A case of persistent HPV-associated high-grade squamous intraepithelial lesion (HSIL) explores the direct application of Viscum album to the cervical transformation zone as an adjunct to conventional gynecologic surveillance and treatment.
Persistent high-grade squamous intraepithelial lesions (HSIL) are conventionally managed with excisional treatment to reduce the risk of progression to cervical cancer. Although Viscum album extract has been investigated for its immunomodulatory properties in integrative oncology, evidence supporting its use in HPV-associated cervical dysplasia remains limited, and direct application to the cervical transformation zone has not previously been described.
Case Presentation:
A 33-year-old female with persistent histologically confirmed HSIL underwent adjunctive naturopathic care while remaining under gynecologic surveillance. Serial cervical cytology and endocervical curettage demonstrated persistent HSIL over a 10-month period despite observation, and loop electrosurgical excision procedure (LEEP) was planned.
Intervention:
Beginning in February 2019, the patient underwent 17 weekly in-office treatments consisting of direct application of Viscum album M to the cervical transformation zone under speculum visualization. The extract remained in contact with the cervix for approximately 15 minutes, after which calendula oil was applied according to the treatment protocol. Treatment was provided as an adjunct to, and not a replacement for, conventional gynecologic management.
Outcomes:
Cervical cytology obtained during treatment continued to demonstrate HSIL. The patient subsequently underwent the planned LEEP in October 2019. Histopathologic examination of the excised specimen demonstrated no residual squamous intraepithelial lesion or malignancy, with only acute and chronic inflammation and reactive epithelial changes identified. Follow-up cervical cytology remained negative in 2020 and 2021, and HPV testing in 2025 was negative.
“The principal observation in this case is not simply the apparent regression of persistent cervical dysplasia. Rather, it is the use of a novel protocol involving direct application of Viscum album to the cervix under visualization.”
Conclusion:
This case describes a novel protocol involving direct cervical application of Viscum album under speculum visualization in a patient with persistent HSIL. Although a causal relationship cannot be established from a single case, the protocol was well tolerated and was associated with an unexpected histopathologic outcome. This observation is hypothesis-generating and supports further investigation of localized Viscum album therapy as a potential adjunctive approach in the management of persistent cervical dysplasia.
Viscum album, HPV, Cervical Dysplasia, HSIL
With more than 200 identified genotypes, human papillomavirus (HPV) is one of the most common viral infections affecting the skin and mucosal epithelium and is the most common sexually transmitted infection worldwide. Although the majority of HPV infections are transient, asymptomatic, and cleared by the host immune system, some progress to clinical disease ranging from benign papillomas and anogenital warts to cervical intraepithelial neoplasia (CIN). Persistent infection with high-risk mucosal HPV types, particularly HPV-16 and HPV-18, is the necessary cause of cervical cancer and is also implicated in the development of anal, oropharyngeal, penile, vaginal, and vulvar cancers.[1–3]
More than 90% of newly acquired HPV infections clear or become undetectable within one to two years, although some infections persist in a latent state and may subsequently reactivate.[1-3] Persistent infection with oncogenic HPV types, particularly HPV-16 and HPV-18 (which together account for approximately 77% of invasive cervical cancers worldwide), may progress to high-grade cervical dysplasia and invasive carcinoma.[3,4]
Current management of histologic high-grade squamous intraepithelial lesions (HSIL/CIN2–3) consists of excisional treatment, with loop electrosurgical excision procedure (LEEP) preferred and ablation reserved for carefully selected cases. Although excisional treatment effectively removes the transformation zone and eliminates high-risk HPV in most patients, detectable HPV persists in approximately 10–23% following treatment, depending on the interval of testing and margin status. Persistent HPV following excision is the strongest predictor of recurrent CIN, with recurrence rates approaching 18% among women with persistent HPV compared with approximately 0.5% among those who achieve viral clearance and have negative surgical margins.[5-8]
Consequently, there is growing interest in adjunctive strategies that may enhance host immune clearance of residual HPV while recognizing that non-surgical therapies are not currently recommended as primary treatment for histologic HSIL outside of clinical trials.[5]
Viscum album (European mistletoe) has been investigated extensively in integrative oncology because of its immunomodulatory, antiproliferative, and pro-apoptotic properties. For more than a century, Viscum album extract (VAE) has been used as an adjunctive cancer therapy, primarily through subcutaneous administration. Experimental studies suggest that Viscum album extract influences both innate and adaptive immune responses through activation of antigen-presenting cells, enhancement of cytotoxic immune function, and modulation of cytokine signaling. Reported effects include increased activity of natural killer cells, macrophages, dendritic cells, granulocytes, and T lymphocytes, together with promotion of a T-helper 1 immune response. Collectively, these findings suggest a potential mechanism by which Viscum album could influence host immune responses in persistent HPV infection, although clinical evidence remains limited.
