colorectal cancer

20.1 introduction. . . . 331

20.2 epidemiology. . . . 332

. 20 2 1. Incidence. . . . 332

. 20 2 2. Etiology. . . . 332

20.3 Biology/Pathology. . . . 333

20.4 diagnosis: Symptoms and clinical Signs .. . . . 334

. 20 4 1. Staging . . . . 335

20.5 treatment/Management. . . . 335

. 20 5 1. Surgery. . . . 336

. 20 5 2. Radiation.Therapy.. . . . 337

. 20 5 3. Adjuvant.Chemotherapy. . . . 337

20.6 Outcome.. . . . 337

20.7 conclusions.. . . . 338

references . . . .339

20.1 introduction

Colorectal cancer (CRC) is the third most common malignant tumor in adults [1]. It was estimated that, in the United States in 2004, 147,000 new cases of CRC were diagnosed and 56,730 would die of CRC [2]. The risk of CRC begins to increase at the age of 40 years, and patients less-than 40 years of age account for only 2–6% of all patients [3]. However, CRC is very unusual in children and adolescents (Fig. 20.1).

contents

colorectal cancer

Wayne.L .Furman.•.D .Ashley.Hill.•..

Michael.LaQuaglia

Incidence.of.colorectal.carcinoma,.United.States.

SEER,.1975–2000 .The.diagonal.line.on.the.semiloga- rithmic.inset.chart.indicates.that.the.incidence.is.

exponential.below.age.40.years.and.extrapolates.to.

a.lower.age.limit.between.10.and.15.years.for.the.

youngest.cases

Figure 20.1

20.2 epidemiology 20.2.1 incidence

The incidence of CRC increases exponentially as a function of age from 15 to 40 years (Fig. 20.1). Over 90% of CRC cases occur after the age of 50 years and are very unusual in children ≤20 years of age, with an estimated annual incidence of about one case in one million persons less than 20 years old in the United States. It is estimated that CRC accounts for 2.1% of all neoplasms in adolescents and young adults (AYA) between the ages of 15 and 29 years [1]. At St. Jude Children’s Research Hospital, where over 20,000 chil- dren and adolescents with cancer have been seen since March 1962, 77 children ≤20 years of age have been diagnosed with CRC.

Relative to non-Hispanic whites and Hispanics/

Latinos, African Americans/blacks have had a higher incidence of CRC and American Indians/Alaska Native have had a low incidence, differences in racial/ethnic incidence rates that are apparent by age 25 years (Fig. 20.2). Since the 1980s, the age-corrected inci- dence of CRC has been declining in the United States for adults over the age of 45 years (Fig. 20.3). Below this age, however, there has been no significant change in the incidence (Fig. 20.3).

The distribution by extent of disease at diagnosis did not differ as a function of age at diagnosis (Fig. 20.4).

The proportion of patients with distant metastases, or with regional extension plus distant metastases was essentially the same in the age groups evaluated: 60%

had regional extension and/or distant metastases.

20.2.2 etiology

It is thought that, in adults, adenomatous polyps are precursors for the vast majority of CRCs. High fat intake and consumption of red meat and alcohol have been implicated as risk factors for the development of CRC. Use of cyclo-oxygenase-2 inhibitors and diets with increased fiber and calcium are believed to reduce the risk. How these factors contribute to CRC develop- ment in patients <20 years old is unknown.

Predisposing risk factors for CRC in AYA include inflammatory bowel disease, prior radiation exposure,

and certain hereditary conditions. Based on familial clustering studies, 20–30% of all CRC cases have a potentially definable inherited cause. However, for the majority of these cases the specific genes remain to be characterized [4]. Well-defined CRC pre-disposition syndromes account for only about 3–5% of all colon cancer and include Peutz-Jeghers syndrome, familial juvenile polyposis, hereditary mixed polyposis syn- drome, hereditary non-polyposis colon cancer, and familial adenomatous polyposis [4]. The most com- mon is familial adenomatous polyposis, which is inherited as a dominant trait with 90% penetrance and may be associated with the appearance of multiple cancers by the age of 37 years [5, 6]. Early diagnosis and total colectomy eliminates the risk of development of CRC for these patients. Other syndromes associated with CRC in young people include Turcot’s syndrome [7], for which the frequent mutation of the adenoma- tous polyposis coli gene has been found [8], Oldfield’s syndrome [9], and Gardner’s syndrome [10]. There may be an association with neurofibromatosis and pol- yposis coli [11], and one individual with multiple ade- nomatous polyps and multiple colonic carcinomas had a constitutional deletion of the p53 gene, also in asso- ciation with neurofibromatosis [11].

