Oncology–Original Article

Veterinary Pathology
2018, Vol. 55(3) 402-408
Immunohistochemical Expression of CD31 ª The Author(s) 2018
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(PECAM-1) in Nonendothelial Tumors of Dogs DOI: 10.1177/0300985817751217
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José A. Ramos-Vara1, Margaret A. Miller1, and Dee M. Dusold1

Abstract
CD31 immunoreactivity has been reported in human nonendothelial tumors of both epithelial and mesenchymal origin. This study
examined CD31 immunoreactivity of 347 formalin-fixed, paraffin-embedded normal, nonneoplastic, and neoplastic canine tissues.
CD31 expression was considered positive if at least 10% of the cell population had membranous reactivity. Labeling with the
CD31 antibody (clone JC/70A) was observed in 16 samples of normal organs (liver, kidney, lymph node), 6 of 6 specimens of
hepatic nodular hyperplasia, 3 of 3 hepatic regenerative nodules, 1 of 4 anal sac carcinomas, 6 of 6 hemangiosarcomas, 18 of 20
hepatocellular carcinomas, 1 of 6 mammary carcinomas, 3 of 5 plasmacytomas, 18 of 53 renal cell carcinomas, and 1 of 5
cutaneous histiocytomas. CD31 expression did not correlate with case outcome in hepatocellular or renal cell carcinomas.
Although distinguishing hemangiosarcoma from other neoplasms is typically straightforward, pathologists should be aware of
potential cross-reactivity when relying on CD31 immunohistochemistry for diagnosis, particularly in small biopsy samples or
when faced with an epithelioid or poorly differentiated vascular neoplasm.

