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Human papillomavirus with co-existing vulvar vestibulitis syndrome and vestibular papillomatosis
International Journal of Gynecology & Obstetrics 64 Ž1999. 259]263
Article
Human papillomavirus with co-existing vulvar vestibulitis syndrome and vestibular papillomatosis M. Origoni a,U , M. Rossi a , D. Ferrari a , F. Lillo b , A.G. Ferrari a a
Department of Obstetrics and Gynecology, Uni¨ ersity of Milano School of Medicine, Milano, Italy b Virology Laboratory, H San Raffaele Scientific Institute, Milano, Italy Received 10 February 1998; received in revised form 24 July 1998; accepted 13 August 1998
Abstract Objecti¨ e: The role of HPV infection in cases of vulvar papillomatosis and vulvar vestibulitis syndrome is still unclear and data from the literature is controversial. In this study we intended to investigate the prevalence of viral infection, with a multidisciplinary approach, in cases with a co-existence of the two patterns. Method: Sixteen consecutive cases with diagnosis of vulvar vestibulitis syndrome and co-existence of vestibular papillomatosis were enrolled in the study and investigated by the means of vulvar cytology, vulvoscopy, histology, ViraPap and Polymerase Chain Reaction. Result: Cytology, vulvoscopy and histology did not demonstrate suitable accuracy for the diagnosis. Viral DNA identification revealed two Ž12.50%. positive cases using PCR and one Ž6.25%. positive case with ViraPap. Conclusion: The results of the present investigation indicate that even in cases of co-existing vulvar papillomatosis and severe vulvar vestibulitis syndrome, the prevalence of HPV infection is too low to be considered causal. Q 1999 International Federation of Gynecology and Obstetrics. Keywords: Human papillomavirus; HPV; Vulvar pain; Vulvar vestibulitis syndrome; Vulvar papillomatosis; HPV DNA
1. Introduction The patient complaining of vulvar burning and chronic discomfort has always represented a hard challenge for the gynecologist. In 1983 the Inter-
U
Corresponding author. Fax: q39 2 26413592.
national Society for the Study of Vulvar Disease ŽISSVD. introduced the terms of ‘burning vulva syndrome’ and ‘vulvodynia’, defining a condition of chronic vulvar soreness w1x. Vulvodinya recognizes multiple aetiologies, thus the use of this term implies the formulation of a correct and precise diagnosis; this approach allowed the identification of different subgroups of vulvodinya,
0020-7292r99r$20.00 Q 1999 International Federation of Gynecology and Obstetrics. PII: S 0 0 2 0 - 7 2 9 2 Ž 9 8 . 0 0 1 5 6 - 8
260
M. Origoni et al. r International Journal of Gynecology & Obstetrics 64 (1999) 259]263
vulvar vestibulitis syndrome being an independent entity. According to Friedrich w2x the syndrome is defined by the concomitant presence of: Ža. severe pain at any attempt of intercourse; Žb. vestibular tenderness at pressure; and Žc. vestibular erythema of various degrees. The etiology of the condition is still unclear: genital infections, irritants, topical medications and physical agents can all be correlated with the syndrome, but none can be definitely recognized as causal. Among genital infections, the role of Human Papilloma Viruses ŽHPVs. has been differently reported, both in terms of cause-effect relation w3,4x and of innocent co-existence w5,6x. The presence of vestibular papillae is quite a common finding in young women, with an estimated prevalence of almost 1% w7x; they are more frequently localized to the posterior vestibule but the observation of a diffuse papillomatosis of the whole introitus is not rare w8x ŽFig. 1.; isolated vestibular papillae are more commonly interpretable as a physiological pattern of the normal vestibule w9x, while diffuse papillomatosis has been often associated with HPV subclinical infection w10,11x. Colposcopic magnification of the vestibule allows in some cases the distinction between HPV-induced lesions and vulvar papillae. In detail, HPV-induced lesions are generally confluent, without distinct vascular supply and acetowhitening. Both these conditions are generally symptomless, however, sometimes they co-exist with a vulvar vestibulitis syndrome w12x. These cases of co-existing vulvar vestibulitis syndrome and vestibular papillomatosis are quite rare; being the two conditions often unexplained, their co-existence represents an additional effort for the clinician, both in terms of interpretation and of treatment. In this study we intended to investigate the presence of genital HPV infection in such cases, in order to clarify the real role of the virus, often thought responsible for these conditions. 2. Materials and methods The study has been performed during 1996 at the Department of Obstetrics and Gynecology of
Fig. 1. Diffuse papillomatosis of the vulvar vestibule.
