female urethral cancer ( uca ) is a rare malignancy ; it accounts for approximately 1% of all female urological cancer ( 1 )
. initial signs of uca , such as voiding symptoms and bloody spotting , are ignored in most patients with female uca because they are not pathognomonic .
in fact , voiding symptoms and bloody spotting are common indicators of non - malignant conditions in normal healthy females . despite improvements in diagnostic imaging ,
delayed diagnosis remains a challenge in these patients ( 2 ) . because initial diagnosis is delayed
, female uca patients often present with large and advanced lesions at initial diagnosis , which results in poor prognosis ( 3 ) .
more importantly , because female uca is rare , the key prognostic factors remain poorly defined , and optimal therapeutic strategies are primarily based on limited evidence ( 4 ) . given these challenges , all available evidence should be shared and discussed so that the current knowledge base about female uca is improved . additionally , previous studies were largely based on western populations , so more evidence is required to improve our understanding of female uca in asian countries . in this study , we evaluated 19 cases of female uca in korea and reported useful information about clinical features , treatment , and prognostic factors .
we reviewed medical records of 21 consecutive patients diagnosed with female uca at our institution between august 1991 and april 2012 .
after two cases were excluded due to undefined histologic features , we finally examined 19 patients of female uca .
we evaluated the following variables associated with patient characteristics : age , initial presenting symptoms , procedure type , whether or not the patient received adjuvant therapy , histologic type , tumor size and location , recurrence and sites , whether or not the patient received salvage therapy , and recurrence - free ( rfs ) , cancer - specific ( css ) and overall survival ( os ) .
tumor location was classified as proximal , distal , and whole urethral involvement , as in a previous report ( 5 ) .
proximal tumors were defined as tumors limited to the proximal two - thirds of the urethra , while tumors were classified as " distal " if they were limited to the distal one - third of the urethra .
pathological stages were determined according to the 7th edition of the american joint committee on cancer ( ajcc ) staging system ( 6 ) .
stage ta , t1 , and t2 tumors with n0 and m0 were defined as low stage tumors , while stage t3 and t4 tumors with n1 - 2 and m1 were classified as high stage tumors ( 6 ) .
however , in cases where there was no documentation of pathological t stage , clinical t stage was used .
local recurrence was defined as cancer reappearance at the operative sites or in the pelvic cavity , and distant recurrence was tumor relapse at other sites besides the pelvic cavity .
the kaplan - meier method was used to calculate survival outcomes ( rfs , css , and os ) after initial treatment , and log - rank tests were used to determine statistically significant differences between survival curves .
we used a cox proportional hazards model to identify significant predictors of survival outcomes according to clinicopathological variables .
we rejected the 2-sided null hypothesis that there was no significant difference in cases where the p value was less than 0.05 .
consistently , we rejected the null hypothesis if the 95% confidence interval ( ci ) of point estimates excluded 1 .
all statistical analyses were performed using spss software , version 19.0 ( ibm corp . ,
armonk , ny , usa ) and graphpad prism ( graphpad software inc . , la jolla , ca , usa ) .
the institutional review board ( irb ) of seoul national university hospital approved this study ( approval number : h-1406 - 072 - 588 ) . because this study was conducted retrospectively
the institutional review board ( irb ) of seoul national university hospital approved this study ( approval number : h-1406 - 072 - 588 ) . because this study was conducted retrospectively
the median patient age at the time of diagnosis was 59.0 yr , and the median follow - up duration was 87.0 months .
voiding symptoms and blood spotting were the most common and only 1 patients had no symptoms .
with regard to tumor staging , 9 patients ( 47.4% ) had low stage tumors and 10 patients ( 52.6% ) had high stage tumors . additionally , the pathological findings were histologically diverse .
