Perspectives

History of Medicine
First case of osteosarcoma in a dinosaur: a multimodal diagnosis
Osteosarcoma is a primary bone malignancy with a the normal (specimen TMP 2014.050.0192) fibulae Division of Orthopaedic
worldwide incidence of 3·4 cases per million people per were collected from mono­ dominant Centrosaurus Surgery, Department of
Surgery (SE), Department of
year. In humans, the incidence of osteosarcoma peaks in apertus bonebeds within the Dinosaur Park and Oldman Medicine (SP, ODG, MAC),
the second decade of life, which is thought to be related formations, respectively, in southern Alberta, Canada. The Department of Mechanical
to the rapid growth velocity of bone at this age. To human specimen (figure) was obtained, with institutional Engineering (GW), and
Department of Radiology (NP),
date, the cause, genetic alterations, oncogenic events, review board approval, from an above-knee amputation McMaster University,
and evolutionary history of osteosarcoma are poorly surgical specimen. The patient was male, aged 19 years, Hamilton, ON, Canada;
understood, thus limiting further advancements in with previously diagnosed high-grade conventional Department of Biosphere-
Geosphere Science, Okayama
genome-informed targeted therapy for osteosarcoma. osteosarcoma on a core biopsy obtained from a radio­ University of Science,
Paleopathology is limited in dinosaurs because of a loss graphically identified lesion in the proximal fibula. The Okayama, Japan (KC);
of soft tissues, and varying states of fossil preservation patient received chemotherapy before the amputation. Department of Biology, Trent
University, Peterborough, ON,
and postmortem damage. Diagnosis has been further Gross pathological examination of the human fibula
Canada (RC); Joint Department
hindered by a hesitation to destructively analyse dinosaur showed a tumour centred within the medullary cavity of Medical Imaging, University
bones given their rarity and uniqueness. Unambiguous associated with cortical destruction and a large soft tissue Health Network, Toronto, ON,
Canada (AKOW); Royal Tyrrell
diagnosis of malignant cancer in a dinosaur has been mass (appendix p 2). Radiographic (x-ray, MRI, and CT)
Museum of Palaeontology,
elusive. There is a single case of reported metastatic examination of the human fibula revealed a Codman Drumheller, AB, Canada (DHT);
malignancy in a dinosaur based only on radiological triangle surrounding the proximal meta-diaphysis of the and Royal Ontario Museum,
and gross morphological examination. The lesion was a fibula, with a large, circumferential soft tissue mass. There Toronto, M5S 2C6 ON, Canada
(DMD, DCE)
suspected Ewing’s sarcoma-like reaction in a hadrosaur was cortical destruction, with ossific spicules extending [email protected]
(duck-billed dinosaur). The authors did not confirm the into the soft tissue mass. Consistent with other human We declare no competing
diagnosis histologically, nor could they confirm the source osteosarcomas, the tumour was not fully calcified and interests
of the lesion. Benign neoplasms have been described in was marked with dispersed islands of bone throughout For more on osteosarcoma
a sauropod, with the lesions confirmed macroscopically, the tumour body. The majority of bone found within evidence see SICOT J 2018; 4: 12

radiologically, and by histological analysis. There has also the tumour was dispersed as these smaller unconnected For more on paediatric
osteosarcoma see Indian J Med
been a case of osteosarcoma reported in a Triassic turtle islands, mostly exhibiting circular morphology. This Paediatr Oncol 2017; 38: 33–43
species based only on gross and radiographic examination. finding is in contrast to trabeculae, which are known to For more on genome-informed
To date, to our knowledge, no cases of malignant cancer show clearer directionality and regular separation patterns targeted therapy for
have been reported in dinosaurs with sufficient reliability aligning with the axis of force application (appendix p 3). osteosarcoma see Cancer Discov
2019; 9: 46–63
to be considered confirmed, at least by modern medical Microscopic examination showed neoplastic osteoid and
For more on the study of
standards, which require biopsy and examination at the immature bone formation with a permeative pattern metastatic malignancy in a
cellular level. replacing the intramedullary cavity and entrapped rem­ dinosaur see
Here we report the first confirmed finding of an nants of host lamellar bone. Although neoplastic cells Naturwissenschaften 2003;
90: 495–500
osteosarcoma in a dinosaur: a specimen of Centrosaurus were not present because of chemotherapy treatment
For more on the sauropod study
apertus, a herbivorous ceratopsian (horned) dinosaur response, the architecture of abnormal neoplastic bone
see Cretac Res 2016; 62: 13–17
from the Dinosaur Park Formation (AB, Canada) which formation and permeation were features sufficient to make
For more on the Triassic turtle
dates from approximately 77·0–75·5 million years ago. a diagnosis of osteosarcoma (figure). case see JAMA Oncol 2019;
This diagnosis is confirmed through gross, radiographic, The pathological dinosaur specimen (TMP 5: 425–26
and histological analysis (appendix p 1) by experts in 1989.018.0108) is the distal half to two-thirds of an For more on herbivorous
musculoskeletal oncology and human pathology, as well adult Centrosaurus fibula (appendix p 2) and is a rare case ceratopsian see Palaios 2001;
11: 482–506
as by direct comparison to a confirmed case of human of pathology of a major appendicular bone in this well
For more on the pathology of
osteosarcoma and a normal Centrosaurus fibula. Given that sampled genus. The bone would have been divided into this fibula and the
birds (as living theropod dinosaurs) and reptiles are much two pieces during the animal’s life, potentially indicating morphological abnormality see
more closely related to non-avian dinosaurs than humans, the presence of a pseudarthrosis, although this diagnosis New perspectives on horned
dinosaurs: the Royal Tyrrell
this comparison is only moderately important from a cannot be confirmed in the absence of the proximal Museum Ceratopsian symposium.
phylogenetic and physiological stand­point. However, given segment. A large morphological abnormality, previously Bloomington, IN: Indiana
the advanced diagnostics already available for human described and attributed to a healing fracture callus, University Press, 2010

