3.2.3: Carcinoma of the Cervix

3.2.3.1 Definition

This is a malignant tumor of the cervix mainly caused by oncogenic strains of HPV. The tumors commonly arise from the transformation zone.

3.2.3.2 Transformation Zone

The ectocervix (i.e., the part of the cervix protruding into the vagina) is lined with squamous epithelium (Figure 3.2.2 A). The epithelial lining of the endocervical canal is columnar mucous-secreting glandular epithelium (Figure 3.2.2 B).

Figure 3.2.2 Ectocervix (A): The ectocervix, like the vagina, is lined by a stratified squamous moist epithelium (Black double-headed arrow). Endocervix (B): The tall, simple columnar epithelium lining the endocervical canal (black arrow) secretes mucus (blue double-headed arrow and grey arrows). Infolds of this epithelium form plicae palmatae (“palm folds”); these are known as cervical crypts or glands. In the presence of high estrogen levels at ovulation, the cells lining he crypts secrete abundant alkaline secretions (grey arrows). This mucus lubricates the vagina and nourishes spermatozoa. Some of this mucus is seen on the surface of the epithelium.
Image Source: Pakurar, Alice S. and John W. Bigbee. Carole W. Christman, Ph.D, Medical Illustrator. Digital Histology, (ND). This work is openly licensed via CC BY SA Creative Commons License. Available from Virginia Commonwealth University. Used with permission.

The squamocolumnar junction SCJ is where the squamous epithelium meets the glandular epithelium. The anatomical location of the SCJ keeps changing, and this is dependent on age, hormonal status, and pregnancy (Figure 3.2.3). Before puberty, the SCJ is located in the endocervical canal above the external os; this is referred to as the original SCJ because it represents the junction between the original two types of epithelia formed during embryogenesis. After puberty and during the reproductive period, elongation of the endocervical canal occurs secondary to hormonal effects resulting in eversion of the columnar epithelium of the lower part of the endocervix (i.e., the columnar epithelium shifts towards the ectocervix). This shift makes the SCJ located on the ectocervix, away from the external os. Due to exposure of the columnar epithelium of the SCJ to the acidic vaginal secretions, it undergoes squamous metaplasia. The metaplastic changes start at the original SCJ and proceed towards the external os, resulting in the formation of a new SCJ between the newly formed metaplastic squamous epithelium and the columnar epithelium. These metaplastic changes occur throughout the reproductive period and until menopause. They are dynamic and vary in rates and cell maturation based on hormonal status and pregnancy. Therefore, the location of the newly formed SCJ keeps changing until it becomes completely invisible in postmenopausal women as it becomes entirely endocervical. The metaplastic epithelium closer to the SCJ is composed of immature metaplastic cells, and the mature metaplastic epithelium is closer to the original SCJ. The area between the original SCJ and the newly formed SCJ is known as the transformation Zone (TZ). The immature squamous cells in the TZ are the most susceptible to Human Papilloma Virus (HPV) oncogenesis, and these are the cells of origin of cervical carcinomas.³⁴

Figure 3.2.3 Development of the transformation zone from fetal life to postmenopausal life. Prendiville W, Ritter J, Tatti SA, Twiggs LB (2003). Colposcopy: management options. Amsterdam: Elsevier Limited.
Image Source: Prendiville, Walter, and Rengaswamy Sankaranarayanan. “Chapter 2. Anatomy of the Uterine Cervix and the Transformation Zone,” in Colposcopy and Treatment of Cervical Precancer, IARC Technical Report, No. 45 (2017). Openly available from NIH National Library of Medicine (NLM) Bookshelf.

