The Adrenal Gland in Dogs with Hyperadrenocorticalism
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Vet. Path. 8: 385-400 (1971)
The Adrenal Gland in Dogs with Hyperadrenocorticalism
A Pathologic Study
D. F. KELLY,E. T. SIEGELand P. BERG
Department of Pathobiology and Department of Clinical Studies,
School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pa.
Abstract. Bilateral adrenocortical hyperplasia was present in 24 of 27 dogs with
hyperadrenocorticalism. Two dogs had a unilateral adenoma, and one had a carcinoma
of the adrenal cortex.
Bilateral cortical hyperplasia was diffuse or nodular. The difference between the two
patterns of hyperplasia was not associated with any consistent varation in the clinical or
endocrinologic features. In the three dogs with adrenal cortical neoplasia there was marked
cortical atrophy of the contralateral adrenal gland. Extracapsular nodular hyperplasia was
common in the adrenals of dogs with hyperadrenocorticalism and also in older control
dogs without endocrine disease. Ten of the dogs with bilateral adrenocortical hyperplasia
were examined postmortem; two had a chromophobe adenoma of the pituitary, but n o
pituitary lesion was found in the others.
Clinical disorders in the dog associated with enlargement of the adrenal
cortex and, putatively, with hyperadrenocorticalism have been known for
some years [l, 3, 7, 11, 171. The recent development of assay methods for
evaluation of steroid metabolism of the dog [ 12, 13, 181 has confirmed that
these clinical disorders are associated with increased excretion of metabolites
of adrenocortical steroids [2, 9, 10, 12-15].
Although the pituitary lesions associated with canine hyperadrenocorti-
calism have been described [2, 5, 161, accounts of the appearance of the
adrenal glands are lacking in detail or are taken mainly from cases in which
endocrinologic confirmation is lacking [3, 5, 16, 171. This paper describes
the gross and microscopic features of the adrenal glands from dogs with
confirmed hyperadrenocorticalism.
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Materials and Methods
Clinical Cases
This study is based on the examination of adrenal glands from 27 dogs with hyper-
adrenocorticalism. Consistent clinical features were polyuria, polydipsia, and a pendulous
abdomen. Most of the dogs developed alopecia. Lymphopenia and eosinopenia were
consistent hematologic abnormalities. Other less consistent features were hyperglycemia
and hypercholesterolemia. All the dogs had either high levels of urinary 17-ketogenic
steroids (17-KGS) (ranging from 3.82 to 24.84 mg/24 h) or an abnormal response to
adrenocorticotrophic hormone (ACTH), or both. After administration of ACTH to dogs
with bilateral adrenocortical hyperplasia there was at the least a twofold increase in
urinary 17-KGS. Adrenalectomy was carried out on 16 dogs with bilateral adrenocortical
hyperplasia. After adrenalectomy there was remission of clinical signs and regrowth of
hair. Thirteen different breeds were represented. Three breeds (dachshunds; miniature and
toy poodles) accounted for 56% of the total. No case was seen in mixed-breed dogs. Age at
presentation varied from 5 to 13 years; the median was 8.1 years. Details of the clinical,
endocrinologic, surgical, and therapeutic studies on these dogs, and the control values for
17-KGS excretion, have been published elsewhere [12-14].
Adrenals were obtained at surgery (16 dogs) or at postmortem examination of dogs (10)
that had not previously had adrenalectomy. In one dog an adrenal was removed after
euthanasia, but complete necropsy was not permitted. Surgically removed adrenals were
fixed immediately in 10% neutral formalin, trimmed free of fat, and measured. Adrenals
from the later dogs in the series were weighed. Relative weights of these adrenals were
expressed as a proportion of body weight (g/kg). After fixation for at least several hours,
the adrenals were cut either longitudinally or transversely into thin blocks that were fixed
further for several days. After routine embedding in a paraffin-polymer mixture1, sections
were cut at 5 pm and stained with hematoxylin and eosin (HE). Other stains included
Masson’s trichrome, Mallory’s phosphotungstic acid-hematoxylin, and Perls’ method
for ferric iron. Sudan I11 was used to stain neutral lipid in frozen sections. Adrenal glands
obtained postmortem were treated in a similar manner.
