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LONG-TERM FOLLOWUP OF PENILE CARCINOMA TREATED WITH PENECTOMY AND BILATERAL MODIFIED INGUINAL LYMPHADENECTOMY
0022-5347/04/1722-0498/0 THE JOURNAL OF UROLOGY® Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 172, 498 –501, August 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000132239.28989.e1
LONG-TERM FOLLOWUP OF PENILE CARCINOMA TREATED WITH PENECTOMY AND BILATERAL MODIFIED INGUINAL LYMPHADENECTOMY CARLOS ARTURO LEVI D’ANCONA, ROBERTO GONC ALVES DE LUCENA, ´ RIO HENRIQUE TAVARES MARTINS, FERNANDO AUGUSTO DE OLIVEIRA QUERNE, MA FERNANDES DENARDI AND NELSON RODRIGUES NETTO, JR. From the Division of Urology, Faculdade de Cieˆncias Me´dicas da Universidade Estadual de Campinas, Sa˜o Paulo, Brazil
ABSTRACT
Purpose: We evaluated modified inguinal lymphadenectomy in the treatment of penile carcinoma, analyzing the rate of complications compared to complete inguinal lymphadenectomy, the complications in performing lymphadenectomy and penectomy concomitantly, and the long-term locoregional recurrence rate. Materials and Methods: A total of 26 patients with squamous cell carcinoma of the penis were clinically assessed, and underwent penectomy and bilateral modified inguinal lymphadenectomy at the same operative time. Frozen section analysis of lymph nodes was performed and if metastases were detected a complete ipsilateral inguinal dissection was performed. Results: A total of 52 modified lymphadenectomies were performed. In 10 procedures lymph node metastasis was present. Clinical staging presented false-positive and false-negative rates of 50% and 7.9%, respectively. The complication rate for modified lymphadenectomy was 38.9% and for complete inguinal lymphadenectomy it was 87.5%. Followup ranged from 5 to 112 months and mean followup of recurrence-free cases was 78 months (range 38 to 112). A total of 18 patients underwent bilateral negative modified inguinal lymphadenectomy and 2 of these experienced locoregional recurrence within 2 years after surgery. Conclusions: Modified inguinal lymphadenectomy causes a lower complication rate than complete inguinal lymphadenectomy. Bilateral modified inguinal lymphadenectomy performed at the same time as penectomy does not increase the complication rate. When frozen section analysis is negative bilaterally, 5.5% of inguinal regions might still harbor occult metastasis. Modified inguinal lymphadenectomy is recommended as a staging procedure in all patients with T2–3 penile carcinoma. A straight followup is required for 2 years since all recurrence was within this period. KEY WORDS: penile neoplasms, lymph node excision, neoplasm metastasis, lymphatic metastasis
Squamous cell carcinoma (SCC) accounts for more than 95% of primary malignant penile neoplasia.1 SCC of the penis is characterized by an essentially locoregional involvement affecting the inguinal, pelvic and periaortic lymph nodes. Hematogenic dissemination is rare even with the invasion of the corpora cavernosa and the rate of distant metastasis ranges from 1% to 10%.2 This makes penile carcinoma one of the few urological malignancies potentially curable with regional lymphadenectomy.3 In patients presenting with SCC of the penis 30% to 60% have palpable lymph nodes in the inguinal region.2, 3 In 50% of these patients this condition is caused by metastatic involvement and in the other half by inflammatory reactions.4 Therefore, clinical staging is not a reliable parameter for guiding treatment. Patients with stage T2–3 penile SCC should undergo inguinal lymphadenectomy regardless of whether lymph nodes are palpable.5 However, in 60% of cases no lymph node metastases are found in the resection specimen.6 These patients underwent unnecessary node dissection and were exposed to the well-known morbidity of the procedure. Knowledge of pelvic and inguinal lymph node anatomy as well as the preferred drainage path of penile tumors stimulated the development of various surgical techniques for greater effectiveness with decreased morbidity.7, 8 Studies Accepted for publication February 27, 2004.
conducted on inguinal lymphadenectomy involving the preservation of the saphenous vein and restricting resection medial to the femoral vessels (modified lymphadenectomy) demonstrated a significant decrease in morbidity, but since locoregional recurrence rates varied is not clear whether local control of the disease might be attempted.9 –11 We assessed the incidence of complications secondary to modified lymphadenectomy and, compared with complete inguinal lymphadenectomy, verified whether the concomitant performance of lymphadenectomy and penectomy increased complications. We analyzed the long-term locoregional recurrence rate to evaluate the results of modified inguinal lymphadenectomy in the treatment of penile carcinoma.
