8 Pathology of the Esophagus

Question 1

Esophagus (p.2-4)

Question 2

Esophagitis (p.6)

Answer 2

• “Inflammation of the esophageal mucosa.”
• common worldwide.
• A variety of physical, chemical, or infectious agents can cause esophageal inflammation and injury.

Question 3

Reflux esophagitis (p.7-10)

• most important cause of esophagitis
• Endoscopically, the esophagus may appear/
• The histologic features of gastroesophageal reflux esophagitis are nonspecific and include/
• the histologic findings must be correlated with/
• Clinically, patients complain of/
• the severity of symptoms/
• Epithelial damage appears to be correlated with/

Answer 3

• Reflux of gastric contents into the lower esophagus is the most important cause of esophagitis.
• Endoscopically, the esophagus may appear red (erythematous) or, in more severe cases, ulcerated.
• The histologic features of gastroesophageal reflux esophagitis are nonspecific and include:
  
  • inflammation, composed of intraepithelial lymphocytes, eosinophils and neutrophils;
  • intercellular edema;
  • hyperplasia of the basal zone of the squamous epithelium (a proliferative response to injury);
  • elongation of lamina propria papillae with capillary congestion, extending into the top third of the epithelial layer.
• the histologic findings must be correlated with the patient’s symptoms and exclusion of other possible etiologies.
• Clinically, patients complain of dysphagia, heartburn, and sometimes regurgitation of sour fluid or blood.
• the severity of symptoms is not closely related to the presence or degree of histologic esophagitis;
  
  • most people experience reflux symptoms without damage to the distal esophageal mucosa, due to the short duration of the reflux.
• Epithelial damage appears to be correlated with prolonged exposure of the lower esophagus to refluxed gastric contents.

Question 4

Infectious esophagitis (p.17-22)

Question 5

Infectious esophagitis:
Herpes simplex virus (HSV) esophagitis (p.23+27)

• most common in/
• the pathogen
• Clinically patients present with/
• causes/
• Histologically, ulceration/
• The diagnostic finding in HSV infection of the esophagus are/
• what must be taken in this location

Answer 5

• most common in immunosuppressed patients, especially transplant patients.
• HSV-1 is the pathogen.
• Clinically patients present with dysphagia and odynophagia (painful swallowing).
• causes the formation of vesicles due to infection of squamous epithelial cells which coalesce and result in mucosal ulceration.
• Histologically, ulceration is a non-specific finding which can be caused by any type of esophagitis.
• The diagnostic finding in HSV infection of the esophagus are viral inclusions in the nuclei of squamous epithelial cells.
  
  • Multinucleated squamous epithelial cells with nuclear viral inclusions are also common.
  • These changes are especially prominent immediately adjacent to the ulcer
• hence a diagnostic biopsy must be taken in this location.

Question 6

Infectious esophagitis:
Cytomegalovirus (CMV) esophagitis (p.25-27)

• CMV esophagitis
• can cause/
• present clinically with/
• The diagnostic finding in CMV esophagitis
• diagnostic biopsies

Answer 6

• CMV esophagitis is an infection which is most common in immunosuppressed patients.
• can cause ulceration of the esophageal mucosa
• present clinically with dysphagia and odynophagia.
  
  • Systemic symptoms may be present.
• The diagnostic finding in CMV esophagitis
  
  • viral inclusions in the cytoplasm and nuclei of infected stromal, inflammatory and endothelial cells at the base of the ulcer.
  • The viral inclusions can cause marked enlargement of the cells
• Given that HSV and CMV infections occur in the same patient population and cause similar symptoms and findings, diagnostic biopsies should be obtained from the base and edge of any ulcer when these infections are suspected.

Question 7

Infectious esophagitis:
Candida esophagitis (p.28-31)

• due to/
• common in/
• Patients report/
• identified in mucosal biopsies
• Accompanying non-specific histologic changes may include/
• in immunosuppressed patients/

Answer 7

• due to infection by the fungal organism Candida albicans.
• common in debilitated or immunosuppressed patients (especially HIV patients) and in patients receiving broad-spectrum antimicrobial therapy.
• Patients report
  
  • _​_a history of odynophagia.
  • White plaques in the esophagus which can be extensive and confluent and associated with ulceration.
  • Oropharyngeal involvement (thrush)
• Fungal organisms in both yeast and pseudohyphal forms are identified in mucosal biopsies.
• Accompanying non-specific histologic changes may include ulceration and acute inflammation (intraepithelial neutrophils).
• in immunosuppressed patients, multiple infectious organisms may be present simultaneously.

