Esophageal cancerEsophageal cancer Data collected by : Ruwida M.S.AshourData collected by : Ruwida M.S.Ashour

It would be so delicious just for those who can

taste and swallow it !

By the end of this session , I hope you can remember the following key

points ...

What’re the symptoms and signs of esophageal cancer ?

What’s the main pathologic type of esophageal cancer?

How can we design the treatment according the staging of esophageal cancer?

Clinical Anatomy • Hollow muscular tube 25 cm in length

• spans from the cricopharyngeus at the cricoid cartilage to gastroesophageal junction (Extends from C7-T10).

• Has 4 constrictions-• At starting(cricophyrangeal junction)

• crossed by aortic arch(9’inch)

• crossed by left bronchus(11’inch)

• Pierces the diaphragm(15’inch)

• Histologically 4 layers:

mucosa, submucosa, muscular &

fibrous layer.

Four regions of the esophagus:

• Cervical = cricoid cartilage to thoracic inlet (15–18 cm from the incisor).

• Upper thoracic = thoracic inlet to tracheal bifurcation (18–24 cm).

• Mid-thoracic = tracheal bifurcation to just above the GE junction (24–32 cm).

• Lower thoracic = GE junction (32–40 cm).

Lymphatic Drainage

•The submucosal plexus drains into the regional lymph nodes in the cervical, mediastinal , paraesophageal, left gastric, and celiac axis regions

Epidemiology• Esophageal cancer is the 7th

leading cause of cancer deaths.

• In some regions, such as areas of northern Iran, southern Russia, and northern China, the incidence reaches 800 per 100,000 population.

• The incidence rises steadily with age, reaching a peak in the 6th to 7th decade of life.

• Male : Female = 3.5 : 1

• Worldwide SCC responsible for most of the cases , usually occurs in the middle 3rd of the esophagus

• Adenocarcinoma now accounts for over 50% of esophageal cancer in the USA, due to association with GERD , Barretts’s esophagus & obesity , Which is most common in the lower 3rd of the esophagus, accounting for over 65% of cases.

• (the ratio of upper : middle : lower is 15 : 50 : 35).

Can it be a place of secondary's ?

• Secondary esophageal carcinoma occurs in about 3% of patients dying with carcinoma

• Esophageal invasion by secondary carcinoma produces obstruction mimics a benign stricture or primary esophageal carcinoma.

• Fifteen cases of secondary esophageal tumor were found. The primary site was lung in seven, breast in four, and one each in the kidney (hypernephroma), pancreas, cervix (squamous cell), and bladder (transitional cell).

Autopsy and surgical pathology files at Stanford University Hospital were reviewed for cases of secondary esophageal tumor occurring during a 6 year period.

Risk Factors : Squamous Cell Carcinoma• Smoking and alcohol (80% - 90%)• Dietary factors

• N-nitroso compounds (animal carcinogens) • Pickled vegetables and other food-products • Toxin-producing fungi • Betel nut chewing • Ingestion of very hot foods and beverages (such as tea)

• Underlying esophageal disease (such as achalasia and caustic strictures, Tylosis)

• Genetic abnormalities:• p53 mutation, loss of 3p and 9q alleli, amp. Cyclin D1 & amp. EGFR

Risk Factors: Adenocarcinoma

• Associated with Barretts’s esophagus, GERD & hiatal hernia.

• Obesity (3 to 4 fold risk)

• Smoking (2 to 3 fold risk)

• Increased esophageal acid exposure such as Zollinger-Ellison syndrome.

Barrett’s esophagus is ametaplasia of the esophageal epithelial lining. The squamous epithelium is replaced by columnar epithelium,with 0.5% annual rate of neoplastic transformation.

CAN HUMAN PAPILLOMA VIRUS BE THE CAUSE ?

• HPV associated with the previously mentioned risk factors tripled the esophageal cancer risk .

• Vaccine-preventable HPV-16 and HPV-18 are the most commonly identified HPV types.

Pathophysiology

Pattern of spread• No serosal covering, direct invasion of contiguous structures occurs early.

• Commonly spread by lymphatics (70%)

• Lymph node involvement increases with T stage. • T1 – 14 to 21%

• T2 – 38 to 60%

• 25% - 30% hematogenous metastases at time of presentation.