PATIENTS AND METHODS
There were 26 patients who presented with squamous cell carcinoma of the penis between 1994 and 1999 and were included in this study. Patient age ranged from 44 to 94 years (mean 62, median 63). The patients were referred to the Urology Division after a disease onset that ranged from 2 to 70 months (mean 14, median 8). The criteria for exclusion from study were poor clinical conditions for surgery, presence of distant metastasis, ulcerated inguinal metastasis, previous oncological treatment involving radiotherapy and/or chemotherapy, unresectable primary tumor, previous surgery of
498
499
LONG-TERM FOLLOWUP OF MODIFIED INGUINAL LYMPHADENECTOMY FOR PENILE CARCINOMA
inguinal nodes, patients with stage T1, carcinoma in situ and verrucous carcinoma. The clinical examination consisted of detailed palpation of the penile shaft to verify the extent of the disease and palpation of the inguinal regions for lymph node assessment. The lymph nodes were considered clinically positive when palpable, fixed to the superficial or deep planes. Cases without any of these characteristics were considered N0. To assess the possibility of distant metastasis, chest x-ray and computerized tomography of the abdomen and pelvis were done. Clinical staging was performed using the 1988 TNM system.12 All patients underwent penectomy and modified inguinal lymphadenectomy at the same operative time. Antibiotic prophylaxis with cefazolin was introduced during anesthetic induction and continued for 7 days. Low molecular weight heparin was administered as prophylaxis for deep venous thrombosis and maintained for 48 hours. An extremity compression hose was prescribed for all patients. Treatment for the penile lesion followed the principle of complete tumor resection with a 2 cm minimum macroscopic safety margin and a histopathological assessment (frozen section) of the incision margins that confirmed absence of neoplasia in the remaining penile stump. Total penectomy associated with perineal ureterostomy was chosen when tumor resection would leave a penile stump smaller than 2 cm. All patients underwent bilateral modified inguinal lymphadenectomy.8 A 5 cm skin incision was made 2 cm below the inguinal arcade along the femoral vessels. The adipose and lymphatic tissues below Scarpa’s fascia were resected en bloc with the adductor longus muscle as the medial border, the medial surface of the femoral and saphenous veins as the lateral border, and the inguinal arcade as the superior border, performing a triangle (see figure). Frozen section analysis of lymph nodes was performed and if metastases were absent, the procedure was concluded and an aspirative drain
was maintained for at least 5 days. When metastases were detected an ipsilateral complete inguinal lymphadenectomy was performed. In followup special attention was given to the inguinal region and the penile stump to verify if there were any nodes or indurations. Followup was performed every 3 months in the year 1, every 6 months in year 2 and then once yearly. RESULTS
There were 26 patients with squamous cell carcinoma of the penis who underwent penectomy and concomitant bilateral modified inguinal lymphadenectomy. The number of inguinal regions was considered in this study and involved a total of 52 lymphadenectomies. The preoperative clinical examination revealed palpable lymph nodes in 10 patients (38.4%), 4 of whom had bilateral adenopathy, totalling 14 (27%) inguinal regions. The modified inguinal lymphadenectomy was negative for metastasis in 42 (81%) procedures. It was bilaterally positive in 2 (7.7%) patients and bilaterally negative in 18 (69%). No significant difference was observed in the number of lymph nodes evaluated in patients with or without lymph node metastasis (6.5 and 5.4, respectively). Preoperative clinical staging presented false-positive and false-negative rates of 50% and 7.9%, respectively, considering the anatomopathological results of modified lymphadenectomy as a standard (table 1). The false-positive and false-negative rates obtained in our study were 50% (7 of 14) and 13% (5 of 38), respectively, considering 3 patients at surgery and 2 others at followup. There were 8 patients whose frozen section biopsy was positive and who underwent complete inguinal lymphadenectomy that was bilateral in 2. In all cases the anatomopathological analysis of the nodal packet from the complete lymphadenectomy revealed no metastasis. In 17 cases the penile tumors were well differentiated, in 8 they were moderately differentiated and undifferentiated in 1. There was a higher rate of positive lymph nodes in the patients with well differentiated tumors but the difference was not statistically significant. Complications were classified as minor and major. Minor complications included skin edge necrosis requiring no therapy, seroma formation not requiring aspiration and lymph drainage. Major complications consisted of lymphedema interfering with ambulation. The minor complication rate for patients who underwent modified lymphadenectomy and penectomy was 36.8%, while in complete lymphadenectomy it was 87.5% (p ⬍0.05). Major complications occurred in 37.5% of patients who underwent complete inguinal lymphadenectomy and were absent in those who underwent modified inguinal lymphadenectomy (table 2). Followup ranged from 5 to 112 months. Mean followup of recurrence-free cases was 78 months (range 38 to 112). One patient was lost to followup after 38 months, he was free from disease and the last clinical evaluation was considered final. Four patients died of causes unrelated to the disease, and they were all free from disease at the last clinical evaluations at 38, 50, 58 and 70 months. Among the 8 patients who underwent complete inguinal lymphadenectomy 3 (37.5%) experienced locoregional recurrence at 5, 8 and 11 months, and died of disease progression.
TABLE 1. Comparison between clinical and surgical staging Surgical
Limits of modified inguinal lymphadenectomy. a, lateral margin– saphenous and femoral vein. b, superior margin–inguinal ligament. c, median margin–adductor longus muscle.
