Congenital anomalies of esophagus
Definition: esophageal segment is usually a thin, noncanalized cord with a proximal blind pouch connected to pharynx and a distal pouch leading to stomach
Present in 1 per 2500 live births, etiology unknown but not genetic (recurrence risk in siblings is only 1%)
Discovered shortly after birth due to immediate regurgitation after feeding
Usually near tracheal bifurcation; fistula present in >80% (see topic below) connecting the upper or lower pouch with the trachea or a bronchus; also associated with congenital heart disease, neurologic disease, GI or GU malformations in 50%; also single umbilical artery
Most common is a blind upper segment, fistula between blind lower segment and trachea
Diagrams: common types of atresia; classification of Esophageal Atresia/TracheoEsophageal Fistula (EA/TEF) #1; #2
Diagnosis: inability to pass a nasogastric tube
Case reports: due to diverticulum of Kommerell (very rare, Pediatr Cardiol 2007;28:303)
Treatment: surgery (diagram, early since incompatible with life) is usually successful, but complications are GERD, esophagitis (J Pediatr Surg 2007;42:370) and tracheomalacia
References: Orphanet J Rare Dis 2007 May 11;2:24 (review), Chest 2004;126:915 (complications), eMedicine #1 (includes classification systems), #2
Ectopic gastric tissue in esophagus
Also called gastric heterotopia, cervical inlet patch
Most common form of heterotopia
Usually in postcricoid region (may be difficult to examine endoscopically, South Med J 2006;99:865), found in 1-4% endoscopically (J Gastroenterol Hepatol 2004;19:891, Int J Clin Pract 2007 May 29 [Epub ahead of print])
May be due to rests of gastric precursor cells that remain after original esophageal mucosa is replaced by stratified squamous epithelium
May cause dysphagia or heartburn
Associated with H. pylori (29-77%, Am J Gastroenterol 2003;98:1266), esophagitis and Barrett’s esophagus (20%, Archives 2004;128:444); Barrett’s has similar mucin profile (Hum Path 1988;19:1301) and keratin expression (AJSP 2005;29:437)
Classified based on symptoms and morphologic changes (Am J Gastroenterol 2004;99:543)
Complications: ulceration, bleeding, stricture or perforation from acid secretion; rarely adenocarcinoma
Endoscopy: circular, red-orange flat area referred to as “inlet patch”
Endoscopy images: salmon colored patch
Case reports: with hypopharyngeal squamous cell carcinoma (Auris Nasus Larynx 2007;34:135), with adenocarcinoma (Am J Clin Oncol 2004;27:644, Dig Dis Sci 1998;43:901)
Gross: resembles gastric mucosa with sharp border from normal squamous epithelium; deep pink and velvety
Micro: usually cardiac-fundic glands with parietal and chief cells, often extensive inflammation causing reactive changes; may ulcerate
Micro images: mucosal biopsy shows antral type mucosa and a small fragment of squamous epithelium; various images
Ectopic pancreatic tissue in esophagus
Also called pancreatic heterotopia
At gastroesophageal junction in 16% of pediatric/young adult patients
May be congenital and independent of Barrett’s esophagus (AJSP 1996;20:1507)
Usually no clinical significance, but may exhibit pathologic changes of pancreatic tissue including ductal carcinoma (Archives 1994;118:568), other malignancy (Ann Thorac Surg 2000;69:259) or pancreatitis (Surg Laparosc Endosc Percutan Tech 2005;15:345, Dig Dis Sci 1995;40:2373)
Micro: benign appearing pancreatic ducts and acini
Cytology: clusters of benign appearing ducts and small acini mixed with inflammatory cells (Diagn Cytopathol 2004;31:175)
Micro images: esophageal squamous mucosa overlying pancreatic type parenchyma, immunostaining for trypsin, lipase and amylase
Positive stains: trypsin, chymotrypsin, amylase, lipase (AJSP 1995;19:1172)
References: Archives 2000;124:1165
Approximately 2% of adult autopsies
May be multiple (Am J Gastroenterol 1994;89:1884); occurs at any level of esophagus
Case reports: 53 year old woman with > 100 minute polyps of mid-lower esophagus (Dig Dis Sci 1995;40:287), 50 year old man with reflux esophagitis (The Internet Journal of Gastroenterology 2007;5(2))
Micro: sebaceous glands in lamina propria; may be metaplastic submucosal gland ducts
Micro images: ectopic sebaceous glands in lamina propria surrounded by lymphocytes; cuboidal/squamoid cells with foamy lipid filled cells
Fistula (congenital) of esophagus
Associated with atresia; also tracheomalacia, Auerbach plexus abnormalities, cardiovascular abnormalities
May be due to abnormality during foregut separation phase or fixation during elongation of trachea (Texas Medical Center)
Gross’s classification:
Type A: no connection with trachea (i.e. atresia but no fistula, 8%)
Type B: upper segment connects with trachea (1%)
Type C: lower segment connects with trachea (87%)
Type D: both segments connect with
trachea (1%)
Type E: both segments join to connect with trachea (H type-4%)
Tracheobronchial remnants often persist in lower esophageal segment as dilated epithelial clusters of seromucous glands and cartilage (Archives 2003;127:1523)
Treatment: surgical repair, possibly through thoracoscopy (Ann Surg 2005;242:422)
Drawings: various types of fistulas #1; #2 (has different Type designations since Netter’s drawings were before Gross’s publication)
Gross images: blind sac of esophagus above (left) and continuation of esophagus from carina inferiorly #1 (right); #2; #3; apparent perforation of membranous portion of trachea into esophagus
Micro images: tracheobronchial remnants - fig 1: GERD with cardiac-type metaplasia; fig 2-3: plates of mature cartilage and acini of minor salivary glands; fig 4: branchial cleft-like cysts
References: Orphanet J Rare Dis 2007 May 11;2:24-review, Chest 2004;126:915 (complications), eMedicine #1 (includes classification systems), #2, Am Fam Physician 1999;59:910
Paterson-Brown-Kelly or Plummer-Vinson syndrome of esophagus
Also called sideropenic dysphagia
Very rare; decreased incidence may be due to better diets (J Gastroenterol Hepatol 1994;9:654)
Occurs mostly in Scandinavia and Great Britain
Usually women ages 30+ years
Pathogenesis not known, may be due to iron and nutritional deficiencies, genetic predisposition, and autoimmune factors.
Upper esophageal web, iron deficiency anemia and dysphagia; also glossitis, cheilitis (scaling and fissures at corners of mouth due to riboflavin deficiency), nail changes; at risk for postcricoid squamous cell carcinoma
Case reports: patients requiring balloon dilation for webs (Turk J Gastroenterol 2005;16:224), post-cricoid carcinoma leading to diagnosis of syndrome (Am J Otolaryngol 2007;28:22), with stomach cancer (rare, World J Gastroenterol 2005;11:7048)
Treatment: iron supplements, mechanical dilation, monitor for upper GI carcinoma
Micro: thin layer of squamous mucosa and submucosa
References: Orphanet J Rare Dis 2006 Sep 15;1:36, eMedicine
Definition: concentric, smooth, thin (3-5 mm) protrusions of normal esophageal tissue (with mucosa, submucosa and muscularis propria) into the lumen
Usually in distal esophagus
May be congenital, or a scar from drinking caustic liquids
Type A: lower muscular ring; rare; thickened circular smooth muscle with overlying squamous mucosa; usually 1.5 cm proximal to squamocolumnar junction, usually asymptomatic (Am J Gastroenterol 2000;95:43)
Type B: lower mucosal ring / Schatzki’s ring; 5% of normal esophagi; upper surface is lined by stratified squamous epithelium, undersurface is lined by columnar-type epithelium; ring contains connective tissue and fibers of muscularis mucosae; located at squamocolumnar junction at proximal margin of hiatal hernia; associated with meat impaction (“steakhouse syndrome”, Surg Endosc 1989;3:195), “swallow syncope” (Dysphagia 2005;20:273), and a reduced incidence of Barrett’s esophagus (Dig Dis Sci 2004;49:770)
Initially described as a constant, symmetrical, diaphragm-like narrowing at the GE junction associated with a small sliding hiatus hernia (Amer J Roentgenol 1953;70:911)
Type C: rare; refers to indentation on radiographic studies caused by diaphragmatic crura; usually asymptomatic
Diagrams: Netter drawings of A and B rings
Case reports: 16 year old boy with dysphagia and Schatzki’s ring (J Postgrad Med 1987;33:99), 54 year old man with dysphagia (Dis Chest 1968;54:465)
Treatment: dilation, possibly anti-reflux medical therapy or surgery (Ann Thorac Surg 1984;37:103)
Micro images: Schatzki’s ring-various images; hypertrophied squamous mucosa, hyperplasia of gastric glandular elements and increased submucosal fibrous connective tissue (fig 2)
References: eMedicine #1, #2 (Schatzki’s ring), GI motility online, Wikipedia
Stenosis of esophagus-congenital
Fibrous thickening of esophageal wall, particularly the submucosa, with atrophy of muscularis propria; thin and ulcerated lining epithelium
Incidence of 1 per 25-50,000 live births
Congenital cases defined as intrinsic alteration of esophageal wall due to ectopic tracheobronchial tissue, membranous diaphragm, muscular hypertrophy or diffuse fibrosis of submucosa (Pediatr Surg Int 2001;17:188)
Associated with esophageal atresia or other congenital malformations in 17-33%
May occur in adults (AJR Am J Roentgenol 2001;176:1179)
Case reports: 1 month old boy (J Pediatr Surg 2006;41:E5), due to tracheobronchial remnants with cartilage (Arch Pediatr 2006;13:1043), due to membranous diaphragm with tracheoesophageal fistula (J Pediatr Surg 2005;40:e11)
Treatment: dilation and resection plus anastomosis (J Pediatr Surg 2002;37:1024)
Acquired cases due to severe esophageal injury with scarring (reflux, radiation, scleroderma, caustic injury); associated with progressive dysphagia, may cause total obstruction
Uncommon, ledge like, semi circumferential protrusions of mucosa into lumen
In upper esophagus are called webs, are covered by squamous mucosa and have vascularized fibrous tissue core; associated with Paterson-Kelly syndrome above
In lower esophagus are called Schatzki’s rings (just above squamocolumnar junction), have gastric epithelium on their undersurface
Rarely protrude more than 5 mm into lumen
More common in women over 40 years
Etiology uncertain, but may be associated with gastric heterotopia (South Med J 1997;90:554)
Cause episodic dysphagia associated with “bolting” solid food
Acquired cases due to radiotherapy or graft vs. host disease
Endoscopic images: various images
Treatment: myomectomy, dilation
References: eMedicine, Wikipedia
Esophagitis
Defined as epithelial damage and inflammation
5% incidence in US (all types, although reflux symptoms in 33-44% of general population), higher incidence in northern Iran and China
Most common cause is gastroesophageal reflux (reflux of gastric contents into lower esophagus); infectious causes are much less common
Histologic changes may be severe (erosion, ulcer, exudates) or subtle
References: eMedicine #1; #2
See also eosinophilic esophagitis
Children with eosinophilic esophagitis often have allergic cause
Increasing incidence, perhaps due to increasing recognition
Diagnose based on esophageal pH probes (not acidic), failure to respond to antireflux therapy, allergic history and biopsy
Associated with dysphagia, strictures, failure to thrive (Dig Liver Dis 2006;38:245), peripheral eosinophilia, eosinophilic infiltration elsewhere in GI tract and abnormal allergen skin test results; is some seasonal variation (J Clin Gastroenterol 2007;41:451)
Patients may have enhanced production of cytokines against both food and environmental allergens (Dig Dis Sci 2006;51:1934)
Endoscopy: white flecks in esophageal mucosa (Gastrointest Endosc 2004;59:835)
Case reports: due to pulses (peas, beans and lentils) and chicken (Digestion 2006;74:49), egg allergy (Allergol Immunopathol (Madr) 2006;34:79)
Treatment: antiallergic therapy (An Pediatr (Barc) 2005;62:333) or dietary modification (Indian J Pediatr 2006;73:919); biopsy for follow up (Curr Opin Pediatr 2004;16:560)
Micro: >20-24 eosinophils per high power field, presence of eosinophil aggregates / microabscesses and superficial intraepithelial eosinophils
Micro images: large number of eosinophils and eosinophilic microabscesses
DD: gastroesophageal reflux disease (acidic pH in esophagus, fewer eosinophils and no eosinophil aggregates, no allergic history, responds to anti-reflux therapy)
References: AJSP 1999;23:390, AJSP 1986;10:75, AJSP 1985;9:475, Children’s Memorial Hospital
Also called aspergillosis
Poor prognosis
Case reports: AML patients (Diagn Cytopathol 2004;30:347)
Treatment: intravenous amphotericin B
Cytology: scattered three dimension groups of fungi with 45 degree angle branching
Gross images: multiple confluent ulcers; focal yellow granular lesions in bone marrow transplant patient
Associated with immunocompromise (Arch Intern Med 1986;146:1345, Dig Dis Sci 1995;40:183), Chagas disease (J Gastrointest Surg 2007;11:199), reflux esophagitis (some bacteria are similar to normal flora, World J Gastroenterol 2005;11:7277), Barrett’s esophagus (possibly, Dig Dis Sci 2004;49:228)
Phlegmonous esophagitis: rare; due to suppurative bacterial infection; high mortality; most common pathogens are Streptococcus, Staphylococcus, Escherichia coli, Hemophilus influenzae, Proteus, Clostridia
Necrotizing infectious esophagitis has a high mortality due to sepsis (Ann Thorac Surg 2003;75:342)
Case reports: Actinomycosis (J Infect 2005;51:E39), staphylococcus (Abdom Imaging 1993;18:225)
Micro: clusters of bacteria invade esophageal wall and blood vessels; may be epithelial necrosis
Micro images: reflux esophagitis associated (fig 1)
Usually due to Candida albicans or Candida tropicalis
Most common cause of infectious esophagitis
Associated with antibiotic use in non-immunocompromised; also acid suppressive therapy, carcinoma, corticosteroids, diabetes mellitus, esophageal motility disorders, gastric surgery, HIV, rheumatic disease (Dis Esophagus 2003;16:66)
Note: fungal invasion is a requirement for diagnosis since Candida is normal flora in GI tract
Often associated with CMV or HSV esophagitis (case report at Hum Path 1982;13:760); also esophageal stricture
Poorer prognosis in the elderly (Dis Esophagus 2006;19:189)
Case reports: 70 year old healthy woman (The Internet Journal of Infectious Diseases 2006;5:1)
Treatment: fluconazole
Endoscopy: gray-white pseudomembrane or plaque in mid to distal esophagus; mucosa is erythematous, edematous, ulcerated or friable
Gross images: tan-yellow plaques with mucosal erythema #1; #2; #3; leukemic patient has pseudomembrane #1; #2; necrotic appearing ulcers; focal erosion; diffuse involvement
Micro: densely matted pseudohyphae and budding spores in squamous debris, fibrinopurulent exudate or necrotic debris; underlying active esophagitis; invasion into muscularis propria and adventitia in HIV patients in past (Mycoses 1997;40 Suppl 1:81)
Micro images: pseudohyphae #1; #2; GMS; PAS #1; #2; #3; #4; #5; #6; #7; #8; neutrophilic infiltrate; various images
Virtual slides: Candidiasis
Positive stains: PAS, GMS
Chemical (corrosive) esophagitis
Children or adults
Causes: ingestion of strong alkalis (see lye stricture below), acids or nonphosphate detergents (may be suicide attempts); cytotoxic chemotherapy
In Taiwan, commonly due to ingestion of alkaline oil (Pediatr Surg Int 2004;20:207)
Complications: stricture, Barrett’s esophagus, rarely squamous cell carcinoma
Treatment: dilation, often surgery (Int J Pediatr Otorhinolaryngol 2001;57:203)
Gross images: reaction to caustic injury
Micro: mucosal or transmural injury with hemorrhage, necrosis and possible bacterial infection
References: Int J Pediatr Otorhinolaryngol 2005;69:1257
CMV - cytomegalovirus esophagitis
Usually immunocompromised patients; up to 30% of AIDS patients have CMV, Candida or Herpes esophagitis; rarely occurs in immunocompetent patients
Inclusions are numerous but may be atypical in HIV patients (Hum Path 1992;23:1019)
Histology is necessary to confirm diagnosis; repeat biopsy may be necessary
Case reports: dialysis patient (Nefrologia 2005;25:201), CMV esophagitis in renal transplant recipient presenting as black esophagus (Transpl Infect Dis 2007;9:42)
Treatment: anti-CMV drugs or reduction of immunosuppression (J Clin Virol 2005;34:219)
Gross: punched out mucosal ulcers with normal surrounding mucosa (similar to herpes simplex), but may lack ulcers (Hepatogastroenterology 2005;52:1236)
Micro: virus present in enlarged endothelium and stromal cells at ulcer base; basophilic cytoplasm often has coarse intracytoplasmic granules; prominent intranuclear basophilic inclusions surrounded by clear halo; macrophage aggregates in perivascular distribution are somewhat specific for CMV or HSV (Hum Path 1997;28:375); features are less obvious in patients receiving antiviral therapy
