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After completing this module, students should be able to:

  1. Define what a good cancer screening test is.

Principles of Screening Tests

Screening is the process of identifying asymptomatic individuals with an elevated risk of cancer such that it warrants further diagnostic testing. Earlier identification of disease typically allows earlier diagnosis and treatment, which in turn may decrease mortality from the disease. A good screening test thus must enable both earlier diagnosis and delay of negative outcomes (morbidity and mortality).

The principles of a good screening test for cancer are [1]:

  • The cancer will be a major health problem (serious and common)
  • The cancer will be more treatable if detected early
  • The test should be acceptable to those eligible
  • The test should be inexpensive
  • The test should have high sensitivity (the vast majority of subjects with the cancer should test positive)
  • The test should have high specificity (the vast majority of subjects without the cancer should test negative)
  • Screening will have been shown to reduce mortality in randomized controlled trials

Colorectal cancer is the third most common malignancy in Canada for both men and women (1). The incidence and mortality of colorectal cancer is low until middle-age, but rises rapidly thereafter (2). Colorectal cancer is more common in men than in women, with a lifetime probability of developing colorectal cancer of 7.5% for men and 6.4% for women (1).

Colorectal cancer is also the second leading cause of cancer-related death, exceeded only by lung cancer (1), with 12% of all cancer-related deaths caused by colorectal cancer (3). In Canada, 1 in 29 men and 1 in 34 women are expected to die from colorectal cancer (3).

Anatomical Site

In the past, colon cancer was believed to almost exclusively affect only the left side of the colon. However, the incidence of right-sided colon cancer appears to be increasing in both North America and Europe. This trend in anatomical localization of disease affects both screening and treatment considerations.

Risk Factors


Age is the most important risk factor for developing colorectal cancer, with risk being significantly higher in patients over 50 years of age (1).

The majority of colorectal cancers occur in patients aged 50 years or older who are otherwise of average risk and have no significant family history (1).

Genetic Factors and Family History


The majority of cases of colorectal cancer are sporadic. Only 15-30% of patients with colorectal cancer appear to have a major hereditary component (4). Nevertheless, the risk of developing colorectal cancer is significantly higher in individuals with a family history of colorectal cancer or a known genetic syndrome associated with colorectal cancer.

Family History

Individuals with a single first-degree relative who was diagnosed with colorectal cancer before the age of 60 years have a significantly elevated risk of developing colorectal cancer themselves (1,3). The risk is similarly increased for individuals who have two or more first-degree relatives diagnosed with colorectal cancer at any age (1). The risk is not significantly increased in individuals with a single affected second-degree relative (1).

Genetic syndromes

Hereditary colorectal syndromes are associated with about 5% of cases of colorectal cancer. The most prevalent predisposing genetic syndromes for colorectal cancer are familial adenomatous polyposis (FAP), and hereditary non-polyposis colorectal cancer (HNPCC). However, additional uncommon genetic syndromes have also been associated with an increased risk of colorectal cancer, including Peutz-Jeghers syndrome and juvenile polyposis syndrome (3).

Familial Adenomatous Polyposis (FAP)

FAP accounts for 1% of all colorectal cancers (3,4). FAP is inherited in an autosomal dominant pattern, and is caused by a mutation in the adenomatous polyposis coli (APC) gene (3). APC is a tumour-suppressor gene; a loss-of-function mutation in this gene therefore results in a decreased ability of the body to prevent the development of tumours. As a result, individuals with FAP develop hundreds to thousands of adenomatous polyps in their colon. Although these polyps are initially benign, the majority of individuals with FAP will develop colorectal cancer by the age of 30 if a prophylactic colectomy is not performed (3).

FAP is thought to result in colorectal cancer via a ‘two hit model’. The inherited mutation in APC represents the first ‘hit’, and the second hit is usually brought about by a sporadic mutation that occurs in the remaining ‘normal’ allele of the APC gene (4). Further sporadic mutations occurring in these APC-mutated cells are much more likely to lead to cancer than they would be in normal non-mutated cells.

Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

HNPCC, also known as Lynch syndrome, is the most common hereditary colorectal syndrome, and accounts for 3% of all colorectal cancers (4). It is inherited in an autosomal dominant pattern, with an 80% penetrance, and is caused by a mutation in a DNA mismatch repair gene. Like FAP, HNPCC follows the two hit model, and thus requires the combination of an inherited mutation and a secondary sporadic mutation to result in malignancy. The presence of loss-of-function mutations in both alleles of the mismatch repair gene results in microsatellite instability; this is a term referring to the contraction and expansion of areas with repetitive nucleotide sequences (microsatellites) (4).

