GYNECOLOGIC

ONCOLOGY

43, 237-241 (1991)

HPV Changes and Their Significance in Patients with Invasive Squamous Cell Carcinoma of the Vulva: A Clinicopathologic Study NADER HUSSEINZADEH,

M.D.,*,’ AND

*Division

of Gynecologic

Oncology,

‘fDepartrnent

TIMOTHY DEEIJLIS, M.D.,* TERRENCE WESSELER, M.D.$

NANCY NEWMAN,

of Obstetrics and Gynecology, and SDepartment Cincinnati, Ohio 45267-0526

M.D.,?

of Pathology, lJniver&y of Ciminn&,

Received March 18, 1991

Recordsof 28 patientswith invasive squamouscell carcinoma of the vulva were analyzed with regard to age-specificincidence rate, associated humanpapillomavirus(HPV) changes,multifocal and unifocal distribution of the lesions,and incidenceof nodal metastasis.The presenceof HPV changes(koilocytosisand condyloma)around the neoplasticepitheliumcorrelatedwith a mean agegroup younger than that of thosewithout HPV changes(47 vs 77 years). All multifocal cancerswere associatedwith HPV changeswhile only 35% of unifocal lesionswere so associated. Patientswith multifocal diseasewere found to have a meanage youngerthan that of thosewith unifocal disease(44 vs. 67). When patientswith microinvasionwereexcluded, no patientswith multifocal invasive cancer and HPV changeswere found to have nodal metastases.In contrast, nodal metastases were presentin 59%of patientswith unifocal invasive cancer. 0 1991 Academic PMS, Inc.

INTRODUCTION Circumstantial evidence suggesting a strong relationship between human papillomavirus (HPV) and squamous cell carcinoma of the vulva continues to accumulate [l-

61.

Condyloma has been reported to be present in 7-26% of patients with squamous cell carcinoma of the vulva [7,8]. The observation that these lesions often merge microscopically suggests more than a coincidental association [2]. Indeed, some condyloma have been observed to undergo malignant changes over time [4], and there also have been case reports of carcinoma of the vulva actually arising in condyloma [9,10]. The significance of associated HPV changes in the prog’ To whom reprint requests should be addressed at Division of Gynecologic Oncology, University of Cincinnati Medical Center, 231 Bethesda Avenue, Cincinnati, OH 45267-0526.

nosis of patients with invasive squamous cell carcinoma of the vulva, as well as unifocal and multifocal distribution of the disease, remains unclear. The present study was undertaken to address this issue and to evaluate the clinicopathologic significance of HPV changes (koilocytosis and condyloma) in invasive squamous cell carcinoma of the vulva. MATERIALS

AND METHODS

From January 1975 through December 1989, all patients with primary invasive squamous cell carcinoma of the vulva who had been diagnosed and treated at the University of Cincinnati Medical Center were studied with regard to age, clinical presentation, presence or absence of coexisting HPV changes (koilocytosis and condyloma), multifocal or unifocal distribution of the lesions, and nodal metastasis. All patients with invasive disease were staged preoperatively according to criteria established by the International Federation of Gynecology and Obstetrics (Table 1). Pathologic slides were reviewed by one of the authors (T.W.). All neoplasms were designated as multifocal or unifocal on the basis of the gross description proven by biopsies and the surgical pathological specimen. To be classified as a muitifocal lesion, two or more discontinuous foci of disease had to be present. Widespread, confluent lesions were classified as unifocal. A diagnosis of condyloma was based on the presence of minimal basal and parabasal cell atypia and orderly maturation and a smooth transition to koilocytotic intermediate and superficial cells in association with hyperkeratosis, parakeratosis, acanthosis, and papillomatosis. Koilocytosis was defined as hyperchromatic, normal to enlarged, mononucleated or binucleated cells with per-

237 OC90-8258/91 $1.50 Copyright 0 1991 by Academic Press, Inc. All rights of reproduction in any form resewed.

238

HUSSEINZADEH

ET AL.

TABLE 1 Distribution of Stagein Patients with Invasive Vulvar Cancer No.

%

5 5 11 3 4

18 18 39 11 14

Microinvasive Stage I Stage II Stage III Stage IV

involving at least the upper l/3 of the epithelium (Fig. 1). Microinvasion or superficially invasive carcinoma of the vulva was defined as a single lesion measuring 2 cm or less in diameter and with a depth of invasion of 1 mm or less. Those tumors with a depth of invasion greater than 1 mm were considered frankly invasive cancer. The depth of invasion was measured from the epithelial stromal junction of the adjacent, most superficial dermal papillae to the deepest point of invasion of tumor [26]. Seventeen of twenty-eight patients were treated with radical vulvectomy and inguinal femoral lymphadenectomy with or without pelvic lymphadenectomy. One patient had radical vulvectomy only. Among the remaining 10 patients, 2 patients had hemivulvectomy. Three patients had simple vulvectomy and five patients had wide local excision with or without groin node biopsy. All clinically suspicious nodes were removed and evaluated microscopically. Postoperative radiation was given to 5 patients.

