Definition
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• Malignant gland forming tumor of esophagus

Epidemiology
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• In developed world, incidence has increased, while incidence of squamous cell carcinoma has remained constant (Ann Oncol 2012;23:3155, J Natl Compr Canc Netw 2011;9:830)
• 50-70% of esophageal carcinomas are adenocarcinoma
• In 2013, American Cancer Society estimates 17,990 new cases of esophageal carcinoma in US with 15,210 deaths
• Mean age is ~60 years old; cases before age 50 are uncommon
• ~80% men
• While the most substantial increase has been among white men, incidence is increasing in women and men of other ethnicities
• Obesity and high BMI are strong risk factors, likely related to increased GERD and Barrett esophagus
• Barrett esophagus is most important risk factor
• Tobacco is moderate risk factor
• Infection with cagA+ Helicobacter pylori appears to be protective against reflux esophagitis, the initial step in development of adenocarcinoma (pathway is reflux to Barrett esophagus to dysplasia to adenocarcinoma); increase in adenocarcinoma may be due, in part, to decline in prevalence of Helicobacter pylori (Cancer Res 1998;58:588, Cancer Prev Res (Phila) 2008;1:329)
• H. pylori infection may cause atrophic gastritis, decreasing acid production and thus decreasing reflux disease

Sites
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• Generally in distal esophagus
• Rarely may arise in submucosal glands or ectopic gastric mucosa

Pathophysiology
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• Dysplasia - carcinoma sequence in Barrett mucosa with stepwise accumulation of genetic mutations, especially p53 gene; additional changes involve HER2/c-ERB-B2, cyclin D1, cyclin E genes, RB, p16 genes

Clinical features
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• Insidious onset, dysphagia to solids, followed by dysphagia to all food
• Extreme weight loss due to loss of nutrition and the tumor itself
• Metastasis generally occurs early even in superficial tumors, due to extensive lymphatic network in esophagus that allows horizontal and longitudinal spread
• Adenocarcinoma occurs in lower esophagus and lymph node metastases involve gastric and celiac lymph nodes
• Visceral metastases to liver, lungs, pleura
• Recurrences are common

Diagnosis
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• Overwhelming majority diagnosed by endoscopic biopsy

Radiology
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• Imaging reveals mass in distal esophagus

Prognostic factors
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• Lymph node metastases, extracapsular lymph node involvement (Am J Surg Pathol 2006;30:171), depth of invasion (but see J Clin Oncol 2007;25:507), status of resection margins; possibly endoglin/CD105 (Hum Pathol 2005;36:955)
• Post-chemoradiation therapy prognostic factors in resection specimens:
  1. Extent of residual carcinoma predicts survival based on 3 groups:
     • P0 (0% residual carcinoma)
     • P1 (1% to 50% residual carcinoma)
     • P2 (>50% residual carcinoma, Am J Surg Pathol 2007;31:58)
  2. Prominent mucin pools in patients with Barrett associated adenocarcinoma are associated with mucinous tumors, but acellular mucin pools are NOT associated with poor survival, even if at radial margin (Am J Surg Pathol 2006;30:28)

Case reports
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• 51 year old man with collision tumor with papillary adenocarcinoma and neuroendocrine carcinoma (Arch Pathol Lab Med 2000;124:411)

Treatment
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• 5 year survival for non-resectable tumors is rare
• Resection if primary treatment modality (if possible); may be preceded by neoadjuvant therapy - report Barrett metaplasia on proximal margin, if present
• Adjuvant chemoradiation often given

Gross description
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• Usually distal esophageal tumor with invasion of gastric cardia; appears as flat patches to nodular masses; may have adjacent Barrett mucosa

Gross images
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Adenocarcinoma in Barrett esophagus

Polypoid tumor

Contributed by Dr. Mark R. Wick

In Barrett metaplasia - contributed by Dr. Mark R. Wick

Micro description
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• Usually moderate or well differentiated, usually mucin producing (intestinal type mucosa), may have foci of squamous or endocrine differentiation
• Usually has adjacent Barrett mucosa with high grade dysplasia (may be displaced by adenocarcinoma)
• Rarely signet-ring cells, papillary structures, Paneth cells, endocrine cells, pagetoid spread of tumor cells

Micro images
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Various images

Moderately differentiated

Metaplasia - contributed by Dr. Mark R. Wick

Adenocarcinoma and neuroendocrine carcinoma collision tumor

Virtual slides
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Adenocarcinoma

