Systematic photodynamic therapy for concurrent cervical-vaginal high-grade squamous intraepithelial lesion: a series of eight cases

Abstract

Concurrent cervical-vaginal high-grade squamous intraepithelial lesion (HSIL) is increasingly prevalent with carcinogenic potential. For gynecologic oncologists, non-invasive, organ-preserving treatment of this condition remains a challenge. While Hiporfin-photodynamic therapy (PDT) has proven effective for cervical HSIL or vaginal HSIL alone, its efficacy in concurrent cervical-vaginal HSIL remains unreported. We treated 8 pathologically confirmed patients with Hiporfin-PDT: 2.0 mg/kg intravenous Hiporfin followed by 630-nm red laser irradiation 48–72 h later, with one session per patient initially. At 3–6 months, the complete response (CR) rate was 75.0% (6/8); the 2 partial response (PR) patients achieved CR after a second PDT session or two sessions of thermocoagulation. Our preliminary findings suggest that Hiporfin-PDT has potential feasibility as a non-invasive option for concurrent cervical-vaginal HSIL, warranting further investigation.

Introduction

Vaginal high-grade squamous intraepithelial lesion (HSIL) frequently coexists with cervical HSIL, with an increasing incidence observed in younger populations in recent years. Concurrent cervical-vaginal HSIL represents a precancerous condition, with conventional treatment options including surgical excision, ablation, and other modalities [1]. However, surgery can alter cervical and vaginal anatomy, leading to complications such as cervical incompetence, vaginal shortening, scarring, or dyspareunia, while ablation for vaginal HSIL is associated with a high recurrence rate [2, 3]. Photodynamic therapy (PDT) is a promising, non-invasive, and highly selective treatment option [4]. PDT involves the administration of a photosensitizer, either systemically or topically. Topical agents may achieve uneven distribution and incomplete illumination, whereas systemic agents enable homogeneous photosensitization across all affected sites [5]. Hiporfin, a hematoporphyrin derivative (HpD) approved by the China Food and Drug Administration (CFDA) [6], has demonstrated efficacy in the treatment of precancerous lesions and cancers in prior studies [6–8]. This study aimed to preliminarily investigate the feasibility, safety, and efficacy of Hiporfin-PDT in the treatment of concurrent multifocal vaginal and cervical lesions, a condition for which currently available evidence remains limited.

Case presentation

This was a retrospective study. A total of eight patients with concurrent cervical-vaginal HSIL were consecutively enrolled at our hospital between September 2019 and July 2023. The study was approved by the Ethics Committee of Peking University Shenzhen Hospital (approval No. XJS20190004), and written informed consent was obtained from all patients prior to treatment. All procedures were performed in accordance with the ethical standards laid down in the Declaration of Helsinki.

Patients were enrolled according to the following criteria. Inclusion criteria consisted of histopathologically confirmed concurrent high-grade squamous intraepithelial lesions (HSIL) of the cervix and vagina, with no restrictions imposed on previous treatment history. Exclusion criteria were defined as follows: concurrent vulvar HSIL; a history of invasive cancer; current pregnancy or lactation; severe underlying systemic diseases; porphyria or known hypersensitivity to porphyrin compounds; and ongoing treatment with high-dose anticoagulants or antiplatelet medications.

Hiporfin (25 mg/vial, Chongqing Milelonge Biopharmaceutical) was administered intravenously at a dose of 2 mg/kg, followed by 630-nm laser irradiation (Shenzhen Laser Medical Technology) 48–72 h later (single PDT session). During treatment, patients were placed in the lithotomy position with an empty bladder, and vital signs were continuously monitored. Laser irradiation was delivered as follows: cervical canal (100–120 J/cm², columnar fiber), cervical surface (150 J/cm², flat-cut fiber), and vaginal lesions (150 J/cm², flat-cut or columnar fiber) [7–9]. The treated fields encompassed the lesions plus a margin of at least 0.5 cm (Fig. 1). After injection, patients were advised to avoid direct sunlight for 4–6 weeks.

Fig. 1.