3.2.3.3 Pathogenesis

Cervical Intraepithelial Neoplasia (CINs) are the precursor lesions of cervical carcinomas. These lesions arise from normal cervical epithelium and are categorized into low-grade and high-grade CINs. The most important factor in the pathogenesis of all types of cervical cancer (squamous and adenocarcinomas) is the High-risk HPV (hrHPV). HPVs are DNA viruses that are categorized into low oncogenic risk (types 6 and 11) and high oncogenic risk (types 16 and 18) based on their genotypes. Infections with hrHPV take a longer time to clear and are usually associated with the formation of precursor lesions (CIN). High-risk HPVs are the main pathogenic factors of squamous cell carcinomas of other tissues (e.g., oropharynx, tonsils, anus, vagina, vulva, and penis). Risk factors associated with HPV infections are early age at first intercourse, multiple sexual partners, and persistent infection with high-risk strains of HPV.³⁵

The hrHPV infection into the cervical epithelium results in host genome alterations, leading to the silencing of various tumor-suppressor factors on one hand and inducing aberrant functioning of various tumor-promoting factors on the other (Figure 3.2.4). The imbalance and instability caused by various hrHPV-derived oncogenic factors in the host genome of the cervical epithelial cells drive neoplastic progression over the course of years. HPV infection causes cervical carcinoma in a small percentage of individuals; other factors contributing to the persistence of this viral infection play a role in HPV-mediated carcinogenesis. These include cigarette smoking and host immune status. ³⁶

Figure 3.2.4 Cervical cancer development, prevention, and treatment. Invasive cervical cancer development from normal to progressive cervical intraepithelial neoplasia (CIN) through high-risk human papilloma virus (hrHPV) oncogenesis and host genome alterations. Available interventions in preventing and treating cervical cancer have also been shown. LEEP: loop electrosurgical excision procedure; RNR: ribonucleotide reductase; PARP: Poly (adenosine diphosphate [ADP]-ribose) polymerase.
Image Source: Olusola, Patti, Hirendra Nath Banerjee, Julie V. Philley, and Santanu Dasgupta. “Human Papilloma Virus-Associated Cervical Cancer and Health Disparities.” Cells 8, no. 6 (2019):622 This work is openly licensed via CC BY license. doi.org/10.3390/cells8060622.88

The major oncoproteins E5, E6, and E7 encoded by the HPV genome are the major drivers of oncogenesis in normal cervical epithelium. They disrupt the normal functioning of the major histocompatibility complex I (MHC class I), p53 and Rb, Notch1, Wnt, MAPK, mTOR, and STAT-associated pathways, which are central players controlling normal cellular growth, differentiation, and immune function (Figure 3.2.5). HPVs induce carcinogenesis through dysregulation of the activity of tumor suppressor proteins such as p53 and RB by the viral E6 and E7 proteins, respectively. HPV infects immature squamous cells of the TZ, and when these cells mature, the viral infection prevents the normal arrest of these cells in the G1 phase of the cell cycle. Hence, viral replication takes place in mature cells. viral genome and for productive shedding of the virus. The viral E6 upregulates telomerase and binds to p53, leading to its destruction. E7 binds to the RB protein, leading to the release of the E2F transcription factors from the inhibitory effect of RB. This results in progression through the cell cycle. High-risk HPVs also integrate into the host cell genome. This integration results in increased expression of the viral E6 and E7 proteins. Also, the integration into the host cell genome increases the genomic instability of these cells, leading to the acquisition of prooncogenic mutations. Low-risk HPVs do not integrate into the host genome.³⁷

Figure 3.2.5 Molecular pathogenesis of HPV-associated cervical cancer. Multiple nuclear and mitochondrial genetic alteration pathways leading to cervical cancer progression and racial health disparities. E6, E7: oncogenic HPV molecules. TSG: tumor suppressor gene; ONCG: oncogene.
Image Source: Olusola, Patti, Hirendra Nath Banerjee, Julie V. Philley, and Santanu Dasgupta. “Human Papilloma Virus-Associated Cervical Cancer and Health Disparities.” Cells 8, no. 6 (2019):622 This work is openly licensed via CC BY license. doi.org/10.3390/cells8060622.

Periodic surveillance for hrHPV and Pap smear-based testing resulted in a remarkable reduction in the incidence of cervical carcinomas in the USA and globally. However, there is still great variability in the occurrence and outcome of cervical cancer in various ethnic populations. Moreover, several social determinants of health, including lack of adequate health insurance, pose a socioeconomic burden for cervical cancer preventive screening in a timely manner. This results in disparate cervical cancer incidence and health outcomes. Therefore, understanding the underlying molecular mechanism and genetic basis behind these disparities is warranted through further research studies.³⁸

For more information

For further details on the molecular pathogenic mechanisms associated with disparities, please refer to Olusola, Patti, Hirendra Nath Banerjee, Julie V. Philley, and Santanu Dasgupta. “Human Papilloma Virus-Associated Cervical Cancer and Health Disparities.” Cells 8, no. 6 (2019):622.