Micro images: intranuclear inclusions (H&E and EM); H&E and CMV immunostain; CMV and leishmaniasis #1; #2; various images
Positive stains: CMV immunostain or in situ hybridization
References: eMedicine
Cannot diagnose on biopsy, need resection specimen
Associated with GI Crohn’s disease; esophageal involvement in 0.2-13% with ileocolic Crohn’s disease; isolated esophageal involvement is extremely rare
Usually extraesophageal Crohn’s disease at time of presentation in esophagus (Inflamm Bowel Dis 2001;7:113)
Case reports: 31 year old man with isolated esophageal involvement (Eur J Gastroenterol Hepatol 2003;15:1123)
Gross: early - mucosal hyperemia and aphthous ulcers; late - discrete ulcers of lower 2/3, fibrosis, stenosis, fistulas
Micro: deep and aphthoid ulcers, transmural inflammation, non-necrotizing granulomas, epithelioid non-necrotizing granulomas in 7-9% (Am J Gastroenterol 1997;92:1467)
Positive stains: often HLA-DR in all layers (AJSP 1999;23:970)
References: J Pediatr Gastroenterol Nutr 2003;36:454 (children)
Also called allergic esophagitis by some authors (Curr Opin Gastroenterol 2006;22:429)
Children are likely to have a clinically identifiable allergic cause (Curr Opin Allergy Clin Immunol 2007;7:274), see allergic esophagitis above
Adults typically don’t have a clinically identifiable allergic cause (Allergy 2006;61:1480), although may have allergen mediated pathophysiology (Dig Dis Sci 2006;51:1934)
Dysphagia in 63% (World J Gastroenterol 2006;12:2328); onset in second or third decade is suggestive; often presents with food impaction (J Clin Gastroenterol 2007;41:356); also part of the rare anticonvulsant hypersensitivity syndrome (Dig Liver Dis 2007 Mar 27 [Epub ahead of print])
May occasionally be familial (Gastrointest Endosc 2007;65:330)
May be part of spectrum of eosinophilic gastroenteritis or associated with peripheral eosinophilia or reflux esophagitis
No actual increase in incidence in past 15 years according to one study (Archives 2007;131:777)
Pathogenesis: systemic CD4+ Th2-cell-mediated immunity and an enhanced eosinophil-CCR3 chemokine receptor 3/eotaxin-3 pathway play a role (J Pediatr Gastroenterol Nutr 2007;45:22)
Endoscopy: white plaques, stipple-like exudates, linear fissures, trachealization (ringed esophagus), strictures
Case reports: 24 year old man with dysphagia (the DAVE project)
Treatment: topical fluticasone propionate (a steroid), allergen elimination if allergic, dilation (Curr Gastroenterol Rep 2007;9:181), possibly anti-IL5 antibody (Allergy Clin Immunol 2006;118:1312)
Micro: prominent intraepithelial eosinophils (15 or more in 2 or more high power fields or 25 or more in any HPF), microabscesses (42%), often with large clusters near surface; also increased intraepithelial CD8+ T cells, intercellular edema, lamina propria fibrosis; peripapillary eosinophils may represent an early stage
Micro images: reflux esophagitis and eosinophilic esophagitis; large number of intraepithelial eosinophils and eosinophilic microabscess #1; #2; #3; GERD features plus extensive eosinophils #1; #2; #3; moth-eaten appearance due to intercellular edema; GERD-like changes; various images
Positive stains: major basic protein (indicates eosinophil activation and degranulation, AJSP 2007;31:598)
Molecular: associated with eotaxin 3 expression (J Clin Invest 2006;116:536
DD: GERD (may have extensive eosinophils-Am J Gastroenterol 2006;101:1666 but see Am J Gastroenterol 2007;102:1301-may not be clear distinction)
References: Mod Path 2006;19:90, GI motility online
Micro images: food granuloma #1; #2
Graft versus host disease (GVHD) esophagitis
Common after allogeneic stem cell transplantation (Ann Hematol 2004;83:101)
Case reports: causing bullous esophagitis (Am J Gastroenterol 1997;92:529), stricture (Bone Marrow Transplant 1988;3:513)
Gross: desquamative esophagitis with web formation
Micro: increased intraepithelial lymphocytes, dyskeratotic squamous cells and apoptosis of individual squamous cells in non-inflamed background is diagnostic; also have increased submucosal fibrosis associated with mucosal esophagitis and ulceration (Gastroenterology 1981;80:914)
Micro images: apoptotic squamous cells; with lymphocytic infiltrate #1; #2
DD: scleroderma (fibrosis, but no apoptotic squamous cells, different clinical history)
Case reports: chronic granulomatous disease of childhood (Radiology 1991;178:189), Crohn’s disease (J Pediatr Gastroenterol Nutr 1988;7:451), tuberculosis (Ann Trop Med Parasitol 1987;81:129), Wegener’s granulomatosis (Arthritis Rheum 1994;37:1404)
Micro images: various Crohn’s disease images
#2 most common cause of infectious esophagitis after Candida
Usually an opportunistic infection in immunosuppressed / AIDS patients, but also affects young immunocompetent children (J Pediatr Gastroenterol Nutr 2004;39:560)
Self-limited in healthy patients; may cause esophageal perforation or disseminate in immunocompromised patients
May have secondary bacterial or fungal infections
Must rule out HSV infection as cause of esophageal ulcers, particularly from immunocompromised patients
Diagnosis: histology, culture, PCR
Case reports: peritoneal dialysis patient with herpes and Candida infections (Am J Med Sci 2007;333:191), immunocompetent host with Mallory-Weiss syndrome (Dis Esophagus 2005;18:340)
Gross: shallow vesicles and ulcers; may coalesce into extensive areas of erosion
Gross images: punched out ulcers #1; #2; #3
Micro: ulcers contain necrotic debris and exudate with neutrophils; viral inclusions are present in multinucleated squamous cells at margin of ulcer; inclusions are usually Cowdry type A (dense eosinophilic intranuclear and cytoplasmic) with thickened nuclear membrane and clear halo; also ground-glass inclusions that fill the nuclei and nuclear molding; aggregates of macrophages with convoluted nuclei are adjacent to inflamed epithelium; inclusions may be absent in endoscopic biopsy specimens
Micro images: ulcer has sharp margin where squamous epithelium is lost and replaced by necrotic tissue; ground glass intranuclear inclusions #1; #2; #3; #4; multinucleated giant cells #1; #2; various images
contributed by Dr. Nilesh Patel, California - 70 year old immunocompentent man with candida and herpes esophagitis - image
Virtual slides: herpes esophagitis
Positive stains: CD68 (large cells with convoluted nuclei)
References: Hum Path 1991;22:541
HIV / human immunodeficiency virus esophagitis
Associated with idiopathic esophageal ulcers and opportunistic infections (Candida, CMV, herpes, TB, J Gastroenterol Hepatol 2005;20:722)
Diagnosis: histology with immunostains is best, viral culture and cytology are not helpful (J Gastroenterol Hepatol 2005;2:564)
Case reports: acute primary HIV esophagitis (Endoscopy 1990;22:184), leishmaniasis infection in HIV+ patient (Mod Path 1996;9:966)
Gross: large ulcers, severe active inflammation
EM: HIV-like viral particles in idiopathic ulcers
DD: CMV esophagitis
Usually restricted to patients with immunocompromise (HIV-J Int Assoc Physicians AIDS Care (Chic Ill) 2002;1:53), diabetes, antibiotic therapy or scleroderma (Semin Arthritis Rheum 2006;36:173)
Most cases due to Candida, herpes simplex virus, cytomegalovirus
Should consider infectious causes if ulcer or exudate is present
Treatment: in immunocompromised, initially systemic fluconazole for presumed Candida (Curr Treat Options Gastroenterol 2003;6:55)
References: eMedicine
Case reports: leishmaniasis infection in HIV+ patient (Mod Path 1996;9:966)
Micro images: leishmaniasis in HIV+ patient #1; #2; CMV and leishmaniasis #1; #2
Recently described subset of chronic esophagitis (AJCP 2006;125:432)
Often age 17 years or younger (55%)
May have no upper GI symptoms
Associated with Crohn’s disease (40%), gastroduodenitis (30%), GERD (20%), carcinoma of esophagus or elsewhere (20%), celiac disease (10%); also achalasia (AJSP 1994;18:327)
Micro: frequent intraepithelial lymphocytes around peripapillary fields; no/rare intraepithelial granulocytes
Micro images: various images; figures 1 & 2
Positive stains: lymphocytes - CD3, CD4 (42%), CD8 (36%)
Negative stains: lymphocytes - granzyme B, TIA
DD: reflux, Candida or postradiation esophagitis (show increased intraepithelial lymphocytes in interpapillary areas)
Pills sticking in esophagus cause local injury, often in mid-esophagus
Often doxycycline and other antibiotics, aspirin and NSAIDs, slow-release potassium, ferrous salts, alendronate (Fosamax, Mod Path 1999;12:1152)
Associated with diabetes and ischemic heart disease (Endoscopy 2005;37:740), advanced age; more common in women
May rarely cause strictures
Prevention: take pills when upright and with adequate fluids (Curr Treat Options Gastroenterol 2004;7:71)
Endoscopy: erosions, kissing ulcers, multiple small ulcerations with bleeding, mainly in mid-esophagus
Case reports: alendronate and doxycycline (Rom J Gastroenterol 2005;14:159), Cal-Ban 3000 diet pill (Am J Gastroenterol 1992;87:1424), oral contraceptive Diane-35 (Int J Clin Pract Suppl 2005;147:79), procardia-extended release (J Assoc Acad Minor Phys 1997;8:38), rifampin (Ann Pharmacother 1999;33:27), tamsulosin for prostatic hypertrophy (Dig Liver Dis 2004;36:632), telithromycin (Turk J Gastroenterol 2006;17:113)
Micro: inflammatory exudate, ulceration, inflamed granulation tissue, prominent eosinophils, necrotic squamous epithelium, polarizable crystalline foreign material, multinucleated giant cells; fungi or viral inclusions present in 20% of cases due to alendronate
Micro images: various images
References: Drug Saf 2000;22:237, J Clin Gastroenterol 1999;28:298
Complication of treatment for cancer of lung, mediastinum or esophagus with doses of 30 gray or higher
Is primary dose limiting acute toxicity for radiation therapy of thoracic neoplasms (Semin Radiat Oncol 2004;14:280)
Use of cytotoxic chemotherapy has an additive effect (World J Gastroenterol 2005;11:2626)
Acute damage: mucosal necrosis, submucosal edema
Chronic injury: due to fractionated doses of 60 gray or more; submucosal fibrosis, capillary telangiectasia, thick-walled arterial vessels, mucus glandular atrophy, atypical fibroblasts; grossly are ulcers, strictures or fistulas
Gross images: esophageal squamous cell carcinoma - radiation has destroyed tumor, resulting in sharply circumscribed erosion with deep ulcer, presumably where tumor had penetrated the deepest; deep ulcer with necrotic base due to destruction of large, deeply invasive tumor
Micro: variably sized cells in all layers, often increased cytoplasm, enlarged nuclei with bizarre shapes, may be hyperchromatic or smudged; may have large eosinophilic nucleoli; usually no mitotic figures
Micro images: normally oriented epithelium is thinner than normal, but contains bizarre cells at all levels #1; #2; radiated esophageal squamous cell carcinoma has clumps of keratin without epithelium but with foreign body giant cell reaction #1; #2; fibrosis and giant cells; neovascularization (highlighted with CD31)
Reflux esophagitis / gastroesophageal reflux disease / GERD
Most common cause of esophagitis
Due to reflux of gastric or duodenal contents into lower esophagus
Affects 3-4% in general population, usually mild or moderate disease
Usually adults over age 40, occasionally children
May be erosive or nonerosive (Clin Gastroenterol Hepatol 2007;5:690)
Causes: alcohol and other central nervous system depressants (clomipramine-Am J Gastroenterol 2007 May 19; [Epub ahead of print]), delayed gastric emptying, hypothyroidism, nasogastric tube, pregnancy, sliding hiatal hernia, systemic sclerosing disorders, tobacco; often unknown
Symptoms: heartburn, dysphagia; severity of symptoms is NOT related to histology (Dig Dis Sci 2002;47:2565); pain may be mistaken for myocardial infarction
Physiology: chronic exposure to gastric juices impairs reparative capacity of esophageal mucosa; gastric acid injury to mucosa is critical (Med Clin North Am 2005;89:219); bile reflux may also contribute (J Pediatr Gastroenterol Nutr 2003;36:266)
Diagnosis: clinical (heartburn, regurgitation), intraesophageal pH monitoring to detect acid, Bernstein acid infusion test to assess mucosal sensitivity to acid, endoscopic and histologic examination (multiple biopsies since changes are non specific, Archives 2005;129:159); methods may not correlate, and no “gold standard” exists for diagnosis
Endoscopy: linear ulcers at distal esophagus, often with exudate; also erythema or edema; normal in 50-60% of symptomatic patients - thus biopsy required if clinically suggestive of reflux esophagitis even if normal endoscopy
Treatment: motility promoting drugs, H2 receptor antagonists, proton-pump inhibitors, surgery to reduce hiatal hernia
Long term consequences are bleeding (almost never massive), stricture, Barrett’s esophagus with possible Barrett’s ulcer
Gross: severe cases have hyperemic mucosa with focal hemorrhage
Gross images: longitudinal ulcers
Reflux esophagitis (continued)
Micro: inflammatory cells in epithelial layer (eosinophils, neutrophils, excess T cells); basal cell hyperplasia exceeding 15-20% of epithelial thickness, elongation of lamina propria papillae into upper 1/3 of epithelium; ballooned squamous cells in 65% (resemble glycogenic acanthosis but PAS negative and positive for immunoglobulin or albumin, Mod Path 1988;1:175), vascular dilatation in 60% (usually at superficial papillae, also associated with varices), also multinucleated squamous epithelial giant cells simulating viral cytopathic effect (AJSP 1998;22:93)
No interstitial cells of Cajal at GE junction (Med Sci Monit 2005;11:BR452)
Eosinophils: seen early in 30% but (a) uncommon in infants (J Pediatr Gastroenterol Nutr 2007;44:27); (b) present in 52% of adults (AJSP 1984;8:899) - correlates best with endoscopic findings; (c) difficult to identify with Bouin’s or Hollande’s fixative, (d) occasional eosinophils are also present in normal lamina propria and in non-GERD esophagitis, (e) rarely large numbers mimic eosinophilic esophagitis (Am J Gastroenterol 2006;101:1666), (f) rare eosinophils in 1/3 of normal adults, so not a reliable diagnostic criterion but, (g) eosinophils not normally present in children, so presence is important in this population
Neutrophils: present in 15%; indicates more severe injury including ulceration and erosion; search for fungi if prominent neutrophils or purulent exudate
Lymphocytes: normal component of squamous mucosa (T cells), no diagnostic significance
Cardiac mucosa at GE junction: GERD causes H. pylori like changes with neutrophils, plasma cell or eosinophilic infiltrates
Micro images: basal cell hyperplasia and elongated papillae; elongated papillae; moderate basal cell hyperplasia; various images; marked neutrophilic infiltrate
DD: normal esophagus (epithelial hyperplasia is present in normal individuals in distal esophagus; tangential artifacts), infectious esophagitis, pill esophagitis, eosinophilic esophagitis, radiation or chemotherapy induced esophagitis
References: AJSP 1984;8:899, J Clin Pathol 1985;38:1265, Wikipedia
Sclerotherapy / sclerosing agent related esophagitis
Treatment for esophageal varices, but is being replaced by endoscopic band ligation (Curr Opin Gastroenterol 2006;22:442)
Sclerotherapy may cause a chemical esophagitis, which may coexist with reflux esophagitis (J Nucl Med 1995;36:1363)
Case reports: causing mucosal bridges (Trop Gastroenterol 2001;22:94)
Gross: superficial and deep mucosal ulceration
Micro: variable necrosis and vascular thrombosis, ulceration and fibrosis (Gastroenterol Jpn 1986;21:99); thrombi may recanalize (Jpn J Surg 1985;15:30)
References: Semin Liver Dis 2002;22:73, Gut 1982;23:615
Tuberculosis (TB) of esophagus
Not that rare in developing countries with high incidences of TB (Am J Gastroenterol 2002;97:287)
Usually direct spread from adjacent structures, associated with mediastinal lymphadenopathy (Gastrointest Endosc 2003;57:588)
Latent infections may be reactivated by HIV
Recommended to treat for TB if clinically suspect, even if cultures or PCR are negative (J Gastroenterol 2003;38:477)
Case reports: spread from mediastinal lymphadenitis resembling carcinoma (Hong Kong Med J 2006;12:473), death due to esophageal hemorrhage from aortoesophageal fistula with aortic aneurysm (Archives 1986;110:965), 48 year old Pakistani woman with primary esophageal disease (Eur J Gastroenterol Hepatol 2005;17:435), 14 year old boy with mid-esophageal ulcer and hilar / mediastinal adenopathy (Indian J Pediatr 2004;71:457)
Gross: fistulas common
Micro: epithelioid granulomas (usually caseating), Langhans giant cells
Micro images: granulomatous inflammation with necrosis; non-caseating epithelioid granuloma beneath squamous epithelium (fig 2)
Non-neoplastic disorders of esophagus
Also called cardiospasm, megaesophagus