Unlike FAP, which is characterized by the growth of thousands of polyps, patients with HNPCC may have only a normal or mildly increased number of polyps (3). However, patients with HNPCC tend to develop polyps at an earlier age, and the polyps they develop are more likely to become cancerous (3). The mean age at diagnosis of colorectal cancer in patients with HNPCC is 43 years (4).

HNPCC is divided into two subtypes. HNPCC type I is characterized by an increased risk of colorectal cancer only, whereas HNPCC type II is associated with an increased risk of colorectal, endometrial, ovarian, gastric, small bowel, bile duct, urinary tract, and skin malignancies (3,4).

Peutz-Jeghers Syndrome

Peutz-Jeghers syndrome is associated with less than 1% of colorectal cancers (4). It is a rare autosomal dominant disease with high penetrance, characterized by hamartomatous polyposis and skin pigmentation (4). Hamartomatous polyps are typically large, but few in number; they may be present in both the small and large bowel. Skin pigmentation consists of freckles on the hands, perioral skin, periorbital skin, and buccal mucosa (4). Peutz-Jeghers syndrome is associated with an increased risk of colorectal, breast, pancreatic, gastric, ovarian, lung and small bowel malignancies (3).

Juvenile Polyposis Syndrome

Juvenile polyposis syndrome is a rare genetic condition inherited in an autosomal dominant manner. Patients with this syndrome develop hamartomatous polyps throughout their gastrointestinal tract, which usually form before age 20 (5). The number of polyps can vary from only a few to several hundred, even among members of the same family. Patients with juvenile polyposis syndrome are estimated to have a 10-50% risk of developing a gastrointestinal malignancy, with colorectal cancer being the most common type to occur (5).

Personal medical history

Previous History of Polyps or Colorectal Cancer

Patients who have previously been diagnosed with colon adenomas or colorectal cancer are at increased risk of subsequently developing new colorectal cancer.

Inflammatory Bowel Disease

Chronic inflammatory bowel disease that involves the colon is associated with an increased risk of developing colorectal cancer. The extent to which risk is increased is determined by the extent of colon involved, the duration of the disease, the presence of dysplasia and other prognostic factors (6).

Lifestyle Factors

A sedentary lifestyle is associated with an increased risk of developing colorectal cancer, while physical activity is thought to be protective against the development of colorectal cancer (3).

Dietary factors are also associated with colorectal cancer. Frequent consumption of red meat is associated with an increased risk of colorectal cancer development, and an increased risk of dying from colorectal cancer (3). Consumption of processed meats (i.e. meats preserved by smoking ,curing, salting or the addition of preservatives such as nitrates/nitrites) are also associated with an increased risk of colorectal cancer, and the risk is thought to increase with greater amounts consumed (3). Diets low in fibre are also associated with an increased risk of colorectal cancer, while consumption of fruits and vegetables is thought to be protective (3).

Obesity is another lifestyle-associated risk factor for colorectal cancer. Individuals with a body mass index (BMI) in the obese range are thought to have a 1.5 times increased risk of developing colorectal cancer compared to those with a BMI in the normal range (3).

Alcohol use at a level greater than 3.5 drinks or more per day is associated with a 1.5 times increased risk of developing CRC compared to non-drinkers (3).

Prolonged cigarette smoking (> 35 pack years) has also been associated with a significantly increased risk of developing colorectal cancer (3,4).


There is a higher risk of colorectal cancer in among members of certain ethnicities, including Ashkenazi Jews and African Americans, due to an increased incidence of genetic mutations that predispose to colorectal cancer (3).

Colorectal cancer also has a substantially higher rate of incidence and mortality in the developed Western world as compared to other geographic regions such as Asia and Africa. This is thought to be explained by the increased consumption of meats and sedentary lifestyle of economically privileged nations (4).

Protective Factors

The protective effect of non-steroidal anti-inflammatory drugs (NSAIDs) on colorectal cancer has been demonstrated by numerous studies (3,4). No clear mechanism of action has been elucidated for this effect. Due to the risk of adverse effects associated with prolonged treatment with these agents, NSAIDs are not currently recommended as primary or secondary prevention for colorectal cancer (3).

Statins have also been shown by a few studies to be protective against colorectal cancer, but results have not been as conclusive as for NSAIDs (4).

The use of oral-contraceptive pills is also associated with a reduced risk of colorectal cancer. This effect is present with any previous use of oral contraceptives; however, a greater reduction in risk is observed with a greater duration of use (7).

Hypercalcemia of malignancy is common in advanced stage cancers affecting over 40% of patients (9). Calcium levels require tight regulation and small variations from normal can cause significant morbidity.

