Figure 1.130 Parakeratosis. Parakeratosis consists of squamous epithelial cells with brightly eosinophilic cytoplasm and retained nuclei, sometimes with sloughing of epithelial cells (arrowheads).
Figure 1.131 Parakeratosis, Candidiasis. In this case, the fungal forms of Candida are seen admixed in the parakeratotic debris (arrowheads).
Parakeratosis describes abnormal retention of the nuclei in the most superficial squamous layers, superficial keratinization, and individual cell desquamation into the lumen. Parakeratosis is a nonspecific injury pattern seen most commonly in the following settings (Figs. 1.130 and 1.131).
CHECKLIST: Parakeratotic Pattern
Gastroesophageal Reflux Disease
Candida Esophagitis
Orthokeratosis is seen in Esophageal Leukoplakia/Epidermoid Metaplasia
Esophagitis Dissecans Superficialis/Sloughing Esophagitis
GASTROESOPHAGEAL REFLUX DISEASE (GERD)
Parakeratosis is commonly seen in the setting of GERD (Figs. 1.132–1.137). See also GERD, Acute Esophagitis and Lymphocytic Pattern, this chapter.
CANDIDA
Sometimes parakeratosis is the only clue to candidiasis (Figs. 1.138–1.146). Candida infections can occur in the complete absence of background inflammation, particularly in immunosuppressed individuals (elderly, pregnant, status post transplant, HIV/AIDS, patients on immunosuppressive therapies, and even children with EoE taking oral steroids). Identification of parakeratosis should always prompt a diligent high-power examination for the pseudohyphal forms of Candida, particularly when single-cell shedding or “flaking” of the surface epithelium is seen.
Figure 1.132 Parakeratosis, GERD. Parakeratosis in a patient with a long-standing history of GERD. The surface squamous cells shows brightly eosinophilic cytoplasm, indicative of keratinization, while intact nuclei are retained.
Figure 1.133 Parakeratosis, GERD. Parakeratosis in a patient with a long-standing history of reflux disease.
Figure 1.134 Parakeratosis, GERD. Parakeratosis in a patient with a long-standing history of reflux disease.
Figure 1.135 Parakeratosis, GERD. Parakeratosis can often be picked up at low power due to the brightly eosinophilic cytoplasm of the surface squamous cells undergoing keratinization.
Figure 1.136 Parakeratosis, GERD. Higher power of previous figure. Retained nuclei are present in squamous cells undergoing keratinization of the cytoplasm, seen as brightly eosinophilic change.
Figure 1.137 Parakeratosis, GERD. Small focus of parakeratosis is seen among squamous balloon cells.
Figure 1.138 Severe candidiasis. The endoscopic image shows a coalescing of white plaques that correspond histologically to parakeratotic debris.
Figure 1.139 Parakeratosis, candidiasis. The corresponding biopsy shows mats of parakeratotic debris and embedded fungal forms. Note how the parakeratotic cells desquamate in a single cell pattern. This “flakiness” is a very helpful red flag to the underlying diagnosis and it is easily spotted at low power.
Figure 1.140 Parakeratosis, candidiasis. A PAS/AB highlights the long fungal pseudohyphae (arrowheads), a requirement for diagnosis. In contrast, the neighboring rounded fungal yeast forms can be seen with oral contamination and are not indicative of candidiasis (circles).
Figure 1.141 Parakeratosis, candidiasis. The “flakiness” seen at low power is the single cell desquamation of parakeratotic cells (arrowheads), a finding which may be the only clue in subtle cases of candidiasis. This patient had a history of eosinophilic esophagitis treated with diet modification and topical steroids. Note the complete absence of acute inflammation, which can be seen in candidiasis from patients on oral steroids, or otherwise immunosuppressed.
Figure 1.142 Parakeratosis, candidiasis (PAS/AB). A PAS/AB highlights both fungal pseudohyphae and rounded yeast forms. Again, take note of the flaky background appearance due to single cell desquamation of parakeratotic squamous cells.
Figure 1.143 Parakeratosis, candidiasis. Although there is no background inflammation in this biopsy, the single cell flaking (parakeratosis) almost certainly indicates Candida lurking within the parakeratotic debris.
Figure 1.144 Parakeratosis, candidiasis (PAS/AB). A PAS/AB highlights the rare fungal pseudohyphae.
Figure 1.145 Parakeratosis, candidiasis. The presence of parakeratosis and single cell detachment of the surface epithelium is highly suspicious for involvement by Candida.
Figure 1.146 Parakeratosis, candidiasis. (PAS/AB). A PAS/AB highlights the rare fungal hyphae (arrowheads).
