osseous metaplasia within a canine insulinoma
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C A S E R E P O R T
Osseousmetaplasia within a canine insulinomaEmily M. Pieczarka, Duncan S. Russell, Kelly S. Santangelo, Famke Aeffner, Mary Jo Burkhard
Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA
KeyWords
Bone, dog, islet cell carcinoma, pancreas
Correspondence
Mary Jo Burkhard, Veterinary Biosciences,
1925 Coffey Rd., Columbus, OH 43210, USA
E-mail: burkhard.19@osu.edu
DOI:10.1111/vcp.12117
Abstract: An 11-year-old male castrated mixed-breed dog was presented
for exercise intolerance, tetraparesis, and persistent hypoglycemia. Abdom-
inal ultrasound examination revealed 2 nodules within the right limb of
the pancreas. Cytology from one nodule was consistent with a carcinoma
of neuroendocrine origin, with a primary differential diagnosis of insulino-
ma. Histologic evaluation and immunohistochemistry for synaptophysin
and insulin confirmed the diagnosis of insulinoma. Additionally, there was
a solitary nodule of mineralized compact bone composing approximately
60% of the mass. To the authors’ knowledge, this is the first report of osse-
ousmetaplasia within an insulinoma (islet cell carcinoma).
Case Presentation
An 11-year-old male castrated mixed-breed dog was
presented to the Ohio State University Veterinary
Medical Center (OSUVMC) for evaluation of exercise
intolerance and tetraparesis for several weeks’ dura-
tion, as well as persistent hypoglycemia. Serum chem-
istry performed at OSUVMC showed sustained marked
hypoglycemia (36 mg/dL; reference interval [RI]
77–126 mg/dL), mild hypokalemia (3.92 mEq/L; RI
4.2–5.4 mEq/L), and mildly elevated total serum ALP
activity (148 IU/L; RI 15–120 IU/L]) with significantly
increased corticosteroid-induced ALP isoenzyme activ-
ity (138 IU/L; RI 0–6 IU/L). An abdominal ultrasound
examination identified 2 hypoechoic nodular struc-
tures measuring 2.9 9 1.9 cm (cranial nodule) and
3.3 9 1.4 cm (caudal nodule) in the right limb of the
pancreas. The echogenicity of these nodules was heter-
ogenous with focal hyperechoic shadowing regions. A
fine-needle aspirate of one pancreatic nodule revealed
many variably sized clusters of large, round to polygo-
nal shaped cells within a background of blood and
numerous bare nuclei (Figure 1). Neoplastic cells dis-
played mild-to-moderate anisocytosis and anisokaryo-
sis. Nuclei were round to oval, centrally placed, and
had a fine chromatin structure with 1–3 prominent
round to ovoid nucleoli. These cells had moderate
amounts of basophilic cytoplasm that frequently con-
tained multiple small punctate vacuoles. Occasional
cell clusters contained distinct intercellular junctions
and/or piling of cells, as well as multiple ruptured cells.
Rare binucleated cells, nuclear molding, and mitotic
figures were observed. These findings were compatible
with a carcinoma of neuroendocrine origin. The
primary differential diagnosis was an insulinoma.
Thoracic radiographs were acquired prior to sur-
gery and revealed no evidence of metastasis. A partial
pancreatectomy was performed of the right limb along
with surgical excision of 2 regional lymph nodes, and
Figure 1. Fine-needle aspirate of a pancreatic mass in a dog. Note a
cluster of malignant epithelial cells with moderate amounts of pale baso-
philic cytoplasm with varying numbers of small punctuate vacuoles, and
round nuclei with a fine chromatin structure and prominent nucleoli.
There are also a few bare nuclei and ruptured cells, suggestive of neuro-
endocrine origin. ModifiedWright–Giemsa. Bar = 10 lm.
Vet Clin Pathol 43/1 (2014) 89–93©2014 American Society for Veterinary Clinical Pathology and European Society for Veterinary Clinical Pathology 89
Veterinary Clinical Pathology ISSN 0275-6382
all tissues were submitted for routine histopathologic
examination. Gross examination of the surgical speci-
men revealed a solitary, hard, roughly round, white to
tanmass about 9 mm in diameter within the right limb
of the pancreas. The second nodule identified via ultra-
sound was not found on gross examination of the sur-
gical specimen despite complete sectioning of the
tissue. Microscopically, approximately 50% of the
mass was composed of densely arranged packets of
monomorphic polygonal cells interspersed by a deli-
cate fibrovascular network. The mass was partially
delineated by a thick fibrous capsule, with nodular
aggregates of neoplastic cells that infiltrated the cap-
sule and the surrounding parenchyma. The architec-
ture of the lymph node had been entirely effaced by
similar cells. They had ample, finely granular eosino-
philic cytoplasm, with basilar to centrally located
round nuclei, which had clumped chromatin, and a
single centrally located nucleolus. There was mild-
to-moderate anisocytosis and anisokaryosis with
occasional binucleated cells. Mitotic figures were rare
(< 1 per 10 high-power fields). Embedded within the
neoplasm and composing the remainder of the mass,
there was a single nodule of broad and irregularly
arranged, anastomosing trabeculae of mineralized
compact bone. Bony trabeculae were lined by a single
layer of osteoblasts, and the matrix contained loosely
arranged osteoblasts within lacunae (Figures 2 and 3).
