient tracking and a lack of personnel training. Quality sampling is crucial to eliminate false-negative and false-positive diagnoses and is therefore the most important factor in improving the sensitivity of cytologic testing [2].

Cervical cytology sampling must be performed when active sexual life starts and then every 2 years; as long as the results are negative, testing should then be performed every 3 years until the patient turns 65 years old.

7.1.1 Cytology Report and the Bethesda System

Since it began in the 1940s, the cervical cytology report has been evolving, from the Papanicolaou classification up to the current day Bethesda system in 1988, when a group of professionals gathered for the first time with the goal of developing a system to report Papanicolaou results, which would report the cytologic interpretation to the gynecologist in a clear, relevant mode.

The Bethesda system has two main objectives: to specify the sample quality and build a unified system to inform or interpret cytologic data in the context of clinical findings and to provide an efficient and clear communication to the physician [3].

The system has three sections: the first is the sample quality (satisfactory or unsatisfactory for evaluation); the second is the general classification, where the existence of anomalies in epithelial (squamous or glandular) cells is reported; and the third corresponds to the results or interpretation section, which specifies whether there is a diagnosis of an intraepithelial lesion or malignancy, be it squamous or glandular (in this section, we can include the presence of microorganisms or other non-neoplastic findings), as well as other neoplasias, such as metastasis or lymphomas [3].

  1. (a)

    Sample quality. This depends on various factors, such as adequate cellularity; for conventional cytology, a minimum of 8000–12,000 cells from the squamous epithelium are required; for liquid-based cytology, the minimum is 5000 cells. Another important factor is the presence of cells from the transformation zone; these are the endocervical and metaplasia cells, and a minimum of 10 properly conserved cells is acceptable, isolated or in groups. Two situations that impair proper sample evaluation are when more than 75% of the squamous cells are not clearly visible (thick smear) or when the smear has more than 75% hemorrhage, inflammation or necrosis, which impairs squamous cell evaluation.

  2. (b)

    General classification. When there are no signs of neoplasia, the term “negative for intraepithelial lesion or malignancy” is used; this classification includes observations concerning microorganisms, radiotherapy-induced changes, atrophy, DIU (Dispositive intra-uterine)-induced changes, and unspecific inflammation; when a lesion or atypia is observed in the squamous epithelium, either associated with atypia of undetermined significance or even to epidermoid carcinoma, the term “squamous cell abnormalities” is used; when there is a lesion or atypia in the glandular epithelium, the term “glandular cells anomalies” is used; this includes glandular cell atypia (endocervical, endometrial, or unspecific) up to adenocarcinoma.

  3. (c)

    Results or interpretation. In this section, we briefly describe intraepithelial lesions and malignancy diagnosis, as well as their clinical significance and recommended management according to the last review of the Bethesda system and the last consensus of the American Society of Colposcopy and Cervical Pathology (ASCCP) [3].

7.1.2 Squamous Epithelial Lesions

Atypical Squamous Cells of Undetermined Significance (ASC-US)

This represents cytological changes suggestive of an intraepithelial lesion that are qualitatively and quantitatively insufficient to diagnose a low-grade squamous intraepithelial lesion. The 5-year risk of developing a high-grade squamous intraepithelial lesion and cancer with an ASC-US in addition to a positive molecular HPV test is 1.1%; for ASC-US with a positive HPV study, it increases to 18%. The suggested initial management consists of performing a molecular HPV test; if the results are negative, it is recommended to repeat the test and make a co-test (HPV test and cytology); if the test yields positive HPV results, it is recommended to perform a colposcopy [3, 4].

Atypical squamous cells, for which it is not possible to rule out a high-grade intraepithelial lesion (ASC-H)

A lesion is observed in immature squamous cells: the cells are usually scarce, and they can show various patterns, including cells with atypical metaplasia, 3D cell clumps, marked atypical repair, severe atrophy, and post-radiotherapy changes suggestive of recurrence. The 5-year risk of a high-grade intraepithelial lesion and cancer, with an ASC-H diagnosis and a negative HPV test, is 12%; for an ASC-H with a positive HPV test, the risk increases to 45%. The suggested management for women with an ASC-H diagnosis is colposcopy regardless of the HPV test results. It is not recommended to perform a molecular HPV test once the ASC-H cytologic diagnosis is performed. There are guides specific for special populations established in the last consensus of the ASCCP [3, 4].

