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colorectal adenocarcinoma

Friday 26 September 2003

colorectal cancer, colorectal adenocarcinoma, colonic adenocarcinoma, colorectal carcinoma; colonic carcinomas

Definition: Adenocarcinoma arising in the colon or rectum.

Colorectal carcinoma is one of the most common cancers and one of the leading causes of cancerrelated death in the United States. Pathologic examination of biopsy, polypectomy and resection specimens is crucial to appropriate patient managemnt, prognosis assessment and family counseling. Molecular testing plays an increasingly important role in the era of personalized medicine.

Colorectal carcinoma is the third most common cancer in the United States after prostate and lung/bronchus cancers in men and after breast and lung/bronchus cancers in women.

Colorectal carcinoma is also the third leading cause of cancer-related death in the United States after lung/bronchus and prostate cancers in men and after lung/bronchus and breast cancers in women.

In 2011, an estimated 141,210 new cases of colorectal carcinoma were diagnosed in United States, with an estimated 49,380 deaths, representing approximately 9% of all newly diagnosed cancers and all cancer-related deaths (excluding basal and squamous cell skin cancers).

Staging

- intramucosal colorectal adenocarcinoma
- invasive colorectal adenocarcinoma

Epidemiology

Colorectal cancer (CRC) is the second most common cause of cancer deaths in the United States. More than one million people are diagnosed with colorectal cancer (CRC) each year, and currently about half of these patients die from this disease.

Development of CRC is a multistep process that results from accumulation of (epi)genetic changes that affect biological functions required to maintain tissue homeostasis.

Pathology

More than 90% of colorectal carcinomas are adenocarcinomas originating from epithelial cells of the colorectal mucosa (3). Other rare types of colorectal carcinomas include neuroendocrine, squamous cell, adenosquamous, spindle cell and undifferentiated carcinomas.

Grading

Conventional adenocarcinoma is characterized by glandular formation, which is the basis for histologic tumor grading:
- In well differentiated adenocarcinoma >95% of the tumor is gland forming.
- Moderately differentiated adenocarcinoma shows 50-95% gland formation, with complicated glandular structures.
- Poorly differentiated adenocarcinoma is mostly solid with < 50% gland formation.
- In practice, most colorectal adenocarcinomas ( 70%) are diagnosed as moderately differentiated.
- Well and poorly differentiated carcinomas account for 10% and 20%, respectively.

It is apparent that the determination of tumor grade is a subjective exercise. Many studies have demonstrated that a 2-tiered grading system, which combines well and moderately differentiated to low grade (50% gland formation) and defines poorly differentiated as high grade ( < 50% gland formation), reduces interobserver variation and improves prognostic significance.

Though controversial, tumor grade is generally considered as a stage-independent prognostic variable, and high grade or poorly differentiated histology is associated with poor patient survival.

It should be emphasized, however, that histologic grading should apply only to conventional adenocarcinoma. Some of the histologic variants, which will be discussed later, may show high grade morphology but behave as low grade tumors because of their MSI status.

Invasion

The vast majority of colorectal carcinomas are initially diagnosed by endoscopic biopsy or polypectomy. The key aspect of microscopic examination is to look for evidence of invasion. However, this can be difficult when the biopsy is superficial or poorly oriented.

- muscularis mucosae

  • If the muscularis mucosae can be identified, it is important to determine whether it is disrupted by neoplastic cells.
  • Invasive carcinoma typically invades through the muscularis mucosae into the submucosa, and is sometimes seen in close proximity to submucosal blood vessels.

- desmoplasia

  • Another important feature of invasion is the presence of desmoplasia or desmoplastic reaction, a type of fibrous proliferation surrounding tumor cells secondary to invasive tumor growth.
  • Desmoplastic reaction is characterized by proliferation of spindle cells surrounding an adenocarcinomatous gland.

- dirty necrosis

  • Invasive colorectal carcinoma also frequently shows characteristic necrotic debris in glandular lumina, so-called “dirty necrosis”.
  • This unique feature can be quite useful to suggest a colorectal primary when a metastasis of unknown origin is encountered.
  • Necrotic debris (“dirty necrosis”) is seen within the lumina of adenocarcinomatous glands.

It should be noted that when a diagnosis of invasive carcinoma is rendered, it means that carcinoma has at least invaded into the submucosa of the colorectum.

This differs from the concept of invasion in other parts of the gastrointestinal tract (esophagus, stomach and small intestine), where the presence of mucosal invasion is sufficient for the diagnosis of invasive carcinoma (pT1).

