LEEP is a type of treatment that prevents cervical cancer. LEEP removes abnormal cells from your cervix, and it’s effective and safe.
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- What’s LEEP?
- How does LEEP work?
- Does LEEP hurt?
- How effective is LEEP?
- Where can I get LEEP?
- Before Your Procedure
- During Your Procedure
- After Your Procedure
- Call Your Doctor or Nurse if You Have:
- What to Expect
- My Experience With HPV & LEEP
- Negative LEEP Is Not Reassuring
- When is hysterectomy appropriate for cervical dysplasia?
- Human Papilloma Virus Persistence after Cone Excision in Women with Cervical High Grade Squamous Intraepithelial Lesion: A Prospective Study
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LEEP stands for Loop Electrosurgical Excision Procedure. It’s a treatment that prevents cervical cancer. A small electrical wire loop is used to remove abnormal cells from your cervix. LEEP surgery may be performed after abnormal cells are found during a Pap test, colposcopy, or biopsy.
How does LEEP work?
You’ll lie down on an exam table like you would for a Pap test. Your doctor or nurse will put a speculum into your vagina and open it. This separates the walls of your vagina so they can see your cervix.
Once your doctor or nurse can see your cervix, they’ll apply numbing medicine to it. Then they’ll use a small tool with an electrical wire loop to remove the abnormal cells. Then your blood vessels in the area will be sealed to prevent bleeding. They might also use a special paste called Monsel’s Solution to prevent bleeding. The cells are sent to a lab to be tested.
LEEP takes about 10 minutes.
Does LEEP hurt?
You may feel mild discomfort or cramping. You won’t feel cutting or heat from the loop. Because numbing medicines are used, a lot of people don’t feel anything at all.
How effective is LEEP?
LEEP removes all abnormal cervical cells most of the time. If LEEP doesn’t remove all of the abnormal cells, you may have to have LEEP again, or your doctor or nurse may recommend more tests or a different treatment.
Where can I get LEEP?
You can get LEEP at your doctor or nurse’s office, some community health clinics, or your local Planned Parenthood health center.
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This information explains what to expect during and after your loop electrosurgical excision procedure (LEEP).
A LEEP is a procedure to remove abnormal tissue from your cervix (the bottom part of your uterus, located at the top of your vagina). It may be done to confirm a cancer diagnosis or treat precancerous conditions of your cervix. During a LEEP, a thin wire loop is used to excise (cut out) abnormal tissue. Your cervix is then cauterized (burned) to stop any bleeding. The area usually heals in 4 to 6 weeks.
The procedure will take about 10 minutes. You’ll be in the procedure room for about 30 minutes. You’ll have little or no discomfort from the procedure.
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Before Your Procedure
- Don’t take aspirin or any medications that contain aspirin for 7 days before your procedure.
- Read our resource Common Medications Containing Aspirin and Other Nonsteroidal Anti-inflammatory Drugs (NSAIDs) for more information.
- Eat and drink as you normally would. You won’t need to change your diet the day of your procedure.
- Schedule your procedure for 1 week after your period. This will help your doctor know the difference between vaginal bleeding caused by your procedure and vaginal bleeding during your period.
- If you think you may be pregnant, tell your doctor.
Call your doctor if you have any of the following symptoms 2 to 3 days before your procedure:
- A fever of 101° F (38.3° C) or higher
- Chills (feeling cold and shivering)
- Abnormal vaginal bleeding
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During Your Procedure
- If you’re between the ages of 11 and 50, your doctor will ask you to take a urine (pee) pregnancy test before your procedure.
- You’ll meet with a nurse and patient care technician. They will show you the LEEP equipment.
- Your doctor will talk to you about the procedure, answer your questions, and ask you to sign a consent form.
- The nurse or technician will help you get into position for the procedure. You’ll be in the same position that you would be in for a regular pelvic exam. Since the procedure uses electricity, a grounding pad will be placed on your thigh. This is used to keep you from getting shocked and to protect you from getting hurt.
