- Email: [email protected]
Primary Signet-ring Cell Carcinoma of the Urinary Bladder
Oncology Primary Signet-ring Cell Carcinoma of the Urinary Bladder Shusuke Akamatsu, Akira Takahashi, Masaaki Ito, and Keiji Ogura OBJECTIVES
METHODS
RESULTS
CONCLUSIONS
To perform a comprehensive review and analysis of the clinical characteristics of primary signet-ring cell carcinoma of the bladder cases reported in Japan. Primary signet-ring cell carcinoma of the bladder is a rare condition. To date, the largest case series conducted for this condition includes only 11 cases. A search of published data was performed using the key words, “signet ring cell” and “urinary bladder.” The Ichusi, which is the largest medical database in Japan, and the PubMed databases were searched. All articles reported from Japanese institutions were reviewed, regardless of their language. Overall, we identified 131 titles reported between 1981 and 2008. Meeting abstracts were excluded, but the unpublished cases managed at our institution were included. In all, 54 cases were comprehensively reviewed and analyzed. The median age at diagnosis was 61.2 years with male dominance (2:1). Among the selected cases, 46% had stage IV tumors. The overall survival rate at 2 years was 43%. However, none of the patients with stage IV disease at diagnosis were alive at 2 years. Multivariate analysis revealed that tumor stage and elevated carcinoembryonic antigen levels were significant prognostic factors. Of the 8 patients who were followed up for ⬎ 2 years and showed no evidence of recurrence, 7 were treated by either radical or partial cystectomy. Although the overall prognosis of this condition is poor, it is still dependent on the tumor stage at diagnosis. With early diagnosis and intervention, it may be possible to achieve long-term survival. UROLOGY 75: 615– 618, 2010. © 2010 Published by Elsevier Inc.
P
rimary signet-ring cell carcinoma of the bladder is a rare condition, accounting for ⬍ 1% of all primary bladder neoplasms. Little is known about its clinical characteristics. To date, only 2 reviews of this condition have been published, which included data from over 40 cases.1,2 Because this condition is extremely rare, it is difficult to collect sufficient data from a single institution. We performed a comprehensive review and analysis of the cases reported in the published data in an attempt to obtain further insights into this rare entity. Because most reported cases of diseases are rare or atypical, reviews and analyses of case reports are subject to publication bias. However, primary signet-ring cell carcinoma of the bladder is sufficiently rare for even typical cases to be considered worthy of publication. Our preliminary review of the published data indicated that the rate of publication of new cases from Japan has not changed significantly since 1981, when the first case of primary signet-ring cell carcinoma of the bladder was reported in Japan.3 This suggests that many typical cases con-
From the Department of Urology, Otsu Red-Cross Hospital, Otsu City, Shiga, Japan Reprint requests: Shusuke Akamatsu, M.D., Department of Urology, Otsu RedCross Hospital, 1-35 Nagara 1-Chome, Otsu City, Shiga 520-8511, Japan. E-mail: [email protected] Submitted: April 2, 2009, accepted (with revisions): June 28, 2009
© 2010 Published by Elsevier Inc.
tinue to be reported. To minimize the selection bias, we included all the relevant reports of cases from Japan, irrespective of the academic rankings of the journals.
MATERIAL AND METHODS Database Search and Inclusion Criteria A search on published data was performed using the key words “signet ring cell” and “urinary bladder.” The Ichusi database, which is the largest medical database maintained by the Japan Medical Abstracts Society, and the PubMed database were searched for relevant articles. All articles originating from Japanese institutions were reviewed, regardless of the language. Articles pertaining to metastatic tumors and urachal tumors were excluded. In all, 131 articles published between 1981 and 2008 were identified. After excluding meeting abstracts, we identified 52 cases that were reported in peer-reviewed articles. We also included 2 cases managed at our institution. A total of 54 cases were therefore analyzed.
