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  
J. Pathol. 186: 178–185 (1998)
EPITHELIAL–MESENCHYMAL
TRANSDIFFERENTIATION AND EXTRACELLULAR
MATRIX GENE EXPRESSION IN PLEOMORPHIC
ADENOMAS OF THE PAROTID SALIVARY GLAND
 *,  ,  ö,     
Institute of Pathology, University of Erlanger-Nürnberg, 91054-Erlangen, Krankenhausstrasse 8–10, Germany
SUMMARY
Mesenchymal and epithelial cell differentiation are assumed to be dichotomic primary events in embryonic development. In this study,
pleomorphic adenomas of the parotid gland were analysed as a model which shows morphological features of both epithelial and
mesenchymal tissue types. Using matrix gene expression profiles as a supplementary criterion for the identification of cellular
phenotypes, areas with unequivocal epithelial and mesenchymal differentiation could be demonstrated. Many areas displayed a
transitional phenotype with cells showing both epithelial and mesenchymal features. The data provide evidence that epithelial–
mesenchymal transitions represent the basic principle of the tisuse heterogeneity in pleomorphic adenomas. Thus, pleomorphic adenomas
demonstrate the potential of adult (neoplastic) epithelial cells to transdifferentiate into mesenchymal cells in vivo. 1998 John Wiley
& Sons, Ltd.
KEY WORDS—pleomorphic
adenoma; cell differentiation; chondrogenesis; collagen; salivary gland; neoplasm
INTRODUCTION
Mesenchymal and epithelial cell differentiation are
principal steps in embryonic development. Transitions
between both cell types have been observed in fetal
palate, neural crest, metanephric, and cardiac development.1 To date, no mature tissue has been reported to
show transdifferentiation of epithelial to mesenchymal
cells or vice versa in vivo, although this has been
reported to be possible in vitro.1 A few neoplasms have
been described which contain both mesenchymal and
epithelial neoplastic components, but in most cases no
real transdifferentiation occurs from differentiated epithelial cells to differentiated mesenchymal cells, or vice
versa. In teratocarcinomas, embryonic precursor cells
form both epithelial and mesenchymal structures similar to their physiological counterparts. Mesotheliomas
originate from cells which express markers of both
differentiation pathways.2 Other neoplasms, like carcinomas with (pseudo)sarcomatous differentiation and
chordomas of the spinal axis, show morphological
mimicry of mesenchymal differentiation.3 A few (rare)
neoplasms debatably show mesenchymal–epithelial
transdifferentiation, such as synovial sarcomas,4 sarcomatoid renal cell carcinomas,5 and adamantinomas of
bone,6 but no comprehensive analyses of these phenomena are available as yet.
In pleomorphic adenomas, there is morphological
evidence for both mesenchymal and epithelial cell
types. Their cellular origin is, however, still unclear.
*Correspondence to: T. Aigner, MD, Institute of Pathology, University of Erlangen-Nürnberg, Krankenhausstrasse 8–10, D-91054
Erlangen, Germany.
Contract/grant sponsor: Wilhelm Sander-Stiftung (München,
Germany); Contract/grant number: 96.050.1.
CCC 0022–3417/98/100178–08$17.50
1998 John Wiley & Sons, Ltd.
Some authors have suggested different—mesenchymal
and (myo)epithelial—origins for the two tumour
components.7–10 In contrast, the single-cell theories
now postulate a solely epithelial,11,12 a (modified)
myoepithelial,9,11,13 or a mesenchymal8,14 origin of all
neoplastic cells.
We have attempted to characterize further the various
tumour cells within pleomorphic adenomas and thereby
to answer the following key questions: are pleomorphic
adenomas ‘mixed’ tumours, containing fully differentiated epithelial and mesenchymal cells; and if so, do the
heterogeneous cell populations show real epithelial–
mesenchymal transitions? We hope thus to establish
whether or not the tumour cells may originate from one
common precursor cell type.
Many studies have investigated the cellular differentiation pattern in pleomorphic adenomas by morphological and cytoprotein analysis.12,15,16 In our study, we
have for the first time analysed the expression of extracellular matrix genes, as highly characteristic markers of
epithelial and mesenchymal cellular phenotypes.
MATERIALS AND METHODS
Tissue preparation and histology
Specimens of 14 pleomorphic adenomas as well as
normal tissues of the parotid gland were routinely fixed
with 10 per cent formalin immediately after removal and
embedded in paraffin.
