Herpes simplex esophagitis

Editorial Board Member: Naziheh Assarzadegan, M.D.
Deputy Editor-in-Chief: Catherine E. Hagen, M.D.
Ruchi Patel, M.B.B.S., M.D.
James Mueller, M.D., Ph.D.

Last author update: 22 March 2023
Last staff update: 22 March 2023

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PubMed Search: Herpes simplex esophagitis

Ruchi Patel, M.B.B.S., M.D.
James Mueller, M.D., Ph.D.
Page views in 2022: 8,814
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Cite this page: Patel R, Mueller J. Herpes simplex esophagitis. website. Accessed September 30th, 2023.
Definition / general
Essential features
ICD coding
  • ICD-10:
    • K20.8 - other esophagitis
    • B00.89 - other herpesviral infection
  • HSV esophagitis occurs most frequently in immunocompromised hosts, such as:
    • Solid organ and bone marrow transplant recipients
    • After the prolonged use of corticosteroid or immunosuppressive drugs
    • HIV / AIDS
  • Self limited in immunocompetent patients
  • More frequent in men than women (World J Gastroenterol 2017;23:3011)
  • Incidence of 1.8% in an autopsy series (Medicine (Baltimore) 2010;89:204)
  • More commonly occurs after reactivation of latent HSV with spread of virus to the esophageal mucosa by way of the vagus nerve or by direct extension of oral - pharyngeal infection into the esophagus (Prz Gastroenterol 2013;8:333)
  • Primary HSV infection is less common
Diagrams / tables

Images hosted on other servers:

Classifications of herpes esophagitis

Clinical features
  • Most common presentations are:
    • Odynophagia
    • Dysphagia
    • Esophageal pain
  • Can have coexistent herpes labialis, glossitis or oropharyngeal ulcers
  • May be associated with various opportunistic diseases, such as candidiasis, CMV and Kaposi sarcoma
  • Endoscopic findings include multiple discrete or coalescent small ulcers, which may be superficial, punched out or volcano-like in appearance (Case Rep Gastrointest Med 2016;2016:7603484)
Prognostic factors
  • Overall good
  • Disseminated disease is rare but may be fatal
Case reports
Clinical images

Images hosted on other servers:

Endoscopic features

Diffuse mucosal erosions and ulcerations

Gross description
  • According to macroscopic appearance, HSV esophagitis is divided into 3 types (Medicine (Baltimore) 2016;95:e3187):
    • Type I: small, punched out lesions with raised margins usually coated with yellowish exudate
    • Type II: small, punched out lesions but no raised margins or exudate
    • Type III: multiple ulcers, with a map-like, confluent appearance over the entire esophagus
  • Typical ulcers are superficial, with size varying from a few millimeters up to 2 cm (Clin Microbiol Infect 1997;3:397)
  • Most lesions are located in the middle to distal esophagus (Medicine (Baltimore) 2016;95:e3187)
  • Nonulcerated erythematous mucosa and pseudomembranes have been noted occasionally
  • See Diagrams / tables for gross appearance versus endoscopic images
Gross images

Images hosted on other servers:

Punched out ulcers

Microscopic (histologic) description
  • Typical histologic findings are only present at the edge of the ulcer (Clin Microbiol Infect 1997;3:397)
  • Early lesions show nuclear swelling of keratinocytes and individual cell necrosis
  • Ulcer bed demonstrates prominent necrosis and acute inflammatory cell infiltrate
  • Marked mononuclear cell infiltrate adjacent to the infected squamous epithelium
  • Infected squamous epithelial cells show 3 Ms:
    • Molding of nuclear contours
    • Margination of chromatin to the periphery of nuclei
    • Multinucleation
  • Intranuclear inclusions:
    • Cowdry type A: acidophilic inclusion with surrounding clear halo
  • Equivocal cases require an HSV immunohistochemical (IHC) stain to confirm the diagnosis
Microscopic (histologic) images

Contributed by James Mueller, M.D., Ph.D.

