OSTEOSARCOMA

Etiology

Osteosarcoma is a cancerous lesion that produces mineralized bone or osteoid matrix. This is
considered as the most common primary malignant bone tumor, irrespective of melanoma and lymphoma.
It accounts for approximately 20% of all primary bone malignancies. It may occur in all ages but
commonly has a bimodal age distribution. The first peak is found in those younger than 20 years, which
may coincide with the adolescent growth spurt. This accounts for 75% of all cases. The second peak
occurs in the older age group, usually after 40 years of age, who have known predisposing conditions
such as Paget disease, bone infarcts, or who have history of radiation. Meanwhile, it is rare in the very
young. Osteosarcoma has a male predilection with the ratio of 1.6:1. It is most commonly seen in the
extremities, specifically in the metaphysis of long bones or in the region of the growth plate, which is the
area where bones grow the fastest. However, it can likewise arise in any bone of the body. Fifty percent of
cases occur in the distal femur or proximal tibia.

Acquired complex structural and numerical genetic aberrations have been found in about 70% of
osteosarcomas. Molecular studies revealed mutations in the following tumor suppressor genes and
oncogenes: RB, TP53, INK4a, MDM2, and CDK4. About 70% of sporadic osteosarcomas contain an RB
germline mutation. Another related finding suggests that the presence of this mutation increases the risk
for osteosarcoma by a thousand-fold. TP53 mutations are also commonly found in sporadic tumors.
INK4a inactivation is another mutation seen in many osteosarcomas. This leads to the cessation of the
encoding of the tumor suppressors, p16 and p14, which may contribute to the dysregulation of cyclin-
dependent kinases and p53 function, respectively. Meanwhile, over expression of MDM2 and CDK4 are
seen in low-grade osteosarcomas. The mechanism behind this is usually via the amplification of 12q13-
q15 chromosome.

Pathogenesis

There are several predisposing risk

factors that could lead to the
development of osteosarcoma.
These are growth-related factors,
somatic alterations, germline
genetics, and environmental factors.
All these can lead to the mutation of
osteoblastic DNA, which will be
further explored below. This mutation
will then enable the proliferation of
malignant osteoblasts that will lead
to the formation of osteoid tissue and
ultimately, overcrowding of osteoid
tissue within the bone.
In this diagram, the molecular
 pathogenesis of osteosarcoma has been
clearly illustrated. As with any cancer, the
etiology of osteosarcoma is DNA damage,
which could lead to either inactivation to
amplification of certain tumor suppressor
genes and oncogenes. Hypoxia is identified
as an etiological agent since it generally
damages the cells.
TP53 is a tumor suppressor gene that
functions as the gatekeeper of cells. It can
induce apoptosis on cells showing
abnormalities and it also plays a role in
transcription. However, in osteosarcoma, this
tumor suppressor gene is found to be
inactivated. On the other hand, MDM2 and
COPS3, which are cell cycle regulators and
are vital in proteasomal degradation, are amplified instead of inactivated. It is important to note that these
cell cycle regulators function to inhibit TP53. Thus, even without mutations that inactivate TP53, its
function could still be compromised when MDM2 and COPS3 have been amplified. Another gene that is
amplified in osteosarcoma is CDKN2A. It inhibits CDK4-CCND1 complex. The inhibition of this complex
leaves the RB1 in a unphosphorylated (inactivated) state. The phosphorylated RB1 will bind to the E2F
transcription factors, which interrupt the progression of the cell cycle to the S phase.

Morphology

Gross Finding. These are the gross appearances of osteosarcoma of the distal femur (A&C) and the
proximal humerus (B). The right most specimen is from the proximal tibia (D). The tan-white tumor has
filled the medullary cavity of the metaphysis likewise, that of the proximal diaphysis and has extended all
the way to the cortex. Soft tissue masses surrounding the bone can also be noted in this specimen. All of

four lesions have

invaded the soft tissues
thereby causing an
elevation of the
periosteum.

Microscopic Finding. These microscopic specimens represent the main histologic variants of conventional
osteosarcoma and these are: osteoblastic osteosarcoma (A), chondroblastic
osteosarcoma (B), and high-grade fibroblastic osteosarcoma (C).

In the last pictomicrograph, the very basophilic osteoid produced by osteosarcoma can be observed. This
is in contrast to the normal osteoid where in it appears eosinophilic and glassy and is difficult to tell apart
from hyalinized collagen. The fungal hyphae-like appearance of the osteoid is also seen here as it
presents as thin, tubular, and anatomosing microtubulae. This appearance of the osteoid is occasionally
seen in osteosarcoma.

Clinical Manifestation
 It presents as a painful and enlarging mass, usually about the knee in individuals aged between
10 to 25. In some cases, the first symptom observed is a sudden bone fracture. This bone fracture is due
to the increasing pressure within the bone that is brought by the enlarging mass. The growing mass could
also lead to marrow suppression. Hence, the patients can also present with decreased blood cell counts.

Prognosis and Treatment

A multi-modal approach is used in the treatment of osteosarcoma. This employs a neoadjuvant

chemotherapy, which is succeeded by surgery. The advent of the neoadjuvant chemotherapy had a
positive impact on the 5-year survival rate of patients with osteosarcoma. The survival rate is now at 60%
to 70% of patients receiving chemotherapy and who have no overt metastases at the time of their
diagnosis. Necrosis is another prognostic factor. Studies on post-chemotherapeutic patients showed that
those whose necrosis is greater than 90% have better prognosis than patients with necrosis below 90%.

An estimated 10% to 20% of patients with osteosarcoma have lung metastasis at initial diagnosis.
The usual pathway of tumor spread is via the hematogenousroute. Metastasis to the lungs show a poor
prognosis. In addition, 90% of the mortalities in osteosarcoma have metastases that were found in the
lungs, bones, or brain. Overall, the 5-year survival rate of those with metastases, recurrence, or
secondary osteosarcoma is less than 20%, which is considered poor. However, recent studies on the
expression of p16 has showed a correlation with response to chemotherapy.
 References

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(2019). Metallothionein: Potential therapeutic target for osteosarcoma. Journal of Oncological
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