patients and the highly specialised expertise in human is located in the proximal half of the specimen. Gross For more on bone growth see
Clin Orthop Relat Res 2010;
medicine, the comparison is of very high value. morphology, radiological examination, and histological 468: 1056–65
Both the pathological (figure; specimen Royal Tyrrell examination by our interdisciplinary team reinterpreted See Online for appendix
Museum of Palaeontology [TMP] 1989.018.0108) and this pathology as an osteosarcoma, with similar confidence

www.thelancet.com/oncology Vol 21 August 2020 1021

A B
regions within the lesion are reminiscent of abnormal new
bone formation. These findings are consistent with, and
similar to, the findings in the human specimen. Histological
examination similarly showed a lack of zonation with bone
maturation that would be seen if the lesion were a fracture
C callus and provided evidence that the tumour extends and
Medullary
cavity
Neoplastic
bone
permeates proximodistally throughout the cortex of the
bone. Again, this bidirectional and distant invasion is not
consistent with a fracture callus.
Normal
cortex The gross, radiographic, and histological appearance
of the dinosaur fibula we describe are very similar to
the known human osteosarcoma, despite the lack of
preserved soft tissue structures in the dinosaur fibula. Other
Medullary differential diagnoses were rejected. Specifically, these
cavity
diagnoses included (1) fracture, which was rejected because
of the extension of abnormal bone very distal to the lesion
despite more normal cortex in this location and the lack of
Normal
host cortex a proximal fracture fragment; (2) osteomyelitis, which was
rejected because of a lack of characteristic pockmarking
D E
and the bone-forming nature of the lesion; (3) non-
Normal host cortex
ossifying fibroma, which was rejected because of the highly
disorganised bone and no well defined zone of transition;
Neoplastic and (4) osteochondroma, which was rejected given that the
bone
lesion clearly does not arise from or near a physis. Thus, our
findings indicate the presence of an osteosarcoma, meeting
all the criteria discussed in terms of the morphological,
Figure: Histology of dinosaur and human osteosarcomas radiological, and histological confirmation of this diagnosis.
Top centre: Centrosaurus apertus skeleton with fibula shown in red. Comparison of
pathological half fibula (A) and normal full fibula (B) of Centrosaurus apertus with
The extensive invasion of the cancer throughout the bone
thin section images. (C) Three-dimensional reconstruction showing expansion of suggests that it persisted for a substantial period of the
the tumour (yellow) distally in contrast to normal cortex (grey) and medulla (red). animal’s life and might have invaded other body systems.
(D) Haematoxylin and eosin image of pathological left human fibula tissue
(200× magnification). (E) Haematoxylin and eosin image of pathological and
A similarly advanced osteosarcoma in a human patient, left
healthy left human fibula tissue (200× magnification). Dinosaur thin section images untreated, would certainly be fatal.
shown as taken from proximal side. Broken lines indicate sampled position of each In conclusion, to our knowledge, we provide the first
thin section. Human specimen images from 5 mm thick sections. Scale bar=5 cm.
confirmed case of malignant bone cancer in a dinosaur.
Our findings highlight the need for multimodal analysis
as would be required to confirm the diagnosis in a human of unclear or uncharacteristic lesions in extinct vertebrae.
sample. This approach is not necessary for all simple and
Gross examination of the dinosaur specimen showed characteristic lesions. However, unusual or uncharacteristic
a mass that takes up the proximal half of the specimen lesions should be considered for further diagnostic using
(appendix p 2). The compact bone covering the tumour is this multimodal approach, including those previously
very thin in some areas, suggestive of neocortex formation described before the availability and accessibility of
(appendix p 4). In addition, multiple large foramina modern diagnostic techniques. We anticipate that this
are visible, consistent with the large and permeable approach of multimodal analysis at all available levels
vessels formed during tumour angiogenesis (appendix (gross morphology, radio­logical examination, and histo­
p 2). The high-resolution x-ray CT scan of the dinosaur logical examination) will facilitate the identification of
fibula shows a Codman triangle, which is indicative of additional illnesses and injuries in other ancient species.
permeation through the cortex with periosteal reaction Evidence suggests that malignancies, including bone
from the tumour. Evidence of gross cortical and medullary cancers, are rooted quite deeply in the evolutionary history
involvement with complete disruption of the cortex is of organisms.
reminiscent of high-grade osteosarcomas. The morphology
of the primary tumour appears semiporous like trabecular Seper Ekhtiari, Kentaro Chiba, Snezana Popovic,
bone, but its organisation is highly irregular with a lack Rhianne Crowther, Gregory Wohl, Andy Kin On Wong,
of anisotropy, suggestive of a pathology that violates Darren H Tanke, Danielle M Dufault, Olivia D Geen,
patterns of bone growth dictated by Wolff’s law. Sclerotic Naveen Parasu, Mark A Crowther, *David C Evans

1022 www.thelancet.com/oncology Vol 21 August 2020