Colorectal Adenocarcinoma

From Anvita Health Wiki

Contents 1 Introduction 2 Etiology 3 Epidemiology 4 Pathology 5 Genetics 6 Clinical-manifestations 7 Laboratory 8 Diagnostic-procedures 9 Radiology 10 Staging 11 Complications 12 Differential-diagnosis 13 Management 14 More General Terms 15 Additional Terms 16 Internet Database 17 References

Introduction

• The second leading cause of death due to cancer in the US, in men after lung cancer & in women after breast cancer.

Etiology

• ( risk factors)

• diet: proposed predisposing factors include

• increased consumption of animal fats
• increased consumption of animal protein
• low-fiber diets [18,40]

• whole grain & cereal fibers linked with lower risk for colorectal cancer
• fruits, vegetables, & legumes are not [40]

• low Ca+2 & low Mg+2 [16] diets
• low vitamin 25-OH vitamin D [32], low vitamin B6 [31]
• diet of fat & sweets associated with recurrence [24]
• coffee & soda not risk factors; tea maybe [33]

• genetics

• intestinal polyposis syndromes

• familial adenomatous polyposis
• hereditary nonpolyposis colon cancer
• familial hamartomatous polyposis

• Peutz-Jeghers syndrome
• juvenile polyposis

• inflammatory bowel disease

• ulcerative colitis
• Crohn's disease

• first degree relatives: 2-3 fold increased risk in the absence of other associated syndromes

• adenomatous polyps; serrated, tubular, villous; not hyperplastic polyps [29]
• history of other cancer

• breast cancer
• ovarian cancer
• endometrial cancer
• prostate cancer

• other etiologic factors:

• uterosigmoidostomy
• Streptococcus bovis bacteremia
• Fusobacterium species, particularly F. nucleatum, may play a role [39]
• cholecystectomy
• acromegaly
• radiation injury to colon

• age > 50 years is risk factor

Epidemiology

• 11% of solid tumors in men
• 14% of solid tumors in women
• 2nd most common cause of death from cancer in men
• 3rd most common cause of death from cancer in women
• incidence race-dependent 31-57/100,000, blacks > non-Hispanic > whites > Hispanic > Asian/Pacific Islanders > American Indian/Alaska Natives [30]

Pathology

• the majority of colorectal carcinomas begin as adenomatous polyps
• prevalence of adenomatous polyps increases with age to > 25% in patients over the age of 50
• most lesions are left sided, but not all right-sided lesions have synchronous left-sided lesions [5]
• 42% of all tumors were located in the proximal colon [30]
• metastases

• regional lymph nodes (53)

• rectal carcinomas metastasize early because of extensive lymphatic drainage

• liver via the portal venous circulation (44%)
• lungs (16%)

• rectal carcinoma may metastasize via the paravertebral venous plexus to the lungs & supraclavicular nodes

• bone (27%)
• brain (11%)
• skin (5%)
• adrenal (31%)
• kidney (16%)

• 37% diagnosed as localized disease, 55% as regional or distant disease, 7% unstaged

Genetics

• familial adenomatous polyposis coli ( APC-gene)
• deleted in colon carcinoma ( DCC) gene
• mutated in colon carcinoma ( MCC) gene
• mutation in k-ras proto-oncogene
• P53 tumor suppressor gene
• defects in PDGFRL are associated with colorectal cancer
• microsatellite instability

• occurs in the germline of patients with hereditary nonpolyposis colorectal cancer & in 15% of sporadic colorectal cancers
• may be associated with defects in AIM2

• oncogenes involved in sporadic colon cancer

• c-myc, c-src, ras, erbB2 [2]

• mismatch repair genes

• MLH1 (hereditary non-polyposis coli)
• MLH3, MSH2, MSH6, PMS1, PMS2
• AXIN2

• base excision repair genes:

• MYH

• susceptibility to colorectal cancer

• SMAP7 (type 3)

• abnormal transcripts of FHIT found in ~50%
• overexpression of SMYD3, TPBG, AAMP, NAV2, PLXNB1, TNFRSF6B, ADAMTS20, BIRC5, ARHGEF4
• underexpression of LLGL1, PDCD4, B3GNT6, CEACAM1
• other implicated genes ACRBP, WFDC2, SPECC1, ATAD2, GCNT3, KAAG1, RNF43, CHRDL2, HES2, PHF20, REG4, RET, ANLN, PRAF2, ARID4B, LEMD1, TAK1L, B3GNT8, ARHGAP8, PRR5, LRRC26, VWA2, LETMD1, OLFM4, MINA, PRAP1, SFRS19, MTUS1, TTYH2, TKT2, MAP2K3, MAP1D, BCL9L, KRT24, NF1, PHF19, XRRA1, PTPRH, CTNNB1, CCNDBP1, CASC2, CLCA1, CLCA2, PCNXL2, SLC5A8, UCHL3, PTPN12, PPAP2A, RUNX1T1, TP63, LEF1, EED, ZNF146, CCKBR, CD97, PPARG, EPHA3, WRN, MMP25, RAC1, EREG, WISP1, TSPAN8, AgSK1, SMAD2, SMAD3, SMAD7, MT-CO1, BRAF, MTHFD1, DYRK1B, ENPP7, ZNF306, TCF7L2

