Cervical intraepithelial neoplasia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]

Synonyms and keywords: CIN; cervical interstitial neoplasia; cervical dysplasia; cervical interstitial neoplasia

Overview

Cervical intraepithelial neoplasia (also known as cervical dysplasia and CIN), is the potentially premalignant transformation and abnormal growth (dysplasia) of squamous cells on the surface of the cervix. Cervical intraepithelial neoplasia was first discovered by Dr. Georgios Nikolaou Papanikolaou, a Greek pathologist, in 1927. There are 4 cytological classifications for cervical intraepithelial neoplasia: Bethesda system, Papanicolaou classification, CIN nomenclature, and dysplasia nomenclature. The most common cytological classification systems for cervical intraepithelial neoplasia is the Bethesda and CIN nomenclature. Cervical intraepithelial neoplasia may be classified according to Bethesda system by cytology description into 3 subtypes: atypical squamous cells, low grade squamous intraepithelial lesion (LGSIL or LSIL), and high grade squamous intraepithelial lesion (HGSIL or HSIL). The pathogenesis of cervical intraepithelial neoplasia is characterized by the premalignant transformation and abnormal growth of squamous cells on the surface of the cervix. The presence of human papillomavirus (HPV) has a crucial role in the pathogenesis of cervical intraepithelial neoplasia. The infection of human papillomavirus (HPV) leads to the first precursor lesion of cervical intraepithelial neoplasia, also known as the koilocyte, which is a squamous epithelial cell that has undergone a number of structural changes.

Historical Perspective

• Cervical intraepithelial neoplasia was first discovered by Dr. Georgios Nikolaou Papanikolaou, a Greek pathologist, in 1927.
• In 1928, the first screening was developed by Aurel Babeș, a Romanian pathologist to diagnose cervical intraepithelial neoplasia.
• In 1980, human papillomavirus (HPV) was first identified in the pathogenesis of cervical intraepithelial neoplasia.
• In 1988, the Bethesda system classification method was introduced to categorize histopathological findings of cervical intraepithelial neoplasia according to degrees of severity.

Classification

• Cervical intraepithelial neoplasia has 4 cytological classifications: Bethesda system, Papanicolaou classification, CIN nomenclature, and dysplasia nomenclature.
• The most common classification systems for cervical intraepithelial neoplasia is the Bethesda and CIN nomenclature.
• Cervical intraepithelial neoplasia may be classified according to Bethesda system by cytology description into 3 subtypes:

• Atypical squamous cells

• Undetermined significance (ASC-US)

• Low grade squamous intraepithelial lesion (LGSIL or LSIL)
• High grade squamous intraepithelial lesion (HGSIL or HSIL)

• Cervical intraepithelial neoplasia may be classified according to CIN nomenclature by histological severity into 3 subtypes:

• Cervical intraepithelial neoplasia I (CIN I)
• Cervical intraepithelial neoplasia II (CIN II)
• Cervical intraepithelial neoplasia III (CIN III)

• Cervical intraepithelial neoplasia may be classified according to Papanicolau by cytology description into 5 subtypes:

• Class I: absence of atypical or abnormal cells
• Class II: atypical cytology, but no evidence of malignancy
• Class III: cytology suggestive of, but not conclusive for, malignancy.
• Class IV: cytology strongly suggestive of malignancy
• Class V: cytology conclusive for malignancy

• Cervical intraepithelial neoplasia may be classified according to dysplasia nomenclature by cytology description into 5 subtypes:

• Negative
• Squamous atypia
• Mild dysplasia
• Moderate dysplasia
• Severe dysplasia
• Carcinoma

• Other variants of cervical intraepithelial neoplasia include carcinoma in situ, typical glandular cells not otherwise specified, and invasive carcinoma.

Pathophysiology

• The pathogenesis of cervical intraepithelial neoplasia is characterized by the premalignant transformation and abnormal growth of squamous cells on the surface of the cervix.
• Cervical intraepithelial neoplasia arises from cells localized in the ectoendocervical squamocolumnar junction (also known as the "transformation zone") of the cervix persistently infected human papillomavirus (HPV)
• The presence of human papillomavirus (HPV) subtypes 16 and 18 play an essential role in the pathogenesis of cervical cancer has a crucial role in the pathogenesis of cervical intraepithelial neoplasia.
• The first precursor lesion of cervical intraepithelial neoplasia is the koilocyte, which is a squamous epithelial cell that has undergone a number of structural changes (these usually occur as a result of infection of the cell by human papillomavirus).
• On gross pathology, there are no characteristic findings of cervical intraepithelial neoplasia.
• On microscopic histopathological analysis, findings of cervical intraepithelial neoplasia will depend on the lesion grade.
• The table below summarizes the histopathological findings of cervical intraepithelial neoplasia according to lesion grade.

