Editor's Choice: Lynch syndrome in the 21st century: clinical perspectives

open access (originally published 2015)

 Summary
Lynch syndrome (LS) is the most common of all inherited cancer syndromes, associated with substantially elevated risks for colonic and extracolonic malignancies, earlier onset and high rates of multiple primary cancers. At the genetic level, it is caused by a defective mismatch repair (MMR) system due to presence of germline defects in at least one of the MMR genes- MLH1, MSH2, MSH6, PMS2 or EPCAM. An impaired MMR function during replication introduces infidelity in DNA sequence and leads to ubiquitous mutations at simple repetitive sequences (microsatellites), causing microsatellite instability (MSI).
Although previously, clinicopathological criteria such as Amsterdam I/II and Revised Bethesda Guidelines were commonly used to identify suspected LS mutation carriers, there has been a recent push towards universally testing, especially in case of colorectal cancers (CRCs), through immunohistochemistry for expression of MMR proteins or through molecular tests (polymerase chain reaction, PCR) for MSI, in order to identify LS mutation carriers and subject them to genetic testing to ascertain the specific gene implicated. In this review, we have discussed the latest diagnostic strategies and the current screening and treatment guidelines for colonic and extracolonic cancers in clinically affected and at-risk individuals for LS.

 Urinary tract cancers
The lifetime risk of urinary tract cancers (transitional cell carcinoma
of bladder, renal pelvis and ureter) ranges from 0.2–25%
in LS patients and appears to be more prevalent with MSH2 mutations.
46 Urine cytology and urinalysis for microscopic hematuria
has not been shown to be sensitive or specific enough and
benefit of ultrasound screening is unclear. However, urinalysis
is inexpensive and usually a part of routine physical examination.
Therefore, consensus opinion is in favor of annual urinalysis
starting at age 30–35 years in individuals at risk for or
affected with LS.47

 Gynecological (endometrial and ovarian) cancers
Endometrial cancer is the second most common cancer in LS
patients, with 20–60% lifetime risk depending upon specific
gene mutation. Fortunately, majority of symptomatic patients
with endometrial cancer have stage 1 disease with 5-year survival
rate in excess of 85%. Therefore, it is unlikely that screening
for endometrial cancer will offer any significant survival
benefit. However, consensus guidelines currently recommend
annual pelvic exam and endometrial sampling starting at age
30–35 years.40
The lifetime risk of ovarian cancer in women with LS ranges
from 0.3 to 20%. Although screening for ovarian cancer through
transvaginal ultrasound and CA-125 has not been shown to be
effective in any study (including patients with hereditary breast
cancer from mutation of BRCA1 or BRCA2), consensus opinion is
in favor of transvaginal ultrasound starting at age 30–35 years in
LS patients.36
Based upon cost-effectiveness analysis, current guidelines
recommend prophylactic hysterectomy and bilateral salpingooophorectomy at age 40 or after having finished childbearing.41
This option should be given to women in large part because of
the ineffectiveness of screening for gynecologic cancers, especially
ovarian cancer.42