the University of Milan School of Medicine, in cooperation with the Department of Pathology and the Virology Laboratory of H San Raffaele Scientific Institute, Milan, Italy. Sixteen consecutive patients have been recruited for the study; all the cases responded to the following inclusion criteria: Ža. demonstration of vulvar papillomatosis; Žb. diagnosis of vulvar vestibulitis syndrome according to the codified parameters; and Žc. microbiological exclusion of urethral and vulvo-vaginal infectious diseases. In particular, vestibular papillomatosis has been diagnosed under 5% acetic acid colposcopic magnification, with the formulation of suspected HPV infection; vulvar vestibulitis syndrome diagnosis has been obtained following the ISSVD recommended criteria: Ža. dyspareunia, classified in 38 according to Turner and Marinoff, I. Causes dis-
M. Origoni et al. r International Journal of Gynecology & Obstetrics 64 (1999) 259]263
comfort but does not prevent sexual intercourse; II. Sometimes prevents sexual intercourse; and III. Completely prevents sexual intercourse w13x; Žb. duration of dyspareunia Ž- 3 months, between 3 and 6, ) 6 months.; Žc. vulvodynia differentiated in mild, moderate and severe; and Žd. vestibular erythema. Patients and their male partners have been interviewed in relation to previous HPV genital infections andror condylomata. The following tests have been performed in all cases: Ž1. vestibular Pap smear by the use of Cytobrush ŽMedscand Ltd. devices: koilocytosis being the cytological pattern considered associated with HPV infection; Ž2. vestibular ViraPap HPV DNA Collection Kit ŽDigene Diagnostics, USA.: the test allowed the determination of specific viral DNA sequences by a molecular liquid phase hybridization; and Ž3. 6 mm Keyes’ punch vestibular biopsy under colposcopic visualization of the most representative areas of micropapillomatosis: half of the specimen has been processed for traditional histological evaluation and koilocytosis demonstration, the other half has been immediately frozen and subsequently processed for HPV DNA determination by the Polimerase Chain Reaction ŽPCR. technique; genic amplification has been obtained with the primers MY09 and MY11 ŽGene Amplimer } Perkin Elmer. which allow the identification of almost 50 different viral types. This latter test has been regarded as the gold standard for the diagnosis of HPV infection, to which compare the others: colposcopy, cytology, histology and molecular hybridization ŽViraPap.. 3. Results The study group accounted for 16 consecutive patients consulting the Vulvo-Vaginal Clinic of the Department of Obstetrics and Gynecology of H San Raffaele Institute for vulvar discomfort; all the cases have been clinically investigated by the same clinicians ŽMO, MR., in order to have uniformity of selection. All patients were sexually active. Mean age was 28.37 years ŽS.D.s 6.17. ranging from 20 to 40 years. In all cases urethral, vulvar,
261
vaginal and cervical microbic infections were excluded by performing cultural exams, which resulted negative. Previous HPV genital infections were reported by two patients Ž12.5%., while in no case did the male partner refer a similar event. Patients reported grade I dyspareunia in four cases Ž25%., grade II in 10 Ž62.5%. and grade III in two cases Ž12.5%.. Eight patients Ž50%. reported a moderate vulvodynia, the other eight Ž50%. defined the symptom as severe; no patients reported a mild vulvodynia. Symptoms’ duration was between 3 and 6 months in six Ž37.5%. cases and longer than 6 months in the remnant 10 Ž62.5%. cases. Vulvoscopic judgment of suspected HPV infection has been formulated in six Ž37.5%. cases. The cytological pattern of koilocytosis Žvestibular Pap smear. resulted negative in all cases. The ViraPap HPV DNA Detection Kit allowed the identification of viral DNA sequences in one Ž6.25%. case. The pathological evaluation of the biopsy specimens revealed three Ž18.75%. cases of histological positivity. The PCR technique identified two Ž12.5%. positive cases. The comparative results are shown in Table 1. 4. Discussion A considerable effort has been done in the last Table 1 Comparative results of the study Case