Esophageal motor disorder characterized by lack of progressive peristalsis and partial/incomplete relaxation of lower esophageal sphincter (LES), preventing passage of food into stomach
Preferentially involves circular layer of muscularis propria, which is hypertrophied
Due to T cell mediated destruction or complete absence of myenteric ganglion cells in lower third of esophagus (Am J Gastroenterol 2005;100:1404)
Most cases are idiopathic, usually young adults with progressive dysphagia, nocturnal regurgitation and aspiration of undigested food; can occur in children
Specific causes: Allgrove’s syndrome (World J Gastroenterol 2006;12:4764), amyloidosis, Chagas’ disease (Trypanosoma cruzi destroys myenteric plexus of esophagus, duodenum, colon, ureter; common in South America), diabetic autonomic neuropathy, polio, sarcoidosis, surgical ablation of dorsal motor nuclei, thyroid disease (World J Gastroenterol 2007;13:594), tumor
Patients with achalasia may also have GERD (Eur J Gastroenterol Hepatol 2006;18:369)
5% risk (33x normal) of esophageal squamous cell carcinoma, at mean 21-28 years after diagnosis of achalasia (Anticancer Res 2000;20:3717)
Also increased risk of Candida, lower esophageal diverticula, aspiration, peptic ulceration, stricture, gastroesophageal reflux and Barrett’s esophagus (Ann Surg 2006;243:196)
Treatment: esophagomyotomy (World J Gastroenterol 2006;12:5921, GI Motility Online), dilation (World J Gastroenterol 2006;12:5763)
Gross: progressive dilation of esophagus above LES, variable wall thickness
Gross images: dilated esophagus #1; #2; massive dilation
Micro: early - Auerbach/myenteric plexus lymphocytic inflammation (cytotoxic T cells, eosinophils) with germinal centers and submucosal glandular atrophy, late - marked depletion / absence of ganglion cells in myenteric plexus (middle of esophagus, may be normal at LES) and replacement of nerves by collagen with muscular hypertrophy; squamous mucosa markedly hyperplastic with papillomatosis and basal cell hyperplasia resembling GERD (J Gastroenterol Hepatol 2006;21:727)
Micro images: various images
Achalasia of esophagus (continued)
Positive stains: p53, T > B cells (AJSP 2001;25:1413)
EM: smooth muscle cells have nuclear and cytoplasmic inclusions, marked loss of small nerve fibers, paucity of granules in nerve fibers; also nonspecific filament disarray, mottling of myocyte fiber density, thick and long cytoplasmic dense bodies, long dense plaques (AJCP 1983;79:319)
DD: visceral neuropathies, normal aging, pseudoachalasia (see below)
References: AJSP 1994;18:327, Wikipedia, eMedicine, GI Motility Online
Atypical regenerative hyperplasia of esophagus
Associated with chronic esophagitis, not with neoplasm
Micro: immature and relatively monotonous small/medium keratinocytes mixed with inflammatory cells; pleomorphism and atypia are common in keratinocytes and endothelial cells; also mitotic figures
Micro images: squamous cell carcinoma versus atypical regenerative hyperplasia; various images
DD: squamous cell carcinoma (stromal infiltration by nests, cords or thin prongs of malignant keratinocytes; also desmoplasia, in situ carcinoma, atypical mitotic figures)
References: Archives 2005;129:899
Also called acute esophageal necrosis
Somewhat rare (~ 100 cases reported, 0.2% of endoscopies); endoscopic finding of black, diffusely necrotic esophageal mucosa, primarily in distal third
80% men, mean age 67 years (J Gastroenterol 2007;42:29)
Due to ischemic injury from atherosclerosis, thrombus or aortic dissection; also associated with alcoholic hepatitis (Endoscopy 2005;37:268) and poor general health (Gastrointest Endosc 2002;56:213)
Patients present with GI bleeding or cardiovascular shock / events
Case reports: after severe alcoholic vomiting in a healthy young man (Surg Endosc 2003;17:521), with cholangiocarcinoma (J Natl Med Assoc 2002;94:735), 79 year old woman with no known cause (CTSNet), herpes simplex esophagitis (Endoscopy 2007 Jul 5; [Epub ahead of print])
Treatment: supportive therapy; usually resolves, although patient may die of other causes (Endoscopy 2004;36:411)
Gross: darkly pigmented esophageal mucosa with ulcerations
Gross images: perforated esophagus (1) with intraluminal hematoma (2); extensive esophageal perforation with distal perforation
Micro: severe acute inflammation with mucosal necrosis; hemosiderin and siderophages, but no melanin; necrosis may extend into muscularis propria and be overlooked at autopsy (APMIS 2003;111:591)
Micro images: extensive ulceration and necrosis
DD: tellurium poisoning in children (found in metal-oxidizing solutions, causes vomiting, blacking of mucosa and garlic odor to breath, Pediatrics 2005;116:e319), activated charcoal deposits (Am J Gastroenterol 1997;92:1359), dye ingestion, melanoma
Present in 10% with lymphocytic esophagitis (AJCP 2006;125:432) but see AJSP 1996;20:865 (no increase in intraepithelial lymphocytes)
Associated with increased incidence of Barrett’s esophagus (Dig Dis Sci 2005;50:126) and esophageal motility disorders (Neurogastroenterol Motil 1995;7:239)
Case reports: with glycogen acanthosis (Acta Paediatr 2004;93:568)
Also called cricopharyngeal spasm or achalasia
Cricopharyngeus muscle is part of inferior pharyngeal constrictor
Prominent clinical findings but subtle microscopic findings
May have multiple etiologies (Eur Arch Otorhinolaryngol 1992;249:216-free full text), may be due to diverticulum
Drawings: cricopharyngeus muscle #1 (drawing on left, near bottom); #2
Treatment: cricopharyngeal myotomy, botulinum toxin
Micro: degeneration and regeneration of cricopharyngeal muscle fibers, interstitial fibrosis (Histopathology 1979;3:223)
Micro images: various images (figs 1-3)
EM images: figs 1-6
References: eMedicine (myotomy), PowerPoint presentation
Considered developmental unless due to cystic degeneration of tumor or otherwise
Rare
Simple cysts are epithelial lined
Duplication cysts have 2 muscle layers
Either intramural or attached to outer layers of esophagus
Often asymptomatic, even if large; may cause obstructive symptoms
See also retention cysts below
References: eMedicine, Archives 1977;101:136
Bronchogenic cysts of esophagus
Often young women with dysphagia or chest pain during exercise (Clin Imaging 2006;30:309)
Developmental cysts with cartilage and mucus glands, smooth muscle and ciliated columnar epithelium
Case reports: 26 year old man with cystic lesion at lower esophagus (Dig Surg 2006;23:209)
Micro images: cyst #1 lined by respiratory epithelium overlies collagen, small vessels and smooth muscle; #2
Duplication cysts of esophagus
Also called gastroenteric cyst, foregut cyst
Congenital anomaly, usually lower esophagus
Most are intramural; duplications external to esophageal wall are associated with vertebral anomalies
90% do not communicate with esophagus
Case reports: with squamous cell carcinoma (Br J Radiol 2003;76:343), 22 day old infant (Indian J Pathol Microbiol 2006;49:396), 52 year old woman (Yonsei Med J 2005;46:859), causing respiratory distress in infants (Pediatr Emerg Care 2005;21:854), with fistula to lung (Eur J Cardiothorac Surg 2000;18:117)
Treatment: surgery (if symptoms) or possibly observation (Endoscopy 2005;37:870)
Micro: mucosa, submucosa and muscular layers similar to GI tract; lined by either esophageal squamous, gastric, primitive, ciliated columnar or small intestinal epithelium
Micro images: respiratory epithelium and two muscle layers (fig D)
Inclusion cysts of esophagus
Lined by squamocolumnar epithelium, may be ciliated
Outpouching of alimentary tract containing all visceral layers
May cause obstruction, aspiration pneumonia, abscess, infection, hemorrhage or be associated with malignancy
Zenker’s diverticula: also called pharyngoesophageal or pulsion diverticula; more common in elderly; above upper esophageal sphincter, usually posterior wall; due to disordered cricopharyngeal motor dysfunction or weakness in esophageal wall at junction with pharynx; may accumulate food, cause regurgitation or aspiration pneumonia or simulate a neck mass; malignancy in 0.3%
Mid-esophageal/traction diverticula: near mid esophagus at level of tracheal bifurcation; previously thought to be due to TB, mediastinal lymphadenitis and scarring; may be due to motor dysfunction, congenital or alkali ingestion (Med Hypotheses 2004;62:931); better prognosis than distal disease (Dysphagia 2006;21:198)
Epiphrenic diverticula: rare; immediately above LES; due to lack of coordination of peristalsis and LES relaxation (Am J Surg 2005;190:891); may cause nocturnal regurgitation of massive amounts of fluid, obstruction, aspiration; contains mucosa, submucosa and muscularis mucosae; lined by squamous epithelium, often markedly inflamed; case report of fatal hemorrhage (Archives 2006;130:867)
False diverticula: mucosa and submucosa only
Case reports: squamous cell carcinoma in Zenker’s diverticula (Dis Esophagus 2007;20:75)
Drawings: Zenker’s
Gross images: Zenker’s #1; #2; epiphrenic diverticula #1; #2; #3-defect in esophageal wall causes arterial perforation (rare)
Micro images: diverticulum #1; #2
Virtual slides: Zenker’s diverticula
References: eMedicine (Zenker’s)
Injectable polymer deposited into esophageal muscularis propria to treat reflux esophagitis (Gastrointest Endosc 2006;63:468) and reduce use of proton pump inhibitors
Now withdrawn due to safety concerns (US FDA, December 2005)
Case reports: causing abscess (Am J Gastroenterol 2004;99:1856)
Fistula of esophagus (acquired)
Aortoesophageal fistulas are usually due to thoracic aortic aneurysm, foreign body ingestion or esophageal malignancy
Case reports: aortoesophageal fistula due to a penetrating atherosclerotic ulcer (J Cardiothorac Surg 2007;2:12), 71 year old woman with nasogastric tube and aortic-esophageal fistula (Hum Path 1989;20:709), tracheoesophageal fistula #1 in HIV+ man with Candida and CMV infections (Chest 1994;106:284), #2 presumably due to tuberculosis (J Postgrad Med 1994;40:83)
Gross images: aortic arch aneurysm that perforated in esophagus; orifice of fistula (fig 3)
Glycogenic acanthosis of esophagus
Common endoscopic finding (25%), often in lower esophagus
Extensive glycogenic acanthosis may be associated with Cowden’s disease (Am J Gastroenterol 1997;92:1038), but otherwise no clinical significance
Gross: multiple white mucosal plaques < 1 cm; may resemble leukoplakia
Gross images: numerous white islands with background of hyperemic mucosa; white nodules; slightly elevated longitudinal plaque of lower esophagus
Micro: epithelial thickening by large squamous cells of prickle cell layer packed with glycogen; no atypia, no inflammation
Micro images: large squamous cells with abundant cytoplasm; thickened superficial squamous epithelium with enlarged squamous cells containing abundant pale to clear cytoplasm #1; #2
Positive stains: PAS (glycogen), diastase sensitive
References: Wikipedia
Due to separation of diaphragmatic crura and widening of space between muscular crura and esophageal wall
Associated with reflux esophagitis, both erosive and nonerosive (BMC Gastroenterol 2005 Jan 9;5:2)
May be axial or nonaxial
Axial (sliding): 95%, protrusion of stomach above diaphragm creates bell shaped dilation
Nonaxial (paraesophageal): 5%, separate portion of stomach enters thorax, usually along greater curvature; may be due to surgery for sliding hernias, but cause often unknown, associated with reflux, but compromise of LES is probably due to the hernia
Incidence: 1-20% of adults, increases with age, also seen in children
Only 9% with sliding hernias have heartburn or regurgitation of gastric juices into the mouth; accentuated by bending forward, lying supine, obesity
Rarely is familial (autosomal dominant, Gut 1999;45:649)
Complications: ulceration, bleeding, perforation; strangulation of paraesophageal hernias; increased risk of esophageal and gastric adenocarcinoma (Cancer 2003;98:940)
Case reports: 11 year old with congenital paraesophageal hernia (Indian J Pediatr 2007;74:310)
Drawings: axial (sliding) hernia #1; #2; nonaxial (paraesophageal) hernia
Gross images: autopsy findings
References: eMedicine #1, #2, Wikipedia
Idiopathic muscular hypertrophy of esophagus
Diffuse thickening of the lower esophageal and upper gastric musculature, luminal diameter usually preserved
Often asymptomatic; incidental finding at autopsy (Chest 1978;73:28)
May present with dysphagia
Case reports: with superficial esophageal carcinoma (Tokai J Exp Clin Med 2003;28:103)
Gross: wall is 0.6 to 0.9 cm thick (normal is 0.25 cm)
Gross images: thickened wall (fig 2); uniform thickening of wall and narrowing of lumen (fig 1)
Micro: marked uniform thickening of muscularis propria, usually the inner circular layer, with variable lymphocytes; no nodules
Micro images: thick fibrous septum divides muscle fibers of circular layer of muscularis propria (fig 3); hypertrophy of muscularis propria and lymphocytic infiltration (fig 3-4)
DD: leiomyomatosis (nodules are present)
Kayexalate damage of esophagus
Kayexalate (sodium polystyrene sulfonate) in sorbitol is used to treat hyperkalemia, may crystallize in the esophagus and produce endoscopic ulcers and erosions resembling carcinoma or Candida
Micro: crystals are lightly basophilic with a faint crystalline mosaic pattern, better seen with PAS/Alcian blue; crystals are refractile but not polarizable, luminal and adherent to intact surface epithelium or mixed with inflammatory exudate in patients with ulcer or erosion
Micro images: crystals in colon
References: AJSP 2001;25:637
Lacerations (Mallory-Weiss syndrome) of esophagus
Longitudinal tears at GE junction or proximal gastric mucosa
Usually due to severe retching associated with alcoholism
Tears may be mucosal or full-thickness
Cause 5-10% of upper GI bleeds, usually limited, surgery not necessary
Rarely causes sudden unexpected death (Arch Kriminol 2002;209:36, Srp Arh Celok Lek 2001;129:257, J Clin Pathol 1991;44:787)
Rare in children; has various etiologies (Dis Esophagus 1999;12:65)
Boerhaave syndrome: esophageal rupture, may be lethal
Case reports: due to pseudodiverticulosis (Surg Today 2002;32:519)
Treatment: support, vasoconstrictors, transfusions, occasionally balloon tamponade
Gross images: laceration at GE junction #1; #2
References: eMedicine
Subacute to chronic mucocutaneous disorder of unknown etiology that involves skin, nails and mucosal surfaces
Mucosal surfaces affected are usually perineum, oral mucosa and pharynx
Rarely involves esophagus, usually upper or mid esophagus
All esophageal cases reported to date are in women, usually ages 40+ years
Tends to be chronic and cause dysphagia due to esophagitis and stricture formation
May be underdiagnosed and a risk factor for squamous cell carcinoma (Eur J Gastroenterol Hepatol 2006;18:1043)
Case reports: isolated esophageal involvement (Z Gastroenterol 2004;42:379)
Treatment: systemic corticosteroids, retinoids, cyclosporine or azathioprine; may relapse when therapy is stopped
Micro: lichenoid, T cell rich lymphocytic infiltrate, basal epithelium degeneration, Civatte bodies (degenerated epithelial cells); often parakeratosis and atrophic epithelium; usually no hypergranulosis
Micro images: skin - various images
DD: gold therapy, thiazides or antimalarials (cause lymphocytic infiltrate), gastroesophageal reflux disease (clinical symptoms, intraepithelial eosinophils, usually lower esophagus)
References: AJSP 2000;24:1678
Also called corrosive or caustic stricture
Usually at bifurcation of trachea
Mean age 6 years at time of ingestion
Associated with motility disorders in children (Braz J Med Biol Res 2004;37:1623)
Treatment: stenting, dilation or surgical resection
Complications: carcinoma, mean 40 years later, usually at tracheal bifurcation
Gross images: stricture (cause unknown)
Micro images: stenosis of lumen and extensive fibrosis
References: Sao Paulo Med J 2001;119:10, eMedicine
Lymphoid hyperplasia of esophagus
Associated with chronic stenosing ulcerating esophagitis and Barrett’s esophagus (AJSP 1985;9:141)
DD: follicular lymphoma (Korean J Pathol 1995;29:393)
2-4% of patients with achalasia-like syndrome
Difficult to diagnosis
Resembles achalasia, but has different pathology; usually associated with a neoplasm, often adenocarcinoma at/near the esophagogastric junction invading into myenteric plexus
Rarely due to a paraneoplastic process (Dis Esophagus 2007;20:168), documented by anti-neuronal antibodies
Reversal of achalasia-like symptoms after treatment of underlying disorder
Case reports: due to metastatic cervical carcinoma to esophagus (JSLS 2001;5:57), due to neurofibromatosis of esophagus (Ann Thorac Surg 2006;81:1138), due to vagotomy (World J Gastroenterol 2006;12:5087), due to other neoplasms (Dis Esophagus 2007;20:168)
References: AJSP 2002;26:784, Scand J Gastroenterol 2005;40:378.
