1. Art and Diseño

American Journal ofPathology, Vol. 137, No. 5, November 1990
Copyright © American Association of Pathologists
Expression of Aminopeptidase N (D1 3)
in Mesenchymal Tumors
Gunhild Mechtersheimer and Peter Moller
From the Institute of Pathology, Heidelberg University,
Heidelberg, Federal Republic of Germany
For a long time, CD13 molecules have been considered to be restricted to myeloid cells and related
neoplasms. Meanwhile, however, expression of
CD13 has also been detected in some hepatocellular,
gallbladder, renal, and lung carcinomas, and even
in somefibrosarcomas and malignant melanomas.
In this study, expression of CD13 antigen was immunohistochemically examined in non-neoplastic
mesenchymal cells, along with 33 benign and 83
malignant mesenchymal tumors (MET) using
CD13 monocolonal antibodies (MAb) My7, U71,
WM- 15, and MoU48. In non-neoplastic mesenchymal cells, expression ofCD13 was restricted to perivascularfibrocytes/blasts, tissue histiocytes, osteoclasts, and to the perineurium ofperipheral nerve
trunks. Under neoplastic conditions, CD13 was detectable in some tumors of smooth muscle, fibrous,
fibrohistiocytic, synovial, osteogenic, and peripheral nerve sheath origin, and even in some tumors
of adipose tissue. Tumors of striated muscle origin,
ofautonomic ganglia, and of cartilage-forming tissues were CD13-negative throughout. Thus in most
but not all tumors studied thepattern ofexpression
of CD13 mirrors the situation found in their cells
of origin. These findings enrich the data on expression of leukocyte differentiation antigens in extrahematopoietic tissues. Expression of CD13, which
meanwhile is known to be identical to aminopeptidase N, an important peptide-cleaving enzyme, in
only some MET might reflect a special functional
state of these neoplasms. (Am J Pathol 1990, 13 7:
1215-1222)
The CD13 antigen, long known as a panmyeloid antigen,
is a 150-kd surface glycoprotein1-3 encoded by a gene
located on chromosome 15 at bands q25-26.4 Its DNA
sequence predicts a 967 amino acid integral membrane
protein with a single, 24 amino acid hydrophobic segment
near the intracellular amino terminus that is not cleaved
but could function both as a signal for membrane insertion
and a stable membrane-spanning segment.4 The large
extracellular carboxyterminal domain contains a pentapeptide consensus sequence characteristic of members
of the zinc-binding metalloprotease superfamily. Recently
the CD1 3 molecule has been proved to be identical to
aminopeptidase N, an important enzyme of the brushborder membranes of the small intestine, renal proximal
tubules, and placenta also found on synaptic membranes
of the central nervous system and on the surface of granulocytes and macrophages.5 Originally the CD13 molecule
was detected on a proliferative subset of committed human myeloid progenitors as well as on normal marrow
granulocytes and monocytes at all stages of differentiation.6 Under neoplastic conditions, CD13 reacts with leukemic blasts of most acute myeloblastic leukemias.267 In
contrast, CD1 3 antigen regularly is absent on the surface
of normal T and B lymphocytes or on lymphocytic malignancies,267 except for a small group of acute leukemias
showing coexpression of CD13 molecules and B-cell
markers and having an increased risk of treatment failure.8-10 Outside the hematopoietic system, the CD1 3 molecule has been found in renal proximal tubular cells, in
bile duct canaliculi, in fibroblasts, and in osteoclasts.11 In
malignancy, CD13 antigen has been observed in hepatocellular, gallbladder, and renal carcinoma cell lines.12'13
Of the CD13 antibody cluster,14 the original monoclonal
antibody (MAb) My7, an IgGl antibody,6 together with
MAbs U71, WM-15, and MoU48,14 was applied in this
study, the objective of which was to investigate the
expression of CD13 antigen in a comprehensive series
of mesenchymal tumors (MET).
Materials and Methods
Tissue
Representative frozen tissue samples of a comprehensive
series of normal tissues containing all kinds of mesenSupported by the Tumorzentrum Heidelberg/Mannheim.
Accepted for publication June 29, 1990.
