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Clinical presentation, diagnosis, and staging of colorectal cancer
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Clinical presentation, diagnosis, and staging of colorectal cancer
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2016. | This topic last updated: Apr 11, 2016.

INTRODUCTION — Colorectal cancer (CRC) is a common and lethal disease. It is estimated that approximately 134,490 new cases of large bowel cancer are diagnosed annually in the United States [1], including approximately 95,270 colon and 39,220 rectal cancers. Approximately 49,190 Americans are expected to die of large bowel cancer each year. Although CRC mortality has been progressively declining since 1990 at a rate of approximately 3 percent per year [2], it still remains the third most common cause of cancer death in the United States. Global, country-specific incidence and mortality rates are available from the World Health Organization Globocan database.

In contrast to these declines, the incidence of CRC in men and women under the age of 50 has been steadily increasing at a rate of 2.1 percent per year from 1992 through 2012 [1]. These increases are driven predominantly by left-sided cancers in general and rectal cancer in particular (3.9 percent per year) [3]. Current literature suggests that over 86 percent of those diagnosed under the age of 50 are symptomatic at diagnosis, and this is associated with more advanced stage at diagnosis and poorer outcomes [4]. At present, screening is not recommended for individuals under the age of 50 unless they have a positive family history or a predisposing inherited syndrome. (See "Screening for colorectal cancer: Strategies in patients at average risk" and "Screening for colorectal cancer in patients with a family history of colorectal cancer" and "Colorectal cancer: Epidemiology, risk factors, and protective factors", section on 'Incidence'.)

CRC is diagnosed after the onset of symptoms or because of occult bleeding in the majority of patients. Screening of asymptomatic individuals for CRC is advocated by major societies and preventive care organizations. Screening has been shown to detect asymptomatic early-stage malignancy and improve mortality. However, while compliance with CRC screening guidelines is steadily improving, it is still relatively low. (See "Screening for colorectal cancer: Strategies in patients at average risk".)

The clinical presentation, diagnosis, and staging of CRC will be reviewed here. The pathology, prognostic determinants, and treatment of colon and rectal cancer are discussed elsewhere.

(See "Pathology and prognostic determinants of colorectal cancer".)

(See "Overview of the management of primary colon cancer".)

(See "Surgical resection of primary colon cancer".)

(See "Adjuvant therapy for resected stage III (node-positive) colon cancer".)

(See "Adjuvant chemotherapy for resected stage II colon cancer".)

(See "Adjuvant therapy for resected colon cancer in elderly patients".)

(See "Overview of surgery for the treatment of primary rectal adenocarcinoma".)

(See "Neoadjuvant chemoradiotherapy and radiotherapy for rectal adenocarcinoma".)

(See "Adjuvant therapy for resected rectal adenocarcinoma".)

CLINICAL PRESENTATION — Patients with colorectal cancer (CRC) may present in three ways:

Suspicious symptoms and/or signs

Asymptomatic individuals discovered by routine screening (see "Screening for colorectal cancer: Strategies in patients at average risk")

Emergency admission with intestinal obstruction, peritonitis, or rarely, an acute gastrointestinal (GI) bleed

There are no symptoms in the majority of patients with early stage colon cancer and these patients are diagnosed as a result of screening. Although the increasing uptake of CRC screening has led to more cases being diagnosed at an asymptomatic stage, most CRCs (70 to 90 percent in two contemporary series [5,6]) are diagnosed after the onset of symptoms. Symptoms of CRC are typically due to growth of the tumor into the lumen or adjacent structures, and as a result, symptomatic presentation usually reflects relatively advanced CRC. (See "Screening for colorectal cancer: Strategies in patients at average risk" and "Screening for colorectal cancer in patients with a family history of colorectal cancer".)

Symptoms from the local tumor — Typical symptoms/signs associated with CRC include hematochezia or melena, abdominal pain, otherwise unexplained iron deficiency anemia, and/or a change in bowel habits [7-12]. Less common presenting symptoms include abdominal distention, and/or nausea and vomiting, which may be indicators of obstruction. A compilation of the most frequent symptoms and findings that prompted diagnostic colonoscopy in a series of 388 consecutive patients diagnosed with a CRC between 2011 and 2014 included the following [5]:

Blood per rectum (37 percent).

Abdominal pain (34 percent).

Anemia (23 percent).

Six patients (1.9 percent) had incidental colonic hypermetabolic activity detected on a positron emission tomography/computed tomography (PET/CT) image done for another reason.

Only four individuals (1.3 percent) underwent diagnostic colonoscopy because of change in bowel habits (diarrhea).

On the other hand, among the 28 patients whose diagnosis was established at the time of surgery, the most common indications for emergent surgery were obstruction (57 percent), a preoperative diagnosis of acute appendicitis on preoperative CT imaging with a cecal adenocarcinoma found in the surgical specimen (25 percent), and perforation (18 percent).

Obstructive symptoms are more common with cancers that encircle the bowel, producing the so-called "apple-core" description seen on radiologic imaging (image 1A-B).

Among symptomatic patients, clinical manifestations also differ depending on tumor location:

A change in bowel habits is a more common presenting symptom for left-sided than right-sided CRCs because fecal contents are liquid in the proximal colon and the lumen caliber is larger, and they are therefore less likely to be associated with obstructive symptoms.

Hematochezia is more often caused by rectosigmoid than right-sided colon cancer.

Iron deficiency anemia from unrecognized blood loss is more common with right-sided CRCs [13]. Cecal and ascending colon tumors have a fourfold higher mean daily blood loss (approximately 9 mL/day) than tumors at other colonic sites [14]. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Search for source of blood and iron loss'.)