Clinical: Pos Neg Totals
No. Pos (%) 7 3 (7.9) 10 (19.2)
No. Neg (%)
No. Total (%)
7 (50) 35
14 (27) 38 (73)
42 (80.8)
52 (100)
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LONG-TERM FOLLOWUP OF MODIFIED INGUINAL LYMPHADENECTOMY FOR PENILE CARCINOMA
TABLE 2. Complications of modified and complete inguinal lymphadenectomy Minor Complication Rate (%)
Major Complication Rate (%)
Modified inguinal lymphadenectomy: Seroma 26.3 Lymph drainage 10.5 Complete inguinal lymphadenectomy: Seroma 37.5 Lymph drainage 12.5 Skin flap necrosis 37.5
Lymphedema 37.5
One case of recurrence in the retroperitoneal lymph nodes was detected by computerized tomography and confirmed by needle biopsy, 1 was in the inguinal area and another in the perineum. The procedure was curative in the other patients who were free of disease at a mean followup of 79 months (range 66 to 112). Of the 18 patients who underwent negative bilateral modified lymphadenectomy, locoregional recurrence developed in 2 at 15 and 16 months of followup, 1 in the upper part of the modified lymphadenectomy area and the other out of this area. Both patients underwent resection of the metastases but died of disease progression. DISCUSSION
Due to the significant prognostic importance of inguinal lymph node involvement in squamous cell carcinoma of the penis, correct staging and, consequently, appropriate treatment of the inguinal lymph nodes are primordial factors in the treatment of this disease.13 Clinical staging obtained with physical examination and imaging modalities cannot reliably confirm the presence or absence of lymph node metastasis.2, 7 Clinical staging presents a false-positive rate of 50%2, 14 that would result in a high number of unnecessary surgeries, and a false-negative rate between 10% and 15%2, 15 that would leave an unacceptable number of patients without adequate treatment. The false-positive and false-negative rates obtained in our study were 50% (7 of 14) and 13% (5 of 38), respectively, considering 3 patients after surgery and another 2 at followup. Our results were similar to those found in the literature. These data reveal the need for a more effective method to indicate lymph node involvement in patients with SCC of the penis. Ultrasonographically guided fine needle aspiration biopsy of lymph nodes has been suggested as the first investigation in clinically node positive and node negative cases. Obviously the result is only reliable when positive and the falsenegative rates attain 15% in clinically node positive cases.14, 16 In many patients the biopsy needs to be repeated, causing anxiety and delay in treatment. Research on dynamic sentinel node biopsy using lymphoscintigraphy has indicated a potential benefit in selecting patients for lymphadenectomy. Promising results have been obtained but further studies are necessary to establish the applicability of this method.17 In this study early modified lymphadenectomy was performed in all patients, allowing pathological staging and concomitant treatment when necessary. Despite the failure of 5.5% of procedures in 11% of patients this staging method is comparable to other diagnostic methods. Studies conducted in patients with carcinoma of the penis and no palpable lymph nodes showed that those who underwent early inguinal lymph node dissection presented a significantly higher survival rate than those treated with surveillance and salvage lymphadenectomy when nodes became palpable.18 Early inguinal lymphadenectomy is criticized for the high complication rates and that many patients undergo unnecessary surgeries. Modified inguinal lymphadenectomy was performed in this study and only minor complications were observed (36.8%), acceptable even for patients without lymph node involvement. Surgical complications of complete
inguinal lymphadenectomy occur in more than half the cases and vary between 50% and 84%.19 Modified lymphadenectomy is associated with lower morbidity and the rate of minor complications is 33% to 44%.10, 11 The minor complication rates in this study were similar to those found in the literature. Modified inguinal lymphadenectomy presented a complication rate of 36.8%, which was significantly lower (p ⬍0.05) than the rate of 87.5% presented with complete inguinal lymphadenectomy. Many authors recommend that penectomy and lymphadenectomy be performed in a 2-stage approach, guaranteeing a lower rate of complications.3, 19 However, in this study the 2 procedures were done at the same operative time and the complication rates were similar to those found in the literature for lymphadenectomy only. There are few data in the literature regarding the incidence of locoregional recurrence after modified lymphadenectomy. One possible explanation is that this is a contemporary technique and its role in the management of SCC of the penis is not yet defined.20 A study with 13 patients demonstrated a local recurrence rate of 15% after modified lymphadenectomy.9 In 2 other studies with 9 and 12 patients there was no locoregional recurrence after bilaterally negative modified lymphadenectomy in a long-term followup.10, 11 Of the 26 patients enrolled in our study 18 (69.2%) underwent a bilaterally negative modified lymphadenectomy and could be spared the morbidity of the complete inguinal lymphadenectomy. Although in these patients surgery could be considered unnecessary, it has to be taken into account since the cure rate is 62.5% with microscopic lymph node metastasis. It is necessary to consider the unfavorable evolution of patients who underwent surveillance and salvage lymphadenectomy when nodes became palpable.2, 18 Of these patients in a mean followup longer than 6 years, 2 (5.5% of procedures or 2 of 36) had locoregional recurrence. This recurrence was in the first 2 years, suggesting the necessity of closer followup. In 8 (30.8%) patients the frozen section analysis was positive and the procedure was extended to a complete inguinal lymphadenectomy. Of these patients 5 (62.5%) were cured and a similar cure rate is observed in the literature.19 Analyzing all patients, the modified lymphadenectomy performed at the same time as penectomy led to correct treatment of the disease in 8 (30.8%), avoided morbidity for 16 (61.5%) and failed in 2 (7.7%) patients. The failure can be explained by the fact that the lymph node involved might have been outside the limits of dissection of the modified lymphadenectomy. We can consider the modified lymphadenectomy a surgical staging procedure that promoted adequate staging and treatment in 92.3% of the patients in this cohort study. In this study the tumor differentiation degree indicated by many authors as a prognostic factor did not present any linear relationship with lymph node involvement.7, 13
CONCLUSIONS
Clinical staging of inguinal lymph nodes in patients with squamous cell carcinoma of the penis should not be considered in the treatment decision. The complication rate in patients who underwent modified lymphadenectomy was significantly lower than in patients who underwent a complete inguinal lymphadenectomy. Modified lymphadenectomy can be performed concomitantly with penectomy since the complication rate is the same when lymphadenectomy is performed alone. The modified lymphadenectomy can be recommended as a staging procedure to promote adequate treatment. Followup is highly recommended every 3 months for the first 2 years since all recurrence was within this period. Ms. Jane Kater Santos provided assistance in this work.