Low-grade squamous intraepithelial lesion (LSIL)

This represents changes in mature squamous cells (superficial or intermediate) associated with HPV, and the morphological changes are equivalent to mild dysplasia or low-grade intraepithelial lesion (NIC1) (Fig. 7.1). The 5-year risk of a high-grade intraepithelial lesion or cancer is 18%, similar to ASC-US with positive HPV results. The suggested management is as follows: women without an HPV study must have cytology testing within 12 months; for women with a positive HPV test, colposcopy is recommended; women older than 25 years must be followed-up with cytology testing within 12 months [3, 5].

Fig. 7.1
figure 1

Low-grade intraepithelial lesion (NIC1)

Full size image

High-grade squamous intraepithelial lesion (HSIL)

This represents changes in the smallest squamous, immature cells (para-basal) whose main feature is the loss of the nucleus/cytoplasm ratio (Fig. 7.2). An HSIL diagnosis in cytology includes NIC2, NIC3, and in situ carcinoma in the histological section. Most of the patients diagnosed with HSIL have an NIC2 or NIC3 biopsy. The suggested management for women older than 25 years is colposcopy with an excisional procedure (cone), if the lesion is identified; however, if the high-grade intraepithelial lesion is not confirmed by biopsy, the recommendation is to perform a revision of the cytology and histological material, with an additional immunohistochemical analysis to assess p16 [3, 6].

Fig. 7.2
figure 2

Immature cells (para-basal)

Full size image

Squamous cell carcinoma

This term refers to an epithelial invasive tumor composed of squamous cells of distinct differentiation degrees. The Bethesda system does not subdivide squamous cell carcinoma similar to the World Health Organization (WHO) classification: keratinizing, non-keratinizing, papillary, basaloid, warty, squamo-transitional, and lympho-epithelial. This is because the morphological characteristics are not clearly distinguishable using the cytology results [3].

Glandular cell alterations: it is important to consider that cytology primarily detects lesions in the flat epithelium, and it does not detect glandular lesions; given the scarce frequency of the latter and low sensitivity, errors in sampling and the interpretation of results [3].

7.1.2.1 Glandular Epithelium Lesions

Atypical glandular cells (AHCs)

This term refers to alterations in the glandular epithelium beyond reactive changes but insufficient to categorize them as adenocarcinoma. The morphological entities that suggest this diagnosis can be benign or malignant: the benign conditions include endocervical and endometrial polyps, endometriosis, endocervical microcystic hyperplasia, adenosis, energetic and lower uterine segment brushings, tubal metaplasia, and Arias-Stella phenomenon; the malignant conditions include high-grade intraepithelial lesions with glandular penetration in situ adenocarcinoma and invasive adenocarcinoma [3].

The Bethesda system subdivides these results as follows:

  1. (a)

    Atypical endocervical cells (unspecified, NOS)

  2. (b)

    Atypical endometrial cells (unspecified, NOS)

  3. (c)

    Atypical glandular cells (unspecified, NOS)

  4. (d)

    Atypical endocervical cells (favors neoplasia)

  5. (e)

    Atypical glandular cells (favors neoplasia)

As discussed in the previous paragraph, the Bethesda system categorizes glandular cells according to their site of origin whenever possible because the clinical follow-up and management vary depending on the cell type; however, on several occasions, it is impossible to determine the cells’ origin. This is why the term “atypical glandular cells” (AGCs) is more pervasively used in cytology [3].

