1. Musculoskeletal
tumors
origins, diagnosis and behavior
Brian G Caserto DVM DACVP
bgc7@cornell.edu
S2-116 Schurman Hall

2. Origin of Neoplasia
• Multistep process
• Accumulation of multiple
mutations leading to
unregulated cell
proliferation
• Tumor progression-
Average of 90 mutant
genes – in general no
single oncogene can fully
transform non-
immortalized cells in
vitro.

3. Cell Cycle Components
G0--> G1
G1-->S

4. Cell Cycle Regulation
• Normal Cell Cycle controls
• Checkpoints
• G1/S- Rb and p53
• Growth factors- upregulate fos, jun, myc - increased levels of cyclin/CDK complexes-
Phosphorylate Rb- dissociates from E2F - upregulation of more cyclins/CDK
• Cyclins/CDK complexes
• DNA damage sensor, repair- DNA damage leads to increased p53 - increased p21 and
Cell cycle arrest- GADD45 repairs DNA- p53 degraded by MDM2- if not degraded
leads to Apoptosis
• Apoptosis
• Epigenetics
• Histone deacetylation, DNA methylation and microRNA
• Hypermethylated in Cancer1 (HIC1)- loss of function by methylation leads to
inactivation of p53 in 50-85% of mouse OSA and 17% of pediatric OSA

5. Classic Theory of
Carcinogenesis
• Classic initiation promotion sequence of
carcinogenesis
• Initiation- Permanent cell mutation
(carcinogen)
• Promotors- Non-tumorogenic by
themselves, but can induce tumors in
initiated cells- non-permanent, multiple acts
of proliferation

6. Carcinogenesis
• Initiator
followed by
promotor
causes
neoplasia

7. Tumor antigens
• Tumor Antigen
• Novel protein or other antigens
• overexpression of endogenous self antigens
• antigens expressed during development-
Oncofetal antigens
• Mouse model of OSA
• MAGE, SSX, and SART-3
• Possible therapeutic targets
• T cell mediated tumor therapy

8. Bone Cells
• Osteoblasts • Chondrocytes • Osteoclasts
• Osteocytes • Blood vessels • monocyte/macrophage
• Hematopoietic cells • Osteoprogenitor lineage
• Stromal fibrous and cells
adipose tissue

9. Bone Formation
(modeling)
• Endochondral
– Cartilage precursor
– Cartilage is removed and replaced by osteoid
• Long bones
• Base of the skull, occipital bone
• Ribs, vertebrae, hips

10. Embryology
• Speckled =
Endochondral
• White =
Intramembranous
• Blue = Neural crest

11. Endochondral
Ossification
• Long bones
• Vertebrae
• Base of the
skull
• Pelvis

12. Intramembranous
ossification
• Direct differentiation of mesechymal cells into
osteoblasts (no cartilage model)
• Calvaria
• Horizontal ramus of the mandible

13. Bone Remodeling
• Bone Metabolic Unit
• Activation of Osteoblasts-
Osteoclasts
• Osteoclast resorption of
bone
• Formation of bone Woven
Bone to Lamellar in normal
remodeling

14. Patterns of Radiographic
Bone Pathology
• Geographic
• Least aggressive
• Well defined margins
• Clearly demarcated
• Possible sclerotic margins
• Motheaten
• gradual transition from normal to abnormal bone
• more aggressive
• malignant tumors and osteomyelitis
• Permeative
• Aggressive lesions with rapid growth and invasion
• Poorly demarcated
• Osteosarcoma and osteomyelitis

15. Bone Response to
Neoplasia
• Periosteal woven bone
• Any damage- clinical or subclinical with
produce periosteal reactive bone
• Response to instability
• Fracture repair
• Bone Lysis
• Increased osteoclastic activity is common
• Sclerosis
• Increased osteoblastic activity is common-
Sclerosis
• from tumor related chemicals
• repair of lost bone
• Generally no inflammation involved

16. Bone and Cartilage
producing tumors
Ossifying fibroma, Osteochondromatosis,
Osteoma, Chondroma, Multilobular tumor
of bone,Osteosarcoma, Chondrosarcoma