Pseudodiverticulosis of esophagus
Also called diffuse intramural esophageal (pseudo) diverticulosis
See retention cysts below
May be due to retention cysts (AJCP 1976;65:314)
More numerous in upper third of esophagus
Usually no clinical findings, rarely dysphagia with markedly enlarged cysts
Case reports: 74 year old woman with dysphagia and vomiting (Archives 1993;117:848), 57 year old man with dysphagia for 2 years (J Postgrad Med 2005;51:328)
Treatment: dilate strictures (if any), reduce inflammation as needed
Gross: numerous 1-3 mm flask shaped diverticula with a pinpoint mouth
Micro: squamous lined, resemble dilated excretory ducts of submucosal mucus glands; often surrounded by chronic inflammatory infiltrate
Micro images: two dilated ducts in superficial submucosa lined by thick metaplastic squamous epithelium
References: Hum Path 1988;19:928
Also called mucocele
Derive from obstructed submucosal gland ducts
Small, usually in lower esophagus
May cause intramural pseudodiverticulosis, with multiple flask like invaginations into esophageal wall (AJCP 1976;65:314)
Associated with chronic esophagitis and fibrosis; also surgically isolated segments of esophagus (Dis Esophagus 2002;15:96)
Micro: saccular or flask-shaped dilation of submucosal gland excretory ducts; rarely reaches muscularis propria; in large lesions, muscularis does not accompany the lesion, so are not true diverticula
Rare; usually associated with pulmonary sarcoidosis (GI Motility online 2006)
Rarely associated with scleroderma (Ann Med Interne (Paris) 1996;147:590)
Case reports: causing achalasia (J Clin Gastroenterol 2002;34:54), with dysphagia and esophageal dysmotility disorder (Am J Gastroenterol 1996;91:1423), with dysphagia and muscle weakness (Am J Gastroenterol 1991;86:1679)
Micro images: granuloma in lamina propria
DD: sarcoid-like reaction of regional lymph nodes in malignancy (Surg Today 1999;29:260), TB or fungi
Scleroderma (systemic sclerosis) of esophagus
Involves esophagus in 75%+ patients, usually distal 2/3, with aperistalsis and reduced tone of lower esophageal sphincter
Commonly causes reflux esophagitis (Semin Arthritis Rheum 2006;36:173), strictures, Candida esophagitis, Barrett’s esophagus (J Clin Gastroenterol 2006;40:769, but similar prevalence as other reflux esophagitis patients-Arthritis Rheum 2005;52:2882)
Case reports: with CMV esophagitis (J Clin Rheumatol 2001;7:384), with achalasia (Dtsch Med Wochenschr 2006;131:1799)
Treatment: no treatment for underlying disease; proton pump inhibitors for reflux esophagitis, dilation for strictures
Micro: resection specimens - atrophy and replacement fibrosis of inner circular layer of muscularis propria and resulting stenosis; longitudinal layer is usually involved; also submucosal fibrosis, mild inflammation, intimal proliferation of arterioles (Gut 2006;55:1697)
biopsies - ulcers or erosions resembling reflux esophagitis, Candida or Barrett’s
Micro images: fibrosis of muscularis propria; trichrome stain shows fibrosis in submucosa and muscularis propria
EM images: collagen between degenerate muscle fiber (left) and necrotic muscle fiber (right); muscle fibers (M) separated by collagenous fibers with widened intermyofibrillar space
DD of muscularis propria fibrosis: Sjogren’s syndrome, systemic lupus erythematosus, primary visceral myopathy, cricopharyngeal dysplasia
Usually caused by chronic gastroesophageal reflux
Consider infectious causes if exudate is present
Case reports: Barrett’s ulcer with perforation (Ann Thorac Surg 2002;73:302), Behcet's disease (World J Gastroenterol 2006;12:2622, Yonsei Med J 2002;43:457), CMV (South Med J 2000;93:818), doxycycline (Gastroenterol Hepatol 2001;24:390), HIV in child (Pediatr Radiol 2002;32:907), metronidazole (Rev Gastroenterol Mex 1998;63:106), myeloma (World J Gastroenterol 2006;12:2305), NSAID (Surg Endosc 1997;11:143), radiotherapy (Dis Esophagus 2002;15:266), tuberculosis (Eur J Gastroenterol Hepatol 2005;17:435)
Gross images: multiple healed ulcers; ulcers related to unspecified tube #1; #2 (Blakemore tube); ulcers (cause unknown)
Micro: granulation tissue with large, atypical mesenchymal cells resembling carcinoma; adjacent epithelium has reactive changes and prominent hyperplasia (pseudoepitheliomatous hyperplasia) that appear as uniformly thick, parallel prongs of primitive squamous cells that penetrate the granulation tissue of the ulcer bed; cells have minimal cytoplasm, large pleomorphic and hyperchromatic nuclei and prominent nucleoli; mitotic figures common; may appear invasive with tangential sectioning
Micro images: surface of healing ulcer (top) shows primitive squamous cells penetrating granulation tissue; cells are large with dark, pleomorphic nuclei #1; #2; base of ulcer shows large abnormal spindle cells #1; #2 with capillary buds; granulation tissue overlying submucosal glands; long prongs of undifferentiated cells in parallel penetrate the granulation tissue at base and edge of ulcer, cells have high N/C ratio, hyperchromasia, pleomorphism and large nucleoli #1; #2; #3; #4; myeloma ulcer (figs 1-4); necrotic epithelium
Negative stains: atypical cells in ulcer bed are keratin negative
Dilated tortuous vessels, usually submucosal, that develop due to portal hypertension (prolonged or severe), which induces formation of collaterals between portal and caval systems
Collaterals in lower esophagus divert flow from portal vein, through coronary veins of stomach, into esophageal veins, then azygous veins, then into vena cava
Present in 90% of cirrhotic patients, usually due to alcoholism; acute alcohol intake may cause death, often outside the hospital
May rupture and cause massive hemorrhage (cause of death in 50% with advanced cirrhosis)
40% die in first episode of bleeding varices; rebleeding occurs in 50% of survivors within 1 year with 40% mortality
Blood stains at death scene and unusual body positions of deceased are clues to fatal esophageal variceal hemorrhage
#2 cause of bleeding varices worldwide is hepatic schistosomiasis
“Downhill” varices occur in upper esophagus from other causes (Rev Esp Enferm Dig 2006;98:359)
Treatment: repeated sclerotherapy (injection of thrombotic agents, Ann Surg 2006;244:764), banding/ligation (Arq Gastroenterol 2005;42:72), balloon tamponade
Gross: varices may protrude into lumen, mucosa may be normal or inflamed
Gross images: linear, dark blue, submucosal dilated veins #1; #2; #3; #4; ruptured varices #1; #2; #3; #4 (esophagus turned inside out); partially thrombosed after sclerotherapy #1; #2; at gastroesophageal junction
Micro images: dilated veins #1; #2; #3; #4; #5; #6; #7; focal rupture; inflamed varix; sclerosed varix
Virtual slides: ruptured varices
DD hematemesis: gastritis, esophageal laceration, peptic ulcer
References: Archives 2002;126:1197 (fatal cases), Wikipedia, eMedicine #1; #2
Benign tumors of esophagus
Benign tumors of esophagus - general
Rare, usually small, polypoid and asymptomatic, but may be confused with malignancy
Treatment: endoscopic resection of small superficial tumors (Semin Thorac Cardiovasc Surg 2003;15:27)
DD: mediastinal bronchial artery aneurysm (J Vasc Surg 2003;38:1125)
See also esophageal gland duct adenoma, Barrett’s tubular adenoma, polypoid dysplasia
Derived from submucosal gland/duct system, parathyroid or thyroid tissue
Benign ductal or glandular neoplasms of the esophagus unrelated to Barrett’s esophagus are very rare
Case reports: with superficial squamous cell carcinoma (Cancer 1993;71:2435), parathyroid adenoma (Archives 1978;102:242), pleomorphic adenoma (Ann Thorac Surg 1987;44:653)
Very rare
May cause perforation and hematemesis
Amyloid (not necessarily in tumor form) may cause achalasia (J Clin Gastroenterol 1990;12:447)
Case reports: with systemic disease (Laryngoscope 1976;86:850)
Very rare
Case reports: 58 year old Chinese woman (Head Neck 2001;23:506)
Micro: dendritic melanocytes in subepithelial connective tissue; no junctional melanocytes, no atypia
Very rare
Immunohistochemistry is similar to normal esophageal gland submucosal duct cells
Usually lower half of esophagus
Case reports: 75 year old Japanese man with incidental finding (AJSP 2007;31:469), 81 year old man with 1 cm mass (AJSP 1995;19:1191)
Treatment: excision
Gross: usually polypoid or pedunculated; rarely flat
Micro: no capsule but well demarcated; tubulopapillary and cystic structures with eosinophilic granular cells but no atypia; basal cell layer present; interstitial lymphocytic infiltrate
Positive stains: duct cells - strong and diffuse CK5/6, CK7, CK19 and high molecular weight cytokeratin; weak CK17 and CK18; myoepithelial cells - S100, alpha smooth muscle actin
Negative stains: CK20, mucin
EM: numerous mitochondria
DD: adenocarcinoma
Fibrovascular polyp of esophagus
Also called fibroma, fibrolipoma, fibromyxoma, lipoma, giant fibrovascular polyp
Uncommon submucosal tumor (1-2% of benign esophageal tumors) that arises in upper esophagus from cricopharyngeal region; may be due to redundant folds that get pulled down by force of swallowing
Lesion is unique to esophagus
Presents with dysphagia or weight loss of ~10 kg
Benign, but may cause death from asphyxia secondary to laryngeal obstruction or be regurgitated into oral cavity
Usually men (75%) age 45+ years
May actually be an acquired malformation or hamartoma
Case reports: giant polyp causing death by asphyxiation (Archives 2006;130:725), 5 month old infant girl (Yonsei Med J 2001;42:264)
Treatment: excision, possibly endoscopically (Laryngoscope 2007;117:944); rarely recurs (South Med J 1991;84:1370), 44 year old man with tumor extending into stomach
Gross: soft, elongated, pedunculated mass up to 20 cm with narrow point of attachment; overlying mucosa may be ulcerated; cut surface is yellow-tan, edematous
Gross images: giant polyp causing asphyxiation; giant tumor is mobilized through esophagotomy incision (top); cut surface has white glistening tissue (bottom); yellow tumor with smooth surface; core is composed of fibrous and adipose tissue (fig 1); various images (fig 4-7)
Micro: squamous epithelial lining with frequent ulceration; core of mature fibromyxoid tissue with scattered thin-walled blood vessels and variable adipose tissue; also stromal edema and occasional lymphocytic infiltrate; may have prominent mast cells
Micro images: adipocytes form lobules of different sizes; myxoid area contains spindle cells and vessels; core contains fibroadipose tissue; figures 2-6; various images (fig 8-10)
DD: inflammatory fibroid polyp (near GE junction, granulation tissue with prominent inflammatory infiltrate)
References: Archives 2003;127:485
Gangliocytic paraganglioma of esophagus
Very rare
Usually periampullary and solitary
Case reports: 58 year old woman with simultaneous occurrence in esophagus and superior mediastinum (Hum Path 2004;35:1288)
Micro: neuroectodermal and neuroendocrine differentiation; nests of epithelioid cells with interspersed ganglion cells
Positive stains: epithelioid cells - CAM 5.2, chromogranin, synaptophysin; ganglion cells - S100, neurofilament; spindle cells - S100, neurofilament, GFAP
Very rare
Case reports: 28 year old woman with glomangioma (Dis Esophagus 2006;19:208), synchronous tumors of esophagus and lung (Hepatogastroenterology 2003;50:687)
Micro: round glomus cells have pale to clear cytoplasm, are arranged around vascular spaces; frequent stromal liquefaction and hyalinization
Micro images: sheets and strands of round glomus cells with clear cytoplasm and hyalinized stroma with dilated vessels #1; #2
Positive stains: smooth muscle actin, calponin, collagen type IV (envelops the cells)
Negative stains: S100, keratin
Granular cell tumor of esophagus
Also called Abrikosoff's tumor, myoblastoma
Most common site in GI tract for these tumors
#2 most common stromal tumor of esophagus after leiomyoma
Usually incidental, in lower esophagus, 90% solitary
May cause obstruction if large
May be of Schwannian origin
Commonly women in 40’s, blacks
May be underdiagnosed on superficial biopsies that lack lamina propria
Endoscopy: sessile, yellow-white, firm, intact epithelium
Case reports: esophageal tumor 7 years after bronchial tumor (APMIS 2006;114:659), associated with esophageal leiomyomas (Dig Liver Dis 2004;36:292), multiple tumors (J Gastroenterol 2003;38:776), with squamous cell carcinoma (Dis Esophagus 2002;15:88)
Treatment: local excision
1-3% are malignant (locally recur) - associated with rapid growth, > 4 cm, tumor necrosis, increased cellularity, atypia, > 2 mitotic figures/HPF
Gross: intramural nodule(s), poorly circumscribed, up to 2 cm
Micro: identical to granular cell tumors elsewhere; sheets or packets of uniform epithelioid cells with abundant eosinophilic granular cytoplasm and small nuclei that interdigitate with overlying epithelium; often pseudoepitheliomatous hyperplasia; often involves superficial lamina propria; may extend into muscularis propria
Micro images: tumor fills lamina propria; tumor extends to base of squamous epithelium, which has spike like rete pegs; tumor cells have fine cytoplasmic granules; various images
Positive stains: PAS, S100
EM: myelin like tubules, cytoplasmic processes surrounded by basal lamina in layers reminiscent of Schwann cells
References: Ann Thorac Surg 1996;62:860
May present with severe bleeding or dysphagia
May be cavernous or capillary or pyogenic granuloma (lobular clusters of small capillaries)
Case reports: 58 year old man with endoscopic mucosal resection of hemangioma (J Med Invest 2006;53:177), pyogenic granuloma (Virchows Arch 2004;444:590)
Micro images: cavernous hemangioma (fig 7)
Hyperplastic polyp of esophagus
Also called inflammatory esophagogastric polyp
Rare, near gastroesophageal junction
May represent an exaggerated mucosal response to esophageal injury, including reflux associated ulceration and repair, protracted vomiting, Crohn’s disease, sclerotherapy for varices, heterotopic gastric mucosa
Usually men
48% associated with GERD; 15% with Barrett’s esophagus; not associated with carcinoma
Case reports: 13 year old boy with hyperplastic polyp and ulcerative colitis (Acta Paediatr Jpn 1993;35:53)
Treatment: endoscopic mucosal resection or other excision (World J Gastroenterol 2006;12:5699)
Micro: hyperplastic gastric-type foveolar epithelium or squamous epithelium with granulation tissue, edematous lamina propria, inflammatory infiltrate; 67% have ulceration or erosion
Micro images: cardiac epithelium with foveolar hyperplasia and cystic dilation of pits (fig 2); adenomatous villous type polyp with low grade dysplasia (fig 3); various images
References: AJSP 2001;25:1180
Inflammatory fibroid polyp of esophagus
Similar to lesions elsewhere in GI tract, but rare in esophagus (<20 reported cases)
Considered to be reactive, with benign behavior
Mid to lower esophagus
Case reports: rapidly growing tumor (World J Surg Oncol 2005;3:30), 76 year old woman with submucosal tumor (Dis Esophagus 2000;13:75), HIV+ man (Dysphagia 1995;10:59)
Treatment: excision
Gross images: 9 cm soft slimy tumor
Micro: submucosal proliferation of fibroblasts and small vessels in a fibromyxoid background with diffuse infiltrate of eosinophils and other inflammatory cells
Micro images: muscularis propria (at bottom) is partially replaced by vascular tumor; tumor contains inflammatory cells, plump stromal cells, blood vessels and collagen; thick and thin walled blood vessels, fibroblasts, lymphocytes and eosinophils
Positive stains: CD34
Negative stains: CD117
DD: fibrovascular polyp (core of fibrovascular tissue, no prominent eosinophils), hyperplastic polyp (hyperplastic epithelium)
References: Am J Dig Dis 1975;20:475
Most common benign tumor of esophagus; 8% incidence in autopsy studies (Hum Path 1981;12:1006)
Median age 35 years, 2/3 men
Usually arises from inner circular muscle; most common in distal esophagus
Minute (1-2 mm “seedling”) tumors are often near the gastroesophageal junction and are asymptomatic
Multiple tumors are associated with MEN1 syndrome (Am J Pathol 2001;159:1121)
Large tumors may cause obstructive symptoms
Case reports: multinodular growth pattern simulating carcinoma (Dis Esophagus 2007;20:187), with early squamous cell carcinoma (Jpn J Clin Oncol 2004;34:751), with coexisting leiomyosarcoma (J Exp Clin Cancer Res 2005;24:487)
Treatment: excise if significant symptoms, endoscopic enucleation for small tumors (Singapore Med J 2006;47:901), esophagectomy for large tumors (World J Gastroenterol 2005;11:4258); benign behavior (Ann Thorac Surg 2005;79:1122)
Gross: circumscribed, mural, solitary mass, 2-5 cm (surgical specimens), bulges into lumen, may be polypoid; pink-gray-white with whorled cut surface; mucosal surface is only rarely ulcerated
Gross images: 5 cm lobulated leiomyoma has bulging, white, whorled cut surface; submucosal tumor #1; #2; #3; #4; #5
Micro: similar to classic endometrial leiomyoma; circumscribed lesion of circular muscularis propria or muscularis mucosae composed of intersecting fascicles of bland spindle cells with abundant cytoplasm; variable fibrosis in center of large leiomyomas; occasional calcification; no/rare mitotic figures; no atypia, no cellular foci
Micro images: incidental leiomyoma; leiomyoma of muscularis propria; cluster of seedling leiomyomas within muscularis propria forms a single multilobular mass; seedling (small) leiomyoma of muscularis propria is distinct from surrounding muscularis, although cells are identical; leiomyoma with overlying squamous epithelium; fascicular growth pattern; seedling leiomyoma composed of mature, hypertrophic smooth muscle cells with abundant fibrillary cytoplasm and elongated nuclei
Cytology images: groups of spindled cells with low cellularity #1; #2
Positive stains: desmin, alpha smooth muscle actin
Negative stains: CD34, CD117, S100
DD: GIST (very rare; solid, myxoid and perivascular patterns; more cellular by H&E and cytology, CD117+, CD34+, variable desmin and actin immunoreactivity)
References: AJSP 2000;24:211, Ann Thorac Cardiovasc Surg 2007;13:78, eMedicine
Uncommon
Some cases may be familial and associated with Alport’s syndrome and deletions of COL4A5/A6 genes (Am J Med Genet A 2003;119:381, Nephrol Dial Transplant 2002;17:70, Orphanet)
Usually children or young adults
May be associated with vulvar, uterine or respiratory tract leiomyomas
Case reports: 22 year old with vulvar leiomyoma and pseudoachalasia (Dis Esophagus 2000;13:165), with vulvar leiomyoma and Barrett’s esophagus (Dig Surg 2000;17:306), causing respiratory compromise in a child (Pediatr Radiol 2000;30:247)
Treatment: resection or myotomy with longitudinal split through muscularis propria
Gross: confluent muscle masses involving most of esophageal length, usually inner circular muscularis propria
Gross images: massively thickened distal esophagus (right) appears to be composed of continuous nodular leiomyomas (stomach is at left)
Micro: diffusely nodular, hypertrophic and disorganized muscularis propria; nodules are continuous with each other and identical to leiomyomas with whorled or fascicular growth of hypertrophied smooth muscle cells; variable collagen, thickened small submucosal vessels and hypertrophied myenteric nerve plexus
