A Preliminary Report

Richard Reid, M.D. Mitchell D. Greenberg M.D. Yahya Daoud, M.A. Mujtaba Husain, M.D. Suzanne Selvaggi, M.D. Edward Wilkinson, M.D.

Of 105 women referred for vulvar discomfort, 77 had idiopathic vulvodynia (pain, dyspareunia, burning or pruritus not explicable by a standard diagnosis). Physical examination showed that patients with those complaints fell into one of two categories: (1) diffuse irritative acetowhitening of both the cutaneous and mucosal surfaces (42 patients), and (2) painful vestibular erythema, with or without acetowhitening (35 patients). The physical findings appeared to be predictive of therapeutic response. Among women with only diffuse, irritative acetowhitening, low-dose topical 5 fluorouracil was about 75% effective in milder cases, while CO, laser photovaporization controlled 77% of cases with moderate and severe symptomatology. In contrast, medical regimens succeeded in just 8% of women with painful vestibular erythema, and only 59% were cured by hymenal resection. Several of the remaining cases have responded to selective argon laser photocoagulation of the hyperemic blood vessels within symptomatic areas.

Introduction

A syndrome characterized by burning vulvar discomfort and introital dyspareunia but associated with essentially normal physical findings was first described in 1889.1 Inexplicably, this problem virtually disappeared from society after the turn of the century, only to reappear about a decade ago. Over the last five years, the prevalence seems to have risen exponentially. Four recent North American series (2-5) studied 181 such cases, and this paper describes another 77 women suffering from this syndrome.

The 1983 International Society for the Study of Vulvar Disease congress(6) named the symptom complex of chronic burning vulvar discomfort vulvodynia (analogous to glossodynia for a sore tongue). Vulvodynia of which no obvious physical cause could be found was called the burning vulva syndrome. Subsequently, the observation that many women had foci of painful erythema, usually surrounding small glandular structures at the base of the hymen, led Woodruff' to propose the term vestibular adenitis. However, histology has, since shown that the inflammation affects the periglandular stroma rather than the glandular ducts or secretory acini per se. Friedrich, therefore coined the term vulvar vestibulitis syndrome to describe severe pain on vestibular touch, point tenderness localized within the vestibule and physical findings apparently confined to vestibular erythema .7

Our experience has been that women presenting with idiopathic vulvar pain or burning do not always have convincing evidence of vestibular erythema. In fact, if those women are examined through the colposcope, other, well-defined physical findings will be seen almost always. Moreover, both symptomatology and colposcopic atypia often extend beyond the anatomic limits of the vulvar vestibule. Hence, we have chosen the term idiopathic vulvodynia to designate otherwise-unexplained complaints of intense vulvar burning, introital pain or superficial dyspareunia. As explained below, we suggest that patients be further subgrouped according to their predominant physical findings.

Presenting Complaints

In 105 women referred to the first author for vulvar pain, acquired dyspareunia, burning or pruritus, the symptoms were attributable to standard diagnoses in only 28 (27%). Such diagnoses included lichen sclerosus (12 cases), hyperplastic dystrophy (7), vulvar intraepithelial neoplasia (5), causalgia (2) and miscellaneous dermatoses (2). The other 77 women fell into the category of idiopathic vulvodynia, with appearances on naked eye examination varying from apparently normal to focal erythema.

Within the vulvodynia group the ages ranged from 18 to 80 years (median, 29), and a disproportionate percentage (96%) were white. Moreover, the two black patients had light brown skin and green eyes. The disease duration extended for as long as 15 years, with a median duration of 2. Diagnostic delays were commonplace; the median number of physicians consulted was seven. Forty-four women (57%) had coexisting cervical human papillomavirus (HPV) infections, and seven (10%) had been treated previously for vulvar condylomas. In three patients the condylomas were seen -growing ouf' of the minor vestibular ducts (Figure 1). Biopsies of the vestibular mucosa almost invariably showed acanthosis, papillomatosis and atypia, suggestive of subclinical HPV infection.(8)

Vulvar burning and dyspareunia were graded as severe if the patient had introital pain and found coitus impossible, moderate if the complaints were sufficient to restrict the frequency of sex and minor if the symptoms were annoying rather than disruptive. By coincidence, about one-third of the 77 patients fell within each of the three severity groups.