Positive stains
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• Rarely needed for diagnosis
• PAS, Alcian blue and mucicarmine (for mucin), usually CK7 and CK19 (Am J Surg Pathol 2002;26:1213), AMACR (Hum Pathol 2006;37:1601); focal positivity is common for somatostatin and serotonin (Histopathology 1987;11:53)

Negative stains
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• CK20

Electron microscopy images
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Adenocarcinoma (site unspecified)

Differential diagnosis
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• High grade dysplasia (no single cell invasion, no infiltration of submucosa or muscularis mucosae), metastatic or adjacent gastric carcinoma (signet ring cells may be present; often CK20+ in background of intestinal metaplasia)
• Note per AJCC criteria, cancers of the gastro-esophageal junction are staged as esophageal carcinomas

Additional references
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• Am J Surg Pathol 1984;8:563, Am J Surg Pathol 2002;26:784 (achalasia due to adenocarcinoma)

Definition
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• Adenocarcinoma arising in ectopic gastric mucosa, or perhaps mucosal/submucosal glands in the upper 1/3 of esophagus, most cases believed to arise in inlet patches

Epidemiology
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• Very rare, only single case reports

Sites
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• Generally upper 1/3 of esophagus

Pathophysiology
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• Embryologically, upper esophagus is last part of esophagus to acquire a squamous lining; if replacement of columnar epithelium is incomplete at birth, ciliated cells may persist, undergo gastric differentiation, and become an inlet patch
• Most inlet patches are clinically insignificant, although peptic ulcer disease is reported
• A pathologic mechanism similar to Barrett associated carcinoma is also proposed (see below)

Etiology
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• Speculative, due to its rarity
• Commonly ectopic gastric mucosa is colonized by H. pylori in individuals with gastric colonization
• Conceivably the same factors that cause gastric adenocarcinoma may be operative in ectopic gastric mucosa
• Alternatively, expression of CK7 and CK20 and mucin core proteins suggests that in at least some cases, a pathogenic link between Barrett esophagus and the cervical inlet patch may exist (Am J Surg Pathol 2005;29:437)

Clinical features
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• Behavior similar to Barrett associated adenocarcinoma

Diagnosis
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• Endoscopic biopsy

Case reports
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• 60 year old man with tumor of upper esophagus and no Barrett esophagus (J Exp Clin Cancer Res 2005;24:325)
• 75 year old man with esophageal adenocarcinoma arising from ectopic gastric mucosa in thoracic esophagus (Rare Tumors 2010;2:e5)
• Cases in cervical esophagus (Am J Clin Oncol 2004;27:644, Clin Gastroenterol Hepatol 2010;8:e91)

Treatment
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• Similar to Barrett associated adenocarcinoma

Gross images
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Cervical esophagus tumor

Micro description
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• Most are intestinal type adenocarcinoma

Micro images
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Well differentiated adenocarcinoma

Positive stains
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• Generally not needed for diagnosis
• Gastric-type mucins (Virchows Arch A Pathol Anat Histopathol 1991;419:159)

Differential diagnosis
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• Carcinoma arising in Barrett epithelium where malignancy has overgrown metaplastic epithelium
• Metastasis

Additional references
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• Mills: Histology for Pathologists

General
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• Per WHO criteria published in 2010, adenocarcinomas that cross the gastroesophageal junction (GEJ) regardless of where the bulk of the tumor lies
• Considered esophageal if entirely above GEJ; considered gastric if entirely below GEJ
• Recommended to NOT use terminology "carcinoma of the gastric cardia"
• Most literature describes GEJ as proximal extent of gastric folds
• AJCC Cancer Staging Manual (7th ed, 2010) includes carcinomas of GEJ within the category "Lower thoracic esophagus / Esophagogastric junction" bordered superiorly by the inferior pulmonary veins and inferiorly by the stomach (Ann Surg Oncol 2010;17:1471)
• Per AJCC criteria, cancers whose epicenter is in the lower thoracic esophagus, the GEJ, or within the proximal 5 cm of the stomach are stage grouped as adenocarcinoma of esophagus

Terminology
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• Siewert classification is commonly used to characterized adenocarcinoma of the GEJ, especially in surgical literature where exact location of tumors of the GEJ may affect management
• Type I arise in the distal esophagus, are associated with intestinal metaplasia and extend distally
• Type II originates in the true GEJ
• Type III is the from subcardial stomach and extends proximally