• Most common site of metastases are • lung, liver, pleura, bone, kidney & adrenal gland

• Median survival with distant metastases – 6 to 12 months

Clinical Features• Dysphagia, the most common presenting

symptom of esophageal cancer, is initially experienced for solids but eventually progresses to include liquids.

• Weight loss - This is the second most common symptom,occurs in more than 50% of dx cases.

• Bleeding - Patients may experience bleeding from the tumor

• Pain - Pain may be felt in the epigastric or retrosternal area; pain over bony structures indicates metastatic disease

• Hoarseness - This is caused by invasion of the recurrent laryngeal nerve

• Respiratory symptoms - These can be caused by aspiration of undigested food or by direct invasion of the tracheobronchial tree by the tumor; the latter is also a sign of unresectability

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Pathology diagnosis - Upper endoscopy

Early, superficial cancer

Circumferential ulceration esophageal cancer

Malignant stricture of esophagus

Barium swallow: is very sensitive for detecting strictures and intraluminal masses, but does not allow staging and biopsy. it may be helpful for studying the distal anatomy in obstructive tumors that are inaccessible by endoscopy.

Barium swallow demonstrating an endoluminal mass in the mid

esophagus

Barium swallow demonstrating stricture

•Staging: • CT chest and abdomen: Essential for staging because it can identify extension

beyond the esophageal wall, enlarged lymph nodes and visceral metastases.

Figure Esophageal cancer with tracheal invasion. CT scan shows circumferential wall thickening of the proximal esophagus (arrowheads), which shows irregular interface with the posterior wall of the trachea (arrows), indicating direct extension into the lumen

Endoscopic Ultrasonography

• Endoscopic ultrasonography (EUS) is the most sensitive test for determining the depth of tumor penetration (T staging) and the presence of enlarged periesophageal lymph nodes (N staging)

• Resolution of EUS permits the distinction of T1, T2, T3, and T4 tumors. Esophageal carcinoma appears as a hypoechoic lesion disrupting the normal circumferential layers.

• At this time, only EUS is useful in distinguishing T1 and T2 lesions.At this time, only EUS is useful in distinguishing T1 and T2 lesions.

PET Scan• most recently, proven to be valuable staging tool

• can detect up to 15–20% of metastases not seen on CT and EUS

• low accuracy in detecting local nodal disease compared to CT / EUS

• addition of PET to CT can improve specificity and accuracy of non-invasive staging

Figure Distant lymph node metastases of esophageal cancer detected by integrated CT PET. A, Integrated CT PET demonstrates para-aortic lymph node metastases showing increased FDG uptake (arrowheads). B, Corresponding CT image shows lymph nodes (arrowheads) measuring 5 to 8 mm in diameter. Based on size criteria, these lymph nodes may be considered benign on CT scan

Imaging and prognosis

• Recent studies found that a higher initial standardized uptake value (PET) scanning is associated with poorer overall survival among patients with esophageal or gastroesophageal carcinoma receiving chemoradiation.

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Other regular tests

TNM stage

T stage (Tumor)

TisT1

T2T3

T4

Mucosa

Staging

a: Includes nodes previously labeled as “M1a”

b : “M1a” designation is no longer recognized in the 7th edn. of the AJCC system

Staging : Squamous cell carcinoma

Staging : Adenocarcinoma

Group T N M Grade

0 Tis (HGD)

N0

M0

1, X

IA T1 1-2, X

IB T1 3

T2 1-2, X

IIA T2 3

IIB T3

Any

T1-2 N1

IIIA T1-2 N2

T3 N1

T4a N0

IIIB T3 N2

IIIC T4a N1-2

T4b Any

Any N3

IV Any Any M1

Prognosis• Survival in patients with

esophageal cancer depends on the stage of the disease. Squamous cell carcinoma and adenocarcinoma, stage-by-stage, appear to have equivalent survival rates.

• In 2001-2007, the overall 5-year survival rate for esophageal cancer was 19%

KIAA0101

• KIAA0101 is emerging as a meaningful marker for poor prognosis in EC, such as early recurrence and short survival.

• study shows that KIAA0101 upregulates cell mitosis via an increase in cyclins A and B, resulting in enhanced cell resistance to cisplatin. These data may provide mechanistic evidence for the reduced chemosensitivity to cisplatin-based therapy seen in EC.

