Locally advanced penile carcinoma : classic emasculation or testis-sparing surgery ?

ARTICLE INFO _________________________________________________________ ___________________ Vol. 38 (6): 750-759, November December, 2012 IBJU | LOCALLY ADVANCED PENILE CARCINOMA: EMASCULATION OR TESTIS-SPARING SURGERY? 751 reas 2 or 3 new cases of PC are observed every month at the Ceará Cancer Hospital in Fortaleza (Northeastern Brazil) (6), a British practicing urologist may not see more than one new case every other year. The causes of penile cancer are not always clear, but major risk factors include poor penis hygiene, phimosis, smegma retention, smoking and sexually transmitted diseases (7,8). In a recent Brazilian multicenter study, the practice of sex with animals was also identifi ed as a risk factor for this malignancy (9). Penile carcinoma metastasizes stepwise via the lymphatic system: from the inguinal nodes to the pelvic nodes to the distant nodes (10). The presence and extent of lymph node metastases are the most important predictors of survival (4). Histological grade and vascular and perineural invasion have been correlated with poor prognosis and unfavorable outcomes (11). Surgical management of malignant PC depends on the grade and stage of the disease (12). The National Institute for Clinical Excellence (U.K) recommends managing PC at centers with a catchment area of 4 million. Each center receives approximately 25 new cases annually. Advanced cases of PC are referred to a supra-regional center for multidisciplinary curative and palliative treatment, including reconstructive surgery (13). At our service, PC patients with proximal corpus cavernosum invasion and scrotal skin erosion are routinely referred to emasculation, including total penectomy (complete penis amputation), scrotectomy and bilateral orchiectomy (14). The present study evaluates the clinical and pathological fi ndings of 16 patients with locally advanced penile squamous cell carcinoma submitted to emasculation and discusses questions related to surgical technique, patient follow-up and the usefulness of bilateral orchiectomy. MATERIALS AND METHODS Between 1999 and 2010, 172 patients with penile invasive squamous cell carcinoma were submitted to surgical treatment at the Ceará Cancer Hospital in Fortaleza, Brazil. Of these, 16 advanced cases (9.3%) underwent emasculation (Table-1). Complete preoperative, operative and postoperative patient data were retrieved from the institution’s prospective database and from a review of the respective medical records. The information included patients’ age, ethnicity, date of surgery, residential setting (rural or urban), level of schooling, time from appearance of fi rst lesion to defi nitive diagnosis, type of reconstruction, duration of follow-up and date of last follow-up visit. The median follow-up time was calculated as the median observation time among patients and the overall survival time was estimated using the Kaplan-Meier method. Specimens were obtained from all patients and evaluated by a single pathologist with regard to tumor stage and grade, inguinal lymph node status, vascular and perineural invasion, invasion Table 1 Cases of penile squamous cell carcinoma submitted to surgical treatment at the Ceará Cancer Hospital between 1999 and 2009. Surgical technique Cases (n) Percent (%) Wide local excision or circumcision 5 3% Partial penectomy 125 73% Total penectomy 26 15%


INTRODUCTION
Penile carcinoma (PC), a potentially fatal malignancy, is rare in developed countries (1).In the United States, for instance, it accounts for only 0.4% of all male malignancies (2), while in less developed regions, especially in Asia, Africa, and South America, the fi gure may be as high as 10% (3).The incidence typically ranges from less than 1/100,000 in the US and Europe to more than 4/100,000 in Uganda and Brazil (4).
Brazil has one of the highest incidences of penile cancer in the world.The disease represents 2.1% of male neoplasms in the country, reaching 5.7% in the Northeast (5) where the human development index is very low.Not surprisingly, the region accounts for more than half (53.02%) of the cases registered in Brazil.In comparison, whe-reas 2 or 3 new cases of PC are observed every month at the Ceará Cancer Hospital in Fortaleza (Northeastern Brazil) (6), a British practicing urologist may not see more than one new case every other year.
The causes of penile cancer are not always clear, but major risk factors include poor penis hygiene, phimosis, smegma retention, smoking and sexually transmitted diseases (7,8).In a recent Brazilian multicenter study, the practice of sex with animals was also identifi ed as a risk factor for this malignancy (9).
Penile carcinoma metastasizes stepwise via the lymphatic system: from the inguinal nodes to the pelvic nodes to the distant nodes (10).The presence and extent of lymph node metastases are the most important predictors of survival (4).Histological grade and vascular and perineural invasion have been correlated with poor prognosis and unfavorable outcomes (11).
Surgical management of malignant PC depends on the grade and stage of the disease (12).The National Institute for Clinical Excellence (U.K) recommends managing PC at centers with a catchment area of 4 million.Each center receives approximately 25 new cases annually.Advanced cases of PC are referred to a supra-regional center for multidisciplinary curative and palliative treatment, including reconstructive surgery (13).
At our service, PC patients with proximal corpus cavernosum invasion and scrotal skin erosion are routinely referred to emasculation, including total penectomy (complete penis amputa-tion), scrotectomy and bilateral orchiectomy (14).
The present study evaluates the clinical and pathological fi ndings of 16 patients with locally advanced penile squamous cell carcinoma submitted to emasculation and discusses questions related to surgical technique, patient follow--up and the usefulness of bilateral orchiectomy.

