The recognition of specific oesophageal infections and the distinction between gastro-oesophageal reflux disease and rarer forms of oesophagitis are key tasks for gastrointestinal pathologists reading mucosal biopsies. Infections can involve the oesophagus either primarily or as part of a wider process. This chapter will highlight their features, discussing in detail the common infections including Herpes Simplex, Cytomegalovirus, and Candida, and summarising the features of the rarer ones. A few additional types of oesophagitis have emerged recently, including eosinophilic oesophagitis and lymphocytic oesophagitis. This chapter will review the recent literature and will discuss the controversies surrounding some of these new entities. There will be an emphasis on the need for correlation between clinical/endoscopic information and microscopic appearances, and there will be discussion of supplementary special studies including immunohistochemistry where relevant.
Infections can involve the oesophagus either primarily or as part of a wider process. This chapter will highlight their features, will discuss in detail the common infections, and will summarise the rarer ones. A few additional types of oesophagitis have emerged recently. This chapter will review the recent literature and discuss the controversies surrounding some of the new entities. There will be an emphasis on the need for correlation between microscopic appearances and clinical/endoscopic information and there will be discussion of supplementary special studies, including immunohistochemistry where relevant.
Protective Mechanisms and Immunosuppression
The oesophagus serves as a conduit for the passage of food and liquids between the mouth and stomach. Therefore, it is prone to injury by noxious stimuli coming from both above and below, with consequent acute and chronic inflammation. It is generally well protected against infection, because stasis and consequent microbiological growth are not common. Other protective mechanisms include a thin layer of mucin derived from submucosal glands, the dense barrier nature of the squamous epithelium itself, and variable elements of the immune system including T lymphocytes and antigen-presenting Langerhans cells.1 Despite these factors, the oesophageal mucosa is not sterile, and both streptococci and Candida appear to be major components of the microbiota of the healthy oesophagus.2
Almost all pathological infections of the oesophagus result in an initial breach of the mucosal barrier, ulceration with concomitant nonspecific active chronic inflammation, and formation of varying amounts of granulation tissue. Inevitably, after the initial barrier disruption, secondary effects of reflux (if present) and other superadded infecting organisms may complicate the histopathological picture further and may influence clinical management.
Both local and systemic immunosuppression, leading to altered microbiota, can contribute to an increased risk of infection within the oesophagus (see also Chapter 4). Steroids from inhalers (swallowed accidentally) or systemic antibiotic therapy may both predispose to infection of the oesophageal mucosa by common fungal organisms such as Candida species. Systemic immunocompromise in association with diabetes and extremes of age predisposes to both fungal and viral infections. General deterioration in health associated with pneumonia has a particular association with herpes simplex virus (HSV) infection in the elderly. The most severe systemic immunosuppression occurs with untreated HIV/AIDS and iatrogenic chemotherapeutic drugs used in cancer treatment or transplantation. In these patients, highly unusual infections may rarely occur. Most but not all of these conditions may be suspected by the endoscopist and recognised by the histopathologist given adequate biopsies or using recently described cytological techniques.3 However, advance knowledge of an immunocompromised state is vital to the correct reading of oesophageal biopsies in these patient groups. This is because the vast majority of inflammatory or ulcerative pathology within the oesophagus is a result of reflux of gastric contents. Therefore, the index of suspicion for infection may be low. The pathologist, if aware of a history of immunosuppression, will in turn be aware of the possibility of infection in an inflamed or ulcerated oesophagus and will perform additional studies, including special stains and immunohistochemistry where appropriate, as detailed in the text that follows.
Herpes Simplex Virus Oesophagitis
As detailed above, clinical immunosuppression and an association with streptococcal pneumonia raise the clinical index of suspicion for this diagnosis. However, HSV infection may also occur in immunocompetent individuals. An association with untreated eosinophilic oesophagitis has been described recently.4, 5 Typical labial/oral herpetic lesions may alert the endoscopist to the diagnosis and is a useful item of information for the reporting pathologist.
