Esophageal and Stomach Pathology

Esophagus

• 1.

  Describe a normal esophagus lining.

  • Esophagus consists of mucosa, lamina propria, muscularis mucosae, submucosa, muscularis propria, and adventitia (lacks serosa) ( Figure 8-1 A ).

    

  • Sebaceous glands can be seen normally in the submucosa.

  • Normal gastroesophageal (GE) junction (see Figure 8-1 B ) shows squamous and columnar epithelium.

• 2.

  What are the histologic features of gastroesophageal reflux disease (GERD) and eosinophilic esophagitis (EE)?

  Histologic Features of GERD include the following ( Figure 8-2 A ):

  • Distal esophagus is more severe than proximal esophagus.

  • Basilar hyperplasia is present.

  • Elongation of vascular papillae occurs.

  • Intraepithelial neutrophils and eosinophils increase ( ≈ 8 eosinophils per high power field [HPF] ).

  • Balloon cells (enlarged squamous cells with abundant accumulation of plasma proteins) indicate chemical injury.

  

  Histologic features of EE are the following (see Figure 8-2 B ):

  • Proximal esophagus is more common than distal esophagus. Distribution can be patchy. Obtain biopsy samples from upper, mid, and distal esophagus.

  • Intraepithelial eosinophils in upper layers of epithelium are increased ( > 15–20 eosinophils/HPF ).

  • Eosinophilic microabscesses appear in superficial layers of epithelium.

  • Extensive degranulation of eosinophils is more common.

  • GERD can coexist in 30% of cases and is difficult to distinguish histologically .

• 3.

  Discuss the infectious causes of esophagitis.

  The infectious causes of fungal esophagitis are the following:

  • Candida esophagitis ( Figure 8-3 A and B ): C. albicans is the most common of the Candida species. Others include C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei. Endoscopy shows whitish, raised plaques with erosions or ulcerations. Histologic examination reveals erosion of superficial layers of squamous epithelium or ulceration with yeast and pseudohyphal forms (highlighted by special stains such as Grocott methenamine silver or periodic acid–Schiff [PAS]). The key to diagnosis is presence of pseudohyphal forms which indicates infection. The presence of yeast forms alone suggests oral contamination.

    

  • Histoplasma: In the United States, Histoplasma is endemic around Mississippi and Ohio River valleys. It is also endemic to Central and South America and the Caribbean islands. Endoscopy may appear normal. Histologic examination reveals subepithelial necrotizing granulomas with giant cells that contain organisms of 2 to 4 μm in diameter.

  • Aspergillus: The most common species are Aspergillus fumigatus and A. flavus. Seen as branching (at 45 degrees) septate hyphae 4 μm in diameter.

  • Mucormycosis: Mucormycosis can be seen in immunocompromised hosts as nonseptate parallel hyphae (10 to 15 μm in diameter) that branch at right angles.

  The infections causes of viral esophagitis are the following:

  • Herpes esophagitis ( Figure 8-4 ): H. esophagitis is seen in immunocompromised patients. Endoscopic examination may reveal vesicles or coalesced shallow ulcers. Histologic examination will reveal infected epithelial cells that show multinucleation with molding and smudged intranuclear inclusions.

    

  • Cytomegalovirus: Cytomegalovirus is seen in immunocompromised patients. The viral cytopathic effect includes intracytoplasmic and intranuclear inclusions seen in endothelial cells, histiocytes, or fibroblasts.

• 4.

  What is the most important differential to be considered in biopsy samples to evaluate graft-versus-host disease (GVHD)?

  Infectious etiologic factors must be ruled out with the use of special stains (fungal and viral) and with serologic and tissue culture examinations. In general, the upper esophagus is usually affected. Histologic examination grades GVHD as mild, moderate, or severe based on the degree of damage seen. Apoptotic bodies are seen in the squamous epithelium; there are intraepithelial lymphocytes and basal vacuolization and, in severe cases, ulceration and necrosis.

• 5.

  What is the histologic prevalence of esophageal Crohn’s disease in endoscopically normal studies?

  Histologic prevalence varies from 5% to 42% and does not correlate with endoscopic findings. Crohn’s esophagitis may be seen with severe cases of ileocolic disease. Histologic features vary from mild inflammation with epithelioid nonnecrotizing granulomas in the lamina propria to ulcerations and transmural involvement with fistula formation.

• 6.

  What are other miscellaneous esophageal conditions?

  • Glycogen acanthosis: Endoscopic examination reveals small, white-gray plaques in the midesophagus. There is an association with Cowden syndrome. Histologic findings include squamous cells distended with increased intracellular glycogen.

  • Gastric inlet patch: Endoscopic examination reveals a patch (2 mm to 3 cm) of gastric-appearing mucosa located just below the cricopharyngeus muscle. Histologic findings consist of oxyntic (parietal)-type mucosa. Intestinal metaplasia may be found.

  • Pancreatic heterotopia: Endoscopic findings are often not apparent to the eye. This tissue is often seen in biopsy samples at the GE junction or distal esophagus. It may represent metaplasia or ectopic foci of pancreatic tissue. Histologic examination reveals acinar cells with dense, coarse eosinophilic granules are seen.

  • Melanosis: Endoscopic findings include tiny 1- to 2-mm brown-black spots. Melanocytes may be seen in the basal layer of squamous epithelium. The differential diagnosis is malignant melanoma. The melanocytes in melanosis are benign-appearing and mature. Pigment can be seen in upper layers of mucosa and in the adjacent lamina propria.

• 7.

  List the dermatologic conditions that can affect the esophagus.