1 is a flow chart of the types of primary and adjuvant therapy used to treat patients .
while 5 patients underwent biopsies without other surgical procedures , 14 patients underwent surgery including pelvic exenteration , urethrectomy , and local mass excision .
for the 7 patients who received adjuvant therapy , such as radiation and systemic chemotherapy , there was no dominantly employed modality .
overall , 57.9% of these patients ( n=11 ) experienced tumor recurrence after primary therapy .
the rates of lymph node and bone metastases were the same ( 27.7% ) , and these were the most common sites of recurrence . summarized information for all 19 patients evaluated in this study is also provided in table 2 .
s1 shows the oncological outcomes ( rfs , css , and os ) of the patients in this study .
the 5-yr rfs , css , and os rates were 34.8% ( standard error [ se ] 22.7%-46.9% ) , 58.9% ( se 46.8%-71.0% ) , and 58.9% ( se 46.8%-71.0% ) .
all oncological outcomes were significantly different between patients with low stage ( stage i - ii ) and high stage cancer ( stage iii - iv ) ( fig .
2 ) . when patients were classified by t stage , patients with advanced t stages ( t3 ) had poor survival outcomes for rfs , css and os compared to patients with localized tumors ( t2 ) ( fig .
patients with positive lymph nodes also had worse survival outcomes by all measurements compared to node - negative patients ( fig .
4 ) . however , only rfs , but not css and os , was worse in patients with tumors involving the entire urethra compared to patients with proximal or distal tumors ( fig .
, we used a cox proportional hazards ratio regression model ( table 3 ) . in this analysis ,
positive lymph node status and advanced t stage ( t3 ) were the significant factors for prediction of all oncological outcomes .
additionally , tumor location ( entire urethral involvement ) was the significant predictor only for rfs , and not for css or os .
in the present study , we examined the clinical experiences of 19 patients with female uca at a single tertiary institution . despite the small sample size and retrospective nature of this study , it is important to report all available evidence so that we can improve our understanding of this rare malignancy .
notably , we found that cancer stage based on the ajcc classification , t stage , and lymph node status were associated with remarkable differences in rfs , css , and os between patient groups in kaplan - meier analysis .
patients with high stage tumors ( stage iii - iv ) , advanced t stage ( t3 ) , and positive lymph nodes had poor outcomes as indicated by all analyzed survival outcomes ( rfs , css , and os ) compared to their counterparts . importantly , lymph node positivity and advanced t stage were significantly predictive for poor outcomes in all survival estimates in cox regression analysis . additionally , involvement of the entire urethra remained as a predictor of rfs , but not css or os .
champ et al . ( 7 ) analyzed the female uca patients in the surveillance , epidemiology , and end results ( seer ) database and reported that older age , pathological t stage , lymph node positivity , and non - squamous histology were significantly related to poor css .
( 5 ) suggested that pathological t stage was a strong predictive factor for rfs and css .
pathological findings about lymph node status were also shown to predict survival in their study . a single center study by thyavihally et al . ( 8) reported that patients with early stage cancer ( stage i - ii ) according to the ajcc staging guidelines for female uca had better survival outcomes compared to patients with advanced stage tumors ( stage iii - iv ) , regardless of the treatment modality .
although other variables such as tumor size , histologic type , and treatment modality were not associated with any oncological outcomes in the present study , these factors have been reported as significant prognostic factors for female uca by other studies .
bracken et al . ( 3 ) evaluated 81 cases of female uca and found that patients with large tumors ( > 4 cm ) had a lower 5-yr survival rate ( about 13% ) compared to patients with small tumors ( < 2 cm ) , ( about 60% ) .
proximal tumors and lesions that involve the whole urethra have commonly been shown to be associated with poor oncological outcomes compared to distal lesions ( 9 ) .
10 ) reported that all patients with proximal urethral tumors died , while 50% of patients with distal urethral tumors survived .
the histologic type of female uca has also been suggested as a key determinant of prognosis ( 2711 ) .
the predominant tumor types are squamous cell carcinoma and urothelial carcinoma , and localized tumors of these histologic types are associated with better survival outcomes compared to tumors of less common histologic types , such as adenocarcinoma ( 21213 ) . in a study by meis et al .
( 14 ) , most patients with adenocarcinoma had locally advanced disease involving adjacent tissues or lymph node metastasis , and approximately 60% of these patients experienced cancer - related death within 2 yr of diagnosis .