Data Extraction Each article was reviewed independently by 2 authors. Discrepancies in the data were resolved by joint consultation between the authors. In cases with inadequate information, the original hospitals were contacted. Patients’ original charts were available for most cases reported after 2003. Data on age, sex, main complaints, cystoscopic appearance, results 0090-4295/10/$34.00 doi:10.1016/j.urology.2009.06.065
615
Table 1. Summary of patient characteristics and treatment Patient Characteristics (N ⫽ 54) Mean age ⫾ SD No. gender (%) Male Female Chief complaint (%) Macroscopic hematuria Irritative symptom Anuric symptom Cystoscopic finding (%)
Received Treatments 61.2 ⫾ 10.9 37 (69) 17 (31) 34 (63) 25 (46) 7 (13)
T stage ⱕ T1 T2 T3 T4 Unknown N stage N⫺ N⫹
Normal Edematous or inflammatory Tumorous Urine cytology (%)
1 (2) 11 (20) 40 (74)
Unknown M stage M⫺ M⫹
ⱕ Class III ⱖ Class IV Signet ring cell Unknown Hydronephrosis (%) Unilateral Bilateral Mixed histology (%) None Urothelial carcinoma Adenocarcinoma Small cell carcinoma CEA (%) Not elevated Elevated Unknown
20 (37) 16 (30) 7 (13) 11 (20)
Unknown Stage (%) I II III IV Unknown
5 (9) 14 (26)
28 15 11 39 8 7
Partial CTx monotherapy Partial CTx ⫹ radiation Partial CTx ⫹ chemotherapy Total no. partial CTx
4 1 2 7 (13)
Radical CTx monotherapy Radical CTx ⫹ radiation Radical CTx ⫹ chemotherapy Radical CTx ⫹ radiation ⫹ chemotherapy Total no. radical CTx (%)
15 4 7 5 31 (57)
Radiation monotherapy Radiation ⫹ chemotherapy (intra-arterial) Chemotherapy alone Best supportive care alone
1 1 7 7
9 (17) 5 (9) 13 (24) 25 (46) 2 (4)
41 (76) 10 (18) 2 (4) 1 (2) 19 (35) 15 (28) 20 (37)
of urine cytology, presence or absence of hydronephrosis, types of mixed histology if present, serum carcinoembryonic antigen (CEA) level, tumor-node-metastasis (TNM) stage, and American Joint Committee on Cancer stage were collected. Cystoscopic appearance was classified as normal, edematous or inflammatory, or tumorous. The CEA levels were recorded as either elevated or not elevated; if exact CEA values were reported, values greater than the upper limit of the normal range were classified as elevated. TNM stages were not reported in some articles. Original pathological specimens, when available, were reviewed by local pathologists to complement the information reported in the articles, and TNM stages were determined on the basis of the available information if possible, or were recorded as unavailable. Likewise, if American Joint Committee on Cancer stages were not reported in the articles, they were determined by the authors on the basis of the data reported in the articles and any additional available data. Data regarding surgery, radiation therapy and chemotherapy, and their effectiveness were also recorded. The dates of diagnosis and the dates and causes of death were also recorded. The period of survival was calculated by the date of diagnosis and the date of death. Patients were censored on the date when they were last confirmed to be alive.
Statistical Analysis Survival rates were calculated according to the Kaplan–Meier method, and differences in the survival between subgroups were estimated using log-rank tests. The prognostic effect of the 616
9 9 15 16 6
variables was evaluated using the Cox proportional hazard model. For all analyses, P ⬍.05 was considered to indicate significance. Only those variables that were associated with survival in univariate analysis were selected for multivariate analysis. Analysis was performed using the JMP software (SAS Institute, Cary, NC).
NEW CASES FROM OUR INSTITUTION Case 1 A 55-year-old woman presented with anuria, appetite loss, and leg edema. Computed tomography and magnetic resonance image revealed bladder wall thickening, retroperitoneal lymph node swelling, and bilateral hydronephrosis. Transurethral biopsy of the bladder mucosa revealed pure signet-ring cell carcinoma. Gastrointestinal and gynecologic examinations revealed no other primary tumor sites. The patient was diagnosed with stage IV primary signet-ring cell carcinoma of the bladder. Nephrostomy tube placement was performed and tegafur-gimeracil-oteracil (S-1), an oral derivative of 5-fluorouracil commonly used in the treatment of gastric signet-ring cell carcinoma, was administered for 4 weeks, followed by a 2-week drug-free period. This 6-week cycle was repeated 3 times. A partial response was obtained in the primary tumor and lymph nodes. However, 1 month later, the tumor showed rapid growth and the patient deUROLOGY 75 (3), 2010
Table 2. The details of the patients who survived for more than 24 months without any evidence of disease recurrence Case Age Gender 1 2
65 69
M M
3 4 5 6 7 8
72 67 70 44 67 62
M M F M M M
T 3 4a (prostate invasion) 1 1 3 3 1 3
Mixed N M Stage Histology
CEA
Treatment
Follow-up Period (mon)
0 0 0 0
III III
UC None
NA Intra-arterial CBDCA Not elevated Radical CTx
44 27
0 0 0 0 0 0
I I III III I III
UC None AC None None None
NA NA Not elevated Not elevated Elevated Not elevated
78 80 26 38 27 29
0 0 0 0 0 0
Radical CTx Radical CTx Partial CTx Radical CTx Partial CTx Radical CTx ⫹ chemotherapy
UC indicates urothelial carcinoma; AC ⫽ adenocarcinoma; NA ⫽ not available; CBDCA ⫽ carboplatin; CTx ⫽ cystectomy.