TABLE 2 Age Distribution in Patients with Invasive Squamous Carcinomaof the Vulva HPV Changes Total

Multifocal

Unifocal

Present

Absent

28 61

8 (29) 44

20 (71) 67

15 (54) 47

13 (46) 77

No. of patients (%) Mean age (years) (range, 28-90)

inuclear cytoplasmic vacuolation

RESULTS

Age The age range in patients with invasive squamous cell carcinoma of the vulva was 28-90 years with a mean age of 61 years. Eight patients (29%) had multifocal lesions and twenty patients (71%) had unifocal lesion. Patients with multifocal lesions and those with associated HPV changes (koilocytosis and condyloma) were much younger than patients with unifocal lesion and those without HPV changes (P = 0.01) (Table 2). Clinical

Presentation

(Table 3)

The most common presenting symptom was vulvar mass followed by pruritus and pain. Four patients were asymptomatic and lesions were noted during examination. Most patients exhibited fungating lesions followed by ulcerative, papillomatous, pigmented, and erythematous

FIG. 1. Koilocytotic changes associated with invasive squamous cell carcinoma of the vulva.

HPV CHANGES

IN VULVAR

TABLE 3 Clinical Presentation Clinical presentation Mass Pruritus Pain Pain and pruritus Asymptomatic (or no description) Fungative Ulcerative Papillomatous Erythematous Pigmented No description Right labium Left labium Labia and clitoris Labia and perineum Both labia No description

No. of patients (%) A. Symptomatology 10 (36)

6 (21) 7 (25) 1 (4) 4 (14) B. Type of lesions 12 (43) 9 (32) 2 (7) 2 (7) 2 (7) 1 (4) C. Anatomic Sites 11 (39) 5 (18) s (18) 4 (14) 2 (7) 1 (4)

Presence of HPV changes (%) s 3 3 1

(50) (50) (43) (100)

3 (75) s (42) 5 (56) 1 (SO) 2 VW 2 WV 4 3 s 4

(36) (60) (100) (100) -

-

Associafed HPV (KoiEocytosis and Condyloma) Changes

with invasive histologic evihad multifocal HPV changes multifocal lewith unifocal

239

PATIENTS

TABLE 5 Nodal Metastasisand HPV Changesin Patientswith Invasive SquamousCell Carcinomaof the Vulva” Patient

lesions. In one patient the type of the lesion was not described. Most lesions were located on the right labium followed by the left labium with fewer lesions& both labia. One patient had no description of the exact location of the lesion. Fifteen of twenty-eight patients (54%) squamous cell carcinoma of the vulva had dence of HPV changes. Of these, 8 patients lesions and 7 patients had unifocal lesion. were present in all 8 patients (100%) with sions compared to 7 of 20 patients (35%) lesions (Table 4).

CANCER

(years)

Lesions

Stage

Grade

VI*

Nodes

HPV changes

28 40 41 63 59 46 49 51 52 53 68 79 12 IS 85 90 84 85 5s 52 83 73 45

M’ M M M M M Ud U U U U U U U U U U U U U U U U

I II II I I III II II II I III II II II IV IV II IV II I IV III II

2 2 2 1 3 1 3 1 1 2 1 2 3 3 2 3 2 3 1 2 2 2 2

+ + ND + + -

ND + ND + + + + + t ND + ND + + -

t + t + + + + + + + + +

Age

GH JH HD MM ML PK LJ MJ BJ JW HH MS ES DB NW BR EL IH SM MG ZR LW GP

* Patients with microinvasion were excluded. b VI, vascular channel involvement. ’ M. multifocal lesions. d U; unifocal lesions. ’ ND, not done.

carcinoma of the vulva, 6 patients (26%) had multifocal and 17 (74%) had unifocal lesions. Regardless of the stage of the disease, no patients with multifocal lesions and HPV change were found to have nodal metastasis. In contrast, of 17 patients with unifocal disease, 10 (59%) had nodal metastasis. Of these 10 patients, 4 patients had vascular channel involvement and 5 patients had Grade 3 tumor. HPV changes were present in 1 patient with nodal metastasis (Table 5).

Nodal Metastasis

With 5 patients with microinvasive disease excluded, of the remaining 23 patients with invasive squamous cell TABLE 4 HPV Changesand Multlfocal and Unlfocal Distribution of Lesionsin Patientswith Invasive Vulvar Cancer HPV changes

Multifocal

Unifocal

Present (15) Absent (13)

8 W’) 0

7 (35) 13 (65)

Total (28)

8 WV

20 (100)

Follow-up

Patients were followed up to 6 years. Two of five patients with microinvasive disease developed recurrences; one had CIS of the vulva 5 years after initial surgery and the other had invasive cancer of the vulva 1 year after treatment, for which she received external radiation. Of 23 patients with invasive vulvar cancer, 7 patients died. Three died of their disease and four died of unrelated cancer (two cervical cancer, one colon and breast cancer, one leukemia). Five patients developed recurrent disease; two had carcinoma in situ of the vulva at 6 months and 6 years after initial treatment. Three had invasive

