Hereditary non-polyposis colorectal cancer: The rise and fall of a confusing term

Table 1 Amsterdam I and II criteria and Bethesda (revised) guidelines

Term	Criteria	Reference
Amsterdam I1	Three 1st degree relatives with CRC	Vasen et al, 1991[13]
	Two generations affected
	One family member below age 50 yr
	Exclude familial adenomatous polyposis
Amsterdam II1	As for Amsterdam I except that CRC may be substituted by cancer of endometrium, small bowel, or pelviureter	Vasen et al, 1999[14]
Bethesda (revised)2		Umar et al, 2004[44]
1	CRC below age 50 yr
2	Multiple CRC or HNPCC-related cancers3
3	CRC with MSI-related histology4, < 60 yr
4	CRC or HNPCC-related cancer in at least one 1st degree relative, < 50 yr
5	CRC or HNPCC-related cancer in at least two 1st or 2nd degree relatives, any age

¹All criteria must be met;

²Any criterion (1-5) can be met;

³Includes cancer of endometrium, small bowel, pelviureter, biliary tract, stomach, ovary, pancreas, and brain (mainly glioblastoma multiforme);

⁴Tumor infiltrating lymphocytes, Crohn-like reaction, mucin/signet ring cell differentation, medullary growth pattern.

Table 2 Conditions and clinical scenarios that may mimic Lynch syndrome

Attenuated Familial Adenomatous Polyposis[37] (polyps may not be numerous)

MYH polyposis[38] (polyps may not be numerous)

Juvenile polyposis[66] (polyps may not be numerous and may be adenomatous)

Germline mutation of TGFbetaRII[67] and AXIN2[68] (is not associated with DNA MSI)

Hereditary mixed polyposis syndrome[69] (polyps may not be numerous and may be adenomatous)

Hyperplastic polyposis[53] (polyps may not be numerous and may be adenomatous)

Serrated Pathway Syndrome[54] (polyps may not be numerous and may be adenomatous and CRCs may show DNA MSI)

Germline hemi-allelic methylation of MLH1[48-51] (multiple, early onset cancers with Lynch syndrome spectrum and having DNA MSI)

Lynch syndrome variants[61,65] (autosomal recessive Turcot syndrome due to PMS2 mutation)

Familial Colorectal Cancer-Type X[40] (Amsterdam criteria met but Lynch syndrome and conditions listed above have been excluded)