Esophagus
Esophagitis
CMV
Author: Gillian L. Hale, M.D., M.P.H.
Editorial Board Member: David J. Escobar, M.D., Ph.D.
Deputy Editor-in-Chief: Aaron R. Huber, D.O.
Last author update: 11 January 2024
Last staff update: 11 January 2024
Copyright: 2003-2024, PathologyOutlines.com, Inc.
PubMed Search: Cytomegalovirus
Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Electron microscopy description | Electron microscopy images | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Hale GL. CMV. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/esophagusCMVesophagitis.html. Accessed November 29th, 2024.
Definition / general
- Esophageal infection of adults and children by cytomegalovirus, a double stranded DNA virus of the Herpesviridae family (human herpes virus 5 [HHV5]) spread by blood and other bodily fluids
- Rare in immunocompetent patients but causes serious disease in the setting of immunosuppression (e.g., AIDS, solid organ or bone marrow transplant, chemoradiation therapy)
- Cytomegalovirus (CMV) is the only herpes virus with both nuclear and cytoplasmic inclusions, identified on routine H&E stain
Essential features
- Severe and potentially life threatening esophageal infections occur in immunosuppressed patients (e.g., people living with HIV / AIDS, solid organ or bone marrow transplant recipients, patients undergoing chemoradiation therapy)
- Diagnosis requires endoscopy with tissue biopsy of areas of ulceration or erosion, which typically occur in the mid or distal esophagus
- Histopathologic features characterized by ulceration or erosion harboring enlarged cells with intranuclear and cytoplasmic inclusions
- Viropathic inclusions can be identified in endothelial cells, stromal fibroblasts or epithelial cells
- CMV immunohistochemistry or CMV in situ hybridization aids in the detection of viropathic inclusions
ICD coding
Epidemiology
- Ubiquitous, worldwide distribution
- Majority of adults are exposed to CMV in their lifetime; seroprevalence rates range from 45 to 100% (PLoS One 2018;13:e0200267, Rev Med Virol 2019;29:e2034)
- Can occur in children and adults secondary to viral reactivation due to immunosuppression from
- HIV / AIDS (CMV esophagitis is an AIDS defining illness)
- Underlying malignancy (particularly lung cancer) and concurrent chemoradiation therapy (Dis Esophagus 2016;29:392)
- Solid organ and hematopoietic cell transplantation
- Systemic steroid or immunosuppressive therapy
- Critical illness (e.g., shock, pneumonia, respiratory failure, intensive care unit [ICU] requirement) (J Clin Med 2022;11:1583)
- Uncommon in immunocompetent patients (Clin Gastroenterol Hepatol 2020;18:736)
Sites
- In the gastrointestinal tract, esophagus is the most common site of infection in symptomatic, immunocompromised children (J Pediatr Surg 2015;50:1874)
- Esophagus is second to the stomach as the most frequent site of upper gastrointestinal site involvement (Scand J Gastroenterol 2011;46:1228, Diagn Pathol 2022;17:9)
Pathophysiology
- CMV transmission
- Sexual contact (Sex Transm Dis 2008;35:472)
- Blood products (transfusion, transplantation) (Am J Transplant 2012;12:2457)
- Close contact with saliva and urine from infected individuals (particularly children) (J Clin Virol 2008;43:266)
- Intrauterine, after primary or nonprimary infections (Rev Med Virol 2007;17:253)
- Primary infection usually asymptomatic but can be associated with mononucleosis-like illness (J Infect Chemother 2019;25:431)
- CMV establishes latency and persists for life but can be reactivated in the setting of immunosuppression due to the dysfunction of cell mediated immunity (QJM 2012;105:401)
- Mucosal infection and replication occur in human epithelial cells, endothelial cells and tissue fibroblasts
