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Nested variant of urothelial carcinoma: A rare presentation
CASE REPORT
NESTED VARIANT OF UROTHELIAL CARCINOMA: A RARE PRESENTATION SUE MIN OOI, JUSTIN VIVIAN, RAJA SINNIAH,
AND
SIMON TROON
ABSTRACT We report a rare presentation of a nested variant of urothelial carcinoma with liver and bone metastases in a 74-year-old man admitted to the hospital with bilateral hydronephrosis and acute renal failure. At cystoscopy, both ureters were obstructed, with the right ureter narrowed along its entire length. Subsequent histopathologic examination from the ureteral resection revealed nested variant of urothelial carcinoma. Bilateral stents were placed, and the patient survived 12 months with a good partial response to chemotherapy. A total of 76 cases of nested variant of urothelial carcinoma have been reported worldwide. Our patient was the first, to our knowledge, to present with bilateral hydronephrosis and tumor extension along one ureter. UROLOGY 67: 845.e3–845.e5, 2006. © 2006 Elsevier Inc.
W
e report a rare presentation of nested variant of urothelial carcinoma (NVUC) in a patient who presented with bilateral hydronephrosis and acute renal failure. The patient had tumor involving both ureters and extending along the entire length of the right ureter. CASE REPORT
A 74-year-old man became anuric after a 2-week history of oliguria and gross hematuria. He had been constitutionally unwell, with anorexia, lethargy, and vague abdominal pain. Computed tomography, performed for investigation of right iliac fossa pain, 4 months previously had shown right hydronephrosis. At that time, flexible cystoscopy detected no abnormality, and the patient failed to attend for follow-up investigations. Serum biochemistry at presentation revealed potassium 7.5 mmol/L, urea 32.5 mmol/L, and creatinine 1420 mol/L. Computed tomography showed bilateral hydronephrosis and a low attenuation liver lesion. Ultrasonography demonstrated multiple hypoechoic liver lesions, the largest measuring 53 ⫻ 54 mm. Irregular epithelial cells and numerous polyFrom the Departments of Surgery, Urology, Pathology, and Medical Oncology, Royal Perth Hospital, Perth, Australia Address for correspondence: Dr. Sue Min Ooi, M.B.B.S., Grad Dip Surg Anat, Department of Clinical Services, Royal Perth Hospital, P.O. Box X2213, Perth, Australia 6847. E-mail: [email protected] Submitted: June 3, 2005, accepted (with revisions): October 4, 2005 © 2006 ELSEVIER INC. ALL RIGHTS RESERVED
morphs and lymphocytes were seen on urine cytology. He underwent hemodialysis four times before undergoing surgery. At cystoscopy, the right ureteral orifice was obliterated by tumor. The orifice was resected, and retrograde pyelography showed a narrow right ureter to the pelviureteral junction. The left ureteral orifice appeared normal superficially, but could not be cannulated beyond 1 cm. The orifice was resected to allow insertion of a catheter. Retrograde pyelography showed a dilated left ureter. Both ureters were stented. The patient required intravenous fluids to manage postobstructive diuresis. The creatinine returned to 190 mol/L. A bone scan was performed to investigate the right leg pain and demonstrated osseous metastatic disease involving the L2, L3, and L4 vertebral bodies, left anterior iliac crest, and left 10th rib. Histopathologic analysis of the ureteral orifice biopsies demonstrated extensive infiltrating urothelial carcinoma forming nests and islands of malignant cells with nuclear pleomorphism, well-defined nucleoli, and mitotic activity (Fig. 1). The tumor invaded deep into the muscularis propria, involving the full thickness of the biopsies, and cells were seen within the vascular channels in the submucosa. The tumor cells were strongly and diffusely positive for cytokeratins AE1/AE3 and CK7 and focally for CK20 and negative for prostate-specific antigen and prostatic acid phosphatase. Four ultrasound-guided aspirates of the liver lesions were obtained, and the smears showed pre0090-4295/06/$32.00 doi:10.1016/j.urology.2005.10.002 845.e3
FIGURE 1. Nests of infiltrating malignant epithelial cells are seen to originate from the surface urothelium (a) and infiltrate deep into muscularis (b). Hematoxylineosin stain, original magnification ⫻210.