Question 8

Eosinophilic esophagitis (p.11-16)

• Definition
• Clinically, occurs/
• related to/
  
  • Some patients have other associated/
• Clinically, patients have symptoms of/
• response to medications
• On endoscopy, there’s a/
• Esophageal biopsies are characterized by/
  
  • patients with GERD/
• the eosinophilic inflammation involves/
• treatment
  
  • All patients with suspected allergic eosinophilic esophagitis should receive/
  • The mechanism by which PPI’s reduce esophageal eosinophilia may include/
  • Patients who do not respond to PPI therapy may require/

Answer 8

• Definition: esophagitis characterized by increased intraepithelial eosinophils in the esophagus with characteristic clinical and endoscopic features.
• Clinically, occurs both in children and adults.
• related to allergen exposure (either ingested or possibly inhaled)
  
  • Some patients have other associated allergic disorders (e.g. asthma, atopic dermatitis, rhinitis).
• Clinically, patients have symptoms of dysphagia, food impaction with or without reflux symptoms.
• Patients do not improve on medications for reflux esophagitis and often respond to anti-inflammatory medications and dietary modification.
• On endoscopy, there’s a “corrugated” (trachealized, ringed) appearance, linear furrows, punctate white plaques and proximal stenosis.
• Esophageal biopsies are characterized by epithelial infiltration by numerous eosinophils
  
  • patients with GERD also have eosinophils—patients with eosinophilic esophagitis typically have many more
• the eosinophilic inflammation involves both the proximal and distal esophagus.
  
  • This would be unusual in simple reflux esophagitis.
• treatment
  
  • All patients with suspected allergic eosinophilic esophagitis should receive a trial of acid suppression (proton pump inhibitors) because a large minority of patients will respond to this treatment.
    
    • This is called PPI responsive esophageal eosinophilia.
  • The mechanism by which PPI’s reduce esophageal eosinophilia may include indirect effects such as reducing the permeability of the esophageal mucosa to allergens by reducing injury caused by acid exposure.
  • Patients who do not respond to PPI therapy may require dietary modification and topical steroids (e.g. swallowed fluticasone).

Question 9

Quiz Questions (p.32-36)

Question 10

Esophageal Neoplasia (p.38-40+42)

• Neoplasia
• Benign tumors
• Malignant tumors
• Both benign and malignant neoplasms can arise within/
• In the esophagus and in the GI tract in general, the most common neoplasms tend to resemble/
• in the colon, the most common malignant neoplasm is/
• Worldwide, the most common form of malignant esophageal neoplasia is/
• in the US, the most common form of esophageal carcinoma is/
• In the esophagus, some neoplasms resemble other cell types, such as/

Answer 10

• Neoplasia
  
  • “new growth.”
  • encompasses both benign and malignant growths or “tumors”.
• Benign tumors tend to grow where they started and are usually cured by complete local excision.
• Malignant tumors invade into the organ and some find their way into blood vessels and lymphatics and spread around the body (metastasize) and may cause the death of the patient.
• Both benign and malignant neoplasms can arise within the esophagus.
• In the esophagus and in the GI tract in general, the most common neoplasms tend to resemble the epithelium lining the organ, most likely because the cells which normally differentiate into epithelial cells are exposed to potential carcinogens and other causes of genetic damage.
• in the colon, the most common malignant neoplasm is the adenocarcinoma which forms glands which resemble the glandular epithelium lining the colon.
• Worldwide, the most common form of malignant esophageal neoplasia is squamous cell carcinoma which resembles the normal squamous epithelium.
• in the US, the most common form of esophageal carcinoma is adenocarcinoma.
• In the esophagus, some neoplasms resemble other cell types, such as smooth muscle cells that reside in the muscularis propria (leiomyomas), melanocytes (melanoma), lymphocytes (lymphoma), and so on.