The 5-year risk of a high-grade intraepithelial lesion after an AGC diagnosis is 10–40%; this seems paradoxical because a high-grade squamous intraepithelial lesion is frequently extended to glandular endocervical spaces, replacing them to such an extent that the smear gives the appearance of a lesion in the glandular epithelium. This is a context in which the cells characteristic of a high-grade lesion are not present in the rest of the smear; based on this, it is the pathologist’s or cytopathologist’s duty to place a note specifying the probable nature of the lesion to guide the gynecologist. With the AGC diagnosis and a negative HPV molecular test, the risk is 0.09%; however, with an AGC with a positive molecular HPV test, the risk of a high-grade lesion in the squamous epithelium increases to 33% [3, 6].

In situ endocervical adenocarcinoma (IEA)

It refers to a high-grade glandular endocervical noninvasive lesion. This cytological interpretation is highly difficult, even for the most experienced cytopthologists, explaining why the “atypical endocervical cells, promotes neoplasia” interpretation is justified. The coexistence of a squamous and a glandular lesion in the cervix must always be considered when an in situ endocervical adenocarcinoma is interpreted. More than half of IEAs frequently have an intraepithelial squamous lesion. According to the ASCCP, the initial management includes colposcopy and endocervical curettage. HPV detection tests are not recommended because they can yield negative results [3].

Adenocarcinoma

An adenocarcinoma diagnosis, either endocervical or endometrial, must be given when the following cytologic criteria are observed: tumoral diathesis, hemorrhagic background, abnormal glandular cells with the presence of macronuclei and architectural atypia. Additionally, because cellular morphology can be difficult to interpret, the cytological classification of morphological variants is discouraged because it is poorly reproducible, especially in extrauterine-originated adenocarcinomas, where the clinical correlation is crucial. Patient management depends on the clinical stage [3].

7.1.3 Liquid-Based Cytology and Molecular Biology Studies

In 1996, the FDA approved the first commercial brand of a liquid-based screening method. In this test, the cervical-vaginal specimen collected is placed in a vial with preserving liquid; then, in an automated processing machine, it is spread apart, collected, and transferred to a slide to be stained and microscopically evaluated. The cytomorphologic characteristics of the liquid-based cytology are different from those observed in conventional cytology; consequently, the cells develop dyscohesion, decreased size, a loss of the pattern in which they are arranged, and a lack the inflammatory, hematic, and necrotic background in which they are located [7].

Scientific evidence has been found both in favor and against the use of liquid-based cytology in the detection of precursor lesions and to decrease the incidence of inadequate samples. This has prompted some developed countries to completely substitute the conventional smear, whereas others have maintained the conventional cytology because the high cost of the liquid-based method is considered to be unjustified [8, 9].

In liquid-based samples, it is possible to perform complementary tests, such as the detection of HPV DNA and immunocytochemistry for the specific detection of p16, among others [10]. Currently, it is an acceptable strategy to simultaneously perform cytology and HPV DNA test as a screening method and as a post-treatment follow-up because performing both tests together has shown greater sensitivity and specificity than using them separately. In 2004, the FDA approved the use of HPV detection tests as a screening tool and guide for patient management; the aim of HPV detection is not the detection of all virus genotypes but of the high risk-associated genotypes either through the hybrid capture assay or using PCR (polymerase chain reaction). In 2014, the FDA approved the co-test, i.e., performing the cytologic evaluation along with the collection of a sample for the molecular test at the same time as the screening [4, 10].