Intramucosal vesus in situ WHO Tis

In the colorectum, submucosal invasion is required for the diagnosis of a pT1 tumor.

For reasons that are not entirely clear but generally thought to be due to the relative paucity of lymphatics, invasion confined to the lamina propria and muscularis mucosae has no risk of nodal or distant metastasis.

Thus, intramucosal carcinoma is preferably called "high grade dysplasia" (discussed later) by pathologists in order to avoid unnecessary surgical intervention.

In the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, mucosal invasion is classified as carcinoma in situ (Tis).

Nevertheless, the term of "intramucosal carcinoma" may still be used by some pathologists.

No matter what term is used by pathologists, the identification of "high grade dysplasia" or "intramucosal carcinoma" in a biopsy or polypectomy specimen should not affect the decision-making for patient management.

The decision to perform surgical resection should be ultimately determined by the gross appearance of the lesion, endoscopic ultrasound findings, and endoscopic resectability.

Types

In World Health Organization (WHO) classification, a number of histologic variants of colorectal carcinomas, such as:
- mucinous,
- signet ring cell,
- medullary,
- micropapillary,
- serrated,
- cribriform comedo-type,
- adenosquamous,
- spindle cell,
- undifferentiated.

Epidemiological types

- sporadic colorectal cancer
- familial colorectal cancer

Predisposition - Susceptibility

- hereditary nonpolyposis colorectal cancer (HNPCC)
- hereditary breast and colorectal cancer phenotype: 1100delC variant of the cell cycle checkpoint kinase CHEK2 gene was present in 18% of 55 families (12690581)

- adenomatous colorectal polyposis

- chronic colitis

  • ulcerative colitis-associated colorectal adenocarcinoma

- colorectal cancer predisposition genes

Staging

- See: colon cancer staging: colorectal adenocarcinoma staging

Pathology reporting

Most pathologists use standardized synoptic report for colorectal carcinoma following the checklist recommended by CAP.

The details that should be included in the report are:
- specimen type,
- tumor site,
- tumor size,
- macroscopic tumor perforation,
- histologic type,
- histologic grade,
- microscopic tumor extension,
- margins (proximal, distal and radial),
- treatment effect (for tumors treated with neoadjuvant therapy),
- lymphovascular invasion,
- perineural invasion,
- tumor deposits (discontinuous extramural extension),
- TNM staging (including the total number of lymph nodes examined and the total number of nodes involved).

Some pathology reports may also include:
- leading edge of the tumor (infiltrative or expansile),
- presence or absence of tumor budding,
- assessment of histologic features that are suggestive of MSI such as:

  • tumorinfiltrating lymphocytes,
  • peritumoral Crohn-like lymphoid response
  • percentage of mucinous component.

Specimen handling and sampling

See "Colon cancer specimen handling and sampling"

Precursor lesions

It has been well established that the vast majority of colorectal adenocarcinomas derive from precursor lesions such as colorectal adenomas and colorectal mucosal dysplasia.

Residual adenoma is a common finding in colorectal adenocarcinomas.

Endoscopic polypectomy decreases the incidence of colorectal cancers in treated population and prevents death from colorectal cancer.

Immunochemistry

The most widely used immunohistochemical markers for colorectal adenocarcinoma are cytokeratins (CKs) CK20, CK7 and CDX2.

- CKs

  • The most common immunophenotype of colorectal adenocarcinoma is positivity for CK20 and negativity for CK7, which is a relatively specific staining pattern for colorectal origin.
  • However, up to 20% of the tumors may exhibit a CK7-positive/CK20 negative or CK7-negative/CK20-negative staining pattern.
  • It has been suggested that reduced or absent CK20 expression in colorectal carcinoma is associated with MSI-H.

- CDX2

  • CDX2 is a marker of enteric differentiation and is positive in >90% of colorectal adenocarcinomas.
  • However, CDX2 can be positive in any carcinoma that shows enteric differentiation, and thus is not entirely colorectal-specific.
  • Interestingly, medullary carcinomas of the colorectum are frequently CK20-negative and CDX2-negative, in line with the concept of MSI.

Molecular biology

- somatic mutions

  • in APC gene
  • in PPARG gene

Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene play a rate-limiting role in the majority of sporadic CRCs by activation of the Wnt signal transduction pathway that stimulates transformation of normal colon epithelium resulting in formation of adenomas.

Moreover, APC mutations increase genetic instability which promotes accumulation of additional genomic alterations that enhance tumor progression and malignant behavior.

