• Nathan Riley, MD

Obgyno Wino Podcast Episode 85 - Lynch Syndrome

“One ought, every day at least, to hear a little song, read a good poem, see a fine picture, and, if it were possible, to speak a few reasonable words.” ― Johann Wolfgang von Goethe

2019 Pinot Noir from Paul Ponnelle

PB #147 - Published November 2014 (Reaffirmed 2016)

Five Pearls

1. Lynch Syndrome is associated with multiple inherited cancers, namely uterine, colorectal, and ovarian.

2. Lynch results in mutations of four specific mismatch repair genes, the absence of which results in microsatellite instability within the genome.

3. Patients diagnosed with Lynch should undergo regular screening for colorectal or uterine cancers.

4. Uterus, tubes, and ovaries should be removed after childbearing has been completed.

5. There are no cost-effective screening options for ovarian cancer.

Lynch syndrome epidemiology

- most common cause of hereditary uterine and colorectal cancer (~2% of patients who present with either type of cancer will test positive for Lynch)

- be especially suspicious in women who present at age <50 (mean age 47-49)

- second most common cause for hereditary ovarian cancer (1st is BRCA)

- there is some evidence to suggest that the endometrial cancers in Lynch trend towards non-endometrioid histology (i.e. the nasty-ass histologic types)

- on the other hand, ovarian cancers in Lynch tend to be detected earlier than those in the general population and they tend to be of the endometrioid or clear cell varieties

- with Lynch: risk of colorectal or endometrial cancer through age 70 is somewhere between 15-60% (compare that with 2% in general population)

- with Lynch: risk of ovarian cancer through age 70 is 5-10% (compared to 1% in general population, 40% in BRCA1, and 12-20% in BRCA2)

- cancer risk in Lynch depends to some degree on the specific mutation

- autosomal dominant inheritance pattern related to a defective mismatch repair gene (e.g. MLH1, MSH2, MSH6, and PMS2)

  • MLH1: 20-54% risk of endometrial cancer by age 70

  • MSH2: 20-50% risk of endometrial cancer by age 70

  • MSH6: 15-60% risk of endometrial cancer by age 70 (also later average age of onset)

- in over half of patients with multiple cancers, gynecologic cancer presented first (so women's healthcare providers are important after all!)

A primer on microsatellite instability

- the mismatch repair genes that, when mutated, cause Lynch syndrome, affect the whole genome

- these mismatch repair genes code for proteins which stabilize non-coding single nucleotide and dinucleotide repeats

- these non-coding repeats are termed "microsatellites"

- if these mismatch repair genes are mutated, these microsatellites will have nucleotides added and removed willy nilly

- this is termed "microsatellite instability"

- microsatellite instability can also occur with methylation of the MLH1 promoter (noniheritable), and this may also result in endometrial and colorectal cancers

- distinguishing whether microsatellite instability is inherited or noninherited is a challenge...

Testing for Lynch syndrome

Direct germline DNA testing

- involves sequencing to identify large rearrangements of the relevant mismatch repair genes

- presence of a deleterious mutation is conclusive of Lynch, but the absence isn't necessarily helpful (high specificity, low sensitivity)

- if ever in discordance with tumor testing, refer to genetics specialist

Tumor testing using immunohistochemistry

- simple: looks for the protein products of the four mismatch repair genes (if protein products found, then the gene must be working well!)

- if MLH1 or PMS2 proteins are absent and no MLH1 promoter methylation is detected, then direct germline DNA testing is recommended

- if all four genes intact, Lynch is effectively ruled out in most cases

- the exception of course is when a protein is present but is dysfunctional

- if clinical suspicion sufficiently high, you can test further through microsatellite instability testing

Tumor testing using microsatellite instability testing

- normal tissue and tumor tissue from the patient with suspected Lynch are compared: are extra nucleotides found in the tumor tissue?

- if no microsatellite instability detected, Lynch is effectively ruled out

Tumor testing using MLH1 promoter methylation testing

- useful if immunohistochemistry doesn't identify MLH1 protein or if microsatellite instability is present

- if MLH1 protein is absent and no MLH1 promoter methylation is detected, then direct germline DNA testing is required

My patient's personal or family medical history is consistent with Lynch (see Box 1)...

Tumor tissue available? Start w/ immunohistochemistry testing.

No tumor tissue available? Start w/ direct germline DNA testing. If positive, then you've got your diagnosis. If negative, Lynch cannot be excluded, and management must be guided by family history.

My patient has Lynch and does not yet have cancer...


- screening methods are recommended at regular intervals

- colonoscopy q1-2 years starting at age 20-25 or 2-5 years earlier than the age of earliest cancer diagnosis in a family member (whichever is sooner)

- EMB q1-2 years beginning at age 30-35

- self-monitoring of menstruation for abnormal uterine bleeding

- no great way to screen for ovarian cancer, unfortunately (US nor CA-125 are specific enough to be cost effective)

Prevention through medication

- starting a COC can decrease risk of uterine cancer by 50% in the general population

- depot medroxyprogesterone and levonorgestrel-releasing IUDs are also helpful in general population

- data w/ Lynch patients hasn't been well-studied, but reasonable to offer these agents...

Risk-reducing surgery

- hysterectomy with bilateral salpingo-oophorectomy (BSO) is recommended for women with Lynch who have completed childbearing (endometrial cancer risk at age 40 is 2-4% and ovarian cancer risk is 1-2%; risk jumps to 8-17% and 3-7% at age 50)

- this doesn't complete reduce the risk of gyn cancer, as primary peritoneal carcinoma can also develop in these patients, and this should be a part of your counseling

- hyst + BSO can be done laparoscopically or vaginally by a generalist

- get screening colonoscopy beforehand, because if colorectal cancer is present, you may consider concurrent surgeries

- HRT for menopausal symptoms can be considered, though its risks haven't been well-studied

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