- Your doctor will numb your cervix by injecting it with a numbing medication called lidocaine. You may feel some pressure and slight burning as it’s injected. The medication may also make your heart beat a little faster.
- Your doctor will turn on the LEEP equipment. The equipment makes a loud noise that sounds like a vacuum.
- Once your cervix is numb, your doctor will pass the thin wire loop through the surface of your cervix to remove the abnormal cells. Sometimes, your doctor may need to do it a second time.
- Your cervix will be cauterized to stop any bleeding.
- Your doctor will place a special solution on your cervix. This will prevent any further bleeding.
- The equipment will be removed. You’ll be helped into a comfortable resting position. We will ask you to rest for 10 to 15 minutes.
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After Your Procedure
Before you leave, your nurse will explain how to care for yourself at home. Here are some guidelines to follow:
- Rest for the rest of the day after your procedure. You can go back to work or school 1 or 2 days after your procedure.
- Take acetaminophen (Tylenol®) or ibuprofen (Advil®, Motrin®) if you have any discomfort.
- You can shower as usual, but don’t take a bath until your doctor says it’s okay.
- Don’t place anything inside your vagina (such as tampons or douches) or have vaginal intercourse for at least 4 weeks after your procedure. It usually takes about this long for your cervix to heal. During your follow-up appointment, your doctor will examine you and see if your cervix has healed.
- You may notice a brown discharge for 1 to 2 days after your procedure. This is from the solution put on your cervix after your procedure. You can use a sanitary pad for vaginal discharge.
- You may also have vaginal bleeding that looks like menstrual flow for 1 to 4 days after your procedure. You may notice more vaginal bleeding 10 to 12 days later as you’re healing. The amount of discharge and bleeding varies for every woman. Use sanitary pads for vaginal bleeding.
- Don’t do any strenuous activity (such as running or aerobics) for 1 week after your procedure.
- You may have a late or heavy period after your procedure. This is normal.
If you don’t already have a follow-up exam scheduled, call your doctor’s office to set up an appointment for 4 weeks after your procedure.
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Call Your Doctor or Nurse if You Have:
- A fever of 101° F (38.3° C) or higher
- Blood clots or heavy vaginal bleeding (needing to change your sanitary pad every 1 to 2 hours) that isn’t because of your period
- Pain that doesn’t get better after taking medication
- Any unexpected or unexplained problems
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What to Expect
A LEEP usually takes about 10 to 20 minutes. In most cases, you can have it done at your doctor’s office. You’ll lie on the exam table and your doctor will use a speculum to open your vagina, as if you were getting a Pap smear.
Your doctor will look at your cervix and the inside of your vagina using something called a colposcope. It looks a little bit like a microscope, and it lets your doctor look at the cells close up. Your doctor will put it near your vagina, but not inside.
To get a good look at the cells, your doctor may clean and soak your cervix with a vinegary liquid. It can make abnormal cells turn white and make them easier to see. It may sting a little. Then you’ll get a small shot in the area to numb it.
Next, your doctor will put the LEEP tool through the speculum into your vagina and take out abnormal tissue. How much your doctor takes depends on whether they’re using the LEEP to figure out what’s wrong or to treat the problem.
During the LEEP, you may feel cramps or like there is pressure inside. Some women feel faint. Tell your doctor if you get lightheaded or you feel like you might pass out.
My Experience With HPV & LEEP
By Darcy Rogers
I moved to NYC in Spring 2011 and in my first year of living here, I contracted HPV. I was crushed to find out the news, especially because I had been practicing safe sex. My doctor informed me that condoms do decrease the risk, but are unfortunately not a complete safeguard against contracting HPV. The results of my Pap test prompted my doctor to schedule me for a colposcopy, an exam that allowed her a closer look at my cervix. During the colposcopy, she also did a biopsy. After the colposcopy was over, I cried. The doctor asked me what was wrong and I told her that having a biopsy felt so serious.
The biopsy revealed a high grade growth which was not good news, but also not bad news. My doctor suggested that the best course of action would be to wait and see. The best case scenario would be that my body would clear the virus on its own and the worst case scenario would be undergoing a procedure to remove the abnormal tissue. She instructed me to schedule a checkup every six months so that she could monitor any changes.
