Urothelial Carcinoma in a Man with Hereditary Nonpolyposis Colon Cancer

Abstract

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.

In 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

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 generally 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. 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 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). 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 follow-up, the patient was recovering well and free of locally recurrent disease.

Figure 1.

Retrograde ureterogram demonstrating a proximal filling defect.

Figure 2.

Ureteroscopic view of an intraluminal polypoid mass.

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 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 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 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:

• 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 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 non-colonic malignancies in patients and families with HNPCC is strongly debated. Guidelines for screening 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.

Table 1.

Screening Recommendations by ICG-HNPCC

Site	Procedure	Lower Age Limit	Interval
Colon	Colonoscopy	20–25 years	25 years
Endometrium (and ovaries)	Gynecologic exam,	30–35 years	1–2 years
	transvaginal sonography,
	CA-125 measurement
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

Specific recommendations for surveillance imaging of the upper tract vary.¹ Indeed, our patient demonstrated 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. 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 salpingo-oophorectomy in women with HNPCC undergoing subtotal colectomy.¹⁹ This obviates continued endometrial 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 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, 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.

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.