Vulvar Intraepithelial Neoplasia 3 in Women Less Than 35 Years

Abstract

Objective

To examine the outcome of women diagnosed with vulvar intraepithelial neoplasia (VIN) 3 at less than 35 years.

Materials and Methods

All cases of VIN 3 treated in women less than 35 years treated at Roswell Park Cancer Institute between January 1973 and January 2008 were reviewed. Medical records were reviewed for year of diagnosis, treatment modality, recurrence and/or progression, associated medical conditions, history of genital condyloma, smoking status, history of cervical pathology, and treatment.

Results

Thirty-one women were identified. The mean age at diagnosis was 29 years. Smoking status was available in 28 patients, of which 82% (23/28) were current or former smokers. Eighty-one percent (25/31) of the women had cervical disease. Fifty-two percent (16/31) had a history of genital condyloma. Ten of the 31 women (32%) were diagnosed with persistence or recurrence of VIN 3. Three women (9.7%) progressed to invasive carcinoma.

Conclusions

Women diagnosed with VIN 3 at less than 35 years are at risk for persistence and/or recurrence of their disease as well as progression to carcinoma, warranting frequent and prolonged follow-up with liberal utilization of directed biopsies of suspicious lesions.

The incidence of vulvar intraepithelial neoplasia (VIN) 3 is increasing in the United States [1]. There has been a trend toward a decrease in the mean age of women diagnosed with VIN [2, 3]. The invasive potential of treated VIN 3 has been reported between 2.5% and 3.9% [2, 4–8]. The invasive potential of treated VIN 3 seems to be related to older age and immunosuppression. In their study of 105 cases of treated VIN 3, Jones and Rowan [9] reported that 3 of 4 women who developed invasive vulvar carcinoma women were older than 40 years, and the 1 patient less than 40 years old was immunosuppressed. Similarly, Buscema et al. [4] reported on 4 of 106 patients with carcinoma in situ of the vulva progressing to invasive cancer. The 2 patients diagnosed with invasive cancer at less than 40 years were both immunosuppressed. Considering the increasingly younger age at diagnosis of VIN 3, this study was initiated to examine the outcome of women diagnosed with VIN 3 at less than 35 years, including the risk of progression to invasive carcinoma.

MATERIALS AND METHODS

The Roswell Park Cancer Institute Tumor Registry was used to identify women treated for VIN 3 at Roswell Park Cancer Institute between January 1973 and January 2008 after institutional review board approval. The histology of referred cases was reviewed by an attending pathologist at our institution.

Patients’ medical records were searched for histologic diagnosis and age at diagnosis. After age and diagnosis were confirmed, the following were recorded: year of diagnosis, treatment modality, recurrence and/or progression, associated medical conditions, history of genital condyloma, smoking status, history of cervical pathology, and treatment. Follow-up was defined as the time from the original treatment of VIN 3 until the last contact with the patient.

RESULTS

Thirty-one women with VIN 3 at less than 35 years were treated at Roswell Park Cancer Institute between January 1973 and December 2007. The mean age at diagnosis was 29 years. Twenty-eight patients were white and 3 were black. Smoking status was available for 28 patients. Of these, 23 (82%) were current or former smokers. Sixteen patients (52%) had a history of genital condyloma. Twenty-five women (81%) had preexisting, synchronous, or subsequent cervical disease. This included 3 women with cervical cancer and 18 women who had surgery for cervical intraepithelial neoplasia (CIN), including conization, loop electrosurgical excision procedure, and hysterectomy. One woman was identified as being immunosuppressed.

Treatment modalities varied. Thirteen women were treated with wide local excision. Ten women underwent either a skinning vulvectomy or a partial vulvectomy. Six women were treated with a combination of excision with vaporization whereas 2 received only laser vaporization.

Mean follow-up time was 13 years, 7 months with a range of 3 weeks to 28 years, 10 months. Twenty-eight patients were followed for 6 months or more. Of these patients, 10 (32%) were diagnosed with either persistence or recurrence of VIN. Nine of these patients underwent treatment. Five of these 9 patients required multiple treatments for their recurrences. Six of the recurrences were diagnosed within 9 months of primary treatment. Treatment of recurrence varied as well as time to recurrence. Mean time to first recurrence was 23 months, with a range of 3 to 67 months.

Three patients originally diagnosed with VIN 3 subsequently developed invasive carcinoma of the perineum. The first patient was treated with an excisional procedure at an outside hospital at 32 years and then lost to follow-up. Three years later, the patient then presented to our institution with biopsy-confirmed invasive, well-differentiated squamous cell carcinoma of the vulva. She was treated with a wide local excision of the right vulvar lesion and right inguinal lymphadenectomy. Pathological examination of the vulva did not reveal any evidence of residual carcinoma, and the lymph nodes were negative for carcinoma. She was without evidence of disease for more than 5 years at the time of last follow-up.