Normal physiology of calcium homeostasis

The large majority of the body’s calcium is stored in bone, and a very small amount is in the blood, with about 65% of the blood calcium bound to albumin, unavailable for use (9). Low serum calcium levels stimulate the parathyroid gland to release parathyroid hormone which increases calcium levels in 3 ways: renal tubular reabsorption, vitamin D activation, and mobilization from bone (9). Vitamin D increases calcium absorption from the GI tract and decreases renal excretion (9). On the other side of regulation, calcitonin is a hormone released by parafollicular/C cells in the thyroid gland that is involved in decreasing serum calcium levels by preventing renal reabsorption and calcium mobilization from bone (9).

Pathophysiology of hypercalcemia of malignancy

There are several mechanisms of hypercalcemia of malignancy including humoral hypercalcemia mediated by increased parathyroid hormone-related peptide (PTHrP), local osteolytic hypercalcemia due to breakdown of bone, excess extrarenal activation of activated vitamin D that promotes calcium reabsorption/retention, and excess ectopic or primary PTH secretion (10). The PTHrP mechanism is the most common (80%) and it’s the peptide’s structural similarity to endogenous PTH that drives increased tubular renal absorption of calcium, decreased renal excretion and stimulates osteoblasts to produce RANKL. Local osteolytic hypercalcemia accounts for roughly 20% of hypercalcemia from bone mets and is thought to be due to excessive osteoclast activation and bone resorption due to tumour cytokine secretion (10).


Clinical presentation

The classic mnemonic for symptoms of hypercalcemia is “stones, bones, abdominal moans, and psychic overtones”. In addition there are characteristic cardiovascular system features of hypercalcemia.

Table 3. Signs and symptoms of hypercalcemia


If hypercalcemia is suspected, measuring serum calcium and serum albumin levels (if serum albumin is abnormal, measured calcium needs to be adjusted) is the first step of investigations. Once confirmed, PTH, PTHrP and vitamin D levels will help to characterize the cause of hypercalcemia.

Table 4. Serum calcium level associated with degree of hypercalcemia


The first step in management is fluid resuscitation with IV normal saline. Patients presenting with hypercalcemia due to bone metastases are usually dehydrated due to hypercalcemia-induced nausea, vomiting, loss of appetite and nephrogenic diabetes insipidus. These factors all contribute to volume depletion and propagate the cycle of further increasing serum calcium (9). In addition to fluids, there are several medications used to reduce serum calcium. Exogenous calcitonin has a fast onset of action and is a good initial therapeutic option while bridging to longer term use therapies (9). It works within 4 hours, but tachyphylaxis often develops around 48 hours which is why it should only be used in the transition period for starting maintenance therapy (10). Bisphosphonates (e.g. zoledronic acid and pamidronate) are used as a longer term therapy, but their calcium lowering effect takes 2-4 days (9). In patients with high levels of PTHrP, bisphosphonates might be less effective and other options such as denosumab may be the next treatment of choice, although this use is off-label (9). Hemodialysis should be considered in patients who cannot be safely rehydrated due to cardiorenal disease.

Breast cancer is primarily classified histopathologically in accordance with the 2003 WHO classification scheme, as seen in overview in the flowchart below. Breast cancer may also be classified by the expression of hormone receptors and genetic mutations that are impactful for treatment and prognosis (1).

Histopathological Classification

1) Non-Invasive Breast Malignancies

Atypical Hyperplasia

Atypical ductal hyperplasia and atypical lobular hyperplasia are conditions in which there is an increase in number of abnormal cells growing in the breast ducts or lobules. While they are not malignant conditions, they are associated with a significant increased risk of future breast cancer development (2).

Lobular and Ductal Carcinoma In-Situ

In-situ carcinomas are composed of malignant epithelial cells that are limited to their site of origin and have not spread or invaded past the basement membrane.  These carcinomas, if left untreated, can progress into invasive carcinomas.

Lobular carcinoma in-situ (LCIS) is a pre-malignant condition arising from the cells of the breast lobules. LCIS is characterized by the presence of atypical cells that have not yet invaded nearby breast tissue (2). It often develops in multiple parts of bilateral breasts at the same time, and is an important marker for the development of future invasive breast cancer. Women with LCIS are thought to have a 10-15% risk per breast of developing breast cancer in the ten to fifteen years subsequent to diagnosis (1). As such, women with LCIS should undergo more frequent screening mammography, and may also be offered hormonal therapy to decrease their risk of future breast cancer development (2).

Ductal carcinomas in-situ (DCIS) are composed of malignant epithelial cells that arise in the breast ducts, and have not yet invaded beyond the basement membrane in their site of origin.  DCIS is responsible for 20% of all abnormal mammogram findings (2). DCIS can be classified as low, intermediate or high grade on the basis of pathology, and this grading has prognostic value for the likelihood of post-operative recurrence.

