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59 Colonic Conditions: Benign Colonic Neoplasia

Fig. 59.6 Segmental resection of right colon demonstrating oncologic resection of cecal polyp with high ligation of the ileocolic vessel and appropriate surgical margins. (Image provided by Charles M.Friel, MD, University of Virginia)

Fig. 59.7 Sessile polyp ablated using an argon plasma coagulator (APC). (Image provided by Charles M.Friel, MD, University of Virginia)

O. The timing and frequency of endoscopic sur-

veillance varies based on pathology and colonoscopy ndings. Recommendations are made based on risk of metachronous polyps

457

Table 59.1 US Multi-Society Task Force recommendations for colorectal cancer screening

Baseline colonoscopy ndings No polyps 10 Small (<10mm) hyperplastic

rectosigmoid polyps 1–2 small (<10mm) tubular

adenomas 3–10 tubular adenomas 3 >10 adenomas < 3

≥1 tubular adenomas ≥10mm

≥1 villous adenomas

Adenoma with high-grade dysplasia 3 Sessile serrated polyp(s) <10mm

with no dysplasia

Sessile serrated polyp(s) ≥10mm Sessile serrated polyp with

dysplasia Traditional serrated adenoma 3 Serrated polyposis syndrome 1

Surveillance interval (years)

5–10

and colorectal cancer (Table 59.1). Patients with no adenomas found on colonoscopy should undergo repeat colonoscopy in 10 years. For patients found to have 3–10 adenomas on baseline examination, repeat colonoscopy should be performed in 3years. Those with over ten adenomas should have a repeat examination in less than 3 years. Patients found to have one or more tubular adenomas over 10 mm, any adenoma with villous features, or one or more adenoma with high-grade dysplasia results in a recommendation for repeat colonoscopy in 3years. Recommendations for serrated polyps are more complicated with less supporting evidence in the literature. Patients with SSP(s) less than 10 mm and without dysplasia should undergo repeat exam in 5years, while patients with SSP(s) 10mm and larger, SSPs with dysplasia, or traditional TSA(s) should undergo repeat colonoscopy in 3 years. Polyps removed in a piecemeal fashion should have a repeat colonoscopy in 3–6 months to evaluate for recurrence. Endoscopic tattooing of these high-risk lesions at the time of resection is critical so that endoscopists can clearly identify to area of concern during follow-up exams. These

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T. E. Hassinger and C. M. Friel

recommendations all assume that the baseline colonoscopy was complete with adequate bowel prep and successful removal of all visible polyps.

Familial Adenomatous Polyposis

EmilySteinhagen

Refer to Algorithm inFig. 60.1

Familial adenomatous polyposis (FAP) is an autosomal-dominant syndrome characterized by more than 100 synchronous adenomatous polyps. Those with 10–99 adenomatous polyps are labelled as attenuated FAP (AFAP). The prevalence of FAP is estimated to be 1in 6850 to 1in 31,250. The incidence is equivalent in all races and geographic regions, and has an equal gender distribution. FAP has a variety of extracolonic manifestations and can be managed with a combination of surveillance and surgical interventions. An algorithm for management of FAP is found in Fig.60.1.

A. Genetics

The etiology of FAP is a germline mutation in the adenomatous polyposis coli (APC) gene on the long arm of chromosome 17 that ultimately regulates cellular proliferation. It is inherited in an autosomal dominant fashion, though up to 30% of cases represent de- novo mutations in the gene. There is nearly 100% penetrance of the gene, meaning that nearly everyone with the mutation will manifest symptoms of FAP. A subset of patients

E. Steinhagen (*) Department of Surgery, University Hospitals Cleveland Medical Center Department, Case Western Reserve University School of Medicine, Cleveland, OH, USA e-mail: Emily.Steinhagen@UHhospitals.org

with APC mutations have a less virulent variant, attenuated FAP (AFAP), which may have varied penetrance and delayed onset of colorectal cancer. There is also a subset of patients who do not have a detectable mutation but clearly have the phenotype. Those patients should be evaluated for MYH- associated polyposis and other syndromes but treatment should be guided by their phenotype if no genetic mutation is identied.

To some extent, there is some correlation between the location of the mutation on the gene and phenotype. This allows some prediction regarding polyposis, desmoid risk, and likelihood of other extracolonic manifestation. However, this correlation is not perfect as there are differences in phenotype amongst individuals who have the same mutation, which are likely due to the effect of other genes and environmental inuences.