LONG-TERM FOLLOWUP OF MODIFIED INGUINAL LYMPHADENECTOMY FOR PENILE CARCINOMA REFERENCES
1. Goldminz, D., Scott, G. and Klaus, S.: Penile basal cell carcinoma. Report of a case and review of the literature. J Am Acad Dermatol, 20: 1094, 1989 2. Horenblas, S.: Lymphadenectomy for squamous cell carcinoma of the penis. Part 1: diagnosis of lymph node metastasis. BJU Int, 88: 467, 2001 3. Ornellas, A. A., Seixas, A. L. C., Marota, A., Wisnescky, A., Campos, F. and de Moraes, J. R.: Surgical treatment of invasive squamous cell carcinoma of the penis: retrospective analysis of 350 cases. J Urol, 151: 1244, 1994 4. Abi-Aad, A. S. and deKernion, J. B.: Controversies in ilioinguinal lymphadenectomy for cancer of the penis. Urol Clin North Am, 19: 319, 1992 5. McDougal, W. S.: Carcinoma of the penis: improved survival by early regional lymphadenectomy based on the histological grade and depth of invasion of the primary lesion. J Urol, 154: 1364, 1995 6. Lopes, A., Hidalgo, G. S., Kowalski, L. P., Torloni, H., Rossi, B. M. and Fonseca, F. P.: Prognostic factors in carcinoma of the penis: multivariate analysis of 145 patients treated with amputation and lymphadenectomy. J Urol, 156: 1637, 1996 7. Catalona, W. J.: Role of lymphadenectomy in carcinoma of the penis. Urol Clin North Am, 7: 785, 1980 8. Costa, R. P., Schaal, C. H. and Cortez, J. P.: Nova proposta de linfadenectomia para caˆncer do peˆnis: resultados preliminares. J Bras Urol, 15: 242, 1989 9. Lopes, A., Rossi, B. M., Fonseca, F. P. and Morini, S.: Unreliability of modified inguinal lymphadenectomy for clinical staging of penile carcinoma. Cancer, 77: 2099, 1996 10. Colberg, J. W., Andriole, G. L. and Catalona, W. J.: Long-term follow-up of men undergoing modified inguinal lymphadenectomy for carcinoma of the penis. Br J Urol, 79: 54, 1997 11. Parra, R. O.: Accurate staging of carcinoma of the penis in men with nonpalpable inguinal lymph nodes by modified inguinal lymphadenectomy. J Urol, 155: 560, 1996 12. American Joint Committee of Cancer: Penis. In: Manual for Staging Cancer, 3rd ed. Philadelphia: J. B. Lippincott, pp. 189 –191, 1988 13. Horenblas, S. and van Tinteren, H.: Squamous cell carcinoma of the penis. IV. Prognostic factors of survival: analysis of tumor, nodes and metastasis classification system. J Urol, 151: 1239, 1994 14. Horenblas, S., van Tinteren, H., Delemarre, J. F. M., Moonen, L. M., Lustig, V. and Kro¨gen, R.: Squamous cell carcinoma of the penis: accuracy of tumor nodes and metastasis classification system, and role of lymphangiography, computerized tomography scan and fine needle aspiration cytology. J Urol, 146: 1279, 1991 15. Horenblas, S., van Tinteren, H., Delemarre, J. F. M., Moonen, L. F. M., Lustig, V. and van Waardenburg, E. W.: Squamous cell carcinoma of the penis. III. Treatment of the regional nodes. J Urol, 149: 492, 1993
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16. Kulkarni, J. N. and Kamat, M. R.: Prophylactic bilateral groin node dissection versus prophylactic radiotherapy and surveillance in patients with N0 and N1–2A carcinoma of the penis. Eur Urol, 26: 123, 1994 17. Tanis, P. J., Lont, A. P., Meinhardt, W., Olmos, R. A. V., Nieweg, O. E. and Horenblas, S.: Dynamic sentinel node biopsy for penile cancer: reliability of a staging technique. J Urol, 168: 76, 2002 18. Theodorescu, D., Russo, P., Zhang, Z.-F., Morash, C. and Fair, W. R.: Outcomes of initial surveillance of invasive squamous cell carcinoma of the penis and negative nodes. J Urol, 155: 1626, 1996 19. Horenblas, S.: Lymphadenectomy for squamous cell carcinoma of the penis. Part 2: the role and technique of lymph node dissection. BJU Int, 88: 473, 2001 20. Bevan-Thomas, R., Slaton, J. W. and Pettaway, C. A.: Contemporary morbidity from lymphadenectomy for penile squamous cell carcinoma: the M.D. Anderson Cancer Center experience. J Urol, 167: 1638, 2002 EDITORIAL COMMENT The authors report on a large group of patients with penile cancer all treated with partial penectomy and simultaneous modified inguinal dissection. They accurately identified all of the patients with superficial metastasis and proceeded with a more complete dissection during the same setting. However, 2 men experienced locoregional recurrence. I have experienced the same results with a few patients having local recurrence earlier than 2 years. This has led me to modify the extent of the modified dissection slightly. I now include the nodal tissue below the fossa ovalis all the way to the femoral canal, and dissect the femoral vein entirely and the medial aspect of the femoral artery below the inguinal ligament. This adds no additional morbidity to the procedure and incorporates some nodal tissue that may be missed with the original modified dissection, thus decreasing the possibility of locoregional recurrence. Raul O. Parra Division of Urology Oregon Health and Science University Portland, Oregon REPLY BY AUTHORS There are few data in the literature regarding the incidence of loco-regional recurrence after modified lymphadenectomy. This scenario leads some investigators to change techniques based on their own experience. Further studies addressing the results of these new approaches are necessary. The role of modified lymphadenectomy should be defined and a consensus on the treatment of penile carcinoma could be achieved. Based on our results complete inguinal lymphadenectomy should be performed only for lymph nodes metastases.
