PART TWO
Diagnostic Cytology
Fig. 7.52 Koilocytic cell.
Vaginopancervical smear (Papanicolaou x HP).
The HPV-infected cells show blunting of the sharp angles of
the squamous cells. The squamous angular forms tend to become
rounded, and the cell assumes a softer, rounded or ovoid appear-
ance. Typically, the cytoplasm shows a peripheral condensation
and produces a "wire looping" effect, in which the cytoproteins
gel at the margins, leaving an almost empty shell. This cytoplasm
generally appears structureless and opaque, or waxy. It may be
acidophilic and appear as a brighter reddish-orange, resembling
a deep pumpkin red or a shade thereof. The typical koilocytic
cell has a large cavity or halo intracytoplasmic space. This space
has a sharp peripheral margin, and the nucleus contained within
this most often is eccentrically located; that is, this is a large para-
nuclear, and not a perinuclear, halo. The latter is generally small
with soft margins and is seen in the infectious process, such as
in trichomoniasis. It may also have a variable pale or faint cyto-
plasm within it. Occasionally, phagocytosed material may be
observed within the koilocytic space (Fig. 7.52).
Ultrastructurally, viral particles can be more easily detected
in warty lesions occurring in the skin than in those in the
genital tract and airways. Intranuclear icosahedral nonenvel-
oped virions of 40 to 50 nm can be observed. At times, some
particles may also be seen within the cytoplasm. Such findings
are believed to be artifactual.
Immunocytologic investigations may reveal high-molecular-
weight cytokeratin within the koilocytic space. No viral antigens
can be demonstrated with the paranuclear halo of koilocytes by
immunoenzymatic techniques.
Diagnostically, the koilocyte is an excellent indicator of HPV
infection. It has a high degree of specificity. Properly selected
and evaluated, nearly 90% of the cases of condyloma with
koilocytic change were found by immunoenzymatic techniques
to have demonstrable HPV antigen. In ALTS, greater than 84%
of LSIL cases contained HR HPV.104 Although highly specific,
the koilocyte alone has low sensitivity for detection of HPV
infection. Based on examination of routine vaginopancervical
smears, in our experience nearly 60% of the cases of condyloma
reveal obvious koilocytes; an additional 20% of the smears will
reveal the diagnostic cells if carefully screened. About one-third
of the cases of HPV infection may be missed cytologically if
the diagnosis is made solely on the basis of koilocytic changes.
Schneider and colleagues have reported that only 20% of cases
of HPV infection may be detected cytologically.109 We feel this
Fig. 7.53 Human papillomavirus (HPV) infection.
This picture represents
the cellular clumping or plaque formation commonly observed in this
infection. Vaginopancervical smear (Papanicolaou x LP).
is too low and probably not correct. It is obvious that the
conflicting reports in the literature about the diagnostic value of
vaginopancervical smears for HPV infection are based on excessive
reliance on the koilocyte as the sole diagnostic feature.
It is well known that the most vulnerable area of the ectocer-
vical-endocervical interface is the transformation zone, an area
situated between the squamous-lined ectocervix and the colum-
nar-lined endocervix.73 HPV infection is believed also to origi-
nate in this region. Once established, the infection may move
proximally or distally and affect the adjacent epithelial cells.
The ectocervical squamous epithelial changes that manifest as
koilocytes and other dyskeratotic forms are more obvious and
more common, but the proper recognition of these nonclassic
changes can improve the diagnostic value of routine vagino-
pancervical smears.
Quite often, a diagnosis of HPV infection or condylomatous
changes can be suspected with the lower magnification exami-
nation of the vaginopancervical smear. The infected cells may
occur with or without inflammation, concomitant infection,
or endocervical component. It is not uncommon to be able
to suggest a diagnosis of HPV infection in an otherwise less-
than-satisfactory smear that is rich in vaginal components and
has minimal endocervical representation.
The HPV-infected cells tend to stick together. The presence of
groups or clumps of deeply acidophilic, opaque squamous cells
in an otherwise well-fixed (no air-drying artifacts in conventional
smears) and -stained smear may be telltale evidence of HPV
infection (Fig. 7.53). A careful evaluation of such groups may
reveal a number of squamous cells that have lost their sharp,
polygonal shapes; they have become rounded and blunt. The
cells may be overlapping, as commonly seen in pregnancy and
late postovulatory smears, but they do not remain transparent
and thin. They become dense and may be opaque. The normal
gradual centrifugal thinning of the intermediate and super-
ficial cell cytoplasm is lost. Any degree of change between a nor-
mal-appearing squamous cell and the typical koilocyte may be
present in these cells. Besides the HPV-infected cells occurring
as aggregates, syncytial or pseudoepithelial formation may be
observed.
Ectocervical involvement by HPV may result in infected cells
with dyskeratosis. Although frequently observed in cases of
squamous cell carcinoma, some of the abnormal cytoplasmic
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