Question 11

Malignant Neoplasms (p.43)

• In the US, malignancies of the esophagus represent/
• The vast majority of malignant esophageal tumors are/
• adenocarcinoma of the esophagus and gastroesophageal junction vs. squamous cell carcinoma
  
  • in the US
  • worldwide

Answer 11

• In the US, malignancies of the esophagus represent about 6% of all cancers of the gastrointestinal tract but cause a disproportionate number of cancer deaths.
• The vast majority of malignant esophageal tumors are epithelial in origin.
• adenocarcinoma of the esophagus and gastroesophageal junction vs. squamous cell carcinoma
  
  • in the US, adenocarcinoma of the esophagus and gastroesophageal junction is more common than squamous cell carcinoma due to the rising incidence of adenocarcinoma over the past several decades.
  • worldwide, squamous cell cancers constitute 90% of esophageal cancers.

Question 12

Adenocarcinoma of the esophagus:
Etiology and Pathogenesis (p.44-45)

• Adenocarcinoma of the esophagus is/
• Etiology and Pathogenesis
• Barrett esophagus affects/

Answer 12

• Adenocarcinoma of the esophagus is a malignant epithelial tumor with glandular differentiation.
• Etiology and Pathogenesis
  
  • First, the epithelial lining of the esophagus changes from squamous to columnar in what is believed to be an adaptation to the abnormal chemical environment caused by acid and bile reflux.
  • This columnar change (or “metaplasia”) is termed Barrett esophagus
• Barrett esophagus affects a large fraction of the adult population because gastroesophageal reflux is so common.

Question 13

Adenocarcinoma of the esophagus:
Barret esophagus (p.49)

• the single most important risk factor for/
• factors known to increase the risk of developing Barrett esophagus include/
  
  • All of these are risk factors for/
• Smoking
• Alcohol

Answer 13

• the single most important risk factor for esophageal adenocarcinoma.
• factors known to increase the risk of developing Barrett esophagus include long duration and severity of gastroesophageal reflux symptoms, obesity, older age, male sex and Caucasian ethnicity.
  
  • All of these are risk factors for developing esophageal adenocarcinoma.
• In patients with Barrett esophagus, smoking is a risk factor for developing adenocarcinoma.
• Alcohol does not appear to be a risk factor for Barrett esophagus or subsequent adenocarcinoma.

Question 14

Adenocarcinoma of the esophagus:
The diagnosis of Barrett esophagus (p.50-52)

• The diagnosis of Barrett esophagus relies on/
• Barrett esophagus is characterized by/
• a diagnosis of Barrett esophagus requires the fulfillment of two criteria
• the diagnosis is made on/

Answer 14

• The diagnosis of Barrett esophagus relies on gross and microscopic findings.
• Barrett esophagus is characterized by replacement of the distal squamous mucosa by columnar epithelium with goblet cells (intestinal metaplasia).
• a diagnosis of Barrett esophagus requires the fulfillment of two criteria:
  
  • evidence of columnar epithelial lining above the gastroesophageal junction within the esophagus
  • goblet cells or intestinal metaplasia in the columnar epithelium.
• the diagnosis is made on endosopy.

Question 15

Adenocarcinoma of the esophagus:
Dysplasia (p.53)

• In some patients with Barrett esophagus, cells acquire
• Dysplasia
  
  • has many histologic features in common with/
  • lacks any evidence of/

Answer 15

• In some patients with Barrett esophagus, cells acquire abnormal molecular and microscopic features collectively termed “dysplasia”.
• Dysplasia
  
  • has many histologic features in common with invasive adenocarcinoma,
  • lacks any evidence of invasion: crowding of glands, nuclear enlargement, nuclear darkening (hyperchromasia), variation in nuclear shape (pleomorphism), nuclear crowding, increased mitotic activity, abnormal mitotic figures, failure to develop normal cytoplasmic appearance (loss of differentiation), among others.

Question 16

Adenocarcinoma of the esophagus:
At the molecular level (p.54)

• At the molecular level, dysplasia/
• the pathogenesis of adenocarcinoma from Barrett esophagus

Answer 16

• At the molecular level, dysplasia
  
  • shares properties in common with invasive adenocarcinoma:
  • abnormal chromosome counts (aneuploidy), mutations in tumor suppressor genes such as TP53 (p53) and CDKN2A (p16). M
• the pathogenesis of adenocarcinoma from Barrett esophagus
  
  • a multistep process with a long latency period associated with multiple genetic changes.
  • The development of dysplasia seems to be a critical step in this process.

