Hysteroscopic cervical biopsy for women with persistent human papillomavirus infection after loop electrosurgical excision procedure: A case report

Abstract

BACKGROUND

Almost all cases of cervical cancer can be attributed to human papillomavirus (HPV) infection. The loop electrosurgical excision procedure (LEEP) is widely used to treat HPV-mediated disease; thus, cervical cancer is highly preventable. However, LEEP does not necessarily clear HPV rapidly and may affect the accuracy of the results of ThinPrep cytology test (TCT) and cervical biopsy due to the formation of cervical scars.

CASE SUMMARY

A 40-year-old woman underwent LEEP for cervical intraepithelial neoplasia grade 1 approximately 10 years ago. Subsequent standard cervical cancer screening suggested persistent HPV-52 infection, but TCT results were negative. Cervical biopsy under colposcopy was performed thrice over a 10-year period, yielding negative pathology results. She developed abnormal vaginal bleeding after sexual activity, persisting for approximately 1 year, and underwent hysteroscopy in our hospital. Histopathologic evaluation confirmed adenocarcinoma in situ of the uterine cervix.

CONCLUSION

Patients with long-term persistent, high-risk HPV infection and negative pathology results of cervical biopsy after LEEP are at risk of cervical cancer. Hysteroscopic resection of cervical canal tissue is recommended as a supplement to cervical biopsy because it helps define the lesion site and may yield a pathologic diagnosis.

Key Words: Loop electrosurgical excision procedure, Persistent human papillomavirus infection, Hysteroscope, Cervical adenocarcinoma, Case report

Core Tip: The loop electrosurgical excision procedure (LEEP) is widely used to treat human papillomavirus (HPV)-mediated disease; thus, cervical cancer is highly preventable. However, LEEP does not necessarily clear HPV infection rapidly, and patients with persistent HPV infection after LEEP are at risk of cervical cancer. The formation of cervical scars after LEEP may affect the accuracy of ThinPrep cytology test and cervical biopsy results; thus, hysteroscopic resection of cervical canal tissue is recommended as a supplement to cervical biopsy because it helps define the lesion site and may yield a pathologic diagnosis.

INTRODUCTION

Cervical cancer is the third most common malignancy in women worldwide. Almost all cases of cervical cancer can be attributed to human papillomavirus (HPV) infection[1]. With ongoing improvement in screening methods, the detection rates of premalignant cervical lesions have increased each year. The cervical loop electrosurgical excision procedure (LEEP) has become the classic treatment protocol for preinvasive HPV-mediated disease. HPV detection using the ThinPrep cytology test (TCT) and colposcopic cervical biopsy have become the primary follow-up approaches after LEEP[2]. However, these tests have led to new challenges; in particular, cervical scars may form after LEEP, which can cause partially or wholly invisible transformation areas in the squamocolumnar junction, thereby affecting the results of TCT and colposcopy.

Herein, we report a case of HPV infection that persisted after LEEP. Multiple TCT and colposcopic cervical biopsies yielded negative results. Through hysteroscopic exploratory diagnostic scraping, adenocarcinoma in situ of the uterine cervix was finally confirmed.

CASE PRESENTATION

Chief complaints

A 40-year-old woman presented to the gynecological department of our hospital with long-term persistent HPV infection but negative pathologic results of cervical biopsy after LEEP.

History of present illness

She had HPV-52 infection for > 10 years. In 2013, she underwent LEEP for HPV-52–induced cervical intraepithelial neoplasia grade 1 (CIN 1; Figure 1A). Subsequent standard cervical cancer screening suggested persistent HPV-52 infection, but TCT results were negative. In July 2015 and May 2019, she underwent cervical biopsy under colposcopy, which yielded negative histopathologic results. Her menstrual cycle was regular with 28-day intervals. Since 2022, she developed abnormal vaginal bleeding after sexual activity. Gynecological examinations revealed that the cervix was smooth after LEEP, and uterine ultrasonography indicated normal endometrial thickness. Short-acting contraceptives did not alleviate the bleeding. In May 2023, a third cervical biopsy and scratching of the cervical canal under colposcopy were performed, which also yielded negative pathology results (Figure 1B). In August 2023, she visited our outpatient department with persistent HPV-52 infection, negative TCT findings, and abnormal vaginal bleeding after sexual activity.

Figure 1 Cervical histopathological results. A: Pathologic examination after loop electrosurgical excision procedure indicated cervical intraepithelial neoplasia grade 1; B: Pathologic examination of colposcopic cervical biopsy specimen revealed chronic inflammation of the cervical mucosa; C: Histopathologic evaluation confirmed adenocarcinoma in situ of the uterine cervix.

History of past illness

The patient had no notable medical history.

Personal and family history

The patient had a no family history.