MATERIALS AND METHODS
Between 1999 and 2010, 172 patients with penile invasive squamous cell carcinoma were submitted to surgical treatment at the Ceará Cancer Hospital in Fortaleza, Brazil.Of these, 16 advanced cases (9.3%) underwent emasculation (Table-1).
Complete preoperative, operative and postoperative patient data were retrieved from the institution's prospective database and from a review of the respective medical records.The information included patients' age, ethnicity, date of surgery, residential setting (rural or urban), level of schooling, time from appearance of fi rst lesion to defi nitive diagnosis, type of reconstruction, duration of follow-up and date of last follow-up visit.The median follow-up time was calculated as the median observation time among patients and the overall survival time was estimated using the Kaplan-Meier method.
Specimens were obtained from all patients and evaluated by a single pathologist with regard to tumor stage and grade, inguinal lymph node status, vascular and perineural invasion, invasion of corpus cavernosum, corpus spongiosum, testicles, scrotum and urethra.All 16 patients were submitted to emasculation, including total penectomy, scrotectomy and bilateral orchiectomy.The technique consisted of an elliptical abdominoscrotal incision with large skin margin and partial preservation of the posterior surface of the scrotum.With the corpus cavernosum and corpus spongiosum exposed, the urethra was dissected and mobilized.The corpus cavernosum was disinserted from the ischial tuberosity followed by en bloc removal of the penis, scrotum and testes.The urethra was tunneled without angulation, spatulated and externalized in the perineum, as described by Campbell (15).
The surgical wound was closed with a scrotal fl ap in 9 patients.Seven patients required two forms of reconstruction: 1) a vertical rectus abdominis myocutaneous fl ap was made through a midline abdominal incision, preserving the posterior layer of aponeurotic and inferior epigastric vessels.The skin grafts were rotated to achieve complete wound closure; 2) an eliptical incision was made in the medial aspect of the thigh, starting 10 cm below the ischium, in order to preserve the medial circumfl ex femoral arteries, followed by wound closure with a gracilis myocutaneous fl ap.Both reconstruction techniques were performed with the assistance of a plastic surgery team.
Tumors were graded with the most commonly used classifi cation system: grade I = well differentiated; grade II = moderately differentiated, and grade III = poorly differentiated (16).
At the moment of recurrence, tumors were large with clinical evidence of scrotal erosion and proximal invasion of the corpus cavernosum and the urethra.
Eleven patients underwent lymphadenectomy due to inguinal lymph node involvement.
Pelvic lymphadenectomy was performed in four patients.The pathological nodal status was defi ned as: N0 = no evidence of lymph node metastasis; N1 = metastasis in a single inguinal lymph node; N2 = metastasis in multiple or bilateral superfi cial lymph nodes and N3 = unilateral or bilateral metastasis in deep or pelvic lymph nodes.The excised tumors were clinically and pathologically staged according to the guidelines of the International Union Against Cancer (2002 TNM UICC) (17).
The study was previously approved by the Institutional Ethics Committee and the principles of the Helsinki Declaration were followed in all study procedures.