3.2.3.4 Squamous Intraepithelial Lesion (SIL) and Cervical Intraepithelial Neoplasia (CIN)

Precancerous cervical lesions caused by HPV infections are known as SIL and usually occur years before invasive carcinoma. Based on cell biology, these lesions are classified into low-grade SIL (LSIL) and high-grade SIL (HSIL). Another classification system categorizes them into three categories: CIN I, CIN II, and CIN III. The LSIL corresponds to CIN I, and the HSIL corresponds to CIN II and III. HSIL has a high risk for progression to carcinoma. Risk factors associated with progression include cigarette smoking and immunocompromised status.³⁹

3.2.3.5 Screening and Diagnostic Testing

The Papanicolaou (Pap) test is the gold standard for screening for cervical cancer. It detects the cytological abnormalities associated with cervical precancerous lesions. The test is performed by scraping the cervical TZ and examining the cells microscopically.⁴⁰

Detection of hrHPV DNA in the scraped cells is an additional step in cervical cancer screening. The Food and Drug Administration (FDA) approved HPV testing for women aged 25 and older. This test detects HPV types 16, 18, and 26 and additional hrHPV types. HPV testing of women younger than 25 years of age is less useful because these infections are usually cleared by the immune system and never progress to SIL.⁴¹

3.2.3.6 Morphology

• Morphologic features of SIL/CIN

The morphological features of SIL/CIN are illustrated in (Figure 3.2.6). LSIL (CIN I) demonstrates dysplastic changes in the lower third of the squamous epithelium with koilocytosis (i.e., cells with halo or vacuolated cytoplasm or empty space cytoplasm) in the superficial layers of the epithelium. In HSIL, the dysplastic changes involve the lower two-thirds (CIN II) or all layers (CIN III). The dysplastic changes include variation in cell and nuclear size, heterogeneity of nuclear chromatin, and the presence of mitoses. In CIN III, in addition to the previously described dysplastic changes, there is also disordered cellular orientation. ⁴²

Figure 3.2.6 Spectrum from normal to high-grade SIL.
Image Source: Ed Uthman (December 23, 2021). This work is openly licensed via CC BY 2.5 license. Available from Wikimedia Commons

The cytological changes of cells collected via Pap smear are illustrated in (Figure 3.2.7). The superficial squamous cells stain either red or blue. The increase in the nuclear/cytoplasmic ratio in both LSIL and HSIL indicates the progressive loss of cellular differentiation.

Figure 3.2.7 Low-grade squamous intraepithelial lesion (LSIL) (A), here compared to an unremarkable intermediate squamous cell.
Image Source: Mikael Häggström (August 29, 2022). This work is openly licensed via CC0 Public Domain license. Available from Wikimedia Commons.
High-grade squamous intraepithelial lesion (HSIL) (B), showing even more prominent features, and decreased cytoplasm, causing a high nuclear/cytoplasmic ratio (The group of cells at the upper left corner of the photomicrograph). Pap smear from a 35-year-old, with no previous Pap on file. Biopsy confirmed the presence of carcinoma in situ, extending over the surfaces of all the biopsy fragments. The endocervical curettage specimen also had numerous fragments of CIS.
Image Source: Ed Uthman (January 26, 2010). This work is openly licensed via CC BY 2.0 License. Available from Wikimedia Commons.