Cytologic findings Lesion grade	Histologic changes Bethesda system	Description	Microscopic findings
CIN I Cervical intraepithelial neoplasia I	Low-grade lesion squamous intraepithelial lesion (LGSIL)	Mild dysplasia, or abnormal cell growth Presence of koilocyte Typical cellular changes in the lower third of the epithelium
CIN II Cervical intraepithelial neoplasia II	High-grade lesion squamous intraepithelial lesion (HGSIL)	Moderate dysplasia Basal two-thirds of the epithelium Preservation of epithelial maturation
CIN III Cervical intraepithelial neoplasia III	High-grade lesion squamous intraepithelial lesion (HGSIL)	Severe atypical cellular changes Greater than two-thirds of the epithelial thickness Carcinoma in situ.

Molecular Pathogenesis

• The progression of cervical intraepithelial neoplasia usually involves the viral replication of human papillomavirus (HPV) following mutation of proteins E6/E7, resulting in the overexpression of these oncoproteins.
• The overexpression of these oncoproteins will generate a deficient cell replication and excessive cell growth.
• The E6/E7 proteins inactivate two tumor suppressor proteins, p53 (inactivated by E6) and pRb (inactivated by E7).
• The viral oncogenes E6 and E7 modify the cell cycle so as to retain the differentiating host keratinocyte in a state that is favourable to the amplification of viral genome replication and consequent late gene expression.
• E6 in association with host E6-associated protein, which has ubiquitin ligase activity, acts to ubiquitinate p53, leading to its proteosomal degradation.
• E7 (in oncogenic HPVs) acts as the primary transforming protein.
• E7 competes for retinoblastoma protein (pRb) binding, freeing the transcription factor E2F to transactivate its targets, thus pushing the cell cycle forward.

Causes

• The most important cause of cervical intraepithelial neoplasia is human papillomavirus (HPV)

• Low-risk type or non-oncogenic, include:

• Subtypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 69, 82

• High-risk type or oncogenic, include:

• Subtypes 6, 11, 40, 42, 43, 44, 54, 61, 72, 81

Differentiating Cervical Intraepithelial Neoplasia from Other Diseases

• Cervical intraepithelial neoplasia must be differentiated from other diseases that cause abnormal vaginal bleeding, dyspareunia, and abnormal vaginal discharge, such as:

• Cervicitis
• Vaginal cancer
• Vaginitis
• Paget disease

Epidemiology and Demographics

Prevalence

• The prevalence of cervical intraepithelial neoplasia I (CIN I) is approximately 54 cases per 100,000 individuals in the United States.
• The prevalence of cervical intraepithelial neoplasia II (CIN II) is approximately 255 cases per 100,000 individuals in the United States.
• The prevalence of cervical intraepithelial neoplasia II (CIN III) is approximately 141 cases per 100,000 individuals in the United States.
• The prevalence of invasive carcinoma is approximately 24 cases per 100,000 individuals in the United States.

Incidence

• The incidence of cervical intraepithelial neoplasia I (CIN I) is 160 cases per 100,000 individuals per year in the United States.
• The incidence of cervical intraepithelial neoplasia II (CIN II) is 120 cases per 100,000 individuals per year in the United States.

Age

• The median age at diagnosis for cervical intraepithelial neoplasia is 30 years.
• Cervical intraepithelial neoplasia is more commonly observed among female patients between 20 to 40 years years old.

Race

• Cervical intraepithelial neoplasia usually affects more frequently individuals of the Hispanic race.
• Hispanic individuals are more likely to develop cervical intraepithelial neoplasia.

Risk Factors

• The most important risk factor in the development of cervical intraepithelial neoplasia is immunosuppression.
• Common risk factors in the development of cervical intraepithelial neoplasia , include:

• Cigarette smoking
• Infections

• Herpes simplex virus
• Chlamydia

• Chronic inflammatory infections of cervix
• Use of oral contraceptives
• Increased sexual activity
• Poor socioeconomical status
• Poor diet

Natural History, Complications and Prognosis

• The majority of patients with cervical intraepithelial neoplasia remain asymptomatic for years.
• Early clinical features include abnormal vaginal discharge, dyspareunia, and abnormal vaginal bleeding.
• If left untreated, 70% patients with cervical intraepithelial neoplasia will regress within one year.

