Breast and colorectal cancer

Question 1

Risk Factors Breast Cancer

Answer 1

• Increasing age
• Female Gender
• Obesity - risk depends on menopausal status
  
  • Postmenopausal - increased risk
  • Premenopausal - reduced risk
• Taller stature
• High Estrogen Levels
• Breast Pathology
  
  • Benign breast disease (i.e., proliferative lesions) are associated with increased risk
  • Dense breast tissue
• Menopausal women - especially is women used hormone replacement therapy (combined estrogen and progesterone therapy; not estrogen alone)
• Ealier menarche or late menopause
• Nulliparity
• Older age at first pregancy
• Personal history of breast cancer - history of ductal carcinoma in situ or invasive or breast cancer increases risk of developing and invasive breast cancer in the contralateral breast.
• Family history of breast cancer
  
  • Specific genes: BRCA 1, BRCA 2, p53, ATM & PTEN
• Alcohol consumption
• Smoking
• Night shift work
• Exposure to therapeutic ionizing radiation

Question 2

Clinical Features Breast Cancer

Answer 2

• Signs and symptoms: Most people present with an abnormal mammogram, however, some present with an abnormal mass either not detected on mammogram or detected between mammograms.
• Breast mass - classic characteristics of a canerous lesions include a hard, immovable, single dominant lesions with irregular borders.
• Other signs - nipple discharge (usually benign - but if blood, from a single duct, or associated with breast it is increased risk cancer), breast pain, cyclic mastalgia
• Signs of locally advanced disease - axillary adenopathy or skin finding suggesting inflammatory breast cancer (eythema, thickening, or dimpling of the overlying skin - peau d’organge).
• Signs metastatic disease - symptoms depend on organs involved - common sites are the bone (back or leg pain), liver (abdominal pain, nausea, jaundice), and lung (SOB, cough).

Question 3

Pathology

Answer 3

• Most common histologic types of epithelial breast carcinoma:
  
  • Ductual carcinoma in situ (DCIS) - a heterogenous group of lesions that differ in their clinical presentation, histologic appearance, and biological potential. DCIS is charactertized by proliferation of malignant epithelial cells within mammary duct system, with no evidence of invasion into surrounding stroma on routine light microscopic examination
  • Infiltrating ductual carcinoma - most common type of invasive breast cancer. Lesions are characterized by cords and nests of cells with varying amounts of gland formation and cytologic features that range from bland to highly malignant.
  • Infiltrating lobular carcinoma - characterize by small cells that insidiously infiltrate mammary stroma and adipose tissue tissue individually in a single file pattern.
  • Mixed ductal/lobular carcinoma - mixed histologic appearance caomprising both ductal and lobular characteristics
  • Other types: metaplastic, mucinous, tubular, medullary, and papillary carcinomas.

Question 4

Mammogram characteristics of breast cancer

Answer 4

• Soft tissue mass/architectual distortion - ~90% of these lesions represent cancer. Tend to irregulary outlined, or have a less specific shape.
• Microcalcifications - Group microcalcifications are calcium particles of various size and shape measuring between 0.1 to 1 mm in diameter and numbering more than 4-5 per cubic centimeter. These are seen in ~60% of cancers.

Question 5

1. ER positive breast cancer
2. PR positive breat cancer

Answer 5

• ER carry a DNA binding domain and exist in the nucleus and cytosol. When estrogen enters the cell, it binds the ER & the complex migrates into the nucleus and leads to production of transcription proteins that induce cell changes. I.e., estrogen induces cell growth
• Cancer cells grow in response to progesterone
• Cancers that are ER/PR positive are more likely to respond to hormone therapy

Question 6

HER2 positive breast cancer

Answer 6

• Belongs to epidermal growth factors receptor family of proto-oncogenes. This proteins has been shown to form clusters with the cells membranes in malignant breast tumour. Overexpression is associated with rapid tumour growth, shortened survival, increase risk of recurrence after surgery and poor response to conventional chemotherapeutic agents.