Abdominal pain can occur with tumors arising at all sites; it can be caused by a partial obstruction, peritoneal dissemination, or intestinal perforation leading to generalized peritonitis.

Rectal cancer can cause tenesmus, rectal pain, and diminished caliber of stools.

These concepts can be illustrated by the distribution of findings at presentation in a series of 253 CRCs that were diagnosed and treated at a teaching/national referral hospital in Kenya between 1993 and 2005, which included 140 rectal cancers, 54 right-sided colon cancers, and 59 left-sided colon cancers (table 1) [11].

Metastatic disease — Patients may also present with signs/symptoms of metastatic disease. Approximately 20 percent of patients in the United States have distant metastatic disease at the time of presentation [1]. CRC can spread by lymphatic and hematogenous dissemination, as well as by contiguous and transperitoneal routes. The most common metastatic sites are the regional lymph nodes, liver, lungs, and peritoneum. Patients may present with signs or symptoms referable to any of these areas. The presence of right upper quadrant pain, abdominal distention, early satiety, supraclavicular adenopathy, or periumbilical nodules usually signals advanced, often metastatic disease.

Because the venous drainage of the intestinal tract is via the portal system, the first site of hematogenous dissemination is usually the liver, followed by the lungs, bone, and many other sites, including the brain. However, tumors arising in the distal rectum may metastasize initially to the lungs because the inferior rectal vein drains into the inferior vena cava rather than into the portal venous system.

Unusual presentations — There are a variety of atypical presentations of CRC. These include:

Local invasion or a contained perforation causing malignant fistula formation into adjacent organs, such as bladder (resulting in pneumaturia) or small bowel. This is most common with cecal or sigmoid carcinomas; in the latter case, the condition can mimic diverticulitis.

Fever of unknown origin, intraabdominal, retroperitoneal, abdominal wall or intrahepatic abscesses due to a localized perforated colon cancer [15,16]. Streptococcus bovis bacteremia and Clostridium septicum sepsis are associated with underlying colonic malignancies in approximately 10 to 25 percent of patients [17]. Rarely, other extraabdominal infections caused by colonic anaerobic organisms (eg, Bacteroides fragilis) may be associated with CRC [18]. (See "Clinical manifestations, diagnosis, and treatment of infections due to group D streptococci (Streptococcus bovis/Streptococcus equinus complex)", section on 'Association with colonic neoplasia'.)

CRC ultimately proves to be the site of origin of approximately 6 percent of adenocarcinomas of unknown primary sites [19]. (See "Adenocarcinoma of unknown primary site".)

CRC may be detected on the basis of discovery of liver metastases that are detected incidentally during studies such as gallbladder or renal ultrasound, or CT scans for evaluation of other symptoms (eg, dyspnea).

Impact of symptoms on prognosis — The presence of symptoms and their particular type provide some prognostic importance:

Patients who are symptomatic at diagnosis typically have more advanced disease and a worse prognosis [5,20]. In one study of 1071 patients with newly-diagnosed colon cancer, 217 of whom were diagnosed through screening, the patients not diagnosed through screening were at significantly higher risk for a more invasive tumor (≥T3: relative risk [RR] 1.96), nodal involvement (RR 1.92), and metastatic disease on presentation (RR 3.37). In addition, patients not diagnosed through screening had significantly higher death rates (RR 3.02) and recurrence rates (RR 2.19) as well as shorter survival and disease-free intervals [20]. (See "Tests for screening for colorectal cancer: Stool tests, radiologic imaging and endoscopy".)

The total number of symptoms may be inversely related to survival for colon but not for rectal cancer [21]. Whether the duration of symptoms influences prognosis is unclear; the available data are mixed [22-24].

Obstruction and/or perforation, although uncommon, carry a poor prognosis, independent of stage [8,25-28]. Among patients with node-negative colon cancer, obstruction or perforation are poor prognostic factors that may influence the decision to pursue adjuvant chemotherapy. (See "Adjuvant chemotherapy for resected stage II colon cancer", section on 'Clinicopathologic variables'.)

Tumors presenting with rectal bleeding (typically those involving the distal colon and rectum) have been thought to have a better prognosis because of their tendency to be diagnosed at an earlier stage [29,30]; however, bleeding is not an independent predictor of outcome [26,31]. Rectal bleeding is more commonly seen with distal tumors, and a larger proportion of distal colon cancers present as early-stage tumors as compared with proximal tumors [30].

Other determinants of prognosis, including clinicopathologic and molecular features, are discussed elsewhere. (See "Pathology and prognostic determinants of colorectal cancer".)

DIAGNOSIS — Colorectal cancer (CRC) may be suspected from one or more of the symptoms and signs described above or may be asymptomatic and discovered by routine screening of average- and high-risk subjects. Once a CRC is suspected, the next test can be a colonoscopy, barium enema, or computed tomography colonography. However, examination of tissue is required to establish the diagnosis; this is usually accomplished by colonoscopy. (See "Screening for colorectal cancer: Strategies in patients at average risk" and "Screening for colorectal cancer in patients with a family history of colorectal cancer" and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Screening and management" and "Familial adenomatous polyposis: Screening and management of patients and families" and "Juvenile polyposis syndrome".)

Histopathologically, the majority of cancers arising in the colon and rectum are adenocarcinomas. The histologic diagnosis of CRC is discussed in detail elsewhere. (See "Pathology and prognostic determinants of colorectal cancer", section on 'Histology and immunohistochemistry'.)