Question 17

Adenocarcinoma of the esophagus:
From a clinician’s standpoint (p.55)

• From a clinician’s standpoint, dysplasia can in theory be entirely cured by/
• in patients with Barrett esophagus who are diagnosed with dysplasia the risk of developing cancer/
  
  • some patients who are diagnosed initially with dysplasia are found to have/
• dysplasia is a risk factor for/
• cells within dysplastic epithelium give rise to/

Answer 17

• From a clinician’s standpoint, dysplasia can in theory be entirely cured by local excision or destruction of the lesion because there is no invasion.
• in patients with Barrett esophagus who are diagnosed with dysplasia the risk of developing cancer is increased several fold over those who have Barrett esophagus without dysplasia.
  
  • some patients who are diagnosed initially with dysplasia are found to have invasive carcinoma on more careful evaluation of the esophagus.
• dysplasia is a risk factor for
  
  • subsequent invasive cancer
  • synchronous carcinoma.
• cells within dysplastic epithelium give rise to cells that have the capacity to invade and ultimately to metastasize if they are allowed to persist.

Question 18

Adenocarcinoma of the esophagus:
Diagnosis of dysplasia

• the diagnosis of dysplasia
• Several different techniques are currently used to eradicate dysplastic Barrett’s esophagus ranging from/
• Patients with successfully treated dysplasia/

Answer 18

• Because patients with dysplasia are at risk of developing cancer in the future or harboring an occult carcinoma at the present, the diagnosis of dysplasia requires
  
  • eradication
  • a very careful search for invasive carcinoma.
• Several different techniques are currently used to eradicate dysplastic Barrett’s esophagus ranging from esophagectomy to endoscopic excision to radiofrequency ablation, liquid nitrogen (cryotherapy) among others.
• Patients with successfully treated dysplasia return to their gastroenterologist for surveillance because they are believed to be at risk for dysplasia and adenocarcinoma in the future.

Question 19

Adenocarcinoma of the esophagus:
The hallmark of carcinoma (p.57-60)

• The hallmark of carcinoma is/
• most adenocarcinomas
  
  • arise/
  • tend to be located in/
  • may invade/
• Early lesions can appear as/
• More advanced lesions/
• early cancers can spread/
• Microscopically,
  
  • most tumors are/
  • less often they are made up of/
• Dysplastic epithelium is frequently located/

Answer 19

• The hallmark of carcinoma is invasion beyond the basement membrane of the mucosal lining of the esophagus.
• most adenocarcinomas
  
  • arise in the setting of Barrett esophagus,
  • tend to be located in the distal esophagus
  • may invade the adjacent stomach.
• Early lesions can appear as small nodules within otherwise intact mucosa.
• More advanced lesions for large tumors can obstruct the lumen and deeply infiltrate the wall of the esophagus causing luminal narrowing.
• early cancers can spread
  
  • to regional lymph nodes via lymphatics that naturally drain the distal esophagus around the esophagus
  • to distant sites such as the liver, lungs and bone marrow by invading into veins.
• Microscopically,
  
  • most tumors are mucin-producing gland-forming tumors;
  • less often they are made up of poorly differentiated signet-ring cells.
• Dysplastic epithelium is frequently located adjacent to the invasive carcinoma, which is one of the reasons dysplasia is believed to give rise to invasive adenocarcinoma.

Question 20

Adenocarcinoma of the esophagus:
The prognosis for esophageal adenocarcinoma

• The prognosis for esophageal adenocarcinoma
• stage refers to/
• For tumors that are confined to the superficial layers (e.g. the mucosa or submucosa) and without metastases five-year survival may be/
• For metastatic cancers, 5 year survival is/
• most adenocarcinomas are still diagnosed/

Answer 20

• The prognosis for esophageal adenocarcinoma
  
  • poor,
  • strongly dependent upon the stage at which it is treated.
• stage refers to the extent of disease:
  
  • how deeply into the wall of the esophagus the tumor invades (T stage),
  • presence or absence of regional lymph node metastases (N stage),
  • presence or absence of distant metastasis (M stage).
• For tumors that are confined to the superficial layers (e.g. the mucosa or submucosa) and without metastases five-year survival may be over 80%.
• For metastatic cancers, 5 year survival is below 10%.
• most adenocarcinomas are still diagnosed at an advanced stage, though screening and surveillance of Barrett esophagus has yielded an increase in the number of patients diagnosed with early cancers that are curable.

