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| Journal of the New Zealand Medical Association,
05-November-2010, Vol 123 No 1325
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Simon J Harper, Alison R McEwen, Elizabeth R Dennett
Cancers of the colon and rectum are the second most common
cancers in New Zealand (NZ). The most recent figures released by the NZ Ministry
of Health show 2716 new cases were registered in
20051 (66 cases / 100,000
population2). The majority of cases are
sporadic but 8–12% are associated with genetic syndrome.
The most common of the known colorectal cancer (CRC)
predisposing syndromes is Lynch syndrome,3 also
known as hereditary non-polyposis colorectal cancer (HNPCC). This is an
autosomal dominant syndrome, which confers a predisposition to colonic and other
cancers. Lynch syndrome is responsible for 2–3% of the colorectal cancer
burden.
Typically, families with Lynch syndrome are diagnosed with
colonic cancers at an earlier age than sporadic colonic cancers and multiple
tumours (either synchronous or metachronous) are more frequent than in sporadic
colon cancer patients. Other tumours associated with the syndrome include
endometrial carcinoma with a lifetime risk of
40–60%4 as well as a modestly increased
risk of ovarian, stomach, small bowel, hepatobiliary, renal pelvic, and ureteric
tumours.5 A personal or family history of any
of these malignancies in a patient with colon cancer should raise the suspicion
of Lynch syndrome.
Lynch syndrome is caused by germline mutations in one of
several DNA mismatch repair genes which results in faulty DNA repair. Laboratory
techniques including microsatellite instability (MSI) testing and
immunohistochemistry (IHC—which tests for the expression of DNA repair
proteins suggesting the possibility of MSI) can help identify patients with
suspected Lynch syndrome. Thus genetic counseling, genetic testing and
appropriate surveillance can be offered to families. The revised Bethesda
criteria6 (Table 1) are the currently accepted
guidelines used when deciding which patients to screen for potential Lynch
syndrome.
Table 1. Revised Besthesda
criteria
* HNPCC associated tumours are; endometrial; ovarian;
stomach; small bowel; hepatobiliary; renal pelvis; and ureteric
Surgeons who treat patients with colorectal cancer need to
be alert to the possibility of Lynch syndrome and arrange appropriate testing in
response to clinical triggers. Previously this required identification of those
that fit the Bethesda criteria and subsequent referral onto a genetic service.
The genetic service would then take a detailed family history and determine if
genetic testing was required.
IHC staining is a relatively rapid method of screening for
those that may benefit from genetic testing. IHC looks for the presence or
absence of certain proteins with the results influencing the decision making
process about the need to refer for a genetics opinion.
We questioned the current knowledge and practice of general
and sub-specialty colorectal surgeons in NZ with regard to IHC testing and
indications for referral to genetic services.
MethodsUsing the revised Bethesda criteria a questionnaire
(Fig 1) was designed. In designing this tool we consulted geneticists in our
institution. There was concern regarding the misrepresentation of IHC as a test
for MSI, which it is not. IHC shows loss of expression of the protein product of
one or more mismatch repair genes. Positive IHC staining merely indicates the
possibility of MSI in the DNA and hence the chance of finding Lynch syndrome
mutations.
In the interest of trying to keep the questionnaire at
a length likely to be responded to we agreed not to have lengthy explanations
before any questions and use the word ‘possible’ in question 2. We
felt that this was an acceptable compromise as the question therefore did not
state categorically IHC was a test for micro satellite instability but an
abnormal result meant that MSI was a possibility.
Our finalised questionnaire was then sent to all NZ
surgeons identified by the Royal Australasian College of Surgeons as general
surgeons, with or without a sub-specialty interest in colorectal surgery (CRS).
The questionnaire was sent out by the college to preserve confidentiality. The
only identifier was a small 'c' on the questionnaire of those surgeons who had
declared sub-specialty interest in colorectal surgery to the college. One month
after the original mailing a follow-up letter was distributed to improve the
response rate.
Figure 1. Questionnaire
 The returned questionnaires were analysed against the
revised Bethesda criteria and the results tabulated. Statistical significance
was set at p<0.05. Chi-squared tests were used to test for this except when a
cell had <5 observed responses Fisher's exact test was used.
Results183 questionnaires were distributed and after reminder
letters 94 (51%) were returned. Of the 94 responses, 77 surgeons were involved
in treating patients with CRC, 23 of these were identified as having a
sub-specialty interest in colorectal surgery. The remaining 17 were no longer
practicing or not involved with CRC. As this was a study of current practice the
responses of the 17 surgeons no longer practicing or not treating CRC were
excluded from the final analysis.