Clinical evidence consists primarily of small observational studies. In one prospective series, Gorter et al. treated 100 women with low- to moderate-grade cervical dysplasia using subcutaneous VAE twice weekly for six months. At the completion of treatment, 77% demonstrated cytologic improvement, while 23% continued to exhibit persistent dysplasia [9]. More recently, small case series have described encouraging outcomes using subcutaneous VAE combined with direct vaginal application in women with persistent HPV infection and cervical dysplasia [10]. Together, the available evidence provides preliminary support for further investigation.
This report presents the clinical course of a patient with persistent histologically confirmed HSIL treated using this novel protocol before a loop electrosurgical excision procedure (LEEP).
Case Presentation
A 33-year-old female presented seeking adjunctive naturopathic management of persistent cervical dysplasia while remaining under the care of her gynecologist.
Serial cervical cytology demonstrated persistent HSIL over a 10-month period. Cytology performed in July 2018 demonstrated HSIL. Repeat cervical cytology in November 2018 again demonstrated HSIL, while endocervical curettage performed the same day confirmed high-grade squamous intraepithelial lesion. Repeat cervical cytology in May 2019 continued to demonstrate HSIL despite ongoing surveillance.
Because of the persistence of high-grade disease, excisional management with LEEP was anticipated.
Beginning in February 2019, the patient underwent 17 in-office treatments using a protocol adapted from educational instruction provided by naturopathic doctors experienced in the use of Viscum album for HPV-associated disease and dermatological cancers. At the time of treatment, we reasoned that direct application to the cervical transformation zone would provide more consistent exposure of the dysplastic epithelium than vaginal administration alone. Although this rationale was based on clinical reasoning rather than comparative evidence, it informed the development of the protocol described in this report.
At each visit, the cervix was visualized using a sterile speculum. Aqueous extract of Viscum album M was applied directly to the cervical transformation zone using a sterile cotton applicator. The extract remained in contact with the cervical epithelium for approximately 15 minutes. Calendula oil was then applied directly to the cervix to reduce local irritation and support epithelial healing following treatment.
The patient tolerated all treatments without adverse effects. Treatment was provided as an adjunct to standard gynecologic surveillance and was not intended to replace conventional management.
Despite completion of the treatment protocol, cervical cytology obtained during treatment continued to demonstrate HSIL. The patient subsequently underwent the planned LEEP in October 2019.
Unexpectedly, histopathologic examination of the excised specimen demonstrated no residual squamous intraepithelial lesion or malignancy. Instead, pathology reported acute and chronic inflammation with reactive epithelial changes.
Follow-up cervical cytology performed in April 2020 was negative for intraepithelial lesion, HPV or malignancy, with repeat cytology in February 2021 remaining negative. The patient was discharged from gynecological care. Her HPV testing in October 2025 remained negative.
Discussion
The principal observation in this case is not simply the apparent regression of persistent cervical dysplasia. Rather, it is the use of a novel protocol involving direct application of Viscum album to the cervix under visualization.
Published reports describing Viscum album for HPV-associated disease have primarily utilized subcutaneous injections or vaginal applications. Direct application to the cervix offers a unique method of delivery, ensuring reproducible contact between the extract and the transformation zone, the site where HPV-associated dysplastic changes most commonly arise. Whether this localized approach offers biological or clinical advantages over subcutaneous injections alone remains unknown but represents an area worthy of future investigation.
Another notable aspect of this case is the persistence of HSIL documented on serial cytology before treatment and again during treatment, followed by the absence of dysplasia within the excised LEEP specimen several months later. While the temporal relationship is intriguing, causality cannot be established. Spontaneous regression of HSIL, sampling variability, removal of dysplastic tissue during prior biopsy procedures, and inflammatory remodeling remain plausible alternative explanations.
An additional limitation is the concurrent application of calendula oil following each treatment. Calendula possesses recognized anti-inflammatory and wound-healing properties and was included as part of the treatment protocol taught by the originating clinicians to reduce local irritation and support epithelial healing following Viscum album application. Because calendula may influence epithelial repair, its contribution to the observed outcome cannot be excluded.
Conclusion and Clinical Implications
Current evidence evaluating Viscum album for HPV-associated cervical dysplasia remains limited to observational studies and case reports. This report contributes to the emerging literature by describing a previously unreported case. Although this protocol should not be considered a replacement for guideline-recommended management of HSIL, it demonstrates that localized cervical administration is technically feasible, was well tolerated, and may represent a promising area for future research. Prospective controlled studies are needed to evaluate the safety, reproducibility, and potential therapeutic role of direct cervical Viscum album application, while also clarifying the individual contributions of Viscum album, calendula oil, and the natural history of cervical dysplasia.
