(CANCER
RESEARCH
26, 172-182, January
1966]
An Electron Microscope Study of Squamous Cell Carcinoma in Merino
Sheep Associated with Keratin-filled Cysts of the Skin
R. BORLAND AND A. J. WEBBER
Department of Veterinary Pathology and Bacteriology and the Electron Microscope Unit, University of Sydney, Sydney, Australia
Summary
The fine structure of a naturally occurring cystic condition of
the skin in Merino sheep and associated squamous cell carcinoma
was studied and compared with the fine structure of the normal
interfollicular epidermis of the sheep. A number of obvious dif
ferences were observed—namely, large intercellular spaces, microvillus formation, gaps in the basement membrane, fewer
desmosomes, and in the tumor cells only, 2 large nucleoli with a
prominent nucleolonema.
Introduction
Recently Carne et al. (8) have shown that squamous cell car
cinoma of the wool-bearing skin in a certain strain of Merino
sheep in Australia was closely associated with a characteristic
and highly inherited cystic condition of the skin. Most of the
tumors were observed to arise from the walls of the cysts, al
though only a relatively small proportion of cysts gave rise to
tumors. Lloyd (18) demonstrated that the formation of keratinfilled cysts in susceptible animals was due to grass seeds pene
trating the skin, dislodging epidermal cells, and carrying them
into the dermis, where they multiplied to form cysts.
This paper records a study of the epidermal cell in its transi
tion from normality to malignancy. Although differences can
be recognized between the histologie structure of normal epider
mis, the walls of cysts, and tumor tissue, the light microscope
does not reveal obvious differences between individual cells from
these 3 sources. The electron microscope has been used in an
attempt to discern any changes in ultrastructure that may occur
in this stepwise transition from normality to malignancy. For
this purpose an examination was made of normal interfollicular
epidermis, cyst lining, and the squamous carcinoma arising from
the cyst wall.
Materials
and Methods
Specimens of skin, cyst lining, and tumor were excised from 3
normal sheep and 8 cyst-bearing sheep, 6 of which had spon
taneous squamous cell carcinomata on the wool-bearing areas
of the body.
The tissue was fixed in either chilled 1'/óosmium tetroxide
solution buffered to pH 7.2 (24) for 3-4 hr or ice-cold 5% glutaraldehyde in cacodylate buffer at pH 7.2 (25) for 1-2 hr and
then in 1% osmium tetroxide for 2 hr. After they were rinsed
Received for publication April 2(1,1905.
172
and dehydrated through a graded series of alcohols, the specimens
were embedded in Araldite (14). In some cases the tissue was
stained with a saturated solution of phosphotungstic acid (PTA)
in absolute alcohol prior to infiltration.
The skin and cyst lining were cut as nearly perpendicular to
their surfaces as possible. Sections were prepared on an L.K.B.
microtome with glass knives (17) and collected on nitrocellulosecoated copper grids. Sections from material not previously
stained with PTA were stained with Karnovsky's lead stain,
Method A (16).
Examination of the sections was carried out in either a Siemens
Elmiskop I or a Philips KM200 electron microscope.
Results
Light Microscopy
THE INTERFOLLICULAR
EPIDERMIS. On wool-bearing areas of
the body this was often only 3-4 cells thick and consisted of a
well-defined stratum germinativum, an ill-defined stratum
spinosum, an ill-defined stratum granulosum, and a stratum
corneum (Fig. 1).
THECYSTWALL. Cysts varied from 2 mm to 3 cm in diameter,
and their walls were composed of stratified squamous epithelium,
usually 3-4 cells thick. However, the thickness of the wall was
often made quite variable by long, finger-like processes of cells
derived from the cyst lining projecting into the dermis. The
cells of the cyst wall were flattened tangentially, and there was a
very distinct stratum granulosum, the cells of which had larger
keratohyaline granules in their cytoplasm. Concentric lamellae
of keratin formed the center of the cyst (Fig. 2).
TUMORS. These took the form of mushroom-shaped masses,
2-12 cm in diameter, raised above the surface of the skin (Fig.
3). In the depths of the tumor there were numerous small
islands of epithelial cells surrounded by dermal connective tis
sue, and nearer the surface the groups of squamous epithelial
cells were larger and had keratin pearls at the center of the cell
masses (Fig. 4).