Histochemical methods
Mucopolysaccharides—Histochemical methods were
used to evaluate the distribution of epithelial- and
Received 15 August 1997
Revised 16 January 1998
Accepted 26 May 1998
179
CELL DIFFERENTIATION IN PLEOMORPHIC ADENOMA
Table I—Primary antibodies and enzymatic pretreatments used for immunohistochemical analysis
Antigen
Pancytokeratin Lu5 (human)
Actin (all muscle types) HHF 35 (human)
Vimentin (porcine)
S-100 protein (bovine)
Collagen II (chick)
Collagen IV (human)
Collagen X (human)
Laminin (mouse)
Type
Dilution
Digestion
Source
m
m
m
r
m
m
m
r
1:100
1:100
1:20
1:1000
1:50
1:50
1:100
1:200
P
H, P
—
P
H, P
H, P
H, Pt
Pp
Dianova (Germany)
Biogenex (U.S.A.)
Dako (Denmark)
Dako (Denmark)
Dr Holmdahl (Uppsala, Sweden)29
Dako (Denmark)
Dr von der Mark (Erlangen, Germany)30
Laboserv (Germany)
m=mouse monoclonal; r=rabbit polyclonal; H=hyaluronidase (ovine testis in 2 mg/ml, phosphate-buffered saline (PBS), pH 5, 60 min at 37C);
P=pronase (2 mg/ml, PBS, pH 7·3, 60 min at 37C; Boehringer Mannheim, Germany); Pp=pepsin (0·4 per cent in 0·01  HCl; Sigma, Berlin,
Germany); Pt=protease XXIV (0·02 mg/ml, PBS, pH 7·3, 60 min at room temperature; Sigma, Berlin, Germany).
mesenchymal-type mucopolysaccharides.8 The epithelial
mucopolysaccharides were detected by the PAS reaction. The cartilage typical glycosaminoglycans (GAGs),
which are found abundantly in cartilaginous tissues,
were visualized by toluidine blue staining [10 min, 0·3
per cent toluidine blue (Merck, Germany), pH 3·65,
room temperature].
To analyse potential binding of the mucopolysaccharides to hyaluronan polymers within the tissue, serial
sections were digested with hyaluronidase (2 mg/ml
in PBS, pH 5, 1 h, 37C; Boehringer, Mannheim,
Germany). Whereas staining for GAGs diminished
strongly or disappeared after hyaluronidase pretreatment, staining for PAS-positive epithelial mucins was
not affected.
Collagens—The presence of collagens in the extracellular tumour matrix was demonstrated by MassonGoldner’s and van Gieson stains.
Immunohistochemistry
selected and transcribed in vitro in order to generate
digoxigenin-labelled antisense and sense riboprobes as
described previously.17–19 The transcripts for aggrecan
core protein and type X collagen were reduced to an
average length of 300 bp by standard alkaline hydrolysis. In situ hybridization was performed as described
elsewhere.19
To control probe specificity, all probes were tested on
fetal growth plate specimens in parallel experiments.18 A
probe for 18S rRNA18 was used as a positive control.
In selected cases, sense transcripts served as negative
controls.
Double-labelling experiments
For simultaneous detection of agrecan mRNA and
cytokeratin polypeptides, in situ hybridization and subsequent immunohistochemistry were performed on the
same sections according to the protocols outlined above.
RESULTS
Normal salivary gland (Figs 1a–1d)
Deparaffinized sections were enzymatically pretreated
(Table I), incubated with primary antibodies (Table I)
overnight at 4C, and visualized using a streptavidin–
biotin complex technique (Biogenex, Hamburg,
Germany: Super Sensitive Immunodetection System
for mouse or rabbit primary antibodies) with alkaline
phosphatase as the detection enzyme and 3-hydroxy2-naphthyl acid 2,4-dimethylanilid as the substrate.
Nuclei were counterstained with haematoxylin. Alternatively, peroxidase-labelled streptavidin and 3,3diaminobenzidine as the colour substrate (detection of
S-100 protein and cytokeratin), or FITC-labelled antimouse IgG+IgM (H+L) rabbit antibodies (Dianova,
Hamburg, Germany) were used (double-labelling
experiments).
As a negative control for immunohistochemical staining, the primary antibody was replaced by non-immune
mouse or rabbit serum (BioGenex, Hamburg, Germany)
U.S.A.) or Tris-buffered saline (pH 7·2).