LEUKOPLAKIA PATTERN/EPIDERMOID METAPLASIA
At scanning magnification, the superficial hypereosinophilia of leukoplakia (epidermoid metaplasia) can appear similar to the parakeratotic pattern described above. Esophageal leukoplakia/epidermoid metaplasia is a clinicopathologic diagnosis that requires satisfaction of clinical criteria (endoscopically apparent white plaque) and histologic criteria (orthokeratosis and hypergranulosis) (Figs. 1.147–1.153).39–42 Orthokeratosis describes anucleated keratinization, whereas, parakeratosis refers to keratinization with retained nuclei. This uncommon finding is associated with scleroderma, distal esophageal dysmotility disorders, and factors associated with oral leukoplakia (including tobacco and alcohol usage and head and neck pathology). Endoscopically, it appears as a white plaque (similar endoscopic images can be seen with candidiasis, glycogenic acanthosis, and lichen planus). Histologically, basal hyperplasia, an acanthotic midzone, superficial hyperkeratosis, and hypergranulosis characterize the lesion. Candida or bacterial colonization is seen in 45% of cases. Recent reports show patients with esophageal leukoplakia/epidermoid metaplasia have an increased risk of squamous cell dysplasia and squamous cell carcinoma, suggesting affected patients may benefit from surveillance, although as of this writing, no official consensus guidelines exist.
Figure 1.147 Esophageal leukoplakia pattern/epidermoid metaplasia. The endoscopic image shows scattered white plaques.
Figure 1.148 Esophageal leukoplakia pattern/epidermoid metaplasia. The corresponding histologic sections show squamous mucosa with hyperkeratosis, hypergranulosis, and bacterial colonization. No dysplasia is seen.
Figure 1.149 Esophageal leukoplakia pattern/epidermoid metaplasia. This striking low-power example shows hyperkeratosis and prominent hypergranulosis. No dysplasia is seen.
Figure 1.150 Esophageal leukoplakia pattern/epidermoid metaplasia. Higher power of previous figure. The presence of a granular layer and keratinization in the esophageal mucosa is never normal and should prompt consideration of esophageal leukoplakia/epidermoid metaplasia, as well as a close examination for associated squamous dysplasia.
Figure 1.151 Esophageal leukoplakia pattern/epidermoid metaplasia. Keratinization of the surface epithelium and the presence of a granular layer are seen. These features are more subtle; the granular layer is attenuated, making high-power evaluation necessary. No dysplasia is present.
Figure 1.152 Dysplasia arising in a background of esophageal leukoplakia/epidermoid metaplasia. Note the jumbled appearance to the squamous epithelium with scattered large, pleomorphic squamous cells and a focal loss of maturation.
Figure 1.153 Dysplasia arising in a background of esophageal leukoplakia. Higher power of previous figure.
SAMPLE NOTE: ESOPHAGEAL LEUKOPLAKIA/EPIDERMOID METAPLASIA
Proximal Esophageal Plaque, Biopsy:
• Esophagus with orthokeratosis, hypergranulosis, and bacterial overgrowth (esophageal leukoplakia/epidermoid metaplasia pattern).
• Negative for dysplasia.
Note: Esophageal leukoplakia/epidermoid metaplasia pattern appears to arise in patients with similar risk factors for squamous cell carcinoma to those associated with oral leukoplakia. Periodic follow-up of this process is recommended, although there are no guidelines for surveillance intervals at this time.
References
Taggart MW, Rashid A, Ross WA, et al. Oesophageal hyperkeratosis: Clinicopathological associations. Histopathology. 2013;63(4):463–473.
Singhi AD, Arnold CA, Crowder CD, et al. Esophageal leukoplakia or epidermoid metaplasia: A clinicopathological study of 18 patients. Mod Pathol. 2013;27(1):38–43.
ESOPHAGITIS DISSECANS SUPERFICIALIS/SLOUGHING ESOPHAGITIS
This is an unusual endoscopic finding of epithelial sloughing that has been associated with medications (bisphosphonates and NSAIDs), heavy smoking, alcohol use, bullous skin disorders (such as pemphigus vulgaris), autoimmune diseases, celiac disease, motility disorders, and physical or thermal injury.43–47 However, many cases lack a recognized clinical association. The clinical presentation ranges from asymptomatic to dysphagia with stricture formation. The endoscopic impression can be dramatic with vertical fissures and intervening patches of peeling and sloughed epithelium (Fig. 1.154). Histologically, on low power, long detached fragments of superficial squamous epithelium are typically present. Most cases demonstrate some degree of intraepithelial splitting at varying intervals above the basal layer. Various stages of splitting can be seen, with some cases demonstrating distinct bullae. Earlier stages may show intraepithelial splitting with fluid-containing and cell-containing cysts in the upper third of the epithelium. Parakeratosis is a consistent and prominent feature in all cases. Other characteristic features include a superficial “mummified” layer (anucleated squamous mucosa), variable necrosis, and bacterial colonization with minimal inflammation (Figs. 1.155–1.160). A study by Carmack et al. showed that four of five patients had complete resolution of endoscopic and histologic findings following PPI therapy, suggesting this could be a potential treatment. There have been no reports of neoplasia associated with esophagitis dissecans superficialis.