Electron Microscopy
EPIDERMIS. The interfollicular epidermis was selected for
study as it was that portion of the integument that most closely
resembled the cyst lining in gross structure. Ultrastructural
studies of human skin by Selby (26, 27), Brody (6, 7), Ödland
(23), and Zelickson (32) have shown the epidermis to be rela
tively thick and to have a more obvious stratification than was
CANCER RESEARCH VOL. 26
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FIG. 1. Normal interfollicular epidermis of the sheep showing the stratum germinativum (G), the stratum corneum (C), and the
dermis (D). II & E, X 2000.
FIG. 2. Cyst wall showing layers of keratin (K), a prominent stratum granulosum (Gr), and tangentially elongate nuclei (Ar). H
& E, X 2000.
FIG. 3. A squamous cell carcinoma showing the mushroom-like growth, the exposed surface (Su) of the tumor, and the adjacent
epidermis (E) and dermis (D). H & E, X 4.
FIG. 4. Groups of squamous carcinoma cells with keratin "pearls" (Kp) showing the relatively large tumor cell nuclei (N) with their
prominent
JANUARY
nucleoli (No).
H & E, X 2000.
I960
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173
li. Borland
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CANCER RESEARCH VOL. 20
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Squamous Cell Carcinoma with Keratin-filled Skin Cysts
found in sheep. The intracellular structures were essentially
the same as those described in human epidermis. In the basal
cells the nuclei tended to be round or slightly oval and their
long axes were usually perpendicular to the skin surface, but in
the region of the stratum corneum the nuclei were more elongate
and their long axes were parallel to the skin surface. Numerous
nucleoli were seen in many of the epidermal cell nuclei examined.
Relatively few mitochondria were present, and the cytoplasm
contained a number of free ribosomes and little obvious endoplasmic rcticulum.
The plasma membranes of adjacent cells were closely applied
to one another; they formed 3 electron-dense layers separated
by 2 clear zones, the center dense line being the "intercellular
contact layer" described by Ödland (23). Many desmosomes
were present on the plasma membranes of adjacent cells (Fig.
7), and they were particularly numerous on the external and
basal surfaces, as compared with the lateral borders, of the cells.
Groups of tonofilaments, approximately 40-60 A in diameter,
were seen to be inserted into the attachment plates of the desmo
somes. The basement membrane formed a regular smooth bar
rier between the dermis and the epidermis (Figs. 1,7), and its
electron translucent area was firmly attached to the basal cells
by numerous desmosomes. Within the basal cells the tono
filaments were not as electron dense as they were in the cells
near the keratinized layer of the epidermis (Fig. 7).
CYSTLINING. The cells of the cyst lining and their nuclei were
flattened tangentially, particularly near the keratin center of
the cyst.
In contrast with the epidermis, there was a very loose contact
between cells, the plasma membranes of adjacent cells being
separated by obvious intercellular spaces and the "intercellular
contact layer" being absent (Fig. 8). This effect was most
pronounced between the basal cells of the cyst and became less
obvious nearer the center of the cyst (Fig. 6). Associated with
this loose contact the cell surfaces showed numerous villus-like
projections that extended into the intercellular spaces (Figs.
8, 10) (cf. human stratum spinosum and embryonic skin).
The basement membrane surrounding the cysts was thrown
into numerous folds by the irregular borders of the basal cells
(Figs. 6, 10), and although the contact between cyst cells and
basement membrane was normally very close, as in the epidermis,
a number of apparent breaks were found. At these breaks, the
cytoplasm of the cyst cells protruded through into the dermis
(Figs. 16, 17). Tonofilaments were numerous and highly kera
tinized in all the cyst cells including the basal cells (cf. epidermal
basal cells) (Figs. 7, 8), but they seemed to be distributed in a
rather haphazard fashion. A very obvious stratum granulosum
was present in the cyst lining, where the cells contained numer
ous large, electron-dense, keratohyaline granules 0.3-0.5 p in
diameter (Fig. 6). Also present in these cells were a number of
prominent mitochondria and ribonucleic protein granules (Fig.
10).
TUMOR. The surface of the tumor cells was very irregular and
formed numerous microvilli (Figs. 11, 13, 14). There were large
spaces between adjacent tumor cells, complete absence of inter
cellular contact, and no formation of intercellular contact layer
except at the desmosomes, which appeared to be reduced in
number compared with the epidermis and cyst lining.
All the clumps of tumor cells were surrounded by a basement
membrane separating them from the dermis (Fig. 12). As in
the cyst wall, apparent breaks were found in the basement mem
brane in 1 tumor, and cell cytoplasm flowed through into the
surrounding dermal tissue (Fig. 15).
