Clinical Features

Early-stage CRC is typically diagnosed only at the time of screening or other, unrelated colonoscopy and does not usually manifest with symptoms, signs, or other laboratory findings. Advanced cancers are more likely to result in clinical symptoms, including a change in bowel habits, constipation, abdominal distention, hematochezia, or tenesmus (rectosigmoid lesions). It is important to appreciate that these “colorectal-type” symptoms and signs apply predominantly to left-sided cancers; right-sided cancers often manifest insidiously with nonspecific systemic symptoms and signs such as fatigue, weight loss, and anemia. Only approximately 40% of patients have localized disease at presentation. Approximately 40% have regional metastases, and approximately 20% have distant metastases. Endoscopy with biopsy is the standard diagnostic approach. Computed tomography and magnetic resonance imaging (MRI) are used to assess depth of invasion, regional spread, and distant metastases; rectal MRI is the gold standard to assess the extent of local spread in rectal cancers, with transrectal ultrasound an alternative for early lesions.

A variety of screening recommendations have been proposed and endorsed by the American Gastroenterological Association, American Medical Association, and American Cancer Society ( Table 27.1 ). Standard guidelines are modified in individuals with a personal or family history of colorectal adenoma or carcinoma. Screening is clinically effective and cost-effective, yet its use remains relatively low. Screening colonoscopy provides the added benefit of polyp removal, and it is well established that polypectomy can prevent CRC. An estimated 90% of CRC deaths could potentially be prevented by implementing a combination of (1) strategies aimed at improving screening, polyp management, and early diagnosis of CRC; (2) lifestyle modifications, including dietary change and increased exercise; and (3) chemoprevention.

Incidence

Malignant epithelial tumors of the colon and rectum are the fourth most common cancer in men worldwide (after lung, prostate, and stomach), and the third most common in women (after breast and uterine cervix), accounting for 9.4% of all cancers in 2008, with more than 1 million new cases diagnosed each year. There is marked variation in the age-standardized incidence, with a 25-fold difference between high-risk regions (affluent countries including Australia, New Zealand, Europe, the Americas, and Japan) and low-risk regions (developing countries including Africa, India, and other parts of southeast Asia) ( Fig. 27.1 ). The likely role of environmental and lifestyle influences, particularly diet, alcohol intake, and physical activity, in the genesis of these differences is supported by abundant data. There are also significant global differences in the age at onset of CRC, with a mean age of only 50 years in developing countries.

Colorectal cancer incidence and mortality worldwide in 2012. The estimated age-standardized rates per 100,000 are shown for both males and females.

(From Globocan 2012. International Agency for Research on Cancer [IARC]. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx . Accessed January 14, 2014.)

In the United States, there were an estimated 103,170 new cases of colon cancer and 40,290 new cases of rectal cancer in 2012. CRC is the third most common cancer in both men and women and the fourth most common cancer overall, representing about 9% of all cancers. Overall, it is the second leading cause of cancer death, behind only lung cancer, and it is the leading cause of cancer death among nonsmokers. The lifetime risk for development of CRC is estimated at about 5%. U.S. Surveillance, Epidemiology, and End Results (SEER) Program statistics reveal an incidence of 30.45 per 100,000 for colon carcinoma and 12.16 per 100,000 for rectal carcinoma in 2009. CRC is significantly more common in men (combined age-adjusted incidence, 54.0 per 100,000, versus 40.2 per 100,000 in women); this difference is more striking for rectal cancer than for colonic cancer, and the increased incidence in men is apparent only after the age of 50 years. Despite the higher incidence in men, women live longer, so there are a similar number of total cases and cancer deaths in men and women. Since 1987, the incidence of colon cancer in the United States has been slowly falling. The incidence increases with age, with approximately 9% of cases occurring before age 50 years and only approximately 1% before age 35 years.

In addition to the global variation in CRC incidence, there are significant regional and ethnic differences in incidence within the United States. The incidence varies by approximately 1.5-fold between high-risk regions (predominantly the northeast Atlantic coast) and low-risk regions (predominantly the South and Midwest). Table 27.2 presents the differences related to racial and ethnic backgrounds. The incidence is highest among African Americans and lowest among individuals of Native American origin.

Epidemiology

The risk of CRC is influenced by both endogenous (constitutional) and exogenous (environmental) factors ( Table 27.3 ). For the practicing surgical pathologist, genetic predisposition and long-standing inflammatory bowel disease (IBD) have the most direct clinical impact, and these topics are discussed later. Age, as discussed previously, is the most powerful risk factor. CRC is predominantly a disease of late middle-aged and elderly individuals. The increased risk in males is thought to be related to differences in hormonal milieu.

Remaining risk factors are largely related to lifestyle and, importantly, are modifiable, suggesting the potential for interventions aimed at significantly reducing the incidence of CRC. The five most convincingly implicated lifestyle factors are obesity, physical activity, and ingestion of red meat, processed meat, and alcohol. Of these modifiable risk factors, diet has been the most extensively studied, and although there is little doubt that elevated risk is consistently associated with a “Western” type of diet, it has been difficult to determine which components are most important. Diets with a high calorie intake and those rich in meat, particularly animal fat, have been implicated in many studies. Possible mechanisms for this effect include the production of heterocyclic amines, stimulation of higher levels of fecal bile acids, production of reactive oxygen species, and elevated insulin levels. In addition to high-risk factors, there are inverse associations with vegetable and fiber consumption, although fiber falls out of some multivariate analyses when adjusted for other dietary risk factors. This effect could be related to anticarcinogens, antioxidants, folate, induction of detoxifying enzymes, binding of luminal carcinogens, fiber fermentation to produce volatile fatty acids, or reduced contact time with epithelium because of faster transit. Several studies, including a large pooled multivariate analysis, have found that high folate intake is associated with a decreased risk of CRC, providing some of the most direct evidence of dietary risk factor relationships. Finally, alcohol intake has been associated with an increased risk of CRC.

