Gardner Syndrome Treatment & Management

Sulindac, a long-acting derivative of indomethacin, has been shown to produce regression of rectal polyps in 80% of cases of familial adenomatous polyposis (FAP), after the patient has undergone total colectomy.^{[6, 7]} The drug's beneficial property is postulated to be sulindac's prostaglandin-inhibitory effects. Sulindac's use is recommended in any patient with rectal polyps, following total colectomy. Some authors advocate the use of tamoxifen, which also has properties of prostaglandin inhibition, either alone or in combination with sulindac. Currently, sulindac, tamoxifen, or a combination of both is recommended for desmoid polyps of the abdominal wall or for extra-abdominal manifestations of FAP.

Doxorubicin with dacarbazine has also been shown to reduce polyps following colectomy. While some authors recommend use of these chemotherapeutic drugs, most recommend their use only when noncytotoxic drugs have been tried and have failed.

Finally, oral calcium has been shown to inhibit proliferation of rectal epithelium. Its mechanism of action is believed to be its ability to reduce colorectal cell turnover.

The decision to operate on individuals affected with familial adenomatous polyposis or Gardner syndrome is not difficult, and surgery should be performed promptly following diagnosis. Early surgical intervention is warranted because 65% of all patients who present with symptoms have carcinoma at the time of diagnosis, and 100% of them will develop colonic adenoma-related cancer (CARC) at some stage. Which surgical procedure is considered best has been an ongoing debate since the mid-to-late 1970s. Several objectives must be taken into consideration when reviewing options for treatment. First, the surgeon wants an informed and educated patient. The next step is to engender a joint decision between the patient and physician regarding the most proper therapy.

The goals of treatment are (1) to treat or eliminate any risk of colorectal cancer,^[8] (2) to preserve function of continence and defecation, (3) to preserve innervation to sexual organs, and (4) to reduce mortality and morbidity.

The types of surgery are (1) proctocolectomy with ileostomy,^{[9, 10]} (2) total colectomy^{[8, 11]} with ileorectal anastomosis (IRA), and (3) proctocolectomy with ileal pouch anal anastomosis (IPAA).^{[12, 13, 14]}

The risk of colorectal cancer after proctocolectomy, mucosectomy, and ileostomy or IPAA is approximately 0%; thus, the ultimate conservative approach for many years was a proctocolectomy and ileostomy. With the emergence of the ileal pouch anastomosis with mucosectomy, ileostomy is obsolete, except in cases of malignant recurrence following an ileorectostomy.

Assessment of the risk of recurrent carcinoma in the rectum following ileorectostomy varies among studies, and the reported rate is as low as 12-32% in 20 years. The risk of recurrence at 30 years is 45%. Of this group, 50% of patients presented with Duke stage C cancers at the time of recurrence. This is a very significant finding because the mean age at the time of initial surgery is in the early 30s. With the development of adhesions, mesenteric shortening, and mesenteric desmoid formation, IRA revision to an IPAA is difficult.^[12]

Reports document 4 individuals with only a mutation at codon 1962 who had colorectal cancer without any evidence of polyps. With this in mind, a scarcity or absence of polyps may be a falsely reassuring finding. Thus, the disease requires a proctocolectomy with mucosectomy and ileostomy or ileal pouch anal anastomosis for the prevention of cancer.

Preservation of motor function of the anus at the site of the performed anastomosis has been studied at length, with minimal difference between IRA and IPAA.^[14] The average number of stools per day with IRA ranges from 3-4, with a daytime soiling rate of 6%. Approximately 13% of patients have 1 stool per night, and the rate of nighttime soiling is approximately 2%. The average number of stools per day with IPAA ranges from 4-5, with a daytime soiling rate of 4%. Approximately 26% of patients have 1 stool per night, and the rate of nighttime soiling is approximately 4%.