Micro images: multiple seedling leiomyomas of muscularis mucosae; enlarged smooth muscle bundles of inner muscularis propria; muscularis propria has large, discrete bundles of hypertrophic smooth muscle
DD: idiopathic muscular hypertrophy (uniformly thick without nodules), multiple discrete leiomyomas
References: Dis Esophagus 2000;13:169
Very rare (<50 cases reported)
Case reports: 55 year old man with esophageal wall mass (Turk J Gastroenterol 2006;17:110), 71 year old with submucosal tumor (J Chin Med Assoc 2005;68:240)
Gross: large, elongated intraluminal mass of upper esophagus with pedicle
DD: fibrovascular polyp
Melanocytes are present in 8% of normal esophageal specimens (Virchows Arch A Pathol Anat Histopathol 1990;417:137), but grossly visible lesion in less than 0.2% of upper endoscopy patients (Endoscopy 1990;22:94)
Benign, involves mid/lower esophagus
May be due to gastroesophageal reflux disease
May be a precursor of esophageal melanoma
Recommended to not use term “melanosis” (Archives 2006;130:552)
More common in men
Gross: no abnormalities
Micro: melanocytic proliferation in basal layer of esophageal squamous epithelium with increased quantity of melanin; overlying epithelium may demonstrate hyperplasia, acanthosis or hyperkeratosis; variable inflammation, melanophages, fibrosis and telangiectasia; no atypia
Positive stains: S100, MelanA, HMB45, Masson-Fontana
Negative stains: Perl’s iron, PAS
EM: long dendritic cytoplasmic processes that extend between keratinocytes, melanosomes; mildly hyperchromatic nuclei with uniform chromatin and indented nuclei; no desmosomes or tonofilaments (Virchows Arch A Pathol Anat Histopathol 1991;418:515)
DD: melanocytic nevi
Very rare
See also Schwannoma in Soft Tissue chapter
Benign
Often causes tracheal compression (Thorac Cardiovasc Surg 2006;54:555)
Case reports: AJSP 1999;23:431, 46 year old woman with dysphagia and dyspnea (Surg Today 2007;37:500), 54 year old man with dysphagia (J Formos Med Assoc 2003;102:346), melanotic schwannoma #1 (Thorac Cardiovasc Surg 2002;50:103), #2 (J Clin Pathol 2002;55:318), plexiform schwannoma (Int J Surg Pathol 2000;8:353)
Treatment: excision, does not recur
Micro: well circumscribed, composed of interlacing bundles of spindle cells interspersed with collagenous strands, scattered inflammatory cells with peripheral cuff of lymphoid aggregates, often PAS+ crystalloids; may exhibit nuclear atypia; no mitotic figures, no epithelioid features, no skenoid fibers
Positive stains: S100, vimentin, GFAP
Negative stains: CD34, smooth muscle actin, CD117/c-kit
DD: gastrointestinal stroma tumor (CD117+, CD34+ usually, S100-)
Squamous papilloma of esophagus
Definition: benign polyp of mature stratified squamous epithelium overlying lamina propria
Rare (< 0.4% of endoscopies), usually an incidental finding during endoscopy
Usually men age 40+ years in lower esophagus
Due to HPV (10-50%) or chronic mucosal irritation from esophagitis or Barrett’s esophagus
Not considered to be premalignant
90% solitary; rarely is papillomatosis, usually in children
Less common in lower esophagus in Japan due to chronic gastritis in this population (Acta Histochem Cytochem 2006;39:23)
Treatment: excision; recurrence is very rare (Orv Hetil 2005;146:547)
Gross: small (5 mm or less), white-pink sessile mass
Micro: mature thickened squamous epithelium covering delicate fibrovascular stalks which may be branching, endophytic or with stromal spikes; may have koilocytosis, parakeratosis and binucleated cells suggestive of HPV infection
Micro images: elaborate branching of lamina propria; lamina propria contains thin walled vessels and is covered by squamous epithelium of normal thickness; endophytic type with thick, irregular prongs of mature stratified squamous epithelium extending into lamina propria; endophytic type resembles a fibroepithelial polyp of skin; spike form has spires of lamina propria that elevate the variably thick squamous epithelium; various images #1; #2; squamous hyperplasia with fibrovascular core #1; #2
DD: verrucous carcinoma (papillary, bland, but larger mass), pseudoepitheliomatous hyperplasia
References: AJSP 1993;17:803, Hum Path 1994;25:536, Baylor College of Medicine
Verruciform xanthoma of esophagus
Usually oral mucosa and genital skin; very rare in esophagus
Case reports: 61 year old man with testicular lymphoma and verruciform xanthoma of mid esophagus (Hum Path 2003;34:814)
Micro: acanthosis of squamous epithelium with neutrophilic infiltration; papillae with foam cells
Positive stains: foam cells - CD68, vimentin
Premalignant lesions of esophagus
Definition: distal squamous mucosa is replaced by metaplastic specialized (intestinalized columnar) epithelium as a response to chronic injury; appears to be irreversible
Also called columnar lined esophagus
Columnar epithelium may be more resistant to acid, pepsin and bile
Appears to be acquired (World J Gastroenterol 2006;12:1521), although some believe it is congenital (Archives 1981;105:546)
Major risk factor for esophageal adenocarcinoma (relative risk: 30-50), particularly in older white men; other types of carcinoma arise uncommonly
Note: Barrett’s patients have similar mortality rate as general population, and death from esophageal adenocarcinoma is rare (Gut 2003;52:1081)
Mean age at diagnosis is 60+ years; usually men, rarely children with cystic fibrosis (causes reflux) or after chemotherapy
May be preceded by a distinctive type of multilayered epithelium at the squamocolumnar junction with features of both squamous and columnar epithelium; superficial aspects are similar to specialized columnar epithelium in Barrett’s esophagus (morphology, mucin types, cytokeratin expression); source of multipotential stem cells may be submucosal gland duct epithelium (AJSP 2001;25:569, Hum Path 2001;32:1157)
Causes: usually chronic gastroesophageal reflux (odds ratio 12.0, World J Gastroenterol 2007;13:1585; Barrett’s is present in 3-12% of GERD patients who are biopsied); almost always associated with sliding hiatal hernia; also associated with also esophageal stricture, lye ingestion, chemotherapy, bile/pancreatic juice reflux, peptic ulceration, decreased resting pressure of lower esophageal sphincter
Symptoms: long history of heartburn and other reflux symptoms; more massive reflux with more numerous and longer episodes than most reflux patients
Specimen processing: obtain 4 levels of step sections to document goblet cell metaplasia; may want additional levels in patients with known Barrett’s to evaluate dysplasia (AJCP 2005;123:886)
Barrett’s esophagus - general (continued)
Diagrams: Barrett’s esophagus is often associated with a sliding hiatus hernia; patterns of involvement are: left-circumferential; middle-short segment with tongues only and right-circumferential with residual white squamous islands
Diagnosis: characteristic endoscopic appearance plus characteristic histologic findings; 8 random biopsies recommended (Am J Gastroenterol 2007;102:1154); optional confirmation with Alcian Blue staining of goblet cells (pH 2.5, detects acid mucins); report should include type of epithelium present and presence/absence of dysplasia
In children, endoscopic Barrett’s esophagus may have only cardiac-type epithelium without intestinal metaplasia
Recommended to take biopsies beginning in stomach, then every 1-2 cm until reach obvious squamous epithelium
Long-segment: Barrett’s mucosa extends 3 cm or more
Short-segment: Barrett’s mucosa extends less than 3 cm
Both long-segment and short-segment Barrett’s esophagus have similar staining patterns to each other and to intestinal metaplasia of GE junction, but different from intestinal metaplasia associated with H. pylori gastritis (AJSP 2001;25:87)
Controversy: significance of intestinal metaplasia at GE junction or in gastric cardia; H. pylori infection is major cause of intestinal metaplasia of gastric cardia, but risk of progression of cardia intestinal metaplasia to dysplasia and adenocarcinoma is significantly lower than in Barrett’s
Treatment: anti-reflux therapy (medical or surgical-Curr Opin Gastroenterol 2007;23:452), endoscopy every 1-2 years to detect dysplasia or early adenocarcinoma with 4 quadrant biopsies using jumbo forceps at intervals of 2 cm or less throughout the length of the Barrett’s segment plus any suspicious lesions (Gastroenterology 1988;94:81); note - there is no clear evidence that surveillance reduces mortality from adenocarcinoma (Am Fam Physician 2004;69:2113)
Endoscopy images: mucosal erythema of lower esophagus
Gross: red velvety GI type mucosa between pale squamous mucosa of lower esophagus and lush pink gastric mucosa; may have tongues extending up from GE junction or a broad band displacing the GE junction proximally; may have preserved squamous islands
Gross images: tongues of tan-orange mucosa #1; #2
Barrett’s esophagus - general (continued)
Micro: esophageal squamous epithelium is replaced by columnar epithelium of intestinal type (stomach, small bowel, colon) with goblet cells (distended, mucin-filled cytoplasm with a barrel-shaped configuration); may be villiform or contain Paneth cells or pancreatic acini (probably metaplastic, AJSP 1995;19:1172); lamina propria is fibrotic with mild chronic inflammation; muscularis mucosae may be thickened or splayed (also called duplicated, Hum Path 1991;22:1158); esophageal glands usually are cystically dilated; may have Helicobacter pylori gastritis but usually negative in esophagus (Hum Path 1997;28:1007); erosions / ulceration may mimic carcinoma due to exuberant granulation tissue or sarcoma due to atypical macrophages; may also be fundic and cardiac type epithelium with mucosal distortion, glandular atrophy and mild inflammation, although these findings are not diagnostic of Barrett’s; rarely heterotopic bone formation (Archives 1996;120:666)
Associated with multilayered epithelium of 4-8 layers of cells that are squamoid in basal aspect and columnar in the luminal aspect
Post-treatment histology: partial squamous reepithelialization of metaplastic columnar epithelium and residual glandular mucosa beneath the squamous epithelium (AJSP 1998;22:239); reepithelialization is often incomplete, and intestinalized glands, representative of residual Barrett’s often remain Underneath areas of reepithelialized Squamous Islands (BUSI); BUSI shows less severe proliferative abnormalities than typical surface BE (AJSP 2005;29:372); occult adenocarcinoma can develop from BUSI (Gastrointest Endosc 2003;58:183)
Micro images: Barrett’s #1; #2; #3; #4; columnar lined surface epithelium with gastric type pits and underlying mucous glands with occasional intestinalized crypts #1; #2; esophageal mucosa with predominantly intestinalized epithelium; mixture of goblet cells and gastric-type columnar cells with apical mucin; tongue of Barrett’s mucosa with squamous epithelium on either side; villous pattern seen in areas of erosion with regeneration #1; #2; granulation tissue with inflammatory infiltrate containing atypical macrophages; acutely inflamed lamina propria with atypical enlarged stromal cells; exuberant granulation tissue with prominent vessels mimics adenocarcinoma; intestinalized epithelium including Paneth cells #1; #2; partial regression with squamous epithelium replacing surface columnar cells; various images; gastroesophageal junction #1; #2 (Alcian blue); Alcian blue #1; #2; #3-blue staining goblet cells and clear staining gastric-type surface columnar cells; #4; #5; PAS/Alcian blue demonstrates acid (blue) and neutral (red-purple) mucins; high iron diamine shows sulfated (brown) and nonsulfated (blue) mucins; classic staining pattern #1: CK7 & CK20; #2; nonclassic staining pattern #1; #2; H&E and CDX2+; various stains #1; #2; #3
Barrett’s esophagus - general (continued)
Positive stains: goblet cells contain acid mucin, usually sialomucin (Alcian blue+ at pH 2.5, although stain may not be needed, AJSP 2006;30:357), columnar cells contain neutral mucins (PAS+); intestinal metaplastic cells are often CK7+/CK20- (or CK20+ only superficially, Hum Path 1999;30:288, although varies by fixative, Hum Path 2005;36:58); also CDX2+ (AJSP 2003;27:1442 but non-goblet columnar cells are also CDX2+, Mod Path 2004;17:1282), guanylyl cyclase C+ (Hum Path 2005;36:170), Hep+ (AJSP 2003;27:952)
EM: mucin granules in metaplastic cells; gastric foveolar-like columnar cells contain Alcian blue+ mucin
DD: intestinal metaplasia of GE junction (normal appearing squamocolumnar junction / Z line at endoscopy, CK staining pattern by itself is not useful to differentiate by itself, Archives 2005;129:181, Hum Path 2004;35:371, but perhaps with other factors-World J Gastroenterol 2005;11:6360), mucus distended columnar cells (Alcian blue weak/negative), hiatal hernia, gastric cardiac-type mucosa normally present in distal esophagus, heterotopic gastric mucosa in upper esophagus, embryonic remnants in infants (ciliated columnar epithelium), sebaceous glands
References: Mod Path 2003;16:316-free full text, Mod Path 2002;15:611 (disputes validity of CK7), eMedicine #1, #2, GI Motility Online
Barrett’s related dysplasia of esophagus
Unequivocally neoplastic epithelium that does not invade the lamina propria, associated with Barrett’s esophagus
Usually patchy and irregular; may appear endoscopically as thickened, velvety mucosa, as a polypoid mass or as Barrett’s mucosa
Brush cytology may be helpful for detection (Hum Path 1997;28:465)
High grade dysplasia and early adenocarcinoma in long-segment and short-segment Barrett’s appear to arise through similar genetic alterations (Hum Path 2001;32:447)
High grade dysplasia: 15-50% risk of invasive adenocarcinoma
Low grade dysplasia: may progress to high grade dysplasia or carcinoma for up to 10 years
Prognostic factors (other): high risk of adenocarcinoma if involvement of > 2 cm of Barrett’s mucosa (relative risk is 30x normal); lower risk for short-segment Barrett’s or intestinal metaplasia at GE junction
Biopsy protocol: four quadrant, well oriented jumbo biopsies at 2 cm intervals (1 cm if high grade dysplasia) throughout the length of Barrett’s area recommended, combined with additional biopsies of endoscopically seen lesions
Treatment: low grade dysplasia - antireflux therapy and increased surveillance
high grade - rebiopsy immediately to rule out missed invasive carcinoma; possibly esophagectomy; recommended to get second opinion on dysplastic biopsies from an experienced GI pathologist
photodynamic therapy - less effective on papillary lesions or distal esophagus lesions-AJSP 2004;28:1466; may cause “buried dysplasia”, AJSP 2007;31:403)
endoscopic mucosal resection - endoluminal therapeutic technique with low morbidity and no mortality; offers improved diagnosis and staging compared with biopsy and ultrasound, but resection is often incomplete and there are high rates of persistence / recurrence (AJSP 2005;29:680, Postgrad Med J 2007;83:367)
Gross: normal appearing or nodule, erosion or polyp
Gross images: high grade dysplasia; dysplasia (grade unspecified)
Barrett’s related dysplasia of esophagus (continued)
Micro: designate low or high grade based on basal (low grade) or apical orientation (high grade) of nuclei (similar to colon criteria); both grades show mucus depletion and prominent cytoplasmic basophilia
low grade dysplasia - preservation of crypt architecture with minimal distortion, atypical nuclei usually limited to basal half of the crypts; variable hyperchromasia, overlapping cell borders with nuclear crowding and irregular nuclear contours; usually shows maturation towards lumen; considerable interobserver variability exists in distinguishing no dysplasia from low grade dysplasia/indefinite for dysplasia (Histopathology 2007;50:920)
high grade dysplasia - more severe atypia and architectural complexity than low grade dysplasia, often with villiform configuration of mucosal surface, more nuclear pleomorphism and hyperchromatism, often nuclear stratification to crypt luminal surface; often easier to diagnose at low power due to nuclear hyperchromasia
dysplasia limited to basal crypts with surface maturation: uncommon, but commonly associated with classic dysplasia or adenocarcinoma (AJSP 2006;30:423)
tubular adenoma - dysplasia in a pedunculated lesion
Micro images: low grade dysplasia - #1; #2; #3; #4; simple straight but elongated tubules lined by dysplastic cells; tubules are lined by pseudostratified epithelium with hyperchromatic elongated nuclei and high N/C ratios; dysplasia is confined to lower half of gland; nuclear enlargement but basal nuclei and only some pseudostratification; dysplasia confined to upper half of mucosa; nuclei are enlarged, elongated and stratified, with indistinct small nucleoli; crowded straight and elongated tubules; atypical cuboidal cells have basal nuclei, enlarged vesicular nuclei and prominent nucleoli; dysplasia of surface foveolar epithelium and cystic dilation of mucous glands #1; #2; #3; dysplasia in lower half of glands #1; #2; various images
high grade dysplasia - #1; #2; cystic dilation of dysplastic glands, glands appear to infiltrate muscularis mucosae; marked distortion of glandular architecture resembling intramucosal carcinoma; cells are cuboidal with loss of nuclear polarity, nuclei are enlarged, rounded and vesicular with prominent nucleoli; high grade (upper 2/3) and low grade dysplasia (lower 1/3); villous pattern; complex villoglandular pattern; marked cytologic atypia with large, vesicular nuclei and prominent nucleoli; dysplastic epithelium replaces Barrett’s mucosa; dilated glandular profiles with atypical cuboidal cells containing enlarged vesicular nuclei and prominent nucleoli; various images
other - tubular adenoma #1; #2; various images #1; #2; H&E and CDX2+; reactive change #1; #2; #3; #4; various reactive images-click on links
Barrett’s related dysplasia of esophagus (continued)
Positive stains: p53 in high grade lesions (Mod Path 2001;14:397-free full text, AJCP 2005;124:519), AMACR, particularly in high grade lesions (AJSP 2006;30:871, Hum Path 2006;37:1601)
DD: intramucosal adenocarcinoma (neoplastic cells infiltrate into lamina propria, usually as single cells or small clusters), reactive changes (if neutrophils present, be conservative in diagnosing dysplasia; reactive cells have more uniform atypia / less pleomorphism, lower nuclear / cytoplasmic ratio, round and regular nuclear contours, basal nuclei, Univ of Washington), baseline atypia (glands at base of Barrett’s mucosa have enlarged, slightly hyperchromatic cells with some stratification and increased mitotic activity but normal surface epithelium)
References: AJSP 1985;9:845, Hum Path 2001;32:379, Mod Path 1991;4:336
Indefinite for dysplasia - esophagus
Rebiopsy after anti-reflux treatment since these patients are at risk for adenocarcinoma
Micro: dysplastic-like epithelial atypia in background of active neutrophilic inflammation and mucosal erosion