Previous HPV
Vulvoscopy
Pap smear
ViraPap
Biopsy
PCR
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
] ] ] ] HPV ] ] ] ] ] ] ] ] ] ] HPV
] HPV HPV ] ] HPV ] ] HPV ] ] ] HPV ] ] HPV
] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ]
] ] ] ] ] HPV ] ] ] ] ] ] ] ] ] ]
] ] ] ] ] HPV ] ] ] HPV ] ] HPV ] ] ]
] ] ] ] ] HPV HPV ] ] ] ] ] ] ] ] ]
262
M. Origoni et al. r International Journal of Gynecology & Obstetrics 64 (1999) 259]263
decades in order to clarify the etiology of vulvar pain syndromes; unfortunately, since the first description of the condition, almost a century ago w14x, no clear explanation of its pathophysiology has been formulated. A large but contradictory amount of studies focused the attention upon the role of HPV infection, both in cases of vulvar vestibulitis syndrome and of vestibular papillomatosis. In 1988 Turner and Marinoff w3x studied seven consecutive cases responding to the Friedrich criteria for vulvar vestibulitis syndrome; using a Southern blot technique for DNA hybridization, all seven specimens resulted positive for HPV DNA. These authors concluded that HPV infection is one of the causes of vulvodynia due to vulvar vestibulitis syndrome and suggested that treatment of the infection may cure vulvar pain. In agreement with this theory, Umpierre et al. w4x in 1991 obtained similar findings in 11 out of 13 Ž84.6%. cases of vulvar vestibulitis investigated using polymerase chain reaction amplification and dot blot hybridization; five of the HPV-positive cases positively responded to interferon therapy. Bornstein et al. w15,16x in two consecutive reports supported, in the last 2 years, the theory of a causal role of HPV in the etiology of vulvar vestibulitis syndrome. On the other hand, Wilkinson w5x reported only a 9% of HPV DNA positivity with the PCR technique in 31 consecutive cases, and Bazin w6x reported a 5.3% positivity with the same technique. Turning to vestibular papillomatosis, data from the recent literature are similarly controversial. Costa et al. w17x, in their study of 20 cases of vestibular papillomatosis investigated with Southern blot DNA hybridization, demonstrated that 80% of cases contained viral DNA sequences, in the majority of which, Ž60%., DNA of HPV 16r18. Moyal-Barracco et al. w9x examined biopsies from 29 patients with vestibular papillae using Southern blot hybridization and found HPV sequences in only two Ž7%.. More recently, Welch et al. w7x demonstrated a 39% of viral DNA positivity in their series of 18 patients; in this experience it is noteworthy that
72% of patients had a history of previous genital warts. It is a common pattern of these previous experiences to associate symptomatic vestibular papillomatosis with a subclinical HPV infection, while in cases of asymptomatic papillae the viral DNA research is more likely to result negative w18x. This is the reason why, in our study, we carefully selected patients who presented at the same time both vestibular papillomatosis and a significative vulvar pain disorder. The paper of Growdon et al. w18x, in particular, is the closest to the present study in terms of cases selection. The authors considered 12 patients with pruritic vulvar squamous papillomatosis and, on the basis of histological and immunohistochemical findings, concluded that HPV infection is responsible for the