The main macroscopic finding is ulceration, which may be focal or diffuse. Rarely, vesicle-like lesions are visible macroscopically. Both type I, which is more common, and type II HSV may infect the oesophagus. Regardless of the subtype, microscopic examination reveals an interrupted squamous epithelium with marked dyscohesion of cells that often gives a ‘falling apart’ pattern to biopsies (Figure 11.1). Viral cytopathic effect is confined to the squamous epithelial cells, because the virus is trophic only to the epithelial layer. The most prominent viral cytopathic effect is often at the edge of biopsy samples derived from ulcer edges that avoid areas of nonspecific necrosis. Cytoplasmic and nuclear enlargement is prominent. Multinucleated giant squamous cell formation is nearly always present. Squamous cells show typical washed-out ground glass nuclei with variably sized inclusions (Cowdry type A and B). Severe non-specific active chronic inflammation is usually also apparent. Although the haematoxylin and eosin (H&E) appearances are usually diagnostic, deeper levels and confirmation by immunohistochemistry may be helpful in some cases. Coinfection with Candida is a possibility, especially in patients with profound immunosuppression.
Figure 11.1 Herpes simplex oesophagitis with florid viral cytopathic effect in squamous epithelium including ground glass nuclear inclusions and giant cell transformation. Abundant necrosis and acute inflammation are also present.
Extremely rarely, herpes zoster virus (HZV) may involve the oesophagus as part of a generalised infection, but oesophageal biopsy is rarely diagnostic.6 It is not possible to separate HSV infection from HZV infection by examining routine H&E stains (Fact Sheet 11.1).
Type I more common than type II
focal or diffuse ulceration
rarely vesicle-like lesions
Interrupted squamous epithelium with marked dyscohesion of cells – ‘falling apart’
Viral cytopathic effect (squamous epithelial cells)
Cytoplasmic and nuclear enlargement
Multinucleated giant squamous cells common
Squamous cells show washed-out ground glass nuclei with inclusions (Cowdry type A and B)
Severe active chronic inflammation usual
Immunohistochemistry may be helpful
Herpes zoster virus (HZV) rarely diagnosed on oesophageal biopsy
Herpes simplex virus and HZV infection have similar H&E features
Cytomegalovirus (CMV) infection occurs almost exclusively in severely immunocompromised patients and is probably the result of reactivated dormant infection.7 Endoscopically, there are ulcers that vary greatly in size and depth, with no appearance being typical. Microscopically, within ulcer bases, CMV may infect many types of stromal cells and macrophages, but most often affects the endothelial cells of granulation tissue. Infected cells appear swollen to a large size and obstruct the lumens of small capillary blood vessels, producing mucosal necrosis. Characteristic purple nuclear inclusions with surrounding clear halos are present, somewhat resembling owl eyes (Figure 11.2). Smaller cytoplasmic granular inclusions are also common and if seen in isolation should prompt a search for further evidence of viral cytopathic effect. Intense background active chronic inflammation is common but may vary with levels of immunosuppression. While CMV inclusions are often readily visible on H&E sections, immunohistochemistry may provide useful additional confirmation in equivocal cases especially when clinical suspicion is marked. In addition, deeper levels may also prove helpful for the pathologist in difficult cases that have sparse viral inclusions.
Figure 11.2 Cytomegalovirus oesophagitis with amphophilic nuclear inclusions in endothelial cells at an ulcer base. There is dense associated acute on chronic inflammation.