Question 21

Adenocarcinoma of the esophagus:
Clinical features of adenocarcinoma

• Patients with adenocarcinoma usually present with/
• gastroesophageal reflux

Answer 21

• Patients with adenocarcinoma usually present with
  
  • progressive dysphagia for solid food accompanied by weight loss.
  • Weight loss is related to dysphagia, dietary modification as well as tumor-associated anorexia.
  • Chronic bleeding may lead to anemia.
• gastroesophageal reflux
  
  • a significant risk factor for esophageal adenocarcinoma,
  • fewer than ½ of new cases are associated with long-term symptoms of GERD (presumably many patients have reflux and are asymptomatic).
  • This is a chief reason why people argue that screening for Barrett esophagus based on reflux symptoms will only prevent a small fraction of esophageal adenocarcinomas.

Question 22

Squamous cell carcinoma (SCC):
Etiology and Pathogenesis

• SCC
  
  • frequency
  • gender
  • incidence
• Etiology and Pathogenesis
  
  • The majority of cancers in the US and Europe are attributable to/
  • Other factors associated with the development of SCC
    
    • Dietary factors
    • lifestyle factors
    • esophageal disorders
    • genetic predisposition
  • Gender/

Answer 22

• SCC
  
  • the most common type of carcinoma in the esophagus worldwide.
  • male-to-female ratio is 4:1.
  • incidence varies widely
• Etiology and Pathogenesis
  
  • The majority of cancers in the US and Europe are attributable to alcohol and tobacco usage.
  • Other factors associated with the development of SCC
    
    • Dietary factors (deficiency of vitamins and trace elements, fungal contamination of foodstuffs; high content of nitrites/nitrosamines, Betel chewing);
    • lifestyle factors (regular consumption of burning-hot beverages or food, alcohol consumption, tobacco use, urban environment);
    • esophageal disorders (long-standing esophagitis, achalasia, Plummer-Vinson syndrome);
    • genetic predisposition (long-standing celiac disease, ectodermal dysplasia, epidermolysis bullosa, racial predisposition—e.g. in the US, SCC is significantly more common among African-Americans).
  • Gender is not a major risk factor in high incidence areas, but in low incidence areas (such as the US) males are more often affected.

Question 23

Squamous cell carcinoma (SCC):
Morphology (p.63-67)

• SCC tend to arise/
• SCC often arise from areas of/
• Early lesions may appear/
• Most cases of SCC are detected late, and appear/
• Histologically, most SCCs are/
• In contrast to adenocarcinoma/

Answer 23

• SCC tend to arise
  
  • 50% in the middle third of the esophagus
  • 20% arising in the upper third
  • 30% in the lower third.
• SCC often arise from areas of squamous dysplasia.
• Early lesions may appear plaque-like.
• Most cases of SCC are detected late, and appear as protruding or ulcerated masses that can circumferentially involve the esophagus.
• Histologically, most SCCs are moderately to well differentiated and deeply invade into the wall of the esophagus.
• In contrast to adenocarcinoma which tends to form gland like structures and produce intracellular mucin, squamous cell carcinoma has features reminiscent of normal squamous epithelium such as the angulated shape of cells, keratin production, presence of desmosomes which form intracellular bridges.

Question 24

Squamous cell carcinoma (SCC):
Clinical Features

• presentation
• Although the insidious growth of these neoplasms often leads to large lesions by the time a diagnosis is established, resectability rates/
• The five-year survival rate
  
  • in patients with superficial esophageal carcinoma
  • in patients who undergo surgery for advanced local disease
  • for all patients with esophageal SCC
• Local and distant recurrence following surgery

Answer 24

• presentation
  
  • a history of progressive dysphagia for solid food and weight loss.
  • Involvement of the recurrent laryngeal nerve may lead to hoarseness.
  • Chronic blood loss may lead to anemia.
• Although the insidious growth of these neoplasms often leads to large lesions by the time a diagnosis is established, resectability rates have improved modestly (from less than half to over 80%) with the advent of endoscopic screening in patient populations at risk and accurate staging by endoscopic ultrasonography.
• The five-year survival rate
  
  • in patients with superficial esophageal carcinoma is about 75%,
  • 25% in patients who undergo surgery for advanced local disease
  • 9% for all patients with esophageal SCC.
• Local and distant recurrence following surgery
  
  • common.
  • The presence of lymph node metastases at the time of resection significantly reduces five-year survival.

Question 25

Quiz Questions (p.68-72)