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1391
Endocrine Tumors of the Cervix
Morphologic Assessment, Expression of Human Papillomavirus, and Evaluation for
Loss of Heterozygosity on 1p, 3p, 11q, and 17p
Ciaran Mannion, M.B., B.CH.1
Won-Sang Park, M.D., Ph.D.2
Yan Gao Man, M.D., Ph.D.1
Zhengping Zhuang, M.D., Ph.D.2
Jorge Albores-Saavedra, M.D.3
Fattaneh A. Tavassoli, M.D.1
1
Department and Laboratory of Gynecologic and
Breast Pathology, Armed Forces Institute of Pathology, Washington, DC.
2
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
3
Department of Anatomic Pathology, University of
Texas Southwestern Medical Center, Dallas,
Texas.
BACKGROUND. Cervical endocrine tumors are rare lesions, with a varied diagnostic
nomenclature. A recent consensus meeting proposed a standardized terminology.
This study evaluated: 1) applicability of histopathologic guidelines; 2) evidence of
loss of heterozygosity (LOH) at selected sites; and 3) the presence of human
papillomavirus (HPV) detected by nonisotopic in situ hybridization (ISH).
METHODS. Thirty-eight cases (patient age range, 19 – 88 years; mean, 48 years)
were retrieved. Outcome data were available for 32 patients. Classification was
based on architectural and cytologic features. Tissue was available from 15
cases for LOH analysis with D3S1234(3p14), D3S1289(3p21), THRB(3p24),
TP53(17p13), D1S468(1p36), and INT-2(11q13). In ten cases, tissue was analyzed by nonisotopic ISH with HPV probes for types 6/11, 16/18, and 31/33.
RESULTS. Tumors were divided into four groups: small cell carcinoma (SCC) (n 5
25); large cell neuroendocrine carcinoma (LCNC) (n 5 5); SCC with focal LCNC
differentiation (n 5 3), and carcinoid tumor (n 5 5). Tumors defined as exclusively
or predominantly SCC had a particularly poor prognosis, with 20 patients dead of
disease (,6 years after diagnosis) and 6 alive with disease (after ,3 years of
follow-up). LOH at various 3p loci (3p14, 3p21, and 3p24) was observed in eight
cases. One patient demonstrated LOH on 17p(TP53). Eight of ten cases assessed by
ISH showed nuclear staining using a combined HPV-16/18 probe.
CONCLUSIONS. Cervical endocrine tumors are highly aggressive and can be subdivided into definable categories. LOH at 3p loci is a frequent finding, as is nuclear
staining with a combined HPV-16/18 probe. LOH at 17p(TP53 locus) appears to be
relatively uncommon, suggesting that p53 mutations may not be developmentally
significant. Cancer 1998;83:1391– 400. © 1998 American Cancer Society.
KEYWORDS: cervical carcinoma, endocrine carcinoma, small cell carcinoma, human
papillomavirus, in situ hybridization, loss of heterozygosity, 3p, p53.
Presented in part at the 86th Annual Meeting of the
United States and Canadian Academy of Pathology,
Orlando, Florida, March 1–7, 1997.
Address for reprints: Jorge Albores-Saavedra,
M.D., Department of Anatomic Pathology, University of Texas Southwestern Medical Center, 5323
Harry Hines Blvd., Dallas, TX 75235-9072.
The opinions and assertions contained herein are
the private views of the authors and are not to be
construed as official or reflecting the views of the
Department of the Army or the Department of
Defense.
Received October 29, 1997; revision received
March 19, 1998; accepted April 8, 1998.