Address reprint requests to Dr. med. G. Mechtersheimer, Institute of
Pathology, University of Heidelberg, Im Neuenheimer Feld 220, D-6900
Heidelberg, FRG.
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Mechterscheimer and MOAler
AJP November 1990, Vol 137, No. 5
Controls
chymal cells, of 33 benign and 83 malignant well-defined
mesenchymal tumors (MET) were collected at our institute
during a period of 3.5 years. Diagnosis of each case was
established on routine paraffin sections (H&E, PAS, Masson-Goldner and Gomori silver stains) according to standard histopathologic criteria, as described Enzinger and
Weiss,15 in conjunction with immunohistochemical analysis
using a broad panel of mono- and polyclonal antibodies
directed against well-established structural antigens of
mesenchymal cells (for review see Enzinger and Weiss15
and Wick and Swanson16). The tissue samples were quick
frozen in liquid nitrogen and stored at -70° C. Frozen
sections of about 1 cm2 and a thickness of 4 to 6 gm
were air dried, acetone fixed at room temperature for 10
minutes, immediately stained, or stored at -20° C for a
short period.
Negative controls were in each case performed by omitting
the primary antibody; no staining was observed, except
for scattered granulocytes. This staining was due to endogenous peroxidase, which was not blocked for the
benefit of optimal antigenicity. The positive results were
confirmed by a control using the isotype-matched MAb
HD39, which gave negative results in each case, precluding nonspecific antibody binding. In addition all My7positive and a representative number of My7-negative tumors were examined for expression of CD1 3 by application of CD13 MAbs U71, WM-15, and MoU48. With the
exception of the dotlike intracytoplasmic My7 positivity in
some tumors of smooth muscle origin, these MAbs confirmed the results obtained by MAb My7.
Reagents
Evaluation
CD1 3 MAb My7 (isotype IgG1) was obtained from Coulter
Immunology, Hialeah, FL. MAbs U71, WM-1 5, and MoU48,
which also recognize the CD1 3 molecule, were gifts from
D. Bourel (Rennes, France), E.J. Favaloro (Westmead,
Australia), and R. Whinchester (New York, NY), respectively. CD22 MAb HD39 (isotype IgGl), which was used
as an isotype-matched control MAb, was provided by B.
Dorken and G. Moldenhauer (Heidelberg, FRG). A biotinylated sheep antibody to mouse Ig (reactive with all mouse
isotypes) and a streptavidin-biotinylated peroxidase complex, serving as detection system for the monoclonal primary antibodies, were provided by Amersham, High Wycombe, U.K. 3-Amino-9-ethylcarbazole (AEC) and N'Ndimethylformamide (DMF) were obtained from Sigma
Chemical Co., St. Louis, MO.
The staining of the tumor cells was evaluated semiquantitatively as follows: +, positive reaction of the entire neoplastic population; +/-, positive and negative tumor cells
in various amounts (for details see Results); and -, negative staining of the entire tumor cell population. Dotlike
intracytoplasmic staining with MAb My7, which was detectable in a few tumors of smooth muscle origin, is indicated separately in Results and in Table 1.
Staining Procedure
After rehydration with phosphate-buffered saline solution
(PBS; pH 7.4), the frozen sections were incubated for 1
hour with primary MAb at appropriate dilutions (My7 [1:
20], U71 [1:100], WM-15 [1:100], MoU48 [1:100]). The
sections were incubated with biotinylated anti-mouse Ig
(1:50) and streptavidin-biotinylated peroxidase complex
(1:100) for 30 minutes each. All incubation steps were
carried out in a humid chamber at room temperature and
were followed by double rinsing with PBS. Using AEC as
the chromogen (0.4 mg/ml in 0.1 mol/l [molar] acetate
buffer, pH 5.0, with 5% DMF and 0.01% H202 for 10 minutes), the peroxidase reaction caused an intense red precipitate. The sections were rinsed in tap water, counterstained with Harris' hematoxylin, and mounted with glycerol gelatin.
