Core Curriculum: Esophageal Cancer Ben Cohen, MD February 1, 2011

Core Curriculum:
Esophageal Cancer
Ben Cohen, MD
February 1, 2011
  Incidence:
  Worldwide
  500,000 worldwide in 2007
  6th leading cancer in men; 9th leading cancer in women
  US
  16,470 in 2008
  Age-adjusted incidence rate
  Men = 7.5/100,000
  Women = 1.8/100,000
  Black men have highest incidence
  Median age at diagnosis is 69
Esophageal Cancer
  Mortality:
  5th leading cause of cancer
death in men and 9th in
  5 yr survival by race and
gender from 1996-2004
  Men: White 16.5%;
Black 9.2%
  Women: White 17.6%;
Black 12.9%
2003-2007 SEER Data
Squamous Cell Cancer
  80% occur in developing countries
  “Asian esophageal cancer belt”
  Within this region there are unexplained shifts in
  Gender differences only seem to exist in lowincidence areas
  Risk factors for diagnosis include low SES and
being single
  Comprised 90% of all Esophageal Cancer in the
Risk Factors for Squamous
Cell CA
  Associated with chronic irritation/inflammation
  Dietary/Nutritional Factors
  N-nitroso compounds from reduced dietary nitrates
  Zinc deficiency potentiates nitrosamine effect
  Selenium is protective
  RCT with Selenium and/or Celecoxib in Chinese patients
with dysplasia showed non-sig trend towards dysplasia
regression and less progression
  In high incidence areas drinking tap water, drinking hot
beverages, and exposure to polycyclic aromatic
hydrocarbons (coal burning stoves) have been shown to be
potentially carcinogenic
  Coffee, fruit, fish, white meat may be protective
Risk Factors for Squamous
Cell CA
  Alcohol and Tobacco
  Dominant risk factor in low incidence area, but not high
incidence area
  Susceptibility may be determined by gene encoding for
alcohol metabolism
  Pre-Existing Esophageal Disease
  Achalasia
  Lye ingestion
  Tylosis
  Autosomal dominant with hyperkeratosis of palms/soles
  40-92% lifetime risk
  Tylosis Esophageal Cancer (TOC) gene locus on chrom 17q25
  Plummer-Vinson Syndrome (US) or Patterson-Kelly Syndrome
Risk Factors for
  Dietary/Nutritional
  High cholesterol and B12 associated with increase
  Antioxidants may be protective
  Alcohol/Tobacco
  Alcohol has no association
  Tobacco confers less risk than with squamous cell
cancer: [HR] 9.3 vs 3.7
Risk Factors for
- BMI > 25 kg/
m2 
and Cardia
Risk Factors for
  Lagergren et al. NEJM 1999
  Swedish Population-Based Study
  Pts with recurrent GERD symptoms have OR [7.7] for
  Risk increased with frequency, severity, duration
  H Pylori?
  Has not been proven that HP eradication leads to new
or recurrent GERD symptoms
  Meta-analysis has shown HP infection more likely in
squamous cell CA than adenoCA
Risk Factors for
  Barrett’s
  Stratified squamous epithelium replaced with
specialized columnar epithelium
  Overall pooled risk is 4.1/1000 person-yrs when
excluding HGD or early incident cancer
  Long Segment
  Annual Risk of developing HGD or Cancer is 1% & 0.5%
  Incidence rate of cancer in HGD is 10x LGD
  Short Segment
  Risk is unknown
Risk Factors for
  Pre-existing Disease
  Diseases causing acid hypersecretion
  Diseases associated with severe GERD (Scleroderma)
  Pre-term birth or low birth weight (GERD related)
Risk Factors for
  Genetic
  Familial aggregation of Barrett’s esophagus and
associated adenocarcinoma occurs
  Genetic polymorphisms likely increase susceptibility
  COX inhibitors did not prevent dysplasia
progression in a 48 wk RCT
Risk Factor Comparison
Molecular Factors
Poor Outcome
  EGF (adeno)
  TGF-α (adeno)
  TGF-β
  C-erbB2 (adeno)
  HER2/neu gene overexpression
  CCND1 (adeno)
  TP53/bcl-2
Better Outcome
  SMAD (squamous)
Pathology: Squamous Cell
  Dysplasia
  Low Grade
  Basal part of the epithelium
  High Grade
  Entire epithelial layer
  Cytologic Abnormalities
  Coarse chromatin, increased nuclear:cytoplasmic ratio,
nuclear hyperchromasia and pleomorphism, and mitotic
  Architectural Abnormalities
  Disorganization, loss of polarity, overlapping nuclei, lack of
surface maturation
  Usually multifocal
Pathology: Squamous Cell
  Where do most squamous cell cancers
  Middle (50-60%), Distal (33%),
Proximal (10%)
  Are most differentiated or
  Poorly differentiated (2/3), Well
differentiated (1/3)
  How aggressive are squamous cell
  Very!