  Dermatologic conditions that affect the esophagus are pemphigus vulgaris, bullous pemphigoid, erythema multiforme, Behçet syndrome, lichen planus, dermatitis herpetiformis, scleroderma, and toxic epidermolysis necrosis.

• 8.

  Discuss the histologic characteristics of Barrett’s esophagus and the grading of dysplasia.

  Barrett’s esophagus is an endoscopic change in esophageal epithelium of any length, confirmed to have intestinal metaplasia at biopsy. Histologic findings include squamocolumnar junctional mucosa with intestinal metaplasia recognized by the presence of goblet cells ( Figure 8-5 A ), which stain blue with Alcian blue stain at pH 2.5 (see Figure 8-5 B ).

  

  Dysplasia in Barrett’s esophagus is graded as follows:

  • None: There is no evidence of dysplasia.

  • Indefinite for dysplasia: This grading is assigned when distinction cannot be made between low-grade dysplasia and inflammatory changes. The surface epithelium shows maturation, but the deeper glands show architectural crowding, nuclear hyperchromasia, and occasionally increased mitotic activity.

  • Low-grade dysplasia (see Figure 8-5 C ): Lack of surface maturation and glandular epithelium shows amphophilic cytoplasm with mucin depletion and nuclear hyperchromasia. Architectural crowding is similar to that seen in colonic tubular adenomas.

  • High-grade dysplasia: Lack of surface maturation with cells shows marked cytologic atypia characterized by loss of polarity, high nuclear-to-cytoplasm ratio, irregular nuclear contours, and prominent large nucleoli. The architecture becomes complex with focal areas of cribriforming. Cytologic abnormalities supersede architectural complexity in diagnosing high-grade dysplasia.

  • High-grade dysplasia with invasion or intramucosal carcinoma—T1 (see Figure 8-5 D): Invasion into the lamina propria or muscularis mucosae has prognostic implications in the esophagus, unlike in the colon, because of the presence of lymphatics in the former. Lymph node metastasis has been reported in 13% of T1 tumors. Duplication of muscularis mucosae can at times be present and should not be mistaken for invasion into the submucosa.

• 9.

  What histologic patterns can be seen in the biopsy samples from the GE junction that do not show typical endoscopic findings of Barrett’s esophagus?

  • Gastric-type mucosa without goblet cells—Gastric cardiac mucosa, mostly associated with inflammation (gastric carditis)

  • Prominent Z-line showing gastric-cardiac mucosa with goblet cells

  • In endoscopically uncertain cases, presence of goblet cells may suggest either Barrett’s mucosa or gastric cardia with goblet cells.

• 10.

  What is the differential diagnosis of esophageal polypoid lesions?

  The differential diagnoses for nonneoplastic lesions are the following:

  • Pancreatic heterotopia/metaplasia is usually seen at distal esophagus. On histologic examination, pancreatic acinar cells are seen, rarely associated with ductal structures.

  • Fibrovascular polyps are benign, submucosal (fibrovascular and adipose) tissue surrounded by squamous epithelium. Occasionally, atypical stromal cells may be seen.

  • Squamous papilloma is not uncommon in the esophagus. Histologic examination reveals lobulated squamous epithelium with fibrovascular cores. Squamous papilloma is seen in less than 0.1% of endoscopic examinations. Dysplasia is not usually seen. These have been related to human papilloma virus (HPV); however, reports also show that most are seen as a result of acid reflux and are not associated with HPV.

  The differential diagnoses for neoplasms are the following:

  • Granular cell tumor of the gastrointestinal (GI) tract occurs most commonly in the esophagus, whereas the most common site in the body is the lingual dorsum. Endoscopic evaluation reveals submucosal nodules that are mostly solitary (multifocal in 10%). Histologic examination reveals pseudoepitheliomatous hyperplasia of overlying squamous mucosa with submucosal collection of neoplastic granular cells with granular eosinophilic cytoplasm ( Figure 8-6 A ), which are PAS and S100 reactive (see Figure 8-6 B ). Most are benign; rare cases of malignant metastasis have been reported.

    

  • Leiomyoma is submucosal benign proliferation of spindled smooth muscle cells. Leiomyoma strongly reacts with muscle markers like smooth muscle actin (SMA) and desmin, and is negative for CD117. Its malignant counterpart, leiomyosarcoma, is rare in the esophagus.

  • Gastrointestinal stromal tumor (GIST) is rare in the esophagus. Histologic examination shows proliferation of spindle cells that react strongly with CD117 and CD34. Malignant potential depends on the extent of mitotic activity, necrosis, and cytologic atypia.

  • Squamous cell carcinoma is most common in the midesophagus. Histologic examination demonstrates neoplastic squamous cells with intercellular bridges, and keratin overproduction with keratin pearl formation. Involvement of mediastinal structures is common because of a lack of serosal barrier. Subtypes include basaloid squamous cell carcinoma, verrucous carcinoma, and adenosquamous carcinoma.

  • Adenocarcinoma ( Figure 8-7 ) is most common in the distal esophagus; if found in the midesophagus, it is usually as a result of Barrett’s esophagus. Variants include mucinous and signet ring cell type. The depth of tumor (superficial versus deep) invasion correlates with tumor stage and prognosis. Lymph node metastasis has been reported in 13% of T1 tumors. The presence of lymphovascular invasion predicts worse overall survival and more tumor recurrence, and is an independent prognostic factor.

    

  • Malignant melanomas are rare in the esophagus and are often larger polypoid lesions involving the distal esophagus. Marked cytologic atypia with prominent nucleoli and increased mitotic figures are seen. Malignant cells may show reactivity with one or more of the following antibodies: S100, Melan A, KBA-62, and HMB-45.

  • Other malignant tumors include metastatic small cell and sarcomatoid carcinomas; these are rare.