Vol. 172, 498 –501, August 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000132239.28989.e1
LONG-TERM FOLLOWUP OF PENILE CARCINOMA TREATED WITH PENECTOMY AND BILATERAL MODIFIED INGUINAL LYMPHADENECTOMY CARLOS ARTURO LEVI D’ANCONA, ROBERTO GONC ALVES DE LUCENA, ´ RIO HENRIQUE TAVARES MARTINS, FERNANDO AUGUSTO DE OLIVEIRA QUERNE, MA FERNANDES DENARDI AND NELSON RODRIGUES NETTO, JR. From the Division of Urology, Faculdade de Cieˆncias Me´dicas da Universidade Estadual de Campinas, Sa˜o Paulo, Brazil
ABSTRACT
Purpose: We evaluated modified inguinal lymphadenectomy in the treatment of penile carcinoma, analyzing the rate of complications compared to complete inguinal lymphadenectomy, the complications in performing lymphadenectomy and penectomy concomitantly, and the long-term locoregional recurrence rate. Materials and Methods: A total of 26 patients with squamous cell carcinoma of the penis were clinically assessed, and underwent penectomy and bilateral modified inguinal lymphadenectomy at the same operative time. Frozen section analysis of lymph nodes was performed and if metastases were detected a complete ipsilateral inguinal dissection was performed. Results: A total of 52 modified lymphadenectomies were performed. In 10 procedures lymph node metastasis was present. Clinical staging presented false-positive and false-negative rates of 50% and 7.9%, respectively. The complication rate for modified lymphadenectomy was 38.9% and for complete inguinal lymphadenectomy it was 87.5%. Followup ranged from 5 to 112 months and mean followup of recurrence-free cases was 78 months (range 38 to 112). A total of 18 patients underwent bilateral negative modified inguinal lymphadenectomy and 2 of these experienced locoregional recurrence within 2 years after surgery. Conclusions: Modified inguinal lymphadenectomy causes a lower complication rate than complete inguinal lymphadenectomy. Bilateral modified inguinal lymphadenectomy performed at the same time as penectomy does not increase the complication rate. When frozen section analysis is negative bilaterally, 5.5% of inguinal regions might still harbor occult metastasis. Modified inguinal lymphadenectomy is recommended as a staging procedure in all patients with T2–3 penile carcinoma. A straight followup is required for 2 years since all recurrence was within this period. KEY WORDS: penile neoplasms, lymph node excision, neoplasm metastasis, lymphatic metastasis
Squamous cell carcinoma (SCC) accounts for more than 95% of primary malignant penile neoplasia.1 SCC of the penis is characterized by an essentially locoregional involvement affecting the inguinal, pelvic and periaortic lymph nodes. Hematogenic dissemination is rare even with the invasion of the corpora cavernosa and the rate of distant metastasis ranges from 1% to 10%.2 This makes penile carcinoma one of the few urological malignancies potentially curable with regional lymphadenectomy.3 In patients presenting with SCC of the penis 30% to 60% have palpable lymph nodes in the inguinal region.2, 3 In 50% of these patients this condition is caused by metastatic involvement and in the other half by inflammatory reactions.4 Therefore, clinical staging is not a reliable parameter for guiding treatment. Patients with stage T2–3 penile SCC should undergo inguinal lymphadenectomy regardless of whether lymph nodes are palpable.5 However, in 60% of cases no lymph node metastases are found in the resection specimen.6 These patients underwent unnecessary node dissection and were exposed to the well-known morbidity of the procedure. Knowledge of pelvic and inguinal lymph node anatomy as well as the preferred drainage path of penile tumors stimulated the development of various surgical techniques for greater effectiveness with decreased morbidity.7, 8 Studies Accepted for publication February 27, 2004.
conducted on inguinal lymphadenectomy involving the preservation of the saphenous vein and restricting resection medial to the femoral vessels (modified lymphadenectomy) demonstrated a significant decrease in morbidity, but since locoregional recurrence rates varied is not clear whether local control of the disease might be attempted.9 –11 We assessed the incidence of complications secondary to modified lymphadenectomy and, compared with complete inguinal lymphadenectomy, verified whether the concomitant performance of lymphadenectomy and penectomy increased complications. We analyzed the long-term locoregional recurrence rate to evaluate the results of modified inguinal lymphadenectomy in the treatment of penile carcinoma.