The risk of sexual dysfunction is frightening in such a young population group. The risk of impotence among males is less than 0.6% and 0.6-2% for IRA and IPAA, respectively. The risk of retrograde ejaculation among males is 5-10% and less than 1% for IRA and IPAA, respectively. Finally, the risk of dyspareunia among females is 13% for IRA and 8% for IPAA. Again, the patient must be informed and counseled about these risks.

The complication rate for IRA is 17%. This does not include fulguration of residual rectal polyps. The risk of subsequent ileostomy and abdominal perineal resection following IRA is 11% for dysplastic polyps, 12-32% for carcinoma at 20 years, and 45% for carcinoma at 30 years.^[15] Approximately 61% of patients with Gardner syndrome require at least one subsequent fulguration of rectal polyps after IRA is performed.

The complication rate for IPAA is 26%, while the reoperation rate is 8-10%. The most common complication is obstruction (15%), followed by pouchitis (1-7%) and pelvic sepsis (4%).

To reiterate, the purposes of surgery are to eradicate the risk of colorectal cancer while safeguarding motor function and sexual function. Patients must be counseled and educated so they can make an informed decision about which operation is best for them.

Remember that the first objective of the surgeon is an informed and educated patient. This is the responsibility of the surgeon. The second objective is a joint decision between patient and physician.

Follow-up evaluations for patients after IPAA should occur yearly to monitor for extracolonic manifestations that may develop. Patients who underwent IRA should undergo endoscopy every 6 months to evaluate the rectal stump. Patients who are asymptomatic following an upper GI pathology should have an EGD every 2 years, while patients with symptoms should be scoped emergently.

Complications can be divided into (1) direct colonic effects and (2) extracolonic manifestations.

The complications secondary to hundreds, if not thousands, of polyps lining the colon include hemorrhage, obstruction, perforation (if an undetected cancer ensues), and, uniformly, cancer (if prophylactic colectomy is not performed).^[8]

Long-term morbidity and mortality are strongly related to the occurrence of mesenteric tumors and ampullary duodenal polyps. Early detection of these using CT scanning, OGD, pouchoscopy may allow control of these by medical therapy, endoscopy, and limited surgical procedures.

The extracolonic manifestations include CHRPE, dental abnormalities, osteomas, epidermoid cysts, desmoids, gastric polyps, duodenal polyps, thyroid cancer, and hepatoblastoma.^[5]

Congenital hypertrophy of the retinal pigmented epithelium

CHRPE occurs in 58-88% of all patients with Gardner syndrome. An ophthalmologist makes the diagnosis based on findings from a slit-lamp examination and indirect ophthalmoscopy. Two variants are described, (1) large CHRPE (greater than one quarter the optic disc diameter) and (2) small pigmented spots. Mutations on the APC gene that correlate with CHRPE are between codon 311 on exon 9 and codon 1444 on exon 15. Again, this proves that the severity of extracolonic manifestations depends on the specific site of mutation in the APC gene.

Dental abnormalities

Abnormalities are present in approximately 70% of all affected individuals. These abnormalities include supernumerary teeth, unerupted teeth, fused roots of first and second molars, and long and tapered roots of posterior teeth. The greatest number of defects and the most severe defects are seen in affected individuals with an APC gene mutation between codons 1444 and 1560.

Osteomas

The incidence is unknown because of the difficulty in classifying an osteoma of the mandible and an abnormal dento-osseous finding as 2 separate entities. Osteomas are most common in the facial skeleton, especially the mandible, but can occur in any bone.

Osteomas are benign but may be serious secondary to local invasion, as evident in a case report of an osteoma in the medial and superior orbital wall encroaching on the globe. Another example is an osteoma of the sphenoid sinuses penetrating the cranium and forming a large open tract and an eventual intracranial abscess. Osteomas are sometimes identified prior to the diagnosis of familial adenomatous polyposis (FAP) or Gardner syndrome.

Epidermoid cysts

These are found in approximately 53% of patients. They may occur on the extremities, face, and scalp and may occur prior to or after the diagnosis of Gardner syndrome.

