Prognostic factors in early vulvar cancer

GYNECOLOGIC

ONCOLOGY

31, 43-49 (1988)

Prognostic

Factors in Early Vulvar Cancer

KENNETH C. ROWLEY, M.D. ,* HOLLY H. GALLION, M.D.,*,’ ELVIS S. DONALDSON, M.D.,* JOHN R. VAN NAGELL, M.D.,*.2 ROBERT V. HIGGINS, M.D. ,* DEBORAH E. POWELL, M.D.,? RICHARD J. KRYSCIO, PH.D.,* AND EDWARD J. PAVLIK, PH.D.* *Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, and TDepartments of Pathology and $Statistics, University of Kentucky Medical Center, Lexington, Kentucky 40536 Received February 2, 1988 Prognostic parameters were evaluated in 22 patients with small (~2 cm) superficially invasive (~5 mm) squamous cell carcinoma of the vulva. Primary surgery included radical vulvectomy with bilateral superficial and deep inguinal lymph node dissection in I I patients, and wide local excision with ipsilateral superficial inguinal lymph node dissection in 1I patients. Of the 22 patients studied, only 2 (9%) had lymph node metastases. Both patients had a single positive ipsilateral superficial inguinal node. Perineural invasion was strongly associated with lymph node metastases (P < 0.01). In this group of patients, grade, depth of invasion, lymph-vascular space invasion, and lymphoplasmacytic infiltration were not predictive of lymph node metastases (P > 0.05). Two patients initially treated with wide local excision and ipsilateral superficial inguinal lymph node dissection developed recurrent vulvar neoplasia on the contralateral vulva, and both were successfully retreated by wide local excision. All patients are presently alive and well with no evidence of disease. None of the histomorphologic parameters studied were predictive of tumor recurrence. These data suggest that wide local excision with ipsilateral superficial inguinal lymphadenectomy is effective in the treatment of patients with small, superficially invasive carcinomas of the Vulva. 0 1988 Academic Press, Inc

INTRODUCTION Carcinoma of the vulva is the fourth most common malignancy of the female genital tract. Over the past 30 years, radical vulvectomy with regional lymphadenectomy has been the mainstay of therapy. With this aggressive surgical approach, 5-year survival rates are excellent, approaching 90% for disease confined to the vulva and 50% for patients with disease metastatic to the regional lymph nodes [I]. However, considerable morbidity is associated with this procedure, including extended recovery time, lymphedema, impaired body image, and sexual dysfunction. Recently, several investigators have questioned the necessity of treating all ’ American Cancer Society Clinical Oncology Career Development Awardee * American Cancer Society Professor of Clinical Oncology. 43 0090-8258/88 $1 SO Copyright 0 1988 by Academic Press, Inc. All rights of reproduction m any form reserved.

44

ROWLEY

ET

AL.

patients with invasive carcinoma of the vulva with the same radical surgical approach. Wharton and co-workers for example, reported no lymph node metastases in a series of 25 patients with Stage I squamous cell carcinomas of the vulva having less than 5 mm of stromal invasion [2]. These authors recommended that this group of patients could be treated by vulvectomy alone without inguinal lymph node dissection. Since this initial report, however, numerous investigators have reported the presence of inguinal lymph node metastases in lo-30% of patients with tumors that meet these histologic criteria [3-71. The present investigation was undertaken to determine the value of histomorphologic factors in predicting lymph node metastases in patients with small, superficially invasive squamous cell carcinoma of the vulva. The efficacy of the surgical methods used in treating these patients was also evaluated. MATERIALS

