Anatomic Pathology / CD44S IN OVARIAN CANCER
Decreased CD44 Standard Form Expression Correlates
With Prognostic Variables in Ovarian Carcinomas
Jeffrey S. Ross, MD,1 Christine E. Sheehan,1 Susan S. Williams, MD,1
John H. Malfetano, MD,2 Wanda M. Szyfelbein, MD,3 and Bhaskar V.S. Kallakury, MD1
Key Words: CD44s; Immunohistochemistry; Ovarian tumors; Prognosis
Abstract
Expression of CD44 standard form (CD44s) was
evaluated by automated immunohistochemical analysis
using the anti-CD44 A3D8 clone in 101 ovarian
epithelial neoplasms including 82 primary tumors (64
carcinomas and 18 tumors of low malignant potential
[LMP]), 9 lymph node metastases, 8 malignant ascites,
and 2 peritoneal implants. Immunostaining was scored
semiquantitatively. Tumors were graded according to
the FIGO (International Federation of Gynecology and
Obstetrics) classification system. Tumor stage and
patient survival were determined from the patient
records. While 9 of 18 LMP tumors expressed CD44s,
only 15 of 64 carcinomas expressed it. In the
carcinomas, univariate analysis revealed that decreased
CD44s expression correlated with high tumor grade,
advanced stage, and shortened survival. Loss of CD44s
expression also was noted in the tumor cells in 8 of 9
lymph node metastases, 7 of 8 malignant ascites, and 1
of 2 implants. Multivariate analysis revealed that only
tumor stage independently correlated with patient
survival.
Loss of CD44s expression determined by
immunohistochemical analysis is more common in
ovarian carcinomas than in LMP tumors; correlates
with prognostic variables including tumor grade, stage,
and survival; and may have an important role in the
dissemination of ovarian cancer.
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Am J Clin Pathol 2001;116:122-128
CD44 is a cell surface hyaluronate receptor1 and cell
adhesion molecule that is widely expressed in a variety of
cells of hematopoietic,2 epithelial,3 and mesothelial4 origins.
The CD44 molecule has been associated with cell-cell adhesion,5 cell-matrix interaction,6 and lymphocyte homing and
circulation.2,4,7 The CD44 cell surface receptor includes a
family of immunologically related integral membrane glycoproteins with molecular weights ranging from 80 to 250
kd.8,9 The CD44 gene is a single gene containing 20 exons10
localized to chromosome 11.11 Alternative splicing of the 10
exons located between exons 5 and 16 (exon v1 to exon v10)
of the CD44 gene may produce variant isoforms
(CD44v).10,12-14 The most abundant form of CD44 protein in
tissues is the standard form (CD44s) or hematopoietic form
(85-95 kd) in which there is no expression of any of the 10
variant isoforms.7,15
A variety of clinical and experimental studies have
linked perturbations of the CD44 molecule with cancer
progression, invasion, and metastasis.16 Enhanced expression
of CD44s and/or its isoforms has been associated with
aggressive disease in non-Hodgkin lymphoma,17 breast carcinoma,18,19 colorectal cancer,20 and high-grade renal cell carcinomas.21 CD44s immunoreactivity has been associated with
the presence of thyroid cancer, especially the papillary
subtype.22,23 Alternatively, down-regulation of CD44 has
been reported in the progression of dysplasia to carcinoma in
esophageal Barrett epithelium,24 metastasis of endometrial
cancer cells through lymph-vascular spaces,25 high-grade
bladder transitional cell carcinoma,26 prostatic adenocarcinoma,27-29 and high-grade brain tumors.30 CD44s immunostaining seems to be more intense in squamous cell carcinomas compared with adenocarcinomas of the lung. 31
Recently, much attention has been drawn to the potential role
of CD44 variant isoforms in tumor metastasis. In animal
© American Society of Clinical Pathologists
Anatomic Pathology / ORIGINAL ARTICLE
models, transfection of a nonmetastatic carcinoma cell line
with a variant isoform containing the v6 exon has been
shown to induce metastatic behavior in tumor cells.32 In
human malignant neoplasms, carcinomas of the stomach,33,34
colon,35,36 breast,37,38 and uterine cervix39 have been associated with a variety of CD44v expression and aggressive
tumor behavior.