Keywords
canine diseases, immunohistochemistry, carcinomas, sarcomas, CD31

CD31 (platelet-endothelial cell adhesion molecule 1 [PECAM-
1]) is a transmembrane glycoprotein with various functions in
multiple physiologic and pathologic pathways, including
leukocyte detachment, platelet activation, T-cell activation,
angiogenesis, atherosclerosis, and maintenance of vascular
integrity.5,24,25,33,45 CD31 also has immunoregulatory roles
in endothelial and hematopoietic cells.42
Originally, CD31 was considered a very specific marker for
endothelial cells and their tumors; however, CD31 is also
expressed in platelets, monocytes, neutrophils, megakaryo-
cytes, plasma cells, macrophages, and some lympho-
cytes.18,26,31,36 Using a different CD31 antibody than the one
evaluated in the current study, Fernández et al.13 demonstrated
expression of this molecule in a variety of human epithelial and
mesenchymal cells using frozen tissues.
In a previous study,32 we observed distinct labeling of tub-
ular epithelial cells in normal kidney with an antibody to CD31.
In the current study, the immunohistochemical expression of
CD31 was evaluated in normal and lesional canine tissues.
Materials and Methods
A total of 347 specimens were examined, including 131 normal
tissues (sections of adrenal gland, cerebrum, heart, small and
large intestine, kidney, liver, lung, lymph node, mammary
gland, ovary, pancreas, parathyroid gland, pituitary gland,
prostate, salivary gland, skin, spleen, stomach, testis, thyroid,
tonsil, urinary bladder, and uterus), 10 nonneoplastic lesions
(hepatic nodular hyperplasia, regenerative hepatic nodules, and
parathyroid hyperplasia), and 206 neoplastic tissues. Neoplas-
tic tissues included benign epithelial tumors (9), endocrine/
neuroendocrine tumors (4), carcinomas (141), sarcomas (12),
melanomas (5), lymphomas (8), plasmacytomas (5), cutaneous
histiocytomas (5), testicular and ovarian tumors (13), thymoma
(1), and mesothelioma (3). All specimens had been fixed in
neutral buffered formalin and paraffin embedded.
Immunohistochemistry
Immunohistochemistry for CD31 was applied to each of the
above-mentioned specimens. The monoclonal anti-CD31 anti-
body (clone JC/70A, Dako-Agilent, Carpinteria, CA) recog-
nizes a fixation-resistant epitope in endothelial cells.31 The
slides were immersed in Reveal (Biocare Medical, Concord,
CA) antigen retrieval solution in a decloaking chamber (Bio-
care) for 30 seconds at 125 C and 18 to 24 PSI. The primary
antibody was diluted at 1/100 using Da Vinci diluent (Biocare
Medical) and incubated for 60 minutes. An immunoperoxidase,
1
Department of Comparative Pathobiology, Purdue University, West Lafay-
ette, IN, USA
Corresponding Author:
José A. Ramos-Vara, Department of Comparative Pathobiology, 406 S Uni-
versity St, West Lafayette, IN 47907, USA.
Email: ramosja@purdue.edu
Ramos-Vara et al
polymer-based detection system was used (PromARK Mouse-
on-Canine HRP-Polymer, Biocare Medical). The chromogen
was diaminobenzidine (DAB). All incubations were at room
temperature. Randomly selected sections of test samples were
treated with Biocare Medical polymer negative control serum
in place of the primary antibody. The target cell population was
considered positive if at least 10% of the cells had a distinct
membranous labeling for CD31. The number of positive cells
was scored semiquantitatively in the hepatic and renal lesions
and plasmacytomas as follows: score 1 (10%-20% positive
cells), 2 (21%-40%), 3 (41%-60%), and 4 (>60%). The inten-
sity of the reaction was subjectively graded as weak, moderate,
or strong based on the target area showing the highest intensity
in each sample.
Results
Immunohistochemistry: Normal Tissues
CD31 labeling of vascular endothelium served as an internal
positive control. In addition, there was moderate to strong
membranous labeling of deferent ductal and epididymal epithe-
lium (Fig. 1) as well as of the lining of lymph node sinuses.
Three of 5 normal hepatic specimens had weak to strong mem-
branous labeling of hepatocytes (in 1 case, this was patchy) but
no distinct labeling of sinusoidal lining cells (Fig. 2). Sixty-one
percent (25/41) of normal renal tissue samples had patchy
membranous to cytoplasmic labeling of cortical tubular epithe-
lial cells (Fig. 3).
Immunohistochemistry: Nonneoplastic Lesions
Hepatic Nodular Hyperplasia. The number of CD31-positive
cells was variable (1 case with score 1; 2 with score 3; 3 with
score 4). All 6 hyperplastic nodules had weak to strong (in 1
case) membranous labeling that outlined hepatic plates (Figs. 4
and 5). Labeling was diffuse or concentrated in centrilobular
and periportal areas. Labeling intensity was, in some cases,
similar to that in adjacent normal hepatocytes, but in other
cases, normal hepatocytes were negative. CD31 labeling inten-
sity in hepatocytes of hyperplastic nodules was moderate to
strong. In hepatic cirrhosis, the hepatocytes in regenerative
nodules had strong membranous labeling in all 3 cases; this
was diffuse in 2 cases and patchy in the third case (2 with a
score of 4 and 1 with a score of 3; Fig. 6). Sinusoidal lining
cells within regenerative nodules were negative, but newly
formed vessels in areas of fibrosis surrounding the nodules
were positive.
Immunohistochemistry: Neoplastic Lesions
Forty-two carcinomas and 6 sarcomas were positive for CD31
(Table 1). One of 4 cases of carcinoma of the apocrine glands
of the anal sac had patchy strong membranous labeling (Fig. 7).
Overall, 18 of 20 hepatocellular carcinomas (HCC) expressed
CD31. Membranous labeling of neoplastic hepatocytes was
weak to strong and patchy to diffuse in 12 of the 20 HCC (2
403
with score 1, 1 with score 3, 9 with score 4; Fig. 8). Variable
labeling of intratumoral sinusoidal lining cells was observed in
11 of 20 HCC (Fig. 9). Labeling of adjacent nonneoplastic
hepatic parenchyma was weaker than in neoplastic tissue in
the few cases available for comparison. Fourteen of 43 (33%)
primary renal cell carcinomas (RCC) and 4 of 10 (40%) meta-
static RCC also expressed CD31. The number of positive cells
and intensity was slightly higher in primary than in metastatic
RCC (7 with score 1, 6 with score 3, 1 with score 2, 4 with score
4). All but 3 of the positive RCC also had CD31 immunoreac-
tivity in adjacent nonneoplastic kidney. Differences in CD31
expression among histologic types of HCC and RCC were not
apparent (Figs. 10 and 11). One of 6 mammary carcinomas had
patchy, membranous, and moderate to strong labeling of all
ductal epithelial cells or of scattered cells in a duct. Plasmacy-
tomas (3/5) had weak to moderate and patchy, membranous
labeling. One of 5 cutaneous histiocytomas had weak and pat-
chy membranous labeling. Other epithelial neoplasms exam-
ined did not express CD31. The only sarcoma positive for
CD31 was hemangiosarcoma (6/6).
Discussion
In this study, we evaluated the immunohistochemical expres-
sion of CD31 in nonendothelial canine tumors. CD31 detection
has been documented in human endothelial tumors of blood
vessel origin12,27,29 and less commonly in tumors of lymphatic
origin.22,27,31,44 Although CD31 was initially considered highly
specific for human vascular tumors,11 various proportions of
nonendothelial tumors also express this protein. Miettinen
et al.27 reported weak labeling of one leiomyosarcoma and
several colonic carcinomas and mesotheliomas, whereas oth-
ers did not find CD31 immunoreactivity in nonendothelial
mesenchymal neoplasms.10 CD31 has been detected in den-
dritic cell neoplasms, different types of lymphomas, and
extranodal histiocytic sarcomas.20,28,37 Evaluation of CD31
reactivity in carcinomas has generated particular interest,
with labeling of some salivary gland, thyroid, cutaneous, and
gastrointestinal carcinomas.9 Although breast carcinomas did
not express CD31 in that study,9 others have reported CD31
immunoreactivity in breast cancer, particularly ductal
carcinoma.1,3,4,30,35,38
CD31 monoclonal antibody, clone JC/70A, is currently used
in a variety of animal species to evaluate the vascular bed in
normal and pathological conditions, including endothelial neo-
plasms of blood and lymphatic vessels.2,14,15,21,34,43 In the cur-
rent study, CD31-positive specimens included normal organs
(liver, kidney, lymph node), 6 of 6 hepatic nodular hyperplasia,
3 of 3 hepatic regenerative nodules, 1 of 4 anal sac apocrine
carcinomas, 6 of 6 hemangiosarcomas, 18 of 20 hepatocellular
carcinomas, 1 of 5 mammary carcinomas, 3 of 5 plasmacyto-
mas, 18 of 53 renal cell carcinomas, and 1 of 5 cutaneous
histiocytomas.
The significance of CD31 expression in normal and lesional
tissues in dogs is not clear. It has been suggested that CD31
immunoreactivity in human epithelial neoplasms or epithelial
404 Veterinary Pathology 55(3)

