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Hematopathology / PAX-5 EXPRESSION IN NONHEMATOPOIETIC TISSUES
Pax-5 Expression in Nonhematopoietic Tissues
Emina Torlakovic, MD, PhD,1 Ana Slipicevic, Msc,2 Chris Robinson, MD,1 John F. DeCoteau, MD,1
G. Cecilie Alfsen, MD, PhD,2 Mogens Vyberg, MD,3 Richa Chibbar,4 and Vivi Ann Flørenes, PhD2
Key words: Pax-5; Immunohistochemistry; Expression; Nonhematopoietic tissues
DOI: 10.1309/XEC7JMW9YRM74RN0
Abstract
We evaluated 123 formalin-fixed, paraffinembedded samples, including neuroendocrine tumors,
adult brain, mesonephric tissues, and from various
other sites. A pre-B lymphoma cell line, Daudi, and a
small cell carcinoma cell line, NCL-H128, were
evaluated by Western blot. All tissues were
immunostained by mouse monoclonal anti–Pax-5
antibody by using standard, synthetic polymer-based
detection methods. Our study describes for the first time
distribution of Pax-5 in adult brain tissue, including
periaqueductal gray matter of the midbrain, area
postrema of the medulla oblongata, and occasional
cells of the spinal trigeminal nucleus (caudal nucleus).
We confirm that Pax-5 is expressed regularly in poorly
differentiated neuroendocrine tumors but never in welldifferentiated classic carcinoid tumors. Pax-5
expression also was found readily in benign and
malignant mesonephric tissues and focally in müllerian
duct–derived tissues and tumors. Expression of Pax-5 in
the Daudi and NCL-H128 cell lines was confirmed by
Western blot. Together, these results are important for
correct interpretation of results in immunophenotyping
of undifferentiated tumors, for diagnosis of
mesonephric carcinoma, and, potentially, for correct
classification of neuroendocrine tumors in small biopsy
samples.
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PAX genes are a family of transcription factors with wider
fundamental roles during organogenesis. Comparison of the
expression patterns of fish, amphibian, and mammalian PAX2/5/8 genes revealed that the tissue specificity of PAX-2/5/8
gene family expression overall is evolutionarily conserved.1
During embryogenesis, the PAX5/B-cell–specific activator
protein (BSAP) gene is expressed transiently in the mesencephalon and spinal cord with a spatial and temporal expression pattern that is distinct from that of other PAX genes in the
developing central nervous system. Later, the expression of
the BSAP gene shifts to the fetal liver, where it correlates with
the onset of B lymphopoiesis.2
Pax-5 is a pan–B cell transcription factor essential for B-cell
commitment by inducing expression of multiple B-cell genes
while at the same time repressing alternative pathways of
hematopoietic differentiation by inhibiting the expression of
cytokine receptors such as M-CSF and Notch-1.3-5 In
hematopoietic cells, Pax-5 expression is limited to B cells and its
expression designates true B-cell differentiation.6,7 Therefore,
Pax-5 expression can be used for diagnostic purposes as a pan–B
cell marker.8 It also was demonstrated recently in a subset of
myeloid leukemia, ie, acute myeloid leukemia with characteristic translocation t(8:21).9 Although Tiacci et al9 also found that
Pax-5 is an excellent marker of B-cell differentiation of acute
lymphoblastic leukemia, Zhang et al10 found its expression in 3
of 6 T-cell acute lymphoblastic leukemias, but it is not clear
which criteria were used for the establishment of T-cell lineage.
The expression of the PAX5 gene also was described as a frequent event in poorly differentiated neuroendocrine carcinomas
and superficial transitional cell carcinoma of the bladder.11,12
The present study evaluated expression of PAX5 in nonhematolymphoid tissues with emphasis on neuroendocrine
© American Society for Clinical Pathology
Hematopathology / ORIGINAL ARTICLE
tumors and evaluated its expression in normal adult brain tissue samples.
Materials and Methods
Tissue Samples
We selected 123 formalin-fixed, paraffin-embedded tissue samples from the archives of the Department of
Pathology, National Hospital-Norwegian Radium Hospital,
Oslo, Norway, and from the Department of Pathology, Royal
University Hospital, Saskatoon, Canada, in an anonymous
manner in agreement with the regulations of the Regional
Ethics Committee.
