9
Glandular Lesions of the Uterine Cervix
adenocarcinoma appear to be more similar to those noted for
endometrial adenocarcinomas. Endocervical adenocarcinoma is
more highly associated with non-smokers and lower parity than
are squamous carcinomas.12-15 Adenocarcinomas and their pre-
cursors have been shown to be associated with hormonal factors,
such as use of oral contraceptives16 and hormone replacement
therapy.17 These types of cofactors suggest that while oncogene-
sis may be primarily associated with the effects of HPV, differen-
tiation along glandular or squamous lines may be more closely
tied to the effects of these cofactors, and their interactions with
the HPV-mediated process (see below).
High-risk HPV types 16 and 18 are the most prevalent onco-
genic viruses found in cervical specimens and together comprise
Fig. 9.8 In this pseudostratified strip of cells, a ciliated luminal margin
can be clearly seen; however, the nuclei are overlapped and enlarged,
and have chromatin that is more heterogeneous than noted in Fig. 9.7A.
The arrangement of the group and the nuclear features show why, in the
absence of cilia, an "atypical” interpretation could easily be rendered in tubal
metaplasia (liquid-based preparation, Papanicolaou x HP).
the viral types associated with over 70% of high-grade lesions
and invasive carcinomas. Squamous cell carcinomas are associ-
ated, in a large predominance of cases (70+%), with HPV 16.18,19
Cervical adenocarcinomas are most commonly associated with
HPV 18; however, HPV 16 is also present in a percentage ranging
between approximately 30 and 40%.19,20 Interestingly, geo-
graphic variants of HPV 16 and 18 appear to be preferentially
present in adenocarcinomas as opposed to squamous carcino-
mas. Conflicting data from differing geographic populations
studied also suggest that geographic variants may react differ-
ently in various populations. This suggests that because viral
and human evolution appear to be linked,21 unknown mecha-
nisms of interaction between virus and host (e.g. HLA status)
may alter phenotypic outcomes.22 Adenocarcinomas have been
shown to be more commonly associated with non-European
variants of both HPV types 16 and 18.22,23 Variant HPVs have
been postulated to have differing performance characteristics in
terms of oncogenicity (e.g. p53 degradation and cellular trans-
formation efficiency may be different between variants, and
may account for differing behaviors among carcinomas).24-27
In addition, poorly characterized risk cofactors as mentioned
earlier, such as smoking and hormone use, may interact in dif-
ferent ways with variant forms of HPVs, leading to alternative
differentiation patterns—providing some insight into why pro-
genitor cells infected by HPV might differentiate as squamous
or adenocarcinomas. In that vein, investigators have identified
variants of HPV commonly associated with adenocarcinomas
that have structural changes in portions of the genome involved
with estrogen responsive elements.23,28-30 This finding may begin
to explain why adenocarcinomas of the cervix have risk factors
more akin to the "hormone-related" risk factors of endometrial
carcinogenesis, including exogenous hormone use, nulliparity,
and obesity. Interestingly, some variants are more commonly
associated with preinvasive lesions but less commonly associ-
ated with invasive carcinomas, again indicating that some vari-
ants may be more powerful in their transforming capabilities.27
Needless to say, studies into these areas are ongoing at present
Fig. 9.9 Spontaneously exfoliated endocervical cells (not directly abraded by the sampling device) travel in the endocervical mucous and will "round-
up" in a fashion similar to cells suspended in fluid media. This process can change cells from a columnar to a rounded configuration. Such cells may closely
mimic metaplastic squamous cells (A). Close attention to cytoplasmic granularity, the presence of vacuoles, and the character of the nuclei—showing evenly
distributed, finely granular chromatin, and small, but well-defined micronucleoli—can aid in their correct identification. In some cases, directly sampled
endocervical cells can present in loosely aggregated honeycombed configurations that also mimic metaplastic (or even dysplastic) squamous cells (B) (liquid-
based preparation, Papanicolaou x HP).
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