There is an inverse association between use of nonsteroidal antiinflammatory drugs and CRC risk. Smoking exposure is associated with CRC, although the relative risk is less than for many other tobacco-related cancers, and some studies consider cigarette smoking only a suggestive risk factor. Sedentary lifestyle, long-standing IBD (see Colitis-Associated Neoplasia ), pelvic irradiation, and ureterosigmoidostomy are also associated with an increased risk of CRC.

Finally, there is evidence that there are important differences in the epidemiologic risk factors associated with different subtypes of CRC. There has been a trend in recent years toward the development of more proximal cancers, which may relate to changes in epidemiologic risk factors. In fact, most of the lifestyle factors are associated specifically with increased risks of colon cancer, and only age and gender are predictive of an increased risk of rectal cancer. Furthermore, there are molecular biologic differences between right- and left-sided CRCs that would support different epidemiologic associations. More recently, research has focused on the complex interactions of hormones, energy balance, intestinal flora, and inflammation.

Genetic polyposis syndromes account for fewer than 0.5% of all incident CRCs ( Table 27.4 ). Nonpolyposis forms of hereditary colorectal carcinoma have a much higher overall contribution to the causation of CRC and are discussed in detail later in this chapter.

Pathogenesis

Genetic Model of Colorectal Cancer Progression

Human cancers are characterized by an accumulation of a variety of genetic alterations, including mutations that either activate oncogenes or inactivate tumor suppressor genes. This accumulation of genetic alterations is a critical event in the progression from adenoma to carcinoma and likely begins in aberrant crypt foci and other precursor cells that may not manifest morphologic features of neoplasms. To accumulate the array of genetic alterations typical of most CRCs, tumor cells must acquire mutations and epigenetic alterations at an increased rate compared with normal crypt epithelial cells. Increased acquisition and tolerance of mutations is a hallmark of CRC development, and is referred to as genome instability . Genes involved in the maintenance of the genome have been likened to “caretakers” of the genome. There are at least two general forms of genome instability important to the development of colorectal neoplasia: chromosomal instability (CIN) and microsatellite instability (MSI). The third major driving pathway for the development of CRC is the widespread accumulation of epigenetic gene silencing (CpG island methylator phenotype, or CIMP).

Chromosomal Instability.

CIN is characterized by a persistently increased rate of gains and losses of chromosomal material; it is present in 70% to 80% of CRCs. The acquisition of abnormalities in the number of whole chromosomes results in aneuploidy. In addition to whole-chromosome abnormalities, CRCs have other forms of somatic copy number abnormalities, including abnormalities of whole chromosomal arms as well as focal gains and losses. The underlying genetic basis of aneuploidy in human cancers is poorly understood, although most studies have focused on genes involved in regulation of mitotic spindle assembly and segregation. CIN is a major underlying genetic aberration in the conventional adenoma–carcinoma progression pathway and is therefore the predominant form of instability in left-sided neoplasms.

Microsatellite Instability.

MSI is characterized by widespread alterations in the sizes of repetitive DNA sequences. It is present in approximately 10% to 15% of CRCs. MSI is caused by defective DNA mismatch repair (MMR) ( Fig. 27.2 ) (see Hereditary Nonpolyposis Colorectal Cancer). In addition to alterations in the sizes of repetitive DNA sequences, MSI results in markedly increased rates of mutation of coding sequences (somatic hypermutation). In general, CRCs with MSI do not harbor abnormalities in chromosomal number or the focal regions of subchromosomal gains or losses that typify cancers with CIN. In most CRCs with MSI, the underlying defect in MMR function is caused by epigenetic CpG island hypermethylation of the promoter region of the MLH1 gene. This is a characteristic feature of many CRCs arising in the serrated neoplastic pathway, and most of these cancers are high-frequency CIMP (discussed later). MSI is also the mechanism that underlies the progression of Lynch syndrome cancers, which are caused by inherited defects in DNA MMR (see later discussion). In Lynch syndrome, MSI develops in conventional adenomas and drives rapid progression to cancer.

Breakdown of the molecular pathogenesis of an unselected population of colorectal cancers (CRCs). The numbers are an approximation based on current knowledge. CIMP , CpG island methylator phenotype; MSI-H , high-frequency microsatellite instability; MSI-L , low-frequency microsatellite instability; MSS , microsatellite stable.

CpG Island Methylator Phenotype.

CpG island methylator phenotype (CIMP) is the acquisition of widespread hypermethylation of CpG dinucleotides in the promoter regions of genes. Referred to as an epigenetic alteration (because it does not change the DNA sequence), this is a major mechanism of inactivation of tumor suppressor genes such as TP16 , CDHI , and MLH1 . Widespread CpG island methylation in a single cancer stands in stark contrast to the very limited methylation silencing that occurs in most CRCs and is known as high-frequency CIMP (CIMP-H). CIMP-H is a characteristic feature of CRCs that arise in the serrated pathway, and it is present in 20% to 30% of CRCs, including almost all cancers that also have MLH1 hypermethylation silencing. The underlying genetic basis of the CIMP-H phenotype is poorly understood, but there is evidence that genetic factors and environmental exposures (e.g., smoking, estrogen withdrawal) may be associated with the development of serrated pathway carcinomas. A working hypothesis is evolving wherein genetic and epidemiologic factors contribute to abnormal methylation events in serrated polyps of the right colon, which predisposes them to methylation silencing of MLH1 , MGMT , and other important genes. Presumably, these events drive progression from dysplasia to adenocarcinoma ( Table 27.5 ). The subsequent carcinomas that develop are referred to as “serrated” adenocarcinomas by some authorities (see later discussion), and they are often found to be MSI-H or CIMP-H, or both, on molecular phenotyping.