Genetic testing and counselling is crucial for patients with FAP to facilitate understanding of cancer risk, help inform decisions about treatment and surveillance, and advise regarding reproductive concerns. Testing is typically performed on DNA from blood leucocytes. If the individual is part of a family with a known FAP mutation, it is possible to look for the specic mutation. In other cases, the entire gene can be analyzed.

Because FAP is both rare and complex, it is best managed by a collaborative group of specialists. Registries can aid with identify-

https://doi.org/10.1007/978-3-319-65942-8_60

459

460

E. Steinhagen

Fig. 60.1 Algorithm for familial adenomatous polyposis. FAP familial adenomatous polyposis, APAP attenuated famil- ial adenomatous polyposis, TPC total proctocolectomy, EI end ileostomy, IRA ileorectal anastomosis, RPC restorative proctocolectomy

ing family members in need of genetic testing, facilitate surveillance for FAP patients and their families, and promote research. Collaboration between registries can be particularly helpful because of small numbers of patients. Participation in registries is associated with higher rates of participation in screening and consequently substantially lower incidence and mortality in FAP patients.

B. Colorectal Cancer

Colorectal cancer in FAP follows the classi-

Table 60.1 Differences between FAP and AFAP

FAP AFAP

Number of polyps >100 10–99

Polyp distribution Pan-colonic Typically right

Average age of polyp onset

Average age of CRC diagnosis

Incidence of CRC >95% if

Mid-teens 20s–40s

39 55

untreated

(average 30)

sided

~70%

cal adenoma to carcinoma sequence. As a tumor suppressor gene, APC deactivation occurs only after both alleles are damaged; the rst one is inherited in the mutated form and the second is lost or damaged by a somatic event. Without prophylactic risk- reducing surgery, the risk of colon cancer in FAP is nearly 100% by age 40, although fortunately cancer is rare in FAP patients before age 20. In those individuals with newly diagnosed FAP who do not have a family

history and therefore have not undergone surveillance, the incidence of colon cancer is 25%.

In the attenuated form of FAP, adenoma and carcinoma development is generally delayed by one to two decades. The cumulative risk of CRC in AFAP by age 80 is 70% with the mean age of diagnosis at 58years. Differences between classical FAP and AFAP are summarized in Table60.1. Because polyp

60 Familial Adenomatous Polyposis

461

distribution in AFAP tends to be more rightsided, full colonoscopy should be used for screening rather than sigmoidoscopy. In cases of AFAP in which the colon can be completely cleared endoscopically and there is reliable surveillance, it may be possible to avoid surgery completely. When they do require surgery, AFAP patients can nearly always undergo colectomy with ileorectal anastomosis (see below).

Patients who are known to have FAP, or those who are at risk, based on family history, should have screening via annual sigmoidoscopy or colonoscopy. Colonoscopy is preferred for patients with AFAP as this condition predominantly features right sided polyps. This surveillance should begin at puberty or earlier if there are symptoms that could be related to polyposis such as diarrhea, bleeding, or pain. In those with FAP surveyed with sigmoidoscopy, once an adenoma is identied, full colonoscopy should be completed. In combination with surgery, surveillance nearly eliminates the risk of death from colorectal cancer in FAP.

C. Extracolonic Manifestations

Because of the abundance of extracolonic and extraintestinal manifestations of FAP, patients should undergo a variety of surveil-

lance tests on a regular basis. These tests and appropriate intervals are detailed in Table60.2.

1. Stomach and Small Bowel Fundic gland polyps are very common

in FAP patients, but adenomas and carcinoma of the stomach are rare. These fundic gland polyps represent hyperplasia of the fundic glands and are considered to be hamartomas. They are typically 1–10mm in size and may have dysplasia on biopsy but do not confer an increased risk of gastric cancer and do not require removal. Adenomas are present in the stomach of 10% of FAP patients. These can undergo malignant degeneration and become cancerous, though this is rare.

Patients with FAP are at high risk for

small bowel adenomas and carcinomas, particularly in the peri-ampullary region, occurring in more than half of FAP patients. The lifetime risk of duodenal cancer is approximately 3–5% and it is one of the leading causes of death in FAP patients who have undergone colectomy. It typically occurs between the ages of 45 and 55years.