( 1 ) examined 72 females with primary uca and reported that primary stage , lymph node status , and tumor site were key independent predictors of survival , but histologic type was not .
( 5 ) also found that tumor histology was not a significant predictor of recurrence or survival for female uca patients .
they noted that pathological stage was the most important factor for prediction of prognosis . in our analysis , nearly half of the patients ( n=9 ; 42.9% ) were diagnosed with adenocarcinoma at the time of presentation ; these patients tended to have poor oncological outcomes , though the results were not statistically significant ( data not shown ) .
as discussed in previous studies , therapeutic policies are typically determined by tumor size , location , and aggressiveness ( 4 ) .
for example , surgical resection or radiation can be applied to small ( < 2 cm ) distal lesions , while a combination of radical surgery and radiation therapy is recommended for more advanced stage disease ( 1516 ) .
our results consistently demonstrated that patients who underwent aggressive surgery and received adjuvant radiation had mainly larger tumors ( 3 - 4 cm ) and tumors that involved the entire urethra .
although multimodal treatment with surgery , radiation , and systemic chemotherapy could be beneficial for selected patients with advanced stage cancer , the role of adjuvant chemotherapy has not yet been definitively shown to improve oncological outcomes ( 25 ) . in the present study ,
2 patients with advanced stage lesions received chemoradiotherapy . despite the use of combination therapy , these patients experienced tumor recurrence to the bone and inguinal lymph node , respectively , and eventually died as a result of their uca .
second , 5 urologic surgeons managed female uca patients at our institution during the long study period . therefore , there was some difference in the treatment and follow - up protocols for the patients with this rare malignancy .
finally , although this is the largest report of female uca in korea , the statistical power of this study was limited by insufficient number of cases . in conclusion , high stage , advanced t stage , and lymph node positivity are associated with poor prognosis for all analyzed survival outcomes ( rfs , css , and os ) in female uca patients after primary treatment .
furthermore , lymph node status and t stage are significantly predictive of all survival outcomes .
therefore , early diagnosis and management with early identification of this rare malignancy can improve the overall prognosis of uca patients . despite the limited case number ,
our results provide valuable information that expands the current knowledge about clinicopathological characteristics and factors that predict long - term prognosis of uca patients .
( a ) recurrence - free survival , ( b ) cancer - specific survival , and ( c ) overall survival of female urethral cancer patients .
( a ) recurrence - free survival , ( b ) cancer - specific survival , and ( c ) overall survival of female urethral cancer patients according to tumor location analyzed by the kaplan - meier method and log - rank tests .
 the aim of this study was to evaluate female urethral cancer ( uca ) patients treated and followed - up during a time period spanning more than 20 yr at single institution in korea . 
 we reviewed medical records of 21 consecutive patients diagnosed with female uca at our institution between 1991 and 2012 . 
 after exclusion of two patients due to undefined histology , we examined clinicopathological variables , as well as survival outcomes of 19 patients with female uca . 
 a cox proportional hazards ratio model was used to identify significant predictors of prognosis according to variables . 
 the median age at diagnosis was 59 yr , and the median follow - up duration was 87.0 months . 
 the most common initial symptoms were voiding symptoms and blood spotting . 
 the median tumor size was 3.4 cm , and 55% of patients had lesions involving the entire urethra . 
 the most common histologic type was adenocarcinoma , and the second most common type was urothelial carcinoma . 
 fourteen patients underwent surgery , and 7 of these patients received adjuvant radiation or systemic chemotherapy . 
 eleven patients experienced tumor recurrence after primary therapy . patients with high stage disease , advanced t stage ( t3 ) , and positive lymph nodes had worse survival outcomes compared to their counterparts . particularly , lymph node positivity and advanced t stage were significant predictive factors for all survival outcomes . 
 tumor location was the only significant predictor for recurrence - free survival . although our study included a small number of patients , it conveys valuable information about this rare female urologic malignancy in a korean population.graphical abstract 
Graphical Abstract
INTRODUCTION
MATERIALS AND METHODS
Ethics statements
RESULTS
DISCUSSION
Supplementary Material