Human Immunodeficiency Virus Oesophagitis
Large, persistent oesophageal ulcers may occur in patients with chronic human immunodeficiency virus (HIV) infection (see also Chapter 4).8, 9 Their endoscopic and microscopic features are not specific and include variable active chronic inflammation and granulation tissue (Figure 4.8). Other coexistent infective organisms, including bacteria, probably cause many of the features. A diagnosis on routine H&E morphological examination is not possible, and the presence of HIV in these ulcers is detectable only with molecular biological techniques. The primary task for the histopathologist in the setting of chronic HIV infection and oesophageal ulceration is the exclusion of other infective causes first. Recently, a lichenoid pattern of chronic inflammation in the oesophagus similar to that seen in lichen planus has been associated with HIV infection, with other infections such as viral hepatitis, and with rheumatological disease.10
Human Papilloma Virus Infection
The role played by human papilloma virus (HPV) infection in oesophageal disease is controversial. There is no evidence, to date, of involvement in inflammatory disease. Studies of HPV are complex because of the many different viral serotypes that exist and the variability in research methods used to detect these serotypes. The advent of reliable in situ hybridisation assays for HPV that are routine at other disease sites such as the oropharynx may help clarify this picture.
The role of HPV in the pathogenesis of oesophageal squamous cell papillomas and other neoplasms is also unclear. Distinction between squamous papillomas (that may or may not be secondary to HPV infection) and the common inflammatory/hyperplastic squamous polyps and nodules (that are probably secondary to reflux) can be difficult. Indeed, the borderline between papillomatous change and well-developed hyperplasia is not always clear (Figure 11.3). In any event, histological diagnosis of an HPV-related lesion requires typical HPV-type cytological changes together with typical viral architectural abnormalities. Immunohistochemistry and in situ hybridisation may be helpful. In one large review, oesophageal squamous papillomas affected men more than women, were usually single, were typically small (average maximum size 5 mm) and were exophytic, endophytic, or ‘spiked’. Half of the lesions had evidence of HPV infection, and many patients had evidence of chronic and often severe mucosal inflammatory injury, e.g. oesophagitis or Barrett’s oesophagus. These observations led to the suggestion that papillomas could arise as a result of both HPV infection and mucosal irritation.11 Reflux probably contributes to the pathogenesis of most oesophageal hyperplastic polyps and papillomas. Caution is advisable, because a diagnosis of HPV infection has management implications.
(A) Papillomatous architecture is obvious at low-power examination in some cases, as in this example, but in others may be less well developed.
(B) The epithelium may show hyperplastic changes and papillary elongation, reminiscent of the features of gastro-oesophageal reflux disease.
Although some bacteria are probably normal commensals in the oesophagus, the role played by bacteria in infective oesophagitis is obscure and controversial. Recent microbiota studies and molecular genetic approaches have challenged the previous view that bacterial infection of the oesophagus is either a consequence of another primary insult, or a complication of immunosuppression/systemic infection, or a product of fastidious organisms. These controversial data suggest an association between the presence of certain bacterial species and gastro-oesophageal reflux disease (GORD), Barrett’s oesophagus, and even dysplasia. Di Palato2 reviews the subject comprehensively. Notably, the detection of these bacteria or otherwise is variable in different studies, has no current role in clinical practice, and warrants more detailed investigation. Similarly, although Helicobacter pylori are very rarely detectable in mucosal biopsies from Barrett’s oesophagus and may be present in the stomachs of some patients with GORD, their eradication has no effect on GORD.12
Primary mycobacterial infection of the oesophagus is rare and may occur in association with other infections.13 Two main culprits, Mycobacterium tuberculosis and Mycobacterium avium-intracellulare (MAI) complex, may cause infection. The former may develop as a consequence of a fistula from an infected hilar node or by swallowing coughed organisms. Granuloma formation is typical, caseous necrosis of granulomas may occur, and rare organisms may be apparent on acid-fast stains. MAI complex infection occurs in the context of systemic immunosuppression, usually in the setting of HIV/AIDS. In MAI infection, granuloma formation is poor and foamy macrophages predominate (Figure 18.13). Both PAS and acid-fast stains reveal abundant intracellular rod-like organisms.