Clinical-manifestations

• often asymptomatic until late stages
• bowel-specific manifestations

• changes in bowel habits - tenesmus
• hematochezia ( rectal bleeding)
• abdominal pain, abdominal distension, pelvic pain
• palpable abdominal mass, rectal mass
• fistulas are rare
• right-sided lesions may not cause obstruction until late due to liquid nature of stool entering cecum
• digital rectal exam

• guaiac positive stool
• rectal may be felt, 30% of colorectal carcinomas arise from rectosigmoid area

• hepatomegaly
• systemic manifestations

• anemia
• fatigue
• weight loss
• fever may occur with metastasis to the liver

Laboratory

• complete blood count ( CBC) may show microcytic anemia
• iron studies may show iron-deficiency anemia

• serum iron, TIBC
• serum ferritin

• metastatic workup

• liver function tests
• serum carcinoembryonic antigen (CEA)
• direct relationship between CEA & Duke's stage
• CEA > 50 ng/mL is associated with poor prognosis
• elevated CEA is associated with greater likelihood of recurrence

• monitoring response to therapy

• liver function tests q6 months
• serum carcinoembryonic antigen (CEA) every 6 months for 1st 2 years, then annually therafter (see Management)
• stool guaiac every 6 months

• investigational:

• no benefit in tumor expression of thymidylate synthetase or TP53 [21]
• VWA2 may be serologic marker
• increased micro RNA expression associated with poor prognosis [26]

Diagnostic-procedures

• colonoscopy

• diagnostic procedure of choic
• screening & yearly monitoring response to therapy

• sigmoidoscopy every 6 months for rectal carcinoma monitoring response to therapy

Radiology

• screening (see screening for colon cancer)
• diagnostic tests

• air contrast barium enema
• single- contrast barium enema (barium only) is not adequate

• chest X-ray ( metastatic workup) & every 6 months monitoring response to therapy

Staging

• see staging of colorectal carcinoma

Complications

• Streptococcus bovis bacteremia
  
• disease interaction(s) of cancer with Alzheimer's disease

Differential-diagnosis

• hemorrhoids
• angiodysplasia
• diverticulosis
• rectal fissures
• inflammatory bowel disease

Management

• surgery

• metastatic workup prior to surgery (see laboratory)
• metastases precludes surgical cure, but surgery may

• relieve obstruction
• prevent bleeding [2]

• RT-PCR for guanylate cyclase-C ( intestinal-specific) in lymph nodes during surgery may predict metastases
• laparoscopic-assisted resection may be an option [17]
• limited distant recurrence may be amenable to for a second attempt at surgical cure in 25% of patients

• * see prognosis after surgical resection of colorectal carcinoma
• chemotherapy

• role is primarily palliative
• stage 3 colon cancer

• prolongs disease-free survival (Stage 3) [11]
• standard of care (Stage 3) [11]
• chemotherapeutic 5-fluorouracil +/- oxaliplatin ( FOLFOX)
• capecitabine +/- oxaliplatin [38]
• levamisole ( Ergamisole) has immunomodulatory activity
• irinotecan ( CPT-11) for 5-FU refractory disease

• metastatic colon cancer

• cetuximab as single agent

• increases survival [25] 6.1 vs 4.6 months for supportive care
• benefit only in KRAS mutation negative tumors [27]

• bevacizumab & cetuximab in combination with standard therapy improves survival [2]
• oxaliplatin is useful adjuvant agent [2]

• investigational therapies [11]

• irinotecan ( CPT-11) + 5-FU + leucovorin [11]
• irinotecan + cetuximab for irinotecan- refractory disease [11]]

• frail elderly may not benefit from chemotherapy [38]

• radiation therapy

• useful in conjunction with surgical excision of Dukes' stage B2 & C colorectal carcinoma
• inhibits metastasis to regional lymph nodes
• especially useful for rectal carcinoma [11]

• rectum lacks peritoneal covering
• local recurrence rate is high

• follow-up

• colonoscopy at 3 years, then at 3-5 year intervals [2] (non- metastatic colon cancer)
• air-contrast barium enema along with sigmoidoscopy may be an alternative to colonoscopy [2]
• serum carcinoembryonic antigen (CEA) for follow-up of stage 1

• every 6 months for the 1st 2 years, annually thereafter
• if serum CEA > 10 ng/mL, colonoscopy vs abdominal CT [11]

• CT of chest & abdomen every 6 months for 1st 3 years if patient would be eligible for surgical resection of metastases [19]