17. Osteosarcoma

18. Osteosarcoma

19. Osteosarcoma

20. 248
Equine OSA
Brief Communications and C
Overal
expans
distort
nounce
areas o
the cas
The ce
border
matrix
entiatio
with in
cytopla
osteoid
Clin
20 year
predile
neutere

21. Genetics of Osteosarcoma
• Rb- Retinoblastomas (hypermethylation), Osteosarcoma
• p53- Osteosarcoma- 30-85%
• CDKN2A/P16 Loss/ and impairment of p14(ARF)
• TP 53- adrenocortical tumors, Choroid plexus carcinoma and to a lesser extent OSA
• Wnt10b- overexpression leads to increased bone formation and stimulates NFkB and Notch signaling in
human OSA
• Epigenetics
• RASSF1A (ras association domain family 1A) - Tumor suppressor gene involved in Apoptosis-
Silenced in human cancer of ovary, kidney, stomach, urinary bladder, thyroid gand, and
neuroblastoma
• Hypermethylated in Cancer1 (HIC1)- loss of function by methylation leads to inactivation of p53 in
50-85% of mouse OSA and 17% of pediatric OSA
• Canine OSA
• Beta Catenin- Increased cytoplasmic concentrations in canine OSA- primary or metastatic. No
relation to survival time. Different mutation than in Human OSA
• P53- Higher cytoplasmic levels in osteosarcoma compared to other sarcomas, and highest in
chondroblastic OSA, lowest in telangiectatic
• PDGF-beta overexpressed as a result of inflammation- astrocytoma and osteosarcoma

22. Diagnosis
• Signalment and history
• Radiographs/CT/MRI can help
• Cytology
• Osteoid can be detected
• Alk phos positive
• 100% sensitive
• 89% specific
• Histopath
• biopsies must include periosteum and endosteum
• osteosarcoma may resemble granulation tissue, fracture callus, reactive
bone
• Osteochondroma require proper orientation to differentiate from
chondroma/osteoma

23. potential OSA specific
markers
• Tropomyosin Related Kinase A
receptor- Nerve and bone
• Binds Nerve Growth Factor- normal
cell differentiation, mitogenesis,
and survivial (anti-apoptosis)
• CXCR4- Metastasis
• pediatric and canine OSA
participates in metastasis
• Metastasis to lungs, bone, lymph
nodes
• receptor for SDF-1 (CXCL12)-
hematopoietic stem cells

24. Teleangiectatic
Osteosarcoma

25. Telangiectatic
Osteosarcoma

26. Variants of
Osteosarcoma
• Osteoblastic
• Chondroblastic Poor Prognosis
• Telangiectatic
• Fibroblastic
• Etiology
• Inherited, Inflammation,
ionizing radiation, viruses

27. Grading and Prognosis
• Tumor Grading
• Young dogs had higher grade tumors
• Osteoblastic more aggressive than
fibroblastic
• Distal tumors higher grade
• Cranial tumors lower grade
• Canine survival- Axial > Appendicular >
Vet Pathol 39:2, 2002 Grading System for Canine Osteosarcoma 241
Mandibular J Comp Pathol (2007) vol. 136 (1) pp. 65-73
Table 1. Classification for tumor grade determination using a predetermined histologic scores for canine osteosarcoma.
Tumor
Grade Pleomorphism Mitoses Tumor Matrix Tumor Cells Necrosis
I 0–1 ( 25%) 10 1 ( 50%) 1 ( 25%) 0–1 ( 25%)
II 2 (25–50%) 10–20 2 (25–50%) 2 (25–50%) 2 (25–50%)
III 3–4 ( 50%) 21 3 ( 25%) 3–4 ( 50%) 3–4 ( 50%)
Veterinary Pathology Online (2002) vol. 39 (2) pp. 240
middle), procurement of a fine-needle aspiration biopsy MNGC; 3 large number of MNGC). The whirl formation
– Cats- Appendicular tumors and axial corrected longer survival and scale of 0 to 3 (0
(FNAB), plasma alkaline phosphatase (AP) level tumors have was estimated on a slower metastasis than dogs formation;
no whirl
for the steroid-induced fraction (normal range, 40–120 U/ 1 minimal whirl formation; 2 moderate whirl formation;
liter),38 presence of metastases at time of diagnosis, and type 3 maximal whirl formation). Number of mitoses was cal-