Other Bacterial Infections of the Oesophagus
Actinomycosis of the oesophagus is rare and usually affects immunosuppressed patients with malignancy, HIV infection, or previous organ transplantation. Ulceration is a feature, and there may be perforation, abscess formation, or sinuses. Histology shows the typical sulphur granules (Figure 27.3).14, 15
Syphilis, Bartonella and Tropheryma whipplei infections may all involve the oesophagus. Confirmation of infection requires special microbiological investigations and other studies. Finally, secondary bacterial colonisation of established ulcers of any cause may occur and may lead to systemic infection in predisposed patients.
Several species of Candida may infect the oesophagus, usually in the context of an immunocompromised patient (see also Chapter 4) but also in patients who have undergone systemic antibiotic treatment. The diagnosis is often suspected at endoscopy, with characteristic white adherent patches or plaques of ‘thrush’ visible on the mucosal surface. These are often present in the mouth as well as in the oesophagus. Peeling off these plaques reveals a bleeding ulcer beneath.
Microscopically the low-power appearances of infected biopsies demonstrate striking desquamation of superficial epithelial cells and variable necrosis. Within these cells, fungal pseudohyphae are readily discernible. They are often orientated at ninety degrees to the axis of the squamous cells, which they appear to skewer (Figure 11.4). Pseudohyphal forms are straight and septated, although the latter feature may be unclear on routine H&E stains. Rounded budding yeast forms are also common. Acute inflammation characterised by neutrophils is present in almost all cases depending on immunocompetence. Deeper infection with granulation tissue may occur but is rare. In cases with fewer readily visible organisms a periodic acid–Schiff (PAS) or Grocott–Gomori methenamine silver (GMS) stain will highlight the infection. A search for other opportunistic infecting organisms including CMV and HSV is always prudent.
Figure 11.4 Oesophageal candidiasis with fungal hyphae skewering disassociated oesophageal squamous epithelial cells. Neutrophils and bacterial colonies are also present.
Aspergillus species may rarely infect the oesophagus as part of systemic infection, most commonly in the context of systemic immunosuppression.16 Aspergillus organisms may be recognisable in biopsy specimens from haemorrhagic and necrotic ulcers. Typically, they are larger than Candida species and demonstrate branching at acute angles, often 45 degrees (Figure 18.16).
Rare Infections of the Oesophagus
Protozoal infections of the oesophagus occur mainly in areas where trypanosomiasis is endemic, typically in South and Central America. The cause of South American trypanosomiasis or Chagas’ disease is Trypanosoma cruzi, which is spread by biting insects but may also be transmitted vertically from mother to fetus. Systemic infection results in the involvement of lymphoreticular, gastrointestinal (GI), and cardiovascular systems and the development of megasyndromes.21 Chronic infection of the GI tract causes destruction of ganglion cells within the myenteric plexus of colon and oesophagus and resultant development of megacolon and megaoesophagus (Figure 18.21). The diagnosis is made by blood film examination or serologically rather than by oesophageal biopsy.22
Amoebic and helminthic infections again are rare outside endemic areas except for immunocompromised individuals. Diagnosis based on oesophageal mucosal biopsy examination is unusual and depends on the recognition of the organism in routine sections. Microbiological analysis of stool samples usually allows initial diagnosis and confirmation of species.
