Diagnostic Cytology
Fig. 14.4 Herpes simplex esophagitis. The nuclei of the squamous
cells are markedly enlarged, have thick nuclear membranes, and have
homogenous ‘ground-glass' chromatin. Molding is well developed. In the
inset, a binucleated virocyte shows prominent intranuclear inclusion bodies
and surrounding halos (Papanicolaou x HP).
in contrast to the finely to coarsely granular hyperchromatic
chromatin of carcinoma cells. Superficially, the inclusion bod-
ies could be mistaken for macronucleoli. Careful attention to
the space between this structure and the nuclear membrane
is helpful. In virocytes, the clear halo is evident, whereas in
cancer cells granules of chromatin would be expected in this
nuclear zone. Finally, except for small-cell undifferentiated
carcinoma, such well-developed molding of the nuclei would
not be expected in malignancy.63 Another entity in the differ-
ential diagnosis is radiation esophagitis. This condition may
also result in enlarged squamous epithelial cells with multiple
nuclei and pale, almost structureless chromatin. In virocytes,
the enlarged nuclei are centrally concentrated and molded
against one another, the N/C ratio is increased, and nuclear
inclusion bodies may be present. On the other hand, in radia-
tion-induced damage, the nuclei are not typically compressed
against one another and may be dispersed in a haphazard man-
ner throughout the cytoplasm. Furthermore, the N/C ratio may
not be elevated. Finally, inclusion bodies are not expected. The
distinction of HSV from cytomegalovirus (CMV) is discussed
later. Additionally, molecular techniques including in situ
hybridization and polymerase chain reaction can be applied to
confirm viral infection.64,65 These methods are more sensitive
than morphology alone.66
Although a fairly common clinical scenario, published
reports concentrating on the cytologic diagnosis of the her-
pes esophagitis are quite infrequent.1
Whereas some authors
apparently believe that endoscopic biopsies are more likely
to yield a diagnosis of herpes esophagitis than are cytologic
brushings, others have found that cytology specimens are more
sensitive for this diagnosis.1,2,4,53 In any case, biopsies and brush-
ings are certainly complementary for the diagnosis of herpes
Cytom egalovirus Esophagitis
The other infection that occurs with some frequency in the
esophagus that may produce viral cytopathic changes is cytome-
galovirus. Although quite rare in the general population, CMV
esophagitis occurs with a relatively high frequency in patients
with AIDS.53,67 Patients may present with dysphagia and/or chest
pain. Unfortunately, the endoscopic and radiographic features
are totally nonspecific. Grossly, alterations range from a mild
nonspecific inflammatory picture to one of irregular ulcers.
The diagnostic mainstay has been endoscopic biopsies, usually
obtained from the base of the ulcer. It is important to remem-
ber that CMV generally does not infect squamous epithelium.
Rather, CMV virocytes include endothelial cells, fibroblasts, and
glandular elements. Accordingly, these infected cells are not
present within the epithelium of the esophageal mucosa but
rather in the lamina propria or submucosa. In esophageal biop-
sies, the virocytes are typically associated with lush granulation
tissue. The infected cells may line small blood vessels in some
instances, but in others they simply reside within the fibropro-
liferative reaction. They are characterized, as their name implies,
by marked increases in cellular and nuclear sizes. Each cell pos-
sesses a massive nucleus with a huge basophilic inclusion body.
Similar to HSV, these inclusion bodies are separated from the
thick nuclear membrane by a clear halo. Some virocytes also
manifest minute cytoplasmic inclusion bodies. Unlike HSV,
CMV virocytes almost never manifest ground-glass chromatin
patterns or multinucleation.
In esophageal smears, only rare CMV virocytes are present
scattered against the background of reactive epithelial cells, acute
inflammation, and cellular aggregates consistent with granula-
tion tissue.53,67 The infected cells present as isolated elements;
that is, they are unassociated with other cells. The diagnostic
cells demonstrate both marked nucleomegaly and cytomegaly,
marginated chromatin, and large oval to reniform basophilic
intranuclear inclusion bodies. As in tissue, these inclusion bod-
ies are surrounded by huge clear zones as a result of chromatin
condensation. Much of the chromatin apparently clumps on the
inner surface of the nuclear membrane, leading to its irregular
thickening. Granular eosinophilic inclusions may be seen in the
cytoplasm of some virocytes (see Fig. 14.23).
Key features of CMV esophagitis
• Marked nucleomegaly and cytomegaly;
• Thick marginated chromatin;
• Ovoid basophilic nuclear inclusions with halo; and
• Eosinophilic cytoplasmic inclusions.
It is important for the endoscopist to biopsy and brush the
base of esophageal ulcers to sample the CMV virocytes. As the
number of infected cells in a given specimen is generally very
low, a diligent search is required for their identification. This
is in contrast to other portions of the GI tract lined by glan-
dular mucosa.1
In these sites, CMV virocytes may be present in
much larger numbers. Although it is generally held that biop-
sies are more sensitive for the diagnosis of CMV esophagitis,
there are reported instances in which only the brushings were
Esophagitis due to infection by HSV is the major entity in the
differential diagnosis (Table 14.2). It is important to recall that
HSV infects squamous epithelial cells, whereas CMV involves
both glandular and stromal elements. Multinucleation and
pale homogeneous (ground-glass) chromatin are frequent in
HSV infections, but are almost never seen with CMV. On the
other hand, cytoplasmic inclusions occur only within CMV
virocytes. In esophageal brushings, HSV virocytes are almost
always present in much larger numbers than CMV virocytes. An
instance in which both types of infections were present in the
same specimen has been reported.67
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