We evaluated 51 neuroendocrine tumors by immunohistochemical analysis for Pax-5 expression. Samples were as follows: small cell carcinoma: lung, 17; cervix or corpus uteri, 7;
gastrointestinal tract, 2; and other sites, 3; carcinoid tumors:
appendix, 6; small bowel, 3; and other sites, 9; atypical carcinoid tumor, cervix, 2; and neuroendocrine tumors, pancreas, 2.
We also studied 15 mesonephric tissue samples, 21 cervical
carcinomas, and 12 various other tissue samples. All cervical
carcinomas were primary tumors. Cervical squamous lesions
were not included.
Representative tissue sections with no pathologic findings of adult brain tissues were obtained as a part of postmortem evaluation of 24 samples from 4 patients with no neurologic disease. Two were male (64 and 24 years old), and 2
were female (67 and 16 years old).
Immunohistochemical Analysis
The paraffin blocks were cut at 4 to 6 µm, dried overnight
at 60°C, and deparaffinized in xylene. Subsequently, sections
were rehydrated through graded alcohols into water. Heatinduced epitope retrieval was achieved by boiling sections in
EDTA buffer, pH 8.9, in an Electrolux microwave oven
(Stockholm, Sweden) at 1,000 W for 20 minutes (4 times for
5 minutes). Thereafter, sections were allowed to cool at room
temperature for 20 minutes, rinsed thoroughly with water, and
placed in Tris-buffered saline (TBS) for 5 minutes.
Endogenous peroxidase was blocked with Peroxidase Block
solution (provided in the EnVision+ kit; DakoCytomation,
Glostrup, Denmark) for 5 minutes, and slides were rinsed and
washed with TBS. The sections were incubated with primary
monoclonal mouse anti-BSAP/anti–Pax-5 (clone 24, dilution
1:40; Transduction Laboratories, Lexington, KY) for 30 minutes at room temperature. The immunostaining was performed
using the EnVision+ method according to the manufacturer’s
instructions. Appropriate positive and negative control samples were used.
Scoring of the immunostaining intensity in the nuclei was
done as follows: 0, no staining; 1+, weak staining; 2+, moderate
staining; and 3+, strong staining. For evaluating the differences in immunostaining in neuroendocrine tumors, the staining was quantitated by recording the exact percentage of positive nuclei in 500 tumor cells.
Cell Culture
The Daudi13 and NCL-H12814 cell lines were obtained
from the American Type Tissue Collection (Rockville, MD).
The cells were grown in RPMI 1640 medium (Gibco/BRL,
Gaithersburg, MD) supplemented with 10% fetal bovine
serum supplemented with L-glutamine and penicillin/streptomycin in 25-cm2 cell culture flasks (Nunc, Roskilde,
Denmark) and incubated in a humidified carbon dioxide incubator at 37°C. The cells were harvested when they reached
90% confluence.
Immunoblotting
Cells were lysed in ice-cold NP-40 lysis buffer (1% NP40; 10% glycerol; 20 mmol/L of Tris hydrochloride, pH 7;
137 mmol/L of sodium chloride; 100 mmol/L of sodium
vanadate; 1 mmol/L of phenylmethyl sulfonyl fluoride; 0.02
mg/mL each of aprotinin, leupeptin, and pepstatin; and 10
µL/mL of phosphatase inhibitor cocktail I). All protease
inhibitors were from Sigma-Aldrich, St Louis, MO. Lysates
were sonicated and clarified by centrifugation. Protein quantitation was done by Bradford analysis, and 25 µg of protein
per lane was resolved by sodium dodecyl sulfate–polyacrylamide gel electrophoresis. Proteins were transferred to PVDF
immobilon membranes (Millipore, Bedford, MA). The membranes were blocked in 5% nonfat dried milk, freshly made in
20 mmol/L of Tris hydrochloride, pH 7.6; 0.136 mol/L of
sodium chloride; plus 0.05% of polysorbate (Tween) (TBST), for 1 hour at room temperature and incubated with Pax-5
monoclonal antibody (Transduction Laboratories), diluted
1:250, overnight at 4°C. Thereafter, the blots were washed 3
times for 10 minutes in TBS-T and then incubated for 45
minutes at room temperature with horseradish
peroxidase–conjugated secondary antibodies (1:5,000) diluted in 5% nonfat dried milk in TBS-T. Immunoreactivity was
detected using the ECL Plus Western blotting system
(Amersham Bioscience, Buckinghamshire, England). To
ensure even loading, the filters were stained with naphthol
blue-black (Sigma-Aldrich) and hybridized with α-tubulin
(Calbiochem-Novabiochem, San Diego, CA).
