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Lynch syndrome, also referred to as hereditary non-polyposis colorectal cancer (HNPCC) is the most frequent hereditary colorectal cancer syndrome. Extra-colonic cancer can occur in this syndrome and includes endometrial cancer, ovarian cancer, cancer of the small intestine, and renal pyelum/uterer cancer. Identification of Lynch syndrome gene carriers facilitates cancer prevention in the families involved. Unfortunately, Lynch syndrome is difficult to diagnose clinically because of the absence of a unique phenotype (as opposed to the large number of polyps in the hereditary polyposis syndromes). Lynch syndrome is caused by germline mutations in genes of the DNA mismatch repair (MMR) system. Germline mutations in MLH1, MSH2, MSH6 and PMS2 have been shown to cause Lynch syndrome, although other MMR genes might be involved as well.

CAP template reporting of IHC, then the interpretation comments we're using, then CAP template reporting of MSI. All of this is in order on the attached file. (At the end is NCCN guidelines for breast which I see is already on the site).


Interpreting Common Abnormal Results on Immunohistochemical Testing

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Reference: J Natl Compr Canc Netw. 2011 Nov;9(11):1311-20.


CAP Template for Reporting of Mismatch Repair Proteins by IHC
Results


Immunohistochemistry Testing (IHC) for Mismatch Repair Proteins (select all that apply)
___ MLH1
___ Intact nuclear expression
___ Loss of nuclear expression
___ Cannot be determined (explain): _____________________
___ MSH2
___ Intact nuclear expression
___ Loss of nuclear expression
___ Cannot be determined (explain): _____________________
___ MSH6
___ Intact nuclear expression
___ Loss of nuclear expression
___ Cannot be determined (explain): _____________________
___ PMS2
___ Intact nuclear expression
___ Loss of nuclear expression
___ Cannot be determined (explain): _____________________
___ Background nonneoplastic tissue/internal control with intact nuclear expression

Interpretation


___ No loss of nuclear expression of MMR proteins: low probability of MSI-H

___ Loss of nuclear expression of MLH1 and PMS2: testing for methylation of the MLH1 promoter and mutation of BRAF is indicated (presence of both BRAF mutation and MLH1 methylation indicates sporadic case; absence of both MLH1 methylation and of BRAF mutation indicates Lynch syndrome and sequencing of germline MLH1 is indicated; presence of MLH1 methylation without BRAF mutation is equivocal for a sporadic case and Lynch syndrome and sequencing of germline MLH1 is indicated)

___ Loss of nuclear expression of MSH2 and MSH6: high probability of Lynch syndrome (sequencing of germline MSH2 is indicated and, if negative, evaluation of EPCAM (TACSTD1) deletion, methylation of MSH2 promoter, and sequencing of germline MSH6 are indicated)

___ Loss of nuclear expression of MSH6 only: high probability of Lynch syndrome (tumor MSI evaluation and sequencing of germline MSH6 are indicated)

___ Loss of nuclear expression of PMS2 only: high probability of Lynch syndrome (tumor MSI evaluation and sequencing of germline PMS2 are indicated)

Note: CAP IHC interpretation may be more detailed than is used in practice as any testing
beyond IHC MMR and MSI is likely to be ordered by a genetic counselor. Below is what
we are using at Saddleback Memorial Medical Center.




Saddleback Memorial Medical Center Mismatch Repair (MMR) IHC Results: Testing Comments


A) IHC NORMAL (ALL 4 PROTEINS EXPRESSED):
A normal result does not completely rule out Lynch Syndrome. Based on age of onset and family history, genetic counseling to consider additional tumor analysis, including microsatellite instability (MSI), DNA analysis, and follow-up may be warranted. Clinical correlation is recommended.

B) IHC ABNORMAL (MLH-1 or MLH-1 & PMS-2 ABSENT):
Loss of MLH-1 expression is concerning for Lynch Syndrome, but may be due to a sporadic event of tumorgenesis. Genetic counseling to consider additional tumor analysis, including hypermethylation of MLH1, DNA analysis and follow-up is recommended.

C) IHC ABNORMAL (MSH2, MSH6, or PMS2 ABSENT):
These findings are informative for Lynch Syndrome. Genetic counseling to consider DNA analysis and follow-up is recommended.

IHC INTERPRETATION:

POSITIVE   =   REPORT AS “EXPRESSED”
NEGATIVE =   REPORT AS “ABSENT”

IHC HNPCC/LYNCH SCREENING COMMENT: 
Tumors from individuals with HNPCC/Lynch syndrome typically demonstrate microsatellite instability (MSI), which is characterized by the expansion of repetitive DNA called microsatellites. Most MSI tumors show a specific loss of Mismatch Repair (MMR) protein expression due to the correlated loss of function of the MMR gene: MLH1, MSH2, MSH6, or PMS2.  

Alternatively, the absence of MLH1 protein expression may be due to somatic hypermethylation of the MLH1 gene within various sporadic cancers including colon and endometrial. 



CAP Template for Microsatellite Instability (MSI) Intepretation


Microsatellite Instability (MSI)
___ MSI–Stable (MSS)
___ MSI–Low (MSI-L)
___ 1%-29% of the markers exhibit instability
___ 1 of the 5 NCI or mononucleotide markers exhibit instability
___ Other (specify): _______________________
___ MSI–High (MSI-H)
___ ≥30% of the markers exhibit instability
___ 2 or more of the 5 NCI or mononucleotide markers exhibit instability
___ Other (specify): _______________________
___ MSI-Indeterminate

Loci Testing
___ Mononucleotide Panel (select all that apply)

BAT-25
___ Stable
___ Unstable
___ Cannot be determined (explain): __________________________

BAT-26
___ Stable
___ Unstable
___ Cannot be determined (explain): __________________________

NR-21
___ Stable
___ Unstable
___ Cannot be determined (explain): __________________________

NR-24
___ Stable
___ Unstable
___ Cannot be determined (explain): __________________________

Mono-27
___ Stable
___ Unstable
___ Cannot be determined (explain): __________________________
___ NCI Panel (select all that apply)

BAT-25
___Stable
___Unstable
___Cannot be determined (explain): __________________________

BAT-26
___Stable
___Unstable
___ Cannot be determined (explain): __________________________

D2S123
___ Stable
___ Unstable
___ Cannot be determined (explain): __________________________

D5S346
___ Stable
___ Unstable
___ Cannot be determined (explain): __________________________

D17S250
___ Stable
___ Unstable
___ Cannot be determined (explain): __________________________