Urothelial Carcinoma in a Man with Hereditary Nonpolyposis Colon Cancer

CASE REVIEW Urothelial Carcinoma in a Man with Hereditary Nonpolyposis Colon Cancer Dean L. Lenz, MD, Lewis E. Harpster, MD Department of Surgery, Division of Urology, Pennsylvania State University, Milton S. Hershey Medical Center, Hershey, PA Although most upper tract urothelial carcinomas are believed to be acquired, patients with hereditary nonpolyposis colon cancer (HNPCC) may have more than 20 times the risk of the normal population for these cancers. Certain mismatch repair mutations are now known to be associated with the disease. Screening and surveillance regimens are still evolving, but urinalysis, urine cytology, cystoscopy, and periodic upper tract imaging are the mainstays. HNPCC should be considered in any patient who develops an upper tract urothelial cancer or has a suggestive family history. [Rev Urol. 2003;5(1):49-53] ©2003 MedReviews, LLC. Key words: Hereditary nonpolyposis colon cancer • Urothelial carcinoma • Urinalysis • Urine cytology • Cystoscopy n the general population, renal cell carcinoma accounts for 90% of upper urinary tract cancers, whereas urothelial tumors account for only about 5%.1 Certain environmental toxins are thought to be etiologic in the development of urothelial tumors, most notably smoking and exposure to certain amine-based chemicals. Although a familial tendency to develop upper tract urothelial carcinomas has been previously noted, most cases are thought to be acquired and not inherited.2-4 I VOL. 5 NO. 1 2003 REVIEWS IN UROLOGY 49 Urothelial Carcinoma and Hereditary Nonpolyposis Colon Cancer continued Hereditary nonpolyposis colon cancer (HNPCC) predisposes its carriers to develop colon cancer, usually in the proximal colon. It is not associated with diffuse polyposis of the large bowel. The disease is inherited in autosomal-dominant fashion. Tumors associated with HNPCC gen- The patient was referred for further evaluation. The patient’s past medical history was significant in that he had undergone a subtotal colectomy in 1999 for right-sided colon cancer. He had a normal urologic history and no voiding complaints. Urine cytology Although a familial tendency to develop upper tract urothelial carcinomas has been previously noted, most cases are thought to be acquired and not inherited. erally occur at a younger age than sporadic cases of colon cancer, with most presenting before age 45. In addition to the increased incidence of colon cancer, the disease has also been associated with an increased incidence of tumors of other organ systems, including urothelial carcinoma of the renal pelvis, the ureter, and possibly the bladder. Hereditary nonpolyposis colon cancer is, therefore, of particular interest to urologists, who undoubtedly miss the opportunities afforded by knowledge of this disease to provide proper early screening to those at risk and intervention to those affected. Discussion of the disease, its pattern of inheritance, and recommendations for screening persons and families affected should increase urologists’ awareness and ability to effectively and efficiently treat the urologic manifestations of HNPCC. Case Presentation A 47-year-old man with a known history of HNPCC underwent computerized tomography (CT) of the abdomen to evaluate a rise in his serum carcinoembryonic antigen level. He was found to have right hydronephrosis and hydroureter to the level of the midureter. At that point, there was an abrupt change in size of the ureter to normal caliber. 50 VOL. 5 NO. 1 2003 REVIEWS IN UROLOGY raised a suspicion of malignant cells. Retrograde urography (Figure 1) was performed, followed by rigid ureteroscopy. This demonstrated an intraluminal polypoid mass consistent with urothelial carcinoma (Figure 2). HNPCC. Warthin first described HNPCC in 1913.5 At that time, he reported on several families with frequent occurrences of carcinoma of the colon, often occurring in association with gastric carcinoma. Since this original description, it has been noted that in addition to stomach cancer, tumors of other organs, including tumors of the urinary tract, occur more frequently in affected individuals.6-9 Also, a great deal has recently been reported on the genetics and molecular biology of this disorder. Much of our current knowledge about HNPCC is credited to Lynch; indeed, “the Lynch syndrome" is synonymous with this acronym.8,10-12 Presently, HNPCC is known to be an autosomal-dominant disorder Cancers of other organs occur with increased incidence in families affected with HNPCC, including cancer of the urinary tract. Nephroureterectomy was subsequently performed. Histologic examination revealed low-grade organ-confined urothelial carcinoma (grade 1, stage Ta, N0, M0). There was no evidence of tumor metastasis. On initial followup, the patient was recovering well and free of locally recurrent disease. Further review