dominantly neoplastic cells similar to those in the ureteral biopsy. The final diagnosis was of high-grade urothelial transitional cell carcinoma, nested variant, with liver and bone metastases. After discussion at a multidisciplinary urologic oncology meeting, a decision was made to treat. After discharge, the patient underwent systemic chemotherapy with gemcitabine and carboplatin. The patient obtained a partial response to treatment, and computed tomography performed after chemotherapy showed resolution of hydronephrosis and a decrease in the size of the liver lesions. The bony deposits remained stable, with no evidence of progressive disease on bone scanning. The patient eventually died of the disease 12 months after diagnosis. COMMENT NVUC was recently acknowledged by the World Health Organization as an “uncommon aggressive tumor,” with few reported cases and a 70% mortality rate 4 to 40 months after diagnosis despite therapy.1 The incidence of NVUC has been estimated to be 0.8% of all invasive bladder carcinoma.2 A literature search revealed 76 cases reported in 15 pub845.e4
lished articles, with 1 to 16 subjects per study.2–10 The prognosis is poor, with two case series reporting survival rates of 19% during a mean of 16.6 months and 30% within 4 to 40 months.2,11 However, a more recent case series by Lin et al.6 reported a 92% survival rate within a mean of 17.6 months. The patients are predominantly male and present with macroscopic hematuria, flank pain, or dysuria. To our knowledge, this is the first case reported in which the patient presented with bilateral ureteral obstruction and acute renal failure with extension of the tumor along the entire length of the right ureter. NVUC is characterized by irregular nests and/or tubules of transitional carcinoma cells infiltrating the lamina propria without involvement of the mucosal layer.3 First described in 1979 by Stern12 as a benign lesion, the malignant nature of NVUC was recognized in 1989 by Talbert and Young.13 The cytologic changes of NVUC are subtle and bland. Cardillo et al.14 reviewed urine specimens from 13 patients with histologically confirmed NVUC and identified morphologically similar cells. Nine of these specimens were initially diagnosed as benign; hence, they concluded that a primary diagnosis based on urine cytology was not recommended owing to the subtleness of the findings. The differential diagnoses include squamous metaplasia, nephrogenic adenoma, reactive changes, and low-grade papillary urothelial carcinoma. The histopathologic features may mimic florid von Brunn nests (cystitis glandularis), cystitis cystica, inverted papilloma, adenocarcinoma, nephrogenic metaplasia, and paraganglioma.15 The optimal modality of treatment is uncertain because NVUC is rare and no randomized studies exist. Holmang and Johansson reported no survival benefit with radiotherapy in their series of 6 patients (Stage T1 to T4b).2 In the series of 12 patients published by Lin et al., 10 of 12 patients underwent cystectomy with or without chemotherapy, suggesting that surgical resection improves the survival rates for patients with nonmetastatic disease.6 Traditionally, the standard treatment for patients with locally advanced or metastatic urothelial carcinoma is chemotherapy using methotrexate, vinblastine, doxorubicin, and cisplatin. The gemcitabine-cisplatin regimen has been shown to have equivalent overall response rates, with less toxicity (range 41% to 57%), a complete response in 15% to 22%, and a median survival of 12.5 to 14.3 months.16 REFERENCES 1. World Health Organization Classification of Tumors. Infiltrating urothelial carcinoma, in Eble JN, Sauter G, Epstein JI, et al (Eds): Tumors of the Urinary System and Male Genital Organs. Lyon, IARC Press, 2004, pp 93–110. UROLOGY 67 (4), 2006
2. Holmang S, and Johansson SL: The nested variant of transitional cell carcinoma: a rare neoplasm with poor prognosis. Scand J Urol Nephrol 35: 102–105, 2001. 3. Tatsura H, Ogawa K, Sakata T, et al: A nested variant of transitional cell carcinoma of the urinary bladder: a case report. Jap J Clin Oncol 31: 287–289, 2001. 4. Ozdemir BH, Ozdemir OG, and Sertcelik A: The nested variant of the transitional cell bladder carcinoma: a case report and review of the literature. Int Urol Nephrol 32: 257–258, 2000. 5. Volmar KE, Chan TY, De Marzo AM, et al: Florid von Brunn nests mimicking urothelial carcinoma: a morphologic and immunohistochemical comparison to the nested variant of urothelial carcinoma. Am J Surg Pathol 27: 243– 252, 2003. 6. Lin O, Cardillo M, Dalbagni G, et al: Nested variant of urothelial carcinoma: a clinicopathological and immunohistochemical study of 12 cases. Mod Pathol 16: 1289 –1298, 2003. 7. Liedberg F, Chebil G, Davidsson T, et al: The nested variant of urothelial carcinoma: a rare but important bladder neoplasm with aggressive behavior. Urol Oncol 21: 7–9, 2003. 8. Badoual C, Bergemer-Fouquet AM, Renjard L, et al: An unusual variant of urothelial carcinoma: the “nested variant of urothelial carcinoma”—report of two cases. Ann Pathol 20: 400 – 401, 2000.
