Any ONE criterion met = indication to test CRC tumour for MSI and MMR-IHC. More sensitive than Amsterdam Criteria. Applies to patients with established or suspected CRC diagnosis.
Guidelines & Evidence
Clinical Details
Section 1
When to Use
When to Use
Selecting CRC tumours for MSI (Microsatellite Instability) and/or MMR-IHC testing to identify Lynch syndrome candidates.
Applicable to patients with newly diagnosed or confirmed colorectal cancer at any age.
More sensitive than Amsterdam Criteria for Lynch syndrome identification — any one trigger criterion is sufficient.
Endorsed by NCI, ASCO, NCCN, and ESMO as clinical screening criteria for Lynch syndrome.
Strategy Note
Many centres now use universal reflex MMR-IHC/MSI testing of ALL colorectal (and endometrial) cancers regardless of Bethesda criteria — this has replaced Bethesda as the frontline strategy in progressive healthcare systems.
Section 2
Formula & Logic
Revised Bethesda Criteria (2004) — Any ONE Met = Test Tumour
Criterion 1: CRC diagnosed in patient < 50 years of age
Criterion 2: Presence of synchronous or metachronous CRC, or other Lynch-associated tumour (endometrial, stomach, ovary, pancreas, ureter, renal pelvis, biliary tract, brain, small bowel, sebaceous glands/keratoacanthoma), regardless of age
Criterion 3: CRC with MSI-H histology (tumour-infiltrating lymphocytes, Crohn's-like lymphocytic reaction, mucinous/signet ring differentiation, medullary growth pattern) diagnosed < 60 years
Criterion 4: CRC diagnosed in ≥ 1 first-degree relatives with Lynch-associated tumour, with ≥ 1 cancer diagnosed < 50 years
Criterion 5: CRC diagnosed in ≥ 2 first- or second-degree relatives with Lynch-associated tumours, regardless of age
Tumour Testing Cascade
01
1. MMR-IHC (MLH1, MSH2, MSH6, PMS2) on tumour block.
02
2. If MLH1 loss: BRAF V600E or MLH1 methylation test to exclude sporadic MSI-H (epigenetic).
03
3. If abnormal IHC (not explained by MLH1 methylation/BRAF): Germline MMR gene testing.
04
4. If IHC normal but Bethesda criteria met: Consider MSI-PCR or germline testing (especially for MSH6/PMS2 with MSS tumours).
Bethesda Criterion 3 (MSI-H histology) is often under-recognised by reporting pathologists — check for TIL, Crohn's-like reaction.
MSH6 and PMS2 germline variants frequently cause microsatellite-stable (MSS) or MSI-Low tumours — Bethesda criteria may be needed for selection.
Synchronous/metachronous tumours (Criterion 2) includes tumours in any Lynch-spectrum tissue — eliciting full cancer history in all first-degree relatives is essential.
Section 4
Evidence Appraisal
Primary Reference
Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability
Umar A et al. • Journal of the National Cancer Institute. 2004;96(4): 261–268
Section 5
Literature
Original Bethesda Guidelines (1997)
The first Bethesda Guidelines were published in 1997 following a National Cancer Institute-sponsored workshop to standardise MSI tumour testing in HNPCC families. They reflected the limited understanding of the full Lynch cancer spectrum at the time and were restricted to CRC.
Revision (2004)
Revised in 2004 (Umar et al., JNCI) to expand the cancer spectrum, lower age thresholds, and incorporate MSI-H histological features as a trigger criterion. The Revised Bethesda Guidelines dramatically improved sensitivity for Lynch syndrome identification and remain in use, though universal reflex tumour testing — adopted by many US academic centres since ~2010 — has further displaced them in practice.