- Infection leads to an ischemic pattern of tissue erosion or necrosis and inflammation (Ann Intern Med 1993;119:924)
Etiology
- Diseases and medications that cause immunosuppression and viral reactivation (Curr Gastroenterol Rep 2008;10:409)
Clinical features
- Third leading cause of infectious esophagitis after Candida spp. and herpes simplex virus (HSV) esophagitis (Dis Esophagus 2018;31:doy094)
- Symptoms include epigastric pain, fever, odynophagia, dysphagia, gastrointestinal bleeding (J Clin Med 2022;11:1583)
- Can occur concomitantly with reflux esophagitis (38.6%), Barrett esophagus (9.1%), esophageal candidiasis (18.2%) and benign gastric ulcers (29.5%) (J Clin Med 2022;11:1583)
- Associated with higher overall mortality and longer hospital admissions compared to those without CMV esophagitis (J Clin Med 2022;11:1583)
- Also occurs in immunosuppressed infants on prolonged antibiotic therapy with broad spectrum antibiotics (J Clin Med 2020;9:939)
- Involvement of additional visceral organs (e.g., stomach, duodenum, colon, lungs) occurs in 20% of cases (Clin Gastroenterol Hepatol 2020;18:736)
Diagnosis
- Endoscopic appearance of lesions is variable but most commonly occurs in distal esophagus (65%), followed by mid esophagus (28%) (Clin Gastroenterol Hepatol 2020;18:736)
- Requires tissue biopsy and histopathologic diagnosis
- Tissue sampling should include granulation tissue or ulcer bed, given predilection for endothelial and stromal cell infection
- H&E stain demonstrates characteristic viropathic inclusions
- CMV immunostain or CMV in situ hybridization
- Finding > 2 positive cells by CMV IHC has higher correlation with CMV viremia versus finding rare positive cells (< 2) (Gastroenterology Res 2016;9:92)
Laboratory
- CMV antigenemia is a poor predictor of gastrointestinal tract involvement but viral load by real time PCR is more reliable (Bone Marrow Transplant 2004;33:431)
Prognostic factors
- ICU requirement and acute kidney injury are risk factors for in hospital mortality
- Upper gastrointestinal tract involvement has a 17% mortality rate 1 month after diagnosis and 25% mortality rate 1 year after diagnosis according to a small study of 12 patients (GE Port J Gastroenterol 2017;24:262)
- Poor outcomes associated with ganciclovir resistant CMV infection (Transplantation 2016;100:e74)
Case reports
- 42 year old man who presented to the emergency department (ED) with a 2 week history of abdominal pain and watery diarrhea was found to have a new diagnosis of HIV / AIDS (Cureus 2022;14:e22455)
- 44 year old man with dermatomyositis on mycophenolate was admitted for acute gastrointestinal bleed (Clin Case Rep 2022;10:e6044)
- 60 year old woman on immunosuppressive therapy for pemphigus vulgaris presented with odynophagia and was found to have ulcerative CMV and HSV esophagitis (IDCases 2020:22:e00925)
- 72 year old man with kidney transplant who complained of dysphagia and unintentional weight loss was found to have distal esophageal stricture (ACG Case Rep J 2022;9:e00836)
- 77 year old immunocompetent man with erosive esophageal lesion was found to have moderately differentiated squamous cell carcinoma and CMV (Gut Pathog 2021;13:24)
Treatment
- Intravenous ganciclovir or foscarnet for 3 - 6 weeks; continued maintenance therapy is indicated for patients with concurrent retinitis or recurrent gastrointestinal disease (Am J Gastroenterol 1998;93:317, Arch Intern Med 1998;158:957)
- Antiviral prophylaxis is standard of care for high risk solid organ transplant recipients; preemptive therapy preferred for hematopoietic cell transplant recipients (Clin Transplant 2019;33:e13512)
- Ganciclovir and foscarnet resistance can occur (Transpl Infect Dis 2022;24:e13733, Case Rep Gastroenterol 2013;7:25)
Clinical images
Contributed by Kathryn A. Peterson, M.D., M.Sci.