How to design the treatment plan ?Staging ,whether the cancer has invaded nearby

structures , whether the cancer has spread to lymph nodes or other organs

where the cancer is located within the esophagus

The general health of patient

Regimen• Endoscopic Mucosal Resection(EMR)

• Surgery

• Chemotherapy

• Radiotherapy

• Combined-modality therapy

• Palliative Therapy

Endoscopic Mucosal Resection(EMR)

• Indication of EMR

Tis or T1a (defined as tumor involving the mucusa but not involving submucosa)

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A population-based study of 1618 patients with grade Tis, T1a, or T1b esophageal cancer found that overall survival times and esophageal-cancer-specific survival times with endoscopic therapy were similar to those with surgery, after adjustment for patient and tumor factors

Endoscopic Therapy for Localized Disease o endoscopic therapy is a safe, less invasive, and effective therapy for very early

esophageal cancer.

o The candidates are Stage 1 patients with tumors invading into the lamina propria (T1 mucosal) or submucosa (T1 submucosal) that do not have regional or distant metastasis. Patients with carcinoma in-situ or high-grade dysplasia can also be treated with endoscopic therapy.

o The two forms of endoscopic therapy that have been used for Stage 0 and I disease are endoscopic mucosal resection (EMR) and mucosal ablation using photodynamic therapy , Nd-YAG laser, or argon plasma coagulation.

o The prognosis after treatment with endoscopic mucosal resection is comparable to surgical resection

The strip biopsy of EMR

• After marking the lesion border with an electric coagulator, saline is injected into the submucosa below the lesion to separate the lesion from the muscle layer and to force its protrusion

• The grasping forceps are passed through the snare loop. The mucosa surrounding the lesion is grasped, lifted, and strangulated and resected by electrocautery  

• The endoscopic double-snare polypectomy indicated for protruding lesions. Using a double-channel scope, the lesion is grasped and lifted by the first snare and strangulated with the second snare for complete resection.

• Endoscopic resection with injection of concentrated saline and epinephrine is carried out using a double-channel scope. The lesion borders are marked with a coagulator. Highly concentrated saline and epinephrine are injected (15–20 ml) into the submucosal layer to swell the area containing the lesion and elucidate the markings. The mucosa outside the demarcated border is excised using a high-frequency scalpel to the depth of the submucosal layer. The resected mucosa is lifted and grasped with forceps, trapping and strangulating the lesion with a snare, and then resected by electrocautery.

• the use of a clear cap and prelooped snare inside the cap. After insertion, the cap is placed on the lesion and the mucosa containing the lesion is drawn up inside the cap by aspiration. The mucosa is caught by the snare and strangulated, and finally resected by electrocautery. This is called the "band and snare" or "suck and cut" technique.

• The resulting "ulcer" heals within 3 weeks

• The major complications of endoscopic mucosal resection include postoperative bleeding and perforation and stricture formation.

• It is important to administer acid-reducing medications to prevent postoperative hemorrhage.

• Perforation may be prevented with sufficient saline injection to raise the mucosa containing the lesion. The "non-lifting sign" and complaints of pain when the snare strangulates the lesion are contrainidications of EMR.

• When perforation is recognized immediately after a procedure, the perforation should be closed by clips. Surgery should be considered in cases of endoscopic closure failure. The incidence of complication range from 0–50% and squamous cell recurrence rates range from 0–8%.

Photodynamic Therapy 

• It involves application of photosensitizer drug which has a preferential localization in high concentration in the dysplastic and malignant tissue.

• In the presence of oxygen, laser light at a specific wavelength activates the drug and results in a photochemical reaction that leads to selective tissue destruction.

• Some patients have experienced dysrhythmias as well as nausea ,photosensitivity and stricture formation (which, in most cases, have responded to endoscopic dilation).

Radiotherapy for CA esophagus

Chemoradiotherapy• While the radiotherapy acts locally at the tumor site, the chemotherapy acts on tumor cells that have

already spread. This combination therapy is usually administered over a 45-day period; esophageal resection is performed after an interval of approximately 4 weeks.

• Chemotherapy and radiotherapy for esophageal cancer are delivered preoperatively , to reduce the bulk of the primary tumor before surgery to facilitate higher curative resection rates and to eliminate or delay the appearance of distant metastases.