AND METHODS

The study group consisted of 22 patients with small (62 cm in diameter), superficially invasive (<5 mm) squamous cell carcinomas confined to the vulva who were treated at the University of Kentucky Medical Center from January 1965 to July 1987. Microscopic slides and/or paraffin blocks were obtained for review in all cases. Multiple step sections of the primary lesion were examined for depth of stromal invasion, histologic differentiation, degree of lymphoplasmacytic infiltration around tumor cells, lymph-vascular space invasion, and perineural invasion. The depth of tumor invasion was measured with an ocular micrometer from the surface of the epithelium to the deepest point of tumor penetration. Lymph nodes were sectioned at l-mm intervals and examined for metastases. Primary surgery included radical vulvectomy with bilateral superficial and deep inguinal node dissection in 11 patients and wide local excision combined with ipsilateral superficial inguinal lymph node dissection in 11 patients (Fig. 1). When superficial inguinal lymph node dissection was performed, only those lymph nodes lying between Camper’s fascia and the cribriform fascia were removed. After completion of therapy, all patients were examined at monthly intervals for 1 year, every 2 months for 2 years and every 6 months thereafter. The vulva was examined with a magnifying lens at the time of each clinical examination, and any area suspicious for tumor recurrence was biopsied. All patients included in this study were followed from 4 to 158 months (mean 41 months) after treatment and none were lost to follow-up. Computerized statistical analysis of this data was performed using Fisher’s exact probability test. RESULTS

The clinical characteristics of the patients studied are presented in Table 1. The mean age of the patients was 60 years (range 28-78 years) and the mean gravidity was 3 (range O-9). Twenty patients were white and two were black. The most common site of disease was the labia majorum (14 pts.), followed by the labia minorum (6 pts.), and perineum (2 pts.). Lesion size ranged from 1.0 to 2.0 cm in diameter (mean 1.6 cm). The mean depth of tumor invasion was 2 mm (range 0.7-4.0 mm). Sixteen patients had well-differentiated (gl) tumors, 4 patients had moderately differentiated (g2) tumors,

EARLY

VULVAR

45

CANCER

SUPERFICIAL

SAPHENOUS

V

FIG. 1. Wide local excision removed are above the cribriform

with ipsilateral fascia.

superficial

lymph

node

dissection.

Lymph

nodes

and 2 patients had poorly differentiated (g3) tumors. Lymphoplasmacytic infiltrate was minimal (1 +) in 10 tumors, moderate (2 + ) in 6 tumors, and marked (3 + ) in 6 tumors. Lymph-vascular space invasion was present in 3 patients and perineural invasion in 2 patients (Fig. 2). No patient had both lymph-vascular space and perineural invasion. Of the 22 patients studied, only 2 (9%) had lymph node metastases. One patient was a 33-year-old white female with a well-differentiated squamous cell carcinoma, 1.5 cm in diameter, involving the labia majorum. This tumor invaded the stroma to a depth of 3.1 mm and a moderate lymphoplasmacytic infiltrate was present. The second patient with lymph node metastases was a 69-year-old white female with a l.O-cm in diameter well-differentiated squamous cell carcinoma of the labia majorum. This tumor had invaded the stroma to a depth of 2.25 mm and a marked lymphoplasmacytic infiltrate was present. Perineural invasion was present in both of these tumors but neither had identifiable lymph-vascular space invasion.

PATIENT

Age (years) &avidity Height (inches) Weight (pounds)

TABLE 1 CHARACTERISTICS

Mean

Range

60 3 64 145

28-78 o-9 58-69 98-236

46

ROWLEY

ET AL.

FIG. 2. Perineural space invasion is illustrated by a group of large hyperchromatic tumor cells (arrow) within a space immediately adjacent to a paler staining peripheral nerve. (Hematoxylin and eosin. X 528).

