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Objectives

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

Human Papillomavirus Virus Exposure (HPV)

HPV is a small DNA virus and is the most important risk factor for cervical cancer. About 90-95% of women with cervical cancer are HPV positive. HPV can infect cells lining the genitals, anus, mouth and throat. It spreads by skin-to-skin contact through micro-abrasions from one person to another. Commonly, it is spread via sexual activity including vaginal, anal, oral, and digital sex.

There are more than 100 HPV related strains. Some are coined low-risk strains of HPV like types 6 and 11 because most people are able to clear the infection and they seldom result in cancer. These aforementioned strains often cause genital warts. Other strains called high-risk types of HPV, such as 16, 18, 31, and 33, cause chronic infection leading to cancer of the cervix and others including vuvla and vagina in women.

HPV is the most common sexually transmitted infection, with over 80% of men and women being infected at some point in their life. Certain patterns of sexual behaviour have been associated with an increased risk of genital HIV acquisition, which consequently increases the risk of cervical cancer.


The following increases HPV Exposure:

1. Sexual Exposure
  • Early age of first coitus
  • Multiple sexual partners
  • History of sexually transmitted diseases

            - Co-infection with chlamydia can make it more difficult to clear HPV infection

  • Partner has cervical cancer or is in contact with partner with cervical cancer 

 The following increases the likelihood of persistent infection resulting in cancer:

2. Immunocompromised
  • Steroids, smoking, renal failure, diabetes, HIV
3. Smoking
  • Smoking is also known to directly damage the DNA of cervical cells   contributing to the development of cervical cancer

Other risk factors:

4. Multiparity
5. Low Socioeconomic class
  • Less access to health care services including pap screening programs
6. Long term oral contraceptive use
7. Prenatal exposure to diethylstilbestrol (DES)
  • DES is a form of estrogen used between 1940 to 1971 during pregnancy to prevent miscarriage. Daughters of women who took DES during pregnancy have a higher risk of developing a rare type of cervical cancer, clear cell adenocarcinoma. They also have a higher risk of developing precancerous changes of the cervix or squamous cell cancer. Disapproved for use in pregnancy since 1970s. 

One in 250 females and one in 98 males are expected to develop esophageal cancer during their lifetime. In BC, the incidence rates of esophageal cancers diagnosed is 9.6 males per 100,000, and 3.7 females per 100,000 per year. It was responsible for 2,200 deaths in Canada in 2017 owing to the advanced stage at which most are diagnosed [6]. It is less common in the West compared to globally where is ranks 9th in incidence and 6th in mortality among cancers [7].

Many esophageal cancer risks depend on the subtype of cancer, for example esophageal adenocarcinoma (EAC) vs. esophageal squamous cell carcinoma (ESCC). There is a trend toward higher incidence rates of EAC and lower incidence rates of ESCC in high-income Western countries and this can be attributed to increasing rates of obesity and GERD, which are strongly associated with EAC, and decreasing rates of smoking, a leading cause of ESCC [9, 10]. 

In general, esophageal cancer affects men 3-4 times more than women. African-americans are twice as likely to develop esophageal cancer than caucasian people. Smoking, alcohol-intake, obesity, and lower esophageal irritation (GERD, Barrett’s esophagus) are major risk factors for esophageal cancers overall.

Summary of risk factors

A summary of risk factors for ESCC and EAC is below in Table 1. Esophageal cancer is relatively rare, so the risk of developing esophageal cancer in most patients with these risk factors remains low. The next section will cover prevention and screening. Please see the expandable section below for details and evidence regarding specific risk factors.

Histology Risk factors
General or unspecified

Male
Higher age
Heat and caustic injury
Radiation therapy exposure

Esophageal adenocarcinoma (EAC) Elevated BMI
Symptoms of GERD
Barrett's esophagus
Tobacco smoking
Diets rich in meat
Diets lacking fruits and vegetables
Caucasian race
Achalasia
Esophageal squamous cell carcinoma Tobacco smoking
Alcohol consumption
Achalasia
Heat and caustic injury
Hereditary conditions: Plummer-Vinson syndrome, Fanconi anemia, Bloom syndrome, tylosis
Personal history of head and neck SCC
HPV infection and nutritional deficiences, but less relevant in Western populations

 

//Expandable header// Risk Factors

We will cover in more detail the specific risk factors for esophageal cancer as outlined in Table 1.

Tobacco smoking

There is a strong relationship between smoking and the risk of developing ESCC and EAC [11]. Tobacco and alcohol consumption appear to have a synergistic effect on the risk of ESCC [12]. 

Alcohol

Heavy alcohol consumption has been found to increase the risk of developing ESCC but not EAC [13]. Alcohol and tobacco smoking synergistically increase the risk of ESCC [12].

Obesity

Overweight and obese patients are at increase risk of developing EAC, possibly as a result of increased GERD [14]. In contrast, elevated BMI appears to have a protective effect in ESCC [15].

GERD

Patients with GERD are at a markedly higher risk of developing EAC. Prolonged, more frequent, and more severe reflux symptoms confers additional risk [16].