7.2 Pathology of Cervical Cancer

7.2.1 Squamous Intraepithelial Lesions

They are defined as “Alterations in the squamous epithelium in the cervix transformation zone, which are induced by HPV infection”. Morphologically, they are characterized by maturation anomalies and nuclear anomalies. The first description was published in 1888 by Sir John Williams. Subsequently, the concept of in situ carcinoma (ISC) was defined, and lesions with abnormal characteristics that did not comply with ISC criteria were identified. From the 1950s, some confusing and imprecise terms were coined to refer to these lesions, such as “anaplasia” and “basal cell hyperplasia”. In 1952, Reagan and Hicks introduced the term “atypical hyperplasia” for cervical lesions with a higher differentiation grade than ISC but a lower risk of developing invasive carcinoma. Shortly thereafter, it was replaced by “dysplasia”, which was stratified as follows: mild, moderate, and severe. In 1956, Koss and Durfee described koilocytes, noting similarities to Reagan’s description of mild dysplasia. In 1976, Meisels and Fortin observed an association between these changes and HPV infection. In 1969, Richart proposed that cervical carcinogenesis comprised a spectrum that went from mild dysplasia to carcinoma and introduced the term “Cervical Intraepithelial Neoplasia” (CIN) to emphasize the role of these lesions as cancer precursors. In 1975, the WHO proposed the terminology unification and, soon after, the International Society of Gynecological Pathologists (ISGYP) replaced the term “dysplasia” with “Cervical Intraepithelial Neoplasia” (CIN). According to the epithelial thickness or affected strata, mild dysplasia corresponds to CIN-I, moderate dysplasia to CIN-II, and severe dysplasia to CIN-III/ISC [11, 12].

Towards the end of the 1980s, our knowledge of the biology and oncogenic mechanisms of HPV increased as the subjectivity in the distinction between CIN 2 and CIN 3 became apparent. Currently, the WHO recommends the use of a two-grade nomenclature (low grade and high grade) based on the Bethesda System because it is more reproducible and more biologically relevant [13].

Low-grade squamous intraepithelial lesions (LSILs)

These are considered the clinical and morphologic manifestations of a productive HPV infection, characterized by basal or parabasal-like cell proliferation that does not occupy more than one-third of the epithelium thickness. Non-atypical mitoses can be observed in the same zone. Maturation exists in the rest of the epithelium, although with an increase in nuclear size and occasionally binucleation. Additionally, viral cytopathic effects can be observed, characterized by hyperchromasia and nuclear outline irregularity, in addition to the presence of a vacuole or perinuclear halo. In superficial stratum cells, parakeratosis or hyperkeratosis can be observed.

Although most LSIL cases are related to high-risk HPV types, infected cells are generally euploid or polyploid.

LSIL patients have a favorable prognosis because many of them present regression within the next 12 months. The risk of progression is related to HPV 16 infection, advanced age, immunosuppression, and tobacco consumption. Currently, there are no biomarkers to predict persistence, progression, or regression in these lesions.

High-grade squamous intraepithelial lesions (HSILs)

They are defined as intraepithelial lesions that bear a significant risk of developing invasive carcinoma if left untreated. They are associated with high-risk HPV infection and tend to occur in a more advanced age group than LSILs, but earlier in life than invasive carcinoma, showing an incidence peak between 35 and 39 years. They predominantly localize to the transformation zone and are microscopically characterized by the proliferation of squamous cells with a lower differentiation than those observed in LSIL. Such cells have hyperchromatic nuclei with an irregular outline, and nucleoli are rarely observed. These alterations extend up to the middle or superficial third of the epithelium. Mitoses are more frequent and can be observed in the outermost strata (Fig. 7.3). Some morphologic variants have been described as follows:

  1. (a)

    “Thin” LSILs. They present histological characteristics of LSILs but have a thickness of less than 10 cells.

  2. (b)

    Keratinizing LSILs. There is keratinization on the epithelium surface. Dyskeratosis and nuclear pleomorphism are characteristically observed. They are most commonly found in the exocervix.

  3. (c)

    Condylomatous. These are lesions with the clinical appearance of a condyloma that present changes to LSIL. Such changes can be focal.

  4. (d)

    Epidermoid papillary in situ carcinoma (“squamo-transitional papillary noninvasive carcinoma”). This consists of a papillary lesion with a thin projections covered by epithelium with HSIL (High-grade squamous intraepithelial lesions) features, morphologically similar to urothelial neoplasms.

Fig. 7.3
figure 3

Mitoses are more frequent observed

Full size image

Most of these are monoclonal and are more frequently aneuploid than polyploid. In contrast to LSIL (Low-grade squamous intraepithelial lesions), it is more frequent to find DNA integration of HPV.

The main recurrence prognostically identified factors are the size of the lesion and reaction margin state. It has recently been shown that the evaluation of HPV DNA presence at 12 months after treatment is the best predictor of residual or recurrent disease [13].