veloped peritonitis carcinomatosa. The patient died 150 days after initial presentation. Case 2 A 76-year-old man presented with bilateral leg edema. He had undergone transurethral resection for superficial bladder cancer 4 years previously. Pathologic examination of the specimen then revealed urothelial carcinoma. Computed tomography at presentation revealed bilateral hydronephrosis and enlargement of retroperitoneal lymph nodes. The cystoscopic appearance was completely normal. Signet-ring cells were detected in the urine collected from both sides of the upper urinary tract, and in a biopsy specimen from the right ureter. Biopsy of the bladder mucosa was not performed. Repeated gastrointestinal examinations revealed no evidence of the primary tumor, and positron emission tomography scans were also negative for tumors. The patient was diagnosed with primary signet-ring cell carcinoma of the urinary tract. Treatment with S-1 and carboplatin was initiated, according to the regimen known to be effective for gastric signet-ring cell carcinoma. CEA levels decreased from 98.1 to 82.8 ng/mL after the first course, although there were no changes in the sizes of the evaluable lesions. A second course was subsequently administered. However, the patient died of pulmonary embolism shortly after the second course. Autopsy findings revealed tumor invading the entire thickness of the bladder wall and extending into the pelvic and abdominal cavities. The tumor had bilaterally metastasized to the lungs and the adrenal glands and also to the left kidney and pancreas. The bladder was confirmed as the primary site of tumor origin.
RESULTS A summary of the extracted data is provided in Table 1. The median age at diagnosis was 61.2 years and the patient population showed a male dominance (2:1). Gross hematuria was a presenting symptom in 63% of cases, whereas symptoms of bladder irritation were reported in 46% and anuric symptoms were noted in 13% of cases. Unlike typical urothelial carcinomas, the tumorous lesions could not be identified by cystoscopy in 22% of cases. The most dominant histologic type was pure UROLOGY 75 (3), 2010
Figure 1. Kaplan–Meier survival curve depicting difference in overall survival between stage I-III and stage IV tumors.
signet-ring cell carcinoma, whereas urothelial carcinoma was the most commonly associated condition in cases of mixed histology. Of the cases with reported CEA measurements, 44% demonstrated increased CEA levels. At the time of diagnosis, 46% of the patients had stage IV disease. The details of the treatments are also listed in Table 1. Radical or partial cystectomy was performed in 70% of cases. The most widely used chemotherapeutic drugs were platinum-based drugs, followed by 5-fluorouracil derivatives and anthracyclines. However, complete responses were only observed in 2 and partial responses in only 3 cases. No standard treatment regimen could be established. The details of the patients who survived for ⬎ 2 years without any evidence of disease recurrence are given in Table 2. It is notable that, of the 8 survivors, 5 had stage III disease at diagnosis and 7 were treated with either partial or radical cystectomy. Overall and cancer-specific survival rates at 2 years were 43% and 45%, respectively. However, no patients with stage IV disease at diagnosis were alive at 2 years (Fig. 1). Univariate analysis revealed that stage IV disease, pure histologic type, and elevated levels of CEA were predictors of poor survival. Multivariate analysis revealed that stage IV 617
Table 3. Analysis of the factors affecting survival Univariate Analysis HR (95% CI) Age (⬍ 65 vs ⱖ 65) CS appearance Tumorous vs nontumorous Stage IV vs I-III Pure signet ring cell vs mixed histology CEA elevation Radical or partial cystectomy
0.76 (0.5-1.22) 2.88 (1.78-5.12) 2.13 (1.16-5.31) 1.62 (1.05-2.55) 0.68 (0.46-1.03)
P
.24 ⬍.0001 .01 .03 .07
Multivariate Analysis HR (95% CI) P 1.18 (0.56-2.4)
.65
2.93 (1.32-7.41) 1.36 (0.54-6.04) 1.82 (1.05-3.36) 0.74 (0.37-1.53)
.008 .56 .03 .41
HR indicates hazard ratio; CI ⫽ confidence interval; CS ⫽ cystoscopy.
disease and elevated levels of CEA were significant independent predictors of poor survival (Table 3).