For children and adolescents there is no evidence that a family history of bowel cancer confers a greater risk for the development of CRC before the age of

Incidence.of.colorectal.carcinoma.by.race/ethnicity,.

United.States.SEER,.1992–2002.[1]

Figure 20.2

20 years [12]. The risk for persons younger than 20 years belonging to families with hereditary CRC, cancer fam- ily syndromes, or familial juvenile polyposis is unclear.

Most do not develop CRC until after the third decade of life. For example, the mean age for CRC develop- ment in patients with familial adenomatous polyposis is 39 years [13]. However, colon cancer in children as young as 5 years of age has been reported [14].

20.3 Biology/Pathology

There is extensive literature on the biology of adult CRC. In contrast, little has been published regarding the biology of this tumor in patients less than 21 years of age. As in adults, the histologic types of CRC include gland-forming non-mucinous adenocarcinomas (Fig. 20.5), mucinous adenocarcinomas (tumors in which >50% of the lesion is composed of mucin;

Fig. 20.6), and signet-ring-cell carcinomas (tumors in which >50% of cells in the lesion contain intra-cellular mucin; Fig. 20.7). Signet-ring cells can occur within the mucin pools of mucinous adenocarcinoma or as a diffusely infiltrative process with minimal extra-cellu- lar mucin. Well-differentiated neuro-endocrine carci- nomas (carcinoid tumors) also occur in this age group, with the majority of colorectal carcinoid tumors occur- ring in the appendix [15]. Perhaps the most striking difference from adults with CRC is the finding reported by multiple authors of a high prevalence of mucinous tumors in AYA. In adults, mucinous CRC occurs in 2–4% of patients. In AYA, however, the prevalence approaches 50% [16–28]. La Quaglia et al. noted that the incidence of signet-ring carcinoma was 45% in a cohort of 29 patients with CRC who were less than or equal to 21 years of age at diagnosis [29]. Karnak et al.

noted a prevalence of mucinous adenocarcinoma in 80% (13 patients of 20 patients reported) [17]. They also described one patient with Bloom’s syndrome and another with a family history of colon cancer in this cohort. Rao et al. reported 30 patients seen at St. Jude Children’s Research Hospital who were under the age of 30 years at the time of diagnosis and 25 of these had mucinous adenocarcinoma [26].

Mucinous adenocarcinoma has been shown in larger series of adults to be associated with a higher incidence of peritoneal, but not hepatic metastases, and a worse prognosis. Consorti et al., in a case- control study matched for age, sex, location, and Dukes stage, reported that patients with mucinous adenocarcinoma had a worse prognosis compared to those with non-mucinous adenocarcinoma [30].

Secco et al. noted that disease recurrence was more frequent with mucinous or signet-ring carcinomas [31]. They also reported that the 5-year survival rate was 45% for non-mucinous adenocarcinoma of the Incidence.of.colorectal.carcinoma.by.era,..

United.States.SEER.[1]

Figure 20.3

Proportion.of.colorectal.carcinoma.cases.that.

are.localized,.have.regional.extension,.or.distant.

metastases.at.diagnosis,.United.States.SEER,..

1975–2000

Figure 20.4

colorectum compared to 28% for mucinous tumors and 0% for signet-ring tumors. Primary signet-ring carcinomas of the colo-rectum have been associated with a higher percentage of stage III or IV tumors, and an increased frequency of peritoneal seeding, lower rate of hepatic metastases, and lower rate of curative resection when compared to non-signet-ring matched controls in adults [32]. Finally, Sugerbaker et al., in reporting patients with peritoneal carcino- matosis, noted that mucinous histology was an adverse prognostic factor [33].

Datta et al. reported micro-satellite instability (MSI) in 6 out of 13 patients who were under 21 years of age at diagnosis and who had available slides and paraffin blocks for analysis [34]. MSI-positive cancers were not associated with distinct clinical, histological, or famil- ial features compared to MSI-negative cancers. How- ever, MSI-positive cancers did have a significantly lower prevalence of K-ras mutation and of loss of het- erozygosity (LOH) at 17p or 18q. Subsequent studies of early-onset CRC (unpublished data, Philip Paty lab- oratory, Memorial Sloane-Kettering Cancer Center) have shown K-ras mutation to be a strong prognostic marker associated with increased cancer mortality. In addition, cancers with K-ras mutation frequently develop aneuploidy of the K-ras locus at 12p21, with

gain of the mutant K-ras allele and loss of the wild- type allele. The frequency and prognostic significance of these genetic changes in pediatric CRC is of consid- erable interest.