Table 27.5

Molecular Pathologic Classification of Colorectal Cancer

Proportion (%)	Precursor	CIMP Status	Mismatch Repair Status	Microsatellite Instability Status	MLH1 Gene Status	Chromosomal Status
75-80	Adenoma	CIMP-L/0	Proficient MMR	MSS/MSI-L	No methylation	Unstable (aneuploid)
40	Adenoma	CIMP-0	Proficient MMR	MSS	No methylation	Unstable (aneuploid)
30-35	Adenoma	CIMP-L	Proficient MMR	MSS	No methylation	Unstable (aneuploid)
5	Adenoma	CIMP-L	Proficient MMR	MSI-L	No methylation	Unstable (aneuploid)
10	Serrated adenoma/polyp	CIMP-H	Deficient MMR (sporadic)	MSI-H	Methylated	Stable (diploid)
2-3	Serrated adenoma/polyp	CIMP-L/0	Deficient MMR (sporadic)	MSI-H	Methylated	Stable (diploid)
5-10	Serrated adenoma/polyp	CIMP-H	Proficient MMR	MSS	No methylation	Stable (diploid)
2-3	Adenoma	CIMP-0	Deficient MMR (Lynch syndrome)	MSI-H	No methylation	Stable (diploid)

 

CIMP , CpG island methylator phenotype; -H , high frequency; -L , low frequency; MMR , mismatch repair; MSI , microsatellite instability; MSS , microsatellite stable.

Data from .

Implications of Progression Pathways for Screening and Prevention.

Screening colonoscopy is more effective for the prevention of left-sided than right-sided CRC, and this difference is thought to be caused by the predominance of the conventional adenoma–carcinoma progression pathway in the left colon compared with the serrated adenoma–carcinoma progression pathway in the right colon. The failure of screening to prevent right-sided colon cancer to the same degree as left-sided cancer appears to be related to the difficulties that exist in the endoscopic identification of SSA/Ps as well as their particular molecular pathogenetic characteristics. Serrated polyps are more difficult to completely excise, which could directly lead to colonoscopic screening failures. Serrated polyps are also at greater risk of undergoing rapid progression in a relatively small lesion, secondary to the acquisition of DNA MMR deficiency and MSI. Indeed, studies of interval cancers have found that they are much more likely to exhibit MSI and CIMP-H, both features of CRCs arising in the serrated pathway.

Molecular Pathway Classification of Colorectal Cancer.

A molecular-pathologic classification of CRC has been proposed that is based, in large part, on the presence or absence of CIN (i.e., CIN− versus CIN+; diploid versus aneuploid), the MMR status (microsatellite stable [MSS] versus MSI), and the status of the methylation pathway (CIMP+ versus CIMP−) (see Table 27.5 ). Although the clinical relevance of the aneuploid and (MMR)-deficient pathways has been delineated (see Prognostic Factors ), the possible clinicopathologic associations of the methylator pathway have not been as well defined.

WNT Signaling Abnormalities.

APC was first identified as the gene mutated in individuals with familial adenomatous polyposis. In this syndrome, affected individuals inherit one mutant copy of APC that is functionally inactive. In tumorigenesis, the second allelic copy of the APC gene is also inactivated, which fulfills Knudsen’s paradigm for tumor suppressor gene inactivation. APC mutations are also present in 70% to 80% of sporadic CRCs, where mutations occur early during neoplastic development, and even in dysplastic aberrant crypt foci. The apparent necessity of APC inactivation for the development of early adenomas has resulted in its designation as a “gatekeeper” gene of colorectal neoplasia.

APC is an important component of the Wingless (WNT) pathway, an evolutionarily conserved signaling cascade that is critical to embryonic development and intestinal epithelial renewal. APC mutations abrogate its role in binding β-catenin, thereby releasing β-catenin from phosphorylation regulation by glycogen synthase kinase-3β GSK3β and allowing it to accumulate in the nucleus, where it is involved in activating transcription of a number of other downstream targets, such as cyclin D and Myc. Recent microarray studies suggest that the transcriptional profile of β-catenin activation resembles the program of intestinal crypt stem cells. APC is also involved in cytoskeletal interactions, and, although the most important potential role in tumorigenesis has not been precisely defined, APC has been directly implicated in cell–cell adhesion, migration, chromosomal segregation (genome stability), and apoptosis.

Further evidence of the importance of WNT signaling abnormalities in colorectal tumorigenesis is evidenced by the presence of mutations in the β-catenin gene ( CTNNB1 ) in some tumors that lack APC mutations. In contrast to the inactivating APC mutations, the CTNNB1 mutations target amino acid residues integral to phosphorylation, resulting in oncogenic activation of WNT signaling. Finally, mutations have been rarely identified in other WNT signaling members in CRCs with wild-type APC, including AXIN1, AXIN2, and TCF4.

Other Genetic Alterations.

Activating mutations in KRAS are present in approximately 40% of CRCs and were one of the first genetic alterations described in any type of solid human tumor. KRAS mutations typically occur early, in aberrant crypt foci or small adenomas, and result in constitutive activation of the gene. KRAS mutations are a major determinant of response to anti-EGFR therapy (see Targeted Therapy ). Mutation and inactivation of the TP53 gene occurs in approximately 50% to 70% of carcinomas, often at the point of development of high-grade dysplasia. Among the most widely studied of human tumor suppressor genes, TP53 is important in the DNA damage response and the cell cycle arrest pathway.

Molecular Profiles of Colorectal Cancer.

Technologic advancements in the past 5 years have allowed major strides in the comprehensive analysis of human cancers. Although many studies focus on the results of one profiling technology, the potential advances of these approaches are most impressive when multiple methodologies are applied to individual tumors. The Cancer Genome Atlas has integrated multiple platforms, including exome sequencing, DNA copy number, promoter methylation, and messenger RNA (mRNA) and microRNA expression, as well as subset whole-genome sequencing, to develop comprehensive profiles of CRC. These profiles have provided remarkable insights into the molecular aberrations present in CRC, ranging from the grouping of cancers into distinct genome instability classes to the identification of 24 genes that are mutated at significant frequencies (including APC, TP53, SMAD4, PIK3CA, KRAS, ARID1A, SOX9, and FAM123B ) . In addition, potentially drug-targetable amplifications of ERBB2 and IGF2 have been found to be present in small subsets of cases, raising the possibility of novel therapeutic approaches personalized to these patients. These and other studies suggest that significant advances in biomarkers and personalized therapies may be achievable in the next 5 to 10 years.