COMMENT Primary signet-ring cell carcinoma of the bladder is an extremely rare tumor that was first described by Saphir4 in 1955. In 1996, Holmäng et al5 identified 10 cases of primary signet-ring cell carcinoma of the bladder from their prospective and retrospective database of 1529 bladder neoplasms in Sweden. In 1991, Grignon et al1 identified 11 cases of this malignancy from the database at the MD Anderson Cancer Center, which included cases reported between 1948 and 1987. Their case series is the largest published on this condition to date, and includes data on 35 previously reported cases, and a review of the clinical characteristics of this rare neoplasm. They reported the median age at diagnosis to be 55.8 years, with a male dominance (3:1). Gross hematuria was recorded in 64.1% of cases, whereas symptoms of bladder irritation were noted in 61.5%. No mucosal or mass lesions were detected during cystoscopy in 47.1% of cases, and cystoscopic appearances were frequently described as “edematous mucosa.” In 2 cases, cystoscopy failed to reveal any mucosal lesions. The tumor stage at the time of diagnosis was reported in 34 cases, of which 22 were stage IV tumors. The 5-year survival rates for patients with stage II, III, and IV tumors were 75%, 38%, and 12%, respectively. Univariate analysis revealed poorer prognoses for pure diffuse tumors and stage IV tumors compared with mixed tumors and stage II tumors, respectively. It is important to note, however, that their definition of mixed tumor was different from ours. They further classified adenocarcinomas into pure signet ring, colloid, enteric, and nonspecific adenocarcinomas. In 1993, Fiter et al2 reviewed the published data available and reported a new case. They found that transitional cell carcinoma (urothelial carcinoma) was associated with signet-ring cell carcinoma in at least one-third of cases, and that CEA levels were elevated in some cases. Our analysis supports these findings and further confirms the use of elevated CEA levels as a prognostic marker.
618
Although reports have indicated that chemotherapeutic agents such as S-1 are effective treatment options for gastric signet-ring cell carcinoma,6 our review failed to validate the effectiveness of this treatment in patients with bladder signet-ring cell carcinoma. The unfavorable results of radiotherapy and chemotherapy suggest that radical surgery is the treatment of choice. Although some authors advocate partial cystectomy for the management of patients with bladder signet-ring cell carcinoma, most reports in published data indicate that radical cystectomy is the more appropriate option. Our study was limited by the fact that its conclusions were based on the analysis of case reports. However, the concordance of our results with those of previous reports supports the reliability of our findings. In a situation where it is difficult to gather a sufficient number of cases, even across multiple institutions, our results could provide important insights into this extremely rare condition.
CONCLUSIONS The overall prognosis of primary signet-ring cell carcinoma is poor, probably because of its delayed presentation, although the prognosis of cases diagnosed as earlystage tumors is encouraging. Elevated CEA levels may be of value as a prognostic marker. Radical cystectomy appears to provide the best outcome. References 1. Grignon DJ, Ro JY, Johnson DE, et al. Primary signet-ring cell carcinoma of the urinary bladder. Am J Clin Pathol. 1991;95: 13-20. 2. Fiter L, Gimeno F, Tejeda LG, et al. Signet-ring cell adenocarcinoma of bladder. Urology. 1993;41:30-33. 3. Yoshida H, Iwata H, Fukunishi R, et al. Primary signet-ring cell carcinoma of urinary bladder. Urology. 1981;17:481-483. 4. Saphir O. Signet-ring cell carcinoma of the urinary bladder. Am J Pathol. 1995;31:223-231. 5. Holmäng S, Borghede G, Johansson S. Primary signet ring cell carcinoma of the bladder: a report on 10 cases. Scand J Urol Nephrol. 1997;31:145-148. 6. Koizumi W, Kurihara M, Hasegawa K, et al. Phase II study of S-1, a novel oral derivative of 5-fluorouracil, in advanced gastric cancer. Oncology. 2000;58:191-197.