Physical examination

During gynecological examination, cotton swabs were blood stained after insertion into the cervical canal, although the cervical surface was smooth without any blood stain.

Laboratory examinations

Squamous cell carcinoma antigen testing yielded negative results.

Imaging examinations

Uterine ultrasonography showed normal results (Figure 2). Pelvic magnetic resonance imaging revealed a normal uterus and cervix (Figure 3).

Figure 2 Uterine ultrasonography showed normal results. A and B: Ultrasonography showed that the uterus measured 5.3 cm × 4.0 cm × 4.1 cm, blood supply was normal, and the endometrium was 0.5 cm thick (A) and depicted a cervix with uniform blood supply and without any space-occupying lesion.

Figure 3 Pelvic magnetic resonance imaging revealed a normal uterus and cervix. A and B: Sagittal (A) and axial (B) pelvic magnetic resonance imaging showed normal uterine size and shape, no abnormal signals, and no obvious abnormal signal shadows in the bilateral adnexa.

FINAL DIAGNOSIS

Histopathologic evaluation confirmed adenocarcinoma in situ of the uterine cervix.

TREATMENT

Written informed consent was obtained (December 9, 2023) from the patient and her family after explaining the condition, and hysteroscopy was performed for diagnosis. During hysteroscopy, endometria were clearly defined, and the inflamed cervical canal tissue (Figure 4) was resected.

Figure 4 Hysteroscopic view. A and B: Hysteroscopic examination revealed no significant hyperplastic changes in the endometrium (A) but showed inflammation of the cervical canal (B).

OUTCOME AND FOLLOW-UP

Histopathologic evaluation confirmed adenocarcinoma in situ of the uterine cervix (Figure 1C).

DISCUSSION

The major stages in cervical carcinogenesis include HPV infection, HPV persistence, progression to dysplasia, and invasion. In 2020, based on statistical data, approximately 604000 new cases of cervical cancer were diagnosed worldwide, leading to approximately 342000 deaths[3]. In the same year, the World Health Organization launched the global Cervical Cancer Elimination Initiative to accelerate the eradication of cervical cancer, which established the “90–70–90” target: 90% of girls should receive HPV vaccine before the age of 15 years, 70% of women should undergo high-quality cervical cancer screening at least twice between the ages of 35 and 45 years, and 90% of women diagnosed with cervical premalignant lesions or cancer should receive treatment and management[4]. Therefore, cervical cancer screening is widely conducted globally, and partial cervical resection is performed in patients with cervical premalignant lesions. LEEP is an established method of early cervical resection, and it contributes to the remission of persistent HPV infection; the rate of complete viral remission is 64.5%[5].

However, HPV infection is a single factor contributing to the development of cervical cancer[6]; therefore, patients with persistent HPV infection after LEEP need more extensive follow-up. Long-lasting HPV infections were traditionally believed to cause CIN in a slow, progressive, and consecutive manner: from normal tissue with HPV infection to CIN 1 (low grade), CIN 2 (moderate grade), CIN 3/CIS (high grade), and finally cancer. However, recent data indicate that CIN 1 may not necessarily precede the development of CIN 3 and that CIN 3 can evolve directly from normal tissue with HPV infection, as described by a molecular switch model. In this model, the severity of dysplasia was determined by the extent of methylation of certain genes, and this progression might not be linear[7].

Adenocarcinoma of the cervix accounts for approximately 25% of all cervical cancers. Compared with squamous cell carcinoma, adenocarcinomas of the cervix are more heterogeneous, with diverse pathologic types and worse prognoses, and early diagnosis significantly affects prognosis[8]. However, the occult lesions of cervical adenocarcinoma are mainly located in the columnar epithelium that coats the cervix as well as the stromal glands[9], which increase the difficulty of early diagnosis. In the current case, gynecological examination revealed cervical canal bleeding, which is one of the signs of cervical adenocarcinoma. TCT may be difficult to obtain the deep part of the cervical canal, and clinicians often do not perform deep sampling during cervical biopsy; thus, results may be inaccurate. Due to inertial thinking and over-reliance on colposcopic cervical biopsy, diagnoses are frequently missed. The formation of scars on the surface of the cervix after LEEP, leading to partially or wholly invisible transformation areas in the squamocolumnar junction, may affect the results of subsequent TCT screening and colposcopy[10].

CONCLUSION

Considering the patient’s 10-year history of HPV infection and abnormal bleeding, we decided to perform hysteroscopy. Histopathologic evaluation confirmed adenocarcinoma in situ of the uterine cervix. Therefore, hysteroscopic resection of cervical canal tissue is recommended as a supplement to cervical biopsy in cases of persistent HPV infection with abnormal bleeding for early diagnosis, treatment, and improved prognosis.