Results
Non-neoplastic Mesenchymal Cells
CD1 3 molecule was strongly expressed in perivascular
fibrocytes/blasts, tissue histiocytes, osteoclasts, and in
the perineurium of peripheral nerve trunks. Smooth muscle
cells of the uterus, of blood vessel walls, and of intestinal
organs, striated muscle cells of skeletal and cardiac muscle, peripheral nerve fibers, ganglion cells, neuroblasts of
adrenal medulla, adipocytes, and chondrocytes were
consistently CD13 negative.
Tumors of Muscle Tissue
Consistent CD13 positivity was observed in one leiomyoma (LM), one leiomyosarcoma (LMS), and one leiomyoblastoma. In two LMs, CD13 was expressed on a major
and on a minor tumor cell population, respectively. In three
LMSs, CD13 was observed in most tumor cells, and in
two LMSs CD13-positive and -negative tumor cells were
detectable in about equal amounts. As an exceptional
finding, one LM and three LMSs showed a dotlike intra-
CD13 in Mesenchymal Tumors
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AJP November 1990, Vol. 137, No. 5
Table 1. Expression ofAminopeptidase N (CD13) in
Mesenchymal Tumors
Number
Phenotype
+
(1)*
1
2
4
11
Leiomyoma
1
5(3)* 10
16
Leiomyosarcoma
8
1
1
Leiomyoblastoma
_
8
8
Rhabdomyosarcoma
1
4
5 SF
Fibroadenoma
_5
ME
_
2
2
Fibroma
4
4
Aggressive fibromatosis
3
1
4
Fibrosarcoma
1
1
Benign giant cell tumor of
tendon sheath
3
1
5
Synovial sarcoma
1
1
Juvenile xanthogranuloma
1
1
Cutaneous fibrous
histiocytoma
4
4
2
10
Malignant fibrous
histiocytoma
2
2
4
Osteosarcoma
1
1
Chondroma
3
Chondrosarcoma
3
2
1
Neurilemoma
3
_
~~~~~1
1
Granular cell tumor
6
2
3
11
Malignant schwannoma
_2
2
Periph. neuroepithelioma
3
3
Ganglioneuroma
_4
4
Ganglioneuroblastoma
3
_3
Neuroblastoma
_4
4
Lipoma
7
2
9
Liposarcoma
2
_2
Hemangioma
3
3
Hemangiopericytoma
_
1
1
Angiosarcoma
_
~~~~~~1
1
Lymphangioma
_
~~~~~~1
1
Lymphangiosarcoma
Cases showing a dotlike intracytoplasmic staining with MAb My7
+l-
are given in parentheses.
SF, stromal fibroblasts; ME, myoepithelial cells.
n= 118.
cytoplasmatic CD1 3 positivity by application of MAb My7
(Figure 1), whereas staining with MAbs U71, WM-1 5, and
MoU48 did not reveal any CD13 positivity. One LM and
ten LMSs were CD1 3 negative throughout. The eight
rhabdomyosarcomas (RMS) studied were completely devoid of any detectable CD13 antigen (Figure 5).
Tumors of Fibrous Tissue
In four aggressive fibromatoses the entire tumor cell population was strongly CD1 3 positive throughout (Figure 3),
and in one fibrosarcoma about one half of the tumor cells
exhibited weak CD13 positivity. Three fibrosarcomas and
two fibromas were CD13 negative.
positive (Figure 7), as were the neoplastic cells in one
synovial sarcoma (SS) of monophasic fibrous type. One
monophasic fibrous SS exhibited weak staining with CD13
MAb in about one half of the tumor cells, whereas three
SSs, also of monophasic fibrous type, were completely
CD13 negative (Figure 4).
Fibrohistiocytic Tumors
One cutaneous fibrous histiocytoma was CD1 3 negative,
as was one juvenile xanthogranuloma. The series of malignant fibrous histiocytomas (MFH) studied comprised 8
of storiform pleomorphic, 1 of myxoid, and 1 of giant cell
subtype. The lafter showed CD13 positivity in the giant
cells and in some of the pleomorphic tumor cells (Figure
8). Furthermore CD1 3 was expressed in the entire tumor
cell population in two and, in a minor tumor cell population,
in three storiform-pleomorphic MFHs, whereas the remaining three cases as well as the myxoid MFH lacked
any detectable CD13 determinants.