Patients should undergo upper endos-

copy and duodenoscopy with a sideviewing scope starting at 25–30 years of age. Duodenal polyps are graded via the

Table 60.2 Surveillance for FAP patients

System Features Screening Interval Upper GI tract Adenomas EGD Beginning at age 20; follow-up dependent on

Carcinomas Fundic gland polyps

Colon and rectum Adenomas Colonoscopy Annually beginning at 12years of age

Cancer

Connective tissue Osteomas None –

Desmoid CT or abdominal

Skin Epidermoid cyst None – Endocrine Adrenal adenoma/

Hepatobiliary Biliary tract

Central nervous system

carcinoma Thyroid carcinoma Thyroid ultrasound Every 1–2years

carcinoma Pancreas None – Hepatoblastoma Ultrasound and

CHRPE None – Brain tumors None –

ultrasound

None –

α-fetoprotein

ndings but typically 1–4years

No clear protocol

No clear protocol; suggested every 6–12months from infancy to age 5–7

462

E. Steinhagen

Table 60.3 Spigelman stage for duodenal polyps

Polyps 1 point 2 points 3 points Number <4 5–20 >20 Size (mm) 0–4 5–10 >10 Histology Tubular Tubulovillous Villous Dysplasia Mild Moderate Severe

Total points Stage Surveillance frequency

0 0 Every 4years 1–4 I Every 2–3years 5–6 II Every 1–3years 7–8 III Every 6–12months 9–12 IV Expert surveillance every 3–6months; surgical evaluation for

intervention

Spigelman criteria (Table60.3), which predicts cancer risk and dictates follow up. In patients with Spigelman stage IV polyps, the risk for cancer in the next ten years is estimated at 36%, and patients should be considered for pancreas preserving duodenectomy. If cancer is present or strongly suspected, a Whipple should be performed. Adenomas can be managed with transduodenal polypectomy. An endoscopist experienced in advanced techniques such as endoscopic mucosal resection is helpful for managing these patients.

2. Thyroid Thyroid cancer appears to be increased

in patients with FAP. The cribriformmorular variant (CMV) is particularly associated with FAP, but papillary thyroid cancer is more common. There is also an increase in nodular thyroid and other benign ndings in FAP patients, though this may be due to increased screening. Thyroid abnormalities appear to be more common in female patients, mirroring the distribution in non-FAP related cases. The optimal regimen for thyroid screening has not been determined but repeating it based on ndings or on an annual or every 2 year basis has been suggested.

3. Liver Hepatoblastoma can occur in infants

and children with FAP, with most occurring before age 3. The estimated prevalence in FAP patients is 1.6% and there is a male predominance. There may be a cor-

relation with mutations at the 5′ end of the APC gene. Serum α-fetoprotein and hepatic ultrasound may be used for screening. Though it has been suggested that this requires genetic testing in infants, it is still possible to perform the screening presumptively and defer genetic testing until the patient is older, with appropriate counseling. Adenomatous changes and cancer in the gallbladder, biliary system, and pancreas have all been described. There is no specic surveillance regimen recommended for these organs.

4. Adrenal The incidence of adrenal adenoma and

carcinoma in FAP patients is about four times that of the general population. Since FAP patients are often undergoing imaging for other reasons, these are often found incidentally and should be treated based on size criteria.

5. Skin Epidermoid cysts and bromas are

benign lesions that may appear in FAP patients. They lack malignant potential and are treated only if there is cosmetic or functional concern.

6. Bone Osteomas and supranumerary teeth

are part of the clinical spectrum of FAP.Osteomas most commonly grow in the jaw and skull but can occur anywhere in the body. They do not have malignant potential but since they may occur prior to the development of colorectal polyps, they can be a marker for FAP.

60 Familial Adenomatous Polyposis

463

7. Eyes Congenital-hypertrophy of the retinal

pigmented epithelium (CHRPE) is present in some individuals with FAP. It has no known clinical signicance but in the family members of the two-thirds of FAP patients who have them, the presence of the lesions may act as a marker of FAP.Isolated CHRPE lesions occur in the general population but the presence of multiple or bilateral lesions is suggestive of FA P.

8. Brain Turcot syndrome is the eponym used to

describe the subset of FAP patients who have brain tumors. Typically, these tumors are medulloblastomas. The risk in FAP patients is approximately 1%.

9. Desmoids Desmoid tumors are benign broblastic

soft tissue tumors; though they are not malignant, they can be locally aggressive and become symptomatic based on size, compression of adjacent organs, or erosion into nearby structures including blood vessels and ureters. The incidence of desmoids in FAP patients is 850 times higher compared to the general population and affect 10–25% of FAP patients.

