Transitional Cell Cancer with Sclerotic Bone Metastases

64 year old male presenting with painless gross hematuria, flank pain, unintentional weight loss, and lower back pain. What is the diagnosis? • Xray of the Week

Figure 1. Abdominal CT. What are the significant findings.

Figure 2.

A,B: Non contrast axial CT images showing a large transitional cell carcinoma obstructing the left renal pelvis (green arrows). There is an incidental renal calculus in left kidney (red arrow).

C: Non contrast coronal CT image showing large transitional cell carcinoma obstructing the left renal pelvis (green arrows).

D,E: Axial and sagittal CT (Bone window) showing sclerotic metastasis of sacral base (blue arrows)

Discussion:

Transitional cell carcinoma (also called Urothelial cell carcinoma) is the second most common type of kidney cancer, behind renal cell carcinomas, but only accounts for 5-10% of all primary renal malignant tumors [1]. It is 50x less common than transitional cell carcinoma of the bladder. They are more common in males and typically diagnosed between 60-70 years of age with a mean age at diagnosis of 73 years [2]. Patients with transitional cell carcinoma typically present with hematuria (70-80%) and flank pain secondary to ureter/uretopelvic junction obstruction from tumor mass (20-40%). Other symptoms include bladder irritation and constitutional symptoms such as fatigue, nausea, or diarrhea [3].

The epithelial surface of the renal collecting tubules, calyces, and pelvis share the same embryonic origin as the ureter, bladder, and urethra termed “urothelium”. Transitional/Urothelial carcinoma tend to be multifocal and is believed to arise via field cancerization from potential carcinogens excreted into the urine or active via hydrolyzing enzyme in the urine. Risk factors for developing transitional cell carcinoma include: tobacco use, prolonged exposure to carcinogens (i.e. azo dye, heavy metals, phenacetin, and aromatic amines), chronic/recurrent UTI, schistosomiasis, and prolonged indwelling bladder catheters [3,4,5,6].

Initial choice for diagnosis for patient with suspected transitional/urothelial carcinoma is abdominal CT or retrograde pyelogram. Transitional/urothelial carcinoma typically appear as a soft tissue density with mild enhancement (far less enhancement than renal parenchyma or renal cell carcinomas) [7,8]. They are usually centered on the renal pelvis, rather than the renal parenchyma, and range in size from small filling defects to large masses which can obliterate the renal sinus fat causing appearance of a “faceless” kidney [9]. However, normal renal shape is maintained even in large infiltrating transitional cell carcinomas, whereas large renal cell carcinomas will cause distortion of the renal outline [8,10]. Larger urothelial tumors may have areas of necrosis [8]. In cases of the tumor being small and located at the ureteropelvic junction with resultant hydronephrosis, a small soft tissue mass should be sought. The most common site of metastasis outside the pelvis is the spine, as seen in this patient [10].

Surgical resection is the only curative treatment for localized transitional cell carcinoma. There is limited data/research indicating efficacy of chemotherapy in patients with advanced upper urinary tract urothelial cancers. Advanced clinical trials have shown response with cisplatin-based chemotherapeutical regimens such as MVAC (Methotrexate, Vinblastine, Doxorubicin, and Cisplatin) or GC (Gemcitabine and Cisplatin) [13,14,15,16]. However, these regimens are often complicated or contraindicated in patients with chronic kidney disease which is a very common comorbid condition in patients with transitional cell carcinoma [17]. For these patients, single-agent chemotherapy or checkpoint inhibitor immunotherapy options are currently being researched. Cisplatin-based chemotherapy is not effective for all patients and those for whom this regimen fails, they are often treated with platinum-based therapies, checkpoint inhibitor immunotherapy with PD-1 (programmed cell death 1) or PD-L1 (programmed death ligand 1) antibodies [18,19,20].

