Institutionen för onkologi-patologi / Department of Oncology-Pathology
Abstract
Squamous cell carcinoma is the most common histological tumor type in the
cervix uteri and oral tongue. Although both cancers are diagnosed at an
early stage in the majority of cases, cervical cancer has a better
prognosis despite similarities in treatment. The aim of this thesis is
to increase our knowledge of tumor progression in squamous cell carcinoma
at the molecular level, and to use this knowledge to explore the clinical
implications of this knowledge in the development of therapeutic
regimens.
We collected archived tissues from squamous cell carcinoma of the cervix
uteri and oral tongue (OTSCC) and applied immunohistochemistry (IHC), DNA
cytometry and fluorescence in situ hybridization (FISH) to
paraffin-embedded tissues.
Proliferative activity and genomic instability are two important factors
in tumor progression. To identify patients with a high risk for
locoregional recurrences we investigated Ki-67 expression (by means of
IHC) and DNA ploidy (using DNA image cytometry) in 76 pretreatment OTSCC
biopsy specimens. We found Ki-67 expression to be associated with an
increased risk for locoregional recurrence in surgically-treated Stage I
cancer patients (P=0.028). Ninety-seven percent of OTSCC specimens were
aneuploid.
Overexpression of epidermal growth factor receptor (EGFR) is associated
with poor prognosis in head and neck cancer, but information on EGFR
status in OTSCC is limited. We analyzed EGFR protein expression (IHC)
and gene copy number (FISH) in 78 pretreatment OTSCC samples. We found
EGFR gene copy numbers to be significantly associated with EGFR protein
expression (P=0.002). EGFR was overexpressed in all OTSCC, suggesting
that patients with this cancer type may benefit from EGFR targeting
treatment. Non-smokers showed higher EGFR gene copy numbers and protein
overexpression than did smokers.
The presence of lymph node metastases is a strong prognostic factor in
early stage cervical cancer and OTSCC. LAMP3, PROX1, PRKAA1 and CCND1 are
genes associated with carcinogenesis. We analyzed these gene copy numbers
using FISH probes in pretreatment cervical biopsies from LN positive and
LN negative Stage IB-IIA cervical cancer patients (N=31) to explore their
role in predicting LN metastasis. A combined marker panel consisting of
amplified probes for LAMP3, PROX1 and PRKAA1 provided a significant (P=0.001)
predictor for LN metastasis and needs to be evaluated in larger studies.
To further explore genetic alterations in OTSCC, and inspired by the
association between smoking habits and EGFR gene copy numbers, we applied
five FISH probe markers (TERC, CCND1, EGFR, P53, CEP®4) to 65
pretreatment OTSCC specimens. CCND1 displayed the highest copy number of
all markers and highest levels of this gene correlated significantly with
better prognosis in Stage II OTSCC (P=0.03). Non-smoking habits were
significantly related to higher copy numbers in all five markers (P=0.002)