Gardner Syndrome

The colon is approximately 1.5 m long, and the rectum is approximately 15 cm long. The cecum is normally 7-8 cm in diameter, whereas the sigmoid colon is 5 cm in diameter.

The colon is embryologically derived from the midgut and hindgut and has a close association with the yolk sac and cloaca. Because of the embryologic derivation of the midgut (ie, ampulla of Vater to middle of transverse colon) and hindgut (ie, middle of transverse colon to anus), the superior and inferior mesenteric arteries provide the colon's arterial supply.

The right colon is supplied by the middle colic artery (a branch of the superior mesenteric artery) and the right colic artery (a branch of the ileocolic artery). The left colon is supplied by the sigmoidal, left colic, and superior rectal branches of the inferior mesenteric artery. Collateral circulation is via the marginal artery of Drummond and the arc of Riolan or the meandering mesenteric artery.

The APC gene located on chromosome 5 is the first mutation in the adenoma-to-carcinoma sequence and is believed to initiate the sequence. (See the image below.) APC is composed of 2844 codons and 8532 nucleotides arranged in 15 exons. The gene is altered by the same mechanism that alters many other genes: (1) nonsense or stop codon, (2) missense transitions, and (3) frameshift mutation due to the addition or deletion of one or several base pairs.

The point at which the APC mutation occurs determines the manifestations and severity of Gardner syndrome. Specific codon mutations correlate with specific extracolonic manifestations and the number, time frame, and malignant degeneration of adenomas. The most consistent description of a mutation on codon 1309 (exon 15) is associated with increased extracolonic manifestations, an increase in the number of polyps, a younger age at the onset of cancer, and the risk of cancer in prophylactically resected specimens.

FAP is generally characterized by the presence of more than 100 polyps in the colon, with a left-side predominance. The number of polyps can range from no detectable polyps at colonoscopy to more than 7000 observed on resected specimens. Patients with more than 1000 polyps have been proved to have 2.3 times the cancer risk of patients with fewer than 1000 polyps, independent of age.[4] The cancer risk increases 2.4 times for each 10-year time frame. The mutations in codons 233, 835, 1179, 1323, and 1407 also correspond to an increased number of polyps and, therefore, the increased risk of cancer.

However, it is not always the case that the presence of few or no polyps correlates the absence of cancer risk. Reports documented four individuals with a mutation only at codon 1962 who had colorectal cancer without any evidence of polyps. Although families that demonstrate a mutation at codon 1982 or 1983 show a significantly less severe form of FAP or Gardner syndrome, they develop fewer polyps later in life and thus have a later progression to cancer.[5]

The initiating step in the adenoma-to-carcinoma sequence is the mutation in the APC gene that allows normal colonic epithelium to proliferate.[6] The epithelial cells increase in number, and the mucosa becomes thickened. A normal APC gene exerts its effects intracellularly by binding to beta-catenin. The actions of beta-catenins are twofold. First, they bind to cadherins, thus promoting cell adhesion and cell-to-cell interaction. Second, they send intracellular signals to the nucleus, promoting proliferation.[2]

The second step in the adenoma-to-carcinoma sequence is the loss of DNA methylation or hypomethylation. This results in the conversion of proliferating epithelium into an adenoma. The adenoma then undergoes further transformation to an intermediate adenoma by an RAS mutation and progresses to a late adenoma by the deletion of DCC.

RAS is located on chromosome 12 and is responsible for coding GTPase (an enzyme that hydrolyzes guanosine triphosphate [GTP] to guanosine diphosphate [GDP]), which is very important in intracellular signaling. GTPase is responsible for converting active p21 to inactive p21 by dephosphorylating the p21 protein. The p21 is converted to its active form by tyrosine kinase via phosphorylation, in the form of GTPase. Active p21 then stimulates the nucleus for the synthesis of DNA.

A mutated RAS gene unable to dephosphorylate p21 produces continuous stimulation to the nucleus by active p21, which causes the "on switch" to stay on. This overstimulation of the nucleus leads to an increased risk of mutation and, therefore, the progression of the adenoma (see the image below).

The deleted colon cancer gene (DCC) is located on chromosome 18 and is active at the cell surface. DCC is responsible for cell-to-cell and cell-to-matrix adhesion and works via contact inhibition. Accordingly, if DCC is deleted, contact inhibition is absent and the progression to a late adenoma occurs.

The TP53 gene, located on chromosome 17, is an antioncogene that is important in DNA repair and apoptosis (programmed cell death). TP53 is responsible for arresting the cell cycle between the G1 phase and the synthesis phase. When the cell has received a mutagenic hit, TP53 codes for the repair of DNA or codes for the cell to be destroyed via apoptosis.

Although TP53 does not actually perform apoptosis, it does regulate cell destruction. Apoptosis is initiated by cytochrome c of the mitochondria. The release of cytochrome c from the mitochondria is stimulated by the BAX gene, which opens channels in the mitochondria. These same channels are closed by the BCL2 gene formed by a translocation of chromosome 18 to chromosome 14.