• Morphologic features of Invasive Carcinoma

The morphological features of Invasive Carcinoma of the Cervix are illustrated in (Figure 3.2.8). Cervical carcinomas develop in the TZ. Squamous cell carcinoma is the most common type; other less common types include adenocarcinoma, adenosquamous carcinoma, and small-cell neuroendocrine carcinoma. The invasive tumors consist of nests of squamous cells that induce a desmoplastic stromal response (i.e., an inflammatory response in the stroma that leads to scar tissue formation and fibrosis). Tumor grading is based on the degree of tumor cell differentiation (i.e., the degree the tumor cells resemble the cells of origin). Well-differentiated tumors demonstrate keratin pearls. Less differentiated, neuroendocrine tumors look like small cell carcinoma of the lungs^.43

Figure 3.2.8 Invasive Squamous Cell Carcinoma of the Cervix. Large squamous carcinoma (bottom of the picture) has obliterated the cervix and invaded the lower uterine segment (A). The uterus also has a round leiomyoma up higher.
Image Source: Ed Uthman (March 28, 2006). This work is openly licensed via a CC BY 2.0 license. Available from Flickr.
Histopathology of a poor-differentiated squamous cell carcinoma of the cervix (B). Nests of malignant cells (marled by blue free lines). Note the stromal desmoplastic reaction between the nests.
Image Source: Li H, Jing X, Yu J, Liu J, Zhang T, and Chen S. (August 26, 2020). This work is licensed under a CC BY 4.0 license. Available from Wikimedia Commons.

3.2.3.7 Clinical Features, Treatment and Prevention

SILs are usually asymptomatic and are detected in Pap smears. These lesions are managed conservatively through follow-up. HSILs are treated by cone biopsy (cervical excision). Follow-up is required due to the increased risk of invasive carcinomas. The gold standard for early detection of invasive cervical tumors is Pap tests and biopsy of suspicious lesions.⁴⁴

Invasive cervical cancer usually presents with abnormal vaginal bleeding and/or discharge (leukorrhea), painful coitus (dyspareunia), or dysuria. Hysterectomy with lymph node removal is the first line of treatment for invasive cervical carcinomas. Adjuvant treatments in the form of radiation or chemotherapy are helpful in case surgery is not curative. The prognosis for invasive carcinoma greatly depends on the stage and tumor grade at the time of diagnosis. High-grade tumors such as neuroendocrine tumors generally have poor prognosis.⁴⁵

Vaccination against high-risk HPV plays a great role in preventing the development of cervical carcinomas. The recommended age for vaccination is 11 to 12 years for boys and girls and 26 for young men and women; they provide approximately 10 years of protection. The quadrivalent HPV vaccine for types 6, 11, 16, and 18, and the more recently introduced 9-valent vaccine, are effective in preventing HPV infections. Due to the fact that current vaccines do not protect against all oncogenic HPV types, vaccines don’t substitute for regular cervical cancer screening.⁴⁶

Glossary Terms

Adenocarcinoma

A malignant epithelial tumor with a glandular organization

Adenosquamous

mixed adenocarcinoma and squamous cell or epidermoid carcinoma

Adjuvant

augment, stimulate, activate, potentiate or modulate action or response of medical treatment

Cervix

elongate inferior end of the uterus where it connects to the vagina

Chromatin

substance consisting of DNA and associated proteins

Cytoplasm

internal material between the cell membrane and nucleus of a cell, mainly consisting of a water-based fluid called cytosol, within which are all the other organelles and cellular solute and suspended materials

Desmoplastic

characterized by the formation of fibrous tissue

Dyspareunia

genital pain before, during, or after intercourse

Dysplastic

abnormal growth or development (as of organs or cells)

Dysuria

painful urination

Ectocervix

neck portion of the UTERUS between the lower isthmus and the VAGINA forming the cervical canal

Embryogenesis

human embryogenesis is a complicated process by which a fertilized egg develops into an embryo

Endocervical

neck portion of the UTERUS between the lower isthmus and the VAGINA forming the cervical canal.