In cells selected from the surface areas of the tumors there
were numerous heavily keratinized tonofibrils that seemed to
have a perinuclear arrangement (Figs. 11, 13). The bundles
of tonofilaments were less distinct and not so heavily keratinized
in cells taken from the deeper portions of the tumor. Mito
chondria were relatively numerous, and there was some rough
endoplasmic reticulum present in the tumor cell cytoplasm (Fig.
11). A few free ribosomes were seen, but they tended to be
arranged in rows unassociated with any obvious membranous
structure rather than to be scattered throughout the cytoplasm
(Fig. 14). The large, round tumor cell nuclei invariably con
tained 2 very large and obvious nucleoli, each with a distinct
nucleolonema (Fig. 11).
Discussion
In this study of a naturally occurring inherited cystic condition
of the sheep skin associated with spontaneous tumor formation,
a number of changes were observed in the fine structure of the
cyst lining and the squamous cell carcinoma when compared with
the normal interfollicular epidermis of the sheep.
Large intercellular spaces were a feature of both the cyst lining
and the squamous carcinoma; since the only close contact was
at the desmosomes, there seemed to be a lack of adhesion between
adjacent cells. Mercer (21), in a review of the cancer cell, sug
gested that in the case of skin tumors this separation could be
due to failure to synthesize adequate amounts of surface adhesive
layers. Setälä
et al. (28), in an electron microscopic examination
of the effect of locally applied carcinogen on the interfollicular
epidermis of the mouse skin, demonstrated abnormal cell-to-cell
surface contact in the treated epidermis. It has long been con
sidered that neoplastic cells are less adhesive and have different
surface properties, such as lack of "contact inhibition," when
compared with normal cells (1-4, 10-12). An ultrastructural
examination of the normal epidermis of the sheep failed to demon
strate any such intercellular spaces (Fig. 5). According to some
studies involving the normal epidermis of humans, rats, and mice
(7, 23, 27), intercellular spaces do exist in the stratum spinosum,
although Hibbs and Clark (15) found only a small true inter
cellular space in an ultrastructural examination of the human
epidermis.
FIG. 5. Interfollicular epidermis showing the keratin (K), the round to oval cell nuclei (A"),the basement membrane (BM), and the
collagen fibers (C). X 7500.
FIG. 6. Cyst-wall epithelium with keratin (K), the flattened cells and nuclei (N), and the prominent keratohyalin granules (Kh).
Note the obvious intercellular spaces (S) and the finger-like projections of the basal cells with associated basement membrane (BM).
X 8500.
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175
R. Borland and A. J. Webber
The plasma membranes of cells of the cyst lining and the squamous carcinoma formed numerous microvillous projections that
extended into the intercellular spaces and were most numerous
and pronounced in the tumor tissue (Figs. 8,14). Other workers,
in electron microscope studies that have included the stratum
spinosum of normal human epidermis (7, 23, 31), have described
the cell surfaces as being markedly plicated and having numerous
microvilli projecting into the intercellular spaces, whereas in
the sheep the main feature of this region of the epidermis is the
convoluted nature of the cell surfaces and the close apposition of
adjacent surfaces (Fig. 7).
In addition to the above surface alterations, there appeared to
be fewer desmosomes between the tumor cells than in the epi
dermis or the cyst wall; although this finding was not confirmed
quantitatively by serial sectioning, it was common to a large
number of sections examined. A similar apparent decrease in
the number of desmosomes in human epidermis was described by
Caulfield and Wilgram (9) in an ultrastructural examination of
Darier's disease; it is interesting to note that this disease is also
an inherited condition.
Two large nucleoli with filamentous nucleolonemata were an
almost constant feature of the tumor cell nuclei. Zbarsky et al.
(30) and Bernhard and Granboulan (5), in studies of tumor cell
nuclei, described similar structures that varied even within a
given neoplasm but did not find that they were constant features
of the tumor cells. Care would have to be taken in interpreting
the variety of these structures owing to the normal pleomorphism
of the nucleolus (22).
Breaks in the basement membrane were found only in the
cysts and tumor (Figs. 15-17) and were not seen in the normal
epidermis. It is thought that these gaps could be related to
malignant transformation and to a possible mechanism for tissue
infiltration in the tumor. Luibel et al. (19), in a study of in
vasive carcinoma of the cervix in humans, and Frei (13), in an
examination of carcinogen-induced epidermal tumors in mice,
described similar defects of the basement membranes; in both
cases the defects were associated with local tissue invasion by the
tumors.