of the patient’s family history revealed early-onset colon cancer in the patient’s father (deceased from the disease) and three brothers. Additionally, two of his brothers were noted to have a total of three urologic malignancies, for which they had undergone surgical intervention. One brother had had asynchronous bladder and upper tract urothelial carcinomas. The second brother had had urothelial carcinoma of the renal pelvis. Discussion History and molecular basis of that carries a 70% to 90% lifetime risk of colorectal carcinoma.9 It is believed to account for up to 5% of all cases of colorectal cancer.11 It is characterized by the early appearance of colon cancer, often prior to age 45, with a distinct predilection for Figure 1. Retrograde ureterogram demonstrating a proximal filling defect. Urothelial Carcinoma and Hereditary Nonpolyposis Colon Cancer the proximal (ascending) colon.8,13 Characteristically, multiple tumors develop but are not associated with colonic polyposis. Cancers of other organs occur with increased incidence in affected families, including cancer of the endometrium, ovary, stomach, biliary tract, central nervous system, and urinary tract.6-9,11 The pathogenesis of HNPCC resides at the molecular level.11 The human genome contains specific genes that code for proteins responsible for repairing DNA replication errors. These genes are termed mismatch repair (MMR) genes. Deficiency of these genes causes replication errors in regions, called microsatellites, that contain highly repetitive DNA. Cancers associated with HNPCC are, therefore, said to possess microsatellite instability (MSI). Mutations of MMR genes have been identified in patients with HNPCC.12,13 The resulting defective MMR proteins can damage the genome. If damage occurs to genes critical for control of cell growth or to genes that aid genomic stability, tumor growth can occur.12,13 To date, MMR genes at five different loci have been identified and are believed to account for the increased tumorigenesis seen in this syndrome.9 Genetic linkage studies have recently demonstrated specific MMR mutations highly associated with HNPCC. These have been designated MSH2 and MLH1.12,13 Diagnosis. There is currently no single diagnostic test that can be used to diagnose HNPCC. Thus, the diagnosis is made on clinical grounds in addition to a thorough family history that emphasizes malignancy. The most widely used and accepted criteria for diagnosing HNPCC are the “Amsterdam criteria"11,14; all of the following must be met to diagnose HNPCC: and 22 times the incidence of ureteral urothelial carcinoma seen in the general population.6 Other authors have also noted an increased incidence of upper urinary tract urothelial carcinoma in association with HNPCC.15,16 Considering that these observations were made using pedigree analysis and review of previously diagnosed, presumably symptomatic patients, the actual incidence of upper tract urothelial tumors in this population might be considerably higher, given the likelihood of asymptomatic lesions. With the increased incidence of upper urinary tract urothelial carcinoma in HNPCC, a similar increased incidence of urothelial carcinoma of the bladder might be expected. Certainly the pedigree presented here would argue for such a correlation. Watson and Lynch, however, showed that no excess urinary bladder cancer was evident in over 20 families with HNPCC compared with the general population.6 Currently, there is some disagreement as to whether or not the incidence of urothelial carcinoma of the bladder is increased in HNPCC. Screening. Screening for noncolonic malignancies in patients and families with HNPCC is strongly debated. Guidelines for screening • At least three relatives have colorectal cancer (one should be a first-degree relative of the other two) • At least two successive generations are affected • At least one of these cancers was diagnosed prior to age 50 Urothelial carcinoma in HNPCC. There is an increased incidence of urothelial carcinoma in patients with this syndrome. In a review of 1317 patients from 23 families with nonpolyposis colon cancer, Watson and Lynch found 17 times the incidence of renal pelvic urothelial carcinoma Table 1 Screening Recommendations by ICG-HNPCC Site Procedure Lower Age Limit Interval Colon Colonoscopy 20-25 years 2 years Endometrium (and ovaries) Gynecologic exam, transvaginal sonography, CA-125 measurement 30-35 years 1-2 years Stomach* Gastroscopy 30-35 years 1-2 years Urinary tract* Sonography, urine analysis 30-35 years 1-2 years *Only if hereditary. ICG-HNPCC, International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer. Data from Weber.17 VOL. 5 NO. 1 2003 REVIEWS IN UROLOGY 51 Urothelial Carcinoma and Hereditary Nonpolyposis Colon Cancer continued recommended by the International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC) are listed in Table 1.17 The recommendations