In summary, MSI status in adults correlates posi- tively with early-age onset, positive family history of colon cancer, right-sided and poorly differentiated tumors, a distinct pattern of molecular genetic altera- tions (diploidy, low LOH, low prevalence of K-ras and p53 mutations), favorable prognosis, and high risk of metachronous tumors. In a pilot study of 13 children and adolescents, the frequency of MSI was 46% and was associated with a low prevalence of LOH and K- ras mutations, but did not correlate with favorable prognosis or other clinicopathologic features. These data suggest that MSI positivity is associated with a unique pattern of molecular genetic development and has a different clinical course in childhood and adoles- cence.

20.4 diagnosis: Symptoms and clinical Signs The presenting symptoms of AYA with CRC, similar to older adults, are usually non-specific. Rarely is the diagnosis made in an asymptomatic AYA patient. The

Mucinous.adenocarcinoma.characterized.by.large.

pools.of.blue.mucin-containing.malignant.glands.in.

an.adolescent/young.adult.patient Figure 20.6

Moderately.differentiated.adenocarcinoma.invading.

into.pericolic.fat.in.an.adolescent/young.adult.

patient

Figure 20.5

most common symptom is vague, usually generalized abdominal pain [18, 26, 29, 35, 36]. Localizing abdom- inal pain is usually an indication of peritoneal involve- ment or perforation. This pain is occasionally sugges- tive of appendicitis [35, 37, 38]. Weight loss is relatively common according to our recent review of St. Jude patients in which approximately two-thirds noted weight loss [median loss 20 lbs (9.1 kg); range 5–81 lbs (2.3–36.8 kg)] [39]. Other less frequent associated symptoms include nausea, vomiting, constipation, diarrhea, pallor, anorexia, rectal bleeding, abdominal distension, dysuria, and intestinal obstruction [18, 26, 29]. In one review of 29 patients, 13 presented acutely whereas 16 had more chronic symptomatology [29].

In our experience, the duration of symptoms before diagnosis has ranged from 3 days to 12 months, with a median of 2 months [18]. A mass or fullness may or may not be palpable on physical exam [26, 35, 37]. Pri- mary tumors of the right colon usually present with less symptomatology than do left-sided tumors, prob- ably because the right colon has a larger diameter and a greater liquid content than the left side. Blood in stools or rectal bleeding is almost always associated with left-sided or rectal primaries.

Unfortunately, CRC is rarely thought of in the differential diagnosis of an adolescent with what would

be considered “usual” symptoms for this diagnosis in an older patient, such as abdominal pain, change in bowel habits, and anemia. This has resulted in a delay in diagnosis and felt to be at least part of the reason why, according to several authors [36, 38] most AYA patients present with advanced-stage disease.

20.4.1 Staging

Staging is performed following the American Joint Commission on Cancer guidelines [40]. An attempt to assign a pre-operative, post-operative, and pathologi- cal stage should be made. This system is depicted in Table 20.1.

20.5 treatment/Management

Since CRC is so rare in children and young adults, treatment guidelines for these young patients are usu- ally extrapolated from adult trials. A multi-disciplin- ary approach is essential for managing these complex patients, and early referral to centers that are expert in the care of young patients with cancer will ensure the best possible outcome. Whenever possible, managing these patients on a clinical trial is preferable.

The diagnosis may be suspected when there is a history of cramping abdominal pain, change in bowel habits, unexplained weight loss, or hematochezia. If the diagnosis is suspected, the patient should undergo a flexible colonoscopy to the cecum unless the lesion is completely obstructing. Any intraluminal mass should be sampled via biopsy and notation made of concomitant polyps. If there are only a few polyps these should be removed for histological analysis.

Computerized axial tomography of the chest, abdomen, and pelvis with both liver and lung win- dows should be done to identify peritoneal, or much less frequently hepatic and pulmonary metastases.

