PROGNOSTIC FACTORS IN INVASIVE SQUAMOUS CELL CARCINOMA OF THE VULVA TREATED WITH SURGERY AND IRRADIATION

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1 Acta Oncologica 29 (990) Fasc. 7 FROM THE DEPARTMENTS OF GYNECOLOGICAL ONCOLOGY, UNIVERSITY HOSPITALS IN LINKOPING, UPPSALA AND UMEA, AND THE DEPARTMENT OF RADIOPHYSICS. UNIVERSITY HOSPITAL, UPPSALA, SWEDEN. PROGNOSTIC FACTORS IN INVASIVE SQUAMOUS CELL CARCINOMA OF THE VULVA TREATED WITH SURGERY AND IRRADIATION H. MALMSTROM, H. JANSON, E. SIMONSEN, S. STENSON and U. STENDAHL Abstract From 958 through 980, 3 women with invasive squamous cell carcinoma of the vulva were treated with vulvectomy. Postoperative irradiation was given with cobalt-60 beam or 0 MV photons from a linear accelerator from anterior fields including the vulva and groins, with the intention of delivering Gy with 2-4Gy/day at a depth of 0.5cm or 2cm. The overall corrected five-year survival rate was 68%. The prognosis was shown to worsen significantly with advancing stages (I/96%, II/75%, III/62% and IV/9%), increasing grades (G/78%, G2/ 70% and G3/22%) and increasing size of the tumor (T/90%, T2/7% and T3/37%), as it also did when there were signs of vascular invasion, multifocal tumors or positive nodes in the inguinal regions. Recurrences were diagnoses in 32% of the patients. With the less aggressive surgical approach used, combined with radiation therapy to eradicate subclinical disease, the morbidity rate was acceptable and the survival rate comparable to that reported after more aggressive surgery. Key words: Vulva cancer, prognostic factors, vulvectomy, irradiation. Cancer of the vulva accounts for 0.9% of all gynaecological cancer in Sweden according to the Cancer Registry (). Invasive cancer of the vulva has been considered typical of the elderly woman. In the last decade, however, the incidence of invasive and preinvasive cancer of the vulva has increased in younger women. Treatment of cancer of the vulva is still controversial and prognostic factors such as tumor extent, histologic grade and age have to be considered when planning treatment. In our department we no longer perform ultraradical surgery but combine simple vulvectomy with adjuvant radiotherapy. This treatment has been made possible by a modern radiation technique which has the potential to eradicate minimal residual disease locally and regionally without causing severe side effects. The purpose of this study is to evaluate the results of simple vulvectomy in combination with adjuvant radiotherapy of the inguinal and pelvic regions considering prognostic factors. Material and Methods During the period 958 to 98, 3 patients with invasive squamous cell carcinoma of the vulva (ISCCV) were treated at the Department of Gynecological Oncology, University Hospital, Uppsala, Sweden. Of 36 cases with vulvar cancer, 3 patients had ISCCV and they constitute the basis of this report. The patients were retrospectively classified according to the FIG0 criteria. Only those in ISCCV stages I to IV were included in the statistical calculations. There were 27, 45, 33 and 8 patients in these four stages respectively. The patients were divided into three subgroups according to tumor size; T < 2 cm, T2 > 2 cm but <5 cm, and T3 > 5 cm in diameter. Forty-nine had well, 49 patients moderately and 5 patients poorly differentiated tumors. In 85% of the cases a simple vulvectomy was performed, which included the lower part of mons pubis, the clitoris, the labia and the vestibulum. Eight patients underwent inguinal node dissection. As fine-needle biopsy or extirpation of the inguinal glands was not performed in most cases, the clinical staging was not microscopically verified. A histopathologic malignancy grading system was used with 8 histologic parameters, each graded in to 3 points, to evaluate the biologic character of the tumor. The tumor cell population and the tumor-host relationship were considered separately. The evaluation of the Accepted for publication 3 January