Pathologic Features

Adenocarcinoma, Usual Type

Most adenocarcinomas are moderately to well differentiated or low grade. Typically, there are medium-sized to large glands, with moderate variability in gland size and configuration and a moderate amount of stroma ( Fig. 27.6 ). In well-differentiated tumors, the epithelial cells are usually tall and columnar and become increasingly cuboidal, or polygonal, with decreasing degrees of differentiation. Mitotic figures are usually abundant. Glandular lumina are usually filled with inspissated eosinophilic mucus as well as nuclear and cellular debris, so-called dirty necrosis ( Fig. 27.7 ). When dirty necrosis is present in a metastasis of unknown primary origin, this feature is sometimes used to infer a colorectal primary. In general, there tends to be little difference between the superficial and deeper portions of the tumor, although the leading edge is often associated with gland rupture and more frequent foci of small, irregular, and often infiltrative-appearing glands. Some tumors have a prominent papillary component, particularly at the surface. Desmoplasia can be prominent, as in cancers of the pancreas and biliary tract. In some instances, the appearance of desmoplasia is caused, in part, by extensive tumor necrosis and hyalinization. In addition to glandular cells, a variable number of Paneth cells, neuroendocrine cells, squamous cells, melanocytes, and trophoblasts can be found in usual adenocarcinoma. Typically, the presence of these other cell types has no prognostic significance.

A and B, Typical colorectal adenocarcinoma, showing irregular glands, some with luminal debris infiltrating a desmoplastic stroma.

Typical colorectal adenocarcinoma. There is a proliferation of complex glandular structures, with infolding and bridging of the epithelium. The cells have cylindrical to ovoid nuclei. The lumen contains abundant eosinophilic and nuclear debris (“dirty” necrosis). This pattern of necrosis is characteristic of colorectal adenocarcinoma.

Mucinous Adenocarcinoma

The World Health Organization (WHO) defines mucinous tumors by the amount of extracellular mucin (i.e., tumor composed of >50% mucin). The terms adenocarcinoma with mucinous features or adenocarcinoma with mucinous differentiation are often used to describe tumors that have a significant mucinous component (>10% but <50%). Most mucinous adenocarcinomas have free-floating strips of neoplastic epithelium or individual tumor cells in the mucin ( Fig. 27.8 ). A variable number of signet ring cells also may be seen ( Fig. 27.9 ). If more than 50% of the tumor is composed of signet ring cells, the tumor is best classified as “signet ring cell carcinoma” (or adenocarcinoma, signet ring cell type), even if more than 50% of the tumor is composed of extracellular mucin.

Mucinous adenocarcinoma. A, The tumor consists of pools of mucin and tumor with a cribriform growth pattern. B, Most of the mucin pools contain islands of free-floating tumor.

Mucinous adenocarcinoma with signet ring cell features. This tumor contains a mixture of “mucinous” and signet ring cell adenocarcinoma. Because the signet ring cell areas constitute less than 50% of the tumor volume, this is best classified as a mucinous adenocarcinoma. The presence of signet ring cells in mucinous carcinomas is quite common.

Mucinous adenocarcinomas represent approximately 10% of all colonic cancers. They are more common in young individuals and in patients with Lynch syndrome, and they are more likely to be at an advanced stage at presentation. The type of genetic alterations in these tumors suggests that the molecular pathogenesis is different from that of usual adenocarcinomas. Defects in DNA MMR and MSI-H are more common in mucinous adenocarcinomas, but a mucinous phenotype shows a low degree of sensitivity as a marker for this genotype. MSI-H mucinous tumors are found more often in younger individuals and are more likely to be exophytic and to have an expanding growth pattern, compared with non–MSI-H mucinous cancers. Immunohistochemical staining for TP53 is less frequently positive (30% versus >50% in the usual type of adenocarcinoma), which suggests that mucinous carcinomas are less likely to have a stabilizing point mutation in TP53 . Expression of HATH1, a transcription factor that activates MUC2 expression in intestinal epithelium, is maintained in both mucinous and signet ring cell carcinomas but is repressed in nonmucinous cancers, which indicates a possible biologic basis for mucinous neoplasms.

Mucinous tumors represent a greater proportion of right colon tumors and are more common in females. The cut surface is typically soft and gelatinous with little fibrous tissue, which imparts a “colloid” appearance to the tumor. The tumor is often composed of small nodules of mucin.

On microscopic examination, mucinous adenocarcinomas contain glandular structures or individual tumor cells embedded in pools of mucin; the mucin can be highlighted if necessary with periodic acid–Schiff or Alcian blue stains. The margins of the tumor are often dissecting and infiltrative, which probably contributes to the overall poor prognosis of patients with these tumors. In one series of 132 mucinous carcinomas, adjacent precursor adenomas were identified in 31%, a figure similar to that found in usual adenocarcinomas.

The association between mucinous subtype and survival is controversial. Whereas many studies have shown that these tumors are associated with a relatively poor prognosis, others have not. Some studies that have examined the behavior of mucinous tumors failed to differentiate mucinous from signet ring cell carcinomas, the latter being more aggressive. A recent meta-analysis showed that mucinous carcinomas do not manifest at a higher stage than usual adenocarcinomas, but there was a 2% to 8% increased hazard of death. Compared with usual adenocarcinomas, mucinous tumors are more likely to develop peritoneal implants and to invade adjacent viscera and less likely to be cured by surgical resection. They are also more likely to show lymph node involvement beyond the pericolonic region. Of likely greater importance is whether the mucinous tumor is MSI-H or MSI-L/MSS; MSI-H tumors are more likely to behave in a low-grade manner, whereas MSI-L/MSS tumors are more apt to be high-grade in behavior.