I religiously attended the six month appointments and embraced healthier habits including more exercise and veggies. I feverently hoped my body would clear the virus on its own as the alternative sounded frightful. Via Google, I had read about a procedure called Loop Electrosurgical Excision Procedure, or LEEP for short. This is an operation in which the doctor takes an electrically charged wire and removes abnormal tissue from the cervix. I am easy to nausea and fainting if hearing about bodily injuries, surgeries, or excessive bleeding. Heck, I one time fainted in a first aid class! My fear of physical pain was in overdrive when researching LEEPs on Google. I had to shut down the computer and lie down.
I was in a holding pattern for two years. Each exam revealed no new changes and I continued to keep my fingers crossed. This health issue was in the back of my mind, but mostly I lived my life as normal. This changed two weeks after an appointment in Spring of 2014. My doctor called to let me know that unfortunately my pap smear had revealed negative growth and it was necessary to remove tissue. I was crushed by this news and felt my stomach drop when she recommended a LEEP.
Reading articles online about what a LEEP entailed had made me feel sick. An anesthetic would be administered via a shot directly into my cervix and a portion of tissue would be removed. I worried about the pain I would feel before and after the procedure. The day of the appointment arrived and I tearfully entered the exam room. Seeing my tears, my doctor assured me that I would not feel pain and it would be over quickly. The nurse also offered to hold my hand which I gladly accepted.
I sat in the chair, with my legs in the stirrups and the doctor inserted the speculum. She gave me four shots of anesthetic. Thankfully, it was not as a painful as I had imagined. They felt like a small pinch. She instructed me to stay completely still. She explained that the wire was electrically charged and any sudden movements on my part could cause unnecessary wounds. I closed my eyes, clenched the nurse’s hand, as the doctor went to work. I heard the hum of the tool as she scraped away part of my cervix, but felt nothing. After 20 minutes she declared that the procedure was over. She instructed me to relax and take my time getting dressed. The nurse went over a few rules for my healing. For the next two weeks I was to avoid exercise, heavy lifting, and sex. I was to call the office immediately if I noticed any bleeding. I felt drained from the anticipation, but also relieved it was over. The LEEP had been quick and painless.
The next few days, I could feel a bit of discomfort on my cervix. There was a tightness, similar to the stretching feeling in the skin surrounding a scabbed over wound. Beyond that I felt no pain and had no bleeding. I took it easy, taking the next day off to relax and indulge in some self care. At the two week follow-up appointment, my doctor declared that the healing process had been successful.
My pap tests since the LEEP have thankfully been normal. I was very scared to undergo this procedure, but in the end it turned out to be fine. I felt very fortunate to be under the care of a skilled and compassionate doctor. She always took time to answer questions and reassure me that I was not alone in this journey. If you need to undergo a colposcopy or LEEP, find a caring doctor you like and can trust. Then, follow their guidelines. My doctor stressed how important it was to attend six month appointments. If left unchecked, HPV can lead to cervical cancer. Undergoing a LEEP was scary, but ultimately it was for my greater health. And for that, I am grateful.
Read more of Darcy’s work here.
Negative LEEP Is Not Reassuring
Loop electrosurgical excision procedure (LEEP) is a common treatment for cervical intraepithelial neoplasia (CIN), with success rates of 60 to 95 percent reported. Several studies have examined the relationship between histologic abnormalities in LEEP specimens and disease recurrence. Occasionally, however, a LEEP sample shows no histologic abnormality. The clinical implications of a negative sample are unknown. Livasy and colleagues studied the medical and histologic records of 674 patients to determine the incidence and clinical significance of negative LEEP samples.
The study included all women at one university medical center who received LEEP therapy for high-grade dysplasia between 1991 and 2001. Follow-up results from Papanicolaou (Pap) smears, cervical biopsies, and hysterectomies through July 2002 were evaluated.
