Diagnostic Cytology
investigated. O'Morchoe and associates have described the
cytomorphologic findings in brushings from patients without
carcinoma of the upper GI tract who received cytotoxic chemo-
therapy with or without associated radiotherapy.74 The cytologic
findings included loss of polarity within aggregates, elevation
of the N/C ratios, variability in nuclear sizes and contours,
hyperchromasia, prominent and often multiple nucleoli, and
chromatin clumping. It appears as if chemotherapy-associated
cytologic atypia more closely mimics cancer than that typically
induced by radiation therapy.
esophagitides includes infections and cancer. More specifically,
as described previously, radiation needs to be distinguished
from HSV virocytes. A much greater diagnostic challenge con-
sists of distinguishing radiation-associated alterations and squa-
mous cell carcinoma.53 For the most part, this distinction needs
to be made only in patients with a prior squamous carcinoma
of the esophagus. Absence of prominent hyperchromasia and a
relative preservation of the N/C ratios are features that may serve
to make this distinction. It is important to remember that these
two diagnoses may not be mutually exclusive in that radiation
atypia may be superimposed on carcinoma cells (Table 14.3).
Gastroesophageal Reflux Disease
Gastroesophageal reflux disease is a clinical term used to encom-
pass all of the various manifestations of regurgitation of gastric
and often duodenal contents through a variably incompetent
lower esophageal sphincter. The stratified squamous epithelium
of the esophagus thus comes in contact with chemicals such as
hydrochloric acid, pepsin, and the various constituents of bile.
These noxious substances irritate the mucosa, leading to reflux
esophagitis. An erythematous mucosa with or without erosion
in the distal segment of the esophagus is the typical endoscopic
Major complications of reflux esophagitis include
peptic ulcers, fibrosing strictures, and Barrett's metaplasia.
Histologically, the major changes in the squamous epithe-
lium with reflux disease can be divided into inflammation and
reactive epithelial alterations.75,76 The latter include basal cell
hyperplasia and papillomatosis. Both consist of proliferative
responses by the squamous epithelium and the vascular con-
nective tissue of the lamina propria. Degenerative changes in the
epithelial elements are also frequently evident. The inflammatory
component consists of infiltrates of neutrophils and eosinophils.
Several authors have claimed that the intraepithelial eosinophil
is the single most specific diagnostic criterion for reflux esophag-
itis. None of these histologic features are totally reliable in terms
of diagnostic sensitivity and specificity. However, in the proper
clinical setting, this constellation of histopathologic features
may be diagnosed as reflux esophagitis.75,76
There are disorders for which only histopathology is diag-
nostic. One good example is reflux esophagitis in that there
are no specific cytomorphologic features. Brushings reflect the
spectrum of histologic changes and thus consist of a nonspecific
picture of acute inflammation and reparative epithelial atypia.
Morphologic features of reparative atypia have been described
previously. Eosinophilic leukocytes have not been noted to any
extent in brushings.4,53 In the presence of an erosion or ulcer,
parabasal epithelial cells may also be present in the smear in
large numbers. With a full-blown ulcer, fibrinopurulent exudate
may obscure other cellular elements.
Barrett's Esophagus
Barrett's esophagus, as mentioned earlier, is a major complica-
tion of reflux esophagitis that may affect 10% or more of patients
with long-standing GERD.77 Barrett's esophagus is a benign meta-
plastic process in which glandular tissue variably replaces the
normal squamous mucosal lining. No specific or even strongly
suggestive clinical signs or symptoms herald the development of
this metaplasia. Retrospectively, patients may actually report a
reduction in symptoms referable to esophagitis.
Histologically, this glandular epithelium may resemble gas-
tric and/or intestinal types of mucosa and has been characterized
by three basic histologic patterns. The first resembles the gastric
cardiac mucosa; that is, the surface and glandular structures are
lined by tall columnar cells with abundant cytoplasmic neutral
mucin, small basally oriented ovoid nuclei, and well-defined
intercellular borders. The mucin presents as finely granular or
multivesicular material. The second type resembles atrophic
fundic-type mucosa with parietal and/or chief cells. The third
is the intestinal or specialized mucosal variant. Its morpho-
logic hallmark is the goblet cell,78 which has a barrel-like con-
figuration, abundant cytoplasmic acidic mucin, a minute round
nucleus, and a very low N/C ratio. A villous architecture and
Table 14.3 Cytomorphologic Differential Diagnosis of Squamous Cell Abnormalities in Esophageal Brushings
Smudged or cleared
Pale, fine granularity, even
Dense or variably granular,
irregular particle size and
Pale, fine granularity, even
Nuclear inclusion body and halo
N/C ratio
Moderately increased
Normal to slightly increased
Slightly to greatly increased
Normal to slightly increased
Intercellular cohesion
RT, radiotherapy; SCCA, squamous cell carcinoma abnormalities.
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