Cancer, Cervical Intraepithelial Neoplasia (CIN)


Article Author:
Vickie Mello


Article Editor:
Renee Sundstrom


Editors In Chief:
Alexandra Caley
Sameh Boktor


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
6/16/2019 9:13:52 PM

Introduction

Cervical cancer incidence and mortality have decreased due primarily to screening programs using the pap smear. As more outcome data has become available, screening, and treatment guidelines for cervical intraepithelial neoplasia (CIN) have evolved. Detection of the disease in a precancerous state, close monitoring, and treatment are paramount in the prevention of cervical cancer.  The screening process for cervical cancer involves pap smear cytology of the cervix, along with with human papillomavirus (HPV) testing in certain circumstances.[1]

Etiology

Human papillomavirus (HPV) infection of the cervix is a sexually transmitted disease and a significant risk factor for the development of cervical intraepithelial neoplasia.  However, only a relatively small percentage of women with the infection will develop severe CIN or invasive cervical cancer. Several factors determine whether the infection will progress to CIN or carcinoma, the greatest of which is the HPV genotype causing the infection. Although there are approximately 100 subtypes of HPV,  a small subgroup has a known association with cervical dysplasia and carcinoma.  HPV subtypes are considered either oncogenic or non-oncogenic.  Persistence of the virus in tissues is another critical factor in the development of CIN and ultimately, carcinoma.[1][2][3][4]

HPV 16 is the most carcinogenic and accounts for 55 to 60% of cervical cancers worldwide. HPV 18 is the second most carcinogenic and accounts for 10 to 15% of cervical cancer. Risk factors such as smoking, immunocompromised state, or HIV infection likely lead to persistence of HPV infection and an increased risk for the development of CIN.[5][6][7]

Although the terminology is changing, cytologic abnormalities on Pap smear are typically described as "squamous intraepithelial lesions" and further classified as "low-grade" or "high-grade."

Epidemiology

HPV infection occurs in sexually active women of any age but is more common in adolescent women and women under the age of 30.  The highest incidence is in women ages 20 to 24.  These young women are the most likely to clear the infection to undetectable levels in an average of 8 months; this is the rationale for increasing the initiation of Pap smear screening to age 21. 

Women over age 30 with HPV detected are more likely to have a persistent infection and warrant more aggressive follow-up to rule out cervical intraepithelial neoplasia.[1]

Pathophysiology

Cervical intraepithelial neoplasia results from HPV infection within cervical cells. These changes, especially in young women, commonly revert to normal cells due to an intact immune response and rapid turnover of cells on the cervix. About 60% of CIN-1 will regress to normal after 1 year. Women with CIN-2 and CIN-3 are at high risk for developing invasive cancer, although the average time for progression is still several years. Therefore, women with CIN-2/3 should receive treatment. Exceptions to this recommendation are women in the 20 to 24 year age group and pregnant women.  Since a significant percentage of low-grade squamous intraepithelial lesions (LGSIL) on Pap smear will have CIN-2 or 3, it makes sense that these pap smears still require colposcopy and biopsy in most cases. The same holds for older women with atypical squamous cells of undetermined significance (ASCUS) pap smears who also have a high-risk HPV. Cytology is the screening test, but histologic characteristics of a tissue biopsy make the diagnosis.[1][8]

Histopathology

The classic microscopic description of HPV infection of cervical epithelial cells is "koilocytosis."  This term refers to the appearance of a perinuclear "halo" within the cell, along with enlarged and irregular nuclei that show evidence of mitosis. The proportion of cervical epithelium exhibiting dysplastic cells determines the grade of the dysplasia. CIN-1 (low-grade) involves the lower 1/3 or less of the epithelium, whereas the more significant CIN-2 and CIN-3 (high-grade) progress to include the entire thickness of the epithelium.  Dysplasia becomes cancer when it invades the basement membrane. 

History and Physical

In most instances, dysplastic lesions of the cervix are not visible to the naked eye, and it is the pap smear which detects abnormalities requiring further evaluation. Some lesions appear as exophytic or plaque-like growths on the cervix.  HPV can cause anogenital warts and thus prompt further investigation into other abnormalities caused by HPV.

Evaluation

Colposcopy with directed biopsy is the preferred method for evaluation of an abnormal pap smear result. "Co-testing" combines cytology and HPV testing for high-risk types, but is still considered screening. The diagnosis ultimately requires tissue sampling.