PATIENTS AND METHODS
There were 26 patients who presented with squamous cell carcinoma of the penis between 1994 and 1999 and were included in this study. Patient age ranged from 44 to 94 years (mean 62, median 63). The patients were referred to the Urology Division after a disease onset that ranged from 2 to 70 months (mean 14, median 8). The criteria for exclusion from study were poor clinical conditions for surgery, presence of distant metastasis, ulcerated inguinal metastasis, previous oncological treatment involving radiotherapy and/or chemotherapy, unresectable primary tumor, previous surgery of
498
499
LONG-TERM FOLLOWUP OF MODIFIED INGUINAL LYMPHADENECTOMY FOR PENILE CARCINOMA
inguinal nodes, patients with stage T1, carcinoma in situ and verrucous carcinoma. The clinical examination consisted of detailed palpation of the penile shaft to verify the extent of the disease and palpation of the inguinal regions for lymph node assessment. The lymph nodes were considered clinically positive when palpable, fixed to the superficial or deep planes. Cases without any of these characteristics were considered N0. To assess the possibility of distant metastasis, chest x-ray and computerized tomography of the abdomen and pelvis were done. Clinical staging was performed using the 1988 TNM system.12 All patients underwent penectomy and modified inguinal lymphadenectomy at the same operative time. Antibiotic prophylaxis with cefazolin was introduced during anesthetic induction and continued for 7 days. Low molecular weight heparin was administered as prophylaxis for deep venous thrombosis and maintained for 48 hours. An extremity compression hose was prescribed for all patients. Treatment for the penile lesion followed the principle of complete tumor resection with a 2 cm minimum macroscopic safety margin and a histopathological assessment (frozen section) of the incision margins that confirmed absence of neoplasia in the remaining penile stump. Total penectomy associated with perineal ureterostomy was chosen when tumor resection would leave a penile stump smaller than 2 cm. All patients underwent bilateral modified inguinal lymphadenectomy.8 A 5 cm skin incision was made 2 cm below the inguinal arcade along the femoral vessels. The adipose and lymphatic tissues below Scarpa’s fascia were resected en bloc with the adductor longus muscle as the medial border, the medial surface of the femoral and saphenous veins as the lateral border, and the inguinal arcade as the superior border, performing a triangle (see figure). Frozen section analysis of lymph nodes was performed and if metastases were absent, the procedure was concluded and an aspirative drain
was maintained for at least 5 days. When metastases were detected an ipsilateral complete inguinal lymphadenectomy was performed. In followup special attention was given to the inguinal region and the penile stump to verify if there were any nodes or indurations. Followup was performed every 3 months in the year 1, every 6 months in year 2 and then once yearly. RESULTS
There were 26 patients with squamous cell carcinoma of the penis who underwent penectomy and concomitant bilateral modified inguinal lymphadenectomy. The number of inguinal regions was considered in this study and involved a total of 52 lymphadenectomies. The preoperative clinical examination revealed palpable lymph nodes in 10 patients (38.4%), 4 of whom had bilateral adenopathy, totalling 14 (27%) inguinal regions. The modified inguinal lymphadenectomy was negative for metastasis in 42 (81%) procedures. It was bilaterally positive in 2 (7.7%) patients and bilaterally negative in 18 (69%). No significant difference was observed in the number of lymph nodes evaluated in patients with or without lymph node metastasis (6.5 and 5.4, respectively). Preoperative clinical staging presented false-positive and false-negative rates of 50% and 7.9%, respectively, considering the anatomopathological results of modified lymphadenectomy as a standard (table 1). The false-positive and false-negative rates obtained in our study were 50% (7 of 14) and 13% (5 of 38), respectively, considering 3 patients at surgery and 2 others at followup. There were 8 patients whose frozen section biopsy was positive and who underwent complete inguinal lymphadenectomy that was bilateral in 2. In all cases the anatomopathological analysis of the nodal packet from the complete lymphadenectomy revealed no metastasis. In 17 cases the penile tumors were well differentiated, in 8 they were moderately differentiated and undifferentiated in 1. There was a higher rate of positive lymph nodes in the patients with well differentiated tumors but the difference was not statistically significant. Complications were classified as minor and major. Minor complications included skin edge necrosis requiring no therapy, seroma formation not requiring aspiration and lymph drainage. Major complications consisted of lymphedema interfering with ambulation. The minor complication rate for patients who underwent modified lymphadenectomy and penectomy was 36.8%, while in complete lymphadenectomy it was 87.5% (p ⬍0.05). Major complications occurred in 37.5% of patients who underwent complete inguinal lymphadenectomy and were absent in those who underwent modified inguinal lymphadenectomy (table 2). Followup ranged from 5 to 112 months. Mean followup of recurrence-free cases was 78 months (range 38 to 112). One patient was lost to followup after 38 months, he was free from disease and the last clinical evaluation was considered final. Four patients died of causes unrelated to the disease, and they were all free from disease at the last clinical evaluations at 38, 50, 58 and 70 months. Among the 8 patients who underwent complete inguinal lymphadenectomy 3 (37.5%) experienced locoregional recurrence at 5, 8 and 11 months, and died of disease progression.
TABLE 1. Comparison between clinical and surgical staging Surgical
Limits of modified inguinal lymphadenectomy. a, lateral margin– saphenous and femoral vein. b, superior margin–inguinal ligament. c, median margin–adductor longus muscle.
