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Objectives

The following module was designed to supplement medical students’ learning in the clinic. Please take the time to read through each module by clicking the headings below. Information on the molecular biology, pathology, and anatomy of basic oncology is discussed. The content of this module is mirrored to the objectives listed by the 2015 Canadian Oncology Goals and Objectives for Medical Students (by the Canadian Oncology Group).By the end of the tutorial, the following objectives should be addressed:

Molecular Biology

  1. Describe in general terms how cancers develop and be able to describe the hallmarks of cancer.
  2. Describe the step-wise progression from normal to pre-malignant to malignant histology and how this relates to the principles of screening and early detection.
  3. Demonstrate an understanding of how hormones influence development of certain cancers and how this may help direct management.
  4. Describe the important genetic/familial syndromes related to cancer development, identify their mode of inheritance and impact on cancer development.
  5. Describe how common carcinogens can cause cancer (e.g. cigarette smoke, asbestos, UV radiation, radiation exposure).
  6. Describe how common infections can cause cancer (e.g. viral hepatitis, H. pylori, EBV, HPV, HIV).

Pathology

  1. Define the terms metaplasia, dysplasia, carcinoma, sarcoma, lymphoma, leukemia, and germ cell tumor.
  2. Describe the histologic differences between benign and malignant tumors
  3. Demonstrate an understanding of common pathological terminology used in cancer diagnosis (ie. stage, grade)
  4. Describe the importance of tissue sampling for diagnosis of malignancy and for identification of molecular predictive factors
  5. Demonstrate an understanding of the differences between fine needle aspiration biopsy, core biopsy, and surgical excision
  6. Demonstrate an understanding of the role of different specialists in obtaining tissue diagnosis of cancer (ie. family physician, radiologist, surgeon, oncologist).

Anatomy

  1. Describe the most common patterns by with cancer spreads (ie. direct extension, lymphatic, hematogenous, transcoelemic). fine the terms metaplasia, dysplasia, carcinoma, sarcoma, lymphoma, leukemia, and germ cell tumor.
  2. Demonstrate an understanding of relevant anatomy for common cancers (ie. prostate, breast, lung, and colorectal) in terms of how they invade and metastasize, with an emphasis on invading adjacent structures, spread through the lymphatic and vascular systems. 

Molecular Biology

What is Cancer?

Cancer is a disease where cells lose normal growth regulation, proliferate abnormally from their normal counterparts, and invade other tissues. Often, it is not a single disease but a collection of multiple cellular abnormalities. Cancer cell behaviour is differentiated from normal cells by four characteristics (Table 1).

Table 1. Four hallmarks of cancer cells

These four characteristics may actually exist in normal, non-cancerous cells. However, this dysregulation is inappropriate and excessive in cancer (1). Additional hallmarks exist to further specify the types of cellular dysfunction from the four characteristics above (Figure 1).

Terms to Describe Tumor Development

Many terms exist to classify cell dysregulation and can describe how cells can develop into cancer. It is important to note that not all these terms are synonymous with the disease of cancer itself (Table 2).

Table 2. Tumors and cancers describe different aspects of cellular dysfunction

The terms benign and malignant describe a property of cells which have abnormal cell growth and proliferation (Table 3). Both terms refer to cells which have lost normal regulation of cell division and death. However, only malignant cells possess the ability to spread and invade other tissues.

Table 3. Tumors may be benign or malignant, and may have the potential to spread

In most literature and in this module itself, several equivalent terms will be used interchangeably. Tumor and neoplasm both refer to abnormal, unregulated growths of tissues. Malignant tumor, malignancy, and cancer all refer to the invasive nature and disease of abnormal, unregulated growths of tissues.

Step-wise Progression of Cancers

Genetic abnormalities cause the vast majority of human cancers (1). Mutations in genetic material are caused by variety of etiologies such as damaging radiation, exposure to carcinogens, or failure in proof-reading mechanisms. These abnormalities result in loss of regulation over cell growth and proliferation.

Abnormal cell growth behaviour is often reversible (Table 4). That is, they are caused by a stimulus and are ceased when the stimulus is removed.

Table 4. Abnormal proliferative growth behaviour may be reversible with removal of the stimulus

Pre-malignant changes in cells are referred to as dysplasia, and is seen as dysfunctional cell growth and morphological changes in cell nuclei (2). Dysplasia results in cells losing specific characteristics from their tissue of origin. This loss in cellular differentiation is classified as grades (low, medium, and high) where lower grade neoplasms resemble their tissue of origin better than higher grade neoplasms. It is important to remember that dysplasia are not necessarily cancers; they simple describe the growth pattern of a neoplasm, which can either be benign or malignant. Metaplasia is the reversible replacement of one cell type by another (2). Like dysplasia, metaplasia are not necessarily cancers and may be reversed upon removal of a certain stimulus. One example of a benign metaplasia is the transformation of respiratory epithelium from columnar to squamous type due to chronic irritation like smoking.