Signet Ring Cell Adenocarcinoma

Signet ring cell adenocarcinoma is defined as a tumor that is composed of at least 50% signet ring cells. For classification purposes, this feature supersedes the presence and amount of extracellular mucin. These tumors represent approximately 0.5% to 1.0% of all CRCs. They are slightly more common in men (male-to-female ratio, 1.3 : 1) and occur at a younger age (mean, 63.5 years). In some studies, more than 50% of signet ring cell adenocarcinomas were detected in individuals younger than 40 years of age. Signet ring cell carcinoma is also more common in ulcerative colitis, with approximately one third of tumors occurring in patients with this form of IBD.

Signet ring cell carcinomas constitute a greater proportion of right-sided colonic tumors. Synchronous tumors are found in 14% of patients. They are usually ulcerating, and approximately two thirds have an infiltrative gross appearance. A linitis plastica growth pattern occurs in up to 20% of cases.

Histologically, tumor cells show a characteristic mucin vacuole that pushes the nucleus to the periphery of the cell ( Fig. 27.10 ). A subset of signet ring cells are round and contain centrally located nuclei, without an apparent mucin vacuole. Compared with gastric signet ring cell carcinomas, those in the colorectum are more likely to be associated with abundant extracellular mucin and less commonly result in diffuse infiltration of the tissues. It can be difficult to differentiate colorectal signet ring cell carcinoma from metastatic gastric signet ring carcinoma on morphologic grounds, and immunohistochemistry is not helpful because tumors from both sites usually are negative for MUC1 and thyroid transcription factor 1 (TTF1) and positive for MUC2 and CDX2+. Metastatic lung tumors are typically MUC1/TTF1+ and MUC2/CDX2−.

Signet ring cell adenocarcinoma. A, There are sheets of signet ring cells. B, Signet ring cells infiltrating through the muscularis propria are highlighted by periodic acid–Schiff stain with diastase digestion.

Similar to mucinous carcinomas, signet ring cell carcinomas are more likely to be diagnosed at an advanced stage. Approximately 80% of patients have stage III or IV disease at the time of diagnosis. Full-thickness penetration of the muscularis propria and peritoneal seeding are more common than in usual adenocarcinomas (36% versus 12%). Some studies have reported distant metastases in as many as 60% of patients at the time of diagnosis. As a result, surgical resection is less likely to be curative. As with mucinous carcinomas, tumors that are MSI-L/MSS are more aggressive. Five-year survival rates of less than 10% are reported. Peritoneal carcinomatosis is present in virtually all patients who die of their disease; liver metastases are present in fewer than 50% of the cases.

Undifferentiated Carcinoma

The term undifferentiated carcinoma is essentially restricted to cancers that contain evidence of epithelial differentiation but are without obvious gland formation, although most undifferentiated tumors probably represent extremely poorly differentiated adenocarcinoma. Some authors accept this designation for tumors with a small component (<5%) of gland formation.

Undifferentiated cancers tend to be bulky and soft because of their high degree of cellularity and relative lack of desmoplasia, and there is often extensive necrosis. There are typically sheets of cells, cords, or trabecular structures, often with an infiltrative growth pattern ( Fig. 27.11 ). The degree of pleomorphism is variable; some tumors show relatively uniform cytologic features, whereas others show marked nuclear variability.

Undifferentiated carcinoma. A, There are sheets of tumor cells without gland formation; the cells were positive for cytokeratin 20 and negative for neuroendocrine markers. B, This area illustrates a trabecular growth pattern with possible gland formation focally.

Although pure undifferentiated cancers are rare, many adenocarcinomas contain an undifferentiated component. These types of tumors are best classified as adenocarcinoma and graded on the basis of the overall percentage of glandular elements. Nevertheless, the presence of an undifferentiated component increases the probability that the tumor contains a DNA MMR deficiency, particularly if it is associated with prominent tumor-infiltrating lymphocytes (see Carcinomas with DNA Mismatch Repair Deficiency ).

Medullary Carcinoma

Medullary carcinomas are characterized by sheets of polygonal cells with vesicular nuclei, prominent nucleoli, and abundant cytoplasm that are associated with numerous tumor-infiltrating lymphocytes ( Fig. 27.12 ). Tumor cells may have an organoid or a trabecular architecture, and focal mucin production may be present. These tumors are more common in women and typically occur in the cecum or proximal colon. Medullary carcinoma has also been referred to as “large cell minimally differentiated carcinoma.”

Medullary carcinoma. A, Low magnification reveals a solid tumor with a well-circumscribed margin at which abundant peritumoral lymphocytes are present. B, Tumor cells have large vesicular nuclei, prominent nucleoli, and amphophilic cytoplasm. There are numerous tumor-infiltrating lymphocytes.

Most medullary carcinomas are associated with a characteristic genomic profile. These tumors are less likely than usual CRCs to show KRAS and TP53 mutations, and they are more likely to harbor defects in DNA MMR (see Carcinomas with DNA Mismatch Repair Deficiency ). Even when it is present as a small subcomponent of the tumor, a medullary pattern is often predictive of an underlying DNA MMR deficiency. Immunophenotypically, these tumors are usually cytokeratin 20 (CK20) negative, are occasionally CK7 positive, and often show reduced CDX2 expression. Differentiation from other nonglandular, undifferentiated carcinomas is important, because medullary carcinomas have a more favorable outcome. Use of immunohistochemistry for calretinin may be helpful in this regard; in one study, calretinin was positive in 73% of medullary carcinomas but only 12% of poorly differentiated adenocarcinomas.