Irrespective of specific symptomatology, the physical findings conformed to one of two basic variants:

Group 1: 42 women in whom naked eye examination of the vulva was essentially normal (Figure 2A) but in whom the vestibular mucosae showed a pronounced acetowhitening on colposcopy (Figure 2B). Although this group did not usually complain of dyspareunia, such symptoms as burning, pruritus and rawness were generally exacerbated by coitus (often leading to avoidance of intercourse).

Group 2: 35 women with tender, erythematous foci surrounding the hymenal, ring, with such reddening sufficiently prominent to be visible to the unaided eye (Figure 3A). However, at colposcopy this erythematous vestibular epithelium also showed prominent acetowhitening in all but three of the women (Figure 311).

Experience has shown these clinical distinctions to predict marked differences in therapeutic responsiveness. Hence, we suggest that women with idiopathic vulvodynia be subclassified according to their physical findings.

Group 1: Diffuse, Irritative Acetowhitening

Diagnostic Criteria

The principal complaint of women manifesting only irritative acetowhitening usually was vulvar discomfort, described as burning rather than itching. Other prominent symptoms included pruritus, rawness, dryness and fissure formation. The symptoms in group 1 generally had a diffuse (rather than focal) distribution.

In about half the patients, naked eye inspection of the medial labia minora revealed a slightly keratotic surface and a granular, micropapillary contour. However, when seen through the colposcope, the entire vestibular mucosae (the nonpigmented, nonkeratinized squamous epithelium lying between Hart's line and the hymen) showed a prominent acetowhite reaction in all 42 women. These changes usually extended beyond the vestibule to involve the minimally keratinized, hairless vulvar skin (covering the interlabial sulci, clitoris and perineum) in 60% of cases. In 25% of Cases the acetowhitening also involved the pigmented, fully keratinized, hair-bearing skin of the labia majora.

The histologic findings (reviewed by M.H. and S.S.) were somewhat enigmatic and often quite unimpressive. Affected epithelium showed moderate to marked acanthosis together with variable surface koflocytosis. Basal layer atypia was also present in eight patients (10%). The underlying stroma usually displayed a mixed, round cell infiltrate and vascular dilation suggestive of chronic,, nonspecific inflammation (Figure 4). AIR in all the histology was generally suggestive (rather than diagnostic) of HPV infection. HPV DNA was detected with Southern blot hybridization in 69% of biopsies collected from areas of similar colposcopic change in 160 women with exophytic condylomas of lower genital tract neoplasia.',` However, the hybridization of ten vestibular biopsies from women with only idiopathic vulvodynia was negative (A. Lorincz, unpublished data). These results could indicate that vulvodynia is not an HPV-associated disease or that the viral types have very little homology with existing probes."

Therapeutic Regimens

Initial therapy employed a medical regimen beginning with twice-daily applications of topical corticosteroid (usually a mixture containing seven parts of 0.1% betamethasone cream and three parts of crotamiton cream). During the second half of the study period, symptomatic areas were treated with weekly applications of 5% 5 fluorouracil. Patients whose vestibular mucosae displayed a granular surface (due to the presence of a myriad of micropapillae) were also treated with painting with 85% trichloracetic acid until the tissue turned white. This application produced burning pain for about three minutes but thereafter was well tolerated. Shedding of the coagulated epithelium over the succeeding two to four days was usually followed by a return to a flattened contour. These micropapillae must be distinguished from the granular contour normally manifested by the skin of the labia minora distal to Hart's line,' resulting from the presence of sebaceous glands just beneath the epithelial surface. Apart from being located caudad to the mucocutaneous junction, physiologic papillae are recognizable by their smooth, round contour, yellow color and absence of any acetowhite reaction.