Architecture may be moderately distorted; nuclear abnormalities less marked than dysplasia; may have more numerous dystrophic goblet cells, more extensive nuclear stratification, diminished or absent mucus production, increased cytoplasmic basophilia or increased mitoses
Limit diagnosis to cases in which changes are too marked for negative but insufficient for dysplasia
Micro images: indefinite for dysplasia; crowding of lower portions of glands with maturation towards surface, but some stratification and nuclear enlargement; enlarged, hyperchromatic, spindled and stratified nuclei; also dystrophic goblet cells with nuclei displaced towards luminal surface of cell; enlarged nuclei are pseudostratified and crowded in lower crypt, but nuclear changes are less pronounced towards surface; various images #1; #2
Polypoid dysplasia of esophagus
Resembles colonic adenoma, but often associated with invasive adenocarcinoma (Hum Path 1999;30:745), so recommended to not use “adenoma” terminology
2% of all dysplasia seen in Barrett’s esophagus
Clinical, pathological and molecular features are similar to flat Barrett’s dysplasia
Case reports: 71 year old man with focus of adenocarcinoma (Ann Pathol 2002;22:124), 62 year old man (Gastroenterology 1977;72:1317)
Gross: well defined sessile or pedunculated polypoid lesion, 4 to 15 mm
Micro: adenocarcinoma is frequently present within the polyp
References: AJCP 1986;85:629
Squamous dysplasia of esophagus
Also called esophageal intraepithelial neoplasia
Frequently found adjacent to carcinoma
Same risk factors as esophageal squamous cell carcinoma
High grade but not low grade dysplasia is a risk factors for invasive disease (Cancer 1994;74:1686)
Treatment: excision, including endoscopic mucosal resection (Endoscopy 2007;39:24)
Gross: normal, erythematous mucosa or plaques/nodules; highlighted by application of Lugol’s solution (Cancer 1998;83:220) or toluidine blue on mucosal surface
Micro: low grade (abnormal cells limited to basal half of epithelium) or high grade (abnormal cells in upper half of mucosa); nuclear enlargement, pleomorphism, hyperchromasia, mitotic figures; epithelial buds bulge into the stroma varying from grade 1 (regular buds, same size), grade 2 (regular buds, variable size), grade 3 (buds of varying length and width with irregular contours); dysplastic involvement of submucosal gland ducts may mimic invasion; may have pagetoid spread of dysplastic cells
Micro images: low grade dysplasia, with disorganization in basal epithelium, pleomorphism and cell crowding, but obvious squamous differentiation in upper half; low grade dysplasia, but disorganization of lower 2/3 of epithelium; almost full thickness epithelial disorganization #1; #2; pagetoid high grade dysplasia #1; #2; #3; suspicious but not diagnostic of invasive carcinoma #1; #2; #3; in situ carcinoma with adjacent normal mucosa #1; #2; in situ carcinoma involving submucosal ducts #1; #2; various images
DD: microinvasive squamous cell carcinoma (usually larger keratinized cells with more atypia and pleomorphism than dysplasia)
References: AJSP 1989;13:685
Basal squamous dysplasia of esophagus
Abnormal cells are confined to basal half or 2/3 of epithelium
Micro images: basal epithelium is composed of tightly packed, small dysplastic basaloid cells, but upper half has obvious squamous differentiation #1; #2; #3; #4; #5; high grade dysplasia #1 due to pleomorphic and hyperchromatic nuclei, although not full thickness; #2
Carcinoma of esophagus
Carcinoma-general of esophagus
Ninth most prevalent cancer worldwide
Less than 1% of all cancers in US, but incidence has been increasing, with a shift from squamous cell carcinoma arising in upper/middle third of esophagus to adenocarcinomas arising in distal esophagus in US (National Cancer Institute), France (Gastroenterol Clin Biol 2005;29:1258), and elsewhere
Most patients are asymptomatic during early stages and present with advanced or metastatic disease
Cure rate less than 10%, similar to lung cancer
Overall 5 year survival rate ~ 14% (Oncologist 2005;10:590), but 47% after resection (J Am Coll Surg 2006;202:588)
Metastases usually to liver, lungs, pleura
Recommended to submit proximal margins for frozen section to rule out carcinoma underneath a normal appearing mucosa (Archives 2005;129:1558)
Occasionally HER2+, although this is not related to survival (Mod Path 2007;20:120), and anti-HER2 therapy does not appear to be effective (Int J Radiat Oncol Biol Phys 2007;67:405)
Treatment: chemoradiation may achieve results similar to surgery (Ann Thorac Cardiovasc Surg 2006;12:234)
DD: reparative processes (atypical cells in granulation tissue, but with fine chromatin, few mitotic figures; cells mature at deeper levels, keratin negative), chemoradiation induced atypia (enlarged hyperchromatic nuclei with prominent mitotic figures, but relatively mild pleomorphism in inflammatory background)
References: Wikipedia, eMedicine
40-50%% of primary esophageal cancers; increasing incidence over past 20 years for unknown reasons
Previously confused with gastric carcinomas, particularly in lower 1/3 of esophagus
Age 50+ years; 80% men
95% arise in setting of Barrett’s esophagus; prevalence in Barrett’s estimated at 5-28% with 30-125x increased risk
Rarely arises from ectopic gastric mucosa in upper esophagus or from submucosal glands
Risk factors: alcohol or tobacco use, family history
Symptoms: progressive dysphagia, weight loss
5 year survival 15-25%, up to 80% with superficial disease and resection
Usually have invaded through esophageal wall at diagnosis (60-80%), often with nodal involvement (30-60%)
Tends to invade via submucosal lymphatics, emphasizing importance of margin evaluation
Similar prognosis by stage as squamous cell carcinoma
Symptoms: progressive dysphagia, weight loss
5 year survival 15-25%, up to 80% with superficial disease and resection
Usually have invaded through esophageal wall at diagnosis (60-80%), often with nodal involvement (30-60%)
Tends to invade via submucosal lymphatics, emphasizing importance of margin evaluation
Similar prognosis by stage as squamous cell carcinoma
Case reports: collision tumor with papillary adenocarcinoma and neuroendocrine carcinoma (Archives 2000;124:411)
Prognostic factors: lymph node metastases, extracapsular lymph node involvement (AJSP 2006;30:171), depth of invasion (but see J Clin Oncol 2007;25:507-not effective for predicting response to chemoradiation), status of resection margins; possibly endoglin/CD105 (Hum Path 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), and P2 (>50% residual carcinoma, AJSP 2007;31:58); (2) prominent mucin pools in patients with Barrett’s associated adenocarcinoma are associated with mucinous tumors, but acellular mucin pools are NOT associated with poor survival, even if at radial margin (AJSP 2006;30:28)
Treatment: resection - report presence of Barrett’s metaplasia on proximal margin, if present; chemoradiation
Gross: usually distal esophageal tumor with invasion of gastric cardia; appears as flat patches to nodular masses; may have adjacent Barrett’s mucosa
Adenocarcinoma of esophagus (continued)
Gross images: small pink plaque just above GE junction; tumor (arrow) in short-segment Barrett’s epithelium-squamocolumnar junction (arrowheads) is irregular; in short-segment Barrett’s epithelium, tumor straddles GE junction and has thickened mucosal folds; nodular tumor in lower esophagus; ulcerated nodular tumor near squamocolumnar junction; large exophytic tumor fills distal esophagus, Barrett’s epithelium is tan mucosa above and to one side of tumor; polypoid tumor; large exophytic tumor occupies full circumference; diffusely infiltrative tumor of distal esophagus
Micro: usually moderate or well differentiated, usually mucin producing (intestinal type mucosa), may have foci of squamous or endocrine differentiation; usually has adjacent Barrett’s 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: arising from Barrett’s epithelium - well differentiated papillary adenocarcinoma; moderately differentiated #1; #2; #3-poorly formed tubules with marked desmoplasia; poorly differentiated tumor with clear cells; poorly differentiated tumor with sheets of uniform epithelial cells with large vesicular nuclei and prominent nucleoli and one poorly formed gland (lower left); poorly differentiated tumor infiltrates submucosa and muscularis propria #1; #2-tumor cells are anaplastic with little glandular differentiation; cystically dilated glands infiltrating mucosa and submucosa #1; #2 shows lining cells are low cuboidal with vesicular nuclei and prominent nucleoli; mucinous adenocarcinoma #1; #2 shows goblet cells and atypical glands floating in mucin pools; various images
other - adenocarcinoma and neuroendocrine carcinoma collision tumor
Virtual slides: adenocarcinoma
Positive stains: PAS, Alcian blue and mucicarmine (for mucin), usually CK7 and CK19 (AJSP 2002;26:1213), AMACR (Hum Path 2006;37:1601); focal positivity is common for somatostatin and serotonin (Histopathology 1987;11:53)
Negative stains: CK20
EM images: adenocarcinoma (site unspecified)
DD: 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)
References: AJSP 1984;8:563, AJSP 2002;26:784 (achalasia due to adenocarcinoma)
Adenocarcinoma arising in ectopic gastric mucosa
Derives from heterotopic gastric mucosa or perhaps mucosal/submucosal glands in upper 1/3 of esophagus
Very rare
Not associated with Barrett’s, but resembles and behaves like Barrett’s associated adenocarcinoma
Case reports: 60 year old man with tumor of upper esophagus and no Barrett’s (J Exp Clin Cancer Res 2005;24:325)
Micro images: invasive carcinoma
Positive stains: gastric-type mucins (Virchows Arch A Pathol Anat Histopathol 1991;419:159)
DD: carcinoma arising in Barrett’s epithelium (lower esophagus, Barrett’s epithelium extends to stomach)
References: AJSP 1987;11:397
Adenocarcinoma of gastroesophageal junction
More common than primary esophageal adenocarcinoma (with historical definitions)
If define gastroesophageal junction as proximal limit of gastric oxyntic mucosa, then most GE junctional adenocarcinomas would be classified as esophageal in origin (AJSP 2007;31:569, Hum Path 2006;37:40)
Classification as “collision tumor” based on histology is inaccurate - need molecular analysis (AJSP 2004;28:1492)
Molecular: frequent deletions of 14q31-32.1 (Hum Path 2006;37:534
Micro: small tumors have intestinal metaplasia, may be overgrown in larger tumors (Dis Esophagus 2007;20:36)
Intramucosal carcinoma of esophagus
Low interobserver agreement, even among GI experts
Usually node negative (J Am Coll Surg 2006;203:152)
Micro: carcinoma that has penetrated through basement membrane of glands of lamina propria but not yet invaded through the muscularis mucosae into the submucosa; most biopsy specimens will not be deep enough to rule out submucosal invasion
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 the 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’s glands, as previously defined by Ormsby (Gut 2002;51:671)
Micro images: image1; high grade dysplasia with intramucosal carcinoma #1; #2 with atypical clusters of cells and glands infiltrating the lamina propria; #3; suggestive of intramucosal carcinoma; tumor adjacent to squamocolumnar junction #1; #2 shows moderately differentiated glands, some cribriform
DD: high grade dysplasia (no syncytial arrangements of cells or complex glandular budding)
Adenoid cystic carcinoma of esophagus
Rare, resembles salivary gland counterpart
Middle age, F>M
Prognosis: better than squamous cell or basaloid carcinoma
Case reports: Int J Clin Pract 2005;59:1101; Surg Today 1997;27:238
Gross: well circumscribed nodule in the submucosa
Micro: both ductal and basaloid cells form solid nest or cribriform spaces with abundant basement membrane material
Positive stains: ductal cells - CEA, keratin; basal cells - S100, actin
DD: basaloid squamous cell carcinoma (more pleomorphism, mitoses)
Adenosquamous carcinoma of esophagus
Diagnosis is reserved for tumors with somewhat equal amounts of each component
Rare, aggressive (although prognosis may be similar to squamous cell carcinoma), variable association with Barrett’s esophagus
May present with smaller tumor size and lower stage than other carcinomas (Oncology 2004;66:218)
Case reports: with prominent spindle cells (Archives 1993;117:544), with Stage IV disease and survival of 6 years (Gan To Kagaku Ryoho 2006;33:231), poorly differentiated tumor producing alpha-fetoprotein (Anticancer Res 2003;23:3837), associated with Barrett’s (Jpn J Thorac Cardiovasc Surg 2002;50:537)
Micro: malignant glandular and squamous components, usually are not mixed together
Micro images: dysplastic surface squamous epithelium and underlying adenosquamous carcinoma; keratinizing squamous cell carcinoma component; various images
Positive stains: CD44 (squamous areas)
Molecular: both components have same origin (Gastroenterology 2002;122:784)
DD: mucoepidermoid carcinoma (intimate mixture of squamous carcinoma, well-formed glands producing mucin and intermediate cells), collision tumor (rare)
Basaloid squamous cell carcinoma of esophagus
2% of squamous cell carcinomas
Many cases were formerly classified as adenoid cystic carcinoma, which is very rare in esophagus
Usually men age 60-70 years
Poor prognosis; as aggressive as counterpart in upper aerodigestive tract
Usually deeply invasive with widespread metastases at presentation, including nodal metastases
Case reports: 48 year old man (Tumori 2005;91:87), with glandular differentiation (Int J Gastrointest Cancer 2003;34:139), with Barrett’s esophagus (Int J Gastrointest Cancer 2003;34:95)
Micro: invasive nests, trabeculae and strands of high grade basaloid cells (larger than adenoid cystic carcinoma cells) with well demarcated outlines surrounded by fibrous stroma; peripheral palisading, round glandular lumina, central necrosis, nuclear crowding and pleomorphism, numerous mitotic figures, foci of squamous differentiation; often has adenoid cystic like features of cribriform-like pseudoglandular lumina with hyaline material surrounding tumor nests and deposits of hyalinized basal lamina; appears to arise from in situ surface component
Micro images: nests and trabeculae of small dark tumor cells, some with central holes, stromal spaces are uniform and resemble adenoid cystic carcinoma; nest of tumor cells has imperfect palisade of peripheral basal-like cells, also some nuclear debris and multiple small holes; focus of squamous differentiation in background of strands of primitive cells; strands of tumor cells touch the epithelium, but this is not the site of origin; various images #1; #2; #3; H&E and bcl2
Positive stains: CK14 (occasional cells), CK19, EMA, p53, AE1/AE3; also bcl2 (Am J Pathol 1999;155:1027), laminin
Negative stains: S100, smooth muscle actin, neuroendocrine markers
EM: relatively undifferentiated cellular characteristics, undeveloped cell organelles, markedly replicated basement membrane
DD: adenoid cystic carcinoma, small cell carcinoma, component of carcinosarcoma (Pathol Int 2004;54:803)
References: AJSP 1996;20:453, Archives 2004;128:1124, Pathol Res Pract 2003;199:713, World J Gastroenterol 1998;4:397, Cancer 1997;79:1871
<20 cases reported
May arise in association with squamous cell carcinoma or Barrett’s associated adenocarcinoma
Aggressive; death within 3 months in reported cases
Case reports: 42 year old Japanese man (Acta Pathol Jpn 1988;38:489), 40 year old woman (Acta Cytol 1979;23:69), component of squamous cell carcinoma (Am J Clin Oncol 2000;23:203, Indian J Gastroenterol 2006;25:42), with diffuse squamous cell carcinoma in situ (Pathol Int 2002;52:147), adenocarcinoma with yolk sac and choriocarcinomatous differentiation (Cancer 1994;73:514)
Gross: large, exophytic tumor that may encircle esophagus; marked necrosis and hemorrhage
Micro: mixture of syncytiotrophoblast and cytotrophoblast with extensive hemorrhage and necrosis, muscularis propria invasion; may have foci of adenocarcinoma
Large cell neuroendocrine carcinoma of esophagus
Very rare
Case reports: collision tumor between papillary adenocarcinoma and large cell neuroendocrine carcinoma (Archives 2000;124:411)
Micro images: various images #1; #2
Lymphoepithelioma-like carcinoma of esophagus
Rare
May have better prognosis than other carcinomas
Case reports: EBV positive cases (Hum Path 2003;34:407, Diagn Mol Pathol 2007;16:27), EBV negative cases (Pathologica 2001;93:221, J Clin Gastroenterol 2001;33:141)
Micro: poorly differentiated / undifferentiated carcinoma with lymphoid stroma
Micro images: various images
Positive stains: EBV LMP1, CD8 (lymphocytes)
DD: metastatic disease, poorly differentiated carcinoma
References: Archives 1994;118:998
May actually be direct spread from lung, stomach, larynx or mediastinal lymph nodes of lung/breast primaries
Rarely blood-borne metastases from prostate, endometrium, skin (melanoma) or breast
Breast metastases: often appears after long latency period (Ann Thorac Surg 2006;81:1136); may cause stricture (Jpn J Clin Oncol 2005;35:483)
Lung metastases: esophagus is most common GI site for lung metastases; may also spread by direct extension
Melanoma: 4% of patients with widely disseminated disease have esophageal metastases; usually small
Gross images: breast metastases near GE junction #1; #2; lung carcinoma extending directly into esophagus #1; #2
Micro images: breast primary - #1-tumor breaks through squamous epithelium; #2-nests of tumor cells in desmoplastic stroma; #3
References: Jpn J Clin Oncol 1997;27:410
Mucoepidermoid carcinoma of esophagus
Rare
Aggressive; usually presents with extensive local invasion and metastases; poor prognosis (J Nippon Med Sch 2003;70:401)
May arise from submucosal esophageal glands
Cases may be salivary gland type or squamous cell carcinomas with glandular differentiation
Case reports: Hum Path 1978;9:352, with coexisting squamous cell carcinoma (Surg Today 2000;30:636), with diffuse squamous cell carcinoma in situ (Pathol Int 2002;52:147)
Micro: intimate mixture of squamous and glandular carcinoma with squamous islands containing well formed glands or mucus-secreting cells
Micro images: H&E, PCNA, p53, CEA (fig 1)
DD: adenosquamous carcinoma
Case reports: AJSP 1995;19:948, associated with adenocarcinoma of distal esophagus #1 (Histopathology 2003;42:61), #2 (Dis Esophagus 2002;15:334); intraepithelial growth (J Clin Gastroenterol 1993;16:130)
Micro: glandular differentiation or mucin production by intraepithelial Paget’s cells
Positive stains: CK7, CAM5.2, CEA, mucin
DD: pagetoid spread of squamous cell carcinoma (no glandular differentiation, negative staining for Alcian blue, CEA, PAS-diastases, Gastroenterol Hepatol 1997;20:360, Cancer 1997;79:1865)
Pleomorphic giant cell carcinoma of esophagus
Very rare
Case reports: Archives 2000;124:135
Gross images: figure 1
Micro: solid sheets of poorly cohesive epithelioid cells with numerous giant cells showing phagocytosis
Micro images: figures 2-5
Positive stains: keratin, vimentin, CD68, synaptophysin
EM: neurosecretory granules
EM images: image1
DD: carcinosarcoma, melanoma.
