Table 2.

Tumor Tissue Test Results, Interpretation, and Additional Testing Options

Tumor Testing 1Plausible EtiologiesAdditional Testing Options for Lynch Syndrome 3, 4, 5
ImmunohistochemistryMSIBRAF V600E 2MLH1 Promoter Methylation
MLH1 MSH2 MSH6 PMS2
++++MSS
  • Sporadic cancer
  • Cancer due to other hereditary cancer syndrome
None 6
++++MSI high
  • Germline MMR gene testing or paired germline/tumor tissue MMR gene testing
  • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing.
MSI high
  • IHC
  • If IHC not available, consider germline MMR gene testing or paired germline/tumor tissue MMR gene testing.
  • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing.
–++–
  • Targeted BRAF &/or MLH1 promoter methylation testing on tumor tissue
  • If BRAF/MLH1 methylation normal, germline MMR gene testing or paired germline/tumor tissue MMR gene testing
  • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing.
–++–Pos
  • Sporadic cancer
  • Germline MLH1 path var (rare)
  • Constitutional MLH1 epimutation
  • If early-onset cancer (< age 50 yrs) or significant family history of cancer: germline MMR gene testing
  • If not: no additional testing
  • For early onset only: constitutional MLH1 epimutation testing 7
–++–NegPos
  • Sporadic cancer
  • Germline MLH1 path var (rare)
  • Constitutional MLH1 epimutation
–++–NegNeg
  • Germline MLH1 path var
  • Germline PMS2 path var (rare)
  • Sporadic cancer
  • Germline MMR testing or paired germline/tumor tissue MMR gene testing
  • If germline testing negative & paired germline/tumor tissue not done: consider tumor tissue MMR gene testing.
+––+
  • Germline MSH2/EPCAM path var
  • Germline MSH6 path var (rare)
  • Sporadic cancer
+++–
  • Germline PMS2 path var
  • Germline MLH1 path var
  • Sporadic cancer
+–++
  • Germline MSH2/EPCAM path var
  • Sporadic cancer
++–+
  • Germline MSH6 path var
  • Germline MSH2/EPCAM path var
  • Sporadic cancer w/treatment effect 8
  • Germline MMR gene testing or germline/tumor tissue MMR gene testing
  • If germline testing negative & paired germline/tumor tissue not done: consider tumor tissue MMR gene testing.
  • If applicable, consider MSI analysis or repeat IHC on nontreated tumor.
–+++
  • Sporadic cancer: MLH1 promoter methylation or somatic MLH1 or PMS2 path var
  • Germline MLH1 path var
  • Germline PMS2 path var
  • Targeted BRAF &/or MLH1 promoter methylation testing on tumor tissue
  • If BRAF & MLH1 methylation normal: germline MMR gene testing or paired germline/tumor tissue MMR gene testing
  • If germline testing negative & paired germline/tumor tissue not done: consider tumor tissue MMR gene testing.
––––
  • Germline MMR gene path var
  • Sporadic cancer
  • Targeted BRAF &/or MLH1 promoter methylation testing AND germline MMR gene testing or paired germline/tumor tissue MMR gene testing (often incl MLH1 methylation testing)
  • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing

Adapted from Gupta et al [2019].

Empty cells indicate either that testing was not done or that results may not influence testing strategy.

– = absent staining of protein; + = normal staining of protein; IHC = immunohistochemistry; MMR = mismatch repair; MSI = microsatellite instability; MSS = microsatellite stability; Neg = negative; path var = pathogenic variant; Pos = positive

1.

Tumor testing strategies apply to colorectal and endometrial cancers. Limited data exist regarding the efficacy of tumor testing in other types of Lynch syndrome tumors.

2.

BRAF testing is not appropriate for tumors other than colorectal cancer.

3.

45%-68% of tumors with evidence of MMR deficiency have biallelic somatic pathogenic variants. If biallelic somatic pathogenic variants are identified, the affected individual and their relatives should be managed based on the family cancer history and NOT as if they had Lynch syndrome.

4.

Prior to germline genetic testing, proper pre-test counseling should be done.

5.

For information on testing for germline pathogenic variants, see Table 1. A multigene panel that includes MLH1, MSH2, MSH6, PMS2, and EPCAM is recommended. Other colorectal cancer-predisposing genes (e.g., MUTYH, POLE, POLD1, NTHL1) should also be considered (see Differential Diagnosis).

6.

In the presence of a strong family history (e.g., Amsterdam criteria are met), or if additional features of a hereditary cancer syndrome are present, additional testing may be warranted in the proband or tumor testing in another affected family member because of the possibility that the original tumor selected for testing was a sporadic colorectal cancer (phenocopy).

7.

Constitutional MLH1 epimutation testing involves MLH1 promoter hypermethylation analysis on blood or other sources of normal tissue.

8.

Absent MSH6 IHC staining in rectal tumors may be due to treatment effect (neoadjuvant chemoradiotherapy).

From: Lynch Syndrome

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