Statistical Analysis
Statistical analyses were performed using the SPSS 9.0
software program, SPSS, Chicago, IL. The associations
between variables were analyzed by using the χ2 test and
Fisher exact test as appropriate. Spearman correlation was
used to determine the correlation of the percentage of positive
cells and the neuroendocrine cell tumor category.
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A
B
C
D
E
F
G
H
❚Image 1❚ Pax-5 expression is very strong in the Daudi (pre-B) cell line (A) and pre-B acute lymphoblastic leukemia (B), whereas
expression is weaker and more variable in the small cell carcinoma cell line, NCL-H128 (C), which generally is comparable to Pax5 expression in small cell carcinoma (D). Non–small cell neuroendocrine carcinomas, including typical carcinoid (E) and other
neuroendocrine carcinomas (F) show no expression of Pax-5. Weak expression was found in these 2 atypical carcinoids (G and H).
Results
Results of immunostaining with anti-Pax-5 antibody are
illustrated in ❚Image 1❚ and summarized in ❚Table 1❚ and
❚Table 2❚. The Daudi cell line showed strong nuclear expression of Pax-5 (Image 1A), comparable to Pax-5 expression in
the pre-B acute lymphoblastic leukemia in the sections of the
bone marrow (Image 1B). The small cell carcinoma cell line,
NCL-H128, demonstrated weaker and more variable expression of Pax-5 (Image 1C), which also was comparable to Pax5 expression in the small cell carcinoma metastatic to the bone
marrow (Image 1D).
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Of the undifferentiated neuroendocrine tumors, 93%
showed expression of Pax-5 in more than 10% of the cells.
Merkel cell tumors also were positive. None of the typical carcinoid tumors expressed Pax-5 (Image 1E and Table 1). Two
atypical carcinoids of the cervix and 2 neuroendocrine tumors
of the pancreas showed variable but generally weak and/or focal
expression of Pax-5. In 1 case, Pax-5 was found in fewer than
10% of the cells and could be considered as negative (Image
1F), whereas 2 of the atypical carcinoid tumors showed weak
positivity (Images 1G and 1H). The difference between small
cell carcinoma of various sites and other neuroendocrine tumors
was significant (P = .002; r = 0.416, Spearman correlation).
© American Society for Clinical Pathology
Hematopathology / ORIGINAL ARTICLE
I
J
K
L
Mesonephric tissues, including mesonephric rest, hyperplasia (I), and mesonephric carcinoma (J), are all positive for Pax-5. Adult
brain tissue continues to express Pax-5 in the neurons of the area postrema of the medulla oblongata (K) and periaqueductal
gray matter in the midbrain (L).
Mesonephric rest and hyperplasia (Image 1I and Table
2) showed strong nuclear staining in all cases. Squamous
epithelium was negative, whereas endocervical glands
showed rare cells with weak focal expression of Pax-5. This
expression was distinctly weaker than the expression of Pax5 in mesonephric tissues. Rete testis and ovarii were mainly
negative, whereas epididymis showed uniformly strong
expression. Mesonephric carcinomas showed distinct nuclear
staining in the majority of cases (Image 1J). Of the cervical
carcinomas, clear cell carcinoma, undifferentiated carcinoma,
and endometrial and endocervical carcinomas were negative
with only focal expression in a small number of cells in 1 case
of endocervical carcinoma. However, serous adenocarcinoma
and adenosquamous carcinoma had focal staining. Sections of
the normal adult brain tissues showed focal expression of Pax5 in the following areas: neurons of the area postrema of the
medulla oblongata (Image 1K), periaqueductal gray matter in
the midbrain (Image 1L), and occasional scattered cells of the
caudal nucleus nervi trigemini. All other mature brain tissues
were completely negative for Pax-5.