Procedure of photodynamic therapy

Follow-up visits were scheduled at 3–6 months, 10–12 months, and then annually. All patients completed the 3–6 month follow-up; however, most 10–12 month visits were delayed due to the Corona Virus Disease (COVID)-19 pandemic. During the scheduled follow-up period, we contacted patients via WeChat to invite them to return to the hospital for follow-up assessments., and all patients exhibited good follow-up compliance. Evaluations consisted of clinical examination, HPV testing (Cobas^® 4800 HPV Test), liquid-based cytology testing (AutoCyte thin-layer cytology test), colposcopy, and cervical biopsy. Treatment response was assessed using the following criteria: complete response (CR) (no high-grade lesions on cytology, colposcopy, or biopsy), Partial response (PR) (≥ 50% reduction in HSIL area), stabilization (< 50% reduction), and progression (invasive carcinoma confirmed by biopsy). The extent of vaginal lesions was mapped at baseline with standardized colpophotographs, which enabled objective assessment of a ≥ 50% reduction in lesion area during follow-up. Adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Briefly, patient demographics, baseline characteristics, and individual treatment outcomes are summarized in Table 1. Notable findings included all patients presented with concurrent cervical and multifocal vaginal HSIL, and four had previously undergone loop electrosurgical excision procedure (LEEP) for cervical HSIL. HPV clearance was achieved in three patients at 3–6 months following treatment, whereas persistent HPV infection was observed in the remaining five patients. Six patients achieved a CR at 3–6 months after primary Hiporfin-PDT, while two patients showed a PR. In Patient 1, cervical lesions achieved complete resolution, with residual HSIL confined to the vaginal vault. In Patient 8, cervical lesions also resolved completely, with residual HSIL remaining in the vaginal wall. Of the two patients with PR, patient 1 attained CR after a second PDT session, and patient 8 achieved CR following two sessions of thermocoagulation (Fig. 2). Patient 4 achieved CR at 3–6 months post-PDT but remained positive for other HR HPV. Due to the COVID-19 pandemic, follow-up was interrupted for more than two years. She later presented with abdominal distension and frequent urination, and a pelvic mass was detected on gynecologic ultrasound. Gynecologic examination revealed vaginal wall adhesions; surgical separation released a large amount of yellow purulent discharge from the uterine cavity. Subsequent biopsy confirmed squamous cell carcinoma of the cervix and vaginal wall. She received radiotherapy and is currently undergoing chemotherapy. The remaining CR patients remain recurrence-free during the limited follow-up period.

Table 1.

Patients’ baseline characteristics, treatment outcome and adverse events of the PDT in the cervical and vaginal HSIL

Patient no.	Age (years)	Duration (months)	Parity	Baseline HPV	Prior cervical treatment	Lesion location	Response at 3–6 months	HPV status at 3–6 months	Subsequent treatment	Final outcome	Adverse events
1	33	36	Two	HPV16	None	Cervical surface, vaginal vault & wall	PR	negative	Second PDT	CR	None
2	36	34	Nulliparous	Other HR-HPV	None	Cervical surface, vaginal vault & wall	CR	Persistent other HR-HPV	-	CR	mild photosensitivity
3	52	24	Two	HPV16	LEEP*	Cervical surface, vaginal vault & wall	CR	negative	-	CR	mild photosensitivity
4	62	36	Three	Other HR-HPV	None	Cervical surface, cervical canal, vaginal vault & wall	CR	Persistent other HR-HPV	Surgery + radiotherapy + chemotherapy	Progression	None
5	58	27	One	Other HR-HPV	LEEP	Cervical surface, vaginal vault & wall	CR	negative	-	CR	None
6	29	19	Nulliparous	Other HR-HPV	None	Cervical surface, cervical canal, vaginal vault	CR	Persistent other HR-HPV	-	CR	None
7	25	12	Nulliparous	HPV18	LEEP	Cervical surface, vaginal wall	CR	Persistent HPV18	-	CR	mild pelvic pain
8	35	12	One	HPV16、18	LEEP	Cervical surface, cervical canal, vaginal vault & wall	PR	Persistent HPV16	Thermocoagulation ×2	CR	None

CR Complete remission, HPV Human papillomavirus, HR-HPV High-risk human papillomavirus, LEEP Loop electrosurgical excision procedure, PDT Photodynamic therapy, PR Partial response

Fig. 2.