Colonoscopy — Colonoscopy is the most accurate and versatile diagnostic test for CRC, since it can localize and biopsy lesions throughout the large bowel, detect synchronous neoplasms, and remove polyps. Synchronous CRCs, defined as two or more distinct primary tumors diagnosed within six months of an initial CRC, separated by normal bowel, and not due to direct extension or metastasis, occur in 3 to 5 percent of patients [32-34]. The incidence is somewhat lower (approximately 2.5 percent) when patients with Lynch syndrome are excluded; the presence of synchronous cancers should raise the clinical suspicion for Lynch Syndrome [35]. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Colonic manifestations'.)

The preparation for, diagnostic use of, and complications associated with colonoscopy are discussed elsewhere. (See "Overview of colonoscopy in adults".)

When viewed through the endoscope, the vast majority of colon and rectal cancers are endoluminal masses that arise from the mucosa and protrude into the lumen (figure 1). The masses may be exophytic or polypoid. Bleeding (oozing or frank bleeding) may be seen with lesions that are friable, necrotic, or ulcerated (picture 1A-B). Circumferential or near-circumferential involvement of the bowel wall correlates with the so-called "apple-core" description seen on radiologic imaging (image 1A-B).

A minority of neoplastic lesions in the gastrointestinal tract (both in asymptomatic and symptomatic individuals) are nonpolypoid and relatively flat or depressed. In one study, nonpolypoid colorectal neoplasms had a greater association with carcinoma than did polypoid neoplasms [36]. Cancers that arise from nonpolypoid (flat) adenomas may be more difficult to visualize colonoscopically than polypoid lesions, but colonoscopy is thought to have superior sensitivity in this situation than does barium enema or computed tomography (CT) colonography. (See "Approach to the patient with colonic polyps", section on 'Morphologic/endoscopic classification'.)

For endoscopically visible lesions, methods for tissue sampling include biopsies, brushings, and polypectomy. For lesions that are completely removed endoscopically (with polypectomy, endoscopic mucosal resection, or endoscopic submucosal dissection), tattooing is important for subsequent localization if an invasive neoplasm is found, and additional local therapy is needed. Tattoos are typically placed adjacent to or a few centimeters distal to the lesion, with the location being documented in the colonoscopy report. Large, laterally spreading colonic polyps can now be safely removed endoscopically, provided they meet endoscopic criteria that predict their benign nature (table 2). (See "Endoscopic removal of large colon polyps", section on 'Patient selection' and "Approach to the patient with colonic polyps", section on 'Management'.)

Among asymptomatic patients, colonoscopic miss rates for CRCs in the hands of experienced operators range from 2 to 6 percent, and are highest on the right side of the colon [37-39]. (See "Tests for screening for colorectal cancer: Stool tests, radiologic imaging and endoscopy", section on 'Sensitivity of colonoscopy'.)

The available data concerning miss rates for CRC among symptomatic patients undergoing colonoscopy are as follows:

In a randomized trial comparing colonoscopy versus CT colonography for individuals with symptoms suggestive of CRC conducted by SIGGAR (Special Interest Group in Gastrointestinal and Abdominal Radiology) investigators, none of the 55 cancers that were diagnosed in the cohort of 1072 patients who were randomly assigned to colonoscopy were missed [40].

In a systematic review and meta-analysis of 25 diagnostic studies providing data on 9223 patients with a cumulative CRC prevalence of 3.6 percent (414 cancers), the sensitivity of optical colonoscopy for detection of CRC was 94.7 percent (178 of 188, 95% CI 90-97.2) [41]. Thus, the miss rate was 5.3 percent.

Large retrospective studies from Canada [42-44] and the United States [45,46] have used administrative databases to identify patients diagnosed with CRC who had had a colonoscopy performed for any indication 6 to 60 months prior to CRC diagnosis. These interval, missed, or post-colonoscopy CRCs accounted for 6 to 9 percent of all CRCs in their series. Other studies of post-colonoscopy CRC (sometimes called interval cancers) have shown a close inverse relationship between the incidence of these cancers in a colonoscopist's practice and that colonoscopist's adenoma detection rate. (See "Overview of colonoscopy in adults", section on 'Quality indicators'.)

If a malignant obstruction precludes a full colonoscopy preoperatively, the entire residual colon should be examined soon after resection.

In the absence of an obstruction, where colonoscopy is incomplete, another option is Pill Cam colon 2, a wireless colon video endoscopy capsule approved for CRC screening, although its use in patients with symptoms suggestive of CRC (eg, anemia, rectal bleeding, weight loss) is controversial. (See "Wireless video capsule endoscopy" and "Tests for screening for colorectal cancer: Stool tests, radiologic imaging and endoscopy", section on 'Capsule endoscopy'.)

Flexible sigmoidoscopy — Over the last 50 years, a gradual shift toward right-sided or proximal colon cancers has been observed both in the United States and internationally, with the greatest increase in incidence is in cecal primaries (picture 2). Because of this, and because of the high frequency of synchronous CRCs, flexible sigmoidoscopy is generally not considered to be an adequate diagnostic study for a patient suspected of having a CRC, unless a palpable mass is felt in the rectum. In such cases, a full colonoscopy will still be needed to evaluate the remainder of the colon for synchronous polyps and cancers (see "Colorectal cancer: Epidemiology, risk factors, and protective factors", section on 'Incidence'). Nevertheless, screening for CRC using a flexible sigmoidoscope is one of the few modalities that have been proven through randomized controlled trials to reduce CRC mortality and incidence [40].

Barium enema — Barium enema is widely available and may be used to investigate patients with symptoms suggesting of CRC (image 1A-B) [47,48]. However, the diagnostic yield of both double-contrast barium enema (DCBE) alone and the combination of DCBE plus flexible sigmoidoscopy is less than that of colonoscopy or CT colonography for the evaluation of lower tract symptoms [48,49].