Nuclear Pax-5 expression also was found in the smooth
muscle of the uterus and in rare nuclei of the small glandular
structures in the prostate consistent with nephrogenic adenoma, whereas no expression was found in lung tissues, kidneys,
skin, or tissues of the gastrointestinal tract or thyroid. In many
organs, small lymphocytes consistent with small B cells
showed strong expression of Pax-5.
Western blot analysis using the same monoclonal antibody used for immunohistochemical analysis confirmed the
expression of Pax-5 in the pre-B lymphoblastic cell line,
Daudi, and the small cell carcinoma cell line, NCL-H128
❚Image 2❚.
❚Table 1❚
Pax-5 Expression in Neuroendocrine Tumors
❚Table 2❚
Pax-5 Expression in Mesonephric and Cervical Tissues
Diagnosis (%)
Pax-5
Expression
0
1
2
3
*
†
Carcinoid
(n = 18)
Poorly Differentiated
Neuroendocrine
Tumor* (n = 29)
18 (100)
0 (0)
0 (0)
0 (0)
2 (6)
11 (38)
9 (31)
7 (25)
Tissue Type
Other
Neuroendocrine
Tumors† (n = 4)
1 (25)
2 (50)
1 (25)
0 (0)
Pax-5 Expression
Mesonephric hyperplasia (n = 7)
Mesonephric carcinoma (n = 8)
Cervical carcinoma, other types
Clear cell (n = 4)
Serous (n = 3)
Undifferentiated (n = 1)
Endocervical or endometrial (n = 12)
Adenosquamous (n = 1)
7
6
0
2
0
1
1
Including 26 small cell carcinomas and 2 Merkel cell tumors. The 2 Merkel cell
tumors showed 80% and 100% positive cells.
Including 2 atypical carcinoid tumors of the cervix and 2 neuroendocrine tumors of
the pancreas.
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NCL-H128
Daudi
50 kd
α-Tubulin
❚Image 2❚ Western blot analysis of Pax-5 using monoclonal
anti–Pax-5 antibody. The membrane was additionally probed
for tubulin as a control.
Discussion
The expression of Pax-5 in neuroendocrine tumors was
reported by Dong and coauthors.11 Although these authors,
in addition to immunohistochemical detection, also demonstrated expression of Pax-5 messenger RNA, we used
Western blot to show that the Pax-5 protein product as
detected by monoclonal mouse antibody is of identical
molecular weight in lymphoblastic and small cell carcinoma
cell lines. Although expression of Pax-5 was described in
developing brain tissue, to the best of our knowledge, adult
brain tissues were believed to show no Pax-5 expression.15-17
However, our results indicate that Pax-5 is expressed focally
even in normal adult brain tissue.
In a previous study11 and in the present study, most
remarkably, the expression of Pax-5 in neuroendocrine
tumors seems to parallel the level of tumor aggressiveness.