  Early lymph node mets due to lymphatic
channels in the esophageal lamina
  Absence of serosal layer leads to local
Pathology: Adenocarcinoma
  Dysplasia
  Low and High grade show similar cytologic and
architectural changes to squamous cell
  High inter-observer variation
  Indefinite
  True dysplasia vs reactive changes
  Alpha-Methylacyl-CoA Racemase (AMACR)
  Immunostaining has high NPV
Pathology: Adenocarcinoma
  Is it common to occur without Barrett’s?
  Rare, but can occur in foci of gastric heterotopia in cervical
  Where are they most often located?
  Distal third
  Are most well poorly differentiated?
  Most are well differentiated
  How common are lymph node mets?
  Equal or less than squamous cell, but also related to depth
of invasion
  Celiac and perihepatic LN at risk due to GE Jxn location
Other Malignant Tumors of the
  Verrucous Carcinoma
  Exophytic papillary growth
  Favorable prognosis
  Basaloid Cancer
  Ulcerative and stricturing
  Poor prognosis
  Lymphoma
  Seen in AIDS patients
  Can occur from extrinsic
compression or LN
  Carcinosarcoma
  Sarcoma
  Small Cell CA
  Metastatic Cancer
  Most common extrapulmonary
  Malignant Melanoma
  From melanoma or breast
Clinical Presentation
  Progressive Dysphagia (74%)
A what diameter does solid food dysphagia begin?
  25 mm
At what diameter is solid food dysphagia always present?
  13 mm
  Odynophagia (17%)
Suggests ulceration
  Chest Pain radiating to back
Indicates local invasion
  Hoarseness
May indicate recurrent laryngeal nerve involvement
  Aspiration
  Hematemesis
Patient Presents with Cough
and Pneumonia
  What lab test may be useful?
  Ca due to PTH in squamous cell
  If performing a contrast study for TE Fistula, what
contrast should be used?
  Barium
  Endoscopy
  Prominent luminal component may not always be
present in which case tunneled biopsies may help get
deeper tissue
Detection of Dysplasia
  Chromoendoscopy
  Lugol’s Iodine:
  Dysplastic or Inflamed tissue (glycogen depleted) does
not pick up
  Used for high risk for squamous cell
  Not proven useful in Barrett’s detection
  Narrow Band Imaging, Confocal Endomicroscopy,
EUS, Tissue Fluorescence not yet recommended for
dysplasia detection
What characteristics of a
disease make it a good
candidate for screening?
  Common
  Epidemiology, risk factors, and natural history are
  Latent period exists
  Early detection will improve outcomes
Why not screen for
  Reflux symptoms are insensitive marker and other early
symptoms are rare
  Small percentage of patients develop cancer
  Only a small percentage of patients with cancer had
  Screening can lead to high emotional and financial costs
  ACG guidelines only recommend screening in selective
populations at higher risk
  Periodic surveillance of dysplastic Barrett’s may be costeffective
Staging of Cancer
Tumor Stage
Mortality by Stage
At diagnosis, >50% are
unresectable or have visible
Staging Modalities
  EGD
  EMR can provide info on tumor depth
  > 5cm stenotic lesions are likely T3 or higher
  CT
  Detect mets to liver, lungs, periaortic LN
  Detect local invasion of mediastinal structures
  Only 50-60% accuracy in staging due to inability to
distinguish between wall layers
  No advantage of MRI
  Poor for detection of locoregional disease
EUS Staging
  Info about depth and nodal involvement
  Accuracy of tumor staging 85-90% in expert hands
  Lowest accuracy is T2 cancer
  Accuracy for nodal mets is 65-86%
  Malignant Nodes
  Hypoechoic, round, >1 cm, clearly demarcated border
  Reactive Nodes
  Hyperechoic, elongated, poorly demarcated
  Should stenotic lesions be dilated to facilitate EUS?