Numerous neoplastic cells and pigment-laden macro-
phages (hemosiderophages) were scattered between
the trabeculae.
Immunohistochemistry of the neoplasm was per-
formed by the avidin-biotin-peroxidase method (ABC
elite reagent; Vector Laboratories, Burlingame, CA,
USA). Primary antibodies included synaptophysin
(1:100; Dako, Glostrup, Denmark), chromogranin A
(1:400; Dako), and insulin (1:50; Invitrogen, Grand
Island, NY, USA). Diaminobenzidine was used as the
chromogen; slides were counterstained with Harris’
hematoxylin. Neoplastic cells showed strong intracel-
lular staining with synaptophysin immunohistochem-
istry (not shown), supportive of the diagnosis of
neuroendocrine carcinoma. Subsequent staining of
the neoplastic cells with insulin was also strongly posi-
tive, compatible with a diagnosis of an insulinoma
(Figure 4). The chromogranin A immunohistochemis-
try was not interpretable due to excessive background
staining.
The dog recovered well following surgery. At the
time of discharge, the tetraparesis had significantly
improved and blood glucose was stable. Within one
month of discharge postoperatively, the dog was re-
presented for increased liver enzymes, tetraparesis,
and respiratory distress. Fluid was noted in the abdo-
men, and cytology of an abdominal fluid sample
showed neutrophilic inflammation with clusters of
malignant neuroendocrine epithelial cells consistent
with an exudate accompanied by a neoplastic effusion.
Based on cell morphology, the neuroendocrine cells
were most consistent with the previously diagnosed
Figure 2. Histologic section of the right limb of the pancreas in a dog.
The parenchyma is disrupted by an expansile, partially encapsulated and
mildly infiltrative, multilobulated mass that consists of densely arranged,
monomorphic polygonal cells. Approximately 50% of the mass is com-
posed of metaplastic, mature trabecular bone. H&E. Bar = 5 mm.
Figure 3. Histologic section of bone within an islet cell carcinoma in
the pancreas of a dog. Monomorphic polygonal cells are interspersed
by delicate fibrovascular stroma, typical of neuroendocrine packeting.
Cells have moderate amounts of finely granular eosinophilic cyto-
plasm, basilar or centrally located round nuclei, clumped chromatin,
and a single prominent nucleolus. Interspersed amongst the neoplas-
tic cells are broad and irregularly arranged, anastomosing trabeculae
of mineralized compact bone containing loosely set osteoblasts within
lacunae. H&E. Bar = 100 lm.
Vet Clin Pathol 43/1 (2014) 89–93©2014 American Society for Veterinary Clinical Pathology and European Society for Veterinary Clinical Pathology90
Osseous metaplasia within a canine insulinoma Pieczarka et al
islet cell carcinoma. However, per owner request, no
further testing was performed to evaluate the extent of
metastasis. Due to the grave prognosis, the dog was
humanely euthanized. A necropsy was declined.
Discussion
Insulin-secreting beta-cell neoplasia (insulinoma) is
the most common tumor arising from pancreatic islets
in the dog.1 The majority of canine insulinomas are
malignant solitary masses, predominantly identified in
the duodenal (right) limb of the pancreas.2–4 Beta-cell
adenomas occur less frequently than carcinomas, but
both tumors may cause significant endocrine distur-
bances and clinical signs through oversecretion of
insulin.5–7 Insulinomas have been found in dogs from
3–15 years of age, with a mean of 9 years.8 There is no
apparent sex predilection and no breed predisposition
has been reported; however, most cases involve
medium- to large-breed dogs.8 Islet cell adenomas
typically occur as small (1–3 cm), single or less often
multiple nodules that are sharply delineated and sur-
rounded by a partial or complete thin, fibrous capsule.