Serrated Adenocarcinoma

The term serrated adenocarcinoma has been used in two settings: to describe cancers that arise from hyperplastic or serrated precursor lesions, including both SSA/Ps and traditional serrated adenomas, and to describe cancers that have a distinctive serrated morphology. Consistent with their origin in the serrated pathogenetic pathway, serrated adenocarcinomas are more often proximal than conventional adenocarcinomas. Morphologically, these tumors are characterized by a variety of features; architecturally, there are epithelial serrations, and some degree of mucin production is common. In mucinous areas, tumor cells are often seen in the form of aggregated balls and pseudopapillary rods that project into mucinous areas. Tumor cells have abundant clear or eosinophilic cytoplasm, and the nuclei are vesicular with peripheral condensation of chromatin ( Fig. 27.13 ). Necrosis is uncommon or focal.

Serrated carcinoma. A, The glands in this adenocarcinoma show infoldings, and there is a prominent mucinous component. Within some mucin pools, there are “balls” of tumor cells and rod-shaped tumor cell clusters. B, Tumor cells have abundant eosinophilic cytoplasm with vesicular nuclei and small nucleoli.

Studies of the molecular pathogenesis of serrated carcinomas have revealed significant heterogeneity, although most of these tumors are associated with a high degree of methylation (CIMP). There are at least two major subtypes of serrated carcinomas: proximal MSI-H cancers that arise from sessile serrated polyps, and distal MSS/MSI-L cancers that arise from traditional serrated adenomas. In one study, only 16.1% of all serrated carcinomas were MSI-H, but 8.2% of the nonserrated adenocarcinomas were also MSI-H. Therefore, most proximal MSI-H cancers do not show histologically identifiable serrated features even though they are believed to arise, in large part, from serrated precursor lesions. In another study of more than 900 CRCs, 9.1% were classified as serrated adenocarcinomas, and about half of these had an identifiable serrated adenoma precursor. In this series, there was a trend toward decreased 5-year survival, particularly for left-sided cancers. Although the presence of a serrated precursor lesion should always be reported, it is probably best to reserve the term serrated carcinoma for tumors that show characteristic features in the malignant component of the tumor, recognizing that this is not considered a distinctive subtype in the current WHO classification and that further clinical validation studies need to be performed.

Carcinoma with Squamous Metaplasia (Adenoacanthoma)

Adenoacanthomas are rare. In one report, they were defined by the presence of adenocarcinoma elements with abundant admixed areas of benign-appearing squamous metaplasia ( Fig. 27.14 ). The natural history and treatment are similar to those of pure adenocarcinomas.

Carcinoma with squamous metaplasia. A, Typical adenocarcinoma with nests of squamous epithelium. B, Malignant glands merge with benign-appearing squamous epithelium.

Adenosquamous Carcinoma

Adenosquamous carcinomas are rare neoplasms, accounting for 0.06% of all CRCs in SEER data, although they were reported to be three times more common than pure squamous cell carcinomas in one series. An association with paraneoplastic hypercalcemia and parathyroid hormone–related protein has been reported with sufficient frequency that a colorectal adenosquamous primary should be considered in the differential diagnosis of this presentation. This tumor type has also been seen in the setting of chronic ulcerative colitis. There is an even distribution between the right and left colon. Morphologically, there are malignant squamous and glandular elements, either as separate components or admixed.

These cancers often have a higher stage at presentation than usual adenocarcinomas; in one study, 50% had metastases at the time of diagnosis. Although the overall survival rate in stage I/II disease is the same as in comparably staged adenocarcinoma, the rate for stage III/IV disease is significantly lower. The overall 5-year survival rate for all adenosquamous carcinomas is 31%.

Squamous Cell Carcinoma

Primary squamous cell carcinomas of the colorectum are rare; only 69 cases were reported before 1985, with most series reporting a prevalence of approximately 0.1% among all CRCs. The etiology and histogenesis are unknown. Most authorities favor an origin from pluripotent stem cells capable of multidirectional differentiation. Some have suggested derivation from foci of squamous metaplasia associated with chronic mucosal irritation. In two separate studies, all 31 cases were negative for human papillomavirus (HPV). One case of HPV-associated dysplasia and invasive squamous cell carcinoma of the rectum was described, suggesting a possible pathogenetic role for this virus in rare cases. Most primary squamous cell carcinomas manifest clinically at an advanced pathologic stage. The initial presentation is often at a more advanced patient age.

The pathologic features are similar to those of squamous cell carcinomas in other organs. Diagnosis of primary squamous cell carcinoma requires (1) exclusion of metastasis from other sites (particularly lung); (2) exclusion of an associated squamous-lined fistula tract (which, if present, is likely the site of origin); and (3) differentiation from carcinomas of the anus that extend proximally into the lower rectum. The 5-year survival rate for lymph node–negative squamous cell carcinomas is reported to be 85%. However, squamous cell carcinomas have been reported to have a worse prognosis than stage-matched adenocarcinomas.

Sarcomatoid Carcinoma (Spindle Cell Carcinoma, Carcinosarcoma)

Sarcomatoid carcinomas, also termed carcinosarcoma or spindle cell carcinoma, are more common in elderly patients, are often bulky or fleshy, and show abundant hemorrhage. Histopathologically, these tumors reveal a biphasic growth pattern that combines both epithelial and mesenchymal elements. Histologic areas of transition may be observed in some cases. The spindle cell component may be entirely undifferentiated, or it may show osseous, cartilaginous, or smooth muscle differentiation.

Similar to sarcomatoid carcinomas in other anatomic locations, these tumors usually express keratins and epithelial membrane antigen (EMA) in both the carcinoma and the spindle cell components. Carcinoembryonic antigen (CEA) positivity is usually limited to the adenocarcinoma element. Focal S100 and myoglobin positivity has also been described in some of these tumors. Metastases may show either or both cellular components. Evidence in favor of a common progenitor cell origin stems from confirmation of shared TP53 mutations in the epithelial and sarcomatoid components. Further subtyping into sarcomatoid carcinomas (which are keratin positive throughout the tumor) and carcinosarcomas (which are keratin negative in the mesenchymal component) has no apparent clinical or prognostic utility. These neoplasms are typically fast growing and aggressive.

