Desmoid Disease

Introduction

Desmoid disease is a benign proliferation of fibroblasts that produces a spectrum of manifestations from rapidly growing tumors to indolent nodules and flat sheets of tissue that distort surrounding organs. Although desmoid disease occurs in the general population, it is rare and generally affects limbs and limb girdles. Colorectal surgeons encounter it in the abdomen, where it is usually associated with familial adenomatous polyposis (FAP). In this context, desmoid disease can cause many different problems because of its effects on surrounding organs and its mass effect. In this chapter, desmoid disease in FAP will be discussed.

Biology

The abnormal proliferation of fibroblasts that is desmoid disease occurs because the growth-controlling function of the wnt/wingless signal transduction pathway has been lost. In sporadic desmoids, this phenomenon is related to a mutation in CTNNB1 , the gene coding for β catenin. β catenin is a cytoplasmic protein that enters the cell nucleus and stimulates downstream activation of a series of genes that produce growth-stimulating proteins. APC is a cytoplasmic protein that acts as a complex with other proteins (GSK and Axin) to degrade β catenin and prevent activation of nuclear growth pathways. In FAP, one allele of APC is dysfunctional because of a germline mutation. The stimulus for the loss of the second allele in the fibroblasts of patients with FAP seems to be surgical trauma, which also activates the scarring process. Uncontrolled fibroblast growth initiates desmoid tumors.

Epidemiology

Desmoid disease is more common in women than in men by a two to one margin. This characteristic suggests a role for estrogen is the development and growth of desmoid disease, a suggestion that is reinforced by the findings that estrogen-modifying agents have some success in treating desmoids and that pregnancy ameliorates the clinical course of desmoid disease.

The true incidence of desmoid disease in patients with FAP is difficult to estimate because desmoid reaction—the flat, sheetlike desmoids that occur in the mesentery—are difficult to detect on a computed tomography (CT) scan and may even escape detection at laparotomy. However, in a series of patients undergoing abdominal surgery for FAP at the Cleveland Clinic, 3% had intra-abdominal desmoids at index surgery, whereas 31% had desmoid disease at a repeat operation. Approximately half had tumors and half had a desmoid reaction. Patients with asymptomatic tumors and desmoid reaction had a similar risk of the later development of clinically significant desmoid disease.

In general, about 45% of FAP desmoid disease occurs in the abdominal wall, 50% is intra-abdominal (mostly mesenteric or retroperitoneal), and 5% is extra-abdominal. Most desmoid disease arises within 4 years of an abdominal surgery (80% of desmoids occur after abdominal surgery).

Genetics and Desmoid Risk

Quite an extensive body of literature maintains that desmoid disease is more common in patients with 3′ mutations in APC. However, recent data show that although desmoid incidence is independent of genotype, desmoid severity is not independent of genotype. Desmoid disease is more severe in patients with APC mutations 3′ (higher than) of codon 1399.

Other risk factors for desmoid disease in FAP are a family history of desmoid disease, female gender, and extracolonic manifestations of Gardner syndrome (epidermoid cysts, osteomas, and extra teeth). These risk factors can be combined into a risk score that informs specialists about the advisability and timing of surgery ( Table 58-1 ).

TABLE 58-1

Desmoid Risk Index

Factor	1 Point	2 Points	3 Points
Gender	Male		Female
Family history of desmoid disease	None	1 relative	>1 relative
Extracolonic manifestations (Gardner syndrome)	None	1	>1
Genotype	5′ of codon 400	Codon 400 to 1399	3′ of codon 1399

4-6 points: low risk (5%)

6-8 points: medium risk (21%)

8-10 points: high risk (40%)

10-12 points: very high risk (>80%)

Desmoid Severity: A Staging System

Desmoid disease varies in the effects it has on patients, from none (asymptomatic, incidental) to lethal. Symptoms include pain and pressure, and complications include bowel obstruction, ureteric obstruction, tumor necrosis with abscess, erosion of the intestinal wall with enteric fistula, ureteric fistula, and a superior mesenteric artery aneurysm. The presentation and symptomatology of desmoid disease varies from patient to patient and within each affected patient. A staging system has been developed to allow easier comparison of patients and their disease, easier documentation of the disease progress, and rationalization of treatment ( Table 58-2 ). This staging system correlates with survival. Most patients with desmoid disease have multiple tumors or multiple plaques. In any patient, the staging system is applied to the worst manifestation.

TABLE 58-2

Desmoid Staging System

Stage	Size	Growth	Symptoms
I	<10 cm	None	None
II	<10 cm	Slow (<50% in 3 mo)	Mild (e.g., some pain)
III	10-20 cm	Slow	Moderate (e.g., small bowel/ureteric obstruction)
IV	>20 cm	Rapid (>50% in 3 mo)	Life threatening (e.g., sepsis, fistula)