Question 7

Treatment Breast Cancer

Answer 7

1. Surgery - breast conservation surgery (lumpectomy or wide local excision), masteoctomy (removal of entire breast, including fasica), axillary lymph node dissection (current evidence suggests it is unnecessary.
2. Radiation - whole or partial breast irradiation. May be used as an adjuvant to surgery to prevent reccurrence. Can also do radiation of metastatic disease.
3. Endocrine therpay - Some types of breast cancer are hormone sensitive. Most are ER positive and will respond to reduction of circulating estrogens
   
   • Antiestrognes - competitively binds ER and inhibits estrogen binding
   • Aromatase inhibitors - aromatase is responsible for estrogen synthesis
   • Ovarian ablation - induction of artifical menopause by ovariectomy significantly reduces breat cancer risk.
   • Ovarian suppresion - GnRH agonist can be used to reversibly suppress LH/FSH release and thus estrogen release
4. Chemotherapy - used in hormone receptor negative or HER2 positive brest cancers. Generally given as a neoadjuvant or adjuvant therapy.

Question 8

BRCA

Answer 8

• Most common cause of hereditary breast cancer is the presence of germline mutations in the tumour suppressor genes BRCA 1 and BRCA 2
• People tend to inherit one copy of the BRCA gene and experience another mutation later in life, known as a loss of heterozygosity.
• Autosomal dominant inheritance for increased risk of developing brest and ovarian cancer in women and breast and prostate cancer in men. (Generally cannot inherit 2 copies of the mutated genes - seems to be imcompatible with life).

Question 9

Breast Cancer Sceening

Answer 9

• Average risk: Women between ages 50-74 should get screened every 2 years with mammography
• High risk: Women between ages 30-69 at high risk for breast cancer should get annual breast mammography and MRI (or screening breast ultrasound if MRI is not appropritate).
  
  • Known to be a carrier of a gene mutation
  • First- degree relative of a mutation carrier, has nad genetic counselling and declined genetic testing
  • Assessed by genetic clinic as having ≥25% personal lifetime risk based on family history
  • Recieved radiation therapy to the chest (not X-ray) before age 30 and at least 8 years ago

Question 10

Classification of Cancers

Answer 10

1. Carcinoma - cancers arising from epithelial cells that cover surfaces such as the skin, lung, GI tract and any gland
2. Saroma - cancers arising from cells of the supporting tissues: bone, cartilage, fat, connective tissues, and muscle
3. Lymphoma - cancers arising within lymphoid tissues of the body’s immune system
4. Leukemia - cancers arising from immature blood cells in the bone marrow, that can spill over into the bloodstream
5. Glioma - cancers of the supporting cells of the CNA
6. Melanoma - cancer that develops from pigment - containing cells (melanoctyes).

Question 11

Colorectal Cancer (CRC)

Answer 11

• Development of cancer from the rectum or colon (majority are adenocarcinoma (malignant tumor formed from glandular structures in epithelial tissue)
• Originates from an adenoma (a benign tumour from glandular strutures in epithelial tissue) or flat dysplasia and evolve into different morphologic patterns with invasion and expansion

Question 12

CRC Right vs. Left Colon

Answer 12

• Tumours in proximal or right colon - Usually appear grossly as polypoid or fungaling exophylic masses. Occult bleeding may occur.
• Tumours in distal or left colon - usually annular or encircling lesions that produce an “apple core” appearance. Bowel lumen becomes constricted and narrowed, producing symptoms of bowel dysfunction (ex. constipation, diarrhea, or bowel obstruction).

Question 13

CRC Metastasis

Answer 13

• CRCs can spread by lymphatic and hematogenous dissemination, as well as continguous (sharing a common border) and transperitoneal spread.
  
  • Most common metastatic sites - regional lymph nodes, liver, and lungs.
  • Due to the venous drainage of the intestinal tract via the portal system, the first site of hematogenous dissemination is usually the liver, followed by the lungs, bone, and other sites. However, tumours from the distal rectum may metastasize initially to the lungs because the inferior rectal veins drain into the IVC rather than into the portal venous system.

Question 14

Clinical Presentation CRC

Answer 14

• May present in 3 ways:

1. Suspicious symptoms and/or signs - symptoms tend to be due to growt of tumour into luman or adjacent structures
2. Asymptomatic individuals discovered by routine screening - generally no symptoms at early stage
3. Emergency admission with intestinal obstruction, peritonitis, or acute GI bleed

Question 15

CRC symptoms of local tumour

Answer 15

• Changes in bowel habits
• Rectal bleeding - hematochezia or melena
• Rectal mass
• Iron deficiency anemia
• Abdominal Pain

Question 16

How to diagnose CRC

Answer 16

• If CRC is suspected from symptoms next step can be colonscopy, barium enemia, or computed tomography colongraphy. Howevere, the tissue needs to be examined for diagnosis which is done via colonscopy (can localize and biopsy lesion throughout the large bowel, detect synchronous neoplasms, and remove polyps).