© 1998 American Cancer Society
O
n a global basis, carcinoma of the uterine cervix is one of the most
frequent causes of death from malignant neoplasms among
women. In developing countries, cervical carcinoma accounts for an
estimated 340,000 new cases and 160,000 deaths every year.1 The
introduction of cytologic screening programs has had some measurable success in developed countries, in which cervical carcinoma
currently ranks as fifth in incidence and seventh in mortality for
female cancer patients of all ages.2 Nonetheless, in 1997, it is estimated that there were 14,500 new cases of cervical carcinoma and
4800 deaths attributable to carcinoma of the cervix in the U.S.3
Four decades ago, criteria were introduced for the classification
of cervical carcinoma.4 This system, which subsequently was adopted
by the World Health Organization, served to divide cervical carcinomas into two broad categories: squamous cell carcinoma (large cell
1392
CANCER October 1, 1998 / Volume 83 / Number 7
keratinizing, nonkeratinizing, and small cell undifferentiated carcinoma) and adenocarcinoma of the cervix. Small cell neoplasms of the cervix have long been
recognized as an uncommon, but highly aggressive,
subset of uterine cervical neoplasms with a particularly poor prognosis compared with other phenotypes.5–10 A similarly aggressive behavior also has been
documented with small cell carcinoma at other extrapulmonary sites.11
Over the past 25 years, a variety of terms have
been used in the diagnosis of cervical lesions with
neuroendocrine differentiation.12–39 This varied and
inconsistent nomenclature has represented a major
impediment to comparative studies of the true incidence, clinicopathologic characteristics, and natural
history of this family of tumors.
A recent consensus workshop was convened to
address the issue of terminology.40,41 The participants
acknowledged that neuroendocrine neoplasms of the
cervix share many clinical and histopathologic features with those in other sites, particularly the lung.42
The proposed terminology was recognized as a first
step toward a more uniform classification.
In view of the limited experience to date with
endocrine tumors of the cervix, the inherent prognostic and therapeutic implications of rendering such
diagnoses, and the lack of understanding of the molecular changes underlying these phenotypes at this
site, the current study resolved to examine cervical
endocrine tumors at the light microscopic and molecular levels. Specifically, we proposed to: 1) evaluate
the applicability of the recently introduced consensus
terminology40 to cervical endocrine tumors from the
case files of two large referral centers; 2) assess these
cases for mutations, in the form of loss of heterozygosity (LOH) at multiple chromosomal loci, some of
which have been associated with small cell tumors at
other anatomic sites43– 48 or with cervical tumors with
nonendocrine phenotypes;49 –55 and 3) document the
presence of human papillomavirus (HPV) by in situ
hybridization (ISH).
MATERIALS AND METHODS
Cases received between January 1970 and June 1996
were retrieved from the files of the Armed Forces
Institute of Pathology (AFIP), the files of the University
of Texas Southwestern Medical Center, and the personal consultation files of one of the authors (J.A-S.)
under a variety of diagnostic codes: small cell carcinoma (SCC), carcinoid tumor (CT), neuroendocrine
carcinoma, and poorly differentiated carcinoma. With
respect to the latter two codes, only cases with positive
staining for chromogranin and/or synaptophysin were
accepted into the study group. In the course of initial
review, cases with a predominantly squamous or glandular morphology with only isolated endocrine cells
were excluded, as advocated by the recent consensus
group.40
Hematoxylin and eosin stained sections were reviewed in 38 cases, the majority of which were biopsies. Using an Olympus BX40 microscope (Olympus
America Inc., Lake Success, NY), each case was assessed for the presence of a variety of architectural
and cytologic attributes: growth pattern; prominent
areas of tumor necrosis at low power (310 wide field
eyepiece, 34 objective 5 340 magnification 5 field
area of 22.89 mm2); character of the tumor margin
(circumscribed versus infiltrative); vascular invasion;
cell shape; nuclear to cytoplasmic ratio; nuclear pleomorphism; nuclear chromatin; nucleoli; mitotic activity at high power (310 wide field eyepiece, 340 objective 5 3400 magnification 5 field area of 0.92 mm2);
apoptotic bodies; cytoplasmic granules; rosette-like
arrangements; metaplastic changes; squamous or
glandular intraepithelial lesion/in situ component;
and concomitant presence of other carcinoma and
dysplasia patterns.
The patients ranged in age from 19 – 88 years
(mean, 48 years). In 26 patients, the major presenting
symptom was a cervical mass protruding through the
cervical os. In the colposcopic impressions and/or
macroscopic descriptions accompanying these consultation cases, the tumors typically were described as
“exophytic” or “polypoid” and showed “ulcerated” or
“friable” surface features. Survival data were obtained
for 32 patients. Of cases defined as SCC or SCC with
focal large cell neuroendocrine carcinoma (LCNC) differentiation, follow-up indicated a very poor prognosis (20 patients were dead of disease , 6 years after
diagnosis; 3 were alive with disease after ,3 years of
follow-up; and 3 were alive with disease after ,1 year
of follow-up). Four patients with CT were alive (after
,3 years of follow-up), 2 with evidence of disease. One
of the 5 patients with a LCNC had died 42 months after
the initial diagnosis, whereas another was alive with
metastatic disease , 3 years after initial presentation.