Choriocarcinoma

Primary choriocarcinoma of the colorectum is rare. These cancers may manifest with massive bleeding from the gastrointestinal tract or from liver metastases. Microscopically, the tumor reveals a variable admixture of choriocarcinoma and adenocarcinoma elements. The choriocarcinoma component stains with human chorionic gonadotropin (β-hCG) and α-fetoprotein. On occasion, choriocarcinoma elements predominate in metastases when the primary tumor was only focally β-hCG positive. Increased serum levels of β-hCG and α-fetoprotein have also been reported. These cancers usually show metastasis to the liver at the time of clinical presentation and follow an aggressive clinical course.

Poorly Differentiated Neuroendocrine Carcinoma

Both small cell and, less frequently, large cell poorly differentiated neuroendocrine carcinomas can occur as a primary tumor of the colorectum, where they usually arise within an adenoma. These tumors typically manifest in younger patients compared with adenocarcinoma (mean age, 57 years), and they can arise anywhere in the colon or rectum. The morphologic features of these neoplasms are identical to those that occur in the lung. Immunohistochemistry usually demonstrates positivity for chromogranin or synaptophysin (and may be focal), the lesions may also show CDX2 positivity.

Poorly differentiated neuroendocrine carcinomas of the colorectum are aggressive tumors. Approximately 70% of patients have distant metastatic (stage IV) disease at presentation. The median survival time is 10.4 months, and the 3-year survival rate is 13%. A recent study showed that patients with neoplasms composed exclusively of large neuroendocrine cells survived longer than those with other morphologic subtypes.

Mixed Adenoneuroendocrine Carcinoma

In some cases, distinct separation of pure glandular from pure neuroendocrine tumors is blurred in neoplasms that show evidence of dual differentiation. At one end of the spectrum are adenocarcinomas that contain scattered endocrine cells and neuroendocrine tumors that contain scattered non-neuroendocrine mucinous tumor cells. These features are common and do not affect either tumor behavior or management; they do not warrant classification as distinct entities.

However, tumors that show a significant mixture of adenocarcinoma and neuroendocrine elements (>30% of each component) are referred to as mixed adenoneuroendocrine carcinomas . In these composite tumors, the adenocarcinoma and neuroendocrine components are, by definition, mixed intimately. Metastases may show both or only one of the cellular components. There are insufficient studies on the clinical behavior of mixed tumors.

In contrast to these mixed tumors, neoplasms that exhibit both neuroendocrine and glandular differentiation in individual cells are termed amphicrine neoplasms. On ultrastructural examination, these tumors show dense-core granules and mucin droplets in single cells. One variant in the colon has similar characteristics to appendiceal goblet cell carcinoid tumor. Some contain cells with multiple cellular phenotypes, such as goblet, endocrine, and Paneth cell differentiation ( Fig. 27.15 ). Because these tumors seem to recapitulate the characteristics of normal intestinal crypts, the term crypt cell carcinoma has been proposed. The malignant potential of these lesions has been well documented, and death is usually the result of intraabdominal rather than disseminated disease.

Mixed crypt cell carcinoma. A, There are relatively uniform glands with a mixed cellular population. B, Mucin stain highlights goblet cell differentiation. C, Chromogranin stain is positive in many tumor cells. D, Paneth cell stain highlights neoplastic Paneth cells.

Diffuse Carcinoma

Non–signet ring cell carcinomas in the colorectum may occasionally exhibit a diffuse pattern of growth similar to those that occur in the stomach. In one study, 15 (0.6%) of 2369 CRCs were “diffuse”; only 7 were signet ring cell type, whereas 8 were “lymphangiosis” type. The lymphangiosis type of diffuse cancer is an adenocarcinoma, often of moderate differentiation, with extensive lymphatic and vascular spread. As expected, the prognosis of this type of cancer is extremely poor.

Other Rare Subtypes of Colon Carcinoma

Melanotic adenocarcinoma of the anorectal junction has been reported as a rare primary tumor, although evidence supports phagocytosis of anal melanocytes rather than true melanocytic differentiation in the pathogenesis of these tumors. Clear cell carcinomas have been described in the colon; they have clear cytoplasm but lack cytoplasmic mucin ( Fig. 27.16 ). Strong CEA staining helps distinguish this tumor from a metastatic renal cell carcinoma.

Clear cell carcinoma. Infiltrating glands contain cells with prominent cytoplasmic clearing. This is typically a result of glycogen accumulation and not mucin.

Carcinomas with DNA Mismatch Repair Deficiency

Inactivation of DNA MMR pathways plays an important role in the pathogenesis of 10% to 15% of CRCs. Although some of these cases are the result of hereditary alterations in one or more of the MMR genes (see Hereditary Nonpolyposis Colorectal Cancer [HNPCC] and Lynch syndrome ), approximately 80% are sporadic, resulting primarily from promoter hypermethylation and silencing of MLH1 transcription. In addition to the characteristic MSI-H genetic alteration, these cancers reveal a variety of specific clinical and pathologic associations of importance to surgical pathologists (see Lynch Syndrome for discussion of immunohistochemical and molecular diagnostics).