Colposcopic findings before and after PDT in a 35-year-old patient (Case 8). a Cervical HSIL before PDT (acetowhite test): Thick white epithelium was visible on the surface and within the cervical canal; b Cervical HSIL before PDT (Lugol’s iodine test): The thick white epithelium area was unstained by Lugol’s iodine and appeared bright yellow; c Cervix at 3-month follow-up after PDT (acetic acid smear test): No obvious white epithelium was observed; d Cervix at 3-month follow-up after PDT (Lugol’s iodine test): The cervical iodine test was positive; e Vaginal HSIL before PDT (acetowhite test): Thick white epithelium was visible in both the vaginal vault and vaginal wall; f Vaginal HSIL before PDT (Lugol’s iodine test): The white epithelium area was unstained by the iodine test and appeared bright yellow; g Vagina at 3-month follow-up after PDT (acetic acid smear test): The white epithelium area was not obvious; h Vagina at 3-month follow-up after PDT (Lugol’s iodine test): The vaginal iodine test was locally negative, with the affected area significantly reduced compared to before PDT. Note: Black arrows indicated the lesion sites

All treatment-related adverse events were mild and self-limiting, including transient photosensitivity in two patients and mild pelvic pain in one patient. Symptoms of photosensitivity resolved within 7–10 days with loratadine and cold compresses, while pelvic pain resolved spontaneously without additional intervention.

Discussion

Surgical resection remains the standard treatment for cervical HSIL and vaginal HSIL. For cervical HSIL, surgery achieves high efficacy, with success rates of 90%–98% [10]. Similarly, surgical excision of vaginal intraepithelial lesion yields favorable outcomes, with success rates ranging from 66% to 81% [2]. Nevertheless, surgical intervention may lead to cervical incompetence, increasing the risk of miscarriage and preterm birth, as well as vaginal shortening or stenosis [2, 3]. In a study of 132 patients with vaginal HSIL, excisional procedures and CO₂ laser ablation both yielded a 69% cure rate, superior to 5-FU cream (46%) and electrocoagulation diathermy (25%). A recent systematic review of 28 patients across five studies, including nine with vaginal HSIL treated with imiquimod, reported a pooled complete response rate of 76%. One study demonstrated that excisional procedures and CO₂ laser ablation yielded an equivalent cure rate of 69% for vaginal HSIL, which was notably higher than that of 5-FU cream (46%) and electrocoagulation diathermy (25%) [11]. A systematic review reported a pooled complete response rate of 76% for imiquimod therapy in vaginal HSIL [12]. Photodynamic therapy represents a targeted, organ-preserving therapeutic modality. Our previous studies demonstrated that Hiporfin-PDT exhibited comparable efficacy to LEEP for cervical HSIL [13], and achieved a 12-month complete response rate of 83.3% for vaginal HSIL [8]. However, data regarding Hiporfin-PDT for concurrent cervical and vaginal HSIL remain extremely limited.

Although second‑generation topical photosensitizers such as ALA offer the practical benefit of not requiring strict sunlight avoidance, their limited tissue penetration may be insufficient to address extensive or deeply seated HSIL, often necessitating multiple treatment sessions. Expert consensus recommends 5-ALA PDT for HSIL/CIN 2 with a visible squamocolumnar junction and lesion upper margin, whereas Hiporfin-PDT is applicable to cervical HSIL without transformation zone limitations. ALA-PDT achieves a complete response rate of 77.8%–91% for HSIL/CIN 2–3 at 3–12 months, with a recurrence rate of 3.7%–13.9% during 12–37 months of follow-up. Published outcomes of ALA-PDT for vaginal HSIL demonstrate substantial heterogeneity, with complete response rates spanning 7.1%–88.89% and recurrence rates of 11.36%–20.0% [2]. The multifocal nature of vaginal lesions in this series provides a strong rationale for systemic photosensitizer therapy, which ensures more uniform drug distribution. Notably, ALA-PDT often requires 2–3 courses (each including three sessions), while Hiporfin-PDT generally only needs one session [9, 14]. For a 50 kg patient, a single Hiporfin-PDT treatment is approximately 2000–3000 RMB cheaper than six sessions of ALA-PDT.