Additional material, in the form of formalin fixed,
paraffin embedded tissue blocks, was available from
15 cases. After hematoxylin staining of sections from
this tissue, microdissection was performed under direct light microscopic visualization, as has been reported previously.56 This involved the manual use of a
disposable, sterile, 30-gauge needle. Tumor cells were
selected to avoid contamination by surrounding elements; in cases with more than one morphologically
distinct malignant cell population, separate areas of
tumor were dissected individually so as to provide
pure representative samples of the respective tumoral
Endocrine Tumors of the Cervix/Mannion et al.
1393
TABLE 1
Analysis of Loss of Heterozygosity in Endocrine Tumors of the Cervix at Multiple Chromosomal Loci
Case no.
Diagnosis
D1S468(1p36)
D3S1234(3p14)
D3S1289(3p21)
THRB(3p24)
INT-2(11q13)
TP53(17p13)
1
2
3
4
5
6
7
8
9
10
SCC
SCC
SCC
SCC
SCC
SCC
SCC
SCC
SCC
SCC
LCNC
SCC
LCNC
SCC
LCNC
SqCCa
LCNC
LCNC
LCNC
NW
NW
NI
NW
NI
NI
NI
NI
NI
NI
NI
—
—
LOH
LOH
LOH
NW
NI
NI
LOH
—
LOH
LOH
NI
NI
—
NI
NI
LOH
—
LOH
—
NI
NI
NI
LOH
—
NI
LOH
NI
LOH
LOH
NI
LOH
—
NW
—
NI
NI
—
NI
NI
NI
NI
NW
—
NW
LOH
NA
NA
NA
NA
NA
LOH
NA
NI
LOH
—
LOH
LOH
NA
NA
NA
NA
NI
NI
NW
NW
—
—
NW
—
NW
LOH
NI
NI
NI
NI
NI
—
—
—
NW
LOH
NI
—
—
—
—
—
—
NI
—
—
NI
NI
—
—
—
—
—
LOH
NI
NI
11
12
13
14
15
SCC: small cell carcinoma; LCNC: large cell neuroendocrine carcinoma; SqCCa: squamous cell carcinoma; NW: test did not work; NI: not informative as a result of homozygosity; —: no loss of heterozygosity; LOH:
loss of heterozygosity; NA: no available tissue remained to assess.
populations. To assess reproducibility, two separate
samples were taken from each area of interest and
from normal internal controls (e.g., benign-appearing
squamous and/or glandular epithelium, adjacent normal stroma, inflammatory cells, etc.). One sample was
processed at the Gynecologic and Breast Pathology
Department at the AFIP, whereas the other was processed in an identical manner at the Laboratory of
Pathology at the National Cancer Institute to assure
consistency of results.
Procured cells were resuspended in a 20-mL solution
containing 0.05 M Tris-hydrochloric acid, 0.001 M ethylenediamine tetraacetic acid (EDTA), 1% Tween 20, and
0.1 mg/mL proteinase K. After overnight incubation at 37
°C, the mixture was boiled for 10 minutes to inactivate
proteinase K.
Polymorphic DNA markers were selected for analysis of loci, based largely on reports of LOH in small
cell neoplasms at other body sites or other tumor
phenotypes in the cervix (Table 1).43–55 These included: D3S1234(3p14); D3S1289(3p21); THRB(3p24);
TP53(17p13); D1S468(1p36); and INT-2(11q13). Polymerase chain reaction (PCR) was performed in 10-mL
volumes and contained 1 mL 10X PCR buffer; 1.5 mL
DNA extract; 50 pM of each primer; 20 nM each of
dCTP, dGTP, dATP, and dTTP; 0.1 mLp32 dCTP (6000
Ci/mM); and 0.1 U Taq DNA polymerase. The reactions were performed in a Perkin-Elmer Cetus thermal
cycler (Perkin-Elmer Cetus Instruments, Norwalk, CT)
as follows: 30 cycles of amplification, each comprised
of 94 °C for 30 seconds, followed by 55 °C for 30
seconds, and finally 72 °C for 30 seconds. The amplified product was mixed with an equal volume of formamide loading dye (95% formamide, 20 nM EDTA,
0.05% bromophenol blue, and 0.05% xylene cyanol).