RESULTS
The 16 patients undergoing emasculation were aged 63.1 years on the average (range: 40-78).Fourteen patients (87%) were white and two (13%) were black.All were illiterate or semiliterate rural dwellers (Table -2).The time from the appearance of the fi rst penile lesion to the defi nitive diagnosis was 8-12 months.
Radical bilateral inguinal lymphadenectomy was performed in 11 patients 3-4 weeks after emasculation.Due to extensive loco-regional disease, in fi ve patients treatment was limited to surgical debulking for palliative and hygiene purposes, followed by reconstruction (Figure -1).
In most patients (n = 9), the surgical wound was closed with a scrotal fl ap.The remainder (n = 7) required reconstruction with either a vertical rectus abdominis myocutaneous fl ap (n = 4) or a gracilis myocutaneous fl ap (n = 3).
The time of follow-up was 31.9 months on the average (range: 1-119).By the time of the last follow-up visit (April 2011), only 7 patients (43.75%) were alive.One of six patients with vascular invasion was alive.A Kaplan-Meier overall survival curve is shown in Figure -2.On the other hand, patients with Grade-II tumors presented lymphovascular and perineural invasion (n = 6), or perineural invasion only (n = 4).A single patient with Grade-II tumor presented no lymphovascular or perineural invasion.The histopathological examination revealed invasion of the urethra (n = 13), scrotum (n

DISCUSSION
The study was motivated by the question of whether bilateral orchiectomy is necessary in patients with locally advanced penile squamous cell carcinoma and scrotal erosion.Emasculation conventionally involves the amputation of penis and testicles and all or part of the scrotum (14).
Although penile amputation can in many subtle and insidious ways give patients an altered sense of masculine identity (18), the crucial question in face of locally advanced PC is not the mutilation per se, but the severity and mortality of the disease.
In our series of PC patients, 9% (16/172) were submitted to emasculation.In comparison, Ornellas et al. referred only 2% (15/688) of their PC patients from Rio de Janeiro to emasculation during a period of 46 years ( 14).However, it seems likely that due to the geographical location of our institution (Northeastern Brazil), a socioeconomically challenged region, PC is more prevalent and emasculation is more often required.
In addition, diagnosis and follow-up of patients from the rural zone can be very diffi cult.Some patients wait until after the rainy season or harvest to seek medical care, giving the disease a seasonal character.
Although earlier studies concluded the incidence of PC peaks at 80 years of age (19), more recent investigations have shown the peak to occur in the sixth decade of life (20).In our series, patients were 40-78 years old (mean: 63.1) upon diagnosis.
PC affects mainly poor, uncircumcised men with poor hygiene and limited access to public health care.The proportion of whites (87%) among the patients emasculated in this study matched fi ndings published by Favorito et al. (75.61%) (5).All our patients were illiterate or semiliterate rural dwellers.
The 2002 TNM classifi cation system was adopted throughout the study since all emasculated patients were treated after 2001.Most tumors were pT3 or pT4.Six patients were classifi ed as pT4 due to invasion of the scrotum (n = 5) or the testicles (n = 1), and two were classifi ed as pT2.One pT2 patient was alive at the time of the last follow-up visit 46 months after surgery.The other surviving patients in our series were staged as pT4 (n = 2) and pT3 (n = 4), suggesting that tumor stage is not the only factor determining survival (14).The two patients staged as pT4 were followed for 119 and 29 months, respectively.
Most cases of PC reported in the literature are low-grade (21).Our cases were staged as Grade I (well differentiated; n = 5) or Grade II (moderately differentiated; n = 11).No tumor was classifi ed as Grade III.Although all Grade-I patients are currently alive, the presence of tumors of both grades (I and II) among the surviving patients suggests a lack of correlation between grade and survival.Johnson reached a similar conclusion in a study of 153 cases (22).On the other hand, Ornellas and Cubillas found histological grade to be a significant adverse prognostic factor for lymph nodes metastasis and survival (16,23).
Clinically, the scrotum appeared to be infi ltrated in all 16 cases, but only 5 were confi rmed by the pathologist.The single case of microscopic focal testicular infi ltration in the absence of scrotal invasion was even more surprising.This infi ltration may have been a retrograde extension from the vas deferens--a very rare occurrence (24).
The fact that microscopic focal testicular infi ltration was confi rmed in only 1 of the 32 testicles in our sample, even in the presence of clinically apparent scrotal invasion, suggests that emasculation without bilateral orchiectomy is a reasonably safe treatment option for patients with locally advanced penile squamous cell carcinoma.As an added benefi t, patients not submitted to orchiectomy are spared the serious physiological and psychological adverse effects caused by the procedure, especially those associated with testosterone deprivation, such as metabolic syndrome, anemia, dyslipidemia, arterial hypertension, fatigue, irritability, depression, mood alterations, osteoporosis, bone-related events, muscular atrophy and sleep apnea (25).
One patient had positive surgical margins, proving the choice of surgical technique to be appropriate.The patient survived for 32 months after surgery.
Vascular invasion seems to be a major prognostic factor in patients with PC.Several studies using multivariate analysis have shown a strong correlation between venous and lymphatic embolizations and nodal metastasis (23,(26)(27)(28).
In a study of 196 patients, Ornelas and coworkers identifi ed 39 (19.9%) cases of lymphovascular embolization (23).In the present study, 6 cases (37.5%) of vascular embolization by cancer cells were detected by the pathologist.The difference in the respective incidences may be due to the greater number of advanced cases in our series.
Only one of our 6 patients with vascular invasion is currently alive.The mean postoperative survival time for the group was 16 months.This fi nding matches results published by Ornelas et al. who reported higher 5-year survival rates in patients without lymphovascular embolization (23).
Cubilla (16) and Ornellas ( 23) demonstrated that vascular invasion is a more important predictor of metastasis than perineural invasion.In our study, perineural invasion was observed in 11 patients (68.7%), three (27.3%) of whom are currently alive.The longest postoperative survival observed in our series (119 months) was a patient with perineural invasion.A recently published paper by Ayalla, Cubilla and Guimaraes et al. correlates higher histological grades, deeper anatomical infi ltration and vascular and perineural invasion with higher rates of nodal metastasis and mortalily (29).
Nodal status is an important prognostic factor for PC (4).Thus, in our sample, four of the seven patients staged as N0 are currently alive, while no patient staged as N2/N3 was alive at the time of the last follow-up.