2 96 H. MALMSTROM ET AL tumor cell population was based on the grading of cell differentiation, structure, nuclear polymorphism and the frequency of mitotic figures in terms of a to 3 point scale. The tumor-host relationship was also estimated in terms of a to 3 point scale by mode of invasion, stage of invasion, vascular invasion and degree of lymphoplasmocytic infiltration. These 8 morphologic parameters permitted a grading with 8 to 24 points totally (2). With survival at 5 years as endpoint the predictive value of all parameters was tested. Seventy-three percent of the patients were treated with a field restricted to the vulva and two anterior fields to the groins, using a cobalt-60 unit, 75 cm SSD. Both inguinal regions were irradiated daily for 5 days a week. This technique was used to deliver 40 to 52 Gy with 4 Gy daily at a depth of 0.5 cm. The dose decreases with depth and with 52 Gy delivered at the surface the doses abssorbed at locm depths and the corresponding CRE values were 29. Gy and 40 reu. Eight patients were treated with a butterfly-shaped field perpendicular to the vulvar region and tilted 30" in the cranial direction. External 0 MV photon irradiation was delivered by a linear accelerator and dose distributions were calculated with a Siemens Si dose-42 dose planning system. This technique was used to deliver either 40 Gy or 52 Gy in different daily doses. The absorbed dose and corresponding CRE values at 0 cm depth with a surface dose of 52 Gy were 37.4 Gy and 50 reu. In 9 patients bleomycin, 5 mg every day for two weeks, was given as adjuvant therapy simultaneously with irradiation. Statistical analysis was performed using the actuarial life-table method. Survival times were calculated from the onset of definitive therapy. In the survival curve, patients dying from intercurrent disease were censored. The material was analyzed at the Uppsala Computer Center (UDAC). Results The number of patients and the 5-year survival rate according to the stage, grade, tumor size, age, involvement of inguinal nodes and multiple sites of origin, are presented in the Table. The overall 5-year survival rate for ISCCV, corrected for mortality due to intercurrent disease, was 68% (Fig. ). A 5-year survival rate of 96% was obtained in 30 stage I patients. In stages, I and IV, the corresponding figures were 75%, 62% and 9% (Fig. 2). The mean age of the patients at the time of surgery was 70 years. Women over 70 had a poorer outcome than younger women: 50% and 72% respectively (Fig. 3). Forty-nine patients with well differentiated tumors had a survival rate of 78%, 49 patients with moderately differentiated tumors had a 70% survival rate and 5 patients with poorly differentiated tumors a survival rate of 22% in 5 years 40- Table Five-year survival rate according to main risk factors in primary invasive squamous cell carcinoma of the vulva for the series Characteristics n 5-year survival (YO) Stage I I IV Grade 2 3 Tumor size TI T2 T3 Age <70 years 70 years Single lesion 6 76 Multifocal lesions Positive nodal findings Negative nodal findings (Fig. 4). Nodal involvement was present in 8%, to 23% and 44% in well, moderately and poorly differentiated tumors respectively. Of 3 patients with ISCCV only 38 patients were clearly eligible in the malignancy grading system, since all histological parameters could not be classified in all specimens or else since the original slides were unobtainable from the referring hospital. In these 38 patients, vascular invasion and cellular response were significant predictive parameters, as reported earlier (2). 20. i I Fig.. Crude survival rate in the total material of cancer of the vulva compared to survival in general population.