Clinical: Pos Neg Totals
No. Pos (%) 7 3 (7.9) 10 (19.2)
No. Neg (%)
No. Total (%)
7 (50) 35
14 (27) 38 (73)
42 (80.8)
52 (100)
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LONG-TERM FOLLOWUP OF MODIFIED INGUINAL LYMPHADENECTOMY FOR PENILE CARCINOMA
TABLE 2. Complications of modified and complete inguinal lymphadenectomy Minor Complication Rate (%)
Major Complication Rate (%)
Modified inguinal lymphadenectomy: Seroma 26.3 Lymph drainage 10.5 Complete inguinal lymphadenectomy: Seroma 37.5 Lymph drainage 12.5 Skin flap necrosis 37.5
Lymphedema 37.5
One case of recurrence in the retroperitoneal lymph nodes was detected by computerized tomography and confirmed by needle biopsy, 1 was in the inguinal area and another in the perineum. The procedure was curative in the other patients who were free of disease at a mean followup of 79 months (range 66 to 112). Of the 18 patients who underwent negative bilateral modified lymphadenectomy, locoregional recurrence developed in 2 at 15 and 16 months of followup, 1 in the upper part of the modified lymphadenectomy area and the other out of this area. Both patients underwent resection of the metastases but died of disease progression. DISCUSSION
Due to the significant prognostic importance of inguinal lymph node involvement in squamous cell carcinoma of the penis, correct staging and, consequently, appropriate treatment of the inguinal lymph nodes are primordial factors in the treatment of this disease.13 Clinical staging obtained with physical examination and imaging modalities cannot reliably confirm the presence or absence of lymph node metastasis.2, 7 Clinical staging presents a false-positive rate of 50%2, 14 that would result in a high number of unnecessary surgeries, and a false-negative rate between 10% and 15%2, 15 that would leave an unacceptable number of patients without adequate treatment. The false-positive and false-negative rates obtained in our study were 50% (7 of 14) and 13% (5 of 38), respectively, considering 3 patients after surgery and another 2 at followup. Our results were similar to those found in the literature. These data reveal the need for a more effective method to indicate lymph node involvement in patients with SCC of the penis. Ultrasonographically guided fine needle aspiration biopsy of lymph nodes has been suggested as the first investigation in clinically node positive and node negative cases. Obviously the result is only reliable when positive and the falsenegative rates attain 15% in clinically node positive cases.14, 16 In many patients the biopsy needs to be repeated, causing anxiety and delay in treatment. Research on dynamic sentinel node biopsy using lymphoscintigraphy has indicated a potential benefit in selecting patients for lymphadenectomy. Promising results have been obtained but further studies are necessary to establish the applicability of this method.17 In this study early modified lymphadenectomy was performed in all patients, allowing pathological staging and concomitant treatment when necessary. Despite the failure of 5.5% of procedures in 11% of patients this staging method is comparable to other diagnostic methods. Studies conducted in patients with carcinoma of the penis and no palpable lymph nodes showed that those who underwent early inguinal lymph node dissection presented a significantly higher survival rate than those treated with surveillance and salvage lymphadenectomy when nodes became palpable.18 Early inguinal lymphadenectomy is criticized for the high complication rates and that many patients undergo unnecessary surgeries. Modified inguinal lymphadenectomy was performed in this study and only minor complications were observed (36.8%), acceptable even for patients without lymph node involvement. Surgical complications of complete
inguinal lymphadenectomy occur in more than half the cases and vary between 50% and 84%.19 Modified lymphadenectomy is associated with lower morbidity and the rate of minor complications is 33% to 44%.10, 11 The minor complication rates in this study were similar to those found in the literature. Modified inguinal lymphadenectomy presented a complication rate of 36.8%, which was significantly lower (p ⬍0.05) than the rate of 87.5% presented with complete inguinal lymphadenectomy. Many authors recommend that penectomy and lymphadenectomy be performed in a 2-stage approach, guaranteeing a lower rate of complications.3, 19 However, in this study the 2 procedures were done at the same operative time and the complication rates were similar to those found in the literature for lymphadenectomy only. There are few data in the literature regarding the incidence of locoregional recurrence after modified lymphadenectomy. One possible explanation is that this is a contemporary technique and its role in the management of SCC of the penis is not yet defined.20 A study with 13 patients demonstrated a local recurrence rate of 15% after modified lymphadenectomy.9 In 2 other studies with 9 and 12 patients there was no locoregional recurrence after bilaterally negative modified lymphadenectomy in a long-term followup.10, 11 Of the 26 patients enrolled in our study 18 (69.2%) underwent a bilaterally negative modified lymphadenectomy and could be spared the morbidity of the complete inguinal lymphadenectomy. Although in these patients surgery could be considered unnecessary, it has to be taken into account since the cure rate is 62.5% with microscopic lymph node metastasis. It is necessary to consider the unfavorable evolution of patients who underwent surveillance and salvage lymphadenectomy when nodes became palpable.2, 18 Of these patients in a mean followup longer than 6 years, 2 (5.5% of procedures or 2 of 36) had locoregional recurrence. This recurrence was in the first 2 years, suggesting the necessity of closer followup. In 8 (30.8%) patients the frozen section analysis was positive and the procedure was extended to a complete inguinal lymphadenectomy. Of these patients 5 (62.5%) were cured and a similar cure rate is observed in the literature.19 Analyzing all patients, the modified lymphadenectomy performed at the same time as penectomy led to correct treatment of the disease in 8 (30.8%), avoided morbidity for 16 (61.5%) and failed in 2 (7.7%) patients. The failure can be explained by the fact that the lymph node involved might have been outside the limits of dissection of the modified lymphadenectomy. We can consider the modified lymphadenectomy a surgical staging procedure that promoted adequate staging and treatment in 92.3% of the patients in this cohort study. In this study the tumor differentiation degree indicated by many authors as a prognostic factor did not present any linear relationship with lymph node involvement.7, 13
CONCLUSIONS
Clinical staging of inguinal lymph nodes in patients with squamous cell carcinoma of the penis should not be considered in the treatment decision. The complication rate in patients who underwent modified lymphadenectomy was significantly lower than in patients who underwent a complete inguinal lymphadenectomy. Modified lymphadenectomy can be performed concomitantly with penectomy since the complication rate is the same when lymphadenectomy is performed alone. The modified lymphadenectomy can be recommended as a staging procedure to promote adequate treatment. Followup is highly recommended every 3 months for the first 2 years since all recurrence was within this period. Ms. Jane Kater Santos provided assistance in this work.