7.2.2 Epidermoid Microinvasive Carcinoma

The FIGO (International Federation of Gynecology and Obstetrics) defines it as an invasive epidermoid carcinoma diagnosed exclusively by microscopic evaluation and classifies it at clinical stage IAI.

Clinical stage IAI: epidermoid carcinomas with stromal invasion of less than 3 mm in depth and up to 7 mm in horizontal extension.

Clinical stage IA2: epidermoid carcinomas with stromal invasion of more than 3 mm, but less than 5 mm in depth and up to 7 mm in horizontal extension.

The presence of lymphovascular invasion does not affect staging.

The SGO (Society of Gynecological Oncologists) defines microinvasive epidermoid carcinomas as neoplastic epithelia (in situ carcinomas) that invade the stroma in one or more spots with a maximum depth of 3 mm measured from the basal membrane of the epithelium (Fig. 7.4). There must not be the presence of lymphovascular invasion [14].

Fig. 7.4
figure 4

Microinvasive epidermoid carcinomas as neoplastic epithelia (in situ carcinomas)

Full size image

7.2.3 Epidermoid Carcinoma

It is the second most common neoplasia among women, with a mean presentation age of 55 years. Macroscopically, it presents as an exophytic lesion of papillary or polyploid aspect. The endophytic pattern can also be observed sometimes covered by epithelium with normal characteristics. Tumors originated in the canal are poorly visible and difficult for biopsy collection. In advanced stages, tumors can look ulcerated and friable in appearance; palpation shows induration of the cervix and parametrial region [11, 12].

The histologic grade is based on nuclear pleomorphism, nucleolus size, mitotic activity, and necrosis. Epidermoid carcinomas are classified from well to poorly differentiated. The epidermoid carcinoma of the usual type can be keratinizing or non-keratinizing. The latter is constituted by progenitor polygonal cells arranged in mantles or nests, with the presence of intercellular bridges (Fig. 7.5). Individual keratinization can be observed but not the formation of corneal beads (Fig. 7.6). The cytoplasms are eosinophilic and dense because of keratinization. Abundant keratohyalin granules can be observed [13, 15, 16].

Fig. 7.5
figure 5

Polygonal cells arranged in mantles or nests, with the presence of intercellular bridges

Full size image
Fig. 7.6
figure 6

Individual keratinization can be observed but not the formation of corneal beads

Full size image

7.3 Epidermoid Carcinoma Histologic Subtypes

Basaloid epidermoid carcinoma

This is an aggressive variant. It is comprised of nests of basal squamous cells with an immature aspect, similar to those found in cervical in situ carcinoma. Individual keratinization can be observed, but the formation of corneal beads is rare. There is nuclear pleomorphism, marked mitotic activity, geographical aspect necrosis, and comedonecrosis. It is associated with high-risk HPVI (Human Papiloma Virus Infection). It is presented in advanced clinical stages and has a poor prognosis, unlike basal cell epithelioma, an entity with which a differential diagnosis must be performed [17].

Squamous cell verrucous carcinoma

This is a very well differentiated squamous cell carcinoma, characterized by an undulating hyperkeratosis, warty surface, and a pushing “infiltrative”, bulbous aspect edge. The cytoplasm of neoplastic cells is abundant, and nuclear atypia is minimal. Cytopathologic changes associated with HPVI are not identified. It is a mildly aggressive neoplasia that can recur but does not present metastasis. Unlike condyloma acuminatum, its papillary projections are wide without fibrovascular septa, and koilocytes are not identified [13].

Condylomatous epidermoid carcinoma

This is a carcinoma with a condylomatous aspect at low magnification. It presents an architecture similar to that of condyloma acuminatum or to that of Bowenoid lesions of the vulva. The outline is infiltrative, and the presence of koilocytic atypia is characteristic of this variety [18].