Overall, 68/77 (88%) surgeons knew about IHC testing.
Predictably, those surgeons with a specialist interest in colorectal surgery had
a greater awareness of the availability of IHC testing than those with no
declared interest (96% vs 85%, p=0.3)
The results for the practice based questions are shown in
Table 2. Forty-five percent of the respondents correctly identified that a
colorectal cancer diagnosed before the age of 50 was one of the Besthesda
criteria. A similar proportion (40%) thought a patient should be younger than 45
years of age.
Table 2. Correct responses (raw numbers and
(%)) to the practice based questionnaire
For the remaining questions the correct response rate ranged
from 32–96%. The questions with the lowest correct response rate are those
about Lynch syndrome associated cancers. Only 32% knew renal tract cancers were
associated with Lynch syndrome , 48% knew about ovarian cancer and 56% about
endometrial cancer. There is no statistically significant difference between the
response rates for those with and without a declared interest in colorectal
surgery.
After receiving a positive IHC result 63/77 (83%) surgeons
would discuss screening/surveillance with the patient and their family,
15/77(19%) would refer the case onto a tertiary surgical unit and 70/77(93%)
would refer to the regional genetic service on the basis of such a result.
DiscussionIHC staining of tumour tissue for the presence or absence of
proteins indicating the possibility of a mismatch repair gene mutation is quick,
inexpensive and efficient, being 100% specific and 94%
sensitive7 compared to genetic testing.
Therefore it is reasonable to regard IHC as an initial screening test for Lynch
syndrome.
IHC testing and results should be regarded as genetic
information and thus appropriate consent should be obtained from patients prior
to testing. Ideally this should be done by the operating surgeon. However, to
obtain valid consent the surgeon needs to be aware of whom to offer the test to.
Our results show that 40% of surgeons would not offer testing to patients older
than 45 years and, depending on the other types of cancer in the family,
50–75% or potentially eligible patients would not be identified and
tested.
The Royal College of Pathologists of Australasia released a
position statement in 2006,8 which recommends
no additional consent is required to perform IHC. However, with the exception of
age, pathologists are not routinely given the necessary clinical information to
make a decision about IHC.9 The surgical team
cannot hope to provide this information on specimen forms if suspicious details
in the patients history are overlooked or not enquired about.
The survey results show that New Zealand surgeons know IHC
is available but knowledge about who to test is lacking. It could be argued that
the results are simply a reflection of the low response rate to the
questionnaire. Surveys of New Zealand Surgeons have in the past achieved
response rates of 70%.10 However, these
previous surveys are of all fellows of the college and not just general
surgeons.
When surveying General Surgeons in NZ this may be the best
we can hope to achieve. Even if we had had a 100% response rate New Zealand
surgeons show gaps in their knowledge of the Besthesda criteria. The 89
non-responding surgeons were included and a sensitivity analysis (not shown
here) was undertaken. The results showed that there would still be approximately
30% of patients with suspicious criteria who would go unidentified.
It is possible that some more knowledgeable surgeons found
the stems of question 3 harder to answer (with a potential skewing effect on the
results) as the main question could be taken to imply that IHC tests directly
for MSI, which as we have noted, is incorrect. As the focus of this paper is
knowledge and education we have made efforts to clarify this point in our
introduction and methodology.
ConclusionThis study has shown a lack of awareness about aspects of
the Besthesda criteria amongst New Zealand general surgeons. Any delay in the
diagnosis of Lynch syndrome may have a negative impact on patients and their
families. For those treating colorectal cancer it is prudent, if not essential,
to be aware of the classic features of Lynch syndrome and test appropriately.
Competing interests: None known.
Author information: Simon J Harper,
Surgical Registrar, Department of Surgery and Anaesthesia, School of Medicine
and Health Sciences, University of Otago Wellington; Alison R McEwen, Genetic
Counsellor, Central Regional Genetic Services, Wellington Hospital, Wellington;
Elizabeth R Dennett, Senior Lecturer (Colorectal Surgery), Department of Surgery
and Anaesthesia, School of Medicine and Health Sciences, University of Otago
Wellington
Correspondence: Dr Elizabeth R Dennett,
Dept. Surgery and Anaesthesia, School of Medicine and Health Sciences,
University of Otago Wellington, PO Box 7343, Wellington 6242, New Zealand. Fax:
+64 (0)4 3895318; email: liz.dennett@otago.ac.nz
References:
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