Critical regions

5q21-5q22 APC
8p21 -

CGH: 16145679

losses 4p 8p 17p 18q 14q
gains 1q 7p 8q Ch.11 12p 13q 17q Ch.19 Ch.20

Proteomics: 15237920

Biomarkers

Importantly, the development and progression of benign lesions into invasive and metastatic carcinomas is a complex process that takes many years, which provides a realistic window of opportunity for detecting colon adenomas and early stage (curable) CRC by screening of asymptomatic individuals.

To this end, low-cost easy to apply stool-based or serum-based tests with CRC related biomarkers are either widely used or under investigation.

Several randomized trials have shown that CRC screening using the fecal occult blood test (FOBT) reduces CRC incidence by about 20%, and CRC mortality by up to 33%.

Blood markers

The test performance of assays that measure blood proteins in feces leaves room for improvement for which novel biomarkers are urgently needed.

Protein biomarkers are well suited for development of in vitro diagnostic tests. One strategy to identify novel biomarkers for blood-based CRC detection is to compare protein content of serum samples from cancer patients to that of healthy control subjects.

Although the advantage of such an approach is that new biomarkers would be discovered directly in a biofluid that can be used for cancer screening, its discovery rate is seriously hampered by sample complexity.

The total dynamic concentration range of blood proteins spans 11 orders of magnitude, while current high-resolution mass spectrometry methods are only capable to detect proteins at concentrations that span up to 4 orders of magnitude, typically restricted to the most abundant proteins within a given biological sample.

Tumor-derived proteins are strongly diluted in the blood circulation, and therefore the concentration of the vast majority of these proteins in blood will fall below the detection limits.

Other complicating factors concern the diversity of human tissue and biofluid sample collections due to genetic and environmental heterogeneity of the human population.

Collectively, these confounding factors cause considerable biological variation between human samples, which significantly hampers biomarker discovery.

Proximal fluids

Concerning sample complexity, the concentration of tissue-excreted proteins is highest in fluids in close proximity to the tissue source itself, further referred to as ’proximal fluids’.

Proximal fluids contain proteins that are either secreted, shed by membrane vesicles, or externalized due to cell death. Therefore, proximal fluids provide a promising avenue for biomarker discovery.

Concerning sample heterogeneity, the use of inbred mouse models for human disease strongly reduces biological variation due to genetic and environmental heterogeneity.

Moreover, the initial molecular changes in disease pathogenesis in genetically engineered mouse models are well defined, and the stage of tumor development at the time of tissue- or biofluid-sampling is well controlled.

Videos

- Colorectal adenocarcinoma

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- Colorectal adenocarcinoma

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Links

- http://www.thejgo.org/article/view/410/821

References

- Chan TA. Prostaglandins and the colon cancer connection. Trends Mol Med. 2006 Jun;12(6):240-4. PMID: 16650804

- Mocellin S, Lise M, Nitti D. Targeted therapy for colorectal cancer: mapping the way. Trends Mol Med. 2005 Jul;11(7):327-35. PMID: 15950539

- Kemp Z, Thirlwell C, Sieber O, Silver A, Tomlinson I. An update on the genetics of colorectal cancer. Hum Mol Genet. 2004 Oct 1;13 Spec No 2:R177-85. PMID: 15358723

- de la Chapelle A. Genetic predisposition to colorectal cancer. Nat Rev Cancer. 2004 Oct;4(10):769-80. PMID: 15510158

- Baglioni S, Genuardi M. Simple and complex genetics of colorectal cancer susceptibility. Am J Med Genet C Semin Med Genet. 2004 Aug 15;129(1):35-43. PMID: 15264271

- Reymond MA, Steinert R, Kahne T, Sagynaliev E, Allal AS, Lippert H. Expression and functional proteomics studies in colorectal cancer. Pathol Res Pract. 2004;200(2):119-27. PMID: 15237920

- Rajagopalan H, Nowak MA, Vogelstein B, Lengauer C. The significance of unstable chromosomes in colorectal cancer. Nat Rev Cancer. 2003 Sep;3(9):695-701. PMID: 12951588

- Kerr D. Clinical development of gene therapy for colorectal cancer. Nat Rev Cancer. 2003 Aug;3(8):615-22. PMID: 12894249

- Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med. 2003 Mar 6;348(10):919-32. PMID: 12621137

- Rhodes JM, Campbell BJ. Inflammation and colorectal cancer: IBD-associated and sporadic cancer compared. Trends Mol Med. 2002 Jan;8(1):10-6. PMID: 11796261

- Bustin SA, Jenkins PJ. The growth hormone-insulin-like growth factor-I axis and colorectal cancer. Trends Mol Med. 2001 Oct;7(10):447-54. PMID: 11597519

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