Ninety-three (14 percent) of the women had negative LEEP specimens. Follow-up data were available on 75 of these patients and 446 of the others. A recurrence of abnormality (i.e., abnormal Pap smear or other diagnosis of CIN) was documented in 18 (24 percent) of the women who had negative LEEP samples compared with 107 (27 percent) of those with positive histologic findings. Recurrent abnormalities in the women with negative LEEP samples consisted of two carcinomas, eight high-grade squamous intraepithelial lesions, six low-grade squamous intraepithelial lesions, and two atypical cells of undetermined significance. Factors that may limit histologic examination, such as cautery, were identified in 15 (16 percent) of the negative LEEP samples compared with 27 (5 percent) of the positive LEEP samples.
the authors conclude that negative histology, while not rare, should not be interpreted as a benign finding, as subsequent abnormality rates were similar in women with negative LEEP samples and those with histologic abnormality. They note that the incidence of factors limiting complete pathological examination was significantly higher in negative LEEP specimens than in positive, and recommend close monitoring of all women who are treated for dysplasia, regardless of LEEP histology.
When is hysterectomy appropriate for cervical dysplasia?
Cervical dysplasia is commonly diagnosed in women who have completed childbearing and don’t desire future fertility. While diagnostic and/or definitive therapy for cervical dysplasia can include hysterectomy, there are important considerations to make when offering this procedure to patients.
Dr. Emma C. Rossi
Hysterectomy is commonly requested by patients upon learning of cervical dysplasia, particularly if they have chronic human papillomavirus (HPV) infection and have experienced years of frequent surveillance and interventions. They may see hysterectomy as an option to avoid this close surveillance and to be free of their dysplasia. There are two main concerns with offering hysterectomy as the primary surgical option for the management of dysplasia. Firstly, it may not be curative, and secondly, it may be an inadequate excisional procedure, particularly if the patient has occult invasive disease that has not been adequately diagnosed with a loop electrosurgical excision procedure (LEEP) or a cone biopsy procedure.
It is important to counsel these patients that surgery is not a treatment for high-risk HPV infection, which is the underlying etiology of their disease. With that etiology, HPV infection is likely to persist after hysterectomy and they may develop vaginal or vulvar dysplasia. Therefore, the American Society for Colposcopy and Cervical Pathology recommends that cytology and/or high-risk HPV surveillance continue following hysterectomy if that surgery was performed for dysplasia.1 Hysterectomy is not a means to avoid years of surveillance testing. Approximately 10% of women who have hysterectomy for cervical dysplasia develop vaginal dysplasia or cancer after surgery.2,3 This is similar to the likelihood of recurrent dysplasia after an alternative excisional procedure. In my experience, this diagnosis is often met with enormous frustration for the patient who thought that her hysterectomy would be the cure of her HPV-related disease. Thorough colposcopic evaluation of the vagina can be technically challenging after hysterectomy because of difficulty adequately visualizing lesions within the vaginal rugations, particularly within the puckered lateral vaginal fornices, the most common location for dysplasia.3 We will explore the diagnosis and treatment options for vaginal dysplasia further in a future column.
It is critical that, if patients are offered hysterectomy for treatment of cervical dysplasia, they are counseled that it may not be curative, that they will require long-term vaginal surveillance, and that they are at continued risk for vaginal and vulvar cancer.
An additional concern with performing hysterectomy for definitive management of cervical dysplasia is the concern that occult cancer may be missed preoperatively, and that the hysterectomy is inadequate surgical clearance of the disease. Approximately 2%-5% of patients with a high-grade squamous intraepithelial lesion or equivocal Pap test have occult cervical cancer.4 A similar proportion of patients with cervical intraepithelial neoplasia stage III or adenocarcinoma in situ on colposcopy biopsy have invasive carcinoma on evaluation of an excisional specimen.5 The traditional surgical approach has dictated that a modified (type II) or extended (type III) radical hysterectomy be performed in the setting of FIGO stage IA2 or greater cervical cancer. Radical hysterectomies remove parametrial tissue, effectively achieving a wider margin around the primary lesion. This is important because cervical cancer primarily spreads via direct extension.