Immunohistochemical analysis allowed the identification of ductal cells within normal salivary glands that
were positive for cytokeratin (Fig. 1a), but negative for
vimentin, S-100 protein (Fig. 1b), and muscle-specific
actin (Fig. 1c). Acinar cells were weakly positive for
cytokeratins, but negative for all other cytoproteins
investigated. Periacinar myoepithelial cells (Fig. 1c:
arrow-heads) as well as smooth muscle cells of the vessel
walls (Fig. 1c: large arrow-heads) were muscle-specific
actin-positive, while interstitial fibroblasts were
vimentin-positive, but negative for cytokeratins, S-100
protein, and muscle-specific actin (Figs 1a–1c).
The epithelial structures were completely surrounded
by collagen type IV (Fig. 1d) and laminin. Collagen
types II and X were not detectable in normal tissues at
the protein or mRNA level. GAGs were also absent.
PAS-positive mucins were detected in mucous gland
epithelia.
In situ hybridization
Pleomorphic adenomas
Suitable fragments of human collagen chains á1(II)
and á1(X) and aggrecan core protein mRNA were
In most cases, the predominant areas of the tumours
showed transitional differentiation. However, some
1998 John Wiley & Sons, Ltd.
J. Pathol. 186: 178–185 (1998)
180
T. AIGNER ET AL.
Fig. 1—Histochemical, immunohistochemical, and in situ mRNA analysis of normal salivary gland tissue (a–d) and tubular areas
of pleomorphic adenomas (e–l). Histochemistry: j: toluidine blue; k: PAS. Immunohistochemistry: a, e: cytokeratin; b, f: S-100
protein; c, g: muscle-specific actin; d, h: type IV collagen; l: type II collagen; i: in situ hybridization for aggrecan mRNA (a–c, f,
h) 90; (d, e, g, i–l) 45
tumour areas exhibited exclusive characteristics of
tubular, myxoid, or cartilaginous differentiation. Areas
of fibroblastic and squamous differentiation were not
studied in this investigation.
Tubular areas (Table II and Figs 1e–1l)
Tubular areas showed morphologically clear ductal
epithelial features. The mono- and bi-layer tubular
structures were surrounded by sparse extracellular
matrix. Histochemically, the stromal matrix consisted
of collagens, but GAGs were below the detection
level (Fig. 1j). PAS-positive mucopolysaccharides
were detected in some tubular lumina (Fig. 1k).
Immunohistochemically, the tubular structures were
always surrounded by collagen type IV and laminin
1998 John Wiley & Sons, Ltd.
(Fig. 1h). No staining for cartilage collagen types II
and X was detectable (Fig. 1l). In situ hybridization
confirmed the absence of aggrecan (Fig. 1i) and collagen types II and X mRNA expression. The luminal
cells in these areas were strongly cytokeratin-positive
(Fig. 1e) and negative for S-100 protein (Fig. 1f),
vimentin, and muscle-specific actin (Fig. 1g). Stromal
cells were in parts positive for cytokeratin, S-100 protein (Fig. 1f), and vimentin. Few cells showed staining
for muscle-specific actin (Fig. 1g). These cells belonged
in many instances to muscular vessel walls.
Myxoid areas (Table II and Figs 2a–2h)
Myxoid tissue differentiation was characterized
by single stellate cells separated by an abundant
J. Pathol. 186: 178–185 (1998)
181
CELL DIFFERENTIATION IN PLEOMORPHIC ADENOMA
Table II—Distribution of cytoproteins and extracellular matrix components in tubular, myxoid, and
cartilaginous tumour compartments and transitional zones of pleomorphic adenomas
Tubular Myxo-tubular Tubulo-myxoid Myxoid Chondro-myxoid Chondroid
CK
S-100
Vim
Col IV
Matrix abundance
Aggrecan/GAGs
Col II
++
++
+ +/(+)*
/(+)*
/+†
++
+
/+*
+ +‡/†
‡/+ +†
‡/+
(+)
++
+
++
(+)
+++
++
+++
++
+++
+++
+
+++
++
+++
+++
+++
*Mainly in outer layers of bilayer structures and stromal cells.
†Stromal (cells).
‡Tubular remnants.
+ + + =strongly positive; + + =positive; + =weakly positive; (+)=only focally positive; =negative. Col =collagen
type; GAGs=glycosaminoglycans.
extracellular matrix, which appeared collapsed after
fixation. This matrix contained considerable amounts of
GAGs (Fig. 2a), but only minor amounts of collagens.