• prophylaxis

• aspirin, NSAIDs may diminish risk of colon cancer [13,14,34,35]

• see Nurses Health Study
• see aspirin & colorectal polyps
• USPSTF recommends against the routine use of aspirin & NSAIDs to prevent colorectal cancer [25]
• aspirin does not reduce mortality from colon cancer [28,34,35]
• dose-independent reduction in mortality due to proximal colon cancer & rectal cancer, but not distal colon cancer [37]

• Ca+2 & vitamin D

• may reduce risk of colorectal adenomas & colon cancer [15,22]
• no benefit in Women's Health Intiative

• 1000 mg Ca+2 plus 400 IU of vitamin D3 per day

• vitamin B6 may reduce risk of colon cancer [31]
• high-fat dairy products reduce risk, speculation that linoleic acid may be protective [20]
• about a quarter of colorectal cancers may be prevented by simple lifestyle choices [36]

• not smoking
• daily physical activity (30 minutes/day)
• no excessive drinking
• healthy diet
• waist circumference control

• < 40 inches men
• < 35 inches women

• screening (see screening for colorectal cancer)

More General Terms

• adenocarcinoma
• colorectal neoplasm

Additional Terms

• chromosomal deletion 18q23.3 (dcc)
• colorectal polyp
• intestinal polyposis syndrome; hereditary colorectal carcinoma
• molecular features of molecular adenocarcinoma
• PCR/southern blot/northern blot for colon cancer
• prognosis after surgical resection of colorectal carcinoma
• screening for colon cancer
• staging of colorectal carcinoma

Internet Database

OMIM: 114500
OMIM: 612229

References

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42. National Guideline Clearinghouse
    - Prevention
    - Routine aspirin and non-steroidal anti-inflammatory drug (NSAID) prophylaxis for colorectal cancer prevention. United States Preventive Services Task Force ngc-guideline: [48]
    - Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi- Society Task Force on Colorectal Cancer, and the American College of Radiology American Cancer Society ngc-guideline: [49]
    - Followup
    - Practice parameters for the surveillance and follow-up of patients with colon and rectal cancer. ngc-guideline: [50]
    - Chemotherapy
    - Oral capecitabine (Xeloda) in the first-line treatment of metastatic colorectal cancer (Program in Evidence-based Care) ngc-guideline: [51]
    - Use of irinotecan in the second-line treatment of metastatic colorectal carcinoma. (Program in Evidence-based Care) ngc-guideline: [52]
    - Use of raltitrexed (Tomudex) in the management of metastatic colorectal carcinoma Program in Evidence-based Care ngc-guideline: [53]
    - Cetuximab for the first-line treatment of metastatic colorectal cancer. National Institute for Health and Clinical Excellence (NICE) ngc-guideline: [54]
    - The role of Bevacizumab (AvastinT) combined with chemotherapy in the treatment of patients with advanced colorectal cancer: a clinical practice guideline. (Program in Evidence-based Care) ngc-guideline: [55]
    - Guidance on the use of capecitabine and tegafur with uracil for metastatic colorectal cancer. National Institute for Clinical Excellence (NICE) ngc-guideline: [56]
    - The role of oxaliplatin combined with 5-fluorouracil and folinic acid in the first and second-line treatment of advanced colorectal cancer: a clinical practice guideline. (Program in Evidence-based Care) ngc-guideline: [57]
    - Bevacizumab and cetuximab for the treatment of metastatic colorectal cancer. National Institute for Health and Clinical Excellence ngc-guideline: [58]
    - Surgery
    - Surgery for hepatic colorectal metastases ngc-guideline: [59]
    - Laparoscopic surgery for cancer of the colon: a clinical practice guideline. (Program in Evidence-based Care) ngc-guideline: [60]
    - Optimization of surgical and pathological quality performance in radical surgery for colon and rectal cancer: margins and lymph nodes. Guideline recommendations. Program in Evidence-based Care ngc-guideline: [61]
    - Management
    - Guidelines for the management of colorectal cancer. Association of Coloproctology of Britain and Ireland ngc-guideline: [62]
    - Practice parameters for colon cancer. American Society of Colon and Rectal Surgeons ngc-guideline: [63]
    - Colon cancer. (Intracorp) ngc-guideline: [64]
    - AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. American Gastroenterological Association Institute ngc-guideline: [65]
    - Diagnosis and management of colorectal cancer. A national clinical guideline. Scottish Intercollegiate Guidelines Network (SIGN) ngc-guideline: [66]
    - Radiology
    - Cross-sectional imaging in colorectal cancer. (Program in Evidence-based Care) ngc-guideline: [67]
    - PET imaging in colorectal cancer: recommendations. Program in Evidence-based Care ngc-guideline: [68]
    - Genetic testing
    - Recommendations from the EGAPP Working Group: can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group ngc-guideline: [69]
    - Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group ngc-guideline: [70]

adenocarcinoma of the colon &/or rectum