They may occur on the trunk or extrem-

ities, but intra-abdominal tumors, which represent more than half of the desmoids in FAP present a more signicant clinical challenge. Typically, desmoid tumors grow in the abdominal wall or small bowel mesentery of FAP patients. Their appearance can range from plaque-like lesions that form puckering in the mesentery leading to kinking, to well circumscribed, large tumors.

About one-third of FAP patients develop

desmoid disease, though only 3% have intra- abdominal desmoids at the time of their rst surgery. Risk factors for desmoid tumors include female sex, family history of desmoid tumors, APC mutation at the 3′ end of the gene, and previous abdominal surgery. The majority of desmoid tumors in FAP, 68–83%, occur after surgery.

Treatment strategies include NSAIDs, anti- estrogens, radiation, chemotherapy, and surgery. Surgical intervention should be used cautiously as it may be difcult to safely remove the tumor and the trauma of the surgery itself likely predisposes to recurrence. The overall high recurrence rate and variable clinical course of desmoids suggests that surgery should be used cautiously and only when necessary. Complications from desmoids include bowel obstruction, ureteral obstruction, stulas to the skin or adjacent organs, erosion into nearby blood vessels, and necrotic degeneration with abscess.

D. Surgical Options

In classical FAP, the risk of colorectal cancer without risk-reducing surgery is nearly 100%. However, surgical procedures and timing should be individualized based on the clinical situation as well as patient preferences.

1. Restorative Proctocolectomy

Restorative Proctocolectomy with ileal pouch anal anastomosis (IPAA) is generally considered the procedure of choice in FAP.It nearly eliminates the risk of cancer in the colon and rectum.

When rst described, IPAA included a mucosectomy and a hand sewn anastomosis between the pouch and anal mucosa at the dentate line. The theoretical advantage to this approach is that all “at risk” mucosa is removed. However, in reality, small islands of mucosa are likely left behind during the dissection and can develop cancer that is now extra-luminal. The introduction of circular staplers allowed for a technically easier procedure that resulted in a better functional outcome while allowing for endoscopic surveillance of the 2–3cm residual rectal cuff.

Adenomas occur in the anal transition zone at a rate of 28–51% after stapled anastomosis and 10–22% after mucosectomy with hand-sewn anastomosis. Cancer is rare, but does occur at a rate of 1–2% following either mucosectomy or stapled anastomosis, so continued surveillance is

464

E. Steinhagen

critical. Polyps in the pouch can be endoscopically managed or locally excised, but large adenomas and carcinoma in the pouch, or profuse polyposis may warrant pouch excision.

After IPAA, patients generally have ve to six bowel movements per day, and one overnight. There is a higher incidence of seepage of mucous and stool, perianal irritation, and anastomotic stenosis in handsewn pouches and it seems that those with stapled pouches have better function. However, patient satisfaction is generally equivalent between the two techniques.

2. Total Proctocolectomy (TPC) with EndIleostomy (EI)

Proctocolectomy with end-ileostomy is appropriate for patients who are unable or unwilling to manage life with an ileal pouch. Those with low rectal cancer near or involving the sphincter are not candidates for restorative surgery. Patients with underlying sphincter dysfunction or incontinence should be counselled about functional result of restorative surgery and may have better quality of life with permanent ileostomy. In patients with pre-existing mesenteric desmoids, it may not be possible to construct a pouch or bring it into the pelvis. At the same time, these patients may not be appropriate for colectomy with ileorectal anastomosis and therefore TPC with EI is a good choice.

3. Colectomy with Ileorectal Anastomosis (IRA)

The decision to leave residual rectum in a patient with FAP should be guided by their phenotype, willingness to undergo surveillance of the residual rectum, and patient preference.

Polyp burden both throughout the colon and in the rectum are both considered when selecting patients for this approach. In general, patients with fewer than 20 adenomas in the rectum that can be completely removed endoscopically are good candidates for this procedure. Those with

<1000 colon polyps and <5 rectal polyps nearly always are able to retain their rectums permanently. It has the advantage of avoiding the pelvic dissection and patients generally have excellent control of bowel function and with 2–4 bowel movements per day and an easily surveyed residual rectum.

IRA may also be performed as a bridging procedure in some patients who eventually plan to have a completion colectomy with or without a restorative procedure. This is most commonly considered in young women with concerns regarding childbearing who may wish to delay pelvic surgery.