A history of surgery for cervical HSIL or cervical carcinoma are key risk factors for the development of vaginal HSIL [2, 15]. In this study, 50.0% (4/8) of patients had previously undergone LEEP for cervical HSIL with persistent HR HPV infection, complicating subsequent colposcopic evaluation and treatment. At 3–6 months post-PDT, the CR rate was 75.0% (6/8): all cervical and endocervical HSIL cases achieved complete response (CR), whereas partial response (PR) was observed only in vaginal lesions, with marked reduction in lesion size compared with baseline. In both patients with PR, residual HSIL was localized exclusively to the vaginal vault or vaginal wall. This may be related to several factors: multifocality of vaginal disease, inadequate distension of vaginal folds during light irradiation, and consequent insufficient light penetration. Two patients with PR at 3–6 months post-PDT underwent either a second Hiporfin-PDT session or two sessions of thermocoagulation, and subsequently showed no evidence of HSIL. Notably, Hiporfin-PDT achieved at least 50% lesion regression and even complete remission in patients with extensive, multifocal vaginal lesions, thus avoiding radical surgical resection of large vaginal lesions.

However, persistent HR-HPV infection was still present in some patients despite histological CR. As persistent HR-HPV infection is a well-established major risk factor for recurrence [2], close monitoring and long-term regular follow-up are essential even in the absence of histologic abnormalities. Disease progression to invasive carcinoma in Patient 4 at 32 months further highlights the risk of late recurrence and malignant transformation in patients with pretreatment multifocal HSIL and persistent HPV infection. These findings emphasize the need for prolonged surveillance to assess the long-term efficacy, durability, and safety of systemic PDT. In this study, two patients experienced mild photosensitivity due to inadequate light avoidance. This underscores the critical importance of strict photoprotection to minimize the incidence of such adverse events.

The limitations of Hiporfin-PDT include prolonged light avoidance (4–6 weeks) which may reduce patient compliance, as well as high drug cost (3800 yuan/25 mg vial) and the lack of cost-effectiveness analyses that limit its clinical application. Inclusion of photosensitizers in medical insurance coverage and the development of intravenous photosensitizers with shorter light-avoidance periods would help make this treatment accessible to more patients.

This study has several limitations. First, the small sample size restricts the generalizability of the results and reduces statistical power, warranting cautious interpretation. In addition, the absence of a randomized design or control group prevents confirmation of the comparative efficacy of Hiporfin-PDT. The partially retrospective single-arm design also diminishes the robustness of the findings. Furthermore, inadequate follow-up—characterized by a short duration and disruptions caused by COVID-19—precludes reliable assessment of long-term outcomes, while late disease progression in one patient further highlights the necessity of extended follow-up. There was no systematic HPV monitoring during follow-up, meaning persistent HPV infection, a major risk factor for recurrence, may have led to an underassessment of recurrence risk. Unstandardized rescue interventions could confound the observed outcomes, and the optimal treatment schedule as well as the role of adjuvant therapy remain unclear. Finally, the use of a combined primary endpoint for both cervical and vaginal lesions compromises the accuracy of efficacy assessment.

In summary, our results suggest that Hiporfin-PDT is feasible and potentially valuable as an organ-preserving approach for concurrent cervical and vaginal HSIL. Nevertheless, due to the inherent limitations of this study, all findings should be interpreted with extreme caution. Further well-designed studies are required to validate its long-term efficacy and clarify its clinical role.

Authors’ contributions

Y.L. wrote the main part of the manuscript. Y.L. and R.L. treated the patient. R.W., C.L., R.L. reviewed the manuscript.

Funding

This project was supported by Shenzhen Key Laboratory on Technology for Early Diagnosis of Major Gynecologic Diseases (SYSPG20241211173501001), Shenzhen High-level Hospital Construction Fund (Grant No.: YBH2019-260), Shenzhen Key Medical Discipline Construction Fund (Grant No.: SZXK027) and Sanming Project of Medicine in Shenzhen (Grant No.: SZSM202011016).

Data availability

No datasets were generated or analyzed during the current study.

Declarations

Ethics approval and consent to participate

This study was approval by Ethics Committee from Peking University Shenzhen Hospital (XJS20190004). All patients provided written informed consent to participate. The authors affirm that human research participant provided informed consent for publication of the images in Fig. 2.

Competing interests

The authors declare no competing interests.