2) Invasive Breast Cancers

Invasive breast cancers are malignant lesions in which atypical cells have spread through the basement membrane to invade surrounding breast parenchyma, lymphatic tissue or beyond.  Over 95% of all invasive breast cancers are adenocarcinomas derived from epithelial tissue. Rarer forms of invasive breast cancer include stromal-derived malignancies, lymphomas and metastasis of other cancers to the breast (2,4).


Invasive ductal carcinomas (IDCs) represent 80% of all invasive breast cancers (5).  IDC can be further classified into subtypes defined by characteristic histopathological features.

  • IDC Not-Otherwise-Specified is a diagnosis of exclusion, and remains the most common form of IDC.  Histopathological characteristics of IDC NOS vary widely (2,4).
  • Medullary carcinomas account for 5-10% of all invasive breast cancers. Histopathologically, they are characterized by syncytial (sheet-like) proliferations of poorly differentiated cells.  They are associated with a good prognosis (2,4).
  • Tubular carcinomas account for 2-3% of invasive breast cancers.  Histopathologically, they are well-differentiated and resemble benign lesions.  They are associated with a good prognosis (2,4).
  • Mucinous carcinomas account for 2% of invasive breast cancers and are found more frequently in women 60-70 years of age.  Histopathologically, they are characterized by large pools of mucin.  They are associated with a good prognosis (2,4).
  • Papillary carcinomas account for 1-2% of invasive breast cancers and occur more frequently in postmenopausal women.  Histopathologically, they are characterized by papillae and may be surrounded by a fibrous pseudocapsule.  They generally have a favourable prognosis (2,4).
  • Scirrhous carcinomas are faster growing that other types and associated with a less favourable prognosis (2).

Invasive lobular carcinomas are the second most common form of invasive breast cancer and represent 10-15% of all invasive breast cancers (2,4).  They are characterized by a single-file of infiltrating cells that invade into breast stromal tissue.  On gross specimen, they have a rubbery hard consistency with irregular borders.  ILC has a tendency to metastasize to atypical sites including the peritoneum, GI tract, ovaries, and uterus, as well as rarely to the lungs and pleural cavity (4).


Inflammatory breast carcinoma is a rare but highly aggressive form of breast cancer.  It is more common in young women and in women of African ancestry. It usually presents as a red, warm, swollen breast. The overlying skin may appear pitted, which is known as ‘peau d’orange’ due to its resemblance to the texture of an orange peel. On histopathology, a finding of malignant cells in dermal lymphatic tissue is a characteristic feature (4).   At the time of diagnosis, the cancer has often already spread to involve the lymph nodes and distant organs. Prognosis is poor, with an estimated five-year survival of 34% (2).


Paget’s disease of breast is another rare form of invasive breast cancer derived from epithelium.  It is more common in women over 50 years of age. It commonly presents clinically, with signs and symptoms including crusting and scaling of skin around the nipple, burning, pruritus, nipple bleeding or discharge, and new nipple inversion.  A lump may be felt near or under the nipple. Histologically, it is characterized by large dendritic neoplastic cells (Paget cells) within the epidermis.  Paget’s disease of breast is often associated with an underlying DCIS or IDC component (2,4).

An example of Paget’s disease of the nipple


Additional rare breast cancers can occur, including stroma-derived malignancies (phylloides tumors and sarcomas), lymphoma, and metastases from other body sites. In combination, these malignancies represent less than 1% of all breast cancers (2).

Molecular Classification

A additional classification scheme is used an adjunct to the histopathological classification model.  This scheme divides cancers based on their expression of certain hormone receptors and genes that have significance for both management and prognosis.

1) Hormone Receptor Status

A malignancy can be classified according to the presence or absence of estrogen and progesterone receptors.  About 75% of breast cancers are hormone receptor positive meaning that the cancer will grow in the presence of estrogen and/or progesterone.  Estrogen receptors are more commonly found than progesterone receptors.  The importance of determining receptor status of a cancer is that it will determine the efficacy of using hormonal therapy as a treatment.  It is important to note that the receptor status of a cancer can change over time.

Both estrogen and progesterone receptor positive cancers are associated with a more favorable prognosis, including higher disease-free survival and reduced mortality.  Estrogen-receptor positive cancers can be treated using anti-estrogen therapy (2,6).  Estrogen-receptor positive cancers are more common in post-menopausal women (6).

2) HER2 Status

Human epidermal growth factor receptor 2 (HER2) is a proto-oncogene for a transmembrane growth factor receptor.  HER2 is present in normal breast epithelial cells, but is overexpressed in 20-25% of all breast cancers. Cancers that overexpress HER2 are considered to be HER2 positive, and are associated with a higher grade and more aggressive rate of spread (2).

