Pathology Thread

IV. Premalignant and Malignant Neoplasms

Objectives

After completing this section you will be able to:

• classify the premalignant conditions and malignant neoplasms of the cervix
• describe their epidemiological features including risk factors
• describe their clinical features
• describe/recognize histologic features and grade various lesions
• determine clinical behavior and discuss factors affecting outcome

1. Cervical Intraepithelial Neoplasia (CIN) (Squamous dysplasia)

Definition

CIN represents a spectrum of intraepithelial changes (dysplasia) with indistinct boundaries that begins with mild atypia and progresses through stages of more marked intraepithelial abnormalities to carcinoma in situ. The various categories form points on a disease spectrum rather than separate disease entities. They are precursor lesions to invasive squamous cell carcinoma.

Dysplasia is a potentially reversible change characterized by an increase in mitotic rate, atypical cytologic features (size, shape, nuclear features) and abnormal organization (cellularity, differentiation, polarity) that fall short of invasive carcinoma (premalignant change).

Dysplasia may progress to cancer and dysplastic changes may be found adjacent to foci of cancer.

Epidemiology

Population distribution of cervical intraepithelial neoplasia/dysplasia resembles the epidemiology of an infectious disease that is sexually transmitted. Multiple male sexual partners, early age at first sexual intercourse and male partner with multiple previous female sexual partners are very important risk factors.

Clinical appearances

CIN lesions are characterized by the appearance of white patches on the cervix following application of acetic acid. Distinct vascular patterns can be seen on colposcopic examination of the cervix in high grade CIN. Lesions occur on the anterior lip twice as commonly as the posterior lip. They are found in the transformation zone and areas of squamous metaplasia in the endocervix and stop abruptly at the junction with the native portio squamous epithelium but can extend along the entire endocervical canal. In general, the portion of CIN on the portio surface is low grade (CIN 1) whereas the portion that extends into the endocervical canal is high grade (CIN 2 and 3).

Histology

Abnormal cellular proliferation, maturation and atypia characterize CIN. Nuclear abnormality is the hallmark of CIN and includes hyperchromasia, pleomorphism, irregular borders, and abnormal chromatin distribution. These nuclear abnormalities persist throughout the epithelium irrespective of cytoplasmic maturation towards the surface. Mitotic rate is increased and abnormal mitotic figures may be seen.

Grading

Histologic grading of CIN is based on the proportion of the epithelium occupied by dysplastic cells. The epithelium is divided into thirds.

CIN 1 (mild dysplasia): Dysplastic cells occupy the lower third of the epithelium.

CIN 2 (moderate dysplasia): Dysplastic cells occupy up to the middle third of the epithelium.

CIN 2. Note superficial koilocytosis.

CIN 3 (severe dysplasia, carcinoma in situ): Dysplastic cells extend into the upper third and may occupy the full thickness of the epithelium.

CIN3. Note adjacent koilocytes (bottom right)

Cytologic grading of CIN also uses a three-tier system. However, the new Bethesda System for cytological diagnosis divides precursors of cervical squamous cell carcinoma into low-grade squamous intraepithelial lesion and high-grade intra-epithelial lesion.

Pap smear of CIN 1. Note large, dark nuclei, but also large amount of surrounding cytoplasm.

Pap smear of CIN 3. Note large, dark nuclei with a lesser amount of surrounding cytoplasm. Compare to superficial cell (lower right hand corner).

Question: What is the correlation between the CIN terminology and the Bethesda System?

Clinical behavior

CIN may regress spontaneously, especially CIN1, persist or progress. If untreated, up to 16% of CIN1 will progress to CIN3 and up to 70% of CIN3 will progress to invasive squamous cell carcinoma in 1 to 20 years. It is not presently possible to predict which lesions will progress. However, the risk of progression to invasive cancer increases and the time required is shorter with increasing severity of the lesion.

2. Invasive squamous cell carcinoma

Epidemiology

Invasive squamous cell carcinoma of the cervix is the most common malignant tumor of the female genital tract worldwide. However, there are marked differences in the relative frequency of the tumor in developed and developing countries. This is due to differences in the availability of screening (Pap smear) programs. While there is decreased relative frequency in developed countries due to screening, cervical cancer continues to be the most frequent malignancy in women in developing countries.

Patients with invasive squamous cell carcinoma have the same epidemiologic features as those with CIN. Most cancers probably begin as CIN with gradual progression over a period of years to carcinoma in situ and then invasive carcinoma. As with CIN, there is a strong association with HPV infection especially high-risk types 16 and 18.

The disease is most common in older women, but there is increasing frequency in younger women.

Question: What is the average age of women with invasive squamous cell carcinoma compared to CIN?