Tumors of Cartilage and Bone-forming
Tissues
One chondroma and three chondrosarcomas were CD13
negative throughout. The four osteosarcomas (OS) studied
comprised three of osteoblastic and one of fibroblastic
subtype. The fibroblastic and one osteoblastic OS expressed CD1 3 on the entire tumor cell population (Figure
9); in two further OS a major and a minor tumor cell population, respectively, were CD13 positive. Osteoclastic
giant cells, present in various densities in all cases studied,
were CD13 positive.
Tumors of Peripheral Nerves
Two malignant schwannomas (MS) expressed CD13 on
virtually every tumor cell (Figure 2); two MS were composed of CD13-positive and CD13-negative tumor cells
in about equal proportions, and one MS as well as one
neurilemoma (NL) exhibited CD13 positivity in a minor
tumor cell population. However six MSs, two peripheral
neuroepitheliomas, and two NLs were completely CD13
negative.
Tumors of Autonomic Ganglia
Tumors of Synovial Tissue
In one benign giant cell tumor of tendon sheath, the total
tumor cell population, including the giant cells, was CD13
In three ganglioneuromas, both the ganglion cell and the
Schwann cell compartments were CD13 negative. Similarly
the ganglion cells in four ganglioneuroblastomas lacked
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Mechterscheimer and MOlIer
AJP November 1990, VoL 137, No. 5
Figure 1. Spindle cell leiomyosarcoma with moderate cell pleomorphisms. Immunostaining with MAb CD13 t (My7) exhibits a dotlike intracytoplasmic positivity of a major tumor cellpopulation (Immunoperoxidase staining offrozen sections, faint hematoxylin
counterstain; same technique for all photographs; X 175). Figure 2. Spindle cell malignant schwannoma with myxoid changes. The
tumor cells, surrounded by unstained myxoid material, are consistently CD13 t (My 7) positive (X87,5). Figure 3. Extra-abdominal
aggressive fibromatosis. The entire tumor cellpopulation arranged in ill-definedfascicles shows strong immunoreactivity with MAb
CD13 t (My7). In addition, perivascular fibrocytes/-blasts are strongly CD13 positive (X 70). Figure 4. Monophasic fibrous synovial
sarcoma. The tumor completely lacks any detectable CD13 t (My7) antigen. CD13 positivity ofperivascularfibrocytes/-blasts and
of some scattered spindle cells of the adjacent tumor capsule serves as intrinsic positive controlfor the reliability of the immunohistochemical reaction (X 140). Figure 5. Undifferentiated embryonal rhabdomyosarcoma. The small round tumor cells are consistently
CD13 t (My7) negative while some scattered tissue macrophages as well as perivascularfibrocytes/-blasts strongly express CD13
antigen (X 175). Figure 6. Neuroblastoma. The undifferentiated, small round neuroblasts lack any detectable CD13 t (My7) antigen.
Once again, strongly CD13-positive perivascularfibrocytes/-blasts serve as intrinsic positive controls (X 175).
any detectable CD1 3 molecules; the same was true for
the small round neuroblasts of these cases as well as for
the neuroblastic tumor cell population in three undifferentiated neuroblastomas (Figure 6).
Tumors of Adipose Tissue
This category comprised four lipomas (one of them an
angiolipoma) and nine liposarcomas (LS). All lipomas and
CD13 in Mesenchymal Tumors
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AJP November 1990, Vol. 13 7, No. 5
seven LSs studied were consistently CD1 3 negative. In
one LS a major tumor cell population expressed CD13
molecules; in one other case CD13-positive and CD13negative tumor cells were detectable in about equal proportions.
Tumors of Vascular Origin
Two cavernous hemangiomas, one benign and two malignant hemangiopericytomas, one angiosarcoma, one
lymphangioma, and one lymphangiosarcoma studied were
CD13 negative throughout. All in all, CD13 determinants
were detectable in some tumors of smooth muscle, fibrous, fibrohistiocytic, synovial, and osteogenic origin as
well as in some neoplasms of peripheral nerve sheath
origin and of adipose tissue. The tumors of striated muscle
and of vascular origin, of cartilage-forming tissues, and
the neoplasms of autonomic ganglia studied were characterized by consistent CD1 3 negativity.