Control Animals
Adrenals were obtained at necropsy from six dachshunds and seven poodles, none of
which had evidence of endocrine disease. The ages of these dogs varied from 7 weeks to
8 % years; the median was 5 % years.
Results
Twenty-four of the 27 dogs had adrenocortical hyperplasia, which was
bilateral in 23 ; in the other dog only one adrenal was available for examina-
tion. The remaining three dogs each had a functioning adrenal cortical tumor
Paraplast@, Arthur H. Thomas, Philadelphia, Pa.
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with cortical atrophy in the opposite adrenal. In two dogs the tumor was an
adenoma, in the other, a carcinoma.
Adrenocortical Hyperplusiu
The size of the adrenals in this group was greater than normal (table I).
Increased volume of the adrenal gland was apparent to naked-eye examina-
tion in some dogs; in others this subjective judgment could not be made.
The adrenals were slightly rounded, and the largest was globular (fig. l), in
contrast to the normal canine adrenal gland, which is flattened in a dorso-
ventral direction. In 16 dogs in which both adrenal glands were weighed the
relative adrenal weights ranged from 0.25 to 1.42 g/kg body weight, with a
mean of 0.54 g/kg.
The external surfaces of the adrenals had extracapsular nodules of firm
hyperplastic cortical tissue (fig. 1). The size and number of these nodules
varied considerably between different dogs. Some of the larger nodules, up
to 0.2 cm in diameter, were evident on casual examination; the smallest
were microscopic. The cut surfaces of the adrenals showed an increased
amount of cortical tissue. Both diffuse and nodular forms of cortical hyper-
plasia were recognized. In the former the width of cortical tissue was in-
creased uniformly in both adrenals; in the latter there were multiple nodules
varying in diameter up to 0.8 cm. Cortical nodularity was usually most con-
spicuous in the juxtamedullary region. The hyperplasia was predominantly
diffuse in 14 dogs, nodular in one, and consisted of both diffuse and nodular
areas in nine dogs (fig. 2). In eight dogs, whose hyperplasia was of the nodular
or nodular and diffuse varieties, the range of relative adrenal weights was 0.25
to 1.42 g/kg body weight; in eight dogs with diffuse hyperplasia the range of
relative adrenal weights was 0.28 to 0.69 g/kg. The hyperplastic cortex was
pale cream, resembling that of normal cortical tissue. In each of two dogs,
Table I. Relative weights of adrenals from control dogs and dogs with bilateral
cortical hyperplasia
Adrenal Number Relative weights of adrenals, g/kg body weight
lesion of cases
0.10-0.20 0.21-0.30 0.31-0.40 0.41-0.50 0.51-0.60 >0.61
None
(control group) 13 8 4 1 - - -
Bilateral cortical
hyperplasia 16 - 2 4 2 4 4
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Fig. 1 . Capsular surface of a hyperplastic left adrenal gland. The gland is bilobed and
globular, and the surface bears several small bulging nodules of cortical tissue (arrows). x 4.
one adrenal contained, in addition, larger cortical nodules of necrotic red-
brown tissue. These nodules, the largest of which measured 1.3 x0.7x0.5 cm,
accounted for a marked difference between the weights of the right and left
adrenal glands (fig. 3).
In all adrenals in this group, cortical nodules were within capsular con-
nective tissue and were also within surrounding adipose tissue (fig. 4). The
cells of the nodules had uniform palely stained cytoplasm. In most cases
the nodules were sharply demarcated from the surrounding connective
tissue, but in one gland cortical cells extended irregularly between adipose
cells of the capsule. Capsular and trabecular collagen frequently had a hya-
line eosinophilic appearance similar to that commonly observed in normal
adrenal glands in older dogs.