The yield of DCBE alone was addressed in a randomized trial comparing DCBE versus CT colonography in 3838 patients with symptoms suggestive of CRC [48]. Of the 2527 patients assigned to DCBE, the detection rate for CRC or large polyps was significantly lower (5.6 versus 7.3 percent with CT colonography). Rates of additional studies after the initial procedure were significantly lower after DCBE than CT colonography (18 versus 24 percent) with three years of follow-up. The need for additional studies following CT colonography was due mostly to the higher polyp detection rate; CRC was subsequently diagnosed in more patients who had initially undergone DCBE (miss rate 14 versus 7 percent).

If a polyp or mass is detected by barium enema, colonoscopy is recommended to establish the histology, remove the polyp, and search for synchronous lesions.

CT colonography — CT colonography (also called virtual colonoscopy or CT colography) provides a computer-simulated endoluminal perspective of the air-filled distended colon. The technique uses conventional spiral or helical CT scan or magnetic resonance images acquired as an uninterrupted volume of data, and employs sophisticated postprocessing software to generate images that allow the operator to fly-through and navigate a cleansed colon in any chosen direction. CT colonography requires a mechanical bowel prep that is similar to that needed for barium enema, since stool can simulate polyps. (See "Overview of computed tomographic colonography".)

CT colonography has been evaluated in patients with incomplete colonoscopy and as an initial diagnostic test in patients with symptoms suggestive of CRC.

Incomplete colonoscopy — Non-completion rates for diagnostic colonoscopy in symptomatic patients are approximately 11 to 12 percent [40,50]. Reasons for incompleteness include the inability of the colonoscope to reach the tumor or to visualize the mucosa proximal to the tumor for technical reasons (eg, partially or completely obstructing cancer, tortuous colon, poor preparation) and patient intolerance of the examination. In this setting, CT colonography is highly sensitive for the detection of CRC and can provide a radiographic diagnosis, although it can over call stool as masses in poorly distended or poorly prepared colons; it also lacks the capability for biopsy or removal of polyps [41,51-54].

CT colonography should be restricted to patients who are able to pass flatus and capable of tolerating the oral preparation. For clinically obstructed patients, a gastrointestinal (GI) protocol abdominal CT scan is a good alternative to CT colonography.

Initial diagnostic test — Systematic reviews of screening studies conducted in asymptomatic patients suggest that CT colonography and colonoscopy have similar diagnostic yield for detecting CRC and large polyps. Comparison of the benefits and costs of the two procedures depends on other factors, one of the most important of which is the need for additional investigation after CT colonography and the exposure to radiation, which is particularly important where recurrent scanning over time may be contemplated such as in screening. (See "Radiation-related risks of imaging studies".)

Abnormal results should be followed up by colonoscopy for excision and tissue diagnosis, or for smaller lesions, additional surveillance with CT colonography. There is controversy as to the threshold size of a polyp that would indicate the need for (interventional) colonoscopy and polypectomy. CT colonography also has the ability to detect extracolonic lesions, which might explain symptoms and provide information as to the tumor stage, but also could generate anxiety and cost for unnecessary investigation and may have a low yield of clinically important pathology [55]. (See "Tests for screening for colorectal cancer: Stool tests, radiologic imaging and endoscopy", section on 'Computed tomography colonography'.)

The performance of diagnostic CT colonography as compared with colonoscopy in patients with symptoms suggestive of CRC has been addressed in the following studies:

A systematic review and meta-analysis included 49 studies (11,551 patients) in which patients underwent CT colonography for the diagnosis of colorectal polyps and cancer with subsequent colonoscopy for verification of the findings; 43 studies (6668 patients) examined a symptomatic or disease-enriched population [41]. There were 394 cancers in the symptomatic population (prevalence 6 percent) and a total of 414 cancers in the entire cohort. CT colonography detected 96.1 percent of the histologically proven cancers (95% CI 93.9-97.7 percent). In a subset of 25 studies (9223 patients) in which the sensitivity of colonoscopy could be assessed independently (ie, when the colonoscopy was performed without knowledge of the prior CT colonography result, an analysis which included predominantly data from asymptomatic individuals), the sensitivity of colonoscopy was 94.7 percent (178 of 188 cancers, 95% CI 90.4-97.2 percent).

The diagnostic performance of CT colonography was directly compared with colonoscopy in the SIGGAR trial in which 1610 patients with symptoms suggestive of CRC were randomly assigned to colonoscopy (n = 1072) or CT colonography (n = 538) [40]. The primary endpoint was the rate of additional colonic investigation after the primary procedure for detection of CRC or large (>10 mm) polyps. Detection rates for CRC and large polyps were 11 percent for both procedures. CT colonography missed 1 of 29 CRCs and colonoscopy missed none of 55. However, patients undergoing CT colonography were more than three times more likely to get additional colonic investigations (30 versus 8 percent). Only one-third of these patients were found to have CRC or a large polyp.

At least one previously unknown extracolonic finding was reported in 60 percent of the 475 patients who had CT colonography and no diagnosis of CRC. Most were judged to be clinically unimportant. Among the 48 patients who were investigated further for extracolonic findings, only approximately one-third received a diagnosis that explained at least one of their presenting symptoms and only nine patients were found to have an extracolonic malignancy.

Overall, CT colonography had superior patient acceptability compared with colonoscopy in the short term (immediately after the test) but the benefits of colonoscopy (being more satisfied with how results were received and less likely to require follow-up colonic investigations) became apparent after longer-term follow-up (three months) [56].