• No survival benefit is obtained when radiation and chemotherapy are administered postoperatively

• British investigators found that preoperative chemotherapy with cisplatin and fluorouracil resulted in a 5-year survival rate of 23.0%, compared with 17.1% for surgery alone.

• Definitive chemoradiotherapy using fluorouracil plus leucovorin and oxaliplatin (FOLFOX) is an easier, less toxic, and cheaper option than chemoradiotherapy with fluorouracil and cisplatin, the researchers note

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• Median overall survival with chemoradiation therapy followed by surgery was 49.4 months, compared with 24.0 months with surgery alone.

• Overall recurrence rates were 35% for CRT plus surgery and 58% for surgery alone.

Surgery

• Prerequisite for surgery• disease should be 5 cm beyond cricophyrangeus.

• Surgery indications• Lower 1/3 rd oesophageal ds involving GE junction.

• Tumor size <5 cm .

• palliative surgery

• (no significant difference between surgical techniques according to results of 2 meta-analyses)

Contraindications of operation• Metastasis to N2 nodes or solid organs

• Invasion of adjacent structures (eg, the recurrent laryngeal nerve, tracheobronchial tree, aorta, pericardium)

In addition, the presence of severe, associated comorbid conditions (eg, cardiovascular disease, respiratory disease) can decrease a patient's chances of surviving an esophageal resection.

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Types of Surgery• Transhiatal esophagectomy: for tumors anywhere in esophagus or gastric

cardia. No thoracotomy. Blunt dissection of the thoracic esophagus. Left with cervical anastomosis. Limitations are lack of exposure of midesophagus and direct visualization and dissection of the subcarinal LN cannot be performed.

• Right thoracotomy (Ivor-Lewis procedure): good for exposure of mid to upper esophageal lesions. Left with thoracic or cervical anastomosis.

• Left thoracotomy: appropriate for lower third of esophagus and gastric cardia. Left with low-to-midthoracic anastomosis.

• Radical (en block) resection: for tumor anywhere in esophagus or gastric cardia. Left with cervical or thoracic anastomosis. Benefit is more extensive lymphadenectomy and potentially better survival, but increased operative risk.

Transhiatal esophagectomy• Transhiatal esophagectomy is most frequently

performed and recommended for early esophageal cancers of the middle (below the level of carina) and lower third of esophagus (type I and II tumors of esophagogastric junction).

• However, transhiatal esophageal resection may be feasible in upper esophageal carcinomas in some cases.

• Transhiatal esophageal resection is also performed for advanced esophageal cancers in patients who are not fit to undergo a thoracotomy.

Transhiatal esophagectomyIncisions and mobilization of the

stomach. Mobilization of Stomach

Widening of hiatus Cervical Incision

Exposure of Cervical esophagus.

Mobilization of Cervicothoracic esophagus.

Esophageal mobilization on anterior aspect.

Esophageal mobilization on posterior aspect.

Transection of Cervical Esophagus Creation of Stomach tube.

Stomach tube Stomach tube pushed through hiatus towards the neck.

Esophagogastric Anastomosis with a Linear Cutting Stapler.

Completion of the esophagogastric anastomosis.

Postoperative Care and Follow-up• feeding through the feeding jejunostomy begins on postoperative day1.

• On postoperative day 6, a swallow study is performed to check for anastomotic leakage. If no leak is present, patients start oral feedings. If a leak is present, the drainage tubes are left in place and nutrition is provided entirely through the feeding jejunostomy until the leak closes spontaneously.

• Patients are seen by the responsible surgeon at 2 weeks and 4 weeks after discharge from the hospital and subsequently every 6 months by an oncologist. Most patients return to their regular level of activities within 2 months.

Complications Respiratory complications

Atelectasis, in 3% of cases, ,may progress to pneumonia in some cases which may prolong patient’s stay in ICU.

Pleural effusion

Postoperative hemorrhage may be mediastinal or intraperitoneal. Source of bleeding include a tear in the azygos vein, large prevertebral collateral veins, or spleen.