References:

1. Andreassen, B. K.; Aagnes, B.; Gislefoss, R.; Andreassen, M.; Wahlqvist, R. (2016). "Incidence and Survival of urothelial carcinoma of the urinary bladder in Norway 1981-2014". BMC Cancer. 16 (1). doi:10.1186/s12885-016-2832-x

2. Raman JD, Messer J, Sielatycki JA, Hollenbeak CS. Incidence and survival of patients with carcinoma of the ureter and renal pelvis in the USA, 1973-2005. BJU Int. 2011 Apr;107(7):1059-64. doi:10.1111/j.1464-410X.2010.09675.x. Epub 2010 Sep 3. PMID: 20825397.

3. Rouprêt M, Babjuk M, Compérat E, Zigeuner R, Sylvester RJ, Burger M, Cowan NC, Gontero P, Van Rhijn BWG, Mostafid AH, Palou J, Shariat SF. European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2017 Update. Eur Urol. 2018 Jan;73(1):111-122. doi:10.1016/j.eururo.2017.07.036. Epub 2017 Sep 1. PMID: 28867446.

4. Yang MH, Chen KK, Yen CC, Wang WS, Chang YH, Huang WJ, Fan FS, Chiou TJ, Liu JH, Chen PM. Unusually high incidence of upper urinary tract urothelial carcinoma in Taiwan. Urology. 2002 May;59(5):681-7. doi:10.1016/s0090-4295(02)01529-7. PMID: 11992840.

5. Lee YL, Shih MC, Wu WJ, Chou YH, Huang CH. Clinical and urographic presentation of transitional cell carcinoma of the ureter in a blackfoot disease endemic area in southern Taiwan. Kaohsiung J Med Sci. 2002 Sep;18(9):443-9. PMID: 12515402.

6. Colin P, Koenig P, Ouzzane A, Berthon N, Villers A, Biserte J, Rouprêt M. Environmental factors involved in carcinogenesis of urothelial cell carcinomas of the upper urinary tract. BJU Int. 2009 Nov;104(10):1436-40. doi:10.1111/j.1464-410X.2009.08838.x. Epub 2009 Aug 18. PMID: 19689473.

7. Leder RA, Dunnick NR. Transitional cell carcinoma of the pelvicalices and ureter. AJR Am J Roentgenol. 1990 Oct;155(4):713-22. doi:10.2214/ajr.155.4.2119098. PMID: 2119098.

8. Browne RF, Meehan CP, Colville J et-al. Transitional cell carcinoma of the upper urinary tract: spectrum of imaging findings. Radiographics. 25 (6): 1609-27. doi:10.1148/rg.256045517

9. Dyer RB, Chen MY, Zagoria RJ. Classic signs in uroradiology. Radiographics. 2004;24 Suppl 1 (suppl 1): S247-80. doi:10.1148/rg.24si045509

10. Vikram R, Sandler CM, Ng CS. Imaging and staging of transitional cell carcinoma: part 2, upper urinary tract. AJR Am J Roentgenol. 2009;192 (6): 1488-93. doi:10.2214/AJR.09.2577

11. Punyavoravut V, Nelson SD. Diffuse bony metastasis from transitional cell carcinoma of urinary bladder: a case report and review of literature. J Med Assoc Thai. 1999 Aug;82(8):839-43. PMID:10511795.

12. Owari T, Miyake M, Nakai Y, Morizawa Y, Itami Y, Hori S, Anai S, Tanaka N, Fujimoto K. Clinical Features and Risk Factors of Skeletal-Related Events in Genitourinary Cancer Patients with Bone Metastasis: A Retrospective Analysis of Prostate Cancer, Renal Cell Carcinoma, and Urothelial Carcinoma. Oncology. 2018;95(3):170-178. doi:10.1159/000489218

13. von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18(17):3068-77. doi:10.1200/JCO.2000.18.17.3068. PMID: 11001674.

14. von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. doi:10.1200/JCO.2005.07.757. PMID: 16034041.

15. Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Raghavan D, Stuart-Harris R, Sarosdy MF, Lowe BA, et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992 Jul;10(7):1066-73. doi:10.1200/JCO.1992.10.7.1066. Erratum in: J Clin Oncol 1993 Feb;11(2):384. PMID: 1607913.