UROLOGY 67 (4), 2006
9. Xiao GQ, Savage SJ, Gribetz ME, et al: The nested variant of urothelial carcinoma: clinicopathology of 2 cases. Arch Pathol Lab Med 127: 333–336, 2003. 10. Rioux-Leclercq N, Staerman F, Patard JJ, et al: Unusual variety of bladder urothelial carcinoma: “nest type” microlobular carcinoma: report of an anatomoclinical case and review of the literature. Ann Urol (Paris) 34: 9 –12, 2000. 11. Drew PA, Furman J, Civantos F, et al: The nested variant of transitional cell carcinoma: an aggressive neoplasm with innocuous histology. Mod Pathol 9: 989 –994, 1996. 12. Stern JB: Unusual benign bladder tumor of Brunn nest origin. Urology 14:288 –289, 1979. 13. Talbert ML, and Young RH: Carcinomas of the urinary bladder with deceptively benign-appearing foci. A report of three cases. Am J Surg Pathol 13:374 –381, 1989. 14. Cardillo M, Reuter V, and Lin O: Cytologic features of the nested variant of urothelial carcinoma: a study of seven cases. Cancer Cytopathol 99: 23–27, 2003. 15. Paik S, and Park M: The nested variant of transitional cell carcinoma of the urinary bladder. Br J Urol 78: 793– 794, 1996. 16. Von der Maase H: Current and future perspectives in advanced bladder cancer: is there a new standard? Semin Oncol 29: 3–14, 2003.
845.e5
NESTED VARIANT OF UROTHELIAL CARCINOMA: A RARE PRESENTATION SUE MIN OOI, JUSTIN VIVIAN, RAJA SINNIAH,
AND
SIMON TROON
ABSTRACT We report a rare presentation of a nested variant of urothelial carcinoma with liver and bone metastases in a 74-year-old man admitted to the hospital with bilateral hydronephrosis and acute renal failure. At cystoscopy, both ureters were obstructed, with the right ureter narrowed along its entire length. Subsequent histopathologic examination from the ureteral resection revealed nested variant of urothelial carcinoma. Bilateral stents were placed, and the patient survived 12 months with a good partial response to chemotherapy. A total of 76 cases of nested variant of urothelial carcinoma have been reported worldwide. Our patient was the first, to our knowledge, to present with bilateral hydronephrosis and tumor extension along one ureter. UROLOGY 67: 845.e3–845.e5, 2006. © 2006 Elsevier Inc.
