Introduction
Lynch syndrome is the hereditary predisposition to several cancers caused by pathogenic
variants in the germline of certain DNA mismatch repair (MMR) genes: MSH2 (and EpCAM),
MLH1, MSH6 and PMS2 [1]. The greatest risks are for colorectal cancer and endometrial
cancer, but other organs are also at increased risk for cancer at earlier than expected
ages [2]. Surveillance colonoscopy every 1–3 years and timely gynecological surgery
can significantly decrease cancer mortality in patients with Lynch syndrome. Managing
cancer risk in other organs is more controversial, and a variety of management regimens
have been suggested over time by different expert panels.
Gastric cancer in Lynch syndrome
Gastric cancer in Lynch syndrome has been a controversial risk problem for a variety
of reasons. The initial report of this disease occurred in 1913, when Warthin reported
“Cancer Family G”. In the first reported generation of this family, gastric cancer
and colorectal cancer each caused the deaths of two individuals. When the pathogenic
germline variant in MSH2 was found, the family was followed up over seven generations,
and gastric cancer was the third most common malignancy in the family, although that
cancer decreased in frequency over the course of the twentieth century [3]. Gastric
cancer fell in incidence throughout the twentieth century in US and European populations,
and perhaps this provides some explanation for why it may have fallen in Lynch syndrome
families as well. The problem here is that the reported incidence of gastric cancer
in Lynch syndrome ranges from 6 to 13% [4], but there may be changes in incidence
over the last 100 years, and there are certainly different incidences in geographical
locations or ethnic groups that have a higher background incidence of this disease
[5]. The data are scant, but 62–79% of gastric cancers in Lynch syndrome are intestinal
type, whereas 23–32% are reported to be diffuse or poorly differentiated; some registries
do not have information on all of the tumors [6, 7]. The tumors occur in the cardia,
body and antrum of the stomach [4, 7].
Surveillance recommendations for gastric cancer risk in patients with Lynch syndrome
At this time, the most effective way to surveille patients for upper gastrointestinal
cancer is through esophago-gastro-duodenoscopy (EGD). This approach permits early
diagnosis in asymptomatic patients, but unlike the colon, there are no premalignant
lesions to remove and reduce cancer incidence. The questions are at what age one should
begin surveillance, how frequently to repeat it, and whether it is possible to identify
specific subgroups of patients with Lynch syndrome for whom a different regimen is
appropriate. In light of the variable estimates of the risk of gastric cancer in this
setting, one challenge is to determine what threshold of cancer risk is required to
trigger an invasive surveillance program. Most expert panels have suggested that endoscopic
surveillance is appropriate, but recommendations differ concerning the age to initiate
surveillance and the frequency of repeating the exams; moreover, some groups advise
against surveillance programs (Table 1) [8–16].
Table 1
Surveillance recommendations for gastric cancer prevention in Lynch syndrome
Organization
Age to consider beginning EGD
Surveillance Interval
Helicobacter pylori testing?
Other
ACG [10]
30–35 years
3–5 years (see recommendation under Other)
Yes, and treat positives
Surveillance if positive family history of GC or duodenal cancer
ASCO [11]
Not stated
1–3 years in high risk populations
Yes, and treat positives
Endorsed ESMO guidelines
EHTG [8]
Not recommended
Not recommended
Yes
Consider surveillance in countries with increased GC (Korea, Japan)
ESDO [12]
30 years
1–2 years in all patients
Yes
ESGE [16]
Not recommended
Not recommended
Yes
ESMO [12]
Not stated
1–3 years (see recommendation under Other)
Yes
Surveillance in “high-risk populations”
NCCN [14]
40 years
3–5 years in all patients
Yes, with each EGD
Asian patients may benefit from surveillance
USMSTF [15]
30–35 years
2–3 years
Yes (biopsy)
Surveillance based upon “patient risk factors”
Adapted from Kim et al. [9]
ACG American College of Gastroenterology, ASCO American Society for Clinical Oncology,
EHTG European Hereditary Tumour Group (formerly the Mallorca Group), ESDO European
Society of Digestive Oncology, ESGE European Society of Gastrointestinal Endoscopy,
ESMO European Society for Medical Oncology, NCCN National Comprehensive Cancer Network,
USMSTF United States Multisociety Task Force, UGI upper gastrointestinal, GC gastric
cancer
Recent research on the subject of EGDs in patients with Lynch syndrome
