Table 7:

Summary of 2021 National Comprehensive Cancer Network Recommendations for cancer surveillance for individuals with Lynch syndrome by pathogenic variant ⁶⁶.

	MLH1	MSH2 and EPCAM	MSH6	PMS2
Cancer Risk Site
Colorectal	• Colonoscopy every 1–2 y, initiated at age 20–25 y, or 2–5 y prior to earliest CRC in family if diagnosed before age 25		• Colonoscopy every 1–2 y, initiated at age 30–35 y, or 2–5 y prior to earliest CRC in family if diagnosed before age 30
Endometrial	• Patient education to monitor for abnormal uterine bleeding or postmenopausal bleeding, which can allow for early detection of endometrial cancer. NCCN recommends evaluation of these symptoms should include endometrial biopsy. • Total hysterectomy can be considered as risk reducing option to reduce incidence, with timing individualized based on childbearing plans, comorbidities, and family history. • NCCN notes that screening via endometrial biopsy does not have proven benefit, but that this strategy is highly sensitive and specific as a diagnostic procedure, and that screening with endometrial biopsy every 1–2 y, starting at age 30–35 y can be considered. • Transvaginal ultrasound may be considered for postmenopausal women at clinician discretion, but sensitivity may be limited. Ultrasound is not recommended as a screening tool in premenopausal women.			• NCCN notes that PMS2 Lynch syndrome appears to be associated with only modestly increased risk of endometrial cancer in contrast to MLH1, MSH2, and MSH6 Lynch syndrome. • Considerations for surveillance are otherwise the same as for MLH1, MSH2, and MSH6 Lynch syndrome
Ovarian	• Individualized consideration for bilateral salpingo-oopherectomy (BSO) based on childbearing plans, menopause status, comorbidities, and family history to reduce ovarian cancer incidence • Patient education to monitor for persistent pelvic/abdominal pain, bloating, increased abdominal girth, early satiety, or urinary frequency/urgency • NCCN currently states data do not support routine screening, and that transvaginal ultrasound has not been shown to be sufficiently sensitive or specific to support a routine recommendation, but may be considered at clinician's discretion. A similar conclusion was reached for serum CA-125-based screening.		• NCCN has noted insufficient evidence to make a specific recommendation for risk-reducing BSO in MSH6 Lynch syndrome, and guidance for those considering prophylactic surgery or screening is otherwise the same as for MLH1 and MSH2 Lynch syndrome	• NCCN has noted insufficient evidence to make a specific recommendation for risk-reducing BSO for PMS2 Lynch syndrome, and that PMS2 pathogenic variant carriers appear to be at no greater than average risk for ovarian cancer and therefore may consider deferring surveillance and may reasonably elect against oophorectomy • For PMS2 pathogenic variant carriers who consider surveillance or surgery, recommendations are the same as for MLH1 and MSH2 Lynch syndrome
Urothelial Cancer (Renal pelvis, ureter, and/or bladder)	• No clear evidence to support surveillance • Surveillance options may include annual urinalysis starting at age 30–35 y, but NCCN stated there is insufficient evidence to recommend a particular surveillance strategy	• NCCN has recommended the same strategy as for MLH1 Lynch syndrome, but has noted that those with MSH2 Lynch syndrome (especially males) appear to be at higher risk for urothelial cancer	• No clear evidence to support surveillance • Surveillance options may include annual urinalysis starting at age 30–35 y, but NCCN stated there is insufficient evidence to recommend a particular surveillance strategy
Gastric and small bowel cancer	• NCCN states no clear data exist to support surveillance for gastric, duodenal, and more distal small bowel cancer for LS. Individuals with a family history of these tumors may have increased risk but the benefit of surveillance is unknown. • Consider baseline EGD with random biopsy of the proximal and distal stomach to evaluate for H. Pylori, autoimmune gastritis, and intestinal metaplasia beginning at age 40 y and surveillance EGD every 3–5 y in those with risk factors for gastric cancer such as: male sex; MLH1 or MSH2 pathogenic variants; first degree relative; Asian ethnicity; residing in or immigrant from country with high background gastric cancer incidence; autoimmune gastritis; gastric intestinal metaplasia; gastric adenoma • Consider testing for H. pylori, and treat if detected.
Pancreas	• For individuals with exocrine pancreatic cancer in ≥1 first- or second-degree relatives from the same side of the family as the identified pathogenic/likely pathogenic germline variant, consider pancreatic cancer screening beginning at age 50 years (or 10 years younger than the earliest exocrine pancreatic cancer diagnosis in the family, whichever is earlier) with annual contrast-enhanced MRI/MRCP and/or EUS at a center of expertisea		• NCCN has specifically noted there are limited data on pancreatic cancer risk for MSH6 Lynch syndrome • Recommendations are otherwise the same as for MLH1 and MSH2 Lynch syndrome	• Current NCCN guidelines conclude that PMS2 carriers have not been shown to be at increased risk for pancreatic cancer, and that patients with family history of pancreatic cancer should be managed based on careful assessment and clinical judgement
Prostate	• The version 1.2021 NCCN Guidelines for Prostate Cancer Early Detection recommend it is reasonable for men with Lynch syndrome to consider beginning shared decision-making about screening at age 40 and to consider screening at annual intervals. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer Early Detection V1.2021 © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed March 22, 2021. To view the most recent and complete version of the guideline, go online to NCCN.org
Breast (female)	• NCCN concluded there is insufficient evidence to support increased screening above average-risk breast cancer screening recommendations or those based on personal/family history of breast cancer
Brain	• Patient education regarding signs and symptoms of neurologic cancer and the importance of prompt reporting of abnormal symptoms to their physicians
Skin	• Consider skin exam every 1–2 years to evaluate for sebaceous adenocarcinomas, sebaceous adenomas, and keratoacanthomas; age to initiate surveillance is uncertain and can be individualized			• NCCN noted that elevated risk of sebaceous tumors and keratoacanthoma has not been documented for PMS2 Lynch syndrome, and that surveillance can be considered using the same strategies as for MLH1, MSH2, and MSH6 Lynch syndrome

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) are updated annually; see nccn.org for most current NCCN recommendations.

^aThe NCCN recommends that such screening only take place after an in-depth discussion about the potential limitations to screening, including cost, the high incidence of benign or indeterminate pancreatic abnormalities, and uncertainties about the potential benefits of pancreatic cancer screening