W
e report a rare presentation of nested variant of urothelial carcinoma (NVUC) in a patient who presented with bilateral hydronephrosis and acute renal failure. The patient had tumor involving both ureters and extending along the entire length of the right ureter. CASE REPORT
A 74-year-old man became anuric after a 2-week history of oliguria and gross hematuria. He had been constitutionally unwell, with anorexia, lethargy, and vague abdominal pain. Computed tomography, performed for investigation of right iliac fossa pain, 4 months previously had shown right hydronephrosis. At that time, flexible cystoscopy detected no abnormality, and the patient failed to attend for follow-up investigations. Serum biochemistry at presentation revealed potassium 7.5 mmol/L, urea 32.5 mmol/L, and creatinine 1420 mol/L. Computed tomography showed bilateral hydronephrosis and a low attenuation liver lesion. Ultrasonography demonstrated multiple hypoechoic liver lesions, the largest measuring 53 ⫻ 54 mm. Irregular epithelial cells and numerous polyFrom the Departments of Surgery, Urology, Pathology, and Medical Oncology, Royal Perth Hospital, Perth, Australia Address for correspondence: Dr. Sue Min Ooi, M.B.B.S., Grad Dip Surg Anat, Department of Clinical Services, Royal Perth Hospital, P.O. Box X2213, Perth, Australia 6847. E-mail: [email protected] Submitted: June 3, 2005, accepted (with revisions): October 4, 2005 © 2006 ELSEVIER INC. ALL RIGHTS RESERVED
morphs and lymphocytes were seen on urine cytology. He underwent hemodialysis four times before undergoing surgery. At cystoscopy, the right ureteral orifice was obliterated by tumor. The orifice was resected, and retrograde pyelography showed a narrow right ureter to the pelviureteral junction. The left ureteral orifice appeared normal superficially, but could not be cannulated beyond 1 cm. The orifice was resected to allow insertion of a catheter. Retrograde pyelography showed a dilated left ureter. Both ureters were stented. The patient required intravenous fluids to manage postobstructive diuresis. The creatinine returned to 190 mol/L. A bone scan was performed to investigate the right leg pain and demonstrated osseous metastatic disease involving the L2, L3, and L4 vertebral bodies, left anterior iliac crest, and left 10th rib. Histopathologic analysis of the ureteral orifice biopsies demonstrated extensive infiltrating urothelial carcinoma forming nests and islands of malignant cells with nuclear pleomorphism, well-defined nucleoli, and mitotic activity (Fig. 1). The tumor invaded deep into the muscularis propria, involving the full thickness of the biopsies, and cells were seen within the vascular channels in the submucosa. The tumor cells were strongly and diffusely positive for cytokeratins AE1/AE3 and CK7 and focally for CK20 and negative for prostate-specific antigen and prostatic acid phosphatase. Four ultrasound-guided aspirates of the liver lesions were obtained, and the smears showed pre0090-4295/06/$32.00 doi:10.1016/j.urology.2005.10.002 845.e3
FIGURE 1. Nests of infiltrating malignant epithelial cells are seen to originate from the surface urothelium (a) and infiltrate deep into muscularis (b). Hematoxylineosin stain, original magnification ⫻210.
dominantly neoplastic cells similar to those in the ureteral biopsy. The final diagnosis was of high-grade urothelial transitional cell carcinoma, nested variant, with liver and bone metastases. After discussion at a multidisciplinary urologic oncology meeting, a decision was made to treat. After discharge, the patient underwent systemic chemotherapy with gemcitabine and carboplatin. The patient obtained a partial response to treatment, and computed tomography performed after chemotherapy showed resolution of hydronephrosis and a decrease in the size of the liver lesions. The bony deposits remained stable, with no evidence of progressive disease on bone scanning. The patient eventually died of the disease 12 months after diagnosis. COMMENT NVUC was recently acknowledged by the World Health Organization as an “uncommon aggressive tumor,” with few reported cases and a 70% mortality rate 4 to 40 months after diagnosis despite therapy.1 The incidence of NVUC has been estimated to be 0.8% of all invasive bladder carcinoma.2 A literature search revealed 76 cases reported in 15 pub845.e4