Discussion
Mesenchymal tissues comprise a range of cell types that
differ in embryologic derivation, morphology, and function.
Presently little is known about the surface antigenic phenotypes of normal or neoplastic mesenchymal cells. Several previous studies, however, have shown that a number
of leukocyte surface antigens may be expressed in various
normal and/or neoplastic extrahematopoietic mesenchymal cells either constitutively or as the consequence of
neoplastic transformation.
Thus CD57(HNK-1) antigen is expressed in neurofibromas and in neurofibrosarcomas 17,18 as well as in other
spindle cell sarcomas17 and even in Ewing's sarcomas9,20
and in peripheral neuroectodermal tumors.21 CD71 (OKT9)
molecules, originally found to bind to immature T cells22
but later shown to recognize the more prevalent human
transferrin receptor,23 are broadly distributed in mesenchymal tissues. Flanagan et al24 found CD1 1 c(3.9.) and
CD68(EBM1 1) determinants to be expressed in osteoclastlike giant cells in giant cell malignant fibrous histiocytoma; based on the expression of CD4(Leu3),
CD1 4(LeuM3), and CD45(T200) antigens, Wood et a125
considered both the mononuclear and the giant cells in
benign giant cell tumor of tendon sheath to be of osteoclastic origin. Similarly CD53(HD77), an antibody that has
been raised at our laboratory against a 36- to 50-kd pan
leukocyte surface antigen,26 reacts with osteoclasts and
with osteoclastlike giant cells in malignant fibrous histiocytoma and in benign giant cell tumor of tendon sheath
(data not shown). Furthermore Pilkington and Pallesen27
found expression of CD9, CD1 0, and CDW32 antigens
.:.1....
l:
8;:
:14f :; I
A
6
Figure 7. Benign giant cell tumor oftendon sheath. CD13 (My7)
antigen shows membrane-bound positivity of both the mononuclear and the multinucleated giant tumor cells (X 175). Figure 8. Giant cell malignant fibrous histiocytoma. The multinucleated giant cells and some of the pleomorphic tumor cells
are CD13 (My 7) positive. Furthermore CD13 (My7) MAb reacts
with scattered tissue histiocytes (X 175). Figure 9. Osteoblastic
osteosarcoma. The tumor cells, some osteoclastlike giant cells
included, show membrane-bound staining for CD13 (My7)
antigen X224).
in some rhabdomyosarcomas, Ewing's sarcomas, and
neuroblastomas. CD10 (CALLA), meanwhile known to be
identical to neutral endopeptidase,28 has been found in a
variety of solid tumors, including gliomas.29 Furthermore
we recently demonstrated expression of CD1 0 antigen in
a series of MET of diverse histogenesis.0 CD1 3 lately has
been identified as aminopeptidase N, an enzyme that in-
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Mechterscheimer and MOler
AJP November 1990, Vol. 137, No. 5
activates several peptides, including enkephalins.5 Although CD10 and CD1 3 antigens show clear differences
in their patterns of expression in hematopoietic cells, both
molecules are integral membrane metalloproteases with
the characteristic zinc-binding motif in their extracellular
carboxyterminal domains27'31 and share the expression in
renal proximal tubular cells and in fibroblasts.11'3233 This
prompted us to study the expression of CD13 determinants in mesenchymal tumors by application of MAbs
My7, U71, WM-15, and MoU48.6"4
We found CD13 molecules to be expressed in some
tumors of fibrous, fibrohistiocytic, synovial, osteogenic,
and smooth muscle origin, as well as in some tumors of
peripheral nerves and of adipose tissue, whereas tumors
of striated muscle origin, of autonomic ganglia, and of
cartilage-forming tissue were consistently CD1 3 negative.