3 ~ Grade CARCINOMA OF THE VULVA \ 6-0 Stage Ill <2 crn >2 crn L Fig. 2. Survival curves according to clinical stages in 3 patients with cancer of the vulva. (Life-table technique with correction for intercurrent death.) 8ol \- 6o I 0 < 70 years a70 years Years Fig. 3. Survival curves according to age ( < 70 years, > 70 years) in 3 patients with cancer of the vulva. 80 Grade 3 I I Fig. 4. Survival curves according to histological differentiation in 3 patients with cancer of the vulva. 2ol 0 i 5 i Years Fig. 5. Survival curves according to tumor size in 3 patients with cancer of the vulva. Tumor size was a prognostic factor, with a survival rate of 90% in tumors with a diameter of less than 2cm. T2 and T3 tumors had a 5-year survival rate of 7% and 37% respectively (Fig. 5). Nodal involvement correlated with tumor size and was present in 5% of T tumors, 4% of T2 and 40% of T3 tumors. To determine whether the primary lesion, disregarding the stage or differentiation of the tumor, had any influence on survival, the material was divided into cases with single primary tumors and tumors with multiple foci. The 5-year survival rates were 76% and 57% respectively. The presence of positive nodes in the inguinal regions significantly influenced the survival rate. Patients with nodal spread had a 5-year survival rate of 26%, compared to 78% in patients without clinically positive nodes. Recurrences were diagnosed in 32% of the patients. Ten percent of the patients who were given radiotherapy had local recurrences. The recurrences were located in the vulva in 27.9% (vulva only in 9.3%), left inguinal region 23.2%, right inguinal region 32.6% and inguinal region without growth in the vulva 2.3%. Forty-nine percent of the recurrences developed within the first year and 78% within the first two years after diagnosis. Seven patients had a second recurrence within 2 months after treatment of the first recurrence. At the conclusion of this study, 32.7% of the patients showed no evidence of disease, 3.8% had died of the disease, and of these 30% died within the first year after diagnosis. Postoperative infections were recorded in 22.3%, problems with the suture in.8% and leukocytopenia in 0.7% of the cases. No severe radiation injury was recorded. None of the patients died as a result of the treatment. Discussion Helgason et al. (3) in their study from 972 considered radiotherapy obsolete in the management of vulvar cancer due to discouraging results and severe irradiation injuries.

4 98 H. MALMSTROM ET AL However, in the last decades the experience in radiotherapy of vulvar cancer has increased with several reports of high survival rate after a combination of surgery and megavoltage irradiation (4-9). Parallel to this development, the enthusiasm for an aggressive surgical approach has faded because of the high risk of postoperative complications in these often poor risk patients. The postoperative mortality rates in major studies range from 2% to 2% after radical surgery, with even higher figures after excessive surgery (0-4). In cases with pelvic metastases the survival after pelvic lympadenectomy is poor due to disseminated disease (5). Several published reports also indicate that early invasive cancer of the vulva may be treated effectively without removal of nodes in the inguinal or pelvic regions, providing prognostic factors are considered (2, 6-23). DiSaia et al. (24) recommend wide local excision of early tumors of the vulva, preserving the mons veneris and clitoris in patients with tumors less than 2 cm and focal invation limited to 5mm. Radical surgery is performed only if superficial inguinal nodes are positive. Iversen et al. (3) and Hacker et al. (8) recommend an individualized treatment of stage I vulvar cancer with hemivulvectomy with ipsilateral inguinal lymphadenectomy in most cases. Pelvic lymphadenectomy does not seem to influence the prognosis. Patients with metastases in the inguinal nodes may benefit from high voltage irradiation of the inguinal region and the pelvic lymph nodes (3, 3, 7). Homesley et al. (20) showed in a randomized prospective study that the addition of adjunctive groin and pelvic radiation therapy after radical vulvectomy and inguinal lymphadenectomy was superior to pelvic node resection. The postoperative irradiation used in the present material is probably adequate for eradication of subclinical or metastatic disease in the inguinal lymph nodes. Edema after dissection of inguinal lymph nodes is a problem in