Chylothorax (1%) is a rare complication and is managed conservatively

Recurrent laryngeal nerve injury

The recurrent laryngeal nerve innervates the upper esophageal sphincter

Injuries occur in 1%-3% of cases. It causes vocal cord paresis and dysphagia ,aspiration,

Placement of a metal retractor alongside the tracheoesophageal groove during the cervical dissection of esophagus should also be avoided. The surgeon should handle the trachea, thyroid, and cervical esophagus with fingers, when possible

Hoarseness due to recurrent laryngeal nerve injury may resolve spontaneously, but cord medialization procedures may be required for persistent vocal cord paresis.

Cervical esophagogastric anastomotic leak

may lead to stricture formation.

Use of a side-to-side stapled cervical esophagogastric anastomosis has reduced the incidence of anastomotic leak.

•Mangement by opening the neck wound at the bedside and local wound packing until healing by secondary intent occurs.

Patient may be put on jejunal feeds until the anastomotic leak is controlled.

For fistula due to anastomotic leak, early bedside esophageal anastomotic dilatation (with 36F, 40F, and 46F dilators) within 1 week is very helpful and results in early closure of the fistula by allowing preferential flow of swallowed esophageal contents down the true lumen rather than through the leak.

 Stent placement can also facilitate fistula closure and is perhaps the preferred avenue when an anastomotic leak is encountered.

• Gastroesophageal reflux

• Performing an anastomosis about 3-5 cm below the highest point on the anterior wall of the stomach in the neck and creating an acute angle of entry of the esophagus into the stomach leaves some retroesophageal stomach to distend with air and may provide some type of antireflux mechanism

• A pyloroplasty or pyloromyotomy ensures adequate gastric emptying and is performed routinely in some centers,avoiding the pyloromyotomy protects from the occurrence of severe complications, such as dumping syndrome, diarrhea, or leakage from the myotomy

•Delayed gastric emptying • is rare if pyloromyotomy is performed,; most of these patients can be managed

with prokinetic agents. However, endoscopic balloon dilatation of the pylorus is occasionally required.

• early removal of the drain from the cervical wound may result in formation of cervical abscess. A closed suction drain should be left for a sufficient period, and oral feeding should be delayed if an anastomotic leak is suspected.]Cervical abscess should be promptly treated, as it may lead to tracheogastric fistula.

Palliative care • In patients who are not candidates for surgery, treatment focuses

on control of dysphagia.

• The most appropriate method is determined for each patient individually, depending on tumor characteristics, patient preference, and the specific expertise of the physician.

• The following treatment modalities are available to help achieve this goal:

• Chemotherapy

• Radiotherapy

• Laser therapy

• Stents[68]

• CHEMOTHERPAY

• Studies found that no consistent benefit with any specific chemotherapy regimen, Cisplatin, 5-fluorouracil (5-FU), paclitaxel, and anthracyclines had promising response rates and tolerable toxicity.

• Radiotherapy

• Radiation therapy is successful in relieving dysphagia in approximately 50% of patients

• In a study, Folkert et al found that high-dose-rate (HDR) endoluminal brachytherapy was well tolerated in medically inoperable patients with superficial primary or recurrent esophageal cancer.

Laser therapy

• Laser therapy (Nd:YAG laser) can help to achieve temporary relief of dysphagia in as many as 70% of patients.

• The photosensitizer porfimer (Photofrin) is FDA approved for palliation of patients with completely obstructing esophageal cancer or partially obstructing cancer that cannot be satisfactorily treated with Nd:YAG laser therapy.

Stents• Patients may be intubated

with expandable metallic stents, which can be deployed by endoscopy under fluoroscopic guidance and can keep the esophageal lumen patent.

• Stents are particularly useful for patients with a tracheoesophageal fistula.

Figure: A proposed treatment algorithm for esophageal cancer.

Conclusion• Esophageal cancer is the 7th leading cause of cancer deaths.

• Adenocarcinoma now accounts for over 50% of esophageal cancer in the USA, due to association with GERD & obesity.

• Dysphagia and weight loss are the two most common presentations in patients with esophageal cancer.

• Endoscopic ultrasound (EUS) is necessary to accompany a complete workup for proper staging and diagnosis of esophageal cancer.

• Surgery is the standard of care for early-stage esophageal cancer.

• The hand-sewn anastomosis technique leads to more leaks, while stapled anastomosis leads to more strictures

• Preoperative chemotherapy and radiation is the standard option for locally advanced esophageal cancer in surgically eligible patients.

Thanks for your attentionThanks for your attention