UROLOGY 75 (3), 2010
METHODS
RESULTS
CONCLUSIONS
To perform a comprehensive review and analysis of the clinical characteristics of primary signet-ring cell carcinoma of the bladder cases reported in Japan. Primary signet-ring cell carcinoma of the bladder is a rare condition. To date, the largest case series conducted for this condition includes only 11 cases. A search of published data was performed using the key words, “signet ring cell” and “urinary bladder.” The Ichusi, which is the largest medical database in Japan, and the PubMed databases were searched. All articles reported from Japanese institutions were reviewed, regardless of their language. Overall, we identified 131 titles reported between 1981 and 2008. Meeting abstracts were excluded, but the unpublished cases managed at our institution were included. In all, 54 cases were comprehensively reviewed and analyzed. The median age at diagnosis was 61.2 years with male dominance (2:1). Among the selected cases, 46% had stage IV tumors. The overall survival rate at 2 years was 43%. However, none of the patients with stage IV disease at diagnosis were alive at 2 years. Multivariate analysis revealed that tumor stage and elevated carcinoembryonic antigen levels were significant prognostic factors. Of the 8 patients who were followed up for ⬎ 2 years and showed no evidence of recurrence, 7 were treated by either radical or partial cystectomy. Although the overall prognosis of this condition is poor, it is still dependent on the tumor stage at diagnosis. With early diagnosis and intervention, it may be possible to achieve long-term survival. UROLOGY 75: 615– 618, 2010. © 2010 Published by Elsevier Inc.
P
rimary signet-ring cell carcinoma of the bladder is a rare condition, accounting for ⬍ 1% of all primary bladder neoplasms. Little is known about its clinical characteristics. To date, only 2 reviews of this condition have been published, which included data from over 40 cases.1,2 Because this condition is extremely rare, it is difficult to collect sufficient data from a single institution. We performed a comprehensive review and analysis of the cases reported in the published data in an attempt to obtain further insights into this rare entity. Because most reported cases of diseases are rare or atypical, reviews and analyses of case reports are subject to publication bias. However, primary signet-ring cell carcinoma of the bladder is sufficiently rare for even typical cases to be considered worthy of publication. Our preliminary review of the published data indicated that the rate of publication of new cases from Japan has not changed significantly since 1981, when the first case of primary signet-ring cell carcinoma of the bladder was reported in Japan.3 This suggests that many typical cases con-
From the Department of Urology, Otsu Red-Cross Hospital, Otsu City, Shiga, Japan Reprint requests: Shusuke Akamatsu, M.D., Department of Urology, Otsu RedCross Hospital, 1-35 Nagara 1-Chome, Otsu City, Shiga 520-8511, Japan. E-mail: [email protected] Submitted: April 2, 2009, accepted (with revisions): June 28, 2009
© 2010 Published by Elsevier Inc.
tinue to be reported. To minimize the selection bias, we included all the relevant reports of cases from Japan, irrespective of the academic rankings of the journals.
MATERIAL AND METHODS Database Search and Inclusion Criteria A search on published data was performed using the key words “signet ring cell” and “urinary bladder.” The Ichusi database, which is the largest medical database maintained by the Japan Medical Abstracts Society, and the PubMed database were searched for relevant articles. All articles originating from Japanese institutions were reviewed, regardless of the language. Articles pertaining to metastatic tumors and urachal tumors were excluded. In all, 131 articles published between 1981 and 2008 were identified. After excluding meeting abstracts, we identified 52 cases that were reported in peer-reviewed articles. We also included 2 cases managed at our institution. A total of 54 cases were therefore analyzed.