condition. At the same time, the authors suggested the use of viral DNA studies for the identification of specific papillomaviruses. The relevant result of the present investigation is the very low rate of viral DNA positivity in our series. One case detected with the ViraPap Ž6.25%. and two cases with the PCR Ž12.50%.; these data seem to acquit HPV from a direct responsibility in our cases, suggesting only a marginal and non-significant correlation. In accordance with this, some other topics may be outlined from our experience. Vestibular cytology, negative in all cases, confirmed the low sensitivity of Pap smear in detecting HPV infection, especially in a site where exfoliated cells are numerically very few as compared to the cervix w19x. Colposcopic magnification of the vulva after 5% acetic acid application revealed a low specificity in terms of identification of HPV vulvar infection in cases of vulvar pain syndromes Ž37.5% of positivity.. This result confirms the position of Reid w11x who discouraged the use of this tool, as non-diagnostic in these specific cases. Histological koilocytosis Ž18.75% of positivity. overdiagnosed HPV infection and demonstrated low specificity. The authors believe that a reliable explanation of this aspect can be found in Wilkinson’s paper w5x: vestibular epithelium of young women is strongly influenced by glycogen produc-
M. Origoni et al. r International Journal of Gynecology & Obstetrics 64 (1999) 259]263
tion that causes a kind of pale turning of cell cytoplasm, easily misinterpreted as koilocytosis. Wilkinson himself reported a 16% of histological positivity compared to 9% of DNA identification. In terms of viral DNA recognition, we identified two cases Ž12.50%. with the PCR technique and one case Ž6.25%. with the ViraPap. Little has been published about the comparison between the two methods w20,21x and in almost all papers a twofold sensitivity of the PCR technique when compared to ViraPap is demonstrated. The very small number of positive cases in our series does not allow any conclusive statement on this topic, but the exact proportion we found Žtwo vs. one positive case with PCR and ViraPap, respectively. is at least suggestive. What is unquestionably objective is the very low prevalence of viral DNA identification in these cases of severely symptomatic vulvar papillomatosis; thus it is reasonable to state that HPV infection can not be advocated as a common cause of painful papillomatosis of the vulvar vestibule. References w1x McKay M. Burning vulva syndrome: report of the ISSVD task force. J Reprod Med 1984;29:457. w2x Friedrich EG. Vulvar vestibulitis syndrome. J Reprod Med 1987;32:110. w3x Turner MLC, Marinoff SC. Association of Human Papillomavirus with vulvodynia and the vulvar vestibulitis syndrome. J Reprod Med 1988;6:533. w4x Umpierre SA, Kaufman RH, Adam E, Woods KV, Alder-Storthz K. Human Papillomavirus DNA in tissue biopsy specimens of vulvar vestibulitis patients treated with interferon. Obstet Gynecol 1991;78:693. w5x Wilkinson EJ, Guerrero E, Daniel R et al. Vulvar vestibulitis is rarely associated with Human Papillomavirus infection types 6, 11, 16 or 18. Int J Gynecol Pathol 1993;12:344. w6x Bazin S, Bouchard C, Brisson J, Morin C, Meisels A, Fortier M. Vulvar vestibulitis syndrome: an exploratory case-control study. Obstet Gynecol 1994;83:47. w7x Welch JM, Nayagam M, Parry G. What is vestibular
w8x
w9x w10x w11x
w12x
w13x
w14x w15x
w16x
w17x
w18x
w19x
w20x
w21x
263