The appropriate radicality of surgery for microscopic lesions is debated. It has been proposed that for very small, low-risk lesions, a traditional extrafascial hysterectomy or trachelectomy, or possibly even a large conization, may be adequate.6 However, this is controversial, and National Comprehensive Cancer Network guidelines still advocate for radical procedures for these lesions.7 Certainly an excisional procedure (LEEP or cone) should first be performed to define the size and histologic features of the lesion, and ideally, evaluation and counseling with a gynecologic oncologist should be performed prior to offering patients with a stage IA2 or greater lesion an extrafascial hysterectomy. Additionally, a separate decision would need to be made regarding the need for lymphadenectomy, as this is typically recommended for patients with stage IA2 or greater lesions.
Patients should be counseled that, if extrafascial (simple) hysterectomy is chosen as the primary excisional procedure, they may require additional therapy (additional surgery, or radiation and possibly chemotherapy) if cancer is found in the specimen and the parametrial margin is inadequate. Additionally, and of more concern, if the lesion is a bulky lesion extending into the parametrium and not recognized preoperatively, a “cut-through” hysterectomy will be inadvertently performed (in which margins are grossly positive). These situations typically feature heavy blood loss with patients at increased risk for immediate surgical complications. Postoperatively, prognosis is substantially worse for patients who have had a cut-through hysterectomy, compared stage for stage with patients who primarily received a radical procedure with negative margins or primary chemotherapy and radiation.8 Otherwise said, their risk for death is higher if this error is made. Therefore a thorough examination is essential prior to performing hysterectomy for dysplasia. Any suspicion of bulky cancer should be considered a contraindication for proceeding.
Human Papilloma Virus Persistence after Cone Excision in Women with Cervical High Grade Squamous Intraepithelial Lesion: A Prospective Study
Background. Persistent human papillomavirus (HPV) infection is a necessary event in cervical cancer tumorigenesis. Our objectives were to estimate the rate of HPV infection persistence after large loop excision of the transformation zone (LEEP) in patients with high grade squamous intraepithelial lesions (HSIL) and to investigate if HPV persistence is type related. Methods. We conducted a prospective study on 89 patients with HSIL treated with LEEP. DNA HPV was performed before surgery and at 6, 12, and 18 months after LEEP. Results. Four patients were excluded from the study. The HPV persistence in the remaining 85 patients was 32.95% (6 months), 14.12% (12 months), and 10.59% (18 months). Type 16 had the highest persistence rate, 23.5% (6 months), 11.8% (12 months), and 8.2% (18 months). Coinfection was found to be 54.12% before LEEP and 18.8% (6 months), 4.7% (12 months), and 3.5% (18 months) after LEEP. The rate of coinfections including type 16 was 46.83% of all coinfections. Coinfection including type 16 was not correlated with higher persistence rate compared to infection with type 16 only. Conclusions. HPV infection is not completely eradicated by LEEP in patients with HSIL lesion on PAP smear. HPV persistence after LEEP is influenced by HPV type. HPV type 16 has the highest persistence rate.
Persistent human papillomavirus (HPV) infection is a necessary event in cervical cancer tumorigenesis. Virtually all tumor cells in a cervical cancer contain sequences of HPV . HPV is the most frequent sexually transmitted disease in the world. The majority of infections are transient, up to 70% regressing in the first year and up to 90% in 2 years; 10–20% of the infections persist, allowing the evolution of preneoplastic lesions to cancer . Only 40 of the 200 known HPV genotypes present tropism for the anogenital mucosa and 18 of those 40 types are directly related to cervical cancer . Fifteen HPV types have been defined as high risk-human papilloma virus (HR-HPV) types with strong oncogenic potential: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82. These HR-HPV types account for 95% of all cervical cancers. Simultaneous infections with multiple HPV types are common .