Data Extraction Each article was reviewed independently by 2 authors. Discrepancies in the data were resolved by joint consultation between the authors. In cases with inadequate information, the original hospitals were contacted. Patients’ original charts were available for most cases reported after 2003. Data on age, sex, main complaints, cystoscopic appearance, results 0090-4295/10/$34.00 doi:10.1016/j.urology.2009.06.065
615
Table 1. Summary of patient characteristics and treatment Patient Characteristics (N ⫽ 54) Mean age ⫾ SD No. gender (%) Male Female Chief complaint (%) Macroscopic hematuria Irritative symptom Anuric symptom Cystoscopic finding (%)
Received Treatments 61.2 ⫾ 10.9 37 (69) 17 (31) 34 (63) 25 (46) 7 (13)
T stage ⱕ T1 T2 T3 T4 Unknown N stage N⫺ N⫹
Normal Edematous or inflammatory Tumorous Urine cytology (%)
1 (2) 11 (20) 40 (74)
Unknown M stage M⫺ M⫹
ⱕ Class III ⱖ Class IV Signet ring cell Unknown Hydronephrosis (%) Unilateral Bilateral Mixed histology (%) None Urothelial carcinoma Adenocarcinoma Small cell carcinoma CEA (%) Not elevated Elevated Unknown
20 (37) 16 (30) 7 (13) 11 (20)
Unknown Stage (%) I II III IV Unknown
5 (9) 14 (26)
28 15 11 39 8 7
Partial CTx monotherapy Partial CTx ⫹ radiation Partial CTx ⫹ chemotherapy Total no. partial CTx
4 1 2 7 (13)
Radical CTx monotherapy Radical CTx ⫹ radiation Radical CTx ⫹ chemotherapy Radical CTx ⫹ radiation ⫹ chemotherapy Total no. radical CTx (%)
15 4 7 5 31 (57)
Radiation monotherapy Radiation ⫹ chemotherapy (intra-arterial) Chemotherapy alone Best supportive care alone
1 1 7 7
9 (17) 5 (9) 13 (24) 25 (46) 2 (4)
41 (76) 10 (18) 2 (4) 1 (2) 19 (35) 15 (28) 20 (37)
of urine cytology, presence or absence of hydronephrosis, types of mixed histology if present, serum carcinoembryonic antigen (CEA) level, tumor-node-metastasis (TNM) stage, and American Joint Committee on Cancer stage were collected. Cystoscopic appearance was classified as normal, edematous or inflammatory, or tumorous. The CEA levels were recorded as either elevated or not elevated; if exact CEA values were reported, values greater than the upper limit of the normal range were classified as elevated. TNM stages were not reported in some articles. Original pathological specimens, when available, were reviewed by local pathologists to complement the information reported in the articles, and TNM stages were determined on the basis of the available information if possible, or were recorded as unavailable. Likewise, if American Joint Committee on Cancer stages were not reported in the articles, they were determined by the authors on the basis of the data reported in the articles and any additional available data. Data regarding surgery, radiation therapy and chemotherapy, and their effectiveness were also recorded. The dates of diagnosis and the dates and causes of death were also recorded. The period of survival was calculated by the date of diagnosis and the date of death. Patients were censored on the date when they were last confirmed to be alive.
Statistical Analysis Survival rates were calculated according to the Kaplan–Meier method, and differences in the survival between subgroups were estimated using log-rank tests. The prognostic effect of the 616
9 9 15 16 6
variables was evaluated using the Cox proportional hazard model. For all analyses, P ⬍.05 was considered to indicate significance. Only those variables that were associated with survival in univariate analysis were selected for multivariate analysis. Analysis was performed using the JMP software (SAS Institute, Cary, NC).
NEW CASES FROM OUR INSTITUTION Case 1 A 55-year-old woman presented with anuria, appetite loss, and leg edema. Computed tomography and magnetic resonance image revealed bladder wall thickening, retroperitoneal lymph node swelling, and bilateral hydronephrosis. Transurethral biopsy of the bladder mucosa revealed pure signet-ring cell carcinoma. Gastrointestinal and gynecologic examinations revealed no other primary tumor sites. The patient was diagnosed with stage IV primary signet-ring cell carcinoma of the bladder. Nephrostomy tube placement was performed and tegafur-gimeracil-oteracil (S-1), an oral derivative of 5-fluorouracil commonly used in the treatment of gastric signet-ring cell carcinoma, was administered for 4 weeks, followed by a 2-week drug-free period. This 6-week cycle was repeated 3 times. A partial response was obtained in the primary tumor and lymph nodes. However, 1 month later, the tumor showed rapid growth and the patient deUROLOGY 75 (3), 2010
Table 2. The details of the patients who survived for more than 24 months without any evidence of disease recurrence Case Age Gender 1 2
65 69
M M
3 4 5 6 7 8
72 67 70 44 67 62
M M F M M M
T 3 4a (prostate invasion) 1 1 3 3 1 3
Mixed N M Stage Histology
CEA
Treatment
Follow-up Period (mon)
0 0 0 0
III III
UC None
NA Intra-arterial CBDCA Not elevated Radical CTx
44 27
0 0 0 0 0 0
I I III III I III
UC None AC None None None
NA NA Not elevated Not elevated Elevated Not elevated
78 80 26 38 27 29
0 0 0 0 0 0
Radical CTx Radical CTx Partial CTx Radical CTx Partial CTx Radical CTx ⫹ chemotherapy
UC indicates urothelial carcinoma; AC ⫽ adenocarcinoma; NA ⫽ not available; CBDCA ⫽ carboplatin; CTx ⫽ cystectomy.