Figure 1. Normal epididymis, dog. Strong labeling for CD31 in the cytoplasmic membrane of tubular epithelial cells. Inset: Detail of labeling.
Immunoperoxidase-DAB. Figure 2. Normal liver, dog. Diffuse, membranous labeling of hepatocytes. Note strong labeling for CD31 in
endothelial cells in portal vessels (v). Inset: Detail of labeling. Immunoperoxidase-DAB. Figure 3. Normal kidney, dog. There is variable labeling
for CD31 in cortical tubular epithelial cells. Inset: Detail of the labeling in glomerular capillaries. Immunoperoxidase-DAB. Figures 4–5.
Nodular hyperplasia, liver, dog. Immunoperoxidase for CD31-DAB. Figure 4. The nodule (h) is highlighted from the more normal hepatic
parenchyma (n) by the CD31 labeling. Figure 5. Detail of the interface between the hyperplastic nodule (h) and the normal (n) liver.
Ramos-Vara et al 405

Figure 6. Cirrhosis, liver, dog. Regenerative nodules (r) are strongly positive for CD31. p ¼ portal area. Inset: CD31-positive hepatocytes have
a distinct membranous labeling pattern. Immunoperoxidase-DAB. Figure 7. Anal sac apocrine carcinoma, dog. There is variable CD31
immunoreactivity in the neoplastic cell population. Inset: Detail of labeling. Immunoperoxidase-DAB. Figures 8–9. Hepatocellular carcinoma,
dog. Immunoperoxidase-DAB. Figure 8. There is a clear demarcation between the carcinomatous nodule (c) and the adjacent normal hepatic
parenchyma (n). Inset: Membranous labeling of neoplastic hepatocytes. Figure 9. In this case, most neoplastic hepatocytes are CD31-negative,
and only scattered cells are faintly positive. However, nonneoplastic sinusoidal cells are strongly positive. Inset: Hepatocellular carcinoma, dog.
Negative reagent control. Figure 10. Renal cell carcinoma (solid type), dog. There is multifocal membranous labeling for CD31 in neoplastic
cells. Inset: Detail of labeling. Immunoperoxidase-DAB. Figure 11. Renal cell carcinoma (papillary type), dog. There is multifocal membranous
labeling for CD31 in neoplastic cells. Inset: Detail of labeling. Immunoperoxidase-DAB.
406 Veterinary Pathology 55(3)