HPV 16 and 18 are the most common HR-HPV types worldwide and account for about 70% of all squamous cells carcinomas (SCC) and for up to 85% of all adenocarcinomas. HPV 16 is the most carcinogenic HPV genotype and HPV 18 causes a greater proportion of glandular cancers compared to squamous cell carcinoma. After HPV 16 and 18, the six most prevalent types that account for an additional 20% are types 31, 33, 35, 45, 52, and 58 .
Cone excision of the uterine cervix such as large loop excision of the transformation zone (LEEP) is not only a diagnostic procedure but also an appropriate treatment for cervical intraepithelial neoplasia (CIN) . However, CIN can recur, and invasive cervical carcinoma can develop, following such CIN treatment. There is increasing evidence that testing for the presence of high risk-human papilloma virus (HR-HPV) after LEEP may help predict the likelihood of persistent or recurrent disease .
The objectives of our study were to estimate the rate of HPV infection persistence after LEEP in patients with high grade squamous intraepithelial lesions (HSIL) and to investigate if HPV persistence is type related.
2. Materials and Methods
Patient Selection. We performed a prospective study. We included in the study all patients with HSIL cytology on PAP smear who were referred for LEEP to the Department of Obstetrics and Gynecology of the University of Medicine and Pharmacy “Victor Babeş”, Timişoara, between January 2010 and May 2014. Conventional cytology was performed and evaluated according to the criteria of Bethesda 2001. All patients were evaluated by colposcopy and the criteria of the International Federation for Cervical Pathology and Colposcopy (IFCPC) were used. All patients underwent LEEP under colposcopic vision after application of Lugol solution. During the procedure, all colposcopically abnormal findings were excised, aiming for a tissue depth of at least 6 mm. All procedures were performed by the same team of surgeons. DNA HPV testing was performed before LEEP in all cases. DNA HPV testing was repeated at 6, 12, and 18 months after LEEP. Patients who were negative for DNA HPV before LEEP were excluded from the study. All samples were examined using LINEAR ARRAY HPV Genotyping Test (CE-IVD), based on reverse hybridization of amplicons. The DNA of 37 HPV types (6, 11, 16, 18, 26, 31, 33, 35, 39, 40, 42, 45, 51, 52, 53, 54, 55, 56, 58, 59, 61, 62, 64, 66, 67, 68, 69, 70, 71, 72, 73, 81, 82, 83, 84, IS39, and CP6108) was detected in cervical samples by multiplex PCR targeted to the conserved L1 region of the viral genome. The Gene Amp PCR System 9700 was used for genotyping test according to the manufacturer’s instructions. Automated hybridization and detection of HPV DNA was done on ProfiBlot 48 (Tecan Trading AG, Zurich, Switzerland).
All specimens were sent for histopathological exam. Patients with positive resection margins after LEEP were excluded from the study.
Informed consent was obtained from all patients prior to their inclusion in the study. All procedures have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments and were approved by the Institutional Review Board and Ethical Committee of University of Medicine and Pharmacy “Victor Babeş”, Timişoara.
Statistical analysis was performed using SPSS v17 and Epi Info 7. For computing values we used nonparametric tests (Wilcoxon sign rank and chi square).
A total of 89 patients were referred to our clinic with HSIL on PAP smear test. After the first DNA HPV testing, 2 patients were found negative and were excluded from the study. We excluded those patients because we wanted to investigate HPV persistence after LEEP. Since there was no infection before LEEP, we excluded the patients from the trial.
Another 2 patients had positive margins on the LEEP specimen and were also excluded from the study. The remaining 85 patients were tested for DNA HPV at 6, 12, and 18 months after LEEP. All remaining patients were positive for HR-HPV before LEEP. The HPV types detected before LEEP were 50.6% type 16, 24.7% type 18, 20% type 31, 24.7% type 33, 11.8% type 35, 7.1% type 45, 27.1% type 52, 9.4% type 58, 9.4% type 6, 5.9% type 11, and 5.9% other types. At 6 months after LEEP, the overall persistence was 32.95% (28 patients), at 12 months 14.12% (12 patients), and at 18 months 10.59% (9 patients). The rate of persistence in our group at 6, 12, and 18 months for each HPV type is shown in Table 1. Viral persistence at 12 and 18 months was observed only in patients positive at 6 months. Type 16 was found to be with the highest persistence rate, 23.5% at 6 months, 10.6% at 12 months, and 8.2% at 18 months. Type 16 was associated with significantly increased risk of persistence compared with the other high risk types (Table 2).
