One article discusses: Lynch syndrome and the third-largest related tumor UTUC

Abstract Upper urothelial carcinoma (UTUC) is the third most common malignant tumor related to Lynch syndrome (LS).
A study systematically reviewed the incidence, diagnosis, clinicopathological features, and oncology results of LS/UTUC And the screening program and other related literature, and analyzed it, hoping to provide urologists with more detailed information about LS and UTUC
.

The research was recently published in the journal European Urology Oncology
.

LS can cause microsatellite instability.
Lynch syndrome (LS) was first proposed in 1966
.

LS is an autosomal dominant genetic disease characterized by a high susceptibility to a variety of primary malignant tumors and an early age of onset
.

From a genetic point of view, LS is caused by germline mutations in one of the four DNA mismatch repair (MMR) genes (hMLH1, hMSH2, hMSH6, and hPMS2), or hMSH2 silencing caused by hEPCAM germline mutations
.

hMSH2 is the most common LS-related gene (60%), followed by hMLH1 (30%) and hMSH6 (5%-8%)
.

The MMR signaling pathway affects the repair of DNA mismatches and causes the accumulation of somatic mutations in the insertion or deletion of DNA microsatellite regions.
This phenomenon is called microsatellite instability (MSI)
.

The occurrence of LS-related tumors From a clinical point of view, malignant tumors only occur when the biallelic of the MMR gene is inactivated
.

Therefore, in addition to the genetic inactivation of the first allele, the occurrence of LS-related tumors also requires a second acquired allele mutation
.

LS-related tumors include colorectal cancer (CRC, lifetime risk 80%~90%), followed by endometrial cancer (40%-60%), upper urinary tract urothelial cancer (UTUC, 1%-28%), Ovarian cancer (1%–24%), stomach cancer (1%–13%), liver and gallbladder cancer (1%–4%), skin cancer (1%–9%) and brain tumors (1%–3%)
.

Methods and main results The study included studies on the incidence, diagnosis, clinicopathological characteristics, oncology results or screening protocols related to LS/UTUC, including retrospective studies, prospective cohort studies, reviews and reviews
.

The search strategy is shown in Figure 1
.

Relevant documents before May 2021 were searched from Medline, Scopus, Google Scholar and Cochrane databases
.

Figure 1 The flow chart of literature screening finally included 43 LS and UTUC related studies
.

01LS population UTUC risk 6 studies analyzed the cumulative lifetime risk or relative risk (RR) of UTUC in LS patients
.

Subgroup analysis showed that at the age of 70, the lifetime risk of UTUC for men and women was 0.
2% to 9.
4% and 0.
1% to 6.
0%, respectively
.

Four studies analyzed different genotypes.
Compared with hMLH1 and hMSH6, hMSH2 carriers have a higher risk of UTUC
.

The cumulative lifetime risk of UTUC in patients with hMSH2 mutant LS at the age of 70 is 6.
9%, which is about 75 times that of the general population
.

Correspondingly, the risk of renal pelvic cancer or ureteral cancer increased by 40 times and 60 times, respectively
.

02 The first primary cancer is the diagnosis of LS in UTUC patients.
Figure 2 Flow chart of LS diagnosis in UTUC patients.
Three studies reported the clinicopathological characteristics of UTUC patients diagnosed with LS
.

Treatment options for these patients include radical nephroureterectomy (RNU) and sequential adjuvant chemotherapy
.

60%~91% of cases have high-grade disease, and 40%~49% of patients have pT≤1
.

Two studies directly compared the clinicopathological characteristics and oncology results of hereditary and sporadic UTUC (Table 1)
.

Regarding long-term oncology results, the study by Audenet et al.
showed that at a median follow-up of 3 years, there was no significant difference in recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS) between the two groups
.

Hollande et al.
's study analyzed the results of 112 patients with high-risk or locally advanced UTUC who received RNU and adjuvant therapy.
The analysis showed that at a median follow-up of 19 months, compared with sporadic UTUC, hereditary UTUC had obvious CSS (P= 0.
005) and OS (P<0.
008) benefit
.

Table 1 Compared with sporadic UTUC, the clinicopathological characteristics of patients with hereditary UTUC are significantly younger than those with sporadic UTUC (62 years old vs 70 years old, P <0.
0001; 61 years old vs 69 years old, P = 0.
005), and no previous smoking history (P=0.
03)
.

In addition, patients with LS-related UTUC showed a general distribution of ureteral tumors: 51% vs 28% (P=0.
001) and 47% vs 18% (P=0.
01)
.

Table 2 Clinicopathological characteristics of UTUC in LS patients 03 Characteristics of UTUC in LS patients 15 studies reported the clinicopathological characteristics of UTUC in 250 LS patients
.

The median age of patients diagnosed with UTUC is between 56 and 67 years old
.

Female gender may be an influencing factor, accounting for 46% to 71% of the total number of cases
.

Two studies reported the symptoms of LS-related UTUC, including massive hematuria (63% and 58%, respectively) and renal colic (5%)
.

Six studies reported the location of UTUC: Compared with the renal pelvis, the ureter is more often involved, and multiple focal lesions are rare
.

Overall, 46% of patients with pT≤1 accounted for 46%, and 1 patient (8%) had metastatic disease
.

04 Molecular detection Considering the diagnostic value of MSI detection and IHC, as well as feasibility and cost-effectiveness, the investigator recommends PCR to detect MSI for all LS patients (meeting the clinical standards of the EAU guidelines), and retain the IHC method to detect high microsatellite instability Sex (H-MSI)
.

However, if the test result is negative, there is a strong clinical suspicion of LS or in the case that tumor specimens are not available, the investigator recommends DNA sequencing of the MMR gene
.

Patients with newly diagnosed LS may benefit from a multidisciplinary team that includes specialists.
Compared with the general population, this type of population needs to be screened for other primary tumors earlier and repeatedly
.

For example, from 20-25 years old, hMSH2 or hMLH1 mutation carriers need to undergo colonoscopy twice a year, from 30-35 years old, hMSH6 or hPMS2 mutation carriers need to undergo colonoscopy once a year until the age of 75, and Transvaginal ultrasound examination is performed every year
.

In addition, considering that LS is inherited as autosomal dominant, genetic counseling should be provided to all first-degree relatives, and relatives should be provided with appropriate screening programs and follow-up
.

05LS patients undergoing UTUC screening 6 studies made recommendations for LS patients to undergo UTUC screening (Figure 3)
.

Figure 3 UTUC screening flowchart for LS patients.
Different MMR genes have different risks of UTUC, and the age of hereditary UTUC is earlier.
Therefore, the researchers recommend that all patients with LS can be screened from 45 to 50 years old, including annual urine Fluid analysis and urine cytology, abdominal ultrasound examination every 2 years
.

In addition, hMSH2 mutation carriers or LS patients with a family history of urothelial cancer (including UTUC or bladder cancer) should increase the frequency of examinations and perform abdominal ultrasound or abdominal CT scans every year
.

Conclusion Urologists should identify high-risk patients with LS and conduct a comprehensive diagnosis of them, including molecular and genetic testing
.

Patients with newly diagnosed LS should be referred to a multidisciplinary team, and genetic counseling should be provided to first-degree relatives
.

References: C.
Lonati, A.
Necchi, J.
Gómez Rivas et al.
, Upper Tract Urothelial Carcinoma in the Lynch Syndrome Tumour Spectrum: A Com[1]prehensive Overview from the European Association of Urology-Young Academic Urologists and the Global Society of Rare Genitourinary Tumors, Eur Urol Oncol (2021), https://doi.
org/10.
1016/j.
euo.
2021.
11.
001