CD44s expression has not been studied extensively in
ovarian epithelial neoplasms. Studies of ovarian cancer cell
lines and xenografts have suggested a potential role of CD44
in ovarian cancer progression.40-43 Studies on human primary
and metastatic ovarian carcinomas using clinical tissue
samples have yielded variable and conflicting results with
regard to the prognostic significance of CD44s and variant
isoforms.44-48 We studied the immunohistochemical expression of CD44s in ovarian tumors, including primary and
disseminated forms, and evaluated its prognostic significance.
Materials and Methods
Tissue Samples
We randomly selected 101 ovarian epithelial neoplasms
(accessioned between August 1991 and September 1995)
from the files of the pathology department at the Albany
Medical Center Hospital, Albany, NY. The cases included 82
tumors at the primary site, 9 lymph node metastases, 8
malignant ascites, and 2 peritoneal implants. All H&E
stained slides, where applicable, were reviewed to confirm
the original diagnoses. The median age of the patients was
59.8 years (range, 30-85 years). A gynecologic oncologist
(J.H.M.) performed exploratory laparotomy on 93 patients.
The remaining 8 cases were aspirated fluid from malignant
ascites in patients with documented ovarian cancer. For
patients with tumors diagnosed at frozen section with histologic features indicative of low malignant potential, hysterectomy and bilateral salpingo-oophorectomy were performed
in 15 of 18 cases; 3 patients underwent unilateral salpingooophorectomy to preserve reproductive capabilities. All 75
women with carcinoma underwent hysterectomy with bilateral salpingo-oophorectomy and received postoperative
multidrug chemotherapy including cisplatin. The 18 patients
with tumors of low malignant potential did not receive additional chemotherapy. The clinical charts were reviewed, and
information on tumor type, stage, recurrence, and survival
rates was recorded for all patients. The follow-up period for
the study ranged from 1 to 70 months (mean, 32 months).
There were 18 tumors of low malignant potential (serous,
13; mucinous-gastrointestinal type, 4; endometrioid, 1) and 64
carcinomas (serous, 45; endometrioid, 9; clear cell, 5; mucinous, 5). Tumors were graded as well, moderate, and poorly
© American Society of Clinical Pathologists
differentiated and staged according to the FIGO (International
Federation of Gynecology and Obstetrics) classification
system. In the carcinoma group, there were 8 grade 1 (12%),
17 grade 2 (27%), and 39 grade 3 (61%) tumors. While 19
primary site carcinomas (30%) were stage I or II tumors, the
remaining 45 cases (70%) were stage III or IV tumors.
Surgical pathology blocks were stored in ambient conditions
for 2 to 6 years before immunohistochemical staining.
Immunohistochemical Staining
After endogenous peroxidase activity was blocked,
unstained 5-µm sections from a representative block of
formalin-fixed, paraffin-embedded tissue in each case were
stained for a 12-hour period with the A3D8 clone of the
mouse monoclonal IgG1 class antihuman antibody against
CD44s (Sigma Immunochemicals, St Louis, MO) at a
concentration of 28 µg/mL. The A3D8 monoclonal antibody
immunoprecipitates the 80-kd form of CD44.46 A papillary
carcinoma of the thyroid known to be positive for CD44s
served as the positive control.22,23 Negative control slides
also were processed in parallel using a nonspecific IgG
(Sigma) at the same concentration as the primary antibody.
Immunohistochemical staining was performed on the
Ventana ES Automated Immunohistochemistry System
(Ventana Medical Systems, Tucson, AZ). After exposure to
the primary antibody, the slides were incubated sequentially
with the universal biotinylated immunoglobulin secondary
antibody, avidin horseradish conjugate, and diaminobenzidine (DAB) followed by copper sulfate enhancement and
counterstained with hematoxylin. Antigen retrieval procedures were not used in the immunostaining protocol.
Staining Interpretation
The staining was assessed semiquantitatively based on
staining intensity and distribution as previously
described.27,49 Tumors that showed intense diffuse, intense
regional, and moderate diffuse patterns were considered
positive for CD44s expression. All cases with other staining
patterns or with no membranous staining were considered as
down-regulated for this protein.
Statistical Analysis
For statistical comparison of CD44s expression with
histologic types and tumor stage, the chi-square test was
used. Univariate survival and recurrence analysis were based
on the Kaplan-Meier and the Breslow-Gehan-Wilcoxon test.
The criterion for significance was P = .05.
Results
Nine (50%) of 18 tumors of low malignant potential
were considered positive for CD44s immunoreactivity in
Am J Clin Pathol 2001;116:122-128
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Ross et al / CD44S IN OVARIAN CANCER
comparison with 15 (23%) of 64 carcinomas (P = .03)
❚Image 1❚ and ❚Image 2❚.