lished articles, with 1 to 16 subjects per study.2–10 The prognosis is poor, with two case series reporting survival rates of 19% during a mean of 16.6 months and 30% within 4 to 40 months.2,11 However, a more recent case series by Lin et al.6 reported a 92% survival rate within a mean of 17.6 months. The patients are predominantly male and present with macroscopic hematuria, flank pain, or dysuria. To our knowledge, this is the first case reported in which the patient presented with bilateral ureteral obstruction and acute renal failure with extension of the tumor along the entire length of the right ureter. NVUC is characterized by irregular nests and/or tubules of transitional carcinoma cells infiltrating the lamina propria without involvement of the mucosal layer.3 First described in 1979 by Stern12 as a benign lesion, the malignant nature of NVUC was recognized in 1989 by Talbert and Young.13 The cytologic changes of NVUC are subtle and bland. Cardillo et al.14 reviewed urine specimens from 13 patients with histologically confirmed NVUC and identified morphologically similar cells. Nine of these specimens were initially diagnosed as benign; hence, they concluded that a primary diagnosis based on urine cytology was not recommended owing to the subtleness of the findings. The differential diagnoses include squamous metaplasia, nephrogenic adenoma, reactive changes, and low-grade papillary urothelial carcinoma. The histopathologic features may mimic florid von Brunn nests (cystitis glandularis), cystitis cystica, inverted papilloma, adenocarcinoma, nephrogenic metaplasia, and paraganglioma.15 The optimal modality of treatment is uncertain because NVUC is rare and no randomized studies exist. Holmang and Johansson reported no survival benefit with radiotherapy in their series of 6 patients (Stage T1 to T4b).2 In the series of 12 patients published by Lin et al., 10 of 12 patients underwent cystectomy with or without chemotherapy, suggesting that surgical resection improves the survival rates for patients with nonmetastatic disease.6 Traditionally, the standard treatment for patients with locally advanced or metastatic urothelial carcinoma is chemotherapy using methotrexate, vinblastine, doxorubicin, and cisplatin. The gemcitabine-cisplatin regimen has been shown to have equivalent overall response rates, with less toxicity (range 41% to 57%), a complete response in 15% to 22%, and a median survival of 12.5 to 14.3 months.16 REFERENCES 1. World Health Organization Classification of Tumors. Infiltrating urothelial carcinoma, in Eble JN, Sauter G, Epstein JI, et al (Eds): Tumors of the Urinary System and Male Genital Organs. Lyon, IARC Press, 2004, pp 93–110. UROLOGY 67 (4), 2006
2. Holmang S, and Johansson SL: The nested variant of transitional cell carcinoma: a rare neoplasm with poor prognosis. Scand J Urol Nephrol 35: 102–105, 2001. 3. Tatsura H, Ogawa K, Sakata T, et al: A nested variant of transitional cell carcinoma of the urinary bladder: a case report. Jap J Clin Oncol 31: 287–289, 2001. 4. Ozdemir BH, Ozdemir OG, and Sertcelik A: The nested variant of the transitional cell bladder carcinoma: a case report and review of the literature. Int Urol Nephrol 32: 257–258, 2000. 5. Volmar KE, Chan TY, De Marzo AM, et al: Florid von Brunn nests mimicking urothelial carcinoma: a morphologic and immunohistochemical comparison to the nested variant of urothelial carcinoma. Am J Surg Pathol 27: 243– 252, 2003. 6. Lin O, Cardillo M, Dalbagni G, et al: Nested variant of urothelial carcinoma: a clinicopathological and immunohistochemical study of 12 cases. Mod Pathol 16: 1289 –1298, 2003. 7. Liedberg F, Chebil G, Davidsson T, et al: The nested variant of urothelial carcinoma: a rare but important bladder neoplasm with aggressive behavior. Urol Oncol 21: 7–9, 2003. 8. Badoual C, Bergemer-Fouquet AM, Renjard L, et al: An unusual variant of urothelial carcinoma: the “nested variant of urothelial carcinoma”—report of two cases. Ann Pathol 20: 400 – 401, 2000.
UROLOGY 67 (4), 2006
9. Xiao GQ, Savage SJ, Gribetz ME, et al: The nested variant of urothelial carcinoma: clinicopathology of 2 cases. Arch Pathol Lab Med 127: 333–336, 2003. 10. Rioux-Leclercq N, Staerman F, Patard JJ, et al: Unusual variety of bladder urothelial carcinoma: “nest type” microlobular carcinoma: report of an anatomoclinical case and review of the literature. Ann Urol (Paris) 34: 9 –12, 2000. 11. Drew PA, Furman J, Civantos F, et al: The nested variant of transitional cell carcinoma: an aggressive neoplasm with innocuous histology. Mod Pathol 9: 989 –994, 1996. 12. Stern JB: Unusual benign bladder tumor of Brunn nest origin. Urology 14:288 –289, 1979. 13. Talbert ML, and Young RH: Carcinomas of the urinary bladder with deceptively benign-appearing foci. A report of three cases. Am J Surg Pathol 13:374 –381, 1989. 14. Cardillo M, Reuter V, and Lin O: Cytologic features of the nested variant of urothelial carcinoma: a study of seven cases. Cancer Cytopathol 99: 23–27, 2003. 15. Paik S, and Park M: The nested variant of transitional cell carcinoma of the urinary bladder. Br J Urol 78: 793– 794, 1996. 16. Von der Maase H: Current and future perspectives in advanced bladder cancer: is there a new standard? Semin Oncol 29: 3–14, 2003.
845.e5