This finding is in accordance with findings of Baumann
Kubetzko et al,18 who reported that PAX5 is expressed in
aggressive N-type neuroblastoma cell lines, whereas no
expression was detected in S-type cells. These authors also
reported that overexpression of PAX5 in the S-type cell line
CA-2E restored several malignant properties, in particular
anchorage-independent growth. In addition, down-regulation of PAX5 in several N-type cell lines significantly
reduced their proliferation rate. It is speculated that reexpressed PAX genes promote tumor development and progression by increasing proliferation and motility while
inhibiting apoptosis.19
PAX transcription factors have been shown to have an
important role in tumorigenesis (reviewed by Schafer19). It
was suggested that Pax-5 may aid in promoting the progression of astrocytomal malignancy.20 Stuart et al21 suggested a
direct role for Pax-5 in the control of p53 transcription. Pax-5
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and its paralogues, Pax-2 and Pax-8, were capable of inhibiting the p53 promoter and transactivation of a p53-responsive
reporter in cell culture. However, this was challenged by
Nutt and coauthors,22 who showed that p53 expression is
totally unaffected by the loss of Pax-5 function. Although its
putative role in repression of p53 promoter is not clear, it is
interesting that a number of PAX genes are located at recurring, tumor-specific chromosomal translocations, suggesting that PAX genes may have oncogenic capacity when
expressed inappropriately. Second, several PAX genes are
reexpressed in malignant neoplasms, usually in tumors
derived from tissue in which the respective PAX gene is
expressed during development. Examples include deregulated expression of PAX5 in glioblastoma multiforme,
medulloblastoma, and lymphomas20,23,24 and PAX3 in
melanoma.25
It is interesting that Pax-5 expression also is found in
mesonephric benign and malignant tissues. As a marker of
mesonephric differentiation, it seems to be possibly better
than CD10 (results not shown) because in our experience,
CD10 is patchy and sometimes only luminal and disturbed
by stromal staining, whereas staining with Pax-5 appears
strong and uniform and there is no background stromal
staining. Positivity for Pax-5 in 2 of 3 serous tumors may
cause diagnostic problems. In our limited experience, WT1, known to be a useful marker of serous carcinoma,26 is
not expressed in mesonephric hyperplasia or mesonephric
carcinoma (data not shown). Further studies of a wide array
of carcinomas are necessary to delineate the diagnostic
usefulness and clinical significance of Pax-5 expression in
carcinomas.
In contrast with previously reported Pax-5 expression in
the adult testis,27 we show that no such expression can be
found by immunohistochemical analysis. However, the presence of Pax-5 in some tissues of the male and female genital
tract may suggest that Pax-5, in addition to Pax-2, may have
a role in multiple steps of urogenital development, which
may be similar to the Pax-2 and Pax-5 cooperation in midbrain and cerebellum development.28,29
Each cell fate is specified by a unique combinatorial
code of transcription factors that function in a hierarchical
and combinatorial manner.3 The interpretation of the significance of transcription factor expression, including Pax-5,
for diagnostic purposes should always take into account that
transcription factors exhibit their effects in regulation of
gene expression and cellular differentiation in lineage- and
stage-appropriate environments. Therefore, it is not surprising that Pax-5 has an entirely different role in the hematolymphoid tissue than in neural and, possibly, urogenital
development. Lagergren et al30 recently demonstrated that
neuroblastoma cells express 3 transcription factors crucial
for B-cell development, including EBF, Pax-5, and E2A, but,
© American Society for Clinical Pathology
Hematopathology / ORIGINAL ARTICLE
nevertheless, fail to express detectable levels of their known
target genes MB-1 and CD19, showing that transcription factors are able to selectively activate target genes in different
tissues. In hematolymphoid tissues, however, Pax-5 seems to
exert its effects on usual B-cell target genes, and it also
seems to be the case when Pax-5 is found inappropriately
expressed in acute myeloid leukemia.9 The expression of
Pax-5 in this setting probably explains the expression of the
B-cell proteins CD79a and/or CD19 (major transcriptional
targets of Pax-5 in B cells), and, indeed, it may be considered as evidence of a partial B-cell differentiation in some
cases of this subtype of myeloid leukemia.
From a practical standpoint, our work stresses the
importance of knowledge of the spectrum of reactivity of
Pax-5 when a diagnostic pathologist is faced with a Pax-5+
tumor. Obviously, one cannot interpret a positive Pax-5
immunostain as an accurate reflection of a B-cell tumor
unless the lymphohematopoietic nature of the tumor has
been established confidently by other means. Failure to do so
could result in a misdiagnosis of a high-grade neuroendocrine carcinoma as a lymphohematopoietic lesion, a mistake that could have significant impact on patient care.
From the 1Department of Laboratory Medicine and Pathology,
Royal University Hospital, College of Medicine, University of
Saskatchewan, Saskatoon, Canada; 2Department of Pathology, the
National Hospital-Norwegian Radium Hospital, Oslo, Norway;
3Institute of Pathology, Aalborg University Hospital, Denmark;
and 4University of Saskatchewan, Saskatoon.
Address reprint requests to Dr Torlakovic: Dept of Pathology,
Royal University Hospital, College of Medicine, University of
Saskatchewan, Saskatoon, SK, Canada.
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© American Society for Clinical Pathology