Table 1 The rate of persistence at 6, 12, and 18 months for each HPV type computed for all 85 subjects. Table 2 The value obtained by comparing HPV 16 to the other HPV types using test.
Coinfection, defined as the presence of more than one HPV type, was found to be 54.12% before LEEP, 18.8% at 6 months, 4.7% at 12 months, and 3.5% at 18 months after LEEP (Table 1). Coinfections including type 16 represented 46.83% of all coinfections. Patients positive for type 16 were found to have significantly higher risk of infection persistence than patients presenting infections or coinfections with other types (Tables 3 and 4). Coinfection including type 16 was not correlated with higher persistence rate than infection with type 16 only (Table 5).
Table 3 The value obtained using test, comparing patients positive for HPV type 16 and patients having coinfections (without HPV 16). HPV 16 was correlated with significantly higher risk of persistence () at 6 and 12 months.
Table 4 The value obtained using test, comparing coinfections including HPV 16 + other HPV types, with coinfections without HPV 16. Coinfection including type 16 was correlated with higher persistence rate than coinfections without type 16.
Table 5 The value obtained using test, comparing coinfections with HPV 16 and other HPV types and only HPV 16. Coinfection including type 16 was not correlated with higher persistence rate than infection with type 16 alone.
Cervical cancer remains a leading cause of morbidity and mortality in women worldwide . It is caused by the acquisition and persistence of types of high risk-human papilloma virus (HR-HPV) infection and the subsequent malignant transformation of cervical epithelial cells . Persistent HPV infection is a major factor in CIN development. The natural history of the progression of HPV infection to cervical lesion or clearance was investigated by Jaisamrarn et al. 2013. They found that overall 53%, 79%, 87%, and 89% of all HPV infections were cleared at 12, 24, 36, and 48 months, respectively, and that HPV 16 and HPV 31 were significantly less likely to clear than a nononcogenic HPV . The persistence of high risk HPV infection is a key factor for the development of cervical cancer , and detection of viral persistence can be used to identify the women with the greatest risk of cervical cancer .
Cone excision of the cervix is considered both diagnostic and therapeutic procedure that can effectively eradicate HR-HPV infection and CIN. Despite the removal of the entire lesion by cone excision with negative margins, the HPV infection can persist in some cases. Studies investigating the clearance/persistence of HPV infection after LEEP have reported that age, lesion grade, and margin status are risk factors for HPV persistence. Our persistence rate at 6 months was 32.95%. Other authors, using the same procedure, reported lower rates of HPV persistence at 6 months, ranging from 14.3% to 21.5% . We consider that the selection of only patients with HSIL and the fact that all patients in our study had HR-HPV infections are responsible for our higher persistence rate. Park et al. and Nam et al. also found that high grade lesions are risk factors for HPV persistence after LEEP .
We excluded patients with positive margins after resection from our study because we wanted to investigate the persistence of HPV infection in patients with negative margins. The presence of positive margins is considered a major factor for HPV persistence and disease recurrence and progression. Alonso et al. 2006 found that positive cone margins were significantly associated with higher risk of recurrence . We selected patients with HSIL because they are more likely to have HPV infection with high risk types, and HSIL lesions are more likely to progress to invasive disease. We excluded patients with negative HPV DNA before LEEP because our goal was to investigate HPV infection persistence after LEEP.
Several authors investigated and found that viral load prior to LEEP is a risk factor for HPV persistence . High viral loads, RLU/PC ≥ 100, were considered risk factors for HPV persistence and disease recurrence . Since the measurement of HPV viral load is not widely available, we investigated if the risk of HPV persistence after LEEP is related to certain types of HPV. We consider this helpful for risk stratification and the selection of the group of patients that should be evaluated more carefully. We focused on type related persistence, because DNA HPV is a more widely used test than HPV viral load evaluation.