Figure 1.154 Endoscopic appearance of esophagitis dissecans superficialis (sloughing esophagitis). The esophageal squamous epithelium has a distinct white appearance with fissuring. Some areas have shed off in sheets, exposing the underlying tissue (arrow). With endoscopic maneuvering, the residual epithelium may lift off with a crepe paper-like quality (arrowhead).
Figure 1.155 Esophagitis dissecans superficialis. The histologic findings from the previous endoscopic photo show features of esophagitis dissecans superficialis (sloughing esophagitis). This entity uniformly demonstrates parakeratosis; retained nuclei (arrowheads) are present in the superficial and keratinizing squamous cells. An intraepithelial split is often frequently seen, but no inflammatory cells are present. Bacterial overgrowth is visualized as a fuzzy basophilic lining along the superficial epithelium. It can also be seen as detached basophilic clusters (arrow), and is a common finding in sloughing esophagitis.
Figure 1.156 Esophagitis dissecans superficialis. A different example of sloughing esophagitis shows an early intraepithelial split above the basal layer. This case shows fluid-containing cysts (arrowheads) within the epithelium, another common finding. Although difficult to visualize at this power, the surface epithelium shows bacterial colonization and parakeratosis. Note the absence of inflammation.
Figure 1.157 Esophagitis dissecans superficialis. This example of esophagitis dissecans superficialis shows a prominent intraepithelial split, with residual fluid-filled cysts (arrowhead), prominent parakeratosis (arrow), and a total lack of inflammation. The etiology of sloughing esophagitis is frequently unidentifiable.
Figure 1.158 Esophagitis dissecans superficialis. Another example of esophagitis dissecans superficialis with an intraepithelial split and small fluid-filled cysts (arrowhead). The lack of inflammation is characteristic for this entity.
Figure 1.159 Esophagitis dissecans superficialis. This example of esophagitis dissecans superficialis shows the characteristic parakeratosis, with development of fluid-filled cyst-like spaces. An intraepithelial split has not yet developed. Note the lack of inflammation.
Figure 1.160 Severe reflux with features of esophageal sloughing. This esophageal biopsy shows sloughed squamous epithelium with parakeratosis and surface bacterial colonization. However, the presence of the intense acute inflammation found at the base of the epithelial split is unusual for esophagitis dissecans superficialis (sloughing esophagitis). Investigation into the clinical and endoscopic findings yielded a history of severe reflux esophagitis.
KEY FEATURES of Esophagitis Dissecans Superficialis/Sloughing Esophagitis:
• The endoscopic appearance can be dramatic, with sloughing or peeling squamous mucosa
• Histology shows a preserved basal layer with mummified and often a splitting superficial layer with “ghost” nuclei, parakeratosis, and fragmentation
• Inflammation is not prominent
• The etiology is usually unknown, but the condition has been associated with some medications, bullous dermatoses, motility disorders, physical/thermal injury, and autoimmune diseases
PEARLS & PITFALLS
Although most cases of esophagitis dissecans superficialis (sloughing esophagitis) will not yield an identifiable etiology, if bullae and epithelial clefting are prominent features, skin disorders that have similar esophageal manifestations should be excluded, such as Stevens–Johnson syndrome, pemphigus and pemphigoid, and dermatitis herpetiformis. In such cases, consultation with a dermatopathologist and biopsy with fresh tissue (tissue not fixed in formalin) submitted for pertinent immunofluorescent studies (IgG, IgM, IgA, C3, fibrinogen) is recommended.
PEARLS & PITFALLS
Detached or split squamous epithelium, alone, does not qualify a diagnosis of esophagitis dissecans superficialis (sloughing esophagitis), as this can result from biopsy trauma or processing artifact (Fig. 1.161). In addition, dilated intercellular spaces (spongiosis) are not seen in this entity; when this feature is seen, other etiologies, such as reflux or changes secondary to a stricture should be considered.
Figure 1.161 Normal esophagus with artifactual split. This intraepithelial split is the result of processing and cutting artifact. While an intraepithelial split is characteristic of esophagitis dissecans superficialis (sloughing esophagitis), this biopsy lacks parakeratosis, fluid- or cell-filled cysts, bacterial overgrowth, or other abnormalities to suggest esophagitis dissecans superficialis. In addition, the endoscopic impression was unremarkable and not suggestive of a esophagitis dissecans superficialis (sloughing esophagitis) pattern of injury.