Both patients were found to have a single positive ipsilateral superficial inguinal node and therefore contralateral superficial and bilateral deep inguinal lymph node dissections were performed. No additional lymph node metastases were noted in the surgical specimens from these cases and no further therapy was given. These patients are alive and well with no evidence of disease 5 and 26 months following therapy. The relationship of various histomorphologic parameters to lymph node metastases is presented in Table 2. Lymph node metastases were present in both patients with perineural invasion (100%) and were absent in all patients without this finding (P < 0.01). However, tumor grade, depth of stromal invasion, lymphvascular space invasion, and lymphoplasmacytic infiltrate were not predictive of lymph node metastases in this series of patients. Two of the 22 patients in this investigation developed recurrent vulvar neoplasia. Both were initially treated with wide local excision and ipsilateral superficial inguinal lymph node dissection. The margins of the vulvectomy specimens were free of disease in both cases. One patient developed vulvar carcinoma in situ 1 year after surgery and the other patient developed a small, superficially invasive (2.0 mm) vulvar carcinoma 6 months after primary therapy. In both patients, tumor occurred on the contralateral vulva and was treated with local excision. Both are currently alive without evidence of further disease 20 and 36 months

EARLY

VULVAR

TABLE PROGNOSTIC

PARAMETERS

RELATED

47

CANCER

2 TO LYMPH

NODE

METASTASIS

Positive nodes Prognostic parameters Grade 1 2 3

No. of patients 16 4 2

No. 2 0 0

7%of total

0% 0%' P 2

Depth of invasion <3 mm 3-5 mm

0.05

6% 25%

18 4

P 2 0.05 Lymphoplasmacytic Mild Moderate Marked

infiltrate IO

6 6

0 1

0%

17% 17% P a 0.05

Lymph-vascular Negative Positive

space invasion 19 3

2 0

11% 0%

P 2 0.05 Perineural invasion Absent Present

20 2

0 2

5% 100%

P < 0.01

following therapy. None of the histologic parameters studied, including tumor differentiation, depth of invasion, lymphoplasmacytic infiltrate, perineural invasion, or lymph-vascular space invasion, were statistically predictive of tumor recurrence in these patients. DISCUSSION

Radical vulvectomy combined with inguinal lymphadenectomy has been considered the treatment of choice for patients with invasive squamous cell carcinoma of the vulva since the work of Taussig and Way three decades ago [8,9]. More recently, the use of adjunctive supportive techniques such as prophylactic antibiotics, low dose heparin, inguinal suction drains, and sartorius muscle transposition have markedly reduced the morbidity and mortality associated with this procedure. Nevertheless, distortion of body image and impaired sexual function remain a consequence of this radical surgical approach. This, in combination with a trend toward occurrence of vulvar neoplasia in younger patients, has led to a major effort to identify those patients with early invasive vulvar cancer who can be treated with a less radical surgical procedure without diminishing prognosis

[lOI. In 1971, Franklin and Rutledge reported the absence of inguinal lymph node metastases or recurrence in 21 patients with small vulvar carcinomas invading

48

ROWLEY

ET

AL.