Laser surgery was never offered to women with mild symptomatology. However, women in the moderate and severe groups who did not respond to topical therapy within four months were considered for surgery. Areas of irritative. acetowhitened epithelium were ablated to the first surgical plane 12 using a partially defocused beam from a C02 laser in the rapid superpulse mode. 13

Success Rates

During the first half of the study period, nonsurgical therapy consisted of topical steroids and applications of 85% trichloracetic acid. The results were universally disappointing. However, the addition of adjuvant 5 fluorouracil cream during the later years successfully controlled the symptoms in 16 (75%) of 24 women (Table D)

Thirty-five women (including several who subsequently developed focal erythema and were therefore assigned to group 2) were treated with superficial laser vulvectomy. Complete remission or a major improvement was achieved in 27 patients, yielding a surgical success rate of 77%. However, this somewhat encouraging picture must be balanced against the fact that these results required 44 operations on 26 women. In the future, we hope, the incorporation of adjuvant 5 fluorouracil cream for six months following laser surgery will reduce the risk of a patient's needing a second or third operation. Of particular concern is the observation that in six women, CO, laser photovaporization appeared to excacerbate an incipient inflammation in previously asymptomatic minor vestibular glands.

Group 2: Painful Vestibular Erythema With or Without Irritative Acetowhitening

Diagnostic Criteria

The symptoms in group 2 tended to be localised to the vulvar vestibule. In addition to vulvar burning, all these patients complained of acquired dyspareunia and point tenderness, related to prominent *erythematous foci surrounding the hymenal ring (vulvar vestibulitis syndrome). The anatomic distribution of these tender, red areas was variable: the minor vestibular glands were affected in all 35 women (100%), Skene's glands in 30 (86%), Bartholin's ducts in 21 (69%) and ectopic areas unrelated to glandular epithelium in 7 (20%) (Figures ~ and 6). In addition to these tender, red foci, 32 of the 35 group 2 women showed prominent acetowhitening of the vestibule (Figure 3). When seen through the colposcope, the areas of marked erythema often showed angry vascular patterns (usually "punctation" rather than "mosaicism") (Figure 7).

The microscope findings were also enigmatic: the histologic picture was generally unimpressive in comparison with the severity of the symptomatology. Mixed round cell infiltrates and vascular dilation affected the stroma rather than the epithelium of the vestibular glands (Figures 8 and 9). When present, ductal epithelium generally showed extensive squamous metaplasia.

Therapeutic Regimen

Although irritative acetowhitening of the surface, epithelium often responded to corticosteroids or topical 5 fluorouracil cream, the inflammation surrounding the minor vestibular glands was refractory to medical regimens. The standard therapy has been an operation described by Woodruff' wherein the posterior three-quarters of the hymenal ring (including the minor vestibular glands) are excised and the defect closed by downward advancement of the posterior vaginal wall. However, our experience with this procedure has been unsatisfactory, for three reasons: (1) excision of the minor vestibular glands cannot cure chronic burning due to lateral extension of the HPV infection involving the interlabial grooves or labia majora; (2) scarring that occurred during healing appeared to exacerbate incipient inflammation of Skene's and Bartholin's glands in six women, resulting in a marked worsening of symptoms; and (3) even when hymenal resection was successful, the cosmetic results were disappointing.

When confronted with recurrence following hymenal resection or attempted laser photovaporization of the minor vestibular glands, our initial approach was to attempt reexcision of the scar and any adjacent foci of chronic inflammation. To facilitate dissection, the openings of any vestibular ducts present within the erythematous areas were canalized with a sialogram catheter and stained by an injection of toluidine blue (Figure 10M. Because blue-stained ducts were seen to extend for up to 1 cm below the epithelial surface, the depth of dissection was extended. In addition, it soon became apparent that the principal focus of erythema often surrounded a Bartholin's duct, leading the first author to undertake both scar excision and en bloc dissection of the periurethral tissue, Bartholin's ducts and Bartholin's glands (Figures 10B and C). Although generally successful, such an operation was technically difficult and did not obviate the problem of vulvovaginal deformity (Figure lOD).