for screening the urinary tract are, however, designed only for patients with documented urothelial carcinoma in the family. Some authors have even stated that such screening is not indicated.9,18 However, given the increased incidence of upper tract urothelial tumors in these patients, combined with the lack of effective adjuvant therapy in cases of advanced disease, screening for urothelial malignancies seems justified. Urinalysis, urine cytology, cystoscopy, and upper tract imaging form the mainstay of the initial evaluation for suspected urothelial carcinoma. Specific recommendations for surveillance imaging of the upper tract vary.1 Indeed, our patient demon- Upper tract imaging by either intravenous pyelography (IVP) or CT scan with delayed drainage, in addition to urinalysis and urine cytology, should begin at age 35. If these studies are normal, cytology and urinalysis should be repeated annually and upper tract imaging should be done every 2 to 3 years, with abnormalities prompting further investigations. As the availability and accuracy of genetic testing for HNPCC improve, a more focused screening regimen will likely evolve. Some clinicians currently offer prophylactic subtotal colectomy to patients in HNPCC families in whom the MSH2 or MLH1 mutations have been found, to preclude lifelong repeated colonoscopy.8,19 Similarly, some clinicians advocate prophylactic hysterectomy and bilateral salpingooophorectomy in women with HNPCC undergoing subtotal colectomy.19 This obviates continued endometrial Screening for noncolonic malignancies in patients and families with HNPCC is strongly debated. strated abnormalities on urinalysis, cytology, and upper tract imaging, including CT scan with delayed drainage. We believe the following recommendations should be applied to patients diagnosed with HNPCC. Specifically, patients should have urinalysis and urine cytology performed at the time of diagnosis. aspiration biopsy. These aggressive recommendations are controversial but should be discussed with affected patients when considering treatment options. The role of genetic screening with regard to the urologic manifestations of HNPCC is just beginning to gain attention.20 A genetic, or familial, basis for disease should at least Figure 2. Ureteroscopic view of an intraluminal polypoid mass. be considered in any patient in whom a urothelial carcinoma develops at a markedly early age or who has a family history consistent with HNPCC.21 Summary Hereditary nonpolyposis colon cancer is an inherited, autosomal-dominant disorder that manifests as an increased propensity to develop proximal colon cancers at an early age. Mutations of MMR genes leading to DNA replication errors form the molecular basis for this disease. Increased tumorigenesis is seen not only in the gastrointestinal system but in other organ systems as well, including the urinary tract. Specifically, patients with HNPCC have a higher-than-usual incidence of urothelial carcinoma of the ureter, Main Points • Urothelial tumors account for about 5% of upper urinary tract cancers. • In addition to a 70% to 90% lifetime risk of colorectal carcinoma, hereditary nonpolyposis colon cancer (HNPCC) is associated with an increased incidence of urothelial carcinoma of the upper and lower urinary tract. • Mutations of MMR genes have been identified in HNPCC patients, and specific mutations have recently been shown to be highly associated with the disease. • The high incidence of upper tract urothelial tumors in HNPCC patients and the lack of effective adjuvant therapy for advanced disease justify screening for urothelial malignancies, initially with urinalysis, urine cytology, cystoscopy, and upper tract imaging. 52 VOL. 5 NO. 1 2003 REVIEWS IN UROLOGY Urothelial Carcinoma and Hereditary Nonpolyposis Colon Cancer the renal pelvis, and possibly the bladder. Initial evaluation of patients diagnosed with HNPCC should therefore include urinalysis, urine cytology, and upper urinary tract imaging with either IVP or CT scan. Annual urinalysis and urine cytology are advised, with repeat upper tract imaging periodically or on detection of abnormalities in the urinalysis or cytology results. Until proper prospective studies can be completed to verify the true incidence of associated urothelial carcinomas and appropriate screening methods for them, these recommendations should provide adequate screening for the HNPCC population. HNPCC demonstrates the role of heredity and the importance of the family history in the field of urology. Recognition of this disease and its sequelae by the urologic community can lead to earlier treatment and improved patient care. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Messing EM, Catalona W. Urothelial tumors of the urinary tract. In: Walsh PC, Retik AB, Vaughan ED Jr, Wein AJ, eds. Campbell’s Urology, 7th ed. 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