18 F-fluorodeoxyglucose-positron emission tomogra- phy imaging has the potential to detect malignant cells by their increased glucose metabolism, and is felt by many to be the best method for staging CRC in all localities. However, this modality is less useful in patients with mucinous histology, which is the histol- ogy seen in a majority of AYA patients. Both intrave- Signet-ring-cell.carcinoma.composed.of.individually.

dispersed.tumor.cells.with.a.single.large.mucin.

droplet.displacing.the.nucleus.to.the.edge.of.the.cell.

in.an.adolescent/young.adult.patient

Figure 20.7

nous and intraluminal contrast should be used both for tumor enhancement and identification of normal bowel. Hydronephrosis may be observed because of infiltration around the distal ureters from peritoneal metastases.

There is no specific tumor marker for colorectal adenocarcinoma in this age group, including carcino- embryonic antigen. Abnormalities of liver function tests, especially lactic dehydrogenase, may indicate hepatic involvement. There are no data evaluating use of the carcinoembryonic antigen in follow-up after therapy in AYA.

20.5.1 Surgery

Radical surgery with curative intent is the mainstay of treatment. In fact, if patients cannot be rendered surgically free of disease, they are rarely cured. Resec- tion should follow guidelines established in adults. In

particular, primary and secondary draining lymph node echelons should be removed. The basic surgical principles are removal of the major vascular pedicle supplying the tumor along with its lymphatics, and en bloc resection of any organs or structures attached to the tumor. At least a 5-cm margin of normal bowel should be obtained on either side of the tumor to minimize the possibility of an anastomatic recur- rence [41]. Adequate lymph node resection is imper- ative because some patients with stage III tumors are cured by surgery alone. A minimum of 14 negative lymph nodes should be examined to define node- negative disease. The surgeon must also remember that the pattern of spread of mucinous CRC may be intra-peritoneal. Therefore an extensive exploration of the peritoneal surface including that overlying Gerota’s fascia and the diaphragm should be under- taken at laparotomy. All peritoneal nodules should be removed if feasible.

table 20.1 American.Joint.Committee.on.Cancer/International.Union.Against.Cancer.(AJCC/UICC).staging.system.for.

colorectal.cancer.[40]

Primary tumor (t) regional lymph nodes (n)

TX Primary.tumor.cannot.be.assessed NX Nodes.cannot.be.assessed.(e g ,.local.

excision.only) T0 No.evidence.of.tumor.in.resected.specimen.

(prior.polypectomy.or.fulguration) N0 No.regional.node.metastases N1 1-3.positive.nodes

Tis Carcinoma.in.situ N2 4.or.more.positive.nodes

T1 Invades.submucosa N3 Central.nodes.positive

T2 Invades.muscularis.propria

T3–T4 Depends.on.whether.serosa.is.present If serosa present:

T3.Invades.through.muscularis.propria.into.

subserosa,..serosa.(but.not.through),.or.

pericolic.fat.within.the.leaves.of.the.

mesentery

T4.Invades.through.serosa.into.free.

peritoneal.cavity.or.through.serosa.into.a.

contiguous.organ

If there is no serosa present (as in the distal two thirds rectum, posterior left or right colon):

T3.Invades.through.muscularis.propria T4.Invades.other.organs.(vagina,.prostate,.

ureter,.kidney)

distant Metastases (M)

MX.=.Presence.of.distant.metastases.cannot.be.assessed M0.=.No.distant.metastases

M1.=.Distant.metastases.present

If the diagnosis is not made pre-operatively or if the patient is urgently explored for an acute abdomen, and CRC is found, the surgeon should convert the proce- dure to a standard colon cancer resection with exci- sion of draining lymphatics. This may necessitate clos- ing the original wound (e.g., appendectomy incision) and using a midline approach.

Cases of localized recurrence may benefit from re- excision. Hyperthermic perfusion of the peritoneal cavity after colon resection and peritonectomy has been applied, but only in a few cases. There is not enough data to recommend this approach in all patients.

Unfortunately, in many AYA patients the initial sur- gery is not done as a cancer operation. In those instances, re-exploration of the abdomen, with the goals of resection of bowel with adequate margins and adequate lymph node sampling should be done at a center experienced with this type of surgery.

20.5.2 radiation therapy

The use of radiation therapy in children and young adults with CRC is dependent on the location of the primary disease. In general, radiation reduces the risk of local treatment failure in primary tumors in the rec- tal area, and occasionally it is useful in inoperable patients with localized disease. The indications for radiation therapy include extension of the tumor to surrounding organs or perforation of the visceral peri- toneum (T4). Radiation has been found to be more effective when given with concurrent continuous-infu- sion 5-fluorouracil (5-FU).