In extrahematopoietic mesenchymal tissues, CD13 molecules have been found in connective tissue elements
and in fibroblasts that showed a collagenlike pattern
around blood vessels.11 In line with these results, we found
CD1 3-positive perivascular and stromal fibroblasts in most
of the METs studied. Furthermore CD1 3 antigen was expressed in stromal fibroblasts of five fibroadenomas of
the breast. Concerning fibrous tumors, the results were
heterogenous. CD13 molecules were expressed consistently in aggressive fibromatoses, whereas fibromas and
most of the fibrosarcomas and of the monophasic fibrous
synovial sarcomas studied lacked any detectable CD13
antigens. From these data we might speculate that the
tumor cells in aggressive fibromatosis exhibit a special
functional and/or physiologic state that is different from
that found in fibromas and in most of their malignant
counterparts. Besides its expression in fibroblasts, CD1 3
antigen also has been described in osteoclasts,1I a feature
that we could confirm in multinucleated osteoclastic giant
cells in a bone marrow metastasis of bizarre giant cell
bronchial carcinoma and in two cases of ossifying myositis
(data not shown). In this study, we found CD1 3 positivity
in osteoclastlike giant cells in four osteosarcomas and in
one malignant fibrous histiocytoma (MFH) of giant cell
subtype. Expression of CD13 antigen, however, was not
restricted to osteoclastlike giant cells but also was present
in pleomorphic and even in spindle tumor cells of all osteosarcomas and of a considerable number of MFHs
studied. The histogenesis of MFH is still controversial.
Some authors favor a histiocytic origin,3435 while others
consider MFH to be of primitive mesenchymal cell origin.-'- Based on the observation of CD13 positivity in
various mesenchymal tumors, the expression of this antigen alone cannot be considered a strong argument in
favor of a true histiocytic origin of MFH. However it should
be noted that our results correspond with those obtained
by Strauchen and Dimitriou-Bonae demonstrating positivity for monocyte/macrophage antigens in MFHs, whereas
Wood et a137 and Lawson et all did not find expression
of any of these antigens in MFHs. Furthermore, in one
case of benign giant cell tumor of tendon sheath (GCTTS),
both the mononuclear cells and the multinucleated giant
cells were CD13 positive. These results correlate with
those of Wood et al,25 who found a monocyte/macrophage phenotype of the entire tumor cell population of
GCTTS. The authors concluded that GCTTS thus might
be a true histiocytic lesion of monocyte/macrophage lineage composed of phenotypically similar mononuclear
and giant cells that most closely resemble osteoclasts.
Although this might well be the case, the presence of
CD13 molecules in GCTTS is but a feable argument on
the background of our data.
Because normal smooth muscle cells and peripheral
nerve fibers are CD13 negative, expression of CD13 in
some tumors of smooth muscle origin and of peripheral
nerves is remarkable. The significance of CD13 expression
in these tumors, however, cannot be explained at present.
As an exceptional finding, some tumors of smooth muscle
origin showed a dotlike intracytoplasmic CD13 positivity
by application of MAb My7, whereas other CD13 MAbs
applied gave negative results in these cases. Nonspecific
antibody binding could be excluded using an irrelevant,
isotype-matched control antibody. Therefore we suggest
that My7 detects the CD13 antigen already in its intracytoplasmic form, before it is processed to the cell surface.
The CD13 negativity in tumors of striated muscle origin,
including small, round, undifferentiated rhabdomyosarcoma in tumors of cartilage-forming tissues and of autonomic ganglia, seems to mirror the situation found in their
cells of origin. It should be noted, however, that our in
situ findings on CD13 negativity of (ganglio-) neuroblastomas contrast with data presented by Favaloro et al,40
who found strong expression of CD13 in two neuroblastoma cell lines studied. In this context, it would be interesting to study other small, round, blue cell tumors, such
as Ewing's sarcomas and even Wilms' tumors, and small
cell bronchial carcinomas for expression of CD13 molecules.
Although to variable extents, expression of CD13 has
been found in a series of METs studied, enriching the
data on expression of leukocyte differentiation antigens
in extrahematopoietic tissues. Because in acute myeloblastic leukemia expression of CD13 has been found to
be associated with decreased survival,41 additional studies
increasing the total number of METs examined for CD13
would be of interest in view of possible correlations between CD1 3 expression and biologic and metastatic behavior of METs.
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Acknowledgments
The authors thank Sybille Menges, Margarethe Kaiser, and John
Moyers for technical assistance and Karin Tinter and Christine
Raulfs for editing the manuscript.