EUS Impact on Outcomes
  Undergoing EUS is an independent predictor of
improved survival in analysis of the SEER database
  Will Rodgers Phenomenon or Stage Appropriate
EUS Images
EUS vs. PET for restaging?
  EUS has difficulty discriminating viable tumor from
  Small prospective studies have shown PET to be
superior in evaluating node status after
  However, systematic reviews suggest equivalence
  PET provides higher internal validity and
reproducibility and FDG uptake is an objective
response to therapy
Treatment of Early Cancer (Tis,
T1a or T1m, T1b or T1sm, no
  Endoscopic Therapy
  Ell C et al. GIE 2007
  100 consecutive pts with Adenocarcinoma
  99% local remission
  Recurrence or metachronous lesion in 11% all treatable
  5 yr survival 98%
Ideal lesion is solitary, nodular, < 20 mm diameter
Endoscopic Submucosal Dissection (ESD) may have a
higher cure rate, especially for larger lesions
Often used with Photodynamic Tx, APC, RFA, or laser
Longterm outcomes compared to surgery unknown
Locally Advanced Resectable
  30-59% are candidates for curative resection
  5-yr survival post-surgery is 15-24%
  Approaches:
  Transhiatal Esophagectomy
  Laparotomy + Blunt Dissection of thoracic esophagus
  Mediastinal exploration and lymphadenectomy not possible
  Lower morbidity
  Ivor-Lewis Transthoracic Esophagectomy
  Laparotomy + Right Sided thoracotomy
  Greater risk of intrathoracic anastomotic leak
  More bile reflux
  May confer survival benefit (14%) in distal adenocarcinomas
Role of Chemoradiation
  Neoadjuvant Therapy
  Gebski V et al. Lancet Oncol 2007
  Neoadjuvant Tx vs Surgery alone
  RR of mortality for chemoradiation = 0.81 [0.7, 0.93] at
2 yrs compared to surgery alone
  Unknown Neoadjuvant vs Chemoradiation Alone
  May have better locoregional control with fewer
palliative procedures, but similar survival
  Adenocarcinoma will need surgery
  Salvage esophagectomy has more complications
Unresectable disease
  Palliative surgery no longer recommended
  Chemotherapy for Metastatic Disease
  Shrinkage commonly occurs, but the response rarely
lasts more than months
5-yr survival for chemoradiation can be up to 25%
1st Line: Cisplatinum, 5-FU, & epirubicin or docitaxel
Alternative = Capecitabine & Oxiplatin instead of 5FU/Cisplatin (NEJM 2008)
EGF receptor antibodies, tyrosine kinase inhibitors,
and VEGF antagonists being studied
Troublesome Symptoms of
Advanced Disease
  Dysphagia
  Restoration or preservation of swallow
  Maintenance of nutritional status
Ablative Techniques for
  Laser Therapy
  Neoymium; Yttrium-aluminum-garnet; potassium
titanyl phosphate
  Start distal and move proximal in circumferential
  Best for polypoid, fleshy, non-circumferential lesion
  Complications:
  4% rate, 1% mortality
  Chest pain, odynophagia, fever, leukocytosis
Ablative Techniques for
  APC
  Not as useful for dysphagia
  May help with slow surface hemorrhage and tumor in
growth in stents
  Photodynamic Therapy
  May have less risk of perforation than laser therapy
  20% of patients are photosensitive
Displacement Techniques for
  Dilation
  Perforation in up to 10%
  Safest to use TTS balloon dilators if scope can’t pass
  Temporary relief
  Self-Expanding Metal Stents (SEMS)
  Covered vs. Uncovered
  Covered required for TE Fistula
  Uncovered may have less migration
  Stents coated with radioactive iodine may be more
PEG in Esophageal Cancer
  Do not place a PEG in anybody who may be a
surgical candidate
  Jejunal feeding tubes are preferred and will have
less aspiration if stent ever placed
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