Targeted therapies are available for HER2 positive cancers, including Herceptin (transtuzumab), a monoclonal antibody against HER2 protein (2).

Colorectal cancer is often asymptomatic, which is why screening is critical to detect pre-malignant and malignant lesions as early as possible (1).

Colorectal cancer may present with a number of symptoms, signs, or complications, including (1):

  • Bowel habit changes (diarrhea, constipation, ‘pencil-thin’ stools)
  • Sensation of incomplete emptiness following bowel movements (tenesmus)
  • Blood in the stool (bright or dark red)
  • Fatigue
  • Abdominal pain or discomfort
  • Nausea or vomiting
  • Loss of appetite
  • Weight loss
  • Palpable mass in the abdomen
  • Anemia
  • Lymphadenopathy
  • Bowel obstruction
  • Bowel perforation

Patients who are symptomatic due to obstruction or perforation at the time of diagnosis carry a worse prognosis than patients who are asymptomatic.

20% of patients with colorectal cancer have metastatic disease at the time of presentation. The most common sites of metastatic spread in colorectal cancer are the regional lymph nodes, liver, lungs and peritoneum; the liver is often the first distant site involved. Colorectal cancer may therefore also present with signs and symptoms concerning for metastatic disease, including:

  • Hepatomegaly
  • Jaundice
  • Ascites
  • Shortness of breath

A more detailed description of the signs and symptoms associated with colon cancer, including their pathogenesis, is included in Table 1 below.

Table 1. Signs and Symptoms of Colorectal Cancer


The current standard for staging non-melanoma skin cancers is the TNM classification system. This classification is only applicable to malignant disease and cannot be applied to precursor lesions. The American Joint Committee on Cancer (AJCC) staging system lacks prognostic accuracy for NMSCs and as a result the use of high risk features is often preferred. There have also been efforts to develop alternative staging systems with better prognostic value. The 8th edition staging system was published in 2017 and was designed for use only with NMSC of the head and neck [8]. The 2017 AJCC guidelines are as follows [8]:

Tumour Staging
Nodal Stage

ENE = extranodal extension

Metastases Stage
Prognostic Stage
In the aforementioned TNM system, imaging is necessary to establish the “N” and “M” stages. However, imaging is not performed on the majority of patients with BCCs or cSCCs because only 1-5% of cSCCs and <0.1% of BCCs metastasize [2,3]. That being said, it is important to note that despite the low rate of mortality incurred by these cancers, there can be significant morbidity. BCCs can be extremely locally destructive to tissues and bones despite being low grade [4].There is no definitive consensus as to how to determine which patients should be imaged. Experts agree that the TNM system is inadequate, as the vast majority of patients have T1 or T2 N0M0 disease and they do not all have the same prognosis [2,5,6]. As such, most guidelines suggest that tumours should be classified as either “high risk” or “low risk” according to their potential for metastasis [2,5,6]. These defining features are not standardized, however, the high-risk features typically increase the 5-year recurrence rate and/or metastatic rate over 15% [3].

High-Risk Features of Basal Cell Carcinoma [2,3,4,9]

Clinical features
  • >6mm for mask area, >1cm for cheek, forehead, scalp and neck, and >2 cm in size other areas
  • High risk locations: nose, eyelid, temple, preauricular, postauricular, lower legs
  • Inadequate margins for excision
  • Poorly circumscribed
  • Recurrent tumour
  • Incomplete excision
  • Lesions in sites of previous radiation therapy
Histologic features
  • Morpheaform,sclerosing, infiltrating, desmoplastic, micronodular, basosquamous, keratotic metatypical subtypes
  • Perineural spread

High-Risk Features of Cutaneous Squamous Cell Carcinoma [2,3,5,6,7,10,11]

Clinical features
  • >2 cm in size
  • High risk locations: ear, lip, genitals
  • Rapid growth
  • Immunosupressed patient
  • Arisen from within a trauma site (chronic wound or irradiation site)
  • Recurrent disease
  • Incomplete excision
  • Multiple tumours
Histologic features
  • Depth beyond subcutaneous tissue (increasing risk with increasing depth beyond 2mm)
  • Close margins (<2mm)
  • Primary mucosal SCC
  • Poorly differentiated
  • Perineural spread
  • Intravascular invasion

The Brigham and Women’s Hospital Tumour Staging system has been designed to improve prognostic value in assessment of tumours [12]. In this staging system tumours are risk stratified based on the presence of risk factors: T1 tumours have zero high risk factors, T2a tumours have one high risk factor, T2b tumours have two to three high risk factors and T3 tumours have over four high risk factors or bone invasion. Risk factors are defined as the following: tumour diameter >/= 2cm, poorly differentiated histology, perineural invasion >/= 0.1mm, or tumour invasion beyond fat (excluding bone).