Basement membrane collagen type IV, as well as
cartilage collagen types II (Fig. 2c) and X, was absent. In
situ hybridization analysis identified the expression of
aggrecan proteoglycan mRNA (Fig. 2b) and confirmed
the absence of expression of mRNAs for cartilage collagen types II (Fig. 2d) and X. The cells of myxoid tumour
areas were typically positive for S-100 protein (Fig. 2f)
and partly for vimentin (Fig. 2g), but were negative for
epithelial cytokeratins and muscle-specific actin (Figs 2e
and 2h).
Chondroid areas (Table II and Figs 2i–2p)
Single or grouped tumour cells occurred in typical
lacunar spaces (Figs 2i–2p), surrounded by an abundant
hyaline-cartilage-like extracellular matrix. Histochemically, a high GAG (Fig. 2i) and collagen content was
found. Immunohistochemically, strong staining for collagen type II was seen throughout the extracellular
matrix (Fig. 2k). The expression of both cartilage matrix
components, collagen type II and aggrecan proteoglycan, was confirmed by in situ hybridization (Fig. 2j and
2l). No expression of collagen type X mRNA or protein
could be found in any of the specimens. No collagen
type IV and laminin could be detected. The cells were
positive for S-100 protein (Fig. 2n) and vimentin (Fig.
2o), but negative for cytokeratins (Fig. 2m) and musclespecific actin (Fig. 2p).
Transition zones
Morphologically, gradual transition from tubular to
myxoid and finally chondroid areas was apparent (Table
II and Fig. 3). Myxotubular areas showed tubular
structures with moderately abundant, toluidine bluepositive stromal matrix (Fig. 3a). Tubulomyxoid areas
showed predominantly toluidine blue-positive myxoid
matrix with mostly single stellate tumour cells and only
a few tubular structures. Chondromyxoid areas showed
1998 John Wiley & Sons, Ltd.
myxoid extracellular tumour matrix with foci of
chondroid matrix formation (Fig. 3i).
In myxotubular areas, high expression of the proteoglycan aggrecan (Fig. 3c) and an increasingly abundant,
GAG-positive, extracellular tumour matrix was
observed (Fig. 3a). Surprisingly, not only ‘stromal’, but
also tubular cells expressed aggrecan mRNA (Fig. 3c).
In these areas, tubular cells were in part positive for
S-100 protein (Fig. 3b). Double-labelling experiments
for aggrecan mRNA and cytokeratin expression showed
that a few cells were positive for both markers of
mesenchymal and epithelial cell differentiation (Fig. 3d).
At the periphery of myxoid areas, some cells were
surrounded by collagen type IV (Fig. 3f) and laminin,
and were positive for cytokeratin (Fig. 3e). Noteworthy
was the absence of co-expression of cytokeratin and
aggrecan mRNA in these cells (Fig. 3e). This was
different for ductular organized remnants in myxoid
areas, in which some cells showed co-expression (Fig.
3g).
In chondromyxoid areas, single cells expressed type II
collagen mRNA (Fig. 3h) and type II collagen protein
was deposited in the pericellular matrix (Fig. 3i).
DISCUSSION
Our study confirms that myoepithelial cell differentiation is only a minor cell differentiation pathway in
pleomorphic adenomas and is not the basic cellular
phenotype of these neoplasms,20 as suggested by some
investigators.9,11,13 Instead, we could further establish
unequivocal epithelial12,20 and mesenchymal11,12,20 cell
differentiation within these neoplasms. All the studies
performed so far have been based on morphology and
cytoprotein analysis, which are significant, but not
unequivocal indicators of mesenchymal and epithelial
cell differentiation within tumours.21,22 The analysis
of the matrix gene expression profiles provides an
additional important criterion by which to identify epithelial and mesenchymal cells.8,9 This is documented, for