Histologic Type
The loss of CD44s immunostaining in the tumors with
serous differentiation was statistically significant (P = .013).
Of 58 serous tumors, 40 (69%) showed CD44 down-regulation as opposed to 10 (42%) of 24 nonserous tumors. There
were no significant differences in the comparative staining in
the individual subtypes of nonserous tumors.
Tumor Grade and Stage
Four (50%) of 8 grade 1 carcinomas demonstrated loss
of CD44s expression in comparison with 45 (80%) of 56
grade 2 and 3 tumors (P = .05). CD44s down-regulation
correlated with tumor stage, with 9 (47%) of 19 stage I and
II carcinomas showing loss of CD44s compared with 40
(89%) of 45 stage III and IV tumors (P = .006). In addition,
tumor cells in 8 (89%) of 9 lymph node metastases ❚Image
3❚, 7 (88%) of 8 malignant ascites ❚Image 4❚, and 1 (50%) of
2 implants ❚Image 5❚ demonstrated CD44s down-regulation.
Survival Analysis
At the time of completion of follow-up analysis, all
patients with tumors of low malignant potential were alive
and free of clinical evidence of disease. While 28 (44%) of
64 patients with carcinomas died of disease, 8 (22%) of 36
patients who were alive had either clinical or surgically
proven evidence of recurrent disease. Univariate analysis
revealed that loss of CD44s was associated with shortened
❚Image 1❚ Mucinous ovarian epithelial tumor of low malignant
potential showing intense diffuse membranous
immunostaining for CD44s (diaminobenzidine and
hematoxylin, ×200).
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Am J Clin Pathol 2001;116:122-128
patient survival (P = .04) ❚Figure 1❚. However, multivariate
analysis revealed that only tumor stage correlated independently with survival (P = .006).
Discussion
CD44 is a widely expressed cell surface antigen that
serves as an adhesion molecule in cell-cell and cell-matrix
interactions. Expression of the CD44 gene becomes disorderly in the early stages of carcinogenesis, and excessive
quantities of many inappropriate alternatively spliced CD44
variants accumulate in cancer cells. The role of the CD44
adhesion molecule has been reported to be variable in
different carcinomas. Increased expression of CD44 has been
postulated to be associated with aggressive tumor behavior
as demonstrated in animal studies32 and in human carcinomas of breast, 18 stomach, 19 and non-Hodgkin
lymphoma.17 In contrast, correlation has been reported of
down-regulation of CD44s with prognostic variables in other
solid cancers including bladder,26 prostate,27 endometrium,25
and neuroblastoma.11 Although the exact basis for this variation seems unclear, we hypothesize that tumor invasion and
metastasis may be enhanced by either increased cell-matrix
interaction (associated with increased CD44) or, alternatively, decreased cell-cell adhesion (associated with
decreased CD44). In bladder carcinomas, the strongest reaction to CD44s was seen in the basal epithelial region next to
the basement membrane, suggesting an important role in the
attachment between basal cell and basal lamina.50 It also is
❚Image 2❚ Infiltrating glands in ovarian carcinoma showing
complete loss of CD44s (diaminobenzidine and hematoxylin,
×400).
© American Society of Clinical Pathologists
Anatomic Pathology / ORIGINAL ARTICLE
❚Image 3❚ Metastatic ovarian carcinoma showing complete
loss of CD44s vs intense diffuse positivity in the surrounding
lymphocytes (diaminobenzidine and hematoxylin, ×200).
❚Image 4❚ Ovarian epithelial tumor cells in malignant ascites
showing complete loss of CD44 compared with intense
diffuse positivity in the adjacent mesothelial cells
(diaminobenzidine and hematoxylin, ×400).
possible that the increased CD44 protein content reported in
some malignant neoplasms may in fact represent the isoform
variant rather than the standard form. Expression of CD44
splice variants has been linked to tumor dedifferentiation and
progression in carcinomas of stomach, lung, breast, colon,
and cervix.19,31,34-39
Studies on CD44 in ovarian tumors have been limited
and yield conflicting data. Kayastha et al,48 in their study of
56 primary epithelial ovarian tumors, found CD44s downregulation in 61% but with no correlation with histologic
type, tumor grade, or stage. However, a significant correlation between CD44s down-regulation and survival revealed
by both univariate and multivariate analysis was reported.48
In contrast, in another study of 115 ovarian carcinomas,46 the
authors reported correlation between loss of CD44s and
carcinomas in comparison with tumors of low malignant
potential; and in the carcinomas, with histologic type and
advanced stage. There was no correlation between CD44s
loss and poor survival in the study.46 The results of the
present study concur with these previously published data in
A
B
❚Image 5❚ Ovarian epithelial tumor of low malignant potential showing intense diffuse positivity at the primary site and complete
loss of CD44s in the peritoneal implant (diaminobenzidine and hematoxylin, ×200 [A] and ×400 [B]).