In most adrenals the zona glomerulosa was of normal width and histo-
logic appearance. Occasionally it appeared to be slightly compressed. The
rest of the widened cortex consisted of cells that resembled those of the
normal zona fasciculata (fig. 5). These polygonal cells had abundant pale
eosinophilic cytoplasm that contained uniformly small, apparently empty
vacuoles. Abundant fine droplets of neutral lipid were present within the
cytoplasm of these cells. In the cortex of many adrenals there were also
occasional solitary small nodules of palely stained cells whose cytoplasm
contained larger vacuoles (fig. 6). The diffuse and nodular patterns of cortical
hyperplasia observcd grossly were confirmed by microscopic examination,
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2
Fig. 2. Cut surfaces of the right adrenal gland from a dog, illustrating the diffuse and
nodular forms of cortical hyperplasia. The cortex is diffusely widened, and a n area of
nodular hyperplasia extends into and compresses the medulla. x 4.
Fig. 3. Cut surface of a hyperplastic left adrenal gland. The dark central area consists
of a necrotic hyperplastic cortical nodule. x 4.
and smaller microscopic nodules were often found in addition to those seen
in the gross specimen. In many adrenals the usual loose arrangement of the
zona reticularis was obscured by nodules of cortical tissue that compressed
the surrounding cortex and medulla (fig. 7). In the inner cortex of several
adrenals were multiple groups of cells with unstained, coarsely vacuolated
cytoplasm and small, densely basophilic nuclei (fig. 8). The cytoplasm of
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Fig. 4 . Hyperplastic cortical tissue extends outside the fibrous capsule (c) into surround-
ing adipose tissue. HE, x 62.
these cells contained neutral lipid and small amounts of lipofuscin. The lar-
ger nodules seen grossly consisted of adenomatous cortical tissue similar to
that in the hyperplastic cortex; these nodules were partially or completely
surrounded by a narrow capsule of dense hyaline fibrous connective tissue.
Organizing thrombi were often in the lumina of arteries within this capsule.
In the largest nodule (fig. 3) the center was necrotic and infiltrated by neutro-
philic leukocytes. Similar smaller nodules were present in the opposite
adrenals.
Other histologic features were seen frequently in the cortices of these
hyperplastic adrenals. They were also common in adrenal glands of normal
older dogs and were considered to be unrelated to hyperadrenocorticalism.
These features were accumulation of hemosiderin within sinusoidal cells,
focal accumulation of lymphocytes and plasma cells, and extramedullary
hemopoiesis. One adrenal cortex contained an area of ectopic adipose
tissue.
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Fig. 5. The cortex of this adrenal gland is widened by the hyperplastic zona fasciculata
(f). The zona glomerulosa (g) is of normal width. HE, x 62.
Adrenocortical Adenoma
In one dog there was a large cortical adenoma in the left adrenal and
marked cortical atrophy of the right adrenal. The weights of the two adrenals
differed by a factor of more than 10. The larger adrenal (3.06 g) was expanded
at one pole by an ovoid nodule that measured up to 1.5 cm in diameter. Cut
surfaces of this nodule were distinctly lobulated, cystic, and pale. The nodule
was sharply demarcated from surrounding compressed tissue (fig. 9). The
Downloaded from vet.sagepub.com by guest on May 24, 2015Fig. 6. A focus of large clear cells in the middle of the zona fasciculata. HE, x 156.
Fig. 7. Two large hyperplastic cortical nodules. There is compression of thz adjacent
medullary tissue. HE, x 156.
Downloaded from vet.sagepub.com by guest on May 24, 2015Fig. 8. A hyperplastic adrenal cortex. Adjacent to the medulla (med), there are small
cortical nodules (n) and clusters of swollen lipid-containing cells. HE, x S1.
Fig. 9. Left adrenal (above) contains an adrenocortical adenoma. The atrophic right
adrenal is below. x 2.