The cumulative risk of rectal cancer after IRA in FAP ranges from 7% to 15%. Indications for completion proctectomy include cancer, dysplasia, large polyps, and the inability to completely remove all polyps endoscopically.

E. Other Surgical Considerations

Laparoscopy

Surgery may be performed via traditional open technique or laparoscopically. There are a variety of modications to laparoscopy including hand assist and single incision techniques, and while many surgeons prefer to create an IPAA through a lower midline or Pfannenstiel incision, using the stoma site has also been described. Laparoscopy has the potential benets of decreased post-operative pain, shorter hospitalization, and quicker return to pre- operative function. There are no differences in complication rates or functional outcomes. For some patients, the cosmetic benet is also appealing. For FAP patients in particular, it has been suggested that laparoscopy reduces the risk of desmoid tumors by decreasing surgical trauma but the data is mixed. For young women, there may also be a benet to fertility with laparoscopic IPAA but this is primarily extrapolated from series where the majority of patients had pouch surgery for ulcerative colitis. Desmoids

60 Familial Adenomatous Polyposis

465

When intra-abdominal desmoids are present at the time of surgery, they can impair the ability to remove the colon if blood vessels are encased, to perform proctectomy, or to achieve adequate mesenteric length to perform anastomosis or IPAA.There is no evidence that colectomy with IRA leads to fewer desmoids than does RPC.Furthermore, the morbidity of desmoid tumors does not vary between those with IRA and RPC.The development of a desmoid tumor may alter surgical planning if a completion proctectomy is required later, but it generally does not preclude it.

Laparoscopy may be benecial in minimizing the surgical trauma that may contribute to desmoid development. A large study from Italy suggested that the cumulative probability of desmoid development was 13% after open surgery versus 4% after laparoscopic surgery. Surgery at a younger age (<18) may also lead to desmoid development in female patients, which may inuence decisions regarding the timing of surgery. Timing of Surgery

For the majority of FAP patients, surgery is prophylactic. The goal is to prevent cancer from developing but physiologic, genotypic, social, and emotional factors also play a role. There are several situations in which delaying surgery is not feasible. In patients whose polyposis is so severe (>1000 polyps) that they cannot be adequately surveyed, surgery should be performed at an early age. If dysplasia or many large polyps are present surgery should not be unduly delayed. When adenoma associated symptoms including diarrhea, bleeding, malnutrition leading to growth delay are present, surgery should be performed promptly.

Patients with milder polyposis (100– 1000 polyps) or those with AFAP (<100 polyps) may defer surgery as long as all adenomas are small (<9 mm), there is no high grade dysplasia, and they are motivated to continue regular surveillance. In AFAP patients with a very mild phenotype whose colons are able to be cleared colonoscopi-

cally and managed via polypectomy, surgery may be deferred indenitely.

In general, most patients are recommended to undergo surgery between the ages of 18–25 when they have physical and emotional maturity, but still have low cancer risk. In patients who do not have prophylactic surgery, the mean age of CRC diagnosis is 39years, with death occurring at 42years. The risk of cancer prior to age 20 is estimated at 1%, but is as high as 32% at age 30.

Concerns about desmoids and fertility may also inuence timing of surgery. Because desmoids appear to occur more frequently in women who undergo surgery at a younger age, it is reasonable to consider deferring surgery beyond age 18 when it is otherwise feasible, particularly in patients at high risk for desmoid tumors. Fertility/Fecundity

Sexual function may be impaired by IPAA. Impotence and retrograde ejaculation are well dened complications of pelvic dissection in men. In women, about half report sexual dysfunction; this appears unrelated to pouch dysfunction.

Reduced fertility has also been reported in women who have undergone IPAA.Compared with ulcerative colitis patients, FAP patients who have undergone IPAA are not as severely affected. One study suggested that IRA had an equal impact on fertility compared with IPAA and neither desmoids nor cancer were associated with infertility. The few small series that have examined fertility problems after IPAA for FAP have identied widely varying rates from 17% to 62%. However, for some women who are concerned about their fertility, colectomy with IRA either as denitive treatment or as a bridge to proctectomy with or without IPAA after childbearing has been completed may be considered. Laparoscopy may also reduce the rates of adhesions following pelvic surgery and may decrease infertility rates so should be offered when feasible.

466

E. Steinhagen