Samples were denatured for 5 minutes at 94 °C and
resolved on 6% acrylamide gel. After electrophoresis at
1800 volts for 2 hours, the gels were transferred to
3-mm Whatman paper (Daigger Scientific, Wheeling,
IL) and dried. Autoradiography was performed with
Kodak X-Omat film (Eastman Kodak, Rochester, NY).
The case was considered informative for a polymorphic marker at a given locus if the DNA retrieved
from the normal tissue showed two different alleles
(heterozygosity). For informative cases, the intensities
of the two alleles in the tumor samples were compared. In this study, LOH was defined as complete or
near-complete ($75%) absence of one allele in the
tumor DNA as assessed by direct visualization. Cases
were classified as “not informative” at the polymorphic locus of interest on the basis of homozygosity in
DNA extracted from histologically normal tissue in the
specimen, thereby precluding evaluation for LOH. In
the instances of test samples that “did not work”, the
sample material was either of insufficient quantity or
possessed degraded, uninterpretable DNA. In some
cases, due to the scant quantity of lesional material in
the biopsy, no tumor remained in deeper sections
1394
CANCER October 1, 1998 / Volume 83 / Number 7
FIGURE 1. (a) Representative example of a case of small cell carcinoma (SCC) of the cervix. Note the high nuclear:cytoplasmic ratio, numerous mitotic figures
(arrow heads), and prominent apoptosis (H & E, original magnification 3240). (b) Large cell neuroendocrine carcinoma (LCNC). Although there are prominent mitotic
figures (arrows), the tumor cells have more abundant cytoplasm than SCC and vesicular nuclei showing occasional prominent eosinophilic nucleoli (arrowhead) (H
& E, original magnification 3300). (c) Carcinoid tumor. The perivascular, rosette-like architecture and uniform appearance of the cell nuclei are evident (H & E,
original magnification 3200). (d) Case of SCC showing focal LCNC differentiation. Nests of tumor cells with more conspicuous eosinophilic cytoplasm (arrowheads)
are evident in a background of hyperchromatic small cells (H & E, original magnification 3150).
from the paraffin blocks and was “not available” for
assessment.
In the 10 cases in which tissue remained after
LOH analysis, consecutive 5-mm sections were prepared on positively charged slides (Fisher Scientific,
Pittsburgh, PA). Sections were deparaffinized and ISH
was performed with HPV typing kits for types 6/11,
16/18, and 31/33 (Kreatech Diagnostics, Amsterdam,
The Netherlands). This process involved incubation
with pepsin digestion solution at 37 °C for 30 minutes,
rinsing with distilled water, and dehydration in ethanol. The sections were incubated with selected HPV
DNA probes at 95 °C for 5 minutes, followed by overnight incubation at 37 °C. The slides were treated with
differentiation solution and washed with Tris-buffered
saline (TBS) buffer. A HPV-infected cell line was used
as a positive control. Several different negative controls were employed including control probe or hy-
bridization buffer (in place of the HPV DNA probes),
use of normal kidney and breast tissue (as a substitute
for cervical tumor sections), and omission of the incubation phase with HRP-conjugated a-digoxigenin.
Reactivity was classified, on the basis of signal pattern,
as punctate and/or diffuse, as outlined in previous
reports.57– 62
RESULTS
Histopathologic Evaluation
In accordance with the terminology guidelines recommended by the consensus workshop,40 three distinct
phenotypic patterns were recognized: SCC (Fig. 1a);
LCNC (Fig. 1b); and CT (Fig. 1c). Based on these profiles, the cases were subdivided into four groups: SCC
(25 cases); LCNC (5 cases); SCC with focal LCNC differentiation (3 cases) (Fig. 1d); and CT (5 cases). Of the
Endocrine Tumors of the Cervix/Mannion et al.
1395
FIGURE 1. (continued)
five carcinoid lesions, four were atypical carcinoid
tumors and one was a single typical (classic) carcinoid.