Because of the benefits of photocoagulating aberrant blood vessels in plastic surgery, ophthalmology and gastroenterology, four patients with a postoperative exacerbation of periglandular inflammation were treated with the argon and Nd:YAG lasers. In all four the hyperemic vessels within areas of symptomatic erythema were successfully sclerosed with selective argon laser photocoagulation' (Figure 11). Hence, we are presently conducting a trial of selective photocoagulation as the preferred primary procedure. Empiric treatment with oral colchicine also appeared helpful in the small subset of patients who developed painful erythema after surgery.

Success Rates

Women with painful erythema were substantially harder to treat than those in group 1. Medical regimens were successful in only 1 of 13 (8%). Hymenal resection also proved disappointing in our hands, yielding a primary success rate of only 59% (Table II). Fortunately, several of these initial surgical failures responded to argon laser photocoagulation of symptomatic areas (Figure 12).

Preliminary Conclusions

We have been able to formulate three preliminary conclusions from our study. First, although painful vestibular erythema is the best-known manifestation of idiopathic vulvodynia, an irritative, acetowhite reaction affecting both the vestibular mucosae and the adjacent vulvar skin is a much more universal finding. Hence, colposcopic assessment is essential to the accurate diagnosis of vulvar pain. Second, patients presenting with only diffuse, irritative, acetowhite epithelium had generally milder symptoms. Several women were observed to progress from having just irritative, acetowhite epithelium to a more florid disease pattern characterized by both painful vestibular erythema and acetowhitening. Thus, it appears that the relationship between these two clinical variants might simply be one of different severity. Third, both rational therapy and the likelihood of success

depend upon an accurate physical examination. Diffuse, irritative acetowhitening usually responds to topical 5 fluorouracil cream or CO, laser photovaporization. In contrast, painful vestibular erythema can seldom be controlled by medical regimens. Although cosmetically disappointing, hymenal resection is the standard surgical approach. However, this operation proved to be only

59% successful in this series. In contrast, the early results of a trial of selective argon laser photocoagulation have been encouraging.

References

1. Skene AJC Treatise on the Diseases of Women. New York, D Appleton, 1889

2. Woodruff JD, Parmley TH: Infection of the minor vestibular gland. Obstet Gynecol 62:609,1983

3. Friedrich EG jr: The vulvar vestibule. J Reprod Med 28:773, 1983

4. Peckham BM, Maki DG, Patterson JJ, et at: Focal vulvitis: A characteristic syndrome and cause of dyspareunia. Am J Obstet Gynecol 154:855,1986

5. Friedrich EG jr: Vulvar vestibulitis syndrome. J Reprod Med 32:110,1987

6. Burning vulva syndrome: Report of the ISSVD Task Force. J Reprod Med 29:457,1984

7. Pyka RE, Wilkinson EJ, Friedrich EC jr, et at: The histopathology of vulvar vestibulitis syndrome. Int J Gynecol Pathol (in press)

8. Reid R: Human papillornaviral infection: The key to rational triage of cervical neoplasia. Obstet Gynecol Clin North Am 14:407,1987

9. Reid R, Campion MJ: The biology and significance of human papillomavirus infections in the genital tract. Yale J Blot Med (in press)

10. Reid R, Greenberg M, jenson AB, et at: Sexually transmitted papillomaviral infections: 1. The anatonfic distribution and pathologic grade of neoplastic lesions associated with different viral types. Am J Obstet Gynecol 156:212, 1987

11. Lorincz A: Detection of human papillomavirus infection by nucleic acid hybridization. Obstet Gynecol Clin North Am 14:451,1987

12. Reid R, Elfont EA, Zirkin RM, et at: Superficial laser vulvectomy: II. The anatomic and biophysical principles permitting accurate control over the depth of dermal destruction with the carbon dioxide laser. Am J Obstet Gynecol 152:261, 1985

13. Reid R: Physical and surgical principles governing expertise with the carbon dioxide laser. Obstet Gynecol Clin North Am 14:513,1987