Sarcomatoid carcinoma of esophagus
Also called carcinosarcoma, squamous cell carcinoma with spindle cell stroma, spindle carcinoma, pseudosarcoma, polypoid squamous carcinoma
Usually mid to lower esophagus of men age 45+ years
Overall 50% survival; better prognosis than squamous cell carcinoma; tends to present at low stage with intraluminal instead of intramural growth
30% have nodal metastases at presentation (usually epithelial or both components)
Sarcomatous component thought to represent sarcomatous metaplasia of malignant epithelial cells; has malignant potential
Case reports: both components are keratin+ (AJSP 1983;7:495), biphasic metastases (AJSP 1978;2:201), metastases with spindle cell features only (Archives 1977;101:604), p53 only in sarcomatous component (Dis Esophagus 2006;19:48), with basaloid squamous carcinoma and rhabdomyosarcoma (Pathol Int 2004;54:803), with extensive bone formation (Indian J Pathol Microbiol 2003;46:49)
Gross: bulky, exophytic and polypoid mass that grows into lumina, often with short pedicle, mean 6 cm; surrounding mucosa is grossly normal
Gross images: large lobulated polypoid mass; tumor has smooth surface; tumor is well circumscribed and penetrates superficial submucosa only
Micro: biphasic carcinomatous and spindle cell components; spindle cells predominate, are elongated with blunt nuclei and atypia resembling pleomorphic MFH; may have bizarre giant cells, bone, cartilage, strap cells; stroma is edematous with scattered or abundant collagen and mucopolysaccharides; epithelial component usually is squamous or basaloid, rarely adenocarcinoma, and often is limited with only superficial invasion or in situ disease; prominent mitotic activity; may have neuroendocrine differentiation
Micro images: small nests of differentiated squamous cell carcinoma in background of bizarre spindle and giant cells; nests of poorly differentiated squamous cell carcinoma in background of bizarre stromal cells; bizarre stromal and spindle cells with only a small focus of carcinoma (not shown); focal membranous bone formation in undifferentiated stroma; resembles MFH with storiform pattern
Positive stains: keratin for epithelial components and some sarcoma-like cells; vimentin; reticulin surrounds individual cells; p53
Negative stains: S100
Sarcomatoid carcinoma of esophagus
EM: dilated cisternae of rough endoplasmic reticulum, peripheral cytoplasmic intermediate filaments; also some intermediate type junctions and subplasmalemmal linear densities; sarcomatous cells may retain epithelial features including tonofibril bundles or desmosomes, or lack epithelial elements and have fibrohistiocytic differentiation (Hum Path 1987;18:692); spindle cells may resemble myofibroblasts
Molecular: derived from single clone (Hum Path 2004;35:322), sarcoma component is more often aneuploid than carcinoma component (Hum Path 1998;29:863)
DD: sarcoma (must section extensively to rule out presence of epithelial component)
Small cell neuroendocrine carcinoma of esophagus
Also called oat cell carcinoma, anaplastic small cell carcinoma
1% of esophageal tumors
Usually men (2/3) ages 50+ years
Associated with heavy smoking
Very aggressive; median survival 18 months (BMC Cancer 2007 Mar 3;7:38), 5 year survival 8% or less (Chin Med J (Engl) 2007;120:355)
Usually lower esophagus; <20% in upper esophagus
Most cases have nodal metastases at surgery (World J Gastroenterol 2004;10:3680, Oncol Rep 2002;9:1245)
Appears to arise from same multipotent epithelial basal cells that produce squamous cell carcinoma; both tumors often intermingle (Hum Path 1984;15:460)
FDG-PET scans may determine extent of disease (Indian J Cancer 2005;42:60)
Case reports: with paraneoplastic neurologic syndrome (Jpn J Clin Oncol 2006;36:109)
Treatment: resection (possibly endoscopic mucosal resection if superficial-Gan To Kagaku Ryoho 2007;34:81), chemoradiation
Gross images: tumor with small cell pattern (between upper two arrows) and squamous cell pattern (between lower two arrows)
Micro: identical to lung counterpart; sheets and nests of small round/oval cells with minimal cytoplasm and hyperchromatic nuclei with salt and pepper chromatin, mitotically active; may have rosettes, carcinoid-type features and focal mucin production, encrustation of vessel walls by tumor DNA (Azzopardi phenomenon), crush artifact; may also have in situ or invasive squamous cell carcinoma or mucoepidermoid carcinoma
Micro images: diffusing infiltrating sheets of small tumor cells; tumor cells have indistinct cell borders, minimal cytoplasm and dense hyperchromatic nuclei; central necrosis; ribbons and rosettes; tumor cells have scant cytoplasm with small, hyperchromatic, round/oval nuclei with extensive nuclear molding; ribbons of cells with angular hyperchromatic nuclei; loosely cohesive cells resembling lymphoma; spindle cells with scant cytoplasm, salt and pepper nuclei with indistinct nucleoli; in situ component resembles poorly differentiated squamous cell carcinoma #1; #2 with focal squamous cell differentiation at top; various images; immunostains; NSE; synaptophysin; chromogranin; fig 1/2: H&E, fig 3: cytokeratin, fig 4: synaptophysin, fig 5: NSE
Cytology: small malignant cells with scant cytoplasm and nuclear molding
Small cell neuroendocrine carcinoma of esophagus (continued)
Positive stains: synaptophysin (95%), CD56 (76%), TTF1 (71%), neuron-specific enolase (62%), chromogranin A (62%), EMA (62%), AE1/AE3 (57%); also p53 (81%), bcl2 (33%), S100 (19%)
EM: dense core neurosecretory granules
EM images: neurosecretory granules #1; #2
DD: metastatic lung carcinoma, lymphoma, carcinoid tumor, basaloid squamous cell carcinoma
References: Hum Path 1999;30:216
Squamous cell carcinoma of esophagus
Historically most common type of esophageal cancer; now being surpassed by Barrett’s related adenocarcinoma in US and other countries
Highest incidence in northern Iran, northern China, Puerto Rico, South Africa and other developing countries
Causes: lack of fruits and vegetables causing deficiencies of vitamins A, B6, C, riboflavin, thiamine, zinc, molybdenum; alcoholism (25x risk for chronic liquor drinkers), tobacco (may be synergistic with alcohol), Betel nuts, fungal contamination, hot foods and beverages, nitrates / nitrosamines (in fermented corn, well water contaminated by animal / human wastes and produced by fungal contaminants), polycyclic aromatic hydrocarbons in China (Hum Path 1998;29:1294), urban environment
Also associated with achalasia, celiac disease, corrosive strictures, epidermolysis bullosa, esophagitis (chronic), HPV in high risk regions (Hum Path 1994;25:920, World J Gastroenterol 2005;11:1200), lye stricture, Plummer-Vinson syndrome, radiation therapy, squamous cell carcinoma of other aerodigestive sites, tylosis palmaris et plantaris (palmoplantar keratoderma-BMC Cancer 2005 Jul 28;5:90); rarely associated with Barrett’s esophagus (Mod Path 1989;2:2)
Usually men (75%) age 50+ years in low risk areas; more common in blacks (4:1) in US
Symptoms: dysphagia, anorexia, weight loss (due to advanced stage at presentation)
90% in mid/lower esophagus
Occasionally multifocal in esophagus or upper aerodigestive tract
Usually invasion into muscularis propria at presentation
In resection specimens, 30-40% have invasion of adjacent mediastinal structures that may cause fistulas; 50% have lymph node metastases (periesophageal or cervical); often widely distributed due to complex anastomoses of esophageal lymphatics; may metastasize to gastric submucosa
Distant metastases to lungs, liver, bones, adrenal glands
Very poor prognosis; median survival is less than 1 year
Exfoliative cytology is accurate, particularly for lesions in lower 1/3 of esophagus; cytology plus biopsy is recommended
Varicoid pattern: disseminates via the vasculature and lymphatics to submucosa, and resembles varices by endoscopy (Radiographics 2006;26:271)
Prognostic factors: stage is most important (AJCP 1991;95:844); tumor grade (well, moderate or poorly differentiated) is not reproducible and not important unless tumor is anaplastic
Treatment: preoperative radiation therapy, esophagectomy; variable chemotherapy
Squamous cell carcinoma of esophagus (continued)
Gross: (a) fungating/exophytic/polypoid lesions (most common), (b) ulcerative (primarily intramural with deep irregular ulcers, protuberant edges around ulcer, may perforate and enter trachea, aorta or mediastinum) or (c) infiltrative (intramural causing thick, rigid esophageal wall with luminal narrowing, linitis plastica pattern and only minor mucosal defect, associated with stricture)
Gross images: fungating/exophytic - tumor in upper esophagus just below and behind the larynx; forms broad sessile plaque in lower esophagus; fungating mass #1; #2; #3
ulcerative - large, bulky tumor of distal esophagus has raised everted margin and caused marked luminal narrowing; small tumor of mid esophagus; prominent edges surround ulcer; huge tumor with necrotic, hemorrhagic and nodular base and piled-up edges; distal esophagus; exophytic ulcerated mass #1; #2; #3; #4; #5
infiltrative - elevated plaque obliterates mucosal folds and thickens the wall; stricture due to infiltrative pattern, also ulcerated foci and nodular areas
other - tumor of mid esophagus; causing tracheo-esophageal fistulas; granular surface; local tumor extension
Micro: usually moderate to well differentiated (based on mix of undifferentiated / primitive basal cells, large flat squamous cells and keratinized foci); tumor clusters may be present distant from main mass (intramural metastases) due to lymphatic spread through submucosa; tumor cells often exhibit keratinization and have intercellular bridges; angiolymphatic invasion (75%); mitotic rate usually correlates with percent basal cells; may have focal glandular or small cell differentiation or lymphoid stroma; occasionally intraepithelial component resembling Paget’s disease; desmoplasia most common with adventitial penetration
lamina propria invasion - elongated rete-like projections which may bud and then break off; little desmoplasia
intramucosal - does not penetrate below lamina propria
submucosal invasion - often pushing type border with expansion circumferentially; variable desmoplasia; note - in situ carcinoma can also invade submucosal ducts without being considered true invasion
Cytology: cells have enlarged nuclei, multiple and enlarged nucleoli, loss of nuclear polarity in cell clusters; similar features also present in reparative epithelium
Squamous cell carcinoma of esophagus (continued)
Micro images: well differentiated #1; #2; #3; #4; #5; #6; moderately differentiated #1; #2 (trabecular growth, mostly small primitive cells but also large differentiated squamous cells); #3; moderate to poorly differentiated tumor has primarily basal cells with a small focus of squamous cells; poorly differentiated tumor has round cells without obvious squamous differentiation; poorly differentiated tumor; undermining surface epithelium; infiltrating nests of tumor; intercellular bridges; nests of tumor cells; infiltration of lamina propria (site of origin is nearby); carcinoma without desmoplasia invades the muscularis propria; desmoplastic stroma with adventitial invasion; expansile growth pattern with smooth invasive edge; infiltrative growth pattern with individual tongues and nests and intense lymphocytic infiltrate; focal glandular component #1 (right); #2; #3 (Alcian blue-PAS with diastase) shows Alcian blue staining of goblet cells and some lumens; small cell type shows cohesive, small, spindly cells with a central nest of squamous cells; in situ carcinoma on left, submucosal invasion on right, veins contain tumor emboli; lymphatic invasion #1; #2; #3; submucosal veins filled with tumor and fibrin; residual tumor after radiation therapy; perineural invasion; intramural invasion likely due to lymphatic spread (note intact epithelium); radiated tumor cells have enlarged and bizarre nuclei with vacuoles and granules; CD44 staining (fig 1A/1B)
Virtual slides: squamous cell carcinoma #1; #2 with liver metastases
Positive stains: cytokeratin; also CD44 (Archives 2000;124:212), p53, EGFR, cyclin D1; coexpression of p63 and CK5/6 is specific for squamous origin in poorly differentiated tumors (AJCP 2001;116:823); variable vimentin
EM images: desmosomes and tonofilaments (site unknown)
Molecular: aneuploid (2/3); various molecular profiles (World J Gastroenterol 2007;13:1438)
DD: reactive changes in ulcer beds (atypical mesenchymal cells in biopsy specimens are pleomorphic and hyperchromatic but usually not mitotically active, are cytokeratin negative), atypical regenerative hyperplasia in biopsies (no stromal infiltration, Archives 2005;129:899), post-radiochemotherapy changes (usually monomorphic and background has inflammation and granulation tissue), pseudoepitheliomatous hyperplasia
References: eMedicine
Superficial squamous cell carcinoma of esophagus
Tumor confined to mucosa and submucosa (T1) regardless of lymph node status
Either stage I (node negative) or IIB (node positive)
Intramucosal tumors have 5% lymph node involvement vs. 35% for submucosal tumors
Accounts for 20% of resections in US/Western Europe
Patients may also have bronchial or oropharyngolaryngeal carcinoma
5 year survival is 85% without vs. 40% with nodal involvement
Diagrams: depth of invasion of superficial esophageal carcinoma
Case reports: with multiple leiomyomas (World J Gastroenterol 2006;12:4588)
Treatment: excision; follow up without node dissection after endoscopic mucosal resection if no lymphatic invasion (Mod Path 2006;19:475)
Gross: polypoid masses, thin plaques or eroded mucosal depressions
Gross images: small ulcer covered by blood clot; plaque-like tumor is irregular, slightly elevated
Micro: invasive nests with irregular borders in lamina propria or submucosa; often multicentric; invasive focus often has larger, more squamous appearing cells than overlying surface component; often adjacent dysplastic epithelium; no invasion of muscularis propria
Micro images: tumor invades into middle of submucosa; with leiomyoma; various images (figs 4-5)
DD: dysplasia involving ducts; tangential sectioning of papillary or undulating dysplastic lesions
References: AJSP 1989;13:535
Verrucous squamous cell carcinoma of esophagus
Rare; identical to similarly named tumors of upper aerodigestive tract
Slow growing, usually only locally invasive without nodal metastases, but still has high mortality with development of fistulas (J Gastroenterol Hepatol 1993;8:107, J Clin Gastroenterol 1991;13:102, Minerva Chir 2005;60:61)
Superficial biopsies may be diagnosed as benign or squamous papilloma (Can J Gastroenterol 2004;18:459, Am J Gastroenterol 1996;91:1031)
Usually men ages 55-65
Case reports: 51 year old man with dysphagia