20.5.3 adjuvant chemotherapy

CRC that has been completely resected with adequate lymph node sampling (≥14 nodes) and does not invade through the muscularis propria (T1

-2, N0, M0; Stage I–II) has an 80–90% overall survival rate when treated with surgery alone. Minimal follow-up recommenda- tions according to the National Comprehensive Can- cer Network include: history, physical exam, measure- ment of carcinoembryonic antigen levels every 3 months for 2 years and then every 6 months for a total of 5 years. Colonoscopy should be done yearly for 2 years and then every 2–3 years thereafter.

For patients whose tumor invades through the mus- cularis propria or into other organs or has either lymph node or distant metastases (T3-4, N1-2, M0-1; Stage III–

IV) adjuvant chemotherapy is necessary. For patients with stage III disease, 6 months of 5-FU and leucovo- rin (LV) has been standard treatment. Recently, com- binations of 5-FU/LV with either irinotecan (FOL- FIRI) or oxaliplatin (FOLFOX) have demonstrated improvements in response and survival. In addition, erbitux (cetuximab), a humanized monoclonal anti- body against the epidermal growth factor receptor, and avastin (bevacizumab), a monoclonal antibody against the vascular endothelial growth factor have both recently been approved by the Food and Drug Administration for patients with advanced CRC.

20.6 Outcome

The outcome of AYA with CRC, similar to adults with this disease, is dependent on the extent of disease at diagnosis. As illustrated in Fig. 20.8, the overall survival for patients <30 years of age was lower than for older patients during the 1990s, whether the 1-, 2-, or 5-year One-,.2-,.and.5-year.relative.survival.for.patients.with.

colorectal.carcinoma.by.age;.United.States.SEER,.

1992–1998.[1] .The.number.of.patients.in.each.5-year.

age.group.is.listed.above.the.abscissa

Figure 20.8

survival rates are evaluated. For adolescents, the 5-year survival rate was about 40%, as opposed to the 60% rate achieved overall in patients over 30 years of age and regardless of the age group between 30 and 70 years.

The lower survival rate in patients diagnosed before age 30 years is not due to a more advanced stage at diagnosis in this age group as compared to older patients, as shown in Fig. 20.4. When survival rates are assessed within localized, regional, and distant disease presentations, a lower survival rates among 15- to 30- year-olds is apparent in each (Fig. 20.9).

When the 5-year survival rate is assessed by era of diagnosis (Fig. 20.10), the least amount of progress is apparent in patients less than 30 years of age.

The prognosis in younger patients has previously been reported to be dismal [16–19, 37, 42–47]. Expla- nations for the poor prognosis have included a delay in diagnosis because of its rarity, a greater percentage of patients having more advanced disease at presenta- tion, and unfavorable histologic characteristics. The SEER data do not appear to substantiate the more advanced stage hypothesis. More likely, the different biology in the younger age group, lacking the sequen- tial mutations induced in part by environmental car- cinogens and driven more by MSI, are contributing to the worse prognosis.

20.7 conclusions

CRC in AYA is rare, but of regular occurrence and repeated challenge. Past studies, mostly limited to col- lections of cases from single institutions, have sug- gested that AYA patients with CRC do worse in com- parison to CRC in adults. This difference is partly explained by a higher frequency of mucinous histol- ogy and more advanced stage disease at diagnosis in these younger patients.

CRC in AYA is rare, accounting for about 2% of all neoplasms in patients between the ages of 15 and 29 years of age. Presenting symptoms, similar to adults, are often chronic, vague, and ill defined. Because of the young age, CRC is not considered early enough in the differential diagnosis. In contrast to adults, most of the reported cases in this young age group have mucinous or signet-ring-cell carcinomas. Although most large series suggest that AYA present with more advanced- stage disease, this is not borne out by the SEER data (Fig. 20.4). This discrepancy may be a result of selec- tion bias in patients referred to academic centers and/

or cases chosen for literature reports. AYA patients with localized CRC have an excellent prognosis and this diagnosis needs to be considered earlier in patients who present with vague abdominal complaints.

Five-year.relative.survival.rate.in.patients.with.

colorectal.carcinoma.by.era,.United.States.SEER.[1]

Figure 20.10 Five-year.relative.survival.rate.in.patients.with.

colorectal.carcinoma.who.were.less.than.45.years.of.

age.at.diagnosis,.by.stage.of.disease.at.diagnosis,.

United.States.SEER,.1975–2000.[1]

Figure 20.9

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