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:
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).
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.
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 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).
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.
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).
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
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).
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).
Prevention includes primarily the avoidance of environmental triggers including quitting smoking or avoiding exposure to tobacco and cigarette smoke. Avoid excessive alcohol use with complete avoiding reducing your cancer risk the most. The American Institute for Cancer Research advises less than two drinks a day for men and one per day for women. Healthy eating and regular physical exercise to maintain a healthy BMI can lower risk for esophageal cancer.
For patients with Barrett’s Esophagus, it is recommended that they receive appropriate treatment and follow their surveillance schedule (see below).
Currently no effective screening program exists for esophageal cancer in any Western organization. There is, however, interest in screening patients with reflux which has been described by the American College of Physicians, the American College of Gastroenterology, and the American Society of Gastrointestinal Endoscopy [25-27].
//Expandable section on Reflux investigations///
Guidelines agree that upper endoscopy is indicated in patients presenting with GERD and concomitant warning symptoms described below [25-27]. The ACP and ASGE recommend investigating reflux symptoms that are refractory to treatment. Endoscopy may also be appropriate in patients with longstanding or severe reflux symptoms and multiple additional risk factors including:
Patients who do not have any evidence of EAC or Barrett’s esophagus on screening endoscopy do not need repeat endoscopy. On the other hand, patients found to have Barrett’s esophagus should consider endoscopic surveillance and treatment of dysplasia.
People with known Barrett’s esophagus have specific screening recommendations (see below).
Severe caustic injury is associated with ESCC, allegedly increasing risk by a thousandfold. There is, on average, a 40-year latency between the time of injury and the development of esophageal cancer. The ASGE recommends beginning endoscopic surveillance 15-20 years after injury .
Achalasia increases the risk of developing esophageal cancer (1 in 300 patient-years). However, the number of endoscopies needed for each early diagnosis (400) and poor prognosis in this patient group has led the ACG and ASGE to withhold their endorsement, and practice within the field varies .
Hereditary cancer syndromes can be considered case-by-case for screening owing to their heterogeneity. The NCCN provides screening recommendations for some genetic conditions implicated in esophageal cancer: https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf.
Inflammation of esophagus is called esophagitis. There are many causes of esophagitis; in North America, the most common cause is regurgitation of gastric contents through the lower esophageal sphincter (Gastro-Esophageal Reflux Disease (GERD)). The acid gastric contents irritate the esophagus squamous mucosa causing inflammation. In some individuals, persistent reflux may cause squamous mucosa to undergo metaplastic transformation into glandular epithelium which is then called Barrett’s esophagus. The risk of progression to adenocarcinoma of the esophagus depends on factors including the length of Barrett’s (short vs. long segment), and the grade of dysplasia (low vs. high-grade dysplasia).
Table 2. Grade of Barrett's Esophagus and recommended surveillance and treatment
Symptoms depend on location of tumor. Early esophageal cancer is usually asymptomatic. Overall, dysphagia and weight loss are the most common symptoms at time of diagnosis, presenting in 74% and 57% of patients respectively .
Diagnosis includes a full detailed history and physical examination. Esophageal cancer specific history questions and physical exam findings are detailed below.
The normal thyroid gland is composed histologically of two main parenchymal cell types: follicular epithelial cells and C or parafollicular cells . Most thyroid cancers are derived from the follicular cells which give rise to both well-differentiated cancers (papillary, follicular) and anaplastic thyroid cancers. In the young (under 40 years of age), thyroid cancer is usually well-differentiated and the overall prognosis is excellent. On the other hand, anaplastic carcinomas (15%), particularly in older patients, have a significantly poorer prognosis and are rarely cured. From C or parafollicular cells arise medullary thyroid carcinoma (MTC).
Papillary carcinoma is the most common form of thyroid cancer in Canada compromising over 80% of all diagnosed thyroid Cancers. It is a slow growing subtype and survival rates are high if diagnosed early. It is often single lobular. Metastases most commonly involve cervical lymph nodes and, less commonly, the lungs .
Follicular carcinoma is the second most common type of thyroid cancer after papillary carcinoma. It arises from follicular cells responsible for thyroid hormone production. It is slow growing and survival rates are high if diagnosed early. Follicular carcinoma is often treated with radioactive iodine since this tumor is most likely to capture radioactive iodine. When metastasized, however, follicular thyroid cancers tend to metastasize hematogenously to distant sites, in particular, to lung and bones.
Anaplastic carcinoma is the least common type of cancer (<1%) and occurs more often in middle ages and elderly patients . It is the most aggressive type and is fast growing with early spread. A metastatic work-up often reveals locoregional disease and distant metastases, most commonly to the lungs followed by bones and brain. Anaplastic thyroid cancer often arises from and can coexist with differentiated thyroid cancer, but can also occur de novo. Clinicians should suspect anaplastic transformation in patients with a history of longstanding differentiated thyroid cancer if they present with symptoms such as hoarseness, dysphagia, and dyspnea. It is often too advanced to surgically resect at diagnosis and therefore treated with radiation therapy alone. The cure rate of anaplastic carcinoma is very low.
On presentation, most patients with anaplastic thyroid cancer have a large, firm palpable mass in the thyroid with or without cervical adenopathy, and patients often develop hoarseness, dysphagia, and dyspnea. Clinicians should suspect anaplastic transformation in patients with a history of longstanding differentiated thyroid cancer if they present with the aforementioned symptoms. 