The available data suggest that CT colonography provides a similarly sensitive, less invasive alternative to colonoscopy in patients presenting with symptoms suggestive of CRC. However, given that colonoscopy permits removal/biopsy of the lesion and any synchronous cancers or polyps that are seen during the same procedure, in our view, colonoscopy remains the gold standard for investigation of symptoms suggestive of CRC. CT colonography is preferred over barium enema where access to colonoscopy is limited.

PILLCAM 2 — A colon capsule for CRC screening has been approved by the EMA in Europe and by the US Food and Drug Administration. In the United States, it is approved for use in patients who have had an incomplete colonoscopy. While its role in screening for CRC is still uncertain, it could be considered in a patient with an incomplete colonoscopy who lacks obstruction.

Laboratory tests — Although CRC is often associated with iron deficiency anemia, its absence does not reliably exclude the disease. There is no diagnostic role for other routine laboratory test, including liver function tests, which lack sensitivity for detection of liver metastases.

Tumor markers — A variety of serum markers have been associated with CRC, particularly carcinoembryonic antigen (CEA). However, all these markers, including CEA, have a low diagnostic ability to detect primary CRC due to significant overlap with benign disease and low sensitivity for early-stage disease [57-60]. A meta-analysis concluded that the pooled sensitivity of CEA for diagnosis of CRC was only 46 percent (95% CI 0.45-0.47) [61]. No other conventional tumor marker had a higher diagnostic sensitivity, including carbohydrate antigen 19-9 (CA 19-9, pooled sensitivity 0.30, 95% CI 0.28-0.32).

Furthermore, specificity of CEA is also limited. In the previously mentioned meta-analysis, the specificity of CEA for diagnosis of CRC was 89 percent (95% CI 0.88-0.92). Non-cancer-related causes of an elevated CEA include gastritis, peptic ulcer disease, diverticulitis, liver disease, chronic obstructive pulmonary disease, diabetes, and any acute or chronic inflammatory state. In addition, CEA levels are significantly higher in cigarette smokers than in non-smokers [62,63].

An expert panel on tumor markers in breast and colorectal cancer convened by the American Society of Clinical Oncology (ASCO) recommended that neither serum CEA nor any other marker, including CA 19-9, should be used as a screening or diagnostic test for CRC [58]. A similar recommendation has been made by the European Group on Tumor Markers [64].

However, CEA levels do have value in the follow-up of patients with diagnosed CRC. ASCO guidelines recommend that serum CEA levels be obtained preoperatively in most patients with demonstrated CRC to aid in surgical treatment planning, posttreatment follow-up, and in the assessment of prognosis [58]:

Serum levels of CEA have prognostic utility in patients with newly-diagnosed CRC. Patients with preoperative serum CEA >5 ng/mL have a worse prognosis, stage for stage, than those with lower levels. (See "Pathology and prognostic determinants of colorectal cancer", section on 'Preoperative serum CEA'.)

Elevated preoperative CEA levels that do not normalize following surgical resection imply the presence of persistent disease and the need for further evaluation. (See "Surveillance after colorectal cancer resection", section on 'Carcinoembryonic antigen'.)

Furthermore serial assay of postoperative CEA levels should be performed for five years for patients with stage II and III disease if they may be a potential candidate for surgery or chemotherapy if metastatic disease is discovered. A rising CEA level after surgical resection implies recurrent disease and should prompt follow-up radiologic imaging. (See "Surveillance after colorectal cancer resection".)

Blood-based tests for early detection of CRC, or to monitor for postoperative recurrence, are under active development at present. Amongst the contenders are Sept9 [65] and the Gemini test [66,67].

DIFFERENTIAL DIAGNOSIS — The signs and symptoms associated with colorectal cancer (CRC) are nonspecific, and the differential diagnosis, particularly among patients presenting with of abdominal pain and rectal bleeding, is broad. (See "Causes of abdominal pain in adults" and "Etiology of lower gastrointestinal bleeding in adults" and "Evaluation of occult gastrointestinal bleeding" and "Approach to acute lower gastrointestinal bleeding in adults".)

Many conditions cause signs or symptoms that are similar to colorectal adenocarcinomas including other malignancies as well as benign lesions such as hemorrhoids, diverticulitis, infection, or inflammatory bowel disease. The risk of CRC posed by particular symptoms has been addressed in the following studies:

A meta-analysis of 15 studies concluded that the sensitivity of individual symptoms (change in bowel habits, anemia, weight loss, diarrhea, abdominal mass) for the diagnosis of CRC was poor (ranging from 5 to 64 percent), and specificity was limited, as would be expected for a low-prevalence disease [68]. However, the specificity was >95 percent for dark red rectal bleeding and for the presence of a palpable abdominal mass on examination, indicating that patients without CRC rarely have these findings and suggesting that the presence of either makes the diagnosis of a CRC likely.

The association between constipation and CRC was addressed in a meta-analysis of 28 cross-sectional surveys and cohort studies, which demonstrated no increase in the prevalence of CRC among individuals with constipation as the primary indication for colonoscopy [69].

A population-based case-control study of clinical features before diagnosis of CRC conducted in 21 primary care practices in Exeter, Devon in the United Kingdom included 349 patients over the age of 40 who were diagnosed with CRC over a four-year period and 1744 controls without CRC who were matched by age, sex, and general practice [9]. Primary care records for two years before diagnosis were reviewed to ascertain symptoms. Of the 349 cases studied, 210 (60 percent) had tumors at or distal to the splenic flexure, and 126 (36 percent) were proximal to it, with the remainder having multiple or unknown sites. Ten features were associated with CRC before diagnosis; in univariate analysis, the likelihood ratios for CRC according to symptoms were: rectal bleeding 10, weight loss 5.1, abdominal pain 4.5, diarrhea 3.9, constipation 1.8, abnormal rectal examination 18, abdominal tenderness 4.6, hemoglobin <10 g/dL 9.5, and positive fecal occult blood 31. The positive predictive values (PPVs) for abdominal pain, constipation, diarrhea, weight loss, and rectal bleeding were higher for older patients (70 and over), especially rectal bleeding. When symptoms were combined, the PPV was highest (>10) for hemoglobin <10 g/dL combined with abdominal tenderness. The very high PPV for a positive fecal occult blood test validates the policy of prompt investigation of patients with positive fecal occult blood tests, particularly if symptomatic. (See "Tests for screening for colorectal cancer: Stool tests, radiologic imaging and endoscopy", section on 'Stool-based tests'.)