There are exceptions to this rule:

For women aged 21 to 24 with LGSIL cytology because of the high rate of disease resolution, repeat cytology at 12-month intervals is the recommendation.  This same age-group of women with Pap smear results showing atypical squamous cells-cannot exclude high grade (ASC-H), atypical glandular cells, or HGSIL results on repeat cytology; colposcopy is the recommendation. For follow-up Pap smears showing ASCUS, LGSIL or negative, the recommendation is to repeat in another 12 months. For those patients with repeated ASCUS or LGSIL at 24 months, colposcopy is the next step.[1]

Patients older than 24 years of age with ASCUS with positive high-risk HPV and LGSIL or higher should undergo colposcopy.   Regardless of age, women with HGSIL or ASCUS-H should have a colposcopy. With a diagnosis of CIN II or greater, excisional treatment is the recommendation.  With the subgroup of younger women, close observation with colposcopy may be appropriate if they are compliant with care.[1]

Treatment / Management

CIN-1 can undergo observation and co-testing repeated in 1 year. If CIN-1 is persistent after 2 years or progresses within that time, treatment is the recommendation.[1]

As stated earlier, CIN -2 or higher requires treatment. Treatment is also recommended when there is more than one degree of difference between pap results and biopsy results. For example, if the pap smear is high-grade intraepithelial lesion (HGSIL), but the biopsy is negative, the potential reasons are a misread of the specimen, or there was a missed a lesion at the time of colposcopy. In this case, a diagnostic excisional procedure is the preferred mode of treatment because it is both therapeutic and diagnostic. The margins of the cervical specimen may then undergo evaluation for complete removal of any abnormal cells.[1]

The usual treatment is via ablation or excision of abnormal cells. Ablation of abnormal cells includes cryosurgery or laser ablation (CO2 laser). Ablation is only acceptable when the endocervical sampling is negative, there are no glandular abnormalities, the entire borders of the lesion are visible, and the patient has not failed other treatments. These techniques were more common before the development of LEEP (loop electrosurgical excision procedure). Ablative procedures have a higher recurrence rate in the setting of severe dysplasia when compared to LEEP.[1]

Excisional procedures for the treatment of CIN include LEEP, cold knife conization, and laser conization. Whether any of these procedures increase a patient’s risk for preterm labor is controversial since the risks for preterm delivery and dysplasia overlap considerably. That said, in women younger than 25 with CIN-2 or 3, there may be a role for close observation with colposcopy in 6 months rather than excision.  However, that is not the currently preferred treatment option. During pregnancy, treatment is postponed until after delivery unless colposcopic surveillance during pregnancy reveals progression to invasive cervical cancer.[1]

Women treated for CIN-2, or greater should have a Pap smear and HPV testing 12 and 24 months after the procedure. Even with positive endocervical margins on an excised specimen, the procedure is deemed 70 to 80% effective. When margins are positive, repeat cytology testing in 4-6 months accompanied by an endocervical curettage is the course of action.  A repeat excisional procedure is one option for treatment of persistent or recurrent CIN-2 or 3. In some circumstances, patients will opt for a hysterectomy, which is also appropriate for recurrent CIN.[1]

Differential Diagnosis

The differential diagnosis should include normal squamous cells, cervical warty lesions, inflammation, infection, and carcinoma.

Prognosis

The prognosis for cervical intraepithelial neoplasia differs depending on the severity. With adherence to ASCCP guidelines, the risk for progression to carcinoma is low. The risk of overt cervical cancer is significantly higher when a woman has missed screening for more than 10 years.

Complications

Complications can arise from cervical biopsy include excessive bleeding or infection, but are rare. Surgical treatments such as a cold knife cone or LEEP carry increased risks, including risks of anesthesia. In those individuals treated with an excisional procedure, there have been concerns regarding the risk of pregnancy complications such as preterm delivery or cervical incompetence.  However, the risk factors for these complications overlap those for cervical dysplasia, so it is difficult to discern the actual impact of the excisional procedure on preterm delivery.[9][10]

Pearls and Other Issues

The American Society for Colposcopy and Cervical Pathology (ASCCP) has published a smartphone application entitled “ASSCP Mobile” that is updated regularly. It has a user-friendly algorithm for screening guidelines and management recommendations.  It is available for Android and IOS platforms for a minimal fee.

Enhancing Healthcare Team Outcomes

Healthcare providers, including the nurse practitioner, should discuss cervical cancer screening protocols and implement a reliable system for follow up, especially for abnormal results.  This system should include a combination of verbal and written notifications about the process of evaluation and the importance of appropriate follow-up.

