1. viral: HSV [LMC-02-5830]; CMV
2. fungal:
3. bacterial:
4. reflux (GERD):
• hyperplastic: epithelial basal zone hyperplasia, elongated lamina propria papillae, scant to many intra-epithelial eosinophiles (be aware of eosinophilic esophagitis, below);
• less common = parakeratosis²
• least common = increased (over-expression, hyper-expression) keratohyalin granules²...hypergranulosis (excessive and/or enlarged keratohyalin granules in the superficial squamous cells [LMC-03-5984; S09-3815]...of uncertain significance [S-02-3671; LMC-02-6689]...possibly/probably a type of hypergranular histological adaptation to relatively constant & low-grade chronic reflux [S-03-12645; S09-7623, S09-7874], rumination, or other topical toxic or irritant injury). It is so commonly seen in endoscopic biopsies that some experts doubt it being abnormal & consider it a variant of normal¹³ (or is it a very common modern abnormality among patients getting esophageal biopsies?).
5. topical toxic effect:

• eosinophilic-stained, injured or necrotic superficial epithelium without evidence of viropathic change ("pill" esophagitis [L07-9490] suggest a dry or hyperosmotic chemical "burn" or irritant effect (also lye or other caustic injury). Polarized light exam MIGHT find some refractile "pill" residua.
• spongiosis might indicate a more local/topical lquid-based chemical irritant effect.
• hypergranulosis?, see above w/ GERD.
1. eosinophilic esophagitis (EE, EO): Distal e sophageal intraepithelial eosinophilia is a GERD finding, with GERD often also accompanied by some spongiosis & eos being as prominent as 52 per hpf⁹; but it is also an EE finding [S-01-4297; S08-13316; S09-2378, S10-2038]. EE tends to be in early middle age males with non-stenotic dysphagia; there is supposed to be a fairly distinct endoscopic appearance to " full blown" cases..."feline change". Independently suspect & mention the possibility when biopsy shows more than a few intra-epithelial eos, most especially when in a clustered (cells-touching-each-other clusters [S09-4412]) & dense presence of intraepithelial eosinophiles (>15 per hpf [FIGERS criteria of 2007⁹]; 15-20 or more per hpf ⁵; >20 per hpf⁶...but eos usually not clustered into tripletts, etc., even when counts >20 [S09-2378]). EE is the best described of the eosinophilic gastrointestinal diseases (EGIDs) & can also be associated with esophageal strictures⁴.

   "Eosinophilic oesophagitis (EO) is an increasingly recognised chronic, relapsing inflammatory condition of the esophagus. There has been a mini-epidemic of EO in the last decade. The incidence of this condition is higher in children and is commoner in males. There is either a family or personal history of atopic conditions present in a significant number of patients and can also be familial in up to 10%. The classical symptom in an adult is chronic, intermittent solid-food dysphagia and food impaction, often necessitating emergency endoscopic removal. Despite the history of dysphagia for a number of years, patients remain well with no weight loss, which can mislead clinicians to diagnose a functional problem with a resulting delay in the diagnosis. There are various endoscopic features of EO; commonly multiple rings and linear furrows ("feline"), though these can be subtle; and the mucosa may be macroscopically normal."

   When the clinical & endoscopic features are compelling but with less intense intraepithelial concentration of eos, a DX can be made, especially if both proximal & distall biopsies both have considerable but not intense eosinophiles [S09-2260]. I think that the >20 per hpf is conservative so as to be quite specific. Peripheral blood eosinophilia may be present¹⁰, but others note that eosinophilia in esophageal involvement in cases of "eosinophilic gastroenteritis"¹¹. But, EE is easily & inexpensively treated with an antihistamine; therefore, I feel that we should more liberally diagnose EE, even if the eos. count is fairly low [L09-4808, S09-2775] if there is feline esophagus & dysphagia (the one BX may not be really representative).

From an authority: "...some have proposed that an estimate of the number of eosinophils is a helpful clue in some cases. If there are fewer than eight eosinophils per 40X field, reflux esophagitis is favored. Likewise, a count of >24 eosinophils per 40X field better supports eosinophilic esophagitis. For cases with intermediate eosinophilic counts, clinicopathologic correlation is required. We do not report "counts" in our practice. But, we do attempt to compare biopsies to prior ones, and estimate whether more or fewer eosinophils are present to help assess response to treatment. The distinction between reflux and eosinophilic esophagitis is worth attempting, as patients with EG show dramatic response to steroids⁷."