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Hyperadrenocorticalism in Dogs 395
Fig. 11. Adrenocortical carcinoma. The tumor cells are variable in size, shape, and
appearance. They surround and are within capsular lymphatic vessels. HE, x 156.
other cortical zones. Occasional normal cortical cells were present, but most
of the atrophic cortices consisted of shrunken, palely stained cells whose
vacuolated cytoplasm contained abundant lipofuscin. Both adrenals had a
small number of well-defined nodules of pale, eosinophilic cortical cells
similar to those found in the adrenals with bilateral cortical hyperplasia
(fig. 10).
In the second dog the cystic right adrenal was lined by sheets and groups
of cortical epithelial cells. Mitoses were not seen. There was extensive necro-
sis and hemorrhage within the adenoma.
Adrenocortical Carcinoma
The right adrenal gland consisted of a spherical mass (2.5 crn in diameter)
of soft tissue that extended around and invaded the adjacent vena cava. The
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Fig. 12. Adrenocortical carcinoma. Tumor embolus is within a pulmonary artery.
HE, x 156.
cut surfaces were soft and yellow with no distinct corticomedullary demarca-
tion. The left adrenal was reduced to approximately half of its expected size.
The architecture of the right adrenal was completely obliterated by a
well-differentiated solid carcinoma. Individual cells of the tumor were large
and polygonal with abundant, pale, eosinophilic vacuolated cytoplasm.
Nuclei were large and vesicular; occasional nuclear atypia and mitoses were
seen. Lobulation of the tumor was produced by fine fibrous trabeculae;
extension of tumor within local lymphatics (fig. 11) and veins was conspi-
cuous, and invasion of the wall of the vena cava was confirmed histologically.
No gross metastasis was found, but numerous microscopic emboli were
within small pulmonary arteries (fig. 12). The left adrenal showed severe
cortical atrophy. Occasional small nodules of clear cortical cells were pre-
sent. This case has been described elsewhere [15].
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Lesions in Other Organs
Twenty-five dogs had alopecia. Histologic examination of the skin showed
various degrees of epidermal atrophy, plugging of hair follicles with keratin,
and fragmentation and mineralization of dermal collagen. In one dog
acanthosis occurred over heavily calcified dermis.
Postmortem examination was performed on 10 dogs. In eight dogs there
was bilateral adrenocortical hyperplasia. One dog had an adenoma, and one
had a carcinoma. Chromophobe adenomas of the anterior lobe of the
pituitary were present in two dogs. No pituitary lesion was found in the other
eight dogs. Hepatic fatty change was a common finding. Calcification was
observed in a variety of soft tissues and was especially conspicuous in the
pulmonary alveolar septae. The extra-adrenal lesions were essentially similar
to those described by other authors [2].
Control Dogs
The range of relative weights of the adrenals was 0.11-0.35 g/kg body
weight. Only one dog, however, had a relative adrenal weight greater than
0.25 g/kg (table I). Usually the weights of the left and right adrenals from
each dog were similar. In dogs up to 3 % years old the capsular surface was
smooth. Dogs older than 4 years usually had protruding extracapsular
nodules of adrenal cortical tissue, similar to those described in the adrenal
glands of dogs with hyperadrenocorticalism.
Histologic examination of the adrenals from the older dogs in the control
group showed that nodules of cortical cells were frequent both in and around
the capsular connective tissue and in the substance of the cortex. The com-
monest site for the latter was in the zona reticularis. In the most obvious
cases nodules of cortical tissue extended into and compressed the underlying
medulla. Change of this kind was not seen in the adrenals of dogs less than
4 years of age. The deeper cortical region in older dogs often contained cells
with swollen, pale, and vacuolated cytoplasm. In some of these cells there was
abundant cytoplasmic lipofuscin and neutral lipid. In some adrenals this
appearance was confined to solitary cells, but frequently there were clusters
of such cells, forming fatty cysts.