veloped peritonitis carcinomatosa. The patient died 150 days after initial presentation. Case 2 A 76-year-old man presented with bilateral leg edema. He had undergone transurethral resection for superficial bladder cancer 4 years previously. Pathologic examination of the specimen then revealed urothelial carcinoma. Computed tomography at presentation revealed bilateral hydronephrosis and enlargement of retroperitoneal lymph nodes. The cystoscopic appearance was completely normal. Signet-ring cells were detected in the urine collected from both sides of the upper urinary tract, and in a biopsy specimen from the right ureter. Biopsy of the bladder mucosa was not performed. Repeated gastrointestinal examinations revealed no evidence of the primary tumor, and positron emission tomography scans were also negative for tumors. The patient was diagnosed with primary signet-ring cell carcinoma of the urinary tract. Treatment with S-1 and carboplatin was initiated, according to the regimen known to be effective for gastric signet-ring cell carcinoma. CEA levels decreased from 98.1 to 82.8 ng/mL after the first course, although there were no changes in the sizes of the evaluable lesions. A second course was subsequently administered. However, the patient died of pulmonary embolism shortly after the second course. Autopsy findings revealed tumor invading the entire thickness of the bladder wall and extending into the pelvic and abdominal cavities. The tumor had bilaterally metastasized to the lungs and the adrenal glands and also to the left kidney and pancreas. The bladder was confirmed as the primary site of tumor origin.
RESULTS A summary of the extracted data is provided in Table 1. The median age at diagnosis was 61.2 years and the patient population showed a male dominance (2:1). Gross hematuria was a presenting symptom in 63% of cases, whereas symptoms of bladder irritation were reported in 46% and anuric symptoms were noted in 13% of cases. Unlike typical urothelial carcinomas, the tumorous lesions could not be identified by cystoscopy in 22% of cases. The most dominant histologic type was pure UROLOGY 75 (3), 2010
Figure 1. Kaplan–Meier survival curve depicting difference in overall survival between stage I-III and stage IV tumors.
signet-ring cell carcinoma, whereas urothelial carcinoma was the most commonly associated condition in cases of mixed histology. Of the cases with reported CEA measurements, 44% demonstrated increased CEA levels. At the time of diagnosis, 46% of the patients had stage IV disease. The details of the treatments are also listed in Table 1. Radical or partial cystectomy was performed in 70% of cases. The most widely used chemotherapeutic drugs were platinum-based drugs, followed by 5-fluorouracil derivatives and anthracyclines. However, complete responses were only observed in 2 and partial responses in only 3 cases. No standard treatment regimen could be established. The details of the patients who survived for ⬎ 2 years without any evidence of disease recurrence are given in Table 2. It is notable that, of the 8 survivors, 5 had stage III disease at diagnosis and 7 were treated with either partial or radical cystectomy. Overall and cancer-specific survival rates at 2 years were 43% and 45%, respectively. However, no patients with stage IV disease at diagnosis were alive at 2 years (Fig. 1). Univariate analysis revealed that stage IV disease, pure histologic type, and elevated levels of CEA were predictors of poor survival. Multivariate analysis revealed that stage IV 617
Table 3. Analysis of the factors affecting survival Univariate Analysis HR (95% CI) Age (⬍ 65 vs ⱖ 65) CS appearance Tumorous vs nontumorous Stage IV vs I-III Pure signet ring cell vs mixed histology CEA elevation Radical or partial cystectomy
0.76 (0.5-1.22) 2.88 (1.78-5.12) 2.13 (1.16-5.31) 1.62 (1.05-2.55) 0.68 (0.46-1.03)
P
.24 ⬍.0001 .01 .03 .07
Multivariate Analysis HR (95% CI) P 1.18 (0.56-2.4)
.65
2.93 (1.32-7.41) 1.36 (0.54-6.04) 1.82 (1.05-3.36) 0.74 (0.37-1.53)
.008 .56 .03 .41
HR indicates hazard ratio; CI ⫽ confidence interval; CS ⫽ cystoscopy.
disease and elevated levels of CEA were significant independent predictors of poor survival (Table 3).
