Core Curriculum: Esophageal Cancer Ben Cohen, MD February 1, 2011 Epidemiology   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   Mortality:   5th leading cause of cancer death in men and 9th in women   5 yr survival by race and gender from 1996-2004   Men: White 16.5%; Black 9.2%   Women: White 17.6%; Black 12.9% http://seer.cancer.gov/ faststats/ 2003-2007 SEER Data Squamous Cell Cancer Incidence   80% occur in developing countries   “Asian esophageal cancer belt”   Within this region there are unexplained shifts in incidence   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 1960s 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 (UK) Risk Factors for Adenocarcinoma   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 Adenocarcinoma OBESITY: - BMI > 25 kg/ m2  Esophageal and Cardia AdenoCA Risk Factors for Adenocarcinoma   GERD   Lagergren et al. NEJM 1999   Swedish Population-Based Study   Pts with recurrent GERD symptoms have OR [7.7] for AdenoCA   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 Adenocarcinoma   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 Adenocarcinoma   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 Adenocarcinoma   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   CTGF   C-erbB2 (adeno)   HER2/neu gene overexpression   CCND1 (adeno)   TP53/bcl-2 Better Outcome   SMAD (squamous) Pathology: Squamous Cell Cancer   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 figures   Architectural Abnormalities   Disorganization, loss of polarity, overlapping nuclei, lack of surface maturation   Usually multifocal Pathology: Squamous Cell Cancer   Where do most squamous cell cancers occur?   Middle (50-60%), Distal (33%), Proximal (10%)   Are most differentiated or undifferentiated?   Poorly differentiated (2/3), Well differentiated (1/3)   How aggressive are squamous cell cancers?   Very!   Early lymph node mets due to lymphatic channels in the esophageal lamina propria   Absence of serosal layer leads to local invasion 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 esophagus   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 Esophagus Epithelial   Verrucous Carcinoma   Exophytic papillary growth   Favorable prognosis   Basaloid Cancer   Ulcerative and stricturing   Poor prognosis Non-epithelial   Lymphoma   Seen in AIDS patients   Can occur from extrinsic compression or LN invasion   Carcinosarcoma   Sarcoma   Small Cell CA   Metastatic Cancer   Most common extrapulmonary site   Malignant Melanoma   From melanoma or breast cancer 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 Diagnosis   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 known   Latent period exists   Early detection will improve outcomes Why not screen for Barrett’s?   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 Barrett’s   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 TNM AJCC Tumor Stage Mortality by Stage At diagnosis, >50% are unresectable or have visible mets 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   FDG PET   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 Management? EUS Images EUS vs. PET for restaging?   EUS has difficulty discriminating viable tumor from scarring/fibrosis   Small prospective studies have shown PET to be superior in evaluating node status after chemoradiation   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 nodes)   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 ablation Longterm outcomes compared to surgery unknown Locally Advanced Resectable Cancer   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 Dysphagia   Laser Therapy   Neoymium; Yttrium-aluminum-garnet; potassium titanyl phosphate   Start distal and move proximal in circumferential fashion   Best for polypoid, fleshy, non-circumferential lesion   Complications:   4% rate, 1% mortality   Chest pain, odynophagia, fever, leukocytosis Ablative Techniques for Dysphagia   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 Dysphagia   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 palliative 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 Question 1 Question 2 Question 3