Barrett’s esophagus

Barrett’s esophagus has a 1-7% general population prevalence and 5-15% in patients with GERD. It is believed to be a precursor to most cases of EAC [17], and patients with Barrett’s esophagus are estimated to have a 0.5% annual risk of developing EAC.

Diet

Diets rich in meat, particularly red, increase the risk of EAC. Alternatively, fruits and vegetable consumption may have a protective role in EAC [18]. There is evidence that nutritional deficiences in riboflavin, nicotinic acid, magnesium, and zinc account for increased risk of ESCC observed in high-risk regions [19].

Achalasia

Achalasia dramatically increases the risk of ESCC and, to a lesser extent, EAC [20]. It is worth noting that obstruction by lower esophageal cancer can resemble achalasia, leading to misdiagnosis. As a result, the risk of esophageal cancer is especially high in the first year following the diagnosis of achalasia.

Sex

When adjusting for age, men are around 4x more likely to develop esophageal cancer [21].

Age

The incidence rate of esophageal cancer increases with age. Among those newly diagnosed with esophageal cancer in the US, 98% are at least 45 years old [22].

Race and Ethnicity

Geographically, the incidence of esophageal cancer is highest in East Asia, followed by Southern Africa, Eastern Africa, and Northern Europe [8]. While most esophageal cancers diagnosed in these high-incidence regions at ESCC, their etiology is less clear than those diagnosed in the West [8]. Possible culprits include HPV infection and dietary deficiencies, but a causal link has not been established [23].

In the US, Caucasians have higher incidence rates of esophageal cancer than Asians, Hispanics, American Indians, and Blacks. Caucasians are at particular risk for EAC, while Blacks and Asians more commonly develop ESCC [22].

Prevention

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).

Screening

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:

  1. Male sex
  2. Age >50
  3. Caucasian race
  4. Elevated BMI
  5. Known hiatal hernia
  6. History of tobacco smoking
  7. Nocturnal reflux symptoms
  8. Positive first-degree family history of EAC or Barrett’s esophagus.

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 [28].

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 [48].

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

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Barrett’s Esophagus

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

Grade of Dysplasia
Endoscopic & Surveillance recommendations
No dysplasia Endoscopic treatment not recommended, surveillance endoscopy every 3 - 5 years
Low-grade dysplasia Endoscopic treatment can be considered, and in its absence, surveillance endoscopy every 6 - 12 months
High-grade dysplasia Endoscopic ablation/esophagectomy recommended, and in its absence, surveillance endoscopy every 3 months

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 [24]. 

Diagnosis

Diagnosis includes a full detailed history and physical examination. Esophageal cancer specific history questions and physical exam findings are detailed below.

Table 3. Assessment of suspected esophageal cancer

Work-Up:
Table 4. Investigative work-up for esophageal cancer

The normal thyroid gland is composed histologically of two main parenchymal cell types: follicular epithelial cells and C or parafollicular cells [7]. 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

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 [7].

Follicular carcinoma

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

Anaplastic carcinoma is the least common type of cancer (<1%) and occurs more often in middle ages and elderly patients [6]. 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. [6]

Medullary carcinoma

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 [6]. 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 [10]:

Figure 2. AJCC 8th edition updated TNM staging for differentiated and anaplastic thyroid carcinoma. Please note that there are specific and separate TNM staging for medullary thyroid cancer discussed in detail in the AJCC 8th edition manual and not covered in this module.

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

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:

  • For tumors < 1cm without extrathyroidal extension and no lymph node involvement: thyroid lobectomy is preferred unless there are clear indications to remove the contralateral lobe (i.e. clinically evidence thyroid cancer in the contralateral lobe, previous history of head and neck radiation, strong family history of thyroid cancer)
  • For tumors 1 - 4 cm in size without extrathyroidal extension and no lymph nodes: either total thyroidectomy or thyroid lobectomy can be performed and would be chosen either based on patient preference, ultrasound abnormalities in contalateral lobe, or on a decision that radioiodine therapy may be beneficial adjuvantly.
  • Any tumors greater or equal to 4 cm, extrathyroidal extension, or metastases deem a total thyroidectomy is recommended.
  • Additionally, total thyroidectomy should also be performed in all patients with any history of childhood head and neck radiation, and in multifocal papillary microcarcinoma (> 5 foci) [8].

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 [5]. 

Radioactive Iodine Therapy

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 [7]. Therefore, the recent treatment guidelines recommend consideration of adjuvant 131-Iodine ablation in postoperative findings of [6]:

  • Large tumor sizes (>= 4cm)
  • FTC with extensive vascular invasion
  • Microscopic or gross extrathyroid extension
  • Central or lateral compartment neck lymph node metastases
  • Distant metastases

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.

Hormonal Treatment

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

External irradiation has a definite role as an adjuvant to surgery or as treatment in the following circumstances:

  1. As an adjuvant treatment following surgery and radioactive iodine ablation when the surgical resection has been incomplete and residual microscopic or macroscopic disease is left behind which does not take up the radioisotope
  2. As a palliative treatment for inoperate unresected tumors or anaplastic carcinomas
  3. As a palliative treatment for symptomatic metastasis.

Chemotherapy

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 [5].

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 [5].

References

  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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