papillomatosis? A study of its prevalence, aetiology and natural history. Br J Obstet Gynaecol 1993;100:939. McKay M, Frankman O, Horowitz B et al. Vulvar vestibulitis and vestibular papillomatosis: report of the ISSVD Committee on vulvodynia. J Reprod Med 1991; 36:413. Moyal-Baracco M, Orth G. Vestibular papillae of the vulva. Arch Dermatol 1990;126:1594. McKay M. Subsets of vulvodynia. J Reprod Med 1988;8:695. Reid R, Greenberg MD, Daoud Y, Husain M, Selvaggi S, Wilkinson E. Colposcopic findings in women with vulvar pain syndromes. A preliminary report. J Reprod Med 1988;6:523. Mann MS, Kaufman RH, Brown D, Jr, Adam E. Vulvar vestibulitis: significant clinical variables and treatment outcome. Obstet Gynecol 1992;79:122. Marinoff SC, Turner MLC. Vulvar vestibulitis syndrome: an overview. Am J Obstet Gynecol 1991; 165:1228. Thomas TG. Hyperesthesia of the vulva. The diseases of women. Philadelphia: HC Lea’s Son and Co, 1880:145 Bornstein J, Shapiro S, Rahat M, Goldshmid N, Abramovici H. Polymerase chain reaction search for viral etiology of vulvar vestibulitis syndrome. Am J Obstet Gynecol 1996;174:139. Bornstein J, Shapiro S, Goldshmid N, Goldik Z, Lahat N, Abramovici H. Severe vulvar vestibulitis. Relation to HPV infection. J Reprod Med 1997;42:514. Costa S, Rotola A, Terzano P et al. Cassai: is vestibular papillomatosis associated with Human Papillomavirus? J Med Virol 1991;35:7. Growdon WA, Fu YS, Lebherz TB, Rapkin A, Mason GD, Parks G. Pruritic vulvar squamous papillomatosis: evidence for Human Papillomavirus etiology. Obstet Gynecol 1985;66:564. Schneider A, Meinhardt G, De-Villiers EM, Gissmann L. Sensitivity of the cytologic diagnosis of cervical condyloma in comparison with HPV-DNA hybridization studies. Diagn Cytopathol 1987;3:250. Burmer GC, Parker JD, Bates J, East K, Kulander BG. Comparative analysis of Human Papillomavirus detection by Polymerase Chain Reaction and ViraPapr ViraType kits. Am J Clin Pathol 1990;94:554. Guerrero E, Daniel RW, Bosch FX et al. Comparison of ViraPap, Southern Hybridization, and Polymerase Chain Reaction methods for Human Papillomavirus identification in an epidemiological investigation of cervical cancer. J Clin Microbiol 1992;30:2951.
Article
Human papillomavirus with co-existing vulvar vestibulitis syndrome and vestibular papillomatosis M. Origoni a,U , M. Rossi a , D. Ferrari a , F. Lillo b , A.G. Ferrari a a
Department of Obstetrics and Gynecology, Uni¨ ersity of Milano School of Medicine, Milano, Italy b Virology Laboratory, H San Raffaele Scientific Institute, Milano, Italy Received 10 February 1998; received in revised form 24 July 1998; accepted 13 August 1998
Abstract Objecti¨ e: The role of HPV infection in cases of vulvar papillomatosis and vulvar vestibulitis syndrome is still unclear and data from the literature is controversial. In this study we intended to investigate the prevalence of viral infection, with a multidisciplinary approach, in cases with a co-existence of the two patterns. Method: Sixteen consecutive cases with diagnosis of vulvar vestibulitis syndrome and co-existence of vestibular papillomatosis were enrolled in the study and investigated by the means of vulvar cytology, vulvoscopy, histology, ViraPap and Polymerase Chain Reaction. Result: Cytology, vulvoscopy and histology did not demonstrate suitable accuracy for the diagnosis. Viral DNA identification revealed two Ž12.50%. positive cases using PCR and one Ž6.25%. positive case with ViraPap. Conclusion: The results of the present investigation indicate that even in cases of co-existing vulvar papillomatosis and severe vulvar vestibulitis syndrome, the prevalence of HPV infection is too low to be considered causal. Q 1999 International Federation of Gynecology and Obstetrics. Keywords: Human papillomavirus; HPV; Vulvar pain; Vulvar vestibulitis syndrome; Vulvar papillomatosis; HPV DNA
1. Introduction The patient complaining of vulvar burning and chronic discomfort has always represented a hard challenge for the gynecologist. In 1983 the Inter-
U
Corresponding author. Fax: q39 2 26413592.