Cases of SCC and/or LCNC could be distinguished
from CT using a combination of architectural and
cytologic features: infiltrative margin, extensive geographic areas of necrosis, relatively high mitotic rate
(. 10/10 high-power fields (hpf) 5 .10/9.2 mm2), and
prominent apoptotic bodies in the former tumors versus a predominantly pushing border, absence of or
only focal necrosis, lower mitotic rate (# 10/10 hpf),
and fewer apoptotic bodies in CT. Of note, vascular
invasion was not a reliable discriminator. Distinction
between SCC and LCNC was achieved on the basis of
cytologic attributes: sparse cytoplasm, finely granular
chromatin, and absence of nucleoli in SCC versus
relatively abundant cytoplasm, vesicular chromatin,
and prominent nucleoli in LCNC.
LOH Analysis
A total of 15 lesions were microdissected and evaluated for LOH with microsatellite markers at 5 chromosomal loci (Table 1): 9 SCCs, 3 cases with SCC and
focal LCNC, and 3 LCNCs. In the remaining cases,
which included the cases diagnosed as CT, analysis for
LOH was not possible either because no archival tissue was available or the only tissue present was tumor
without adjacent uninvolved tissue for comparison.
Several markers for loci in the short arm of chromosome 3 (Fig. 2) showed a high frequency of LOH,
with .50% of the informative cases showing at least 1
loss (Table 1). Of note, two of the three cases with SCC
and focal LCNC revealed LOH for D3S1234 in the SCC
component, but not in the LCNC elements (Fig. 2; a1,
Case 11). Although only one case proved informative
for LOH with D1S468, the findings are intriguing in
that three different tumor phenotypes (SCC, LCNC,
and squamous cell carcinoma) were present in the
lesion and all showed LOH under direct visualization
with this marker (Fig. 3a; Case 12). This case was
unique with respect to the demonstration of LOH in
association with both LCNC and squamous cell carcinoma phenotypes. Remarkably, the LOH in the squamous cell samples involved a different allele than that
observed with the endocrine elements. LOH at TP53
was uncommon, being present in only 1 of 11 informative cases (Fig. 3b; Case 13). With INT-2, LOH was
detected in two of six informative cases (Fig. 3c;
Case 8).
1396
CANCER October 1, 1998 / Volume 83 / Number 7
FIGURE 3. (a) Sequencing gel demonstrates loss of heterozgosity (LOH) for
FIGURE 2. (a) Sequencing gels demonstrate loss of heterozygosity (LOH) for
D3S1234 (3p14) in the small cell carcinoma (SCC) component, but not in the
coexistent large cell neuroendocrine carcinoma (LCNC) (a1; Case 11) or
squamous carcinoma (SqCCa) (a2; Case 1). (b) Sequencing gel shows LOH for
D3S1289 (3p21) in a SCC (Case 4). Sq Epi: squamous cell epithelium tissue; N:
normal tissue.
HPV In Situ Hybridization
In ten cases, sufficient lesional material remained for
HPV analysis (Table 2). Eight of the ten cases demonstrated positive staining with the combined HPV type
16/18 probe (Fig. 4a and 4b), which exclusively was a
punctate nuclear staining pattern. Of note, this staining was confined to viable tumor cells and was not
present in the background stroma or adjacent necrotic
areas. Three of these eight cases showed similar, but
rare, punctate staining for the HPV type 31/33 probe
in a few tumor cells. None of the cases were found to
be positive for the HPV type 6/11 probe.
DISCUSSION
Little is known regarding the genetic alterations underlying cervical carcinoma. This is particularly true of
D1S468 (1p36) in three coexistent phenotypically distinct tumors (large cell
neuroendocrine carcinoma [LCNC], small cell carcinoma [SCC], and squamous
cell carcinoma [SqCCa]) from the same patient (Case 12); although the same
allele is involved in the LCNC and SCC lesions, the other allele is lost in the
SqCCa. (b) LOH for TP53 (17p13) in Case 13. (c) LOH for INT-2 (11q13) in Case
8.
endocrine tumors of the cervix, which are rare, but
highly aggressive, malignancies. In addition to reaffirming the particularly poor prognosis associated
with these lesions,5–10,13,31,33,37,39 the current study
also provided an uncommon opportunity to evaluate a
large number of these tumors at both the light microscopic and molecular levels.