TP53 has been coined the "molecular policeman" for its role in repairing mutant cells and destroying cells that cannot be repaired. When TP53 is mutated, the regulation of DNA repair and apoptosis is lost, and, therefore, cells with a mutagenic hit undergo transformation to malignant cells. Proliferation of these cells then follows as the cell cycle progresses (see the image below). This represents the final step in the adenoma-to-carcinoma sequence.

In a 2018 report that used whole‑exome sequencing of two affected individuals from a Chinese family with Gardner syndrome, Lv et al identified a mutL homolog (MLH)1 missense mutation, thereby adding to the mutated genes associated with Gardner syndrome.[7]

The causes of FAP are as follows:

• Mutation of APC, located on chromosome 5
• Loss of DNA methylation
• Mutation of RAS, located on chromosome 12
• Deletion of DCC, located on chromosome 18
• Mutation of TP53, located on chromosome 17

The incidence of FAP is 1 case in 7500 live births and is due to congenital inheritance in a mendelian dominant fashion in 80% of patients. The remaining 20% represent spontaneous mutations, with no family history reported. The polyposis predominantly affects the left colon (80-90% of cases). In cases of attenuated FAP, a right-side predominance is often present.

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 ileal pouch–anal anastomosis (IPAA) is nearly 100%.

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

The first objective of the surgeon is an informed and educated patient. Ensuring that the patient receives adequate unformation and education is the responsibility of the surgeon. The second objective is management decisions that are made jointly by the patient and the physician.

As familial adenomatous polyposis (FAP) progresses in the colon, the patient may present with bleeding per rectum, diarrhea, exhaustion, and fatigue. These manifestations are secondary to malnutrition. Obstipation, emesis, peritonitis, and other signs of sepsis are usually secondary to obstruction.

The extracolonic manifestations produce numerous symptoms.[8] Desmoids can cause parietal lumps, obstruction, and bleeding. Dental abnormalities may develop and may result in jaw pain.[9, 10] Epidermoid cysts may develop, but they manifest as only cosmetic defects. Gastric polyps may manifest as epigastric pain or bleeding. Duodenal polyps may cause pain, bleeding, or jaundice, whereas ileal polyps may cause obstruction. Thyroid carcinoma may manifest as a neck mass (with or without pain), hoarseness of voice, and signs of hypothyroidism or hyperthyroidism.

The physical examination may reveal positive findings from hemoccult testing. Findings can also include palpable rectal polyps or masses, desmoid tumors or osteomas,[9, 10] and thyroid masses. Distinctive oral mucosal findings may be noted.[11]

Laboratory studies that may be useful include the following:

• Testing of peripheral leukocytes to evaluate for APC and its mutation
• Complete blood count (CBC), carcinoembryonic antigen (CEA) testing, and liver function tests (LFTs) to evaluate for possible metastasis
• Thyroid function tests

Imaging studies that may be helpful are as follows:

• Computed tomography (CT) of the abdomen and pelvis
• Panoramic dental radiography, chest radiography, and skull radiography to evaluate for osteomas

Diagnostic procedures that may be useful include the following:

• Slit-lamp examination and indirect ophthalmoscopy to evaluate for congenital hypertrophy of the retinal pigmented epithelium (CHRPE)
• Colonoscopy with direct visualization of polyps that carpet the colon - Criterion standard for the diagnosis of familial adenomatous polyposis (FAP)
• Esophagogastroduodenoscopy (EGD) for evaluation of gastric and duodenal polyps

The presence of colonic polyps carpeting the colon is an indication for surgical treatment. Prophylactic surgery is the only curative treatment. There has long been debate regarding surgical choices for prophylaxis in familial adenomatous polyposis (FAP). The choices are as follows:

• Proctocolectomy ^[12] with ileostomy
• Proctocolectomy, mucosectomy, and ileal pouch–anal anastomosis (IPAA)
• Total colectomy with ileorectal anastomosis (IRA)

Contraindications for surgery in patients with polyps blanketing the colon are relative. Because these polyps eventually undergo malignant degeneration in 100% of cases, contraindications for surgery are limited to those general medical conditions that would make survival from general anesthesia and a prolonged operation unlikely.

Because the natural history of the progression of these polyps occurs over several years, surgery also may not be warranted in patients with medical conditions that make their survival likely to be less than a couple of years.

Finally, the presence of significant metastatic disease is also a relative contraindication for curative surgery. Surgery is still appropriate for palliation in the presence of obstruction, perforation, or hemorrhage.

Sulindac, a long-acting derivative of indomethacin, has been shown to produce regression of rectal polyps in 80% of cases of FAP, after the patient has undergone total colectomy.[13, 14] The drug's beneficial property is postulated to be sulindac's prostaglandin-inhibiting effects. It is recommended in any patient with rectal polyps after total colectomy. Some authors advocate the use of tamoxifen, which also has prostaglandin-inhibiting properties, 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 after colectomy. Whereas 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 FAP or Gardner syndrome is not difficult, and surgery should be performed promptly after 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 1970s. Several objectives must be taken into consideration in reviewing options for treatment. One such objective is to have an informed and educated patient. Another is to ensure that the decision about the most proper therapy is made jointly by the patient and the physician.