national Society for the Study of Vulvar Disease ŽISSVD. introduced the terms of ‘burning vulva syndrome’ and ‘vulvodynia’, defining a condition of chronic vulvar soreness w1x. Vulvodinya recognizes multiple aetiologies, thus the use of this term implies the formulation of a correct and precise diagnosis; this approach allowed the identification of different subgroups of vulvodinya,
0020-7292r99r$20.00 Q 1999 International Federation of Gynecology and Obstetrics. PII: S 0 0 2 0 - 7 2 9 2 Ž 9 8 . 0 0 1 5 6 - 8
260
M. Origoni et al. r International Journal of Gynecology & Obstetrics 64 (1999) 259]263
vulvar vestibulitis syndrome being an independent entity. According to Friedrich w2x the syndrome is defined by the concomitant presence of: Ža. severe pain at any attempt of intercourse; Žb. vestibular tenderness at pressure; and Žc. vestibular erythema of various degrees. The etiology of the condition is still unclear: genital infections, irritants, topical medications and physical agents can all be correlated with the syndrome, but none can be definitely recognized as causal. Among genital infections, the role of Human Papilloma Viruses ŽHPVs. has been differently reported, both in terms of cause-effect relation w3,4x and of innocent co-existence w5,6x. The presence of vestibular papillae is quite a common finding in young women, with an estimated prevalence of almost 1% w7x; they are more frequently localized to the posterior vestibule but the observation of a diffuse papillomatosis of the whole introitus is not rare w8x ŽFig. 1.; isolated vestibular papillae are more commonly interpretable as a physiological pattern of the normal vestibule w9x, while diffuse papillomatosis has been often associated with HPV subclinical infection w10,11x. Colposcopic magnification of the vestibule allows in some cases the distinction between HPV-induced lesions and vulvar papillae. In detail, HPV-induced lesions are generally confluent, without distinct vascular supply and acetowhitening. Both these conditions are generally symptomless, however, sometimes they co-exist with a vulvar vestibulitis syndrome w12x. These cases of co-existing vulvar vestibulitis syndrome and vestibular papillomatosis are quite rare; being the two conditions often unexplained, their co-existence represents an additional effort for the clinician, both in terms of interpretation and of treatment. In this study we intended to investigate the presence of genital HPV infection in such cases, in order to clarify the real role of the virus, often thought responsible for these conditions. 2. Materials and methods The study has been performed during 1996 at the Department of Obstetrics and Gynecology of
Fig. 1. Diffuse papillomatosis of the vulvar vestibule.
the University of Milan School of Medicine, in cooperation with the Department of Pathology and the Virology Laboratory of H San Raffaele Scientific Institute, Milan, Italy. Sixteen consecutive patients have been recruited for the study; all the cases responded to the following inclusion criteria: Ža. demonstration of vulvar papillomatosis; Žb. diagnosis of vulvar vestibulitis syndrome according to the codified parameters; and Žc. microbiological exclusion of urethral and vulvo-vaginal infectious diseases. In particular, vestibular papillomatosis has been diagnosed under 5% acetic acid colposcopic magnification, with the formulation of suspected HPV infection; vulvar vestibulitis syndrome diagnosis has been obtained following the ISSVD recommended criteria: Ža. dyspareunia, classified in 38 according to Turner and Marinoff, I. Causes dis-
M. Origoni et al. r International Journal of Gynecology & Obstetrics 64 (1999) 259]263
comfort but does not prevent sexual intercourse; II. Sometimes prevents sexual intercourse; and III. Completely prevents sexual intercourse w13x; Žb. duration of dyspareunia Ž- 3 months, between 3 and 6, ) 6 months.; Žc. vulvodynia differentiated in mild, moderate and severe; and Žd. vestibular erythema. Patients and their male partners have been interviewed in relation to previous HPV genital infections andror condylomata. The following tests have been performed in all cases: Ž1. vestibular Pap smear by the use of Cytobrush ŽMedscand Ltd. devices: koilocytosis being the cytological pattern considered associated with HPV infection; Ž2. vestibular ViraPap HPV DNA Collection Kit ŽDigene Diagnostics, USA.: the test allowed the determination of specific viral DNA sequences by a molecular liquid phase hybridization; and Ž3. 