28. Non-medullary OSA
• Periosteal- Low grade malignancy, slow growth, may not
be invasive
• can be chondroblastic or fibroblastic
• Parosteal- rare in animals
• Well differentiated but malignant
• fibrous, osseous, cartilage
• long bones, skull
• rare in dogs
• better clinical course and long term survival than
medullary OSA in humans

29. Multilobular Tumor of
Bone
• Slow growing, potentially malignant
• Skulls, dogs, horse, cat (intramembranous bones)
• Histo
• Islands of crude bone or cartilage surrounded by thin rim
of poorly differentiated spindle cells
• Can compress brain, spinal nerves
• Malignant transformation distorts normal architecture-
infiltrative growth into adjacent tissues or metastasis to the
lungs
• Recurrence after removal
• Radiographs- nodular to stippled pattern

30. ogical interpretation was the frontal neoplasm, probably an osteosarcoma or
a mesenchymal sinuses and extended caudally to the external occipital protuberance. A stippled mi
identified dorsal to and including the calvaria, frontal, parietal, and occipital bones. The mass a
MUltilobular Tumor of
and left frontal sinuses. Proliferation of new bone was observed involving the frontal, parietal,
bones. The mass extended into the cranial vault, compressing the cerebral hemispheres and th
Case History
There was a slight deviation of the falx cerebri to the left. The mass measured approximately 1
Bone
An 11-year-old, spayedin depth, and 9 terrierin length. Enhancement was not appreciated with intravenous administratio
female, Staffordshire cm was presented to the University of Georgia Veterinary Teaching
Hospital for examination of a mass on the cranium (Fig. 1 A and B). The owners first noticed atrophy of the
musculature of this dog!s head in October,(Conray 400).
lothalamate 2003 and a noticeable incline of the head had developed by April, 2004. The
owners also related that the dog had experienced several episodes of disorientation over the past few months.
pearance of a Wright-stained biopsy imprint of a multilobular tumor of bone. A. Two
a stellate to spindle appearance. B. Neoplastic cells with a plasmacytoid (upper left) and
pearance. C. A multinucleated cell resembling an osteoclast.
composed of multilobulated neoplastic tissues consisting of irregular islands of well defined
4). The neoplastic islands consisted of osteoblasts and osteoclasts surrounded by spindle cells.
nt within irregular lacunae and were occasionally binucleated. Mitotic figures were rare (< 1
ew). The histologic diagnosis was a low-grade multilobular tumor of bone.
Figure 1. Frontal and lateral views of a multilobular tumor of bone on the cranium of a dog (the haircoat has
been shaved prior to surgery).
Physical examination revealed a large mass on the head. On palpation, the cranial mass was very firm, immobile, and
non-painful. It measured 25 cm across the dorsum of the head from ear to ear, 15 cm from the base of the ear
forward to the frontal bone, and 8.5 cm from the base of the ears to the dorsum of the head. The remainder of the
physical examination was within normal limits.
3
Clinical laboratory abnormalities included mild leukocytosis (WBC = 15,600 x 10 /"l; reference interval = 5.1 to 13 x
3
10 /"l), increased alkaline phosphatase activity (ALP = 240 U/L; reference interval = 13 to 122 U/L), and a urine
specific gravity of 1.005.
Thoracic radiographs were unremarkable. There was no evidence of pulmonary metastases. Computed tomography
(CT) of the head was performed to evaluate the extent of the mass (Fig. 2). Transverse images were made from the
level of the third maxillary premolar caudally to the second cervical vertebra. The mass was visualized at the level of
the frontal sinuses and extended caudally to the external occipital protuberance. A stippled mineral opacity mass was
identified dorsal to and including the calvaria, frontal, parietal, and occipital bones. The mass also involved the right
and left frontal sinuses. Proliferation of new bone was observed involving the frontal, parietal, and dorsal occipital
bones. The mass extended into the cranial vault, compressing the cerebral hemispheres and thalamus bilaterally.
There was a slight deviation of the falx cerebri to the left. The mass measured approximately 12.4 cm in width, 7.5 cm
in depth, and Histologic section of a multilobular tumor of bone with intravenous administration of 60 ml of sodium
Figure 4. 9 cm in length. Enhancement was not appreciated
Figure 2. Multilobular tumor of bone involving the skull and