The identification of the same HPV type before and after LEEP was considered persistence. We did not find new types of HPV after LEEP in any patient. Viral persistence at 12 and 18 months was found only in patients positive at 6 months after LEEP. We consider that the probability of reinfection during the study is low, although it is difficult to completely exclude it.
In our study HPV type 16 was found to be a factor that favors HPV persistence after LEEP. Our results are in agreement with Nam et al. 2009 who investigated the factors associated with HPV persistence after conization in a similar group (77 patients) and found that preoperative HPV type 16 infection was the only significant independent factor () for HPV persistence out of age, cytology, punch biopsy histology, HPV viral load, and conization histology.
Our results also indicate that most HPV infections are cleared at 12 months after surgery, and very few are cleared after this interval. We suggest that the HPV DNA follow-up endpoint after LEEP should be 12 months. We also consider that patients with infection persistence after 12 months are more likely to develop disease progression than infection clearance, but more data are necessary in order to prove this statement. We suggest that HPV DNA at 12 months after LEEP could be a useful tool, in order to identify the patients that are likely to experience disease progression.
Persistence or clearance of HPV DNA is considered an early valid prognostic marker of failure or cure after treatment for cervical dysplasia and is more accurate than cytology or section margin status at the time of LEEP . According to the meta-analysis performed by Kocken et al. 2012 HPV test should be included in posttreatment testing 6 months after treatment, because it has a higher sensitivity than cytology in detecting high grade posttreatment disease and has a similar specificity . The recurrence of cervical dysplasia after LEEP is also related to HPV persistence. Several investigators have analyzed the sensitivity and specificity of HPV DNA testing compared with follow-up cytology to more accurately detect residual/recurrent disease after treatment . HPV testing was found to be more sensitive than follow-up cytology, with comparable specificity . Women who are HPV positive after surgery are at higher risk for treatment failure .
We noticed the persistence of types 6 and 11 at 12 months. This was also reported by Brismar et al. Those are not considered high risk types, but they are associated with condyloma .
The interest regarding coinfection with multiple types of HPV has increased in the past years, along with the possibility of vaccination and also due to the discovery that the immune response seems to be type specific .
The incidence of coinfection reported in literature is variable, ranging from 19% to up to 43.2%. This is due to factors such as age, sexual behavior, and immune response and HPV detection method. Our coinfection rate was 54.12%, and the rate of coinfections including type 16 was 46.83% of all coinfections .
On a study on 1124 patients, Liaw et al. found that HPV 16 had persisted longer than other types, but it did not alter subsequent persistence of other concomitant HPV infections. This concurs with our results that type 16 has the highest persistence rate (Table 2). We also found that infection with type 16 has higher persistence rate than coinfection without type 16 (Table 3). The coinfection including type 16 was not correlated with higher persistence rate compared to infection with type 16 alone (Table 5). This indicates that the presence of type 16 is the most important factor for infection persistence .
The strengths of study are represented by the prospective nature of the study and the fact that only patients with HSIL were selected. This way we investigated the very category of patients that are likely to be infected with HR-HPV and that are exposed to recurrence after LEEP and disease progression to cancer.
HPV infection is not completely eradicated by LEEP in patients with HSIL lesion on PAP smear. HPV persistence after LEEP is influenced by HPV type. HPV type 16 has the highest persistence rate.
Our results strongly advocate introducing the HPV DNA test in the follow-up of the patients that underwent LEEP for HSIL, especially if HPV type 16 was identified prior to LEEP.
Name of register is Laurențiu Pirtea.
The authors declare no conflict of interests.
This paper was supported by Grant PII-C2-TC-2014-06, University of Medicine and Pharmacy “Victor Babeş”, Timişoara, Romania.
The data used for the statistical analysis regarding HPV infection with the tested HPV-DNA, determined before LEEP (1 = present, 0 = absent), and at 6, 12, and 18 months after LEEP, and also the age of the patients investigated.