up to 70% of all patients (25). These are the reasons why we have been restrictive over the last 0 to 5 years in surgical interventions in the inguinal region and the pelvis, especially in elderly patients with poor general health. There was no postoperative mortality in the present material. Edema of the inguinal region did not occur and the morbidity rate was low after surgical treatment of the primary tumor in combination with adjuvant radiotherapy of the inguinal and pelvic lymph nodes. With this combined treatment, the quality of life in most cases did not seem to deteriorate and the overall 5-year survival of 68% is comparable to the survival reported by Bartholdson et al. (lo), Iversen et al. (3), Kucera et al. (26) and Morley et al. (27). Age, stage, histologic differentiation, tumor size, involvement of inguinal nodes, multiple size of origin, vascular invasion and cellular response were found to be prognostic factors in this series. Iversen et al. (3) found statistical significant differences in survival between the individual stages. This is in agreement with our findings. Many of the elderly patients in our population were suffering from other medical conditions such as hypertension, diabetes, adipositas and heart diseases, constituting a group with poor general health, and 29% of the patients died from intercurrent disease, although most of them had an early stage disease. The 5-year survival rate was considerably lower in patients over 70 (50%) than in patients below this age (72%). Several authors have shown a strong correlation between lymph node involvement and survival. In the study by Hoffman et al. (2), size and number of nodal metastases were found to be of predictive value and correlated with tumor grade. Metastatic involvement of inguinal lymph nodes is significantly correlated with tumor size and differentiation (20). In the present study, TI tumors had nodal involvement in 5% whereas the incidence was 40% in T3 tumors. Inguinal lymph node metastases reduced the chance of 5-year survival from 78% to 26%. Several attempts have been made to select treatment modality according to histopathologic grading of tumor specimens. At the Department of Tumor Pathology of Radiumhemmet, Stockholm, an attempt has been made to classify squamous cell carcinoma of the palate. A similar system has been applied on squamous cell carcinoma of the cervix (29) and vulva (2, 30, 3). In the present study these principles were applied to the classification of invasive squamous cell carcinoma of the vulva, to improve the histopathologic evaluation of biopsy specimens. The present malignancy grading system was adopted and modified by Stendahl et al. (29) in 979 on squamous cell carcinoma of the uterine cervix. Kabulski & Frankman (30, 3) using the same system in vulvar cancer found vascular invasion as the only factor discriminating different prognostic groups. They recommended a less radical vulvectomy in stages I and I patients with a histologic malignancy value not exceeding 4 points. In this retrospective investigation it was difficult to draw any definite conclusions as only 38 out of 3 patients with ISCCV were evaluable. Tumor size appears to be a significant prognostic factor. Tumors less than 2cm in diameter had a high survival rate, viz 90%. Survival decreased with increasing tumor diameter. Multifocal lesions had a 5-year survival rate of 57% compared to 76% for single lesions. The majority of recurrences developed within the first two years. Most of the recurrences were localized to the vulva. Only 2.3% of the recurrences were located to the inguinal region indicating a sufficient adjuvant radiotherapy to these regions in most of the patients. In conclusion, adjunctive radiotherapy seems to effectively reduce the risk of lymph node or local recurrence and to be a good alternative to more extensive surgery. The morbidity rate is low and the survival rate acceptable compared to that reported after more extensive surgery (3). The treatment of squamous cell carcinoma of the vulva should preferably be differentiated with consideration of