the stroma to a depth of 5 mm or less [l 11. Likewise, Wharton and co-workers reported a lack of lymph nodal metastasis in a series of 25 patients with vulvar cancers having less than 5 mm of stromal invasion [2]. These authors questioned the value of routine lymphadenectomy in this subset of patients with “microinvasive” disease. Since these initial reports, however, numerous investigators have reported the presence of inguinal lymph node metastases in up to 36% of patients with small vulvar lesions and early stromal invasion [3-71. Therefore, much effort has been directed toward the identification of histologic features in addition to lesion size and stromal invasion, which may help predict regional lymph node metastasis. Parker and co-workers, for example, reported that the presence of tumor cells in lymph-vascular spaces was associated with an increased incidence of lymph node metastases in patients with early invasive vulvar cancer [4]. The prognostic importance of lymph-vascular space invasion was confirmed by Donaldson and co-workers [ 121. In this series of 38 patients with variable lesion sizes and stromal invasion ~5.0 mm, 84% of patients with lymph-vascular space invasion had inguinal lymph node metastases compared to an absence of nodal metastases in patients without this finding (P < .05). Similarly, the presence of a confluent pattern of tumor infiltration, a poorly differentiated tumor, and a lack of lymphoplasmacytic infiltrate have all been associated with metastases in patients with early stromal invasion [4,6,13]. The findings of the present investigation suggest that perineural invasion is also associated with lymph node metastases even if present in patients with minimal stromal invasion and no apparent lymphvascular space invasion. DiSaia and co-workers were the first to recommend the use of wide local excision with bilateral superficial inguinal lymphadenectomy as the initial surgical procedure in patients with early invasive squamous cell carcinoma of the vulva [ 141. This surgical approach limited superficial inguinal lymphadenectomy to those nodes above the cribriform fascia and replaced vulvectomy with wide excision of the primary lesion. Radical vulvectomy with bilateral deep inguinal lymphadenectomy was performed only in those patients having metastatic disease in the superficial inguinal lymph nodes. Data from the present investigation suggest that contralateral superficial inguinal lymphadenectomy may not be necessary in patients with early invasive squamous cell carcinoma of the vulva. None of the patients in this series had contralateral inguinal lymph node metastases, and the two patients who developed tumor recurrence were treated successfully with wide local excision. The findings of this investigation also confirm the conclusions of DiSaia and colleagues [14] that selected patients with early invasive vulvar cancer can be effectively treated with wide local excision and superficial inguinal lymphadenectomy. REFERENCES 1. Podratz, K. C., Symmonds, R. E., Taylor, W. F., and Williams, T. J. Carcinoma of the vulva: Analysis of treatment and survival, Obstet. Gynecol. 61, 63-67 (1983). 2. Wharton, J. T., Gallagher, S., and Rutledge, F. N. Microinvasive carcinoma of the vulva, Amer. .I. Obster. Gynecol. 118, 159-162 (1974).

EARLY VULVAR CANCER

49

3. Magrina, J. F. Microinvasive squamous cell cancer of the vulva, Presented to the Society of Gynecologic Oncology, Scottsdale. Arizona, January, 1979. 4. Parker, P. T., Duncan. I., Rampone, R., and Creasman, W. Operative management of early invasive epidermoid carcinoma of the vulva. Amer. J. Ubstet. Gynecol. 123, 349-355 (1975). 5. Dipaola, G. R., Gomez-Rueda, N., and Arrighi. L. Relevance of microinvasion in carcinoma of the vulva, Obstet. Gynecol. 45, 647-649 (1975). 6. Wilkinson. E. J., Rico, M. J.. and Pierson, K. K. Microinvasive carcinoma of the vulva. Int. J. Gynecol. Pathol. 1, 29-39 (1982). 7. Sedlis, A., Homesley, H.. Bundy, B. N., Marshall, R., Yordan. E.. Hacker. N., Lee, J. H., and Whitney, C. Positive groin lymph nodes in superficial squamous cell vulvar cancer, Anwr. J. Obstet. Gynrd. 156, 1159-l 164 (1987). 8. Way, S. Carcinoma of the vulva. Amer. J. Obstet. Gynceo/. 79, 692-697 (1960). 9. Taussig, F. J. Carcinoma of the vulva: An analysis of I55 cases (191 l-1949), Amer. J. Obstet. Gynecol. 40, 464-779 (1949). 10. Hughes. R. P. Early diagnosis and management of premalignant lesions and early invasive cancers of the vulva, South. Med. J. 64, 1490 (1971). Il. Franklin, E. W., and Rutledge, F. D. Prognostic factors in epidermoid carcinoma of the vulva. Obstet. Gynrcol. 37, 892-901 (1971). 12. Donaldson, E. S., Powell, D. E., Hanson, M. B.. and van Nagell, J. R., Jr. Prognostic parameters in invasive vulvar cancer, Gynecol. Ond. 11, 1X4-190 (1981). 13. Barnes, A. E.. Crissman. J. D.. Schellhas, H. F.. and Azoury, R. S. Microinvasive carcinoma of the vulva: A clinicopathologic evaluation, Obstet. Gynrd. 56, 234-238 (1980). 14. DiSaia, P. J., Creasman, W. T., and Rich, W. M. An alternate approach to early cancer of the vulva, Amer. J. Obstet. G.vrr~ol. 133, 825-832 (1979).