2. lymphocytic esophagitis (LE): Suspect & mention it when the biopsy contains many intraepithelial lymphocytes, usually along with some spongiosis; mild LE is increased IELs in the perpapillary first 5 layers of epithelium & worse includes increases also in the interpapillary epithelial layer; there is no particular comorbid disease association. Almost all esophageal biopsies for any reason contain a very few intraepithelial mononuclear cells. A rarely made diagnosis by at least one expert, currently practicing GI pathologist unless impressively striking¹³.
3. other:
   • granular cell tumor: [S-05-8669]

1. IMPORTANT!!: Defined as (1) any endoscopically visible change of esophageal mucosa that (2) has intestinal metaplasia.

• esophageal "gastric patches": from an "inlet patch" [S-02-9518] to other patches throughout the esophagus, EGDs encounter misplaced patches of gastric mucosa, especially little tongues extending upward from the GEJ...not BE unless intestinal metaplasia (esophageal BE vs. gastric antral-type metaplasia?). Some GEJ intestinal metaplasia has been noted in various biopsy series in from 9-36% of cases...12-15% probably a better figure³.A histological diagnosis of BE can't be made unless goblet-cells demonstrated...and it may take an AB-PAS stain to do so (one can be highly suspicious if EGD offers it, AB-PAS is negative, but the CD10 is positive for cells with an intestinal-type brush border). AB stains goblets blue (sometimes the foveolar cells can stain a little blue at superficial aspect) and PAS stains the foveolar cells pink/red³. Watch out for pseudo-goblet cells by H&E only³. It is exceedingly rare to not be able to demonstrate intestinal metaplasia (IM) in a columnar-lined segment 2CM or more in length³. When evaluating short segment or ultra-short segment patches at the GEJ, it is BE if cardia biopsies are negative for IM³...IHC might help (but you need good-sized, well oriented biopsies³. The GEJ is defined by EGD as the point of the proximal endings of the gastric folds...a zone which may be known as the "Z" line (but it can migrate due to GERD³); it can be statically (hiatal hernia) or dynamically (breathing &/or peristalsis during the EGD) misplaced³.
• dysplasia implications: when you think you see "dysplasia", put the brakes on & go to great measures to get clinico-endoscopic correlation and discuss the case with the gatsroeneterologist (if this is an initial finding in an endoscopically inflammed lesion, it is best to make the "real" definitive committment to a tissue diagnosis on a rebiopsy after a period of proton pump medical treatment [L07-3961]; low grade promotes an increased rate of endoscopic follow up; high grade warrants serious consideration of esophagectomy¹ or photoablation or other type ablation; most who develop adenocarcinoma are elderly Caucasian males³. [dysplasia histological criteria with link to Johns Hopkins grading photos]
• which type of intestinal metaplasia: Barrett's intestinal metaplasia vs. gastric-type intestinal metaplasia in biopsies of distal esophagus at GE junction MAY be resolved by IHC for ck7/20 [**] but is probably better judged clinically by an experienced gastroenterologist who can discern a proximally advance Z line vs. short segment BE.

1. dysphagia: this is a global term for "swallowing problems" (see GI motility problems), but it usually connotes food seeming to "hang up" in the esophagus, possibly due to a GERD-related stricture, a Schatzki ring,  a cancer, or a dilated dysfunctional esophagus in diseases such as scleroderma or polymyositis. Nerve interference in motility could be due to stroke or peripheral neuropathy or any other means of interfering with nerve function. Biopsies may reveal evidence of GERD, but are usually more important in showing that there is no microscopic evidence of superficial mucosal disease in that case of any type of "swallowing problem"...whatever the final diagnosis
   • globus hystericus:  The sensation of having a lump in the throat when there is nothing there. Sometimes simply called "globus"
   • achalasia: difficulty swallowing because of slow emptying due to a dilated esophagus related to increased distal sphincter tone (though not a standard medical term, it might be called "esophagoparesis"); or deterioration of muscular peristalsis (muscular or neural reasons).
   • EE is a common cause of dysphagia.
   • lichen planus is a cause of dysphagia & odynophagia & tends to be proximal and endoscopically show lacy white papules, pinpoint erosions [S07-5954], desquamation, or pseudomembranes; may be mediated by cytotoxic CD8 positive lymphocytes somewhat as in GVH disease; histology = parakeratosis, epithelial atrophy, and LACK of hypergranulosis⁸.
2. hemorrhagic esophagopathy: this may be freshly present as blood in lamina propria as mechanical artifact of the endoscopic process and/or a result of intentional (prescribed) or unintentional anticoagulation or antiplatelet therapy.