6 mm Keyes’ punch vestibular biopsy under colposcopic visualization of the most representative areas of micropapillomatosis: half of the specimen has been processed for traditional histological evaluation and koilocytosis demonstration, the other half has been immediately frozen and subsequently processed for HPV DNA determination by the Polimerase Chain Reaction ŽPCR. technique; genic amplification has been obtained with the primers MY09 and MY11 ŽGene Amplimer } Perkin Elmer. which allow the identification of almost 50 different viral types. This latter test has been regarded as the gold standard for the diagnosis of HPV infection, to which compare the others: colposcopy, cytology, histology and molecular hybridization ŽViraPap.. 3. Results The study group accounted for 16 consecutive patients consulting the Vulvo-Vaginal Clinic of the Department of Obstetrics and Gynecology of H San Raffaele Institute for vulvar discomfort; all the cases have been clinically investigated by the same clinicians ŽMO, MR., in order to have uniformity of selection. All patients were sexually active. Mean age was 28.37 years ŽS.D.s 6.17. ranging from 20 to 40 years. In all cases urethral, vulvar,
261
vaginal and cervical microbic infections were excluded by performing cultural exams, which resulted negative. Previous HPV genital infections were reported by two patients Ž12.5%., while in no case did the male partner refer a similar event. Patients reported grade I dyspareunia in four cases Ž25%., grade II in 10 Ž62.5%. and grade III in two cases Ž12.5%.. Eight patients Ž50%. reported a moderate vulvodynia, the other eight Ž50%. defined the symptom as severe; no patients reported a mild vulvodynia. Symptoms’ duration was between 3 and 6 months in six Ž37.5%. cases and longer than 6 months in the remnant 10 Ž62.5%. cases. Vulvoscopic judgment of suspected HPV infection has been formulated in six Ž37.5%. cases. The cytological pattern of koilocytosis Žvestibular Pap smear. resulted negative in all cases. The ViraPap HPV DNA Detection Kit allowed the identification of viral DNA sequences in one Ž6.25%. case. The pathological evaluation of the biopsy specimens revealed three Ž18.75%. cases of histological positivity. The PCR technique identified two Ž12.5%. positive cases. The comparative results are shown in Table 1. 4. Discussion A considerable effort has been done in the last Table 1 Comparative results of the study Case
Previous HPV
Vulvoscopy
Pap smear
ViraPap
Biopsy
PCR
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
] ] ] ] HPV ] ] ] ] ] ] ] ] ] ] HPV
] HPV HPV ] ] HPV ] ] HPV ] ] ] HPV ] ] HPV
] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ]
] ] ] ] ] HPV ] ] ] ] ] ] ] ] ] ]
] ] ] ] ] HPV ] ] ] HPV ] ] HPV ] ] ]
] ] ] ] ] HPV HPV ] ] ] ] ] ] ] ] ]
262
M. Origoni et al. r International Journal of Gynecology & Obstetrics 64 (1999) 259]263
decades in order to clarify the etiology of vulvar pain syndromes; unfortunately, since the first description of the condition, almost a century ago w14x, no clear explanation of its pathophysiology has been formulated. A large but contradictory amount of studies focused the attention upon the role of HPV infection, both in cases of vulvar vestibulitis syndrome and of vestibular papillomatosis. In 1988 Turner and Marinoff w3x studied seven consecutive cases responding to the Friedrich criteria for vulvar vestibulitis syndrome; using a Southern blot technique for DNA hybridization, all seven specimens resulted positive for HPV DNA. These authors concluded that HPV infection is one of the causes of vulvodynia due to vulvar vestibulitis syndrome and suggested that treatment of the infection may cure vulvar pain. In agreement with this theory, Umpierre et al. w4x in 1991 obtained similar findings in 11 out of 13 Ž84.6%. cases of vulvar vestibulitis investigated using polymerase chain reaction amplification and dot blot hybridization; five of the HPV-positive cases positively responded to interferon therapy. Bornstein et al. w15,16x in two consecutive reports supported, in the last 2 years, the theory of a causal role of HPV in the etiology of vulvar vestibulitis syndrome. On the other hand, Wilkinson w5x reported only a 9% of HPV DNA positivity with the PCR technique in 31 consecutive cases, and Bazin w6x reported a 5.3% positivity with the same technique. Turning to vestibular papillomatosis, data from the recent literature are similarly controversial. Costa et al. w17x, in their study of 20 cases of vestibular papillomatosis investigated with Southern blot DNA hybridization, demonstrated that 80% of cases contained viral DNA sequences, in the majority of which, Ž60%., DNA of HPV 16r18. Moyal-Barracco et al. w9x examined biopsies from 29 patients with vestibular papillae using Southern blot hybridization and found HPV sequences in only two Ž7%.. More recently, Welch et al. w7x demonstrated a 39% of viral DNA positivity in their series of 18 patients; in this experience it is noteworthy that