Question 17

Treatment CRC

Answer 17

• Surgical Resection - can be used for localized colon cancer. Goal is to remove the tumour, the major vascular pedicle, and lymphatic drainage basin of the affected colon segment. In most patients, you are restore boewel continuity using primary anastomosis.
  
  • Neoadjuvant chemoradiotherapy or chemotherapy is common, as well as adjuvant chemotherapy.
• Metastatic disease can be treated with systemic chemotherapy as well as surgery if patient has limited metastatic disease.

Question 18

Genetic Issues CRC

Answer 18

• Most CRCs are sporadic, but some specific genetic disorders have been identified (mostly autosomal dominant)

1. Familial adenomatous polyposus (FAP) - characterized by presence of multiple colorectal adenomatous polyps
2. Lynch syndrome - hereditary nonpolyposis colorectal cancer

Question 19

Familial adenomatous Polyposus (FAP)

Answer 19

• Characterized by presence of multiple colorectal adenomatous polyps.
• Caused by germline mutations in the tumour suppressor gene, Adenomatous Polyposis Coli (APC).
• Autosomal dominant pattern with almost complete penetrance of colonic polyposis but variable penetrance of extracolonic manifestations of the disease.
• Need inactivity mutations of both APC alleles for development of adenomas in FAP (one mutation is inherited and the other is spontanous).
• Absence of functional APC proteins leads to transcriptional activation of Wnt signalling pathway and its target genes that control cell growth

Question 20

Extracolonic manifestations Familial adenomatous Polyposus (FAP)

Answer 20

• Upper GI tract, thyroid, heptoblastomas, desmoid tumours (noncancerous growths that occur in connective tissue).

Question 21

Lynch Syndrome

Answer 21

• Hereditary nonpolyposis colorectal cancer - accounts for 2-3% of colonic adenocarcinomas
• Caused by a defect in one of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) or the EPCAM gene. The role of the MMR system is to maintain genomic integrity by correcting base substituion mismatches. People with Lynch syndrome have a germline mutation in one allele of a MMR gene and the secon allele is inactivated somatically by mutation, loss of heterozygosity or epigenic silencing. Inactivation of MMR results in an increased mutation rate due to failure to repair DNA mismatches that occur during normal DNA synthesis.
• Lynnch syndrome is characterized by early age of onset and predominance of right sided lesions.

Question 22

Lynch Syndrome extracoloinc manifestations

Answer 22

• Extracolonic cancers are also very common in Lynch syndrome - endometrium, ovaries, stomach, small bowel, hepatobiliary system, brain, renal pelvis or ureters, and sebaceous neoplasms of the skin.

Question 23

Risk Factors CRC

Answer 23

• Genetic Predisposition - FAP, Lynch syndrome, or personal or family hisotry of sporadi CRCs or adenomatous polyps.
• Ulcerative colitis
• Crohns disease (less conclusive than UC)
• Abdominal radiation
• Cystic Fibrosis
• African American
• Acromegaly
• Renal transplantation
• Obesity
• Diabetes and insulin resistance
• Consumption of red and processed meat
• Smoking
• Alcohol

Question 24

Screening guidelines CRC

Answer 24

• Average risk - ages 50-74 with no first degree relative who has been diagnosed with colorectal cancer + no personal hisotry for pre-cancerous colorectal polys requrining surveillance or IBD
  
  • Fecal occult blood test (FOBT) every 2 years if asymptomatic
  • Abnormal FOBT should be followed up with colonscopy within 8 weeks
• Increased risk - people with family history for CRC that includes one or more first degree relatives who have been diagnosed with CRC, but dont meet criteria for colorectal hereditary syndrome
  
  • Asymptomatic people should get screened with colonscopy starting at age 50, or 10 years earlier than the age their relative was diangosed (whichever comes first), every 5 years with relative was diagnosed before 60 or 10 years if diagnosed after 60.
• Colorectal hereditary syndromes
  
  • Screening should begin at age 25 or 5-10 years younger than the youngest colorectal cancer diagnosis (colonscopy)