In this study the main distinguishing features of the premalignant and malignant tissues when compared with the normal
epidermis were changes in the cell surface—namely, microvillus
formation, large intercellular spaces, poorer cell-to-cell contacts,
and basement membrane defects.
The main distinguishing features of the ultrastructure of the
malignant tissue as outlined above were suggestive of the char
acteristics of malignant cells described by Abercrombie and
Ambrose (1) and others—namely, alteration in surface properties
and lack of "contact inhibition." It is important to note, how
ever, that each one of the fine structural changes observed in
cyst lining and tumor cells has been described for other animals
as occurring separately in normal skin and embryonic skin (20)
and in other pathologic conditions of the skin (9, 29). However,
it would appear to be significant that all occur together only in
the cyst wall and in tumor cells.
The finding that cyst-lining cells have many of the fine struc
tural features of the carcinoma cells implies that morphologically
there is a very narrow gap between the premalignant and the
malignant tissue. On the other hand, a number of features dis
cernible by the electron microscope indicate that both the cyst
wall and the squamous carcinoma differ markedly from the nor
mal epidermal cell.
Acknowledgments
We wish to thank Professor H. R. Carne for his help and interest
in this work, Dr. E. H. Mercer for helpful suggestions and discus
sion, and Dr. D. G. Drummond for affording us the facilities of the
Electron Microscope Unit. We should also like to thank Mrs. S.
MacLeman for cutting the sections and Mr. L. Whitlock and staff
and Mr. R. F. Jones for the preparation of the photography of the
histopathologic specimens. One of us (R. B.) carried out this
work while holding an N. S. W. State Cancer Council Research
Fellowship.
FIG. 7. Basal cell of the epidermis showing the oval nucleus (-V),the relatively regular basement membrane (BM) with the associated
half-desmosome (d), and a few tonoh'laments (T), some attached to an intercellular desmosome (D). X 15,000.
FIG. 8. Basal cells of the cyst wall showing the irregular shaped nuclei (N), the prominent intercellular spaces (S) with cellular
projections (P), electron-dense bundles of tonofilaments (T), and the irregular projections of the basal border of the cells with the
associated basement membrane (BM). X 15,000.
FIG. 9. Adjacent epidermal cells at higher magnification showing the involuted cell borders and closely applied plasma membranes
(Pm) with an obvious intercellular contact layer (Cl). Desmosomes (D) with attached bundles of tonofilaments (T) can be seen.
X 60,000.
FIG. 10. Adjacent cyst-wall cells at higher magnification showing the prominent intercellular spaces (S) with villous like cell projec
tions (P) extending into the spaces. Other cytoplasrnic constituents present include mitochondria (A/), ribonucleoprotein granules
(R), and tonofilaments (T). X 60,000.
FIG. 11. Tumor cells showing the large nuclei (N) with prominent nucleoli (Aro), intercellular spaces (S), and microvillus projec
tions (Mv). Mitochondria (A/), eridoplasmic reticulum (ER), and tonofilaments (T) are also present. X 12,500.
FIG. 12. A cell from the periphery of a tumor cell group showing the relatively large nucleus (N), basement membrane (BM), and
collagen fibers (C) in the dermis. X 15,000.
FIG. 13. Tumor cell showing a perinuclear arrangement of tonofilaments (T). X 28,500.
FIG. 14. Adjacent tumor cells at a higher magnification showing the very prominent microvilli (Mv), the intercellular space (S), and
the numerous free ribonucleoprotein granules (R), some of which are lined up unassociated with a cytomembrane (ßi). X 46,500.
FIG. 15. Part of the basement membrane (BM) surrounding a group of tumor cells showing three apparent breaks (Br) where tumor
cell cytoplasm (Cm) flows through into the dermis (D). X 28,500.
FIGS. 16, 17. Portions of basal cells from 2 cysts each showing an apparent break (Br) in the basement membrane (BM). Fig. 16,
X 30,000; Fig. 17, X 38,500.
176
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Squamous Cell Carcinoma with Keratin-filled
JANUARY
Skin Cysts
1966
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R. Borland and A. J. Webber
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CANCER
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CANCER RESEARCH VOL. 26
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An Electron Microscope Study of Squamous Cell Carcinoma in
Merino Sheep Associated with Keratin-filled Cysts of the Skin
R. Borland and A. J. Webber
Cancer Res 1966;26:172-182.
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