To help illuminate this problem, Ladigan-Badura et al. evaluated the effectiveness
of EGD surveillance in patients with Lynch syndrome using data from the German Consortium
for Familial Intestinal Cancer that dates back to 1999 [4]. In this prospective (but
non-randomized) multi-cohort study of 2009 registered people with Lynch syndrome,
1128 underwent 5176 upper endoscopic exams at the time of their surveillance colonoscopies,
which were typically done every 1–3 years. The investigators observed 49 gastric cancers
in 47 patients. Patients undergoing surveillance EGDs were significantly more likely
to be diagnosed with early stage disease (IUCC 1a-1b) than in those diagnosed because
of symptoms (83% vs 25%, P = 0.23). Most of the patients (68%) reported no family
history of gastric cancer. The median age for the diagnosis of gastric cancer was
51 years (range 28–66), and 13 (28%) were younger than age 45. Almost all cases were
in patients with pathogenic variants in MSH2 or MLH1; one was related to MSH6, one
with EpCAM, and none were reported in PMS2 patients. Males made up 62% of the gastric
cancer group. The authors conclude that finding significantly fewer advanced gastric
cancers demonstrates the effectiveness of screening EGDs, and recommended routine
surveillance in Lynch syndrome beginning at age 30.
The role of H. pylori and gastritis
An issue not addressed here is the value of testing for H. pylori infection at the
time of the EGD. Although this does not add serious time or morbidity to an EGD and
is listed in virtually all of the guidelines (Table 1), there is not much evidence
that this is actually helpful. A recent study by Kumar et al. reported that in their
cohort of 295 patients with Lynch syndrome who underwent 660 EGDs, 6 gastric cancers
were found (2.8%), and just 6 in the whole cohort (again 2.8%) were H. pylori carriers.
Although not specifically stated in the publication, none of the gastric cancers occurred
in the context of a H. pylori infection (personal communication, BW Katona) [17].
This group also reported that 4 of the 5 upper gastrointestinal cancers detected on
surveillance occurred within 2 years of the prior EGD [17]. Perhaps surveillance intervals
require additional scrutiny. Equivalent rates of H pylori infection have been reported
for patients with Lynch syndrome with or without a first degree relative gastric cancer
[18]. Also, it has been recently reported in a small series that gastric cancer in
Lynch syndrome is associated with underlying chronic autoimmune gastritis unrelated
to H. pylori infection, which opens another avenue for screening and risk assessment
[19].
Proposed conclusions
What can the reader conclude from the study by Ladigan-Badura and colleagues? First,
it takes a lot of EGDs to find early stage asymptomatic gastric cancers in Lynch syndrome.
A diagnosis of gastric cancer was made in only 47/2009 (2.3%) of all their patients
and in 48/5176 (0.93%) of their exams. That is a lot of negative exams. However, given
the lethality of an advanced gastric cancer, this may be acceptable, especially since
the exam could be done on an already sedated patient who is in the endoscopy suite
for a colonoscopy, which should add only a few minutes and minimal morbidity to the
effort. Secondly, the findings here and elsewhere [6] indicate that only a minority
of individuals with Lynch syndrome-associated gastric cancer will have a family history
of gastric cancer. Although a recent study found that a patient with Lynch syndrome
is significantly and incrementally more likely to develop gastric cancer when there
are first degree relatives with gastric cancer, more than two thirds of patients with
Lynch syndrome-associated gastric cancers have no family history, so a reliance on
this finding alone to guide EGD surveillance would likely miss the majority of cases
[9]. Additionally, there would appear to be reason to focus this surveillance on patients
with Lynch syndrome who carry pathogenic variants in MSH2, MLH1 and (probably) EpCAM,
but not do this on patients with MSH6 pathogenic variants (probably) and PMS2 (certainly).
Using large genetic testing panels will also lead to the identification of lower penetrance
genes and pathological variants in genes that are not suspected to raise the risk
of gastric cancer. Future research is required to determine the optimal response to
these situations [20].
Final caveat
Finally, this work stems from a European population, and one cannot assume that the
data would be similar in countries with very high risks for gastric cancer, such as
Japan and Korea, where the clinical picture appears to be quite different [21].