Transformation of normal to pre-malignant to malignant cells follows a course of step-wise histological changes (Figure 2). In epithelium, normal cells initially undergo low to medium grade dysplasia due to a stimuli such as a genetic abnormality. This initial dysplasia does not involve the entire epithelial height and is not cancerous. It can either revert back to normal or progress to high grade dysplasia. Should it progress, the dysplastic cells can involve the entire epithelial thickness and accumulate to push against the underlying basement membrane (Table 5). Penetration through the basement membrane would allow the neoplasm to invade other tissues, thus deeming it cancerous.

Table 5. The intactness of the basement membrane dictates neoplasm invasiveness

By these definitions, dysplastic cells are not malignant and cannot disseminate to other tissues until the basement membrane is broken. Thus, carcinomas in situ are not malignant and are technically benign neoplasms. However, carcinomas in situ are automatically high-grade dysplasia and its cells have the potential to become malignant. Consequently, most carcinomas in situ eventually progress to malignant carcinoma.

Hormones Influence the Development of Cancers

Hormones act as stimuli which influence cancer development in tissues such as the breast, endometrium, ovary, prostate, testes, thyroid, and bone. Endogenous and exogenous hormones regulate cell growth and proliferation at normal levels. Increased hormone levels can lead to excessive cell proliferation which can accumulate genetic abnormalities (3).

Breast cancer is the most common cancer in women, and is driven by hormones. Germline mutations in breast epithelial cells, such as those in the BRCA1 gene, predisposes cells to genetic mutations (3). Estradiol (or estrogen) produced in the ovaries further drives cell proliferation and following the cell proliferation model, leads to an accumulation of genetic abnormalities. Eventually, these abnormalities produce a malignant phenotype consistent with breast cancer.

Hormone driven cancers can be managed by controlling endogenous hormone levels. Hormonal anticancer pharmacotherapy is currently a major method of control. Examples include hormonal antagonists to block target receptors, or hormonal analogues which mimic hormones and induce negative feedback reduction of hormone production. Pharmacotherapy can also block enzymes in hormone synthesis pathways such as aromatase inhibitors required for estrogen production (3). Surgical removal of the hormone-producing organ is the final option in hormone therapy. Thus, hormone therapy is a specific form of treatment and can be used to predict treatment success in certain cancers. For example, estrogen and progesterone receptor statuses direct the management algorithm in breast cancer.

Various molecular markers exist to indicate the presence of cancer. These markers mainly aid diagnosis and assess prognosis (2). As well, the presence of certain markers offer insight into possible treatment. For example, hormone epidermal receptor 2 proteins (HER2) are present in approximately one-fifth of breast cancers (6).

Familial and Genetic Effects on Cancer

Family history is a major determinant of risk for developing and having certain cancers. However, it is interesting that only five percent of cancers have hereditary relationships. The two-hit hypothesis explains the increased genetic predisposition in patients with a positive family history. Various genes exist in the body to suppress cancer development. One example is a type called the tumor suppressor gene. Recall that genes in a cell exist as two copies (two alleles) with one copy from each parent. Thus for a cancer to develop, two hits are required to compromise both alleles and cause cancer. Patients with a hereditary syndrome have one hit already, and are born with only one normal allele. They are predisposed to cancer since they only require one additional hit to result loss of both genes.

Carcinogenic Mechanisms

Carcinogens are substances which induce malignancy by altering normal cellular genetics. They can be classified in three general categories: chemicals, radiation, and viruses. Chemicals and radiation cause biochemical damage and alterations to normal DNA. Common chemical carcinogens include cigarette smoke and asbestos, and common radiation carcinogens include UV radiation from the sun and radiation therapy. Viruses act differently by introducing new genetic material to a cell. The new genetic material may alter existing genetic material leading recombination which may be malignant (5).

Pathology

Staging vs. Grading

Staging and grading of cancers are different classification methods. The grade of a neoplasm refers to the histological and pathological features of the cells in a neoplasm. Recall that dysplasia is the abnormal proliferation of deregulated cells. As dysplasia develops, the neoplastic cells lose features of their tissue of origin, become less differentiated, and are presumed to be of higher grade.

The stage of a neoplasm provides a sense for how advanced a cancer is. Many (but not all) cancers are staged using the TNM staging system. This system is divided into three components: the tumor (T), nodal status (N), and metastasis (M), universally called the TNM staging system (Table 6). The TNM status will be different for each patient depending on their tumor and cancer. Different combinations can further be classified into general stages I, II, III, IV. We stage cancers for the following reasons: it provides a common language of communication, guides treatment, estimates prognosis, allows comparison of results, and standardizes clinical trials. Stage I cancers are early cancers that are often curable. Stage IV cancers are usually incurable. The TNM and staging differ for each tissue of origin and thus, specifically predict the management and prognosis of individual cancers (2).

Table 6. TNM staging provides a universal classification of tumor description

Biopsies for Diagnosis

Confirmatory diagnosis of cancer often requires direct histological analysis of tissue. Obtaining a biopsy is the process of removing and examining tissue, and is performed through various methods. With cancer, suspicious regions of tissue are often biopsied for analysis; these could include abnormal lumps or regions identified by imaging.