72% of patients had a history of previous genital warts. It is a common pattern of these previous experiences to associate symptomatic vestibular papillomatosis with a subclinical HPV infection, while in cases of asymptomatic papillae the viral DNA research is more likely to result negative w18x. This is the reason why, in our study, we carefully selected patients who presented at the same time both vestibular papillomatosis and a significative vulvar pain disorder. The paper of Growdon et al. w18x, in particular, is the closest to the present study in terms of cases selection. The authors considered 12 patients with pruritic vulvar squamous papillomatosis and, on the basis of histological and immunohistochemical findings, concluded that HPV infection is responsible for the condition. At the same time, the authors suggested the use of viral DNA studies for the identification of specific papillomaviruses. The relevant result of the present investigation is the very low rate of viral DNA positivity in our series. One case detected with the ViraPap Ž6.25%. and two cases with the PCR Ž12.50%.; these data seem to acquit HPV from a direct responsibility in our cases, suggesting only a marginal and non-significant correlation. In accordance with this, some other topics may be outlined from our experience. Vestibular cytology, negative in all cases, confirmed the low sensitivity of Pap smear in detecting HPV infection, especially in a site where exfoliated cells are numerically very few as compared to the cervix w19x. Colposcopic magnification of the vulva after 5% acetic acid application revealed a low specificity in terms of identification of HPV vulvar infection in cases of vulvar pain syndromes Ž37.5% of positivity.. This result confirms the position of Reid w11x who discouraged the use of this tool, as non-diagnostic in these specific cases. Histological koilocytosis Ž18.75% of positivity. overdiagnosed HPV infection and demonstrated low specificity. The authors believe that a reliable explanation of this aspect can be found in Wilkinson’s paper w5x: vestibular epithelium of young women is strongly influenced by glycogen produc-
M. Origoni et al. r International Journal of Gynecology & Obstetrics 64 (1999) 259]263
tion that causes a kind of pale turning of cell cytoplasm, easily misinterpreted as koilocytosis. Wilkinson himself reported a 16% of histological positivity compared to 9% of DNA identification. In terms of viral DNA recognition, we identified two cases Ž12.50%. with the PCR technique and one case Ž6.25%. with the ViraPap. Little has been published about the comparison between the two methods w20,21x and in almost all papers a twofold sensitivity of the PCR technique when compared to ViraPap is demonstrated. The very small number of positive cases in our series does not allow any conclusive statement on this topic, but the exact proportion we found Žtwo vs. one positive case with PCR and ViraPap, respectively. is at least suggestive. What is unquestionably objective is the very low prevalence of viral DNA identification in these cases of severely symptomatic vulvar papillomatosis; thus it is reasonable to state that HPV infection can not be advocated as a common cause of painful papillomatosis of the vulvar vestibule. References w1x McKay M. Burning vulva syndrome: report of the ISSVD task force. J Reprod Med 1984;29:457. w2x Friedrich EG. Vulvar vestibulitis syndrome. J Reprod Med 1987;32:110. w3x Turner MLC, Marinoff SC. Association of Human Papillomavirus with vulvodynia and the vulvar vestibulitis syndrome. J Reprod Med 1988;6:533. w4x Umpierre SA, Kaufman RH, Adam E, Woods KV, Alder-Storthz K. Human Papillomavirus DNA in tissue biopsy specimens of vulvar vestibulitis patients treated with interferon. Obstet Gynecol 1991;78:693. w5x Wilkinson EJ, Guerrero E, Daniel R et al. Vulvar vestibulitis is rarely associated with Human Papillomavirus infection types 6, 11, 16 or 18. Int J Gynecol Pathol 1993;12:344. w6x Bazin S, Bouchard C, Brisson J, Morin C, Meisels A, Fortier M. Vulvar vestibulitis syndrome: an exploratory case-control study. Obstet Gynecol 1994;83:47. w7x Welch JM, Nayagam M, Parry G. What is vestibular
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