Get the PDF version of this article
Part III, Hereditary Nonpolyposis colorectal cancer (HNPCC)
The Surgeon, The Pathologist and The Geneticist
Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome accounts for four percent of all colorectal cancers. HNPCC is usually the result of an inherited mutation in one of the group of genes known as mismatch repair genes (MMR). This mutation has also been known to arise spontaneously. MMR genes correct errors that result from faulty DNA replication. Colorectal cancer occurring in the absence of polyps or polyposis is the final phenotypic expression of this DNA mutation, although an occult polyp remains the precursor lesion of the cancer.
UNDERSTANDING THE DISEASE: THE PATHOLOGIST
HNPCC, or Lynch syndrome, is divided into Lynch I and Lynch II.
In Lynch I, colorectal cancer is the most commonly occurring malignancy. The lifetime risk of developing a colorectal cancer in an individual with Lynch I syndrome is eighty percent. The average age at diagnosis is forty-four years old, compared to age sixty-four in the sporadic form of colon cancer. Most of the neoplasms are located proximal to the splenic flexure. Synchronous and metachronous lesions are not uncommon, signaling a possible underlying genetic defect.
Lynch II describes the association of colorectal cancer with other malignancies. In women with Lynch II, there is a fifty to seventy percent lifetime risk of developing endometrial cancer, with the average age of diagnosis being forty-six. Other malignancies associated with Lynch II are: ovarian cancer, gastric cancer, transitional cell carcinoma of the ureter and renal pelvis, small bowel cancer occurring most commonly in the duodenum and jejunum, central nervous system tumors, most often glioblastomas, and hepatobiliary cancer.
The diagnosis of HNPCC is often suggested in the postoperative period upon finding mucin, signet ring cells or tumor-infiltrating lymphocytes in the surgical specimen, leading to further investigation. The pathologist and then the geneticist are often the first physicians to diagnose HNPCC.
Understanding The Genetics: the Geneticist
The HNPCC mutation is transmitted in an autosomal dominant fashion and is highly penetrant. The commonly involved genes are MSH2 and MSH6, located on chromosome two, MLH1, located on chromosome three, and PMS2, located on chromosome seven. These genes normally produce enzymes responsible for removing and repairing specific nucleotide sequences which may have become corrupt during faulty DNA replication. Without these MMR enzymes, the rapid accumulation of somatic mutations initiates a neoplastic cascade leading to tumor development.
The defect in mismatch repair also leads to mutations in “bystander” genes, known as microsatellites. Microsatellites are short, non-coding, tandemly repeated DNA sequences of one to six nucleotide bases scattered throughout the human genome. These sequences are unique to each individual. They can be affected by a mutation termed microsatellite instability (MSI). MSI results from the erroneous insertion, deletion or mis-incorporation of bases during DNA replication or recombination, with failure of the mismatch repair system to correct these errors. In HNPCC, mutant microsatellites begin to accumulate and can be detected in the tumor tissue of ninety five percent of affected patients using fluorescent multiplex polymerase chain reaction-capillary electrophoresis.
An alternative detection technique consists of using antibodies to normal MMR gene proteins, combined with imunohistochemistry fluorescent staining (IHC). Lack of staining is usually considered to be a positive test result, indicating loss of the normal protein product due to the existence of a mutant, non-functioning mismatch repair gene. A diagnosis of HNPCC is likely but not necessarily confirmed. Both MSI testing and IHC staining evaluate the phenotypic results of the HNPCC MMR gene mutation and are both considered to be surrogate markers for HNPCC. Higher detection sensitivities have been reported when using MSI testing in combination with IHC. As testing is highly sensitive, HNPCC is effectively ruled out in tumors that exhibit microsatellite stability, or exhibit normal protein expression on IHC testing.
Whole blood samples are used for germline analysis. This may highlight the exact nucleotide mutation and can be used in screening and genetic counseling of family members or in those postoperative patients with tumor tissue displaying microsatellite instability.
Who should be screened?
A complex situation arises when a patient presents in a routine fashion and gives a family history of colorectal cancer or has a family member who carries a diagnosis of HNPCC. Beginning with the 1990 Amsterdam criteria, clinical guidelines used to screen patients for HNPCC have been modified successively as new genetic information has become available. Presently, clinicians use the Bethesda guidelines, which have been reported to be more accurate than the Amsterdam criteria. The clinical guidelines for proceeding with further evaluation in patients suspected of harboring a MMR mutation are:
- Colorectal carcinoma diagnosed in a patient who is less than
fifty years old;
- Presence of synchronous or metachronous colorectal carcinoma
or other Lynch syndrome-associated tumors, regardless of age;
- Colorectal carcinoma with high microsatellite instability
histology or lack of IHC staining diagnosed in a patient
less than sixty years old;
- Colorectal carcinoma diagnosed in one or more first-degree
relatives with a Lynch syndrome-associated tumor, with one
of the cancers being diagnosed at less than fifty years of age;
- Colorectal carcinoma diagnosed in two or more first-degree
or second-degree relatives with Lynch syndrome-associated tumors,
regardless of age.