Gross: large exophytic polypoid mass
Gross images: large plaque of carcinoma with base in lamina propria, luminal aspect has epithelial spikes of thick keratin
Micro: similar to oral cavity counterpart; well differentiated with papillary fronds covered by squamous epithelium; bland cytologic features with mild atypia; variable parakeratosis and hyperkeratosis; pushing type of invasion with blunt epithelial projections
Micro images: squamous spikes covered by keratin; blunted base is very well differentiated #1; #2; atypical squamous eddies
DD: carcinoma cuniculatum-deeply penetrating and burrowing growth pattern (Ann Diagn Pathol 2005;9:134)
Other malignancies of esophagus
Very rare, <20 cases reported
Previously considered to have poor prognosis (J Exp Clin Cancer Res 1998;17:47), but recent study suggests good prognosis (AJSP 2002;26:517)
May be incidental finding associated with Barrett’s esophagus and adenocarcinoma
Tumors > 2 cm (World J Gastroenterol 2005;11:7028) or high stage (Cancer 1997;79:1476) have poorer prognosis
Case reports: 11 mm tumor of lamina propria (J Gastroenterol 1998;33:541), atypical carcinoid tumor with death due to liver metastases (Ann Thorac Cardiovasc Surg 2002;8:302)
Micro: nests, islands and trabeculae of uniform cells, may have Paneth cell differentiation
Micro images: incidental carcinoid tumor is strongly chromogranin positive; spindled tumor cells in atypical carcinoid (fig 2); NSE and chromogranin positive (fig 3)
Positive stains: chromogranin, synaptophysin, NSE
DD: small cell carcinoma (necrosis, Azzopardi phenomenon, high mitotic rate), large cell neuroendocrine carcinoma (necrosis, mitotic activity, large cells with abundant cytoplasm and prominent nucleoli), glomus tumor (Hepatogastroenterology 2003;50:687)
References: eMedicine (GI carcinoid)
Very rare
Case reports: 56 year old man with polypoid tumor of lower esophagus (Hum Path 2002;33:130)
Micro: small round cells with prominent fibrillar cytoplasmic processes and intracytoplasmic glycogen
Positive stains: CD99/MIC2
Molecular: t(11;22) (q24;q12) (EWSR1/FLI1) or t(21;22) (q22;q12) (EWSR1/ERG)
Gastrointestinal stromal tumor (GIST) of esophagus
Very rare, <20 cases reported
Median age 63 years (range 49-75 years), no gender preference
Usually lower third of esophagus
50% of cases are malignant; usually >10 cm and > 5 mitotic figures/50 HPF
Case reports: recurrent and metastatic tumor with complete response to Gleevec (Gan To Kagaku Ryoho 2007;34:237), 61 year old man with response to Gleevec (Saudi Med J 2006;27:1236), epithelioid tumor in HIV+ man (Ann Diagn Pathol 2005;9:49), metastatic tumor with paraneoplastic features (Dtsch Med Wochenschr 2005;130:2380), GANT tumor (Cancer 1996;78:1651)
Features to report: size, mitotic rate, cellularity, mucosal invasion (yes/no), margin status; recommended to state if tumor is histologically benign, malignant, or of uncertain malignant potential
Micro: identical to gastric GIST; solid, myxoid and perivascular patterns; usually spindle cells, variable epithelioid differentiation
Cytology: cellular groups or occasional single spindled cells with fine, delicate cytoplasm, round/oval nuclei with fine chromatin and rare/occasional nucleoli; single cells may have stripped nuclei; often atypia and occasional epithelioid cells (AJCP 2003;119:703)
Cytology images: site unknown - spindle cells with high cellularity #1; #2; #3; cells with stripped nuclei; epithelioid cells; cell block shows mildly haphazard arrangement of spindle cells with somewhat basophilic cytoplasm and round/oval nuclei; cell block shows epithelioid cells
Positive stains: CD117 (diffuse cytoplasmic or perinuclear accentuation), CD34 (80-90%), smooth muscle actin (30%), desmin (<5%), S100 (<5%)
Molecular: mutations in exon 11 of c-kit
Cytogenetic: losses in chromosomes 14 and 22 are common in both malignant and benign GISTs
References: Mod Path 2003;16:366-free full text, AJSP 2000;24:211, Ann Diagn Pathol 2007;11:39
Hemangiopericytoma of esophagus
Only a few cases reported
Microscopic and ultrastructural features similar to tumors at other locations
Case reports: #1 (Hum Path 1981;12:96), #2 (Br J Radiol 1995;68:1031)
See discussions in Soft Tissue Tumor chapter and Oral Cavity chapter
Usually in AIDS patients
Gross: multifocal mucosal involvement
Micro: spindle cells, usually with cytoplasmic PAS+ hyaline globules; vascular slits with extravasated red blood cells
Positive stains: CD34, HHV8
Negative stains: CD117
DD: pyogenic granuloma (Virchows Arch 2004;444:590)
Rare, but 90% of esophageal sarcomas
Poor prognosis
Case reports: with leiomyoma (J Exp Clin Cancer Res 2005;24:487), 52 year old woman with dysphagia (Archives 2000;124:1391)
Gross: large, soft tumor with hemorrhage and necrosis
Gross images: intramural sarcoma (not necessarily leiomyosarcoma) has focal hemorrhage and necrosis; arising from remnant esophagus after prior squamous cell carcinoma; polypoid lesion with ulceration; hemorrhagic and nodular tumor #1; #2
Micro: fascicles of blunt-ended (cigar shaped) spindle cells with nuclear pleomorphism and variably eosinophilic cytoplasm; high mitotic activity (> 50 mitoses per 50 HPFs); usually not epithelioid
Micro images: tumor from remnant esophagus: H&E, smooth muscle actin+, keratin negative; interlacing bundles of spindle cells with atypia and mitotic figures
Cytology: cellular spindle cell lesion with marked cytologic atypia and nuclear pleomorphism (Diagn Cytopathol 2007;35:167)
Positive stains: smooth muscle actin, desmin, keratin (variable), CD34 (variable)
Negative stains: CD117, S100
DD: bizarre stromal myofibroblasts / fibroblasts in beds of chronic ulcers (background granulation tissue)
References: AJSP 2000;24:211
Very rare (< 20 cases reported)
Case reports: pleomorphic liposarcoma (Archives 2004;128:922), well differentiated liposarcoma #1 (J Postgrad Med 2006;52:231), #2 (Chin Med J (Engl) 2006;119:438), #3 (World J Gastroenterol 2006;12:1149), #4 (Yonsei Med J 2003;44:715), mediastinal tumor invading the esophagus (Rays 2006;31:17)
Micro images: pleomorphic liposarcoma-various images; well differentiated liposarcoma (figs 7-8)
Rare; usually secondary to gastric or hilar nodal disease
May present with dysphagia if diffuse esophageal involvement
Usually diffuse large B cell lymphoma
Case reports: 61 year old man with AIDS and Hodgkin’s lymphoma (AJCP 1997;108:593), MALT lymphoma causing esophageal perforation, MALT lymphoma with BALT of lung; mantle cell lymphoma (lymphomatoid polyposis) throughout GI tract including esophagus (Archives 2003;127:1028), plasmacytoma (Ann Diagn Pathol 2003;7:174), T cell lymphoma (Indian J Gastroenterol 2005;24:119)
Gross images: Hodgkin’s lymphoma-mixed cellularity
Micro images: diffuse large B cell lymphoma - lymphomatous infiltrate extends to squamous epithelium; atypical large lymphocytes mixed with normal appearing small lymphocytes; monomorphous large atypical lymphocytes; atypical large lymphocytes in an ulcer; CD20+; Ki-67+; tumor cells are CD3 negative but infiltrating T cells are CD3+
MALT lymphoma - various images
Positive stains: PAX5 and MUM1 for Hodgkin’s lymphoma (Can J Gastroenterol 2007;21:185)
DD: leukemic infiltrate of esophageal wall, lymphoid hyperplasia (AJSP 1985;9:141)
References: eMedicine
Malignant peripheral nerve sheath tumor (MPNST) of esophagus
Rare
Case reports: with Barrett’s esophagus and nodal metastases (Gastroenterol Hepatol 2004;27:467), with nodal metastases (J Gastroenterol 2001;36:772)
Gross images: primary in esophagus or stomach
Micro: spindle cells with marked atypia
Micro images: pleomorphic sarcoma #1; #2 with tumor giant cells; atypical spindle cells #1; #2; #3 with necrosis
Positive stains: S100, vimentin
Negative stains: CD117
Rare, 0.1% of esophageal malignancies
Usually men (2/3), age 50+ years
Should have junctional component in overlying or adjacent mucosa to call an esophageal primary
Poor prognosis; most patients die within 2 years of diagnosis
Metastases to regional lymph nodes, liver, lung, brain, mediastinal soft tissue
Case reports: with melanosis exhibiting atypia extending to melanoma in situ (AJCP 1989;92:802), presenting with dysphagia (J Korean Med Sci 2007;22:149, The Internet Journal of Gastroenterology), 5 years after stomach melanoma (World J Gastroenterol 2005;11:2197), amelanotic tumors (Int J Dermatol 2006;45:1207, Minerva Chir 2006;61:45), solitary pulmonary metastasis (World J Surg Oncol 2006;13;22), multiple esophageal lesions (Nat Clin Pract Gastroenterol Hepatol 2007;4:171)
Gross: large polypoid pigmented mass, often ulcerated, limited vertical growth, usually in lower esophagus; may be amelanotic
Gross images: polypoid mass with hemorrhage; black ulcerated nodules; pigmented, ulcerated and hemorrhagic tumor; residual tumor after resection
Micro: similar to cutaneous melanomas; epithelioid or spindled cells in sheets, nests or fascicles; tumor cells have clear or pale cytoplasm with occasional melanin granules, large round/oval nuclei with vesicular chromatin and prominent nucleoli; often nuclear pseudoinclusions; frequent mitotic figures; may have in-situ junctional component or melanosis; usually expansile rather than infiltrative growth pattern
Micro images: large, sessile, polypoid melanoma invading superficial mucosa, black dot is at junctional component; tumor cells are epithelioid with abundant pale cytoplasm containing some melanin, pleomorphic nuclei; atypical junctional melanocytic hyperplasia is present next to melanoma, consists of single cells / small clusters that obliterate basal layer; focally pigmented tumor; in situ (left) and invasive (right) components; lentiginous proliferation of atypical melanocytes; nests of atypical melanocytes; GE junctional tumor-various images; cellular tumor; H&E and HMB45; various images; lung metastasis #1; #2-HMB45+; HMB45+ melanoma
Positive stains: S100, HMB45. Mart1/MelanA; also Fontana-Masson
Negative stains: cytokeratin, CD45/LCA
EM: premelanosomes
DD: metastatic melanoma
References: AJSP 1987;11:46, Hum Path 1983;14:727
Extremely rare
May be a component of carcinosarcoma (Hepatogastroenterology 2001;48:137)
Case reports: Hum Path 1982;13:680
Miscellaneous
Staging of esophageal carcinoma
Does not apply to sarcomas
Clinical staging is similar
Note: recommended to state in words the basis of the staging (i.e. “invasion of lamina propria but not submucosa”, and not just pT1b), because classification systems change over time and vary between institutions
Changes from AJCC 6th to 7th edition include changes to T, N, M and stage groupings
Primary tumor (T)
TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis: High grade dysplasia (includes all noninvasive neoplastic epithelia that was formerly called carcinoma in situ, a diagnosis that is no longer used for columnar mucosae anywhere in the GI tract)
T1: Tumor invades lamina propria, muscularis mucosae or submucosa
T1a: Tumor invades lamina propria or muscularis mucosae
T1b: Tumor invades submucosa
T2: Tumor invades muscularis propria
T3: Tumor invades adventitia
T4: Tumor invades adjacent structures
T4a: Resectable tumor invading pleura, pericardium or diaphragm
T4b: Unresectable tumor invading other adjacent structures, such as aorta, vertebral body, trachea, etc.
Notes:
Maximal dimension of tumor must be recorded
Multiple tumors require the T(m) suffix
Regional lymph nodes (N)
NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastases
N1: Metastasis in 1-2 regional lymph nodes
N2: Metastasis in 3-6 regional lymph nodes
N3: Metastasis in 7 or more regional lymph nodes
Notes:
Number must be recorded for total number of regional nodes sampled and total number of reported nodes with metastasis
Distant Metastasis (M)
M0: no distant metastasis
M1: distant metastasis
Stage grouping
Squamous cell carcinoma
Also includes mixed histology including a squamous component or NOS
Stage 0: Tis (HGD) N0 M0, grade 1, X; any location
Stage IA: T1 N0 M0, grade 1, X; any location
Stage IB: T1 N0 M0, grade 2-3, any location or
T2-3 N0 M0, grade 1, X: lower or X location
Stage IIA: T2-3 N0 M0, grade 1,X; upper or middle location or
T2-3, N0 M0, grade 2-3, lower or X location
Stage IIB: T2-3 N0 M0, grade 2-3; upper or middle location or
T1-2 N1 M0, any grade, any location
Stage IIIA: T1-2 N2 M0 or T3 N1 M0 or T4a N0 M0; any grade, any location
Stage IIIB: T3 N2 M0, any grade, any location
Stage IIIC: T4a N1-2 M0 or T4b any N M0 or any T N3 M0; any grade, any location
Stage IV: Any T, any N, M1, any grade, any location
Notes:
Location of the primary cancer site is defined by the position of the upper (proximal) edige of the tumor in the esophagus
Adenocarcinoma
Stage 0: Tis (HGD) N0 M0, grade 1, X
Stage IA: T1 N0 M0, grade 1-2, X
Stage IB: T1 N0 M0, grade 3 or
T2 N0 M0, grade 1-2, X
Stage IIA: T2, N0 M0, grade 3
Stage IIB: T3 N0 M0, any grade or
T1-2 N1 M0, any grade
Stage IIIA: T1-2 N2 M0 or T3 N1 M0 or T4a N0 M0; any grade
Stage IIIB: T3 N2 M0, any grade
Stage IIIC: T4a N1-2 M0 or T4b any N M0 or any T N3 M0; any grade
Stage IV: Any T, any N, M1, any grade
Diagrams: various stages; TNM diagram; staging form #1; #2
References: J Am Coll Surg 2005;201:884
Grossing esophagectomy specimens
Take photographs and measurements and check coloration when specimen is fresh
Open esophagus longitudinally, ink deep margin, pin flat overnight
Dissect fat for lymph nodes (adjacent, proximal and distal to tumor)
Take sections from resection margins, tumor / lesion (4-5), deep margins to tumor, normal mucosa proximal and distal to tumor, lymph nodes, other structures
Features to report for esophageal carcinoma
Biopsy
Specimen type (incision or excisional biopsy)
Site of biopsy (if known)
Histologic type
Histologic grade
Depth of invasion (even in superficial tumors, AJSP 2005;29:1079)
Additional findings
Excision / resection of esophagus
Specimen type (procedure)
Anatomic site
Tumor size (greatest dimension)
Histologic type
Histologic grade
Depth of invasion (even in superficial tumors, AJSP 2005;29:1079)
Lymph node involvement (total involved, total examined)
Tumor stage (TNM)
Margin involvement (proximal, distal, radial/adventitial) - indicate if involved or not by invasive or in situ carcinoma and closest distance of invasive carcinoma
Optional features to report
Multifocality
Involvement of adjacent structures
Angiolymphatic invasion
Perineural invasion
Size of largest tumor involvement in metastatic lymph node (Ann Surg Oncol 2002;9:1010, Ann Thorac Surg 2007;83:1265)
Extracapsular lymph node involvement (AJSP 2006;30:171)
Presence or absence of histologic tumor regression in patients with preoperative chemotherapy (Dis Esophagus 2006;19:329)
Other features (esophagitis, Barrett’s esophagus, dysplasia, specific types of infection)
References: Michigan Cancer Consortium checklist
