A 52-year-old patient status postabdominoperineal resection, colostomy and chemoradiation for Lynch syndrome (LS)-associated colorectal cancer is referred to urology after being found to have a positive voided NMP-22 assay. The patient has a confirmed pathogenic germline mutation of the PMS2 gene, a negative voided cytology, no red blood cells on urine microscopy and no family history of urothelial or kidney cancer, and is a never smoker. Computerized tomography (CT) of the abdomen and pelvis with excretory phase is normal (fig. 1). What would you recommend next, and why?

Figure 1. CT of abdomen and pelvis with excretory phase in LS patient with pathogenic mutation of PMS2 gene, status postabdominoperineal resection with permanent colostomy and chemoradiation, who was referred after being found to have positive voided NMP-22 during routine screening visit in high risk GI clinic. Patient has negative voided cytology and no red blood cells on urine microscopy, there is no family history of urothelial or kidney cancer, and patient is never smoker. What should we recommend?

LS patients have germline inheritable mutations of mismatch repair genes, leading to high rates of DNA alterations predisposing to a variety of cancers, primarily colorectal, endometrial and upper tract urothelial cancer (UTUC), and to a lesser extent bladder, prostate, kidney and adrenal cortical cancers. LS patients may be referred to a urologist for evaluation of microscopic hematuria or other urological suspicion. Very few primary data and few opinion articles are available to guide urological screening of LS patients,^1-3 treatment of LS-related urological cancers, prevention⁴ or surveillance of LS-related cancer after treatment. This article will focus on surveillance of patients with known LS.

Most tertiary centers have a specialized “high risk” gastroenterology (GI) clinic for LS patients, who can comprise a frequent source of urology referrals for evaluation of microscopic hematuria, positive urinary biomarkers (as part of their screening process, such as in the case above) or incidental imaging findings. Care is generally directed as per standard urological practice and guidelines, but there are additional factors that should be considered in the LS patient. These include:

1. Knowing the specific mutation: MSH2 and MSH6 mutations are the most frequently associated with UTUC (while we have seen MLH1 and PSM2-related UTUC, this is much less common)
2. Asking about a family history of UTUC: Make sure to ask about bladder cancer and “kidney cancer,” both of which can be commonly confused with UTUC
3. History of pelvic radiation
4. History of tobacco use and environmental/occupational exposures

All of these factors can help determine the index of suspicion and extent of workup, which could range from simply repeat urinalysis or a renal and bladder ultrasound for reassurance in a very low suspicion setting (such as a never smoker patient with a MLH1 mutation, negative urinalysis and no family history of UTUC) to a full hematuria workup with CT urography and office cystoscopy (such as a patient with MSH2 or MSH6 mutation and active or former smoker, or a LS patient with a family history of UTUC).

Figure 2. Patient with known LS having MSH2 mutation and history of colorectal cancer who was found to have new parenchymal renal mass on surveillance CT for his colon cancer. After partial nephrectomy, pathology showed stage pT1a, grade 2 clear cell renal cell carcinoma (RCC). Patient asks if this is LS-related cancer. Immunohistochemical staining of RCC specimen demonstrates intact expression of all 4 mismatch repair proteins, including MSH2, suggesting this was in fact sporadic (ie not LS-related) RCC. Nonmalignant cells serve as internal positive controls (seen in middle-right side of panels). After 6 years, he remains without recurrence of RCC. Immunostains and slides courtesy of Kanishka Sircar. Reduced from ×10.

Figure 3. Patient presenting with left UTUC and bladder cancer, and family history of multiple gastrointestinal cancers, some occurring before age 50 years. Immunohistochemical staining of urothelial cancer for 4 mismatch repair proteins shows absence of MSH6 in tumor cells. Nonurothelial cells serve as internal positive controls (seen in upper left corner of H&E panel and upper portion of other panels). Patient underwent genetic counseling and targeted germline testing for MSH6, confirming pathogenic mutation. Patient’s family was then also referred for testing, and patient was referred to high risk GI clinic for surveillance and risk reduction measures. Tumor also underwent microsatellite instability (MSI) molecular testing, but interestingly it was MSI stable. It is thought that MSH6 mutant tumors may not display high MSI. Immunostains and slides courtesy of Kanishka Sircar. Reduced from ×10.

In 2010, Acher et al proposed a risk-stratified strategy, whereby low risk patients (no personal/family history of UTUC or MSH2 mutation) undergo annual urinalysis, voided cytology and NMP-22 assay; intermediate risk patients (family history of urothelial cancer or MSH2 mutation) undergo the 3 urinary tests above plus a renal ultrasound; and high risk patients (personal history of UTUC) have in addition contrast CT and flexible cystoscopy.¹ In 2015, Mork et al, based on consensus expert opinion, recommended frequent urinalysis for LS patients as it represents a noninvasive, low cost method that patients can even do by themselves at regular, frequent intervals.² Weaknesses of this approach are that it may have high false-positive results and can also be falsely negative in the presence of a urothelial tumor. However, in these cases, the repetitiveness of testing may mitigate this disadvantage, while a positive result provides objective data to escalate a workup, although indeed it is not optimal.

Patients with prior pelvic radiation, kidney stones or other benign causes of microscopic hematuria also pose a challenge. In these cases, I usually do a full initial workup and then either monitor with urinalysis and look for subjective changes in the character of the microhematuria, rather than its presence/absence, or for the patient who has tolerance for willful ignorance, omit urinalysis altogether and instead rely on ultrasound or monitoring of other surveillance imaging they may be already receiving (see below). Admittedly, I am not aware of good data to provide further guidance in these settings, which are driven by patient informed decisions and are highly individualized. I no longer order urinary markers such as cytology or NMP-22 as I have not found them helpful, either for reassurance or for early diagnosis. Cytology in fact has specifically been shown not to be useful in LS patients.³

Since many LS patients are already receiving surveillance scans for followup of colorectal or other cancers, we ask the ordering teams to modify their CT of the abdomen and pelvis to include an excretory phase or convert it to a urogram once a year, to allow surveillance of the urinary tract if the patient is at higher risk for UTUC. This helps minimize cost and radiation exposure, which is especially important in a population that has mutational susceptibility and is subjected to a lifetime of multiple tests by different providers.

One other factor to consider is that even LS patients may have sporadic urological cancers. Immunohistochemistry of the tumor specimen for mismatch repair proteins, which is routinely done for colorectal and endometrial cancers but often overlooked by urologists, can aid in these settings. If the tumor shows intact expression of these ⁴ proteins (PMS2, MLH1, MSH2 and MSH6), then that tumor is not LS-related, and the risk of recurrence may not necessarily be any different than any other sporadic case (fig. 2). However, if there is absent expression of one or more of the proteins, then it is likely a LS-related tumor (fig. 3), which additionally may have implications for surveillance and recurrence, as well as response to systemic treatments.⁵ Tumor immunohistochemistry for mismatch repair proteins is also an excellent and low cost initial LS screening test when tumor tissue is available, as absent expression of one of the proteins is an indication for genetic counseling and confirmatory germline testing.