Basal Cell Carcinoma

As it is exceedingly rare for BCCs to metastasize, there is no standardized approach for imaging high risk BCCs. BCCs that do metastasize most commonly spread to the local lymph nodes, lung and bone [3].

Cutaneous Squamous Cell Carcinoma

The protocol for imaging cSCCs is much more established than that for BCCs because of their higher rate of nodal spread and metastasis. cSCCs most commonly spread to regional lymph nodes, however they can also metastasize to the lung, liver, bone and brain [3].

A suggested approach for investigating invasive cSCC is depicted in the image below [modified from reference 3]:

All cSCC patients should have a regional lymph node examination to detect clinical lymphadenopathy [10]. Patients with palpable lymphadenopathy must undergo a lymph node biopsy to establish whether there is evidence of disease in the palpable node. The biopsy is typically conducted using a fine needle aspiration technique. If the cytology confirms that the node is positive for disease, the patient should undergo imaging tests to characterize the extent of nodal involvement along with complete nodal dissection. If the cytology does not indicate that there is disease in the palpable lymph node, the physician should consider whether the tumour is “high-risk”. Physicians may decide to send patients with sufficient high-risk features, with or without palpable lymphadenopathy, for imaging of the regional lymph nodes. Ultrasound of lymph nodes may also be considered for high risk cSCCs. In large infiltrating tumours with signs of involvement of underlying structures imaging such as CT or MRI may be required to assess the extent or tumour spread. The most common imaging modality used for staging nodal involvement is CT. Other imaging techniques that may be considered are MRI, PET and ultrasound [2,3].

Patients with confirmed nodal involvement and/or extremely high-risk disease may undergo full-body imaging for distant metastases. The options for full-body imaging include CT, PET and PET-CT. The gold standard is currently unknown [3].


The prognosis for NMSCs is extremely good in most cases with a greater than 95% disease free survival at 5 years for low stage disease [2]. However, this prognosis changes considerably for high-risk lesions with rates dropping down below 50% for T4 lesions [3]. This underscores the importance of properly staging NMSCs.

The most widely accepted system for colorectal cancer staging is TNM staging, as outlined by the American Joint Committee on Cancer (AJCC) (1,2). This system stages colorectal cancer according to three primary features. The first feature is the tumor size, represented by ‘T’. The second feature is the extent of spread to regional lymph nodes, represented by ‘N’, which can be determined either clinically (‘cN’) or pathologically (‘pN’). The third feature used to classify colorectal cancer is the presence of any distal metastasis, represented by ‘M’. On the basis of these features, colorectal cancer is assigned a TNM status, which correlates to a certain stage of colorectal cancer.

Tumor (T) (1)

TX – primary tumour cannot be assessed

T0 – No evidence of primary tumour

Tis – Carcinoma in situ: intraepithelial or invasion of lamina propria.

T1 – Tumour invades submucosa

T2 – Tumour invades muscularis propria

T3 – Tumour invades through the muscularis propria into pericolorectal tissues

T4a – Tumour penetrates to the surface of the visceral peritoneum

T4b – Tumour directly invades or is adherent to other organs or structures

Regional Lymph Nodes (N) (1)

During surgical resection of the colon or rectum, the surgeon aims to obtain a minimum of 12 lymph nodes for staging purposes. In general, the more nodes attained, the better the prognostic accuracy. For similar reasons, the pathologist must make a note of how many nodes were actually analyzed in the determination of the pathological N-stage of the tumour.

Nx - regional lymph nodes cannot be assessed

N0 - no regional lymph node metastatis

N1 - metastasis in 1-3 regional (pericolic or perirectal) lymph nodes

  • N1a - metastasis in 1 regional lymph node
  • N1b - metastasis in 2-3 regional lymph nodes
  • N1c - tumor deposit(s) in the subserosa, mesentery, or non-peritonealized pericolic or perirectal tissues without regional nodal metastasis

N2 - metastasis in 4 or more regional (pericolic or perirectal) lymph nodes

  • N2a - metastasis in 4-6 regional lymph nodes
  • N2b - metastasis in 7 or more regional lymph nodes

N3 - metastasis in any node along the course of a named vascular trunk and/or metastasis to apical node

Distant Metastasis (M) (1)

Mx - metastasis cannot be assessed

M0 – no distant metastasis

M1 – distant metastasis

  • M1a – metastasis confined to one organ or site (e.g., liver, lung, ovary, nonregional node)
  • M1b – metastasis in more than one organ/site or the peritoneum
  • M1c - metastasis to the peritoneum with or without other organ involvement

Stage Groupings

The table below delineates the stage groupings for colorectal cancer based on their TNM status.