The second patient was diagnosed at 32 years with multifocal severe intraepithelial neoplasia involving the vulva, vagina, and perianal skin. She underwent multiple excisions and ablative procedures for 15 years for severe intraepithelial neoplasia of the perineum until she ultimately had a biopsy that showed invasive anal cancer. She was treated with chemotherapy and radiation therapy and was alive without evidence of disease for more than 6 years at time of last follow-up.

The third patient had a past medical history significant for long-standing insulin-dependent diabetes mellitus with resultant kidney disease. She required a cadaveric renal transplant at 23 years for which she took chronic immunosuppressive medications. She presented at 25 years in the second trimester of her pregnancy with large, extensive condylomata acuminata, which obliterated the vaginal introitus and made it difficult for her to void and to ambulate. She underwent a partial vulvectomy with removal of the involved vulvar area and laser ablation of the vulva, the vagina, and the perineum. The patient required laser excision for recurrent condyloma 9 months later. She was followed with excision and ablative procedures for carcinoma in situ for 6 years until she was ultimately diagnosed with perineal and anal carcinoma for which she underwent a posterior exenteration. The patient was without evidence of any recurrence for 7 years until she was diagnosed with condyloma, which was successfully treated with podophyllin.

DISCUSSION

This case series, although limited by its relatively small size and retrospective nature, demonstrates a risk of progression from treated VIN 3 to invasive cancer in women diagnosed at less than 35 years. We are unable to comment on the overall rate of progression from VIN 3 to cancer because our study lacks a true denominator of the number of VIN 3 cases. Our practice is primarily referral based and thus likely to see only those cases that are more extensive and/or unusual. This study has the advantage of extended patient follow-up as well as a focus on a younger segment of the population, representative of an age group that has experienced an increase in the incidence of VIN and VIN-related invasive vulvar cancers [10, 11].

The high incidence of tobacco smoking, history of genital warts, and CIN in this patient population reaffirm the association between these risk factors and VIN 3 seen in other studies [2–4, 6, 9, 12–15]. The coexistence of cervical dysplasia with VIN 3 in the young female should alert the physician to the increased likelihood of multifocal neoplastic vulvar lesions, as first described by Andreasson and Bock [16].

The first 2 cases of invasive cancer described in our series represent the 2 patterns of invasive vulvar cancer after treatment of VIN described by Jones et al. [2] in their study of 405 women with VIN. The first case, with its short treatment-to-progression interval, likely represents the progression of inadequately treated VIN or the presence of inadequately biopsied invasive cancer. The second case, with its long interval between treatment of VIN and development of anal cancer, typifies the ability of human papillomavirus to generate neoplastic changes in areas adjacent to the original vulvar neoplasia. These cases, along with the observed 32% recurrence rate, highlight the importance of frequent and sustained surveillance visits for patients previously treated for VIN 3. Initiation of screening should not be delayed long after original treatment, considering that retreatment was necessary within 9 months of original treatment in a majority of patients in our series requiring retreatment. Thus, these patients likely represent persistence of VIN rather than recurrence, necessitating follow-up colposcopy to determine the adequacy of initial treatment.

The case of invasive perineal and anal carcinoma developing in an immunosuppressed renal transplant patient highlights the increased risk of carcinoma in these patients. Penn [17] reported a 100-fold increase in the incidence of carcinoma of the vulva and anus in renal transplant recipients compared with the general population. The carcinomas developed an average of 88 months after the transplant, emphasizing the need for long-term follow-up in this patient population.

The goal in treating VIN 3 in this patient population is 3-fold: (1) to rule out invasive carcinoma, (2) to perform the least disfiguring operation possible, and (3) to alleviate symptoms. Although, a majority of patients in this study were treated primarily with surgery and the surgical approach offers the possibility of negative margins, it does have its limitations in the treatment of VIN 3. Modesitt et al. [14] have shown a decreased recurrence with negative margins, but there is still no way to accurately predict which patients will recur because 54% of patients with positive margins in their study did not experience a recurrence. The pursuit of negative margins may result in a more radical surgery and the associated sexual dysfunction and psychological issues associated with extensive vulvar surgery [18–20]. Furthermore, a recent meta-analysis of 3,322 patients was unable to show that uninvolved surgical margins alter the progression from neoplasia to carcinoma [7]. Future consideration in the treatment of VIN 3 should be given to less invasive therapies after the exclusion of coexistent malignancy. Treatment modalities for VIN 3 that offer effective treatment without the scarring and anatomic distortion associated with surgery include the cavitational ultrasonic surgical aspirator, topical imiquimod, and podophyllin [21–23].

In conclusion, women treated for VIN 3 at less than 35 years are at risk for development of invasive carcinoma. Initiation of early, often, and prolonged follow-up with a low threshold to biopsy any suspicious lesion of the perineum to rule out invasive carcinoma is imperative. In this patient population, there is an especially high association with cervical neoplasia, which should alert the health care provider to the multifocal nature of this disease and the need to screen for coexistent neoplasia.