Another systematic review of 62 studies assessing the relationship between symptoms and CRC used estimates of sensitivity and specificity to calculate a diagnostic odds ratio (DOR = [sensitivity/(1-sensitivity)]/[(1-specificity)/specificity]), which provided a single summary measure of accuracy for each symptom; a high DOR indicates a high correlation between the symptom and the disease, while a DOR of one means that the symptom presence is no better than chance in discriminating between disease and non-diseased patients [70]. The DORs, sensitivity, likelihood ratio of having the disease if the symptom was present, and likelihood of having CRC in the absence of the symptom for a variety of symptoms are outlined in the table (table 3). The authors concluded that only rectal bleeding and weight loss were associated with the presence of a CRC and even these had relatively low DORs.

The differential diagnosis of a colonic mass as seen on radiographic or endoscopic studies includes a number of benign and malignant disorders, the differentiation of which can generally requires biopsy and histologic evaluation (table 4). In particular, rare malignancies other than adenocarcinomas that are primary to the large bowel include Kaposi sarcoma (KS), lymphomas, carcinoid (well-differentiated neuroendocrine) tumors, and metastases from other primary cancers. (See "Pathology and prognostic determinants of colorectal cancer", section on 'Histology and immunohistochemistry'.)

Disseminated KS can involve the colon, particularly in patients with AIDS, manifested as characteristic violaceous macules or nodules [71]. (See "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis", section on 'Gastrointestinal tract'.)

Primary non-Hodgkin lymphoma of the large bowel most commonly arises in the cecum, right colon, or rectum and usually presents at an advanced stage in adults. Colonic lymphoma typically appears as a large solitary mass, although multiple polypoid lesions or diffuse involvement can occur [72]. (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas".)

Colonic carcinoid tumors are found most commonly in the appendix, rectum, and cecum, and they tend to develop at a younger age than adenocarcinomas of the colon. Appendiceal and rectal carcinoids, most of which are less than 2 cm, appear as submucosal nodules and tend to be indolent. In contrast, primary colonic carcinoid tumors can present as large apple-core lesions, which can be clinically aggressive and may metastasize. (See "Clinical characteristics of carcinoid tumors".)

Metastases from other primary cancers, most often ovarian cancer, can mimic a primary large bowel malignancy. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis", section on 'Differential diagnosis'.)

STAGING — Once the diagnosis of colorectal cancer (CRC) is established, the local and distant extent of disease is determined to provide a framework for discussing therapy and prognosis. A review of the biopsy specimen is important prior to making a decision about the need for clinical staging studies and surgical resection, especially for a cancerous polyp. Polyps with an area of invasive malignancy that have been completely removed and lack associated adverse histologic features (positive margin, poor differentiation, lymphovascular invasion) have a low risk of lymphatic and distant metastases; in such patients, polypectomy alone may be adequate. This is more easily determined if the polyp is pedunculated. (See "Approach to the patient with colonic polyps".)

TNM staging system — The Tumor Node Metastases (TNM) staging system of the American Joint Committee on Cancer/Union for International Cancer Control (table 5) is the preferred staging system for CRC [73]. Use of the older Astler-Coller modification of the Duke's classification is discouraged.

The most recent 2010 TNM staging classification includes a number of changes compared with the older 2002 classification [73]:

Subdivision of T4 lesions into T4a (tumor perforates the surface of the visceral peritoneum) and T4b (direct invasion or histologic adherence to other organs and/or structures).

Further substaging of stage II into IIA (T3N0), IIB (T4aN0), and IIC (T4bN0) disease.

N1 and N2 categories are subdivided according to the number of involved nodes.

Satellite deposits that are discontinuous from the leading edge of the cancer and lack evidence of a residual lymph node are classified as N1c disease.

Several stage groupings of stage III disease have been revised based upon refinement in prognostic stratification.

M1 is subdivided into M1a for single metastatic site and M1b for multiple metastatic sites.

These changes were supported by analysis of data on both colon and rectum cancer from the population-based Surveillance, Epidemiology and End Results (SEER) registry [74,75]. However, the revised edition of the TNM staging classification is not used in all countries. As examples, in some areas of the Netherlands, the fifth edition of the TNM staging classification is still used purposely for rectal cancer as later modifications were not considered to represent an improvement, whereas in Japan, none of the revised criteria on satellite deposits that lack evidence of a residual lymph node were adopted in the seventh edition of the National Cancer Staging Manual edited by the Japanese Society for Cancer of the Colon and Rectum because of the lack of sufficient justification for this change [76].

Radiographic, endoscopic, and intraoperative findings can be used to assign a clinical stage, while assessment of the pathologic stage (termed pT, pN, pM) requires histologic examination of the resection specimen. Preoperative radiation and chemotherapy can significantly alter clinical staging [77]; as a result, post-therapy pathologic staging is designated with a yp prefix (ie, ypT, ypN). (See "Pathology and prognostic determinants of colorectal cancer".)