COMMENT Primary signet-ring cell carcinoma of the bladder is an extremely rare tumor that was first described by Saphir4 in 1955. In 1996, Holmäng et al5 identified 10 cases of primary signet-ring cell carcinoma of the bladder from their prospective and retrospective database of 1529 bladder neoplasms in Sweden. In 1991, Grignon et al1 identified 11 cases of this malignancy from the database at the MD Anderson Cancer Center, which included cases reported between 1948 and 1987. Their case series is the largest published on this condition to date, and includes data on 35 previously reported cases, and a review of the clinical characteristics of this rare neoplasm. They reported the median age at diagnosis to be 55.8 years, with a male dominance (3:1). Gross hematuria was recorded in 64.1% of cases, whereas symptoms of bladder irritation were noted in 61.5%. No mucosal or mass lesions were detected during cystoscopy in 47.1% of cases, and cystoscopic appearances were frequently described as “edematous mucosa.” In 2 cases, cystoscopy failed to reveal any mucosal lesions. The tumor stage at the time of diagnosis was reported in 34 cases, of which 22 were stage IV tumors. The 5-year survival rates for patients with stage II, III, and IV tumors were 75%, 38%, and 12%, respectively. Univariate analysis revealed poorer prognoses for pure diffuse tumors and stage IV tumors compared with mixed tumors and stage II tumors, respectively. It is important to note, however, that their definition of mixed tumor was different from ours. They further classified adenocarcinomas into pure signet ring, colloid, enteric, and nonspecific adenocarcinomas. In 1993, Fiter et al2 reviewed the published data available and reported a new case. They found that transitional cell carcinoma (urothelial carcinoma) was associated with signet-ring cell carcinoma in at least one-third of cases, and that CEA levels were elevated in some cases. Our analysis supports these findings and further confirms the use of elevated CEA levels as a prognostic marker.
618
Although reports have indicated that chemotherapeutic agents such as S-1 are effective treatment options for gastric signet-ring cell carcinoma,6 our review failed to validate the effectiveness of this treatment in patients with bladder signet-ring cell carcinoma. The unfavorable results of radiotherapy and chemotherapy suggest that radical surgery is the treatment of choice. Although some authors advocate partial cystectomy for the management of patients with bladder signet-ring cell carcinoma, most reports in published data indicate that radical cystectomy is the more appropriate option. Our study was limited by the fact that its conclusions were based on the analysis of case reports. However, the concordance of our results with those of previous reports supports the reliability of our findings. In a situation where it is difficult to gather a sufficient number of cases, even across multiple institutions, our results could provide important insights into this extremely rare condition.
CONCLUSIONS The overall prognosis of primary signet-ring cell carcinoma is poor, probably because of its delayed presentation, although the prognosis of cases diagnosed as earlystage tumors is encouraging. Elevated CEA levels may be of value as a prognostic marker. Radical cystectomy appears to provide the best outcome. References 1. Grignon DJ, Ro JY, Johnson DE, et al. Primary signet-ring cell carcinoma of the urinary bladder. Am J Clin Pathol. 1991;95: 13-20. 2. Fiter L, Gimeno F, Tejeda LG, et al. Signet-ring cell adenocarcinoma of bladder. Urology. 1993;41:30-33. 3. Yoshida H, Iwata H, Fukunishi R, et al. Primary signet-ring cell carcinoma of urinary bladder. Urology. 1981;17:481-483. 4. Saphir O. Signet-ring cell carcinoma of the urinary bladder. Am J Pathol. 1995;31:223-231. 5. Holmäng S, Borghede G, Johansson S. Primary signet ring cell carcinoma of the bladder: a report on 10 cases. Scand J Urol Nephrol. 1997;31:145-148. 6. Koizumi W, Kurihara M, Hasegawa K, et al. Phase II study of S-1, a novel oral derivative of 5-fluorouracil, in advanced gastric cancer. Oncology. 2000;58:191-197.
UROLOGY 75 (3), 2010