Islet cell carcinomas are usually larger than adenomas,
are multilobular, invade adjacent pancreatic paren-
chyma, and may metastasize. Histologic evidence of
capsular invasion is considered a critical diagnostic
feature of malignancy.9
The clinical signs of tetraparesis and clinicopatho-
logic findings of persistent hypoglycemia, mild hypo-
kalemia, and mildly increased serum ALP activity in
the current case are consistent with previous reports of
dogs with insulin-secreting islet cell tumors.2–4 In
healthy dogs, hypoglycemia of less than 80 mg/dL is
corrected through complete inhibition of insulin
secretion, while counterregulatory hormones such as
glucagon, catecholamines, growth hormone, and
glucocorticoids are increased.8 However, neoplastic
beta cells secrete insulin independent of blood glucose
concentration, resulting in persistent and unregulated
hypoglycemia accompanied by normal or increased
blood insulin levels in most cases. As a consequence,
hypoglycemia of the central nervous system or neuro-
glyocopenia leads to the clinical signs of tetraparesis.8
It is well-recognized that hyperinsulinism induces
hypokalemia via intracellular potassium shifting, inde-
pendent of glucose transport.10 Although serum insu-
lin was not measured in the current case, the mild
hypokalemia is likely the result of hyperinsulinemia
due to unregulated insulin secretion from tumor cells.
The mechanism of increased ALP in dogs with insuli-
nomas has not been clearly defined, but may be associ-
ated with increased secretion of glucocorticoids in
response to the hypoglycemia, and/or chronic stress.
This explanation is supported in the current case
because the majority of increased serum ALP activity
was attributable to the corticosteroid-induced ALP iso-
enzyme. Although bone ALP has been linked to
increased osteoblastic activity in tumors such as osteo-
sarcoma,11 the amount of bone formation in the cur-
rent case was likely insufficient to appreciably
contribute to total ALP activity. In a study comparing
dogs with mammary tumors with and without the
presence of osseous transformation, there was no
significant difference in bone ALP activity between the
2 groups.12 Furthermore, when the 2 groups were
independently compared to a control population, bone
ALP activity was significantly increased only in the
group with mammary tumors lacking bone, suggesting
that small amounts of bone formation in tumors may
not significantly affect measured serum activity of
bone ALP.
Intratumoral bone can be found in a variety of epi-
thelial and mesenchymal neoplasms other than those
primarily derived from osteoblasts. In people, mature
bone has been reported in a number of extra-osseous
neoplasms. In veterinary species, bone is commonly
identified in fibromas derived from the periodontal lig-
ament, maxillary fibromas of young horses, canine
mixed mammary tumors, and in some chondrosarco-
mas.13–16 Less frequently, bone has been described
within canine mixed thyroid tumors, mixed apocrine
sweat gland tumors, gastrointestinal adenocarcinomas,
oral malignant melanomas, and a pancreatic exocrine
adenocarcinoma in a ferret.17–22 The current case
Figure 4. Histologic section of an islet cell carcinoma in a dog. Strong
positive staining for insulin within neoplastic cells, consistent with a diag-
nosis of insulinoma. Diaminobenzidine chromogen, Harris’ Hematoxylin
counterstain. Bar = 25 lm.
Vet Clin Pathol 43/1 (2014) 89–93©2014 American Society for Veterinary Clinical Pathology and European Society for Veterinary Clinical Pathology 91
Pieczarka et al Osseous metaplasia within a canine insulinoma
represents the first report of bone formation within an
insulinoma (islet cell carcinoma) in animals or people.
Intratumoral bone formation can originate from
2 basic mechanisms, either osseous metaplasia or
endochondral ossification. In osseous metaplasia,
nonosteoblastic cells are directly transformed into os-
teoblasts. However, identifying the cell of origin
responsible for metaplastic bone can be challenging.
In canine mammary tumors, for example, it is still
unclear whether bone forms from metaplasia of
epithelial cells, stromal connective tissue, or basal/
myoepithelial cells.23,24 In endochondral ossification,
ground substance is secreted and converted into
hyaline cartilage, which subsequently undergoes
endochondral ossification. For instance, myoepitheli-
al cells in benign or malignant mammary tumors can
secrete a mucinous ground substance that converts
to cartilage, and then undergoes endochondral ossi-
fication.16 As there was no evidence of ground
substance or cartilage in the current case, it was con-
cluded that the bone formed via osseous metaplasia.
Acknowledgments
Special thanks to Drs. Bridget Urie and Andrew Mercurio
for their clinical management and follow-up with the case.
The authors also thankMarc Hardman for providing techni-
cal assistance with the images.
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