Table 2. TNM staging for colorectal cancer (1)

The treatment of breast cancer varies widely depending on the stage of the cancer.  Similarly, the goals of treatment also vary from curative to palliative depending on tumour, patient, and treatment factors.

Surgery, radiation therapy, chemotherapy and hormone therapy are the main treatment modalities employed in breast cancer management.

Initial Considerations

As soon as a confirmed tissue diagnosis of breast cancer has been made, the patient should be referred to the appropriate treating physicians as soon as possible. The patient is usually seen first by a surgeon for consideration of resection of the malignancy, unless the disease is identified as metastatic at the time of diagnosis (1). Referral to medical and radiation oncologists is usually done by the surgeon post-operatively, unless the patient wishes to discuss his or her options with the oncologist prior to making a decision about surgery (1).

Other referrals to be considered include genetic counselling if there is suspicion for a hereditary cancer gene, and a fertility program if the patient is pre-menopausal and would like to have children in the future (1).

Treatment Modalities


Surgery is a core component of breast cancer treatment and is offered for all breast malignancies with the exception of stage IV (metastatic) disease (2).  For non-metastatic breast cancer, surgery is considered the primary treatment. Adjuvant systemic therapies may then be employed post-operatively to decrease cancer recurrence by eliminating micrometastic lesions that may have spread from the original primary tumour (3).

Several surgical procedures are employed in the management of breast cancer.

Breast conserving surgery (BCS), also known as a ‘lumpectomy’ or partial mastectomy, is a procedure in which the surgeon aims to remove the breast tumour along with a margin of healthy tissue, while sparing the remaining healthy breast tissue (2). When BCS is performed in patients with DCIS or early invasive breast cancer, and followed by external beam radiation therapy, it has been shown to achieve survival rates equal to those of patients treated with complete mastectomy (3). Contraindications to BCS include multicentric tumours, inflammatory breast cancer, persistent positive margins after prior surgical resections, and contraindications to radiation such as pregnancy or history of previous breast irradiation (4). BCS is also not a good option for women with large tumour size relative to breast volume, as a good cosmetic result may not be achieved under these conditions (4).

Mastectomy is a surgical procedure in which the whole breast is removed. In a simple mastectomy, only the breast tissue is removed, with the surrounding musculature and lymph nodes remaining in place. This procedure was historically performed in patients with DCIS and early invasive breast cancer (2). In a modified radical mastectomy, the breast tissue, nipple, axillary lymph nodes and pectoralis fascia are all removed. This procedure continues to be performed in patients for whom BCS is contraindicated or who prefer not to undergo radiation therapy (2).

Some women at high risk of developing further invasive breast cancer may choose to undergo prophylactic total bilateral mastectomy (2). This is not commonly performed as it is considered to be an aggressive treatment.

Surgical management also includes procedures to biopsy lymph nodes for use in cancer staging. A sentinel lymph node biopsy is usually recommended for patients with no clinically palpable lymph nodes (clinically N0) (5). In this procedure, the single axillary lymph node to which cancer is most likely to spread is removed and sent for pathology. If the sentinel lymph node is negative, the cancer is unlikely to have spread to any lymph nodes. If the sentinel lymph node is positive, the patient should undergo complete axillary lymph node dissection to remove the remaining axillary lymph nodes and allow assessment of the extent of the cancer’s lymphatic involvement (5).  Patients should proceed immediately to axillary lymph node dissection if they have clinically node positive disease or inflammatory breast cancer (5).

Finally, surgery may be considered for palliative intent.  Mastectomies may be considered for patients with large, painful, or fungating breast lesions.  Surgery for isolated brain or spinal cord metastases, isolated lung metastases, and/or isolated liver metastases may be considered to help control pain and other symptoms of metastatic disease (2,3).


External beam radiation therapy is an important component of breast cancer management. Radiation therapy is offered to breast cancer patients following breast-conserving surgery in order to reduce the risk of cancer recurrence (5). For early invasive breast cancer, the use of external beam radiation therapy results in a 20% absolute reduction in risk of recurrence at 10 years post-diagnosis, which in turn results in a 5% reduction in breast cancer mortality (5).

Radiation treatment is usually not performed in patients who have undergone modified radical mastectomy for early invasive breast cancer. However, radiation therapy may be offered to these patients if certain high-risk features are present, including lymph-node positive disease (2).

External beam radiation may also target the lymph nodes if they are found to be positive, as well as the chest wall if certain high-risk features are present (2).