Epidermoid carcinoma with papillary pattern

This is an epidermoid carcinoma characterized by the formation of thick or thin papillae with fibroconnective tissue septa, covered by an epithelium with similar characteristics to those of ISC (In Situ Carcinoma). Unlike condylomatous carcinoma, it lacks koilocytic atypia and Bowenoid aspect. Given its growth pattern in superficial biopsies, it is frequently impossible to determine the presence of invasion [19].

Epidermoid squamotransitional carcinoma

It is a low-frequency variety of cervical carcinoma, occurring in atrophic women; from a histological standpoint, it is indistinguishable from urothelial bladder carcinoma. It can be found in a pure form or with squamous differentiation areas. It is characterized by a papillary growth pattern with fibrovascular septa covered by an atypical stratified epithelium with a urothelial or squamous aspect. Transitional metaplasia has not been proven to be a precursor lesion [20].

Lymphoepithelioma-like epidermoid carcinoma

Similar to its counterpart of the head and neck region, this subtype comprises squamous cell nests or trabeculae that are poorly differentiated and surrounded by lymphoplasmacytic inflammatory infiltrate rich in eosinophils. Neoplastic cells are polygonal, with a vesicular prominent nucleus and eosinophilic cytoplasm with poorly defined edges. This explains why the diagnosis by biopsy is discouraged. The prognosis is favorable, with metastatic lymphatic node metastasis lower than that of other epidermoid carcinoma varieties [21].

7.3.1 Glandular Lesion Precursors

In situ adenocarcinoma/high-risk intraepithelial glandular cervical neoplasia (ISA/HIGCN)

This is defined as an intraepithelial lesion that contains a malignant aspect glandular epithelium and bears a significant risk of developing invasive adenocarcinoma if left untreated. The most common presentation is through a cytological finding of endocervical atypical glandular cells, frequently associated with HSILs [22].

It is associated with high-risk HPV types, mainly 16 and 18. Morphologically, it is characterized by the presence of atypical epithelial cells that replace the normal endocervical gland cover. Neoplastic cells are columnar, they are arranged in a pseudostratified arrangement, and depletion of the mucous content of the cytoplasm is frequently found. The lobular pattern is conserved because abnormal cells are distributed along the pre-existent glandular outlines (Fig. 7.7). “Usual” endocervical-type ISA is the most common form. It presents enlarged hyperchromatic nuclei with thick chromatin and, sometimes, a prominent nucleus. Intestinal differentiation with calciform cells can be observed, or “endometrioid” morphology, characterized by the presence of smaller nuclei and scarce mucus vacuoles in the apical edge of the cytoplasm. It is sometimes possible to identify neuroendocrine or Paneth cells. It is important to recognize intestinal differentiation zones in endocervical glands because their presence almost always indicates a premalignant or malignant lesion, even when cellular atypia is mild.

Fig. 7.7
figure 7

The lobular pattern is conserved because abnormal cells are distributed along the pre-existent glandular outlines

Full size image

A morphological variant named “Stratified Mucinous Intraepithelial Lesion” (SMILE) has been described. It consists of a stratified epithelium consistent of atypical nucleus cells that contain small vacuoles with mucin or clear cytoplasm in all of its layers. Additionally, numerous mitoses and apoptotic bodies are observed, as well as a high proliferation index. SMILEs are usually associated with HSILs and/or ISA.

There are lesions with cytologic atypia previously referred to as “Endocervical Glandular Dysplasia” (EGD) or “Low Grade Glandular Cervical Intraepithelial Neoplasia” (LCIN) with cytological changes with atypia that do not comply with ISA/HCIN. However, the criteria are not well defined, and reproducibility is very low; therefore, it is not considered a specific entity [22].

7.3.2 Early Adenocarcinoma

Unlike squamous neoplasias and glandular neoplasias, there is no consensus to determine microinvasive adenocarcinomas. The SGO (Society of Gynecological Oncologists) applies this term to adenocarcinomas that infiltrate the stroma in one or more spots with a depth less than 3 mm from the base of the epithelium and in the absence of lymphovascular permeation. The FIGO (International Federation of Gynecology and Obstetrics) defines them as invasive adenocarcinomas diagnosed by only microscopic evaluation and classified as clinical stage IA.