Epidemiology
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• Significant increase in incidence (similar to esophageal adenocarcinoma in general), although efforts to categorize tumors as either of gastric or esophageal origin hinder determination of exact incidence
• This supports contention that pathophysiology of most adenocarcinomas of GEJ is similar to adenocarcinoma of esophagus

Pathophysiology
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• Most adenocarcinomas of GEJ arise in background of reflux esophagitis, and follow Barrett metaplasia-dysplasia-carcinoma sequence
• A small number occur in background of Helicobacter pylori gastritis with same presumed mechanisms as H pylori associated gastric adenocarcinoma (Am J Surg Pathol 2007;31:569, Hum Pathol 2006;37:40)
• Both mechanisms involve intestinal metaplasia
• Very rarely, signet ring carcinoma occurs in GEJ; may have same underlying pathophysiology as gastric signet ring carcinoma
• Classification as "collision tumor" based on histology is inaccurate - need molecular analysis (Am J Surg Pathol 2004;28:1492)

Clinical features
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• Dysphagia, pain, weight loss
• Often symptoms of GERD, less often of peptic ulcer disease

Diagnosis
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• Endoscopic biopsy

Prognostic factors
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• Stage, especially presence of metastatic disease, completeness of resection, post-surgical complications

Case reports
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• 63 year old woman (N Engl J Med 2009;360:2656)

Treatment
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• Surgical resection if possible, often with neoadjuvant therapy
• Chemotherapy

Gross images
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Various images

Micro description
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• Papillary, tubular, mucinous, signet ring cell, poorly cohesive without signet ring cells, mixed
• Well to poorly differentiated
• Greater tendency towards poorly differentiated tumors than esophageal adenocarcinoma
• Often adjacent intestinal metaplasia / Barrett esophagus (Dis Esophagus 2007;20:36)

Micro images
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Adenocarcinoma of GEJ

   

Signet ring - contributed by Dr. Mark R. Wick

Positive stains
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• May be Her2/neu positive, patients may be candidate for trastuzumab treatment

Molecular / cytogenetics description
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• p53 is most common mutation
• Frequent deletions of 14q31-32.1 (Hum Pathol 2006;37:534)
• Gains or losses of chromosomal loci have been reported involving 1q, 3p, 4q, 5q, 7p, 8q, 9q, 17q, 18q, 19q, 20pq, y
• MYC, ERBB2, EGFR, APC, α-catenin, SMAD4, DCC, APC, CDX2, RAS, and Cdk6 may be affected
• At present, molecular testing is NOT used to determine treatment

Differential diagnosis
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• Well differentiated adenocarcinoma may resemble hyperplastic or dysplastic lesions

General
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• Carcinoma that has penetrated through basement membrane of glands of lamina propria but not yet invaded through muscularis mucosae into submucosa; most biopsy specimens will not be deep enough to rule out submucosal invasion
• Epidermiology, sites, pathophysiology similar to adenocarcinoma above

Terminology
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• In AJCC staging, invasion of lamina propria or muscularis mucosae without involvement of submucosa is a T1a primary tumor

Clinical features
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• True intramucosal carcinoma is asymptomatic although patients often have GERD symptoms

Diagnosis
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• Endoscopic biopsy

Prognostic factors
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• Usually node negative (J Am Coll Surg 2006;203:152)
• 10 year survival after esophagectomy for stage IA (T1aN0M0) is 75% world-wide, similar to stage 0 disease

Treatment
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• Esophagectomy, mucosectomy, radiofrequency ablation

Micro description
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• Odze requires one of these findings (J Clin Path 2006;59:1029)
  • Single cells or small clusters of tightly compact back-to-back glands in lamina propria
  • Complex gland-in-gland or "cribriforming" pattern, with expansion of lamina propria and distortion of surrounding crypts
  • Neoplastic cells or glands show back-to-back or highly irregular architectural glandular arrangement, which cannot be explained by the pre-existing Barrett glands, as previously defined by Ormsby (Gut 2002;51:671)

Micro images
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Intramucosal carcinoma

Various images

Suggestive of intramucosal carcinoma

Differential diagnosis
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• High grade dysplasia: no syncytial arrangements of cells or complex glandular budding; low interobserver agreement, even among expert GI pathologists (Am J Gastroenterol 2008;103:2333)

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