Esophageal biopsy

Prominent acute inflammation

Cowdry A inclusion

3 Ms


Glassy chromatin

Edge of the ulcer

Viral cytopathic effect

HSV IHC stain

Positive stains
  • HSV complex (HSV1 and HSV2) IHC stain: stains infected squamous epithelial cells
Negative stains

Overview of HSV esophagitis

Gross and histopathologic findings of HSV esophagitis

Sample pathology report
  • Esophagus, biopsy:
    • HSV esophagitis
Differential diagnosis
  • CMV esophagitis:
    • More commonly presents as a single, isolated and deep, large ulcer rather than multiple small, shallow ulcerations as in HSV esophagitis
    • Intranuclear and intracytoplasmic inclusions are more common in mesenchymal and endothelial cells than epithelial cells
    • Positive CMV IHC stain
    • Negative HSV IHC stain
  • Herpes zoster / varicella:
    • Undistinguishable histologically
    • Clinically, patients often have the cutaneous manifestations of chicken pox or shingles
    • Positive VZV IHC stain
    • Negative HSV IHC stain
  • Candida esophagitis:
    • Pseudohyphae and budding spores present
    • Pseudomembrane formation under endoscopic examination
    • Positive GMS and PAS special stains
    • Negative HSV IHC stain
  • Varicella zoster virus (VZV) esophagitis (Am J Surg Pathol 2021;45:209):
    • Viral cytopathic changes are similar to HSV, but it is often pronounced in peripapillary epithelium as compared to superficial epithelium in HSV esophagitis
    • Esophageal ulcers are more hemorrhagic and less inflammatory as compared to HSV
    • Clinically, patients often have the cutaneous manifestations of chicken pox or shingles
    • Positive VZV IHC stain
    • Negative HSV IHC stain
Board review style question #1

A patient who underwent liver transplantation had a recent episode of Candida esophagitis treated with fluconazole. Symptoms of pain and dysphagia persisted and repeat endoscopy showed multiple sharply demarcated and superficial ulcers ranging from 2 mm to 2 cm. What is the biopsy diagnosis?

  1. Cytomegalovirus (CMV) esophagitis
  2. Herpes simplex virus (HSV) esophagitis
  3. Nonspecific ulcer
  4. Recurrent or persistent Candida esophagitis
Board review style answer #1
B. HSV esophagitis. The latter image shows the classic histologic findings of herpes esophagitis, including molding of nuclei, margination of nuclear chromatin and multinucleation. CMV infected cells are large and show distinctive intranuclear inclusions in mesenchymal cells. Candida esophagitis shows pseudohyphae or budding spores.

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Reference: Herpes simplex esophagitis
Board review style question #2

A 63 year old woman presented with dysphagia and esophageal ulcers. The image above shows a section stained with a polyclonal antibody to herpes simplex virus type 1 (HSV1). Which of the following statements about HSV immunohistochemistry is true?

  1. Immunohistochemistry is more sensitive and specific than in situ hybridization for HSV1 and HSV2
  2. The section is likely to react with anti-HSV2 antibody because of cross reactivity
  3. The section is likely to stain positively with an anti-HSV2 antibody because a combined HSV1 and HSV2 infection is common
  4. The section is not likely to stain with an anti-HSV2 antibody because a combined infection with HSV1 and HSV2 is uncommon
Board review style answer #2
B. The section is likely to react with anti-HSV2 antibody because of cross reactivity. Immunohistochemistry of HSV is useful when histology is equivocal. Most antibodies stain both HSV1 and HSV2 precluding reliable identification of the specific HSV. In situ hybridization allows the distinction of HSV1 and HSV2 but is more labor intensive. HSV antibodies may weakly cross react with varicella zoster virus (VZV) but this is usually not a problem.

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Reference: Herpes simplex esophagitis
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