Medullary carcinoma arises from parafollicular neuroendocrine cells of the thyroid - C-cells which are responsible for the production of calcitonin. It is uncommon and constitutes 1-2% of thyroid cancers . It is slow growing and survival rates are high if diagnosed early. It may spread to lymph nodes or metastasize elsewhere. It generally occurs on one side of the thyroid only. MTC is the most prominent clinical diagnosis in multiple endocrine neoplasia (MEN) 2A and MEN 2B - a quarter of medullary thyroid cancer cases occur in patients with an inherited MEN syndrome.
The American Joint Committee on Cancer (AJCC) uses different tumor-node-metastasis (TNM) classification for differentiated and anaplastic thyroid cancer, and for medullary thyroid cancer. For the purposes and level of this module we will provide the staging for only the differentiated and anaplastic thyroid cancers below in Figure 2. For specific staging guidelines, see AJCC 8th edition TNM classification :
There are additionally separate stage groupings based on AJCC 8th edition staging guidelines for differentiated, medullary, and anaplastic carcinomas seen in Table 2.
Table 2. AJCC 8th edition specific stage groupings for differentiated, anaplastic, and medullary carcinoma
Management of thyroid cancer can be highly individualized and treatment may differ depending on patient, center, or physician factors. The details of management decision is beyond the scope of this module, however, general approaches and treatment options will be briefly reviewed.
The pathological assessment of the thyroid tumor is of paramount importance as it will not only give the degree of differentiation of the tumor but will assess multicentricity, the extent and site of nodal involvement and the completeness of the surgical resection. Overall, surgery is the mainstay of the majority of thyroid subtype treatments.
Surgery is the primary mode of therapy for patients with differentiated thyroid cancer and should be performed by an experienced thyroid surgeon to minimize the risk of hypoparathyroidism and recurrent laryngeal nerve (RLN) injury.
Operative management can include either a thyroid lobectomy or a total thyroidectomy. The choice to pursue either depends on extent of disease, patient factors, and presence of comorbid conditions:
Post-operative thyroid hormone is generally not started for patients who received a lobectomy, however, is started for patients who received a total thyroidectomy.
Intra-operatively, careful search for lymph nodes in the area must be made and all obvious nodes removed. More extensive resection is required for different types and sizes of tumors and its spread to surrounding lymph nodes .
131-Iodine ablation may be used adjuvantly after surgery to target remaining thyroid tissue where recurrence may occur, or to treat already recurring or metastasized disease. In studies showing a benefit with 131-I ablation, patients with larger tumors, multifocality, residual disease, and nodal metastasis seem to benefit from treatment . Therefore, the recent treatment guidelines recommend consideration of adjuvant 131-Iodine ablation in postoperative findings of :
Only papillary and follicular cancers will take up iodine, and only 50% of less of these tumors are able to take up enough iodine for it to be therapeutic.
Treatment with thyroxine is important in management of patients with thyroid carcinoma. The aim of such treatment is to suppress TSH stimulation of the thyroid which can be achieved by maintaining the serum T4 at the upper limit of normal. The starting dose of thyroxine is 1 mcg/lb/day. The level will equilibrate in one month and then the T4 and TSH can be checked. The dosage can then be altered to achieve the desired level.
External irradiation has a definite role as an adjuvant to surgery or as treatment in the following circumstances:
The role of chemotherapy in thyroid cancer is limited. The single chemotherapeutic agent most commonly used for thyroid cancer is doxorubicin (Adriamycin) with partial response rates of 30% and up to 45% in some series. For surgically unresectable local disease that has not responded to radioiodine, the best treatment may be a combination of hyperfractionated radiation treatments plus Adriamycin. Response rates of more than 80% have been reported using this regimen, but even in this situation, complete responses are rare and limited in duration.
Initial follow-up is generally undertaken by an endocrinologist, surgeon, or at a cancer centre. Thereafter, most patients are referred back to the care of their family physician .
The follow-up is variable from centre to centre and from patient to patient, however, generally it is recommended a visit every 3 to 4 months for the first two years. If there is no evidence of recurrence after 2 years then visits should be every 6 months for the next two years, with annual visits thereafter.
Initial investigations may include neck ultrasonography (every 6 - 12 months), TSH levels, and serum thyroglobulin (Tg) levels on thyroid hormone suppression (every 3 to 6 months for the first year). Iodine scanning is typically continued until there is no evidence of uptake in the neck or elsewhere and only repeated if the thyroglobulin starts to rise of recurrence or metastasis is clinically detected.
If a patient is high risk and demonstrate either a biochemical or structural incomplete response to therapy, additional imaging can be considered, including MRI, CT, and FDG-PET. Gross residual disease in cervical lymph nodes identified by physical examination or ultrasonography should be confirmed by FNA and surgical resection considered. Diagnostic whole-body radioiodine scanning may have a role in the follow-up of patients with high or intermediate risk.
Most recurrences of differentiated thyroid cancer occur within the first five years after initial treatment, however, recurrences may occur many years or even decades later, particularly in patients with papillary cancer. Therefore, ongoing follow-up after one year post-treatment is guided by individual assessment of the patient’s response to therapy during the first year of follow-up .