Clinical staging evaluation — Preoperative clinical staging is best accomplished by physical examination (with particular attention to ascites, hepatomegaly, and lymphadenopathy, and potential fixation of rectal cancers), computed tomography (CT) scan of the abdomen and pelvis, and chest imaging. Although frequently obtained preoperatively, liver enzymes may be normal in the setting of small hepatic metastases and are not a reliable marker for exclusion of liver involvement (picture 3). The single most common liver test abnormality associated with liver metastases is an elevation in the serum alkaline phosphatase level [78].

CT scan — In the United States and elsewhere, the standard practice at most institutions is that all patients with stage II, III, or IV CRC undergo chest, abdomen, and pelvic CT, either prior to or following resection, an approach endorsed by the National Comprehensive Cancer Network. In general, it is preferable to obtain these scans prior to, rather than after surgery, as the scan results will occasionally change surgical planning.

Abdomen and pelvis — In patients with newly-diagnosed CRC, preoperative abdominal and pelvic CT scans can demonstrate regional tumor extension, regional lymphatic and distant metastases, and tumor-related complications (eg, obstruction, perforation, fistula formation) [79,80]. The sensitivity of CT for detecting distant metastasis is higher (75 to 87 percent) than for detecting nodal involvement (45 to 73 percent) or the depth of transmural invasion (approximately 50 percent) [79,81-85]. The sensitivity of CT for detection of malignant lymph nodes is higher for rectal than for colon cancers; perirectal adenopathy is presumed to be malignant since benign adenopathy is typically not seen in this area in the absence of demonstrable inflammatory process (eg, proctitis, fistula, perirectal abscess) [86].

CT scan is not a reliable diagnostic test for low-volume tumor on peritoneal surfaces [87]. The sensitivity of CT for detecting peritoneal implants depends on the location and size of the implants. In one study, the sensitivity of CT for nodules <0.5 cm was 11 percent and it was only 37 percent for implants 0.5 to 5 cm [88].

Although commonly obtained, the necessity of preoperative abdominal/pelvic CT for all patients with CRC is debated. In a retrospective review of 180 resected patients, only 3 of 67 patients had incidental findings on CT that altered the surgical approach [84]. Assessment of hepatic metastases by intraoperative ultrasound and manual palpation of the liver may provide a better yield than preoperative CT, particularly for patients who are found to have transmural involvement (T3/4) at the time of exploration [89-91]. However, the increasing use of laparoscopic colonic resections precludes manual palpation, and even with open procedures surgeons may not have adequate access to the liver depending upon the location of the incision and the extent of adhesions from prior surgery.

The finding of liver metastases on preoperative studies may not necessarily alter the surgical approach to the primary tumor, particularly in patients who are symptomatic from their primary tumor (eg, bleeding, impending obstruction). In patients with four or fewer hepatic lesions, resection may be curative, with five-year relapse-free survival rates of 24 to 38 percent. Although most surgeons advocate resection of the primary tumor and synchronous hepatic metastases at two different operations, some approach both sites at the same time. (See "Management of potentially resectable colorectal cancer liver metastases".)

Chest — The clinical benefit of routine clinical staging with chest CT is also controversial. At least in theory, imaging of the chest might be of more value for rectal cancer since venous drainage of the lower rectum is through the hemorrhoidal veins to the vena cava, bypassing the liver, and lung metastases might be more common [92].

The major issue is the frequent finding of indeterminate lesions (10 to 30 percent), which add to the clinical complexity (ie, should further preoperative diagnostic workup be undertaken) but are seldom malignant (7 to 20 percent). A systematic review of 12 studies including 5873 patients undergoing staging for a newly diagnosed CRC [93] found that 732 (9 percent) had indeterminate pulmonary nodules on preoperative chest CT. Of these, 80 (11 percent) turned out to be colorectal metastases at follow-up. Generally, the presence of regional nodal metastases at the time of resection, multiple numbers of indeterminate pulmonary nodules, size ≥5 mm, rectal as compared with colon cancer, parenchymal versus subpleural location of the nodule, and distant metastases elsewhere were significantly associated with malignancy, while calcification was associated with a benign etiology. Overall, the risk of malignancy for most patients with indeterminate pulmonary nodules (approximately 1 percent) seems sufficiently low that further preoperative diagnostic workup is unnecessary.

Liver MRI — Contrast-enhanced magnetic resonance imaging (MRI) of the liver can identify more hepatic lesions than are visualized by CT, and is particularly valuable in patients with background fatty liver changes [94]. A meta-analysis concluded that MRI is the preferred first-line imaging study for evaluating CRC liver metastases in patients who have not previously undergone therapy [95]. However, newer-generation CT scanners and the use of triple-phase imaging during contrast administration has improved sensitivity of CT for detection of liver metastases. In current practice, liver MRI is generally reserved for patients who have suspicious but not definitive findings on CT scan, particularly if better definition of hepatic disease burden is needed in order to make decisions about potential hepatic resection. (See "Management of potentially resectable colorectal cancer liver metastases", section on 'Patient selection'.)

PET scans — Positron emission tomography (PET) scans do not appear to add significant information to CT scans for routine preoperative staging of CRC [96,97]. The established role of PET scanning in patients with CRC as an adjunct to other imaging modalities is described in the following settings:

Localizing site(s) of disease recurrence in patients who have a rising serum carcinoembryonic antigen (CEA) level and nondiagnostic conventional imaging evaluation following primary treatment. In this setting, PET scanning can potentially localize occult disease, permitting the selection of patients who may benefit from exploratory laparotomy [98-101]. (See "Surveillance after colorectal cancer resection".)