240

HUSSEINZADEH

cancer 7-13 months following therapy. Two had local recurrence and one had distant metastasis. Eight patients had no recurrence and three patients were lost to followUP* HPV changes were not present in seven patients who had died. Five of eight patients with no recurrence, one of three patients with recurrent invasive cancer, and two patients with recurrent CIS had histologic evidence of HPV changes in their original tumor. DISCUSSION The incidence of HPV infection appears to have been increasing during the past decade. In concert with an apparent increased incidence of condyloma, cases of invasive vulvar carcinoma associated with condyloma have been reported in the literature [4,9]. Earlier reports suggested that venereal disease could be a predisposing factor in young patients with invasive vulvar carcinoma [ll-131. In addition, patients with condyloma acuminata of the vulva may also develop invasive vulvar carcinoma at a younger age [4,14]. There are differences of opinion in the literature with regard to the precancerous potential of condyloma acuminata. Some [15] consider the association of vulvar carcinoma and condyloma to be more than a coincidence; however, others [16] recognize that malignant transformation may occur in vulvar condyloma, but is rare. Some authors [17-191 have demonstrated a transition from areas of typical condyloma to papillary dysplasia and then to squamous cell carcinoma, leaving the impression that condyloma has undergone a transition to malignancy. The potential role of human papillomavirus in the etiology of cancer was originally suspected following the observation of malignant conversion of HPV-induced tumors affecting the skin and mucosa [20,21]. Viral particles and a nucleotide sequence of papillomavirus were detected in neoplastic vulvar lesions [4,17,24,25]. At the present time the exact biologic mechanism by which condyloma evolves into invasive cancer has not been determined, and the involvement of HPV infection in vulvar cancer is evidenced by the fact that patients who have coexisting HPV infection are significantly younger than the patient population as a whole [22]. Pilotti et al. [23] reported their results on 21 patients. Fourteen patients showed microscopic evidence of HPV changes, whereas seven patients did not. Of the former group, 7 patients had foci of invasion. In all patients, the foci of invasion were separated by areas of intraepithelial neoplasia and condyloma with transitions from one lesion to another. Of 7 patients without HPV changes, foci of invasive cancer were identified in 4 patients and 2 of them were found to have regional nodal metastases. This is in agreement with our findings, in which 10 of 17 patients

ET AL.

with unifocal disease had nodal metastasis, and HPV changes were present in 1 patient with nodal metastasis. In addition, their immunohistochemical studies for papillomavirus internal capsid antigen (PV-Ag) were positive in 64% of patients with associated HPV changes and PVAg was not found in those without HPV changes. In conclusion, our study clearly demonstrates a strong association between HPV infection and squamous cell carcinoma of the vulva. It appears that patients with HPV changes follow a clinical pattern different from that of those without HPV changes. As evidenced in this study, patients with associated HPV changes were younger and had multifocal lesion, unlike those without HPV changes, who were older and had unifocal disease. Interestingly, patients with HPV changes were found to have earlystage vulvar cancer and rarely had nodal metastasis. Therefore, patients suspected of having condyloma of the vulva should have histologic diagnosis prior to any ablative therapy. REFERENCES I.

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HPV CHANGES

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plasia verruciforms as a model in studies on the role of papovaviruses in oncogenesis, Cancer Res. 32, 583-589 (1972). Zur Hausen, H. Human papillomaviruses and their possible role in squamous cell carcinoma, Curr. Top. Microbial. Immunol. 78, l30 (1977). Crum, C. P., Liskow, A., Petras, P., Keng, W. C., and Frick, H. C. Vulvar intraepithelial neoplasia (Severe atypia and carcinoma in situ), Cancer 54, 1429-1434 (1984). Pilotti, S., Rilke, F., Shah, K. V., Torre, G. D., and De Palo, G. Immunohistochemical and ultrastructural evidence of papillomavirus infection associated with in situ and microinvasive squamous cell carcinoma of the vulva, Am. J. Surg. Pathol. 8,751-761(1984). Gissmann, L., de Villiers, E. M., and Zur Hausen, M. Analysis of human genital warts (condylomata acuminata) and other genital tumors for human papillomavirus type 6 DNA, ht. /. Cancer 29, 143-146 (1982). Zachow, K. R., Ostrow, R. S., Bender, M., Wuhs, S., Okagaki, J., Pass, F., and Faras, A. J. Detection of human papillomavirus DNA in anogenital neoplasia, Nature 300, 771-773 (1982). Wilkinson, et al. Report of the 1SSVD terminology committee, J. Reprod. Med. 31, 973-974 (1986).

HPV changes and their significance in patients with invasive squamous cell carcinoma of the vulva: a clinicopathologic study.

Records of 28 patients with invasive squamous cell carcinoma of the vulva were analyzed with regard to age-specific incidence rate, associated human p...
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