The goals of treatment are as follows:

• To treat or eliminate any risk of colorectal cancer ^[15]
• To preserve function of continence and defecation
• To preserve innervation to sexual organs
• To reduce mortality and morbidity

The types of surgery performed in this setting are as follows:

• Proctocolectomy with ileostomy ^{[12, 16]}
• Total colectomy ^{[15, 17]} with IRA
• Proctocolectomy with IPAA ^{[18, 19, 20]}

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 IPAA with mucosectomy, ileostomy has come to be regarded as obsolete, except in cases of malignant recurrence following an ileorectostomy.

Assessment of the risk of recurrent carcinoma in the rectum after 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, revision of an IRA to an IPAA is difficult.[18]

Reports have documented four 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 IPAA for the prevention of cancer.

Preservation of motor function of the anus at the site of the performed anastomosis has been studied at length, and minimal difference has been found between IRA and IPAA.[20] The average number of stools per day with IRA is three to four, with a daytime soiling rate of 6%. Approximately 13% of patients have one stool per night, and the rate of nighttime soiling is approximately 2%. The average number of stools per day with IPAA is four to five, with a daytime soiling rate of 4%. Approximately 26% of patients have one 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% for IRA and 0.6-2% for IPAA. The risk of retrograde ejaculation among males is 5-10% for IRA and less than 1% for IPAA. 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 (APR) following IRA is 11% for dysplastic polyps, 12-32% for carcinoma at 20 years, and 45% for carcinoma at 30 years.[21] 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%, and 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.

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

Complications secondary to hundreds, if not thousands, of polyps lining the colon include the following:

• Hemorrhage
• Obstruction
• Perforation (if an undetected cancer ensues)
• Cancer (if prophylactic colectomy is not performed) ^[15]

Long-term morbidity and mortality are strongly related to the occurrence of mesenteric tumors and ampullary duodenal polyps. Early detection of these by means of computed tomography (CT), esophagogastroduodenoscopy (EGD), or pouchoscopy may allow control of these through medical therapy, endoscopy, and limited surgical procedures.

Extracolonic manifestations include the following[8] :

• Congenital hypertrophy of the retinal pigmented epithelium (CHRPE)
• Dental abnormalities
• Osteomas
• Epidermoid cysts
• Desmoids
• Gastric polyps
• Duodenal polyps
• Thyroid cancer
• Hepatoblastoma

Congenital hypertrophy of retinal pigmented epithelium

CHRPE occurs in 58-88% of all patients with Gardner syndrome. An ophthalmologist makes the diagnosis on the basis of findings from slit-lamp examination and indirect ophthalmoscopy. The following two variants are described:

• Large CHRPE (greater than one quarter the optic disc diameter)
• 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 and may include the following:

• Supernumerary teeth
• Unerupted teeth
• Fused roots of first and second molars
• Long and tapered roots of posterior teeth

The greatest number of defects and the most severe defects are seen in affected individuals with APC 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 two 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 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 Gardner syndrome than in the general population. Sporadic desmoids occur in the abdominal wall and extra-abdominal areas, whereas Gardner syndrome desmoids occur in the mesentery (50-75%) and in the abdominal wall (25-50%). 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.[22]

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, because of the high recurrence rate (65-85%). Surgery is reserved for life-threatening complications of infected fistula, hemorrhage, and obstruction. The mortality associated with desmoid tumors is in the range of 18-31%, which is a higher than that associated with periampullary carcinoma (22%) and retained rectal carcinoma (8%).

Medical treatments beneficial in the treatment of desmoid tumors include the following:

• Sulindac
• Sulindac with tamoxifen
• Doxorubicin and dacarbazine
• Oral calcium

A case report by Cobianchi et al suggested that radiofrequency ablation (RFA) might be a promising alternative for treatment of extra-abdominal desmoid tumors in patients with Gardner syndrome.[23]

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, albeit extremely rarely.

Duodenal lesions

Duodenal polyps occur in as many as 90% of all affected individuals. Duodenal polyps have a predilection for the periampullary region and are premalignant lesions for periampullary carcinoma. The mortality for periampullary carcinoma in patients with Gardner syndrome is approximately 20-25%. The risk is 300 times higher than in the general population. Two cases of cholangiocarcinoma and familial polyposis coli (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 undergo EGD immediately. Asymptomatic individuals should undergo 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 are an indication for 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 a 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.

Follow-up evaluations for patients who have undergone IPAA should occur yearly to monitor for extracolonic manifestations that may develop. Patients who have undergone IRA should have endoscopy every 6 months to evaluate the rectal stump. Patients who are asymptomatic after an upper gastrointestinal pathology should undergo EGD every 2 years; patients with symptoms should undergo endoscopy on an emergency basis.