Table 1. CD31 Immunoreactivity in Pathologic Specimens From carcinoma, CD31 expression in neoplastic cells correlates with
Dogs.a poor overall and metastasis-free survival in patients with no
Organ Diagnosis Results
nodal metastasis.4 In the current series, patchy CD31 reactivity
was detected in only 1 of 6 canine mammary carcinomas.
Adrenal Adenoma, adrenocortical 0/1 Based on the limited number of cases studied, the significance
Pheochromocytoma 0/2 of this finding is unknown.
Carcinoma, adrenocortical 0/3 In the current study, CD31 immunoreactivity was common
Gallbladder Carcinoid 0/1
in normal and lesional canine liver and kidney. Normal, hyper-
Intestine, large and Carcinoma 0/10
small plastic, and regenerative nodules and neoplastic hepatocytes
Kidneyb Carcinoma, renal cell 18/53 (34%) expressed CD31 in various percentages and intensities, typi-
Liver Insulinoma, metastatic 0/1 cally with higher intensity in neoplastic tissues than in adjacent
Carcinoma, cholangiocellular 0/3 parenchyma. CD31 was expressed in sinusoidal cells in HCC
Carcinoma, hepatocellular 18/20 (90%) but not in normal canine liver or nonneoplastic liver lesions. In
Cirrhosis, regenerative 3/3 (100%) humans, CD31 immunoreactivity is not observed in normal
nodules
hepatic parenchyma, and its expression in the sinusoidal
Nodular hyperplasia 6/6 (100%)
Lung Carcinoma 0/1 endothelium is controversial.6–8,16,17,23,40 However, the sinu-
Lymph node Lymphoma 0/8 soids of hepatic regenerative nodules—especially in dysplastic
Mammary gland Carcinoma 1/6 (17%) nodules and hepatocellular carcinoma—undergo a process
Mesothelium Mesothelioma 0/3 called capillarization, in which sinusoidal cells develop struc-
Oral Osteosarcoma 0/3 tural and molecular changes typical of endothelial cells such as
Melanoma 0/5 loss or reduction of cytoplasmic fenestrations, deposition of
Ovary Dysgerminoma 0/1
basement membrane, and expression of adhesion molecules
Granulosa cell tumor 0/1
Pancreas Carcinoma 0/5 including CD31.6,16,19,39 Although not detected in all stud-
Parathyroid Hyperplasia 0/1 ies,17,39,46 this CD31 expression by sinusoidal lining cells
Carcinoma 0/2 might be the result of neovascularization of cancerous parench-
Adenoma 0/6 yma (tumor angiogenesis) or abnormal differentiation of pre-
Salivary gland Carcinoma 0/2 existing sinusoids.16,39 One reason for such differences among
Skin Adenoma apocrine 0/1 studies is the type of CD31 antibody used, although clone
Trichoblastoma 0/1
JC/70A was used in most studies.4,6,8,13,43,44
Carcinoma, basal cell 0/3
Carcinoma, apocrine, anal sac 1/4 (25%) With the exception of sinusoidal capillarization in hepatic
Carcinoma, ceruminous 0/4 lesions, CD31 expression has not been reported in human hepa-
Carcinoma, hepatoid gland 0/4 tocellular or renal cell neoplasms. In the current study, CD31
Carcinoma, sebaceous 0/4 was expressed in a proportion of various normal, nonneoplas-
Carcinoma, squamous cell 0/4 tic, and neoplastic canine tissues. The neoplasms that most
Plasmacytoma 3/5 (60%) commonly expressed CD31 were hepatocellular carcinoma and
Histiocytoma 1/5 (20%)
renal cell carcinoma, and a correlation between immunoreac-
Spleen Sarcoma, histiocytic 0/3
Stomach Carcinoma 0/8 tivity and case outcome was not apparent. Although the histo-
Testis Interstitial (Leydig) cell tumor 0/2 logic distinction of HCC or RCC from a vascular neoplasm is
Seminoma 0/4 generally straightforward, pathologists should be aware of
Sertoli cell tumor 0/5 CD31 cross-reactivity, especially if the epithelioid variant of
Thymus Thymoma 0/1 hemangiosarcoma is a differential diagnosis or if the sample
Urinary bladder Carcinoma, urothelial 0/5 size is small.
Various organs Hemangiosarcoma 6/6 (100%)
Total positive cases 57/216
a
Acknowledgments
The data show the number of CD31-positive cases and the number tested.
b
Renal carcinomas included 10 metastatic lesions. We thank the histology technicians, pathologists, and pathology res-
idents at the Indiana Animal Disease Diagnostic Laboratory and Dr
Tyler Peat for his input in the early stages of this work.

tissues is the result of partial cross-reaction of the antibody with

related cell adhesion molecules41 or abnormal expression of
CD31.9 The second possibility would explain the increased
expression of this marker in pathologic liver tissue (eg, regen-
erative nodules in cirrhosis and hepatocellular carcinoma), but
we did not find a consistent expression in the cases examined.
CD31 contributes to cellular differentiation and migration in
physiologic and pathologic states. 1,35 In human breast
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship,
and/or publication of this article.
Ramos-Vara et al 407

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