In an illustrative series, 105 such patients underwent PET scanning and subsequent abdominopelvic CT scans [98]. Compared with CT and other conventional diagnostic studies, PET scanning had a higher sensitivity (87 versus 66 percent) and specificity (68 versus 59 percent) for the detection of clinically relevant tumor. In a second report, PET scan findings led to a potentially curative resection in 14 of 50 patients (28 percent) with elevated serum CEA levels and a completely normal or equivocal conventional diagnostic work-up [99].

Evaluation of patients who are thought to be present or future candidates for resection of isolated CRC liver metastases. The routine use of PET prior to attempted resection reduces the number of nontherapeutic laparotomies. (See "Management of potentially resectable colorectal cancer liver metastases", section on 'PET scans'.)

Recent chemotherapy may alter the sensitivity of PET for the detection of colorectal liver metastases, an effect thought related to decreased cellular metabolic activity of the tumor. However, generally, the benefit of a PET scan is to detect extrahepatic metastases in patients considered liver resection candidates, and in this situation, it is appropriate to obtain a PET prior to initiation of chemotherapy. This subject is addressed in detail elsewhere. (See "Management of potentially resectable colorectal cancer liver metastases", section on 'PET scans'.)

Locoregional staging for rectal cancer — An accurate determination of tumor location within the rectum and disease extent is necessary prior to treatment in order to select the surgical approach and to identify those patients who are candidates for initial chemoradiotherapy prior to surgery. (See "Neoadjuvant chemoradiotherapy and radiotherapy for rectal adenocarcinoma", section on 'Indications for neoadjuvant treatment'.)

Digital rectal examination (DRE), rigid sigmoidoscopy, transrectal ultrasound, transrectal endoscopic ultrasound, and pelvic MRI can all assist in determining the need for radical resection versus local excision, and whether the patient is a candidate for preoperative therapy. This subject is discussed elsewhere. (See "Pretreatment local staging evaluation for rectal cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Colon and rectal cancer (The Basics)")

Beyond the Basics topics (see "Patient education: Colon and rectal cancer (Beyond the Basics)" and "Patient education: Colorectal cancer treatment; metastatic cancer (Beyond the Basics)")


Patients with colorectal cancer (CRC) may present in three ways (see 'Clinical presentation' above):

Patients with suspicious symptoms and/or signs

Asymptomatic individuals discovered by routine screening (see "Screening for colorectal cancer: Strategies in patients at average risk")

Emergency admission with intestinal obstruction, peritonitis, or rarely, an acute gastrointestinal (GI) bleed

Although the increasing uptake of CRC screening has led to more cases being diagnosed at an asymptomatic stage, most CRCs are diagnosed after the onset of symptoms (most commonly rectal bleeding, abdominal pain, otherwise unexplained iron deficiency anemia and/or a change in bowel habits). A change in bowel habits is a more common presenting symptom for left-sided as compared with right-sided cancers. Hematochezia is more likely with rectal than colon cancers, and occult colonic bleeding is more common with cecal and ascending colon cancers. (See 'Symptoms from the local tumor' above.)

One in five patients with CRC presents with metastatic disease. The most common metastatic sites are the regional lymph nodes, liver, lungs, and peritoneum. (See 'Metastatic disease' above.)

Unusual presentations of CRC include malignant fistula formation, fever of unknown origin, sepsis from Streptococcus bovis and Clostridium septicum, and adenocarcinoma of unknown primary. (See 'Unusual presentations' above.)

A positive fecal occult blood test has a much higher predictive value for CRC than any single or combination of symptoms, warranting high priority for colonoscopic follow-up. (See 'Differential diagnosis' above.)

The vast majority of colon and rectal cancers are endoluminal adenocarcinomas that arise from the mucosa. Colonoscopy is the most versatile diagnostic test in symptomatic individuals (see 'Colonoscopy' above). Computed tomography (CT) colonography provides a similarly sensitive, less invasive alternative to colonoscopy in patients presenting with symptoms suggestive of CRC. However, given that colonoscopy permits removal/biopsy of the lesion and any synchronous cancers or polyps that are seen during the same procedure, colonoscopy remains the gold standard for investigation of symptoms suggestive of CRC. CT colonography is preferred over barium enema where access to colonoscopy is limited. (See 'Initial diagnostic test' above and 'Barium enema' above.)

In patients in whom for technical reasons the tumor cannot be reached by colonoscopy (eg, partially obstructing cancer, tortuous colon, poor prep) or because of patient intolerance, CT colonography can provide a radiographic diagnosis.

Once the diagnosis is established, the local and distant extent of disease spread is determined to provide a framework for discussing therapy and prognosis. Preoperative clinical staging is best accomplished by physical examination, CT scan of the abdomen and pelvis, and chest imaging. (See 'Clinical staging evaluation' above.)

Positron emission tomography (PET) scans do not appear to add significant information to CT scans for routine preoperative staging of a newly-diagnosed CRC except for the evaluation of patients who are thought to be candidates for resection of isolated CRC liver metastases. (See 'PET scans' above.)

Additional procedures (digital rectal examination [DRE], rigid sigmoidoscopy, transrectal endoscopic ultrasound, and/or magnetic resonance imaging [MRI]) are indicated for locoregional staging of patients with rectal cancer to select the surgical approach and to identify those patients who are candidates for initial radiotherapy or chemoradiotherapy rather than surgery. (See 'Locoregional staging for rectal cancer' above.)

There is no diagnostic role for routine laboratory testing in screening or staging CRC. However, serum carcinoembryonic antigen (CEA) levels should be obtained preoperatively and postoperatively in patients with demonstrated CRC to aid surgical treatment planning and assessment of prognosis. (See 'Tumor markers' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Dennis J Ahnen, MD, who contributed to an earlier version of this topic review.

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