Clinical appearance

The presenting symptoms depend on size and stage of the tumor. Patients with tumors confined to cervix are usually asymptomatic and detected because of abnormal Pap smear result. Those with clinically visible tumors present with various degrees of abnormal bleeding.

Early lesions may be indurated or ulcerated while more advanced tumors form exophytic fungating masses or endophytic ulcerated or infiltrative masses that produce an enlarged, hard, barrel-shaped cervix.

Ulcerated fungating carcinoma of the cervix.

Histology

The histologic appearances vary considerably with different degrees of differentiation. Keratinizing types show various sizes and shapes of well-differentiated nests or cords of squamous epithelium with keratin pearls. The nonkeratinizing types contain sheets of tumor cells, some of which show single cell keratinization, or basaloid cells with no evidence of keratinization.

Keratinizing squamous cell carcinoma. Note keratin pearls in nests of squamous epithelium.

Nonkeratinizing squamous cell carcinoma.Basaloid cells with no evidence of keratinization.

Clinical behavior

Invasive squamous cell carcinoma of the cervix spreads mainly by direct extension and through lymphatics and rarely by hematogenous route. The more extensive the local disease, the more the likelihood of lymph node involvement. The more advanced the disease, the greater the likelihood of distant organ metastases. Liver is the commonest site for distant metastases.

Question: What is the most important prognostic factor in cervical carcinoma?

Question: What is the commonest cause of death in patients with cervical cancer?

3. Microinvasive squamous cell carcinoma (MICA)

Definition: The term microinvasive carcinoma is used to describe the earliest form of invasive squamous cell carcinoma detectable in patients with CIN. In MICA, one or more tongues of carcinoma extend down from the dysplastic epithelium and break through the basement membrane to invade the underlying stroma. There is no general agreement as to what exactly constitutes MICA.

The International Federation of Gynecologists and Obstetricians (FIGO) defines MICA as: invasive carcinomas identified only microscopically i.e. Stage 1a. Divided into Ia1 cancers with stromal invasion up to 3mm in depth and no greater than 7mm wide; Ia2 when invasion is at 3-5mm depth and no greater than 7mm wide. Lymphatic vascular involvement would not exclude a patient from this definition. All grossly visible lesions even with superficial invasion are excluded.

Most gynecologic oncologists in U.S. use the Society of Gynecologic Oncologists (SGO) definition: cancer in which a neoplastic epithelium invades the stroma in one or more places to a depth of 3mm or less below the base of the epithelium and in which lymphatic or vascular involvement is not demonstrated.

The concept of MICA should be applied only to squamous cell carcinomas. All invasive adenocarcinomas should be regarded as frankly invasive and treated as the same.

Clinical appearances

MICA cannot be clinically differentiated from CIN with certainty although the presence of abnormal vascular pattern may suggest the diagnosis. The diagnosis is made by histologic examination of a cone biopsy, which allows multiple step sections at 2mm interval.

Histology

Usually, the intraepithelial lesion is high grade, but in a few cases may be more differentiated. Typically the tumor cells forming the invading tongues of MICA look better differentiated than the dysplastic cells forming the CIN in the adjacent epithelium.

Microinvasive carcinoma showing tongue of tumor invading the stroma.

High power view. Note the well-differentiated appearance of the MICA.

Clinical behavior

MICA extends more deeply to become clinically invasive squamous cell carcinoma if not removed. Likelihood of lymph node metastases depends on the depth of invasion and, probably, on lymphatic vascular involvement. The incidence of lymph node involvement is rare for cancers invading up to 3mm while it is about 3% for those invading between 3mm and 5mm.

4. Adenocarcinoma

This is a heterogeneous group of malignant glandular neoplasms of the cervix with different histological features. The commonest is the mucinous type.

Epidemiology

There is no significant difference in age distribution with cervical squamous cell carcinoma. Epidemiologic risk factors are also similar.

Question: What are the epidemiologic risk factors for invasive carcinoma of the cervix?

Clinical appearances

The majority of patients present with abnormal vaginal bleeding, some with vaginal discharge or pelvic pain. Most of the tumors arise in the transformation zone. Most form exophytic, fungating, papillary or polypoid masses, while others are endophytic with either diffuse or nodular enlargement or produce no grossly visible lesion on examination. Some of those with inapparent gross lesions have early invasive carcinoma, but others are frankly invasive carcinoma arising deep, and hiding, in the canal beyond vision.

Histology

Well-differentiated exophytic tumors often have papillary pattern, while the endophytic ones show a tubular, glandular pattern. Poorly differentiated tumors are largely composed of solid sheets of tumor cells with only occasional evidence of gland formation.

Clinical behavior

Invasive adenocarcinoma of the cervix spreads by direct extension and lymph node metastasis similar to squamous cell carcinoma. However, lymph node metastases tend to occur earlier and overall survival rate is poorer than in squamous cell carcinoma.