Watchful Waiting Or Surgical Prophylaxis?
After using the Bethesda clinical screening guidelines to direct evaluation and testing, newly diagnosed carriers of the MMR mutation should begin full colonic surveillance every one to two years beginning at age twenty, or ten years earlier than the youngest age of onset of colorectal cancer in the family. This should continue to age forty, at which time surveillance should be conducted yearly. The entire colon must be evaluated, as tumors tend to occur in the more proximal colon.
As endometrial cancer is the most common extracolonic malignancy, women at risk for HNPCC should have a yearly transvaginal ultrasound with consideration given to regular endometrial biopsies and CA-125 levels after age twenty-five. Females should be made aware of the value of prophylactic hysterectomy and oophorectomy, especially after the childbearing years are complete.
Upper gastrointestinal endoscopy should be performed regularly. Families having a predilection for genitourinary tumors should undergo ultrasound and urine cytology screening every two years beginning at age twenty-five. Prophylactic intervention is not recommended however.
The risk-benefit ratio for prophylactic colectomy versus endoscopic surveillance is equivocal. Therefore, recommendations for surgical intervention in asymptomatic patients are complex. In the most straightforward case, a prophylactic resection is indicated in those patients with a mismatch repair mutation in whom surveillance is not technically possible, in noncompliant patients or in those with a personal preference toward prophylactic operative intervention. The goal of a prophylactic resection is to remove as much at-risk tissue as possible while retaining normal colorectal functioning. Even with a prophylactic resection, patients remain at risk for the development of extracolonic neoplasms, and continued surveillance is necessary.
Understanding Surgical Options: The surgeon
In patients with HNPCC, a choice exists between a standard oncologic segmental resection, a total proctocolectomy with a permanent ileostomy, a total abdominal colectomy with an ileorectal anastomosis or a total proctocolectomy with an ileal pouch-anal anastomosis (IPAA). There are advantages and disadvantages with each option.
First, a thorough evaluation should be undertaken to locate any sites of extracolonic disease that could be removed concomitantly during a colonic resection, or which would suggest widespread, late stage disease precluding a colonic resection for cure.
A total proctocolectomy with an end ileostomy will remove all at-risk tissue and will prevent the development of a metachronous colorectal lesion. However, this will leave the patient with a permanent stoma.
Any procedure which does not remove all of the colorectal mucosa exposes the patient to a forty five percent increased risk of a metachronous lesion developing. However, the functional results are generally considered to be better with a greater amount of colon or rectum left intact. A total abdominal colectomy with an ileorectal anastomosis removes most of the colonic tissue while attempting to preserve normal rectal reservoir functioning. However, the remaining rectum is at risk for developing a second cancer and will require frequent lifetime surveillance. A total proctocolectomy with an ileal pouch-anal anastomosis removes almost all colorectal tissue. However, microscopic islands of tissue may remain and are subject to malignant transformation. Lifetime proctoscopic examinations are necessary. Frequent daytime and nocturnal bowel movements can strongly impact the postoperative quality of life. Sexual functioning may be impacted with extended resections and immediate postoperative morbidity is higher as well.
In those patients harboring a rectal cancer, a low anterior resection with sparing of the colon may be offered. Patients may have better bowel function after this but will require regular, lifetime surveillance of all remaining colonic tissue. Alternatively, a total proctocolectomy with IPAA may be performed. Again, data supporting this more extensive resection show a forty five percent rate of development of a metachronous cancer in those patients undergoing the less extensive low anterior resection as the definitive mode of treatment.
Finally, in women with HNPCC who are undergoing a colon resection or other abdominal operations or who have completed childbearing, a prophylactic hysterectomy and bilateral salpingoophorectomy may be offered. This recommendation is emphasized in women with a specific family history of endometrial or ovarian cancer in addition to the MMR mutation.
Better Understanding, Better Survival
HNPCC is associated with a lower rate of nodal metastases compared with the sporadic form of colorectal cancer. When matched for age of onset and tumor stage, HNPCC colorectal cancers are associated with a significantly better survival rate than in those patients with sporadic colorectal tumors. The reason for this is unknown. Understanding HNPCC is the first step in diagnosing, treating and curing the disease.