By adhering to the guidelines of the recent consensus workgroup,40 it was possible to define distinct
light microscopic phenotypes within the endocrine
category. SCC represented the most common cervical
endocrine tumor by far, confirming the observations
of the workgroup.40 The presence of foci of LCNC
differentiation in three cases of otherwise typical SCCs
points to a close relation between these two phenotypes and is in keeping with the hypothesis of a common cell of origin,63 possibly a reserve or stem cell in
the cervix. However, the finding of different LOH profiles on the short arm of chromosome 3 in respective
Endocrine Tumors of the Cervix/Mannion et al.
1397
FIGURE 4. (a) Section of small cell carcinoma showing punctate positive (brown) staining with combined kit for human papillomavirus type 16/18, (HRP-conjugated
a-digoxigenin, original magnification 3400). (b) Corresponding area on hematoxylin and eosin stained section confirms that the positive staining with the
a-digoxigenin is confined to the viable tumor cells (arrowhead), but was not observed in the adjacent degenerated cells (arrow) (H & E, original magnification 3400).
SCC and LCNC elements from the same lesion in two
patients provides support for the practice of distinguishing between these definable phenotypic patterns.
Numerous studies have reported a high frequency
of LOH on 3p in malignancies with a variety of phenotypes at different body sites, most commonly in the
lung43– 48,64 – 66 and kidney.67,68 Reports of LOH on 3p
in tumors with SCC at noncervical sites43– 46,48 and in
nonendocrine cervical carcinoma49 are particularly
noteworthy. The high frequency of LOH on 3p in the
current study cases provides further evidence that 3p
deletions represent an important step in cervical tumor pathogenesis and also are a characteristic finding
in endocrine tumors at this site. In view of the emerging concept of carcinogenesis as a multistep process
involving more than one genetic change, the association of 3p loss with various tumor phenotypes suggests that this finding may, in some instances, represent an early change in such a process. Indeed, the
observation of deletions of 3p in the early stages of
lung carcinogenesis66,69,70 and the presence of LOH on
multiple chromosomal loci45,48 in small cell lung carcinoma are consistent with such a model. Although a
similar archetype may well apply in the evolution of
cervical endocrine tumors, a number of fundamental
differences exist between neuroendocrine tumors in
the lung and those in the cervix, most notably in the
response to therapeutic modalities. The biologic basis
for these differences remain unclear.
In contrast to SCLC,47 our cases of cervical SCC
showed a low frequency of LOH of chromosome region 17p13 (p53 locus). This finding is provocative
when viewed in the context of the rather high rate of
detection of high risk HPV types in these lesions and
supports the evidence from other studies of the inverse relation between the presence of HPV and p53
mutations in cervical carcinoma.51–55,71,72 Previous investigators have demonstrated in vitro that E6 oncoprotein from high risk HPV types has the capacity to
1398
CANCER October 1, 1998 / Volume 83 / Number 7
TABLE 2
Detection of Human Papillomavirus by Nonisotopic In Situ
Hybridization Using HRP-Conjugated a-Digoxigenin
Case no.
HPV 6/11
HPV 16/18
HPV 31/33
1
2
3
7
9
10
11
12
13
15
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(2)
(1)
(2)
(2)
(2)
(2)
(2)
(1)
(1)
(1)
(2)
(2)
(2)
9.
10.
HPV: human papillomavirus; 1: positive staining; 2: no staining.
11.
12.
13.
14.
15.
bind and degrade wtp53 protein,73,74 whereas other
studies have provided evidence that such E6-wtp53
interaction may be functionally equivalent to p53 mutations.51,75 Such a model would be consistent with
our results. The punctate pattern of HPV expression,
observed with the digoxigenin probes in this study,
has been shown to be indicative of physical integration of HPV DNA.60 – 62 Other investigators have shown
an association between SCC of the cervix and high risk
HPV types, particularly HPV type 18.63,76
It is conceivable that certain tumors, including
endocrine tumors of the cervix, require both 3p loss
and HPV integration to transform an epithelial precursor stem cell into a cell with malignant potential.
Although previous studies have provided some evidence in support of such a hypothesis,50,77,78 the precise relation between integration of HPV and 3p deletion remains to be defined.
16.
17.
18.
19.
20.
21.
22.
23.
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