Epithelium

sheets of cells that cover the exterior surfaces of the body, line internal cavities and passageways, and form certain glands; also known as epithelial tissue

Eversion

foot movement involving the intertarsal joints of the foot in which the bottom of the foot is turned laterally, away from the midline

External os

the opening of the uterine cervix into the vagina

Fibrosis

process in which muscle fibers are replaced by scar tissue

Histocompatability

state of mutual tolerance that allows some tissues to be grafted effectively to others

Hysterectomy

surgery to remove the uterus and, sometimes, the cervix

Immunocompromised

human or animal whose immunologic mechanism is deficient because of an immunodeficiency disorder or other disease or as the result of the administration of immunosuppressive drugs or radiation

Keratin pearls

formed by local squamous epithelium accumulation which is easily recognized under a microscope [5] and is considered a marker of well-differentiated squamous cell carcinoma

Koilocytosis

the presence of koilocytes (vacuolated pyknotic epithelial cell that has either a clear cytoplasm or a perinuclear halo and that tends to be associated with certain human papillomavirus infections) usually in the anogenital region or the uterine cervix

Lesions

areas of abnormal tissue

Leukorrhea

clear or white discharge from the VAGINA, consisting mainly of MUCUS

Metaplasia

condition in which there is a change of one adult cell type to another similar adult cell type

Mitosis

type of CELL NUCLEUS division by means of which the two daughter nuclei normally receive identical complements of the number of CHROMOSOMES of the somatic cells of the species

Neuroendocrine

of, relating to, or being a hormonal substance that influences the activity of nerves

Oncogene

gene that is a mutated form of a gene involved in normal cell growth and may cause the growth of cancer cells (National Cancer Institute, n.d.)

Oncoproteins

proteins coded by oncogenes; they include proteins resulting from the fusion of an oncogene and another gene (ONCOGENE PROTEINS, FUSION)

Oropharynx

part of the pharynx continuous with the oral cavity that functions in respiration and digestion

Squamocolumnar junction (SCJ)

the region in the uterine cervix in which the squamous lining of the vagina is replaced by the columnar epithelium typical of the body of the uterus and which is a common site of neoplastic change

Squamous

of, relating to, or being a stratified epithelium that consists at least in its outer layers of small scalelike cells

Stroma

the tissue that forms the structure of an organ or body part

Telomerase

essential ribonucleoprotein reverse transcriptase that adds telomeric DNA to the ends of eukaryotic CHROMOSOMES

Upregulation

the process by which a cell increases its response to a substance or signal from outside the cell to carry out a specific function. For example, a cell may increase the number or activity of protein receptors or other molecules on its surface to make it more sensitive to a hormone or drug

Vacuolated (cytoplasm)

containing one or more vacuoles (small cavity or space in the tissues of an organism containing air or fluid)

 

Footnotes

34. Prendiville, Walter and Rengaswamy Sankaranarayanan. “Chapter 2. Anatomy of the Uterine Cervix and the Transformation Zone,” in Colposcopy and Treatment of Cervical Precancer, IARC Technical Report, No. 45 (2017). Openly available from NIH National Library of Medicine (NLM) Bookshelf.
35. Olusola, Patti, Hirendra Nath Banerjee, Julie V. Philley, and Santanu Dasgupta. “Human Papilloma Virus-Associated Cervical Cancer and Health Disparities.” Cells 8, no. 6 (2019):622 This work is openly licensed via CC BY license. doi.org/10.3390/cells8060622.
36. Olusa et al, 2019
37. Olusa et al, 2019
38. Olusa et al, 2019
39. Olusa et al, 2019
40. Olusa et al, 2019
41. Olusa et al, 2019
42. Olusa et al, 2019
43. Olusa et al, 2019
44. Olusa et al, 2019
45. Olusa et al, 2019
46. Olusa et al, 2019

Image Acknowledgements

• Olusola, Patti, Hirendra Nath Banerjee, Julie V. Philley, and Santanu Dasgupta. “Human Papilloma Virus-Associated Cervical Cancer and Health Disparities.” Cells 8, no. 6 (2019):622 This work is openly licensed via CC BY license. doi.org/10.3390/cells8060622.
• Pakurar, Alice S. and John W. Bigbee. Carole W. Christman, Ph.D, Medical Illustrator. Digital Histology, (ND). This work is openly licensed via CC BY SA Creative Commons License. Available from Virginia Commonwealth University. Pakurar, Alice S. and John W. Bigbee. Carole W. Christman, Ph.D, Medical Illustrator. Digital Histology, (ND). This work is openly licensed via CC BY SA Creative Commons License. Available from Virginia Commonwealth University.