Consistent condom use is among the most effective methods for women to protect themselves from HPV transmission.  HPV vaccines also protect against HPV-related diseases.[11] They are FDA approved and show nearly 100% efficacy in preventing cervical neoplasia from HPV subtypes included in the vaccine. These vaccines provide immunity for several subtypes of HPV. All women should receive cervical cancer screening per ASCCP guidelines, regardless of their HPV immunization status.

Cervical intraepithelial neoplasia requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Cancer, Cervical Intraepithelial Neoplasia (CIN) - Questions

Take a quiz of the questions on this article.

Take Quiz
Which is not true regarding CIN and cancer of the cervix in pregnancy?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following human papillomavirus (HPV) types is most often associated with CIN III or CIS?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 36-year-old female patient presents to a physician for follow up after colposcopy with cervical biopsy. She has had an abnormal pap that showed high-grade squamous intraepithelial lesion (HGSIL). She has had three pregnancies and has given birth vaginally three times. She has a history of tubal ligation. She has no other medical or surgical history. Her menstrual cycles are regular, and she denies pain with periods. She is having some vaginal spotting with intercourse. Her cervical biopsy showed moderate cervical dysplasia. Her endocervical curettage was negative. Which of the following is the most accurate regarding the best possible treatment option for this patient?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 21-year-old female with no medical history who smokes a pack of cigarettes per day has a pap smear that shows HGSIL (high-grade intraepithelial neoplasia). What is the best next step for this patient?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 22-year-old female has a low-grade squamous intraepithelial lesion (LGSIL) pap smear. What is the next best step in management for this patient?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 25-year-old woman presents for her annual gynecologic exam. Her last pap smear was normal 3 years ago, and she has completed the HPV (Human papillomavirus) vaccine series. What is the most appropriate management for this patient regarding cervical cancer screening?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 25-year-old woman undergoes pap smear screening. She reports being sexually active over the last five years. She had three partners in the past year. Her recent Pap smear result is positive for atypical squamous cells of undetermined significance (ASC-US). Which is the next best step for evaluating this abnormality in this patient?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 35-year-old woman underwent a LEEP (loop electrosurgical excision procedure) procedure for CIN-3 (cervical intraepithelial neoplasia). ectocervical margins were positive. Which of the following is the most appropriate method for follow-up in this patient?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Cancer, Cervical Intraepithelial Neoplasia (CIN) - References

References

Massad LS,Einstein MH,Huh WK,Katki HA,Kinney WK,Schiffman M,Solomon D,Wentzensen N,Lawson HW, 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Journal of lower genital tract disease. 2013 Apr     [PubMed]
de Sanjose S,Quint WG,Alemany L,Geraets DT,Klaustermeier JE,Lloveras B,Tous S,Felix A,Bravo LE,Shin HR,Vallejos CS,de Ruiz PA,Lima MA,Guimera N,Clavero O,Alejo M,Llombart-Bosch A,Cheng-Yang C,Tatti SA,Kasamatsu E,Iljazovic E,Odida M,Prado R,Seoud M,Grce M,Usubutun A,Jain A,Suarez GA,Lombardi LE,Banjo A,Menéndez C,Domingo EJ,Velasco J,Nessa A,Chichareon SC,Qiao YL,Lerma E,Garland SM,Sasagawa T,Ferrera A,Hammouda D,Mariani L,Pelayo A,Steiner I,Oliva E,Meijer CJ,Al-Jassar WF,Cruz E,Wright TC,Puras A,Llave CL,Tzardi M,Agorastos T,Garcia-Barriola V,Clavel C,Ordi J,Andújar M,Castellsagué X,Sánchez GI,Nowakowski AM,Bornstein J,Muñoz N,Bosch FX, Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. The Lancet. Oncology. 2010 Nov     [PubMed]
Wheeler CM,Hunt WC,Joste NE,Key CR,Quint WG,Castle PE, Human papillomavirus genotype distributions: implications for vaccination and cancer screening in the United States. Journal of the National Cancer Institute. 2009 Apr 1     [PubMed]
    [PubMed]
    [PubMed]
    [PubMed]
    [PubMed]
    [PubMed]
    [PubMed]
    [PubMed]
    [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of CNS-Public Community Health. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for CNS-Public Community Health, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in CNS-Public Community Health, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of CNS-Public Community Health. When it is time for the CNS-Public Community Health board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study CNS-Public Community Health.