16. Saxman SB, Propert KJ, Einhorn LH, Crawford ED, Tannock I, Raghavan D, Loehrer PJ Sr, Trump D. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1997 Jul;15(7):2564-9. doi:10.1200/JCO.1997.15.7.2564. PMID: 9215826.

17. Galsky MD, Hahn NM, Rosenberg J, Sonpavde G, Hutson T, Oh WK, Dreicer R, Vogelzang N, Sternberg C, Bajorin DF, Bellmunt J. A consensus definition of patients with metastatic urothelial carcinoma who are unfit for cisplatin-based chemotherapy. Lancet Oncol. 2011 Mar;12(3):211-4. doi:10.1016/S1470-2045(10)70275-8. PMID: 21376284.

18. Burgess EF, Livasy C, Hartman A, Robinson MM, Symanowski J, Naso C, Doherty S, Guerrieri R, Riggs S, Grigg CM, Clark PE, Raghavan D. Discordance of high PD-L1 expression in primary and metastatic urothelial carcinoma lesions. Urol Oncol. 2019 May;37(5):299.e19-299.e25. doi:10.1016/j.urolonc.2019.01.002. Epub 2019 Jan 17. PMID: 30660491.

19. Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, Loriot Y, Necchi A, Hoffman-Censits J, Perez-Gracia JL, Dawson NA, van der Heijden MS, Dreicer R, Srinivas S, Retz MM, Joseph RW, Drakaki A, Vaishampayan UN, Sridhar SS, Quinn DI, Durán I, Shaffer DR, Eigl BJ, Grivas PD, Yu EY, Li S, Kadel EE 3rd, Boyd Z, Bourgon R, Hegde PS, Mariathasan S, Thåström A, Abidoye OO, Fine GD, Bajorin DF; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017 Jan 7;389(10064):67-76. doi:10.1016/S0140-6736(16)32455-2. Epub 2016 Dec 8. Erratum in: Lancet. 2017 Aug 26;390(10097):848. PMID: 27939400; PMCID: PMC5568632.

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Jay Vora is a medical student at Edward Via College of Osteopathic Medicine (VCOM) – Virginia and plans to pursue a residency in diagnostic radiology. He graduated from UMBC in 2015 with a major in Biochemistry and Molecular Biology. He worked as a research assistant at Brimrose Engineering Corporation of America for 5 years where he completed projects in nanodot detection using imaging and helped develop cancer detection methods in cells using polarized near-infrared autofluorescence and near-infrared reflectance imaging with laser diodes and continuous-wave imaging. He graduated from Eastern Virginia Medical School with a masters in Biomedical science where he was completed research in the study of the barriers that the homeless population faces when seeking healthcare as well as genetic analysis of brain tissue from patients diagnosed with Alzheimer’s. He discovered his passion for radiology during the first radiology lecture at VCOM. Seeing the radiographic images made medical education come to life for him. While shadowing and on rotations, Jay saw how integral the field of radiology is to every other specialty in medicine and its key role in patient care. In his free time, Jay enjoys playing golf and basketball, playing guitar, and technology.

Follow Jay Vora on Twitter @JS_Vora

Kevin M. Rice, MD is the president of Global Radiology CME

Dr. Rice is a radiologist with Renaissance Imaging Medical Associates and is currently the Vice Chief of Staff at Valley Presbyterian Hospital in Los Angeles, California. Dr. Rice has made several media appearances as part of his ongoing commitment to public education. Dr. Rice's passion for state of the art radiology and teaching includes acting as a guest lecturer at UCLA. In 2015, Dr. Rice and Natalie Rice founded Global Radiology CME to provide innovative radiology education at exciting international destinations, with the world's foremost authorities in their field. In 2016, Dr. Rice was nominated and became a semifinalist for a "Minnie" Award for the Most Effective Radiology Educator.

Follow Dr. Rice on Twitter @KevinRiceMD

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