Ulcerated esophageal mucosa
Gross description
- Variably superficial to deep / punched out ulcers, serpiginous and circumferential ulcers (Medicine (Baltimore) 2019;98:e15845)
- Can be associated with esophageal strictures (IDCases 2020:21:e00795, J Pediatr Surg 2015;50:1874)
Microscopic (histologic) description
- Ulceration and inflamed granulation tissue with necroinflammatory debris
- Cytologic enlargement by both intranuclear and intracytoplasmic inclusions
- Intranuclear basophilic or amphophilic inclusions; can have owl eye appearance when associated with peripheral clearing (an artifact of fixation) and margination of nuclear chromatin (Cowdry type A body)
- Intracytoplasmic basophilic or amphophilic inclusions; can also appear as coarse, eosinophilic inclusions
- PAS and GMS stains may weakly highlight intracytoplasmic inclusions, not intranuclear inclusions (Semin Diagn Pathol 2017;34:510)
- Viropathic inclusions identified in endothelial cells, stromal cells and epithelial cells
Microscopic (histologic) images
Contributed by Gillian L. Hale, M.D., M.P.H.
Inflammation and CMV inclusions
Numerous viropathic inclusions
Infected endothelial cells
Granular inclusions
CMV IHC
Positive stains
- CMV immunohistochemistry or CMV in situ hybridization
- Does not supplant routine H&E evaluation (Hum Pathol 2017:60:11)
Negative stains
Electron microscopy description
- Spheroid shaped virions, diameter of 150 - 200 nm, each with dense, protein core comprised of linear, double stranded DNA genome, surrounded by a hyperlucent halo
Electron microscopy images
Images hosted on other servers:
Spheroid virions
Sample pathology report
- Esophagus, ulcer, biopsy:
- Ulcerated squamous mucosa with intranuclear and basophilic intracytoplasmic inclusions, morphologically consistent with cytomegalovirus (CMV); confirmed by CMV immunohistochemistry
Differential diagnosis
- Herpes simplex virus 1 / 2:
- More typically presents as discrete ulcers with vesicles or bullae versus deep / punched out ulcers (Medicine (Baltimore) 2019;98:e15845)
- Viropathic inclusions more common in squamous epithelial cells than in stromal and endothelial cells
- Intranuclear type A Cowdry inclusion without nuclear enlargement
- 3 Ms of nuclear changes: molding of nuclear contours, margination of chromatin and multinucleation
- No intracytoplasmic inclusions
- Varicella zoster virus:
- Features similar to HSV 1 / 2 but multinucleation is uncommon
- No intracytoplasmic inclusions
Board review style question #1
In the biopsy of the esophagus shown above, what is the most likely clinical presentation of the patient?
- 2 year old immunocompetent boy with new onset projectile vomiting
- 21 year old immunocompetent woman presenting with symptoms of gastroesophageal reflux
- 67 year old female cyclist with new onset shortness of breath and chronic cough
- 86 year old man undergoing chemoradiation for squamous cell carcinoma
Board review style answer #1
D. 86 year old man undergoing chemoradiation for squamous cell carcinoma. Underlying malignancy and chemoradiation is a risk factor for CMV infection. Answer A is incorrect because the patient is immunocompetent without reported risk factors for CMV infection. Answer B is incorrect because the patient is immunocompetent, which is an unlikely presentation for CMV esophagitis. Answer C is incorrect because the clinical symptoms suggest an acute respiratory infection.
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Reference: CMV
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Reference: CMV
Board review style question #2
Which herpes virus demonstrates both intranuclear and intracytoplasmic viropathic inclusions?
- Cytomegalovirus
- Epstein-Barr virus
- Herpes simplex virus 1 and 2
- Varicella zoster virus
Board review style answer #2
A. Cytomegalovirus. Only CMV virus demonstrates both intranuclear and intracytoplasmic viropathic inclusions. Answer C is incorrect because herpes simplex virus 1 and 2 causes an intranuclear inclusion (Cowdry type A) without an accompanying intracytoplasmic inclusion. Answer D is incorrect because varicella zoster virus also demonstrates an intranuclear Cowdry type A inclusion without an intracytoplasmic inclusion. Answer B is incorrect because Epstein-Barr virus does not cause inclusions in infected cells.
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Reference: CMV
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Reference: CMV