example, by the prevalence of two different types of
J. Pathol. 186: 178–185 (1998)
182
T. AIGNER ET AL.
Fig. 2—Histochemical and immunohistochemical analysis of myxoid (a–h) and chondroid (i–p) tumour areas in pleomorphic
adenomas for glycosaminoglycans (a, i: toluidine blue staining), type II collagen (c, k), cytokeratins (e, m: visible only nuclear
counterstains), S-100 protein (f, n), vimentin (g: arrow-heads, o), and muscle-specific actin (h, p). In situ hybridization analysis was
performed for proteoglycan aggrecan (b, j) and type II collagen mRNA d,l (a–f, i–n) 45; (g, h, o, p) 90
mucopolysaccharide in the mesenchymal and epithelial
compartments in pleomorphic adenomas.8 Thus,
PAS-positive mucins indicated acinar differentiation
1998 John Wiley & Sons, Ltd.
of a proportion of the neoplastic cells. In contrast,
the hyaluronan-linked, toluidine blue-positive glycosaminoglycans were restricted to myxoid and
J. Pathol. 186: 178–185 (1998)
CELL DIFFERENTIATION IN PLEOMORPHIC ADENOMA
183
Fig. 3—Myxotubular tumour areas: toluidine blue staining (a), immunodetection of S-100 protein (b), in situ hybridization for aggrecan
mRNA (c: arrow-heads marking positive ductal cells), and double-detection for cytokeratins (green) and aggrecan mRNA (black) (d).
(e–g) Myxoid tumour areas: double-detection (e) of cytokeratins (red) and aggrecan mRNA expression (black) and immunolocalization
of pericellular type IV collagen (f) in peripheral parts of myxoid areas. Double-labelling for cytokeratins (red) and aggrecan mRNA
expression (black) in tubular cell complexes (g). (h, i) Chondromyxoid tumour areas: in situ hybridization and immunohistochemical
detection of type II collagen mRNA (h) and protein (i). (a, c) 45; (b, e, f, h, i) 90; (d, g) 180
1998 John Wiley & Sons, Ltd.
J. Pathol. 186: 178–185 (1998)
184
T. AIGNER ET AL.
cartilaginous areas. In situ mRNA analysis suggested the
latter to be the hyaluronan-bound cartilage proteoglycan aggrecan. The co-expression of collagen type II and
aggrecan proteoglycan mRNA found in chondroid
tumour areas identifies neoplastic and non-neoplastic
chondrocytes.17,23,24 It is noteworthy that no expression
of type X collagen was found. Type X collagen is closely
linked to endochondral ossification in fetal development,25 a feature which was not seen in our specimens.
In tubular areas, the presence of the basement
membrane components collagen type IV and laminin,
and the absence of mesenchymal gene expression, supported the pure epithelial character of the cells in these
areas.13
In line with previous morphological observations9,11,13,14,26 and in vitro studies,27,28 our results
establish a complete transition pathway from a pure
epithelial to a mixed and finally a true mesenchymal
cell phenotype within pleomorphic adenomas (Table
II). Whereas cells in purely tubular areas showed only
epithelial characteristics, many cells in tubulomyxoid
areas had a mixed phenotype.11 The detection of
aggrecan proteoglycan mRNA in ductal cells, which
were partly still cytokeratin-positive, demonstrated
the onset of mesenchymal gene expression in originally epithelial cells and suggested that ductal cells
are the origin of myxoid matrix formation. In these
areas, tubular cells separate from the ductal structures
via the synthesis of an increasingly abundant
glycosaminoglycan-positive extracellular matrix.9,11 In
myxoid areas, the ongoing deposition of extracellular
matrix resulted in the disappearance of tubular structures. Finally, only single neoplastic cells remained,
which were surrounded by an abundant proteoglycanpositive matrix. The epithelial origin of the cells in the
myxoid areas was still reflected by occasional staining
for cytokeratins and for basement membrane components at the periphery of these areas.11–13 The
next step in mesenchymal cell differentiation was the
onset of collagen type II expression, resulting in a
chondromyxoid extracellular matrix. The formation
of a cartilaginous matrix with typical chondrocyte
lacunae represented the end stage of this epithelial–
mesenchymal transdifferentiation process.
In summary, our study demonstrates unequivocal
epithelial and mesenchymal differentiation in pleomorphic adenomas, with most tumour areas showing a
transitional phenotype. Our findings delineate a new
concept of pleomorphic adenoma tumourigenesis:
epithelial–mesenchymal transdifferentiation. In general,
mesenchymal and epithelial differentiation are considered to be dichotomic in adult tissues. However, pleomorphic adenomas represent an in vivo model system of
epithelial–mesenchymal cell transdifferentiation in the
adult.
ACKNOWLEDGEMENTS
We thank Drs L. Sorokin and G. Niedobitek for
critically reviewing the manuscript and Ms G. Herbig,
Ms S. Blank, and Ms Knoll for expert photographic
1998 John Wiley & Sons, Ltd.
and technical help. This worked was supported by the
Wilhelm Sander-Stiftung (München, Germany; grant
96.050.1).
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