5 CARCINOMA OF THE VULVA 99 prognostic factors. Strong predictors of outcome are tumor size, nodal involvement, tumor grade and patient age. Surgery is the mainstay of therapy in combination with radio- and/or chemotherapy. Knowledge of clinical and histologic parameters may help to identify prognostic subgroups in order to optimize therapy in individuals. ACKNOWLEDGEMENTS The authors wish to thank Dr. A. Lindgren for reviewing the vulvar biopsy specimens. Request for reprints: Dr Henric Malmstrom. Department of Gynecological Oncology, University Hospital, S Linkoping, Sweden. REFERENCES I. National Board of Health and Welfare. The cancer register. Cancer incidence in Sweden 979. The Swedish Cancer Register, Stockholm, Malmstrom H, Lindgren A, Stendahl U. A histopathologic malignancy grading system for indication of prognosis in invasive squamous cell carcinoma of the vulva. Nordisk Forening Gynekologi Obstetrik, Odense, Helgason NM, Hass AC, Latourette HB. Radiation therapy in carcinoma of the vulva: A review of 53 patients. Cancer 972; 3: Boidi A, Tardy A, Burke P, Tomassone W. Results of treatment with fast electrons in 24 patients with carcinoma of the vulva. Minerva Ginecol 980; 32: Daly JW, Million RR. Radical vulvectomy combined with elective node irradiation for Tx NO squamous carcinoma of the vulva. Cancer 974; 34: Fairey RN, McKay PA, Benedet JL. Boyes DA, Turko M. Radiation treatment of carcinoma of the vulva, Am J Obstet Gynecol 985; 5: Fletcher GH. Elective irradiation of subclinical disease in cancers of the head and neck. Cancer 972; 29: Miyazawa K, Nori D, Hilaris BS, et al. Role of radiation therapy in the treatment of advanced vulvar carcinoma. Reprod Med 983; 28: Simonsen E. Malignant tumors of the vulva (Dissertation). Lund, Bartholdson L, Eldh J, Eriksson E, Peterson LE. Surgical treatment of carcinoma of the vulva. Surg Gynecol Obstet 982; 55: Brunschwig A, Daniel W. Pelvic exenterations for advanced carcinoma of the vulva. Am J Obstet Gynecol 956; 72: Cavanagh D, Roberts WS, Bryson SC. Marsden DE, Ingram JM, Anderson WR. Changing trends in the surgical treatment of invasive carcinoma of the vulva. Surg Gynecol Obstet 986; 62: lversen T, Aalders JG. Christensen A, Kolstad P. Squamous cell carcinoma of the vulva: A review of 424 patients Gynecol Oncol 980; 9: Rutledge FN, Smith, JP, Wharton JT, O Quinn AG. Pelvic exenteration: analysis of 296 patients. Am J Obstet Gynecol 977; 29: Andreason B, Nyboe J. Value of prognostic parameters in squamous cell carcinoma of the vulva. Gynecol Oncol 985; 22: Boyce J. Fruchter RG, Kasambilides E, Nicatstri AD, Sedlis A, Remy JC. Prognostic factors in the carcinoma of the vulva. Gynecol Oncol 985; 20: Frankendal B, Larsson L-G, Westling P. Carcinoma of the vulva. Results of an individualized treatment schedule. Acta Radio Ther Phys Biol 973; 2: Hacker NF, Berek JS, Lagasse LD, Nieberg RK, Leuchter RS. Individualization of treatment for stage I squamous cell vulvar carcinoma. Obstet Gynecol 984; 63: Hacker NF, Berek JS, Lagasse LD, Leuchter RS, Moore JG. Management of regional lymph nodes and their prognostic influence in vulvar cancer. Obstet Gynecol 983; 6: Homesley HD, Bundy B, Sedlis A, et al. Radiation therapy versus pelvic node resection for carcinoma of the vulva with positive groin nodes. Obstet Gynecol 986; 68: Hoffman JS, Kumar NB, Morley GW. Prognostic significance of groin lymph node metastases in squamous cell carcinoma of the vulva. Obstet Gynecol 985; 66: Kurzl R, Messerer D. Prognostic factors in squamous cell carcinoma of the vulva : A multivariate analysis. Gynecol Oncol 989; 32: Shimm DS, Fuller AF, Orlow EL, Dosoretz DE, Aristizabal SA. Prognostic variables in the treatment of squamous cell carcinoma of the vulva. Gynecol Oncol 986; 24: DiSaia PJ, Creasman WT, Rich WM. An alternative approach to early cancer of the vulva. Am J Obstet Gynecol 979; 33: Rodratz KC, Symmonds RE, Taylor WF. Carcinoma of the vulva: Analysis of treatment failures. Am J Obstet Gynecol 984; 43: Kucera H, Weghaupt K. The electrosurgical operation of vulvar carcinoma with postoperative irradiation of inguinal lymph nodes. Gynaecol Oncol 988; 29: Morley GW, Lindenauer SM, Cerny JC. Pelvis exenterative therapy in recurrent pelvic carcinoma. Am J Obstet Gynecol 97; 79: Eneroth CM, Moberger G. Histological malignancy grading of squamous cell carcinoma of the palate. Acta Otolaryngol (Stockh) 973; 75: Stendahl U. A histopathologic malignancy grading system for indication of prognosis in invasive squamous cell carcinoma of the uterine cervix (Dissertation). Uppsala, Kabulski Z, Frankman 0. Histologic malignancy grading in invasive squamous cell carcinoma of the vulva. Int J Gynaecol Obstet 978; 6: Frankman 0, Kabulski Z. Malignancy grading and prognosis from a biopsy only in cases of electrocoagulated squamous cell carcinoma of the vulva, stages I and. Int J Gynaecol Obstet 983; 2: 9-24.