Fine needle aspiration biopsy uses a fine needle and syringe sample a tissue. Negative pressure through suction provides the force to remove the tissue. Deep tissues such as the lungs or liver may require radiological guidance. Biopsies with simpler imaging modalities such as ultrasound may be performed in a non-specialist’s clinic. However, more complicated procedures may require a radiologist or trained surgeon in the hospital.  Superficial tissues such as the prostate or breast do not require additional guidance (7).

Core biopsy uses a larger cylindrical needle and extracts cylinders, or cores, of tissue. This provides a larger sample of tissue to analyze than fine needle aspiration biopsies. Similarly, simple procedures may be performed in the office setting by a non-specialist (7).

Surgical biopsy involves extracting large amounts of tissue. There are two types of surgical biopsy: incisional and excisional. Incisional surgical biopsies removes parts of abnormal tissue, similar to fine needle and core biopsies but in a larger amount. Excisional surgical biopsies removes the entire abnormal area or tumor, and may additionally excise normal tissue around it. Excisional biopsies may very well be curative intents to remove affected parts of an organ or the entire organ itself, with tissue analysis following the excision. Surgical biopsies are typically performed in the hospital with local or general anesthesia depending on the extent of analysis (7).

Anatomy

Spread of Cancer

Benign tumors grow slowly, resemble the tissue of origin, and do not invade other tissues. Thus, benign tumors are localized and can be cured by removal. Some benign tumors may develop into malignant tumors (cancer), which grow much faster, do not resemble the tissue of origin, and invade other tissues. Malignant tumors metastasize and spread to other parts of the body, making them more dangerous and less curable (2).

Cancer spread is classified into three mechanisms: local, lymphatic, and hematogenous spread. The TNM staging mimics these three patterns of spread.

Local spread is the spread of a cancer within an organ or structure. The cancer is still considered malignant since it has likely broken the basement membrane and has disseminated within intra-organ passages. The tumor may now exist as a direct extension of the original tumor, or appear as multiple, discrete tumors throughout the organ (2). This corresponds with the T stage of the TNM.

Recall that the lymphatic system is a network of circulatory vessels to collect and redistribute excess fluid in the body. Superficial channels in the skin and subcutaneous tissues drain into deeper channels which ultimately collect into large ducts that drain into the vascular system. Along the way are lymph nodes, which are accumulations of lymphoid tissue, which play a role in the immune system. Lymphatic invasion correlates with the N stage of the TNM.

Cancers often disseminate into the lymph pathways and follow the drainage of lymph into lymph nodes. This may allow detection and localization of cancers through physical exam, as cancerous lymph nodes are often hard, tender, and matted-down. For example, cancer in the outer breast spreads to ipsilateral axillary lymph nodes, while cancer in the inner breast spreads to the internal mammary chain lymph nodes (Figure 4).

Hematogenous spread of cancer follows the vascular circulation of blood. Metastases from organ to organ almost always requires hematogenous spread. Cancers may simply follow the path of circulation, such as gastrointestinal cancers spreading to the liver via the portal vein. However, cancers may also directly invade a vessel such as a renal cancer spreading into the renal veins. Tumors often invade veins but rarely invade arteries (2).

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 CARCINOMA

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 CARCINOMA (ILC)

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

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

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

OTHER

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

TNM

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).

Imaging

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].

Prognosis

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

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).

Radiation

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

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).

Prognosis

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).

References

  1. Isselbacher K, Harrison T. Harrison’s principles of internal medicine. New York: McGraw-Hill; 1995.
  2. Shah A. Essentials of clinical oncology. Vancouver: Somerset Pub.; 2004.
  3. Henderson B. Hormonal carcinogenesis. Carcinogenesis. 2000;21(3):427-433.
  4. Schwartz S. Principles of surgery. New York: McGraw-Hill, Health Professions Division; 1999.
  5. Murray R. Harper’s illustrated biochemistry. New York: McGraw-Hill Medical; 2012.
  6. Uptodate.com. Adjuvant medical therapy for HER2-positive breast cancer [Internet]. 2015 [cited 17 June 2015]. Available from: http://www.uptodate.com/contents/adjuvant-medical-therapy-for-her2-positive-breast-cancer?source=search_result&search=her+2+breast+cancer&selectedTitle=1~150
  7. Cancer.org. Types of biopsy procedures [Internet]. 2015 [cited 19 June 2015]. Available from: http://www.cancer.org/treatment/understandingyourdiagnosis/examsandtestdescriptions/forwomenfacingabreastbiopsy/breast-biopsy-biopsy-types
  8. Cancer.org. What is breast cancer in men? [Internet]. 2015 [cited 19 June 2015]. Available from: http://www.cancer.org/cancer/breastcancerinmen/detailedguide/breast-cancer-in-men-what-is-breast-cancer-in-men

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