31. Chondrosarcoma

32. Ferret Chordoma

33. Multiple Cartilaginous
Exostoses

34. Osteochondroma
• Osteochondroma/ Multiple Cartilaginous
Exostoses
• scapula, ribs, vertebrae, pelvis
• cartilage capped protrusions near regions
of endochrondral ossification
(metaphysis)
• marrow cavities continuous with
underlying bone
• Dogs, horse
• Growth ceases at skeletal maturity
• malignant transformation is rare
• Polyostotic form (MCE) has poor prognosis-
rapid progression and euthanasia

35. Feline
Osteochondromatosis
• Progressive enlargement (neoplastic)
• 16 months- 8 years old
• Disfigurement, pain, encroachment of
joints or tendons
• Random distribution including
intramembranous bones
• Rib > Scapula > Vert > Skull > Pelvis
> Limbs
• Not limited to metaphysis
• Underlying cortex remains intact
• Presence of viral particles- importance
in not understood

36. Vitamin A toxicosis
• Cervical
Vertebal
Exostosis

37. Ossifying fibroma
• Intramembranous bones only
• Horse, slow progressive,
may cause disfigurement,
may recur
• mandible, maxilla, nasal
sinuses, face, skull,
monostotic, well
demarcated, not capped
with cartilage
• DDX: Fibrous dysplasia
(non-neoplastic)

38. Dog Ossifying Fibroma
204 Brief Communications and Case Reports Vet Pathol 45:2, 2008
Fig. 1. Computed tomographic scan; skull; dog. An expansile mass destroys alveolar and cortical bone in the
dorsal aspect of the left hemimandible and extends into gingival tissue along the buccal and lingual aspects of the
first molar tooth. Inset: Cross-section of the left hemimandibulectomy specimen through first molar tooth.

39. Nasal Osteoma Cow

40. Other Mesenchymal
Tumors of Bone
myxoma, hemangioma/sarcoma, fibrosarcoma,
liposarcoma, giant cell tumor of bone

41. Hemangiosarcoma

42. Hemangiosarcoma

43. Hemangiosarcoma
• Breeds
• Boxer, German Shepherd, Great
Danes
• Medullary and expansive, eventually
lytic

44. Hemangiosarcoma

45. Hemangiosarcoma

46. Liposarcoma

47. Metastatic Liposarcoma

48. Giant Cell Tumor of
Bone
• Rare in animals
• expansile osteolytic
• ends of long bones
• Resemble osteoclasts
but IHC suggests
histiocytic origin
• Mostly benign in
humans but locally
recur

49. Benign Tumor-like
lesions
• Exhuberant fracture callus
• Cysts
• Solitary bone cysts
• Metaphyses of long bones
• young dogs and chicldren
• Mono/Polyostotic, lytic,
expansile
• Narrowing of cortex, little
bone reaction
• Surrounded by shelves of bone
• Pathologic fracture is common
• cysts filled with clear or
sanguinous fluid

50. Benign Tumor-Like
Lesions
• Aneuysmal bone cysts
• Expansile, lytic, contained by a
thin periosteum, internal soap
bubble appearance on rads
• Tubular bones, spine in
humans
• May contain solid areas, loose
connective tissues
• Intra-osseous epidermoid cysts
• contain pale cream colored
crumbly keratin
• Digits skull in humans
• rare in dogs, and horse

51. Invasive and
Metastatic Neoplasms
Squamous cell carcinoma, malignant melanoma,
prostatic carcinoma, histiocytic sarcoma,
acanthomatous epulis, subungual melanoma, nail
bed keratoacanthoma, bronchial adenocarcinoma