The schedule for radiation therapy typically involves treatments being given five days per week for a duration of five to seven weeks (6). Patients may experience side effects from radiation therapy, including (2,5):

  • Fatigue
  • Skin changes: radiation dermatitis (clinically akin to a sunburn), moist desquamation of the axilla or inframammary fold, post-inflammatory pigmentation changes, skin fibrosis
  • Breast pain
  • Lymphedema
  • Esophagitis
  • Respiratory effects: radiation pneumonitis, radiation fibrosis (late effect)

External beam radiation may also be considered for palliation. It may be used to control pain and other symptoms arising from localized metastases, such as bone metastases, spinal cord metastases, metastases causing bronchial obstruction, and large or painful chest wall metastases (2).

Hormonal therapies

Hormonal therapies are offered as adjuvant therapies to patients with hormone-receptor positive DCIS or invasive breast cancer of any stage. The duration of recommended use ranges from five years for DCIS to ten years for more advanced breast cancers (2,5). Options for hormonal therapy include selective-estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), ovarian suppression with luteinizing hormone-releasing hormone (LHRH) agonists, and surgical removal of the ovaries.

SERMs are competitive partial agonists for the estrogen-receptor (ER) and have variable agonist and antagonist action on ERs throughout the body. AIs inhibit the enzyme aromatase, which functions to convert androgen precursor molecules to estrogen in the body’s peripheral tissues.  AIs are ineffective in pre-menopausal women, as the main source of estrogen in these women is the ovaries (not the peripheral tissues) (2).

In pre-menopausal women, SERMs are the first-line hormonal therapy for estrogen or progesterone-receptor positive breast cancers (2). Tamoxifen is the most commonly used SERM, and has been shown to reduce the risk of breast cancer recurrence by 30-50% in premenopausal women (7). Tamoxifen is also the most commonly used agent in post-menopausal women, in whom it reduces the risk of breast cancer recurrence by 40-50% (7). However, in post-menopausal women with stage 4 breast cancer, AIs are considered first-line due to their greater efficacy in this population (2). The most commonly used AI is letrozole (2).

Tamoxifen is associated with an increased risk of endometrial cancer, DVT/PE and stroke (2,5). It is therefore relatively contraindicated in women with a personal history of venous thromboembolism or endometrial cancer (5). AIs are associated with an increased risk of osteoporosis and dyslipidemia, and caution should be therefore be used when prescribing AIs to women with a history of these conditions (2,5).

Side effects of hormonal therapy may include the following (2):

  • Hot flashes and other symptoms of treatment-induced menopause
  • Sexual dysfunction
  • Weight gain
  • Constipation
  • Diarrhea
  • Nausea
  • Fatigue
  • Hair thinning
  • Change in vaginal discharge
  • Osteoporosis (with AIs)
  • Dyslipidemia (with AIs)


Chemotherapy is most often used as an adjuvant therapy for breast cancers that are stage II or greater. It is particularly important for breast cancers that are ER and PR negative, as these malignancies do not qualify for hormonal therapy (2). The age, medical comorbidities, and values of the patient should be considered prior to starting any chemotherapy regimen (3).

Chemotherapy may also be used as a neoadjuvant therapy to reduce the size of the tumor prior to surgery. This may render previously non-operable tumors operable or allow breast-conserving surgery in a patient for whom this was not previously feasible goal (2,3).

Multiagent chemotherapy regimens are usually employed due to their greater efficacy (2). Herceptin (trastuzumab) is a monoclonal antibody against the HER2 receptor that is used in the treatment of HER2 positive breast cancers (5).

Treatment of Breast Cancer by Stage

Table 3. Treatment of breast cancer by stage of disease

Information in the table above was derived from the Canadian Cancer Society and the American Cancer Society (2,8,9).


As demonstrated in the table below, the prognosis of breast cancer is determinedly largely by the stage of disease. Stage 0 and Stage 1 disease has a 5-year survival of 98-100%, while Stage 4 disease has a median survival of 18-24 months (2,3,5).  Within staging, the presence or absence of spread to lymph nodes is the most important prognostic factor (2). Higher numbers of positive lymph nodes are associated with a worse prognosis (2).  The second most important prognostic factor within staging is the size of the tumour, with larger tumours having a worse prognosis (2).

Table 4. Prognosis of breast cancer by stage

Information in the table above was derived from the Canadian Cancer Society (2).

Additional factors also have an influence on prognosis and may guide treatment decisions. Positive hormone-receptor status is associated with a better prognosis, as these tumours are usually less aggressive and respond well to hormonal therapies (2). HER2 positive status is associated with a worse prognosis, as these tumours are usually more aggressive and more likely to metastasize (2). Younger age at diagnosis (age < 35 years) is also associated with more aggressive, higher-grade tumours, and thus a worse prognosis (2).


  1. ‍Screening for cancer [Internet]. BC Cancer Agency; 1999 Sep [updated 2009 Jul 19; cited 2010 Jul 14]. Available from: http://www.bccancer.bc.ca/HPI/CancerManagementGuidelines/ScreeningforCancer.htm

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