© American Society of Clinical Pathologists
Am J Clin Pathol 2001;116:122-128
125
Ross et al / CD44S IN OVARIAN CANCER
1.00
Survival Probability
CD44s 1
0.75
0.50
CD44s 0
0.25
0.00
0
20
40
60
80
Analysis Time (Months)
❚Figure 1❚ Kaplan-Meier survival estimates by CD44s. CD44s
1 represents CD44+ tumors, while CD44s 0 represents
CD44 down-regulation. The difference between the 2 groups
was statistically significant (P = .04).
that CD44s down-regulation correlated with prognostic variables in ovarian carcinomas, including shortened survival,
albeit on univariate analysis.
Although we did not evaluate the expression of CD44
variant isoforms that are produced due to alternatively spliced
exons (v1-10), others have reported a site-dependent prognostic significance for these proteins. CD44v3 expression was
reported to be an independent predictive factor for poor
survival in ovarian carcinomas.46 In contrast, Schroder et al47
evaluated the expression of CD44v5-10 in ovarian carcinomas and reported no correlation with survival. Although
the prognostic role of CD44 variant isoforms in ovarian carcinoma is unclear from these limited data, the isoform CD44v6
has been widely reported to confer aggressiveness and
metastatic potential in numerous other human malignant
neoplasms, including carcinomas of lung,51 liver,52 stomach,34
breast,53 and non-Hodgkin lymphoma.54 In the colon, while
normal mucosa was negative for CD44v6, this protein was
demonstrated to progressively increase with increasing grades
of dysplasia and transformation to carcinoma.55
Studies on other müllerian tumors, notably endometrial
carcinomas, have been scarce and report variable findings.
Fujita et al,25 using both immunohistochemical and molecular analysis, demonstrated progressive loss of CD44 variants in endometrial hyperplasia and carcinoma in comparison with normal endometrium. In addition, these authors
found a propensity for vascular space involvement by cancer
cells in the CD44– group compared with the CD44+ group,
suggesting an important role for CD44 and variant forms in
the evolution and spread of endometrial cancers. In contrast,
Saegusa et al56 reported increased expression of CD44s in
endometrial carcinomas compared with proliferative phase
endometrium and hyperplasia and found no application for
CD44s and variants v3 and v6 as prognostic markers.
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Am J Clin Pathol 2001;116:122-128
The polysaccharide hyaluronic acid is ubiquitously
present in the extracellular matrix and modifies cell–extracellular matrix interactions, thus regulating cell migration. It
has been shown previously that interactions between
hyaluronic acid and CD44 are directly implicated in the
development and progression of tumors.57 Ovarian carcinomas frequently exfoliate into body cavities and induce
accumulation of ascites. In vitro studies have shown that a
significant subpopulation of human ovarian tumor cells
attach to peritoneum via CD44.40,58 Yeo et al42 evaluated this
phenomenon using freshly harvested mouse ovarian tumor
cells from peritoneal cavities and demonstrated that the
majority of the tumor cells that attached to the mesentery
during the early stages of invasion expressed CD44. Interestingly, these authors reported that in the later stages, approximately 90% of the tumor cells showed loss of CD44 and
exfoliated into the ascitic fluid. While our study is not
designed to evaluate the role of CD44s in mediating tumor
cell–peritoneum attachment, our finding of loss of this
protein in tumor cells of ascitic fluid and metastatic lymph
nodes concurs with the data reported for animal models.
The loss of CD44s in ovarian carcinomas compared
with tumors of low malignant potential and tumor cells at
disseminated sites supports the role of this protein in the
evolution and spread of ovarian cancer.
From the Departments of 1Pathology and Laboratory Medicine
and 2Obstetrics and Gynecology, Albany Medical College, Albany,
NY; and the 3James Homer Wright Pathology Laboratories,
Massachusetts General Hospital and Harvard Medical School,
Boston.
Address reprint requests to Dr Ross: Dept of Pathology and
Laboratory Medicine, Albany Medical College A-81, 47 New
Scotland Ave, Albany, NY 12208.
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© American Society of Clinical Pathologists