52. Tumors of the Jaw
• Squamous cell carcinoma
• 77 percent have osteoclastic resorption
(dogs)
• Maxillary fibrosarcoma
• 68% invasive, may be periosteal in origin
• Melanoma
• Invasive in 50% of cases

53. Mandibular SCC

54. Mandibular SCC

55. Maxillary Fibrosarcoma

56. Maxillary Fibrosarcoma

57. Metastatic Carcinoma
• Metastasis of
carcinomas can
cause bone lysis,
sclerosis or
periosteal
proliferation

58. Prostatic Carcinoma
No. 5 OSTEOMALACIA IN SCLEROTIC BONE METASTASES * C'hlarhon CJi a/.
• Common in humans and dogs
• Sclerotic bone metastasis
(humans)
• hypocalcemia,wide band of osteoid
FIG.2. The
tissue (black)embedded in calcified
hypophosphatemia, with-
bone corresponds to a period
out vitamin D therapy. Notice the
elevatedmarrow (Goldner stained in bone
nests of malignant cells
Alk Phos section,
undecalcified bone).
• Increased production of
poorly mineralized
osteoid (50% of cases)
• Prostatic osteoblastic
ing two to six months of treatment with vitamin D and and/or his calcium absorption which is dependen
factor produced by 1 patients does provide indirect
calcium in four Group a relative vitamin D deficiency.
evidence, however, that a relative vitamin D deficiency Other factors may contribute to the bone chan
cancer cellsincrease the histologic indications of osteomalacia,
may observed in sclerotic bone metastasis from prostatic
which is also dependent on the increased bone formation cer such as estrogen therapy. The role of estrogens ei
level. The marked reduction in the prostatic cell pop- on vitamin D or bone metabolism cannot be determ
ulation noted on biopsies following estrogen therapy in this study since all of the patients except one w
could thus also encourage the regression of osteomalacia estrogen treated. Estrogens are known to inhibit the
by decreasing the bone formation rate. In this regard, sorption process in vitrd' and in vivo" and to decr

59. Neoplasia of the Digits
• Dogs
• Cats
• Squamous cell
carcinoma – Squamous cell carcinoma
• more metastatic • median survival 73 days
potential – Fibrosarcoma
• Melanoma (subungual) – Metastatic adenocarcinoma
• poor prognosis and – Osteosarcoma
median survival of
– Mast cell tumor
365 days
– Hemangiosarcoma
• Soft tissue sarcoma
– Malignant fibrous histiocytoma
• Mast cell tumor
Vet Pathol (2007) vol. 44 (3) pp. 362-5
Vet Pathol (2007) vol. 44 (3) pp. 355-61

60. Acrometastasis
• Mets to distal limbs
• Cats- Bronchial carcinoma, mammary
carcinoma
• Humans- Mammary, prostate,
pulmonary carcinoma

61. Tumors of the
Joint
Synovial carcoma, histiocytic sarcoma,
myxosarcoma

62. Synovial Sarcoma
• Origin
• Joint capsule
• Tendon Sheaths
• Behavior
• Invasive, ostelytic
• Metastatic
• Differentiation
• Spindyloid to stellate cells
• Fibroblastic
• Myxomatous

63. Hematopoietic
tumors
Plasma cell myeloma, lymphoma

64. Lymphoma-Subperiosteal

65. Lymphoma
• Occurs most often with Multicentric
lymhoma
• Dogs, cats, cattle
• Multiple discrete punched out lesions
in multiple bones in appendicular and
axial skeleton
• Rare hypercalcemia

66. LGL Leukemia
• Dog, Rats
• Large
Granular
Lymphocytic
Leukemia
• Ostelytic

67. Plasma cell myeloma
• Multicentric, lytic lesions
• Active hematopoietic areas
• Produce Ig or fragments
• Monoclonal spikes on serum
electrophoresis
• Bence jones proteinuria less
often
• Hyperviscosity syndrome and
hypercalcemia occasional and
have poor response to therapy
• Radiographic lesions in 2/3
dogs and 30% horses

68. Questions?