The clinical stage IAI corresponds to an adenocarcinoma with invasion to the minor stroma of less than 3 mm in depth and up to 7 mm in horizontal extension.

Clinical stage IA2 corresponds to an adenocarcinoma with invasion to the stroma of more than 3 mm, but less than 5 mm and up to 7 mm in horizontal extension.

The presence of lymphovascular invasion does not affect staging. Because there is no consensus, it is recommended, in invasive neoplasias, to determine the depth of the invasion without using the term “microinvasion”. Notably, in adenocarcinomas with an invasion less than 3 mm, the incidence of positive lymphatic nodes is less than 1% [14].

7.3.3 Adenocarcinoma

Endocervical adenocarcinoma corresponds to 10–25% of cervical carcinomas. Their increase corresponds to improvements in screening methods and better identification of glandular lesions.

Ninety-four percent of endocervical adenocarcinomas are associated with high-risk HPV infection; the most common are isotypes 18, 16, and 45. Their clinical manifestations include transvaginal bleeding and cervical tumor of the exophytic aspect, with ulceration foci or an infiltrative pattern.

7.4 Adenocarcinoma Histologic Subtypes

Endocervical adenocarcinoma of the usual type

It is the most frequent and corresponds to 90% of all uterine cervical adenocarcinomas. Macroscopically, most have an exophytic aspect. Histologically, they present a complex architectural pattern constituted by glands arranged in cribiform or papillary structures with the presence of mucoproduction. Neoplastic cells show stratification, mitotic activity, nuclear enlargement and hyperchromatism, as well as prominent nuclei. Cytoplasms can be eosinophilic (Fig. 7.8) or clear [22].

Fig. 7.8
figure 8

Cytoplasms can be eosinophilic or clear [22]

Full size image

Mucinous adenocarcinoma

This is classified into four variants: usual type, gastric type (minimal deviation adenocarcinoma), intestinal type, and signet ring cells.

Usual type mucinous adenocarcinoma corresponds to a mucoproductor adenocarcinoma that cannot be classified in any other specific variant.

Gastric type adenocarcinoma (minimal deviation adenocarcinoma) corresponds to 1% of cervical adenocarcinomas and, in most cases, are not related to HPVI. An association with the Peutz-Jeghers syndrome has been reported. Histologically, it corresponds to a very well differentiated adenocarcinoma surrounded by stroma that shows scarce or no desmoplastic reaction in some areas. Cases with gastric differentiation present cells with a clear cytoplasm and sharp outlines, with a large, hyperchromatic nucleus. In immunohistochemical analysis, the cells are positive for MUC6 and HIK1083. Their behavior is more aggressive than conventional adenocarcinomas.

Intestinal type mucinous adenocarcinoma is similar to that originated from the intestinal mucosa, with the presence of calciform, argentaffin, and Paneth cells. It is associated with HPVI.

Signet cell mucinous adenocarcinoma is characterized by the focal or diffuse presence of broad cytoplasm cells, occupied by mucus vacuoles that push the nucleus towards the periphery. It can be associated with or without HPVI [22].

Villoglandular adenocarcinoma

This presents in young women (mean age of 35 years), and it is associated with high-risk HPVI. Clinically, these are exophytic tumors. Histologically, they show an exophytic pattern constituted by villous or papillary structures covered by an endocervical type columnar epithelium, with mild or moderate atypia and a decrease in mucoproduction. When it is superficial, its prognosis is excellent. Nonetheless, the prognosis changes if the invasive component is poorly differentiated or if it presents lymphovascular permeation [22].

Endometrioid adenocarcinoma

This represents 5% of endocervical adenocarcinomas, and it is associated with high-risk HPVI. Histologically, they are similar to its endometrial cavity-originated counterpart. By immunohistochemistry, they are diffusely positive for p16 and express CEA; unlike endometrial cavity endometrioid adenocarcinomas, they are negative for estrogen receptor and vimentin. Their prognosis is better than the usual type mucinous adneocarcinomas [22].