CONCLUSIONS
Almost ten percent of our patients with locally advanced penile squamous cell carcinoma were referred to emasculation at the Ceará Cancer Hospital (Fortaleza, Brazil) over a period of 11 years.The fact that microscopic focal testicular infi ltration was confi rmed in only 1 of the 32 testicles in our sample, even in the presence of clinically apparent scrotal invasion, suggests that emasculation without bilateral orchiectomy may be a reasonably safe treatment option for patients with locally advanced penile squamous cell carcinoma,

EDITORIAL COMMENT
This is an interesting study, showing several clinical epidemiological and demographic aspects of patients with agressive locally advanced penile cancer, some of them under 50 years old, treated by a skilled team from a tertiary cancer center located in a highly prevalent penile cancinoma area.
Despite its reduced casuistry (16 cases), it brings us a very important new information, that probably has been noted in the daily practice, but was not present in the scientifi c literature: In the vast majority of debulking surgeries for locally advanced penile cancer, the testis are spared by the disease, probably due the anatomical barriers, as dartos muscles, albuginea and vaginal layers, then they do not deserve to be removed.
Many of this patients will die early due the disease progression.However more than a third of them can be cured or will develop later recurrences (in this present series 7 are alive for long time).
Testosterone plays several important roles in male physiology.If the castration is avoided in this clinical scenario, the long term survivors, will not develop several serious health conditions due androgen defi ciency like: metabolic syndrome, anemia, dyslipidemia, arterial hypertension, fatigue, irritability, depression, mood alterations, osteoporosis, bone-related events, muscular atrophy, sleep apnea and others.And for the anedoctal minority of cured subjects seeking for penile reconstruction, the libido persistence will be warranted.
As shown, vascular invasion was a unfavorable anatomopatological pattern, probably this patients deserve an adjuvant chemotherapy or can be candidates for future clinical trials.

Figure 1 A
Figure 1 A-C: Patient with locally advanced penile squamous cell carcinoma submitted to emasculation and reconstruction with a vertical rectus abdominis myocutaneuos fl ap.Ceará Cancer Hospital, Fortaleza, Brazil.

Figure 2 -
Figure 2 -Kaplan-Meier survival curve of 16 patients submitted to emasculation.Data expressed as percentage of live patients over time.Median overall survival was 16 months.

Table 2 -Demographic information, date of surgery, type of reconstruction and last follow-up visit of 16 patients with penile squamous cell carcinoma submitted to emasculation at the Ceará Cancer Hospital in Fortaleza, Brazil, between 1999 and 2010.
*Last follow-up visit: April 2011 DF = disease-free