Desmoids

Occurrence rates vary from source to source; they can be as low as 10% to as high as 35%. Desmoids are 852 times more common in patients with FAP or Garner syndrome than in the general population. Sporadic desmoids occur in the abdominal wall and extra-abdominal areas, while Gardner syndrome desmoids occur in the mesentery (50-75%) and in the abdominal wall (25-50%).

Desmoid tumors are benign and of a fibroaponeurotic source; however, local invasion or expansion can cause significant morbidity and mortality. Approximately 65-83% of all desmoids occur after prior abdominal surgery. The median age at diagnosis is 28 years. The signs or symptoms and complications of desmoid tumors are painful abdominal mass (50%); obstruction; and ureteric obstruction leading to hydronephrosis, hemorrhage, and fistula.

Surgical excision is not recommended for desmoids; the recurrence rate is high (65-85%). Surgery is reserved for life-threatening complications of infected fistula, hemorrhage, and obstruction. The mortality rate associated with desmoid tumors ranges from 18-31%, which is a higher than that associated with periampullary carcinoma (22%) and retained rectal carcinoma (8%).

Medical treatment beneficial in the treatment of desmoid tumors includes sulindac, sulindac with tamoxifen, doxorubicin and dacarbazine, and oral calcium. The most common mutation associated with desmoids is on codon 1309; desmoid tumors have also been noted in persons with mutation of codons 1445, 1578, 1924, and 1962.^[16]

Gastric lesions

Gastric fundic gland polyps occur in approximately 90% of affected individuals. Most of these lesions are hyperplastic and carry no malignant potential. However, adenomatous polyps and their progression to gastric cancer have been observed but are extremely rare.

Duodenal lesions

Duodenal polyps occur in up to 90% of all affected individuals. Duodenal polyps have a predilection for the periampullary region and are premalignant lesions for periampullary carcinoma. The mortality rate for periampullary carcinoma in patients with Gardner syndrome is approximately 20-25%. The risk is 300 times higher compared to the general population. Two cases of cholangiocarcinoma and FPC have been reported, which carries a more severe prognosis. Patients with periampullary lesions may present with abdominal pain, emesis, bleeding, and gastric or biliary obstruction manifesting as jaundice. Duodenal polyps in persons with Gardner syndrome have also been associated with pancreatitis secondary to polyps obstructing the ampulla of Vater.

Symptomatic patients should have an EGD immediately. Asymptomatic individuals should have an EGD in their early 20s and should have repeat examinations every 1-2 years. Sulindac therapy has been shown to reduce epithelial proliferation and is being used. Rapidly growing or dysplastic polyps require a prophylactic pancreaticoduodenectomy.

Thyroid cancer

Carcinoma of the thyroid has been reported in sporadic cases of individuals affected with Gardner syndrome. Females with Gardner syndrome who are younger than 35 years have a 160-times greater risk of developing thyroid cancer, with 90% predilection for papillary histology. Thyroid cancer in affected patients has been shown to be associated with a mutation on codon 1309 and codon 764. Patients diagnosed with thyroid cancer after they have undergone prophylactic colectomy are treated with total thyroidectomy.

Other carcinomas

Adrenal adenoma and carcinoma have been reported in patients affected with Gardner syndrome. Hepatocellular carcinoma is known to be associated with Gardner syndrome, and children with maternal ancestors who were affected with the syndrome have developed hepatoblastoma. One individual developed a concomitant diagnosis of Gardner syndrome and Turcot syndrome after colectomy for polyps of the colon and rectum and a partial resection of a grade II astrocytoma.

The 5-year survival rate for patients older than 45 years who do not receive operative management is 0%.

The 5-year survival rate for patients who undergo proctocolectomy and mucosectomy with IPAA is nearly 100%.

The recurrence rate in 20 years after total colectomy with IRA is 30%. The recurrence rate in 30 years after total colectomy with IRA is 45%.

To recapitulate the debate, which has been ongoing since the 1970s, the surgical choices for prophylaxis in familial adenomatous polyposis are proctocolectomy^[9] with ileostomy versus proctocolectomy, mucosectomy, and IPAA versus total colectomy with IRA.