Discussion
The clinical syndrome with which the adrenal gland changes were
associated was caused by hyperadrenocorticalism. The evidence for this is
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the demonstration of abnormal production of adrenocortical steroids and
the striking remission of clinical signs after adrenalectomy [14]. Only a
minority (20%) of the dogs examined postmortem had pituitary lesions, and
generally lesions of the endocrine system seemed to be confined to the
adrenal. Most of the dogs that had adrenalectomy were alive at the time of
this writing and have yet to be examined postmortem. The observation of a
low incidence of pituitary lesions in this series is thus based on examination
of dogs that have not had surgical treatment. It remains to be determined if
this observation can be confirmed for the dogs that had successful adrenalec-
tomy. In another series of dogs with hyperadrenocorticalism, three out of 15
had chromophobe adenoma of the pituitary [9].
The commonest adrenal lesion was bilateral cortical hyperplasia. The
range of relative weights of the adrenal glands in this group tended to be
above that of the control dogs, although some overlap was evident. (table I).
The control group contained only a small number of dogs chosen randomly
from the two breeds in which hyperadrenocorticalism occurred most com-
monly. The concept of normality with regard to weight and morphology of
the adrenal gland may be somewhat illusory since this organ is known, in
many species, to undergo marked changes during stress. The use of glands
obtained postmortem may increase the variability within the control group,
but, with this reservation, it is clear that in most dogs with hyperadreno-
corticalism there was a marked increase in the relative weight of the adrenal
glands.
Bilateral hyperplasia was caused by diffuse widening of the cortex or by
the presence of cortical nodules of various sizes. The difference between the
two principal morphologic patterns was not associated with any consistent
difference in clinical or endocrinologic features. This morphologic distinction
is, therefore, arbitrary and without obvious functional implications.
The appearance of the abnormal adrenals described in this report appears
similar, in many respects, to that described in the simple and nodular forms
of bilateral cortical hyperplasia in Cushing’s syndrome in man [8]. The clear
histologic differentiation between the cortex of the surgically removed human
adrenal and the lipid-depleted cortex of the human gland at postmortem
examination [8] was not apparent in adrenal glands of dogs. The larger
cortical nodules appeared grossly and microscopically similar to cortical
adenoma. Histologic criteria alone, applied to these large nodules, were not
adequate to sustain a distinction between nodular hyperplasia and adenoma
of the cortex. Similar difficulties of interpretation are recognized in man
[4, 61.
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Examination of adrenal cortex adjacent to the nodules, however, allowed
a clear histologic distinction between cortical hyperplasia and adenoma. In
the latter there was diffuse atrophy of the cortical inner zones, although
occasional micronodules were present in the atrophic cortex. By contrast,
the cortex adjacent to large hyperplastic nodules was hyperplastic also. The
different appearance of the adrenal with adenoma and its contralateral
atrophied member was reflected in the gross disparity of the weights of the
two adrenal glands. At surgery the distinction between adenomatous and
hyperplastic enlargement of the adrenal should be attempted since the latter
necessitates bilateral adrenalectomy, whereas in the former case excision of
the adenomatous adrenal alone is adequate.
In all the hyperplastic adrenal glands the enlargement of the cortex
appeared to involve the zona fasciculata and zona reticularis. Extreme de-
grees of hyperplasia compressed the zona glomerulosa in a few instances but
without appreciable atrophy, as has been described by some authors [9].
Extracapsular nodules of cortical tissue were common in hyperplastic adre-
nals and tended to be larger than in adrenals of control dogs. The common
occurrence of extracapsular nodules and the variability of adrenal size makes
this feature of little value in assessing the degree of hyperplasia in an indi-
vidual dog.
The gross and microscopic features of the adrenal carcinoma allowed
confident recognition of its malignancy. The cortex of the opposite adrenal
was atrophied and contained occasional micronodules. It is not clear whether
these nodules precede the development of the tumor or whether they share
the pituitary dependence of the adrenal gland.
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Author’s address: Dr. D. F. KELLY,Department of Pathology, University of Bristol,
Medical School, University Walk, BrBtol BS8 ITD (England)
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