Sporadic MMR-deficient MSI-H CRCs with MLH1 methylation silencing show a marked female predominance (about 4 : 1), increase in prevalence with age, and are particularly common in women older than 70 years. Approximately 90% of sporadic MLH1-deficient MSI-H CRCs are located in the right colon, where they constitute approximately 50% of all right-sided cancers in women older than 70 years of age. Precursor lesions often reveal characteristics of SSA/Ps in sporadic cases and conventional adenomas in hereditary cases (e.g., HNPCC). A number of specific pathologic associations have also been described in MSI-H CRCs, and many of these are similar to HNPCC cancers, which are also caused by DNA MMR deficiency ( Table 27.8 ). MSI-H cancers are also more likely to be multiple, to have a polypoid or exophytic growth pattern, and to show sharply circumscribed, pushing margins and marked grossly visible necrosis. Furthermore, MSI-H tumors are more likely to show mucinous or signet ring cell features, as well as microglandular differentiation. The association between these histologic features and DNA MMR deficiency is high, even when less than 50% of the tumor reveals these features. Therefore, the sensitivity and specificity of these histologic features for the diagnosis of MSI-H cancer vary according to the specific criteria used. The presence of a component of any one of the associated histologic variants (mucinous, signet ring cell, microglandular, or undifferentiated) or of a prominent tumor-infiltrating lymphocytic response provides a relatively sensitive threshold to identify possible MSI-H cancers.

The character of the host lymphoid response is another feature that shows a striking difference between MSI-H and MSS cancers. The presence of tumor-infiltrating lymphocytes ( Fig. 27.17 ) is highly predictive of MSI-H cancer, particularly when present in combination with an undifferentiated tumor (which may or may not be of the classic medullary subtype). In one study, the presence of at least 5 tumor-infiltrating lymphocytes per 10 high-power fields (HPFs) had a sensitivity of 93% and a specificity of 62% for the detection of MSI-H CRC. A number of complex algorithms have been proposed in an attempt to achieve a high degree of specificity for the presence of MSI-H in any single colon carcinoma. However, in one study, the pathologist’s “opinion” (based on an overall evaluation of the features described previously and his or her prior experience with known MSI-H cancers) was the best predictive factor. Overall, compared with MSI-H HNPCC–associated colon cancer, sporadic MSI-H cancers are more frequently het­erogeneous, poorly differentiated, mucinous, proximally located, and, as mentioned earlier, associated with a prominent tumor-infiltrating lymphocyte reaction.

Adenocarcinoma with numerous tumor-infiltrating lymphocytes. This tumor has an undifferentiated growth with focal trabecular architecture and numerous tumor-infiltrating lymphocytes. Such cancers often exhibit high-frequency microsatellite instability.

Clinically, patients with MSI-H CRCs are more likely to have an advanced T stage at presentation, but they are less likely to show regional lymph node metastases. In fact, most T4 N0 M0 CRCs are deficient in DNA MMR enzymes. When controlled for stage and other standard prognostic parameters, most studies have shown that MSI-H CRCs are associated with better overall survival compared with MSS colon cancers (see Molecular Genetic Markers ).

Villous Adenocarcinoma

Recently described, this subtype consists of more than 50% villous architecture. It accounted for 8.6% of all CRCs in one series. Fewer than half of the lesions had severe atypia, and differentiation from a benign adenoma with or without prolapse changes was made based on the presence of epithelial islands in desmoplastic stroma, which were present in almost all cases. Clinical follow-up of 35 cases revealed a favorable prognosis. Additional studies of diagnostic criteria and outcome are needed before novel management approaches can be considered.

Differential Diagnosis

Natural History

The overall survival rates for CRC at 1, 5, and 10 years are 83%, 64% and 58%, respectively. As with most solid tumors, survival correlates with the presence of locoregional disease and distant metastasis. For instance, the 5-year survival rate is 90% for patients with localized disease, 69% for those with regional metastases, and 12% for patients with distant metastasis. However, only 39% of new cases are diagnosed with only localized disease. Pathologic staging in colon cancer (AJCC system) is based on depth of invasion into the bowel wall and surrounding structures, spread to regional lymph nodes, and distant metastasis. With progression, tumors may penetrate the peritoneal lining, resulting in intraabdominal spread or invasion into other abdominal and pelvic structures. Spread through lymphatics or blood vessels may occur at any time (or stage) during the evolution of disease. With further progression, cancer may invade the portal vein tributaries, leading to liver metastases, or the vena cava, leading to lung and bone marrow as well as other distant metastases.

Treatment

Investigational Agents

In addition to the aforementioned agents, a number of other chemotherapeutic and biologic compounds are under investigation and development. Although this is more limited in terms of chemotherapeutic agents, there are ongoing or planned trials with new topoisomerase inhibitors and new platinum compounds. In comparison, a wide array of new targeted therapeutic agents are in phase II and III trials, including tyrosine kinase inhibitors, cyclooxygenase-2 inhibitors, matrix metalloproteinase inhibitors, and various forms of immunotherapy ( Table 27.11 ).

Table 27.11

Investigational New Targeted Therapeutic Agents in Colorectal Cancer *

Biologic Activity	Gene	Compound (Drug Class; Company)
Angiogenesis	VEGFR-2	Ramucirumab (monocloncal antibody; ImClone)
	VEGFR-2/FGFR/PDGF	BIBF1120 (RTKI † ; Boerhinger Ingelheim)
	Protein kinase C ( VEGF pathway)	Enzastaurin (small molecule inhibitor; Eli Lilly)
Tumor growth (EGFR pathway)	EGFR	Necitumumab (monocloncal antibody; BMS/Eli Lilly)
	EGFR/EGFR-2	BIBw 2992 (RTKI † ; Boerhinger Ingelheim)
Tumor growth (RAS-RAF-MEK-ERK pathway)	RAF	BMS-908662 (small molecule inhibitor; BMS)
	MEK	Selumetinib (small molecule inhibitor; AstraZeneca)
Tumor growth (IGF-1R pathway)	IGF-1R	Dalotuzuman (monoclonal antibody; Merck)
Tumor growth (PI3K-Akt-mTOR pathway)	mTOR	Everolimus (small molecule inhibitor; Novartis)
Apoptosis induction	TRAIL (TNFSF10)	Conatumumab (monoclonal antibody; Amgen)
	Eg5	LY2523355 (small molecule inhibitor; Eli Lilly)
Immune modulator	TLR9	MGN1703 (double-stem loop DNA immunostimulator; Mologen)
DNA repair	PARP	Veliparib (small molecule inhibitor; Abbott)

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