Clear cell adenocarcinoma

This is uncommon in the cervix, and it can present in young women with diethylstilbestrol sporadic exposition history in the uterus. It can be associated with high-risk HPVI. Histologically, they are arranged in a tubular-cystic, papillary or solid pattern. The cells are clear; some have the shape of a tack and a high grade. Hiliary intra- or extracellular globes can be observed. The prognosis is similar to that of conventional endocervical adenocarcinoma [22].

Derous carcinoma

This neoplasia is extremely rare in the cervix, and it is similar to that originated in the endometrium, salpingo, or ovary. It is most frequently associated with HPVI in young women. It is arranged in a complex papillary pattern covered by cubic cells with a high nuclear grade. Exfoliation of cells or psammoma bodies can be observed. The behavior is associated with patient age, advanced clinical stage, tumors larger than 2 cm, invasion larger than 1 cm, and the presence of lymphovascular permeation [22].

7.4.1 Other Epithelial Neoplasias

Adenosquamous carcinoma

This is a neoplasia constituted by adenocarcinoma and epidermoid carcinoma areas in which both components are histologically recognizable (Fig. 7.9). Epidermoid carcinomas with mucoproduction but with a lack of glandular formation or with a solid pattern and absence of squamous differentiation must not be included.

Fig. 7.9
figure 9

This is a neoplasia constituted by adenocarcinoma and epidermoid carcinoma areas in which both components are histologically recognizable

Full size image

HPVI subtypes 16 and 18 are the most prevalent, and precursor lesions are in situ epidermoid carcinoma and in situ adenocarcinoma.

Although there is some controversy in relation to its prognosis, there is consensus regarding its behavior being similar to that of endocervical adenocarcinoma, stage by stage [23].

Other cervical malignant epithelial neoplasia subtypes include glassy cell carcinoma, adenoid basal carcinoma, adenoid cystic carcinoma, and undifferentiated carcinoma [23].

7.5 Neuroendocrine Tumors

It is recommended to use the terminology of gastric-enteric-pancreatic neuroendocrine tumors for cervical neuroendocrine tumors.

Low-grade neuroendocrine tumor.

  • Carcinoid tumor

  • Atypical carcinoid tumor

High-grade neuroendocrine tumor.

  • Small cell neuroendocrine carcinoma

  • Large cell neuroendocrine carcinoma

Cervical neuroendocrine neoplasias are associated with HPVI, particularly subtype 18. In immunohistochemistry, they are positive for chromogranin, synaptophysin, and CD65.

Low-grade cervical neuroendocrine neoplasias are rare in this location; they are arranged in an organoid pattern, nests, islets, or trabeculae, constituted by cells with an abundant cytoplasm, nuclei with granular chromatin, and prominent nuclei. The difference between carcinoid tumors and atypical carcinoid tumors is based on the presence of nuclear atypias, mitotic activity, and necrosis foci, which are observed in the latter.

The prognosis for carcinoid tumors is indolent but with metastatic potential. The atypical carcinoid behavior is similar to that of large cell neuroendocrine carcinoma.

Within high-grade neuroendocrine carcinomas, small cell carcinoma is the most frequent, and it is characterized by a monotonous population of small cells with ovoid hyperchromatic nuclei, scarce cytoplasm, and nuclear molding (Fig. 7.10). There are many mitoses, apoptosis, extended necrosis, perineural invasion, and lymphovascular permeation. Large cell neuroendocrine carcinoma is arranged in a diffuse, organoid, trabecular pattern, or similar to laces, constituted by cells with abundant cytoplasm, large nuclei, prominent nuclei, and a high mitotic index. Focal glandular differentiation can be observed.

Fig. 7.10
figure 10

Within high-grade neuroendocrine carcinomas, small cell carcinoma is the most frequent, and it is characterized by a monotonous population of small cells with ovoid hyperchromatic nuclei, scarce cytoplasm, and nuclear molding

Full size image

High-grade neuroendocrine carcinomas are extremely aggressive and are detected in advanced clinical stages. The 5-year survival is 14–39% for large cell neuroendocrine carcinoma in any clinical stage [24].