• 90% of patients with low grade cervical intraepithelial neoplasia will regress within two years.
• 50% of patients with high grade cervical intraepithelial neoplasia will regress within 2 years without treatment.
• Progression to cervical carcinoma in situ (CIS)

• 11% of low grade cervical intraepithelial neoplasia
• 22% of high grade grade cervical intraepithelial neoplasia

• Progression to invasive cancer (cervical cancer)

• 1% of low grade cervical intraepithelial neoplasia
• 5% - 13% high grade grade cervical intraepithelial neoplasia

• Common complications of cervical intraepithelial neoplasia include infertility, maternal-fetal transmission of human papillomavirus, and recurrent human papillomavirus infection.
• Prognosis is generally good if detected on time, and the 5-­year survival rate of patients with high-grade cervical intraepithelial neoplasia is approximately 98%.

Diagnosis

Diagnostic Criteria

• The diagnosis of cervical intraepithelial neoplasia is made with the following histopathological findings:

Cytologic findings Lesion grade	Histologic changes Bethesda system	Description	Microscopic findings
CIN I Cervical intraepithelial neoplasia I	Low-grade lesion squamous intraepithelial lesion (LGSIL)	Mild dysplasia, or abnormal cell growth Presence of koilocyte Typical cellular changes in the lower third of the epithelium
CIN II Cervical intraepithelial neoplasia II	High-grade lesion squamous intraepithelial lesion (HGSIL)	Moderate dysplasia Basal two-thirds of the epithelium Preservation of epithelial maturation
CIN III Cervical intraepithelial neoplasia III	High-grade lesion squamous intraepithelial lesion (HGSIL)	Severe atypical cellular changes Greater than two-thirds of the epithelial thickness Carcinoma in situ.

Symptoms

• Cervical intraepithelial neoplasia is usually asymptomatic.
• Symptoms of cervical intraepithelial neoplasia may include the following:

• Abdominal pain
• Vaginal discomfort
• Dyspareunia
• Dysmenorrhea
• Frequent urination

Physical Examination

• Patients with cervical intraepithelial neoplasia usually are well-appearing.
• Digital examination findings of the vagina and cervix, may include:

• Cervical nodularity or hardness of tissue

Laboratory Findings

• Laboratory findings associated with cervical intraepithelial neoplasia, include:

• HPV DNA Testing

Imaging Findings

• There are no imaging findings associated with cervical intraepithelial neoplasia.

Other Diagnostic Studies

• The most important diagnostic study for cervical intraepithelial neoplasia is vaginal colposcopy.
• The most common finding of cervical intraepithelial neoplasia on vaginal colposcopy is acetowhite lesions with atypical vessels
• Other findings on vaginal colposcopy, include:

• Greyish-white or yellowish-white lesions
• Irregular longitudinal vessels

• Cork screw or tree appearance

• Cervical nodularity

Treatment

Medical Therapy

• Medical treatment for cervical intraepithelial neoplasia, include:

• Observation
• Observation is indicated for cervical intraepithelial neoplasia lesions that are:

• Highly likely to regress
• High grade lesions associated with a high risk of developing cervical cancer

Surgery

• Surgery is the mainstay of therapy for cervical intraepithelial neoplasia.
• The management of patients with cervical intraepithelial neoplasia will depend on the age of the patients, dividing patients into two groups: patients between 21-24, and patients above 25.
• According to the American Society for Colposcopy and Cervical Pathology guidelines, indications for ablative surgery among patients with cervical intraepithelial neoplasia should include:

• Persistent low-grade cervical intraepithelial neoplasia
• Cervical intraepithelial neoplasia grade II and grade III

• Common surgical procedures for cervical intraepithelial neoplasia, include:

• Cryocautery
• Electrocautery
• Laser cautery
• Cervical conization

• Cold knife conization
• Loop electrical excision

• The most common approach to the treatment of cervical intraepithelial neoplasia will depend on the histopathological lesion grade.
• Cervical conization can only be performed for patients with suspicion of invasive cancer.
• Common cervical conization complications, include:

• Intraoperative bleeding
• Uterine perforation
• Postoperative bleeding
• Infection

Prevention

• The most effective measure for the primary prevention of cervical intraepithelial neoplasia is the vaccination against oncogenic human papillomavirus (HPV) infection.
• Once diagnosed and successfully treated, patients with cervical intraepithelial neoplasia are followed-up every 3, 6 or 12 months depending on the lesion grade.
• Follow-up testing include periodical vaginal colposcopy examinations.