Once thought to be a rarity, eosinophilic oesophagitis (EO) is an increasingly common diagnosis and is recognised by pathologists and endoscopists as an important cause of oesophageal inflammation.23, 24 Histopathology plays a key role in helping to make the diagnosis but its distinction from gastroesophageal reflux disease (GORD) may be difficult.25 Both its pathogenesis and treatment remain controversial.26–28
EO was clearly recognised as distinct from reflux oesophagitis in the 1990s with reports of persistent oesophageal eosinophilia in children following fundoplication, and improvement in symptoms with amino acid diet.29, 30 Previous dogma stipulated that, with few exceptions, the presence of eosinophils in oesophageal mucosal biopsies indicated GORD.31
Subsequently EO has been described in many populations, both adult and paediatric, with a peak incidence in the third and fourth decades. An apparently increasing incidence may partly reflect an increase in numbers of endoscopies and in awareness of the condition. Estimated overall incidence is between 0.4 and 1.4/10,000 population, and in some reports is higher. There is a male over female predominance of 2–3:1. EO is associated with other atopic type diseases, including asthma and allergic rhinitis. Peripheral eosinophilia and raised serum immunoglobulin (Ig) E levels are variable associations. There are several reviews of further clinical features.32 The association with many features of atopy has led some authors to favour an alternative and more appropriate label of allergic oesophagitis.33 A possible association with coeliac disease is the subject of dispute. There may also be a link with herpes simplex oesophagitis5, 6 and an inverse relationship with H. pylori infection.34
Understanding of the pathogenesis is incomplete, and there are several theories in circulation. All theories suggest, at least in part, a genetic predisposition conferring a susceptibility to environmental triggers in certain patients. Theories include defective mucosal barrier function, inhalation and swallowing of trigger antigens, failure of immunoregulation (Treg cell deficiency), IgG4-mediated disease, a response to dietary components, and polymorphisms in an atopic response mediator eotaxin.35 Interestingly, EO may occur in patients who have undergone cardiac transplantation and may be associated with immunosuppression.36
EO symptoms and clinical presentation vary with age. In young children they include food refusal, choking, and failure to thrive, and, in older patients, food impaction and dysphagia. There may be a significant element of dysmotility in some patients, which may reflect involvement of deeper oesophageal structures. There is a poor relationship between symptom severity, including response to therapy, and histological findings.37 Endoscopically, various appearances are described in EO including, most commonly, a ringed oesophagus (trachealisation or feline oesophagus), longitudinal furrows, white exudates, oedema, mucosal fragility, stricture formation, and in some cases normal appearances.38 Therefore, no endoscopic features are pathognomonic, and histopathological assessment is necessary to establish the diagnosis. All patients with symptoms suggestive of EO or in whom EO is a clinical possibility should be biopsied, but routine random biopsies of oesophageal mucosa without clear indication are not appropriate. There should be two to four biopsies from both proximal and distal oesophagus, as EO may be very patchy in distribution. GORD affects the lower oesophagus rather than the upper oesophagus. Therefore, high numbers of eosinophils in upper oesophageal mucosal biopsy specimens should favour a diagnosis of EO rather than GORD.
Biopsy specimens from EO mucosa often appear large and may detach in strips. The low-power histopathological impression is of an expanded epithelial layer that is paler than usual. On higher power inspection, abundant intraepithelial eosinophils are apparent, and the number of eosinophils often exceeds 30–40 per high-power field (Figure 11.5A). Secondary features include a tendency for eosinophils to concentrate near the epithelial surface, which is disrupted and may show squamous cell necrosis as a dense eosinophilic band (Figure 11.5B). The number of eosinophils is sufficiently large that eosinophil microabscesses (more than four contiguous eosinophils) (Figure 11.5C) may form again prominently in the superficial epithelium.33, 39 Eosinophil degranulation with intercellular eosinophilic dust is almost constant (Figure 11.5D). The epithelial layer may show remarkable squamous cell vacuolisation and intercellular oedema (spongiosis) with visible desmosomes, generating a paler expanded biopsy. Basal cell expansion and rete peg elongation are also present. Submucosal hyalinised fibrosis may be dramatic but its presence in the sample depends partly on biopsy depth. Collagen stains may highlight fibrosis (Figure 11.5E and F). Neutrophils and frank ulceration are uncommon in index biopsies and should prompt consideration of GORD. Immunohistochemistry can demonstrate a variety of lymphocyte subtypes, especially T cells, as well as mast cells and antigen-presenting cells. However, these studies are currently useful only in the research setting and their routine diagnostic value is uncertain.