LONG-TERM FOLLOWUP OF MODIFIED INGUINAL LYMPHADENECTOMY FOR PENILE CARCINOMA REFERENCES
1. Goldminz, D., Scott, G. and Klaus, S.: Penile basal cell carcinoma. Report of a case and review of the literature. J Am Acad Dermatol, 20: 1094, 1989 2. Horenblas, S.: Lymphadenectomy for squamous cell carcinoma of the penis. Part 1: diagnosis of lymph node metastasis. BJU Int, 88: 467, 2001 3. Ornellas, A. A., Seixas, A. L. C., Marota, A., Wisnescky, A., Campos, F. and de Moraes, J. R.: Surgical treatment of invasive squamous cell carcinoma of the penis: retrospective analysis of 350 cases. J Urol, 151: 1244, 1994 4. Abi-Aad, A. S. and deKernion, J. B.: Controversies in ilioinguinal lymphadenectomy for cancer of the penis. Urol Clin North Am, 19: 319, 1992 5. McDougal, W. S.: Carcinoma of the penis: improved survival by early regional lymphadenectomy based on the histological grade and depth of invasion of the primary lesion. J Urol, 154: 1364, 1995 6. Lopes, A., Hidalgo, G. S., Kowalski, L. P., Torloni, H., Rossi, B. M. and Fonseca, F. P.: Prognostic factors in carcinoma of the penis: multivariate analysis of 145 patients treated with amputation and lymphadenectomy. J Urol, 156: 1637, 1996 7. Catalona, W. J.: Role of lymphadenectomy in carcinoma of the penis. Urol Clin North Am, 7: 785, 1980 8. Costa, R. P., Schaal, C. H. and Cortez, J. P.: Nova proposta de linfadenectomia para caˆncer do peˆnis: resultados preliminares. J Bras Urol, 15: 242, 1989 9. Lopes, A., Rossi, B. M., Fonseca, F. P. and Morini, S.: Unreliability of modified inguinal lymphadenectomy for clinical staging of penile carcinoma. Cancer, 77: 2099, 1996 10. Colberg, J. W., Andriole, G. L. and Catalona, W. J.: Long-term follow-up of men undergoing modified inguinal lymphadenectomy for carcinoma of the penis. Br J Urol, 79: 54, 1997 11. Parra, R. O.: Accurate staging of carcinoma of the penis in men with nonpalpable inguinal lymph nodes by modified inguinal lymphadenectomy. J Urol, 155: 560, 1996 12. American Joint Committee of Cancer: Penis. In: Manual for Staging Cancer, 3rd ed. Philadelphia: J. B. Lippincott, pp. 189 –191, 1988 13. Horenblas, S. and van Tinteren, H.: Squamous cell carcinoma of the penis. IV. Prognostic factors of survival: analysis of tumor, nodes and metastasis classification system. J Urol, 151: 1239, 1994 14. Horenblas, S., van Tinteren, H., Delemarre, J. F. M., Moonen, L. M., Lustig, V. and Kro¨gen, R.: Squamous cell carcinoma of the penis: accuracy of tumor nodes and metastasis classification system, and role of lymphangiography, computerized tomography scan and fine needle aspiration cytology. J Urol, 146: 1279, 1991 15. Horenblas, S., van Tinteren, H., Delemarre, J. F. M., Moonen, L. F. M., Lustig, V. and van Waardenburg, E. W.: Squamous cell carcinoma of the penis. III. Treatment of the regional nodes. J Urol, 149: 492, 1993
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16. Kulkarni, J. N. and Kamat, M. R.: Prophylactic bilateral groin node dissection versus prophylactic radiotherapy and surveillance in patients with N0 and N1–2A carcinoma of the penis. Eur Urol, 26: 123, 1994 17. Tanis, P. J., Lont, A. P., Meinhardt, W., Olmos, R. A. V., Nieweg, O. E. and Horenblas, S.: Dynamic sentinel node biopsy for penile cancer: reliability of a staging technique. J Urol, 168: 76, 2002 18. Theodorescu, D., Russo, P., Zhang, Z.-F., Morash, C. and Fair, W. R.: Outcomes of initial surveillance of invasive squamous cell carcinoma of the penis and negative nodes. J Urol, 155: 1626, 1996 19. Horenblas, S.: Lymphadenectomy for squamous cell carcinoma of the penis. Part 2: the role and technique of lymph node dissection. BJU Int, 88: 473, 2001 20. Bevan-Thomas, R., Slaton, J. W. and Pettaway, C. A.: Contemporary morbidity from lymphadenectomy for penile squamous cell carcinoma: the M.D. Anderson Cancer Center experience. J Urol, 167: 1638, 2002 EDITORIAL COMMENT The authors report on a large group of patients with penile cancer all treated with partial penectomy and simultaneous modified inguinal dissection. They accurately identified all of the patients with superficial metastasis and proceeded with a more complete dissection during the same setting. However, 2 men experienced locoregional recurrence. I have experienced the same results with a few patients having local recurrence earlier than 2 years. This has led me to modify the extent of the modified dissection slightly. I now include the nodal tissue below the fossa ovalis all the way to the femoral canal, and dissect the femoral vein entirely and the medial aspect of the femoral artery below the inguinal ligament. This adds no additional morbidity to the procedure and incorporates some nodal tissue that may be missed with the original modified dissection, thus decreasing the possibility of locoregional recurrence. Raul O. Parra Division of Urology Oregon Health and Science University Portland, Oregon REPLY BY AUTHORS There are few data in the literature regarding the incidence of loco-regional recurrence after modified lymphadenectomy. This scenario leads some investigators to change techniques based on their own experience. Further studies addressing the results of these new approaches are necessary. The role of modified lymphadenectomy should be defined and a consensus on the treatment of penile carcinoma could be achieved. Based on our results complete inguinal lymphadenectomy should be performed only for lymph nodes metastases.