A Literature Review and Case Report

Osteosarcoma: A Clinical Aspect

Zachariah Hawkins
Osteosarcoma also known as osteogenic sarcoma is a type of malignant tumor
affecting osteocytes and osteoclasts [01,02]. There are only 3 cases/million
population/year of osteosarcoma [02]. It accounts for 0.2% of malignant tumors
[02]. This type of cancer is found in people in their 20s and 30s [01]. It usually
affects the shafts of long bones i.e. around the knee, upper femur or upper
humerus [01].

Background
Osteosarcoma generally arises from soft tissue tumors that infiltrate underlying bone
[03]. These soft tissue tumors include “squamous cell carcinoma, malignant melanoma,
and connective tissue tumors such as synovial cell sarcoma (malignant synovioma),
rhabdomyosarcoma, and fibrosarcoma” [03].This type of osteosarcoma is considered
diaphyseal, tumors that arise by metastiszes [03]. Tumors that are not diaphyseal are
metaphyseal [03]. Metaphyseal tumors arise without the help tumorgenic surrounding
tissue [03].

Metastatic and Benign Tumors

There are four different types of bone cells osteoprogenitor cells, osteoblast, osteocytes,
and osteoclasts [03]. Of these four different cell types osteocytes and osteoclasts play a
major role in osteosarcoma [01]. Osteocytes are responsible for bone formation. While
osteoclasts are directly opposite of osteocytes they are bone destroyers [01]. Specifically,
osteocytes make up the main cells of bone [01]. They are responsible for maintance of the
bone matrix to which they are located among the lucanae [03]. Osteoclasts are
responsible for the reabsorption during bone remodeling [01]. They are found on the
surfaces of bones [01].A sarcoma can be described as, “soft fleshy with a pseudocapsule
of pentrated by invading sarcoma [01].” Sarcomas are considered to be very metastatic in
nature [01]. Metastatsis of sarcoma cells occurs easily because they are able to excite
stroma that have thin walled vascular spaces [01]. Metastatic progression can be
described in eight steps disruption of the basement membrane, cell detachment, cell
motility, invasion, penetration of the vascular systems , circulating cancer cells, arrest,
and extravasation and proliferation [01]. For disruption of the basement membrane to
take place you must clonal expansion of the primary tumor [01]. Disruption of the
basement membrane allows cell detachment to take place [01]. This is considered the
underlying basis of metastatic progression [01]. Cell detachment is not normal among
healthy people [01]. One suspect of cell detachment is a mutation in the gene that
encodes for the protein e-cadherin. E-cadherin is a protein that keeps cells together. Cell
motility is the ability of cancer cells to move around the body through invasion of blood
vascular type systems and lymphatic system [01]. Invasion is caused by cell penetration
of the vascular system. These cancer cells are now able to circulate among the vascular
system to arrest by proliferating through yet another basement membrane this process can
be described as extravasation due to the formation of a metastaic tumor [01].Benign
tumors take residency among adjacent tissue [01]. These types of tumors are generally
considered harmless [01]. Malignant tumors are known for their “numerous normal and
abnormal mitotic figures [01].” These types of tumors are considered to be anaplasitic
[01]. Meaning the cells are able to replace normal cell on organs with malignant causing
damage to the organ [01]

Diagnosis and Epidemiology

When someone is suspected to have osteosarcoma a biopsy must be preformed [02].Out
of “all biopsy-analysed primary bone tumors” osteosarcoma accounts for approximately
15% cases [02]. Osteosarcoma largely affects males rather than females [03]. It primarily
affects people between the ages 15-25 [02]. The frequency of osteosarcoma greatly
resides in the femur, tibia, and humerus account for about 85% of all the cases of bone
cancer [02]. Out of all cases of bone cancer less than 1% occurs in the hands and feet
[02]. Stress fractures, primary swelling, “weight loss, pallor, fevor,” and anorexia are
symptoms of osteosarcoma [02].

Staging and Treatment

Treatment

There are three different types high grade osteosarcoma localized, metastatic, and
recurrent osteosarcoma [03]. Localized osteosarcoma is characterized as a primary bone
cancer. Metastatic osteosarcoma is cancer that has spread [03]. Recurrent osteosarcoma is
cancer that has reappeared without the regard of past treatments [03]. The first treatment
for localized, metastatic, or recurrent osteosarcoma is a combination of surgery along
with postoperative chemotherapy [03]. Surgery involves amputation, limb salvage, or
rotationplasty. Metastatic osteosarcomas may also include removal of metastatic nodules
[03]. Recurrent osteosarcoma treatment may result in a second-line chemotherapy
treatment [03].The primary chemotherapy drugs that are used include: “methotrexate
(MDMTX), cisplatin (CDP), adriamycin (ADM), and isofamide (IF) [03].”

Methotrexate, N-[4[[[2,4-diamino-6-pteridinyl)methyl]methy-amino]benzoyl]-L-
plutamic acid, has a chemical formula of C20H22N8O5 with a molecular weight of 454.5
[04]. MDMTX works by preventing the replication of DNA [04]. It does this by
preventing the vitamin, folic acid, present in vitamin B from playing a crucial role in
DNA synthesis, repair, and cellular replication [04, 05].

Cisplatin, cis-diaminedichloroplatinum, has a chemical formula of PtCl2H6N2 with a

molecular weight of 300.05 [07]. CDP is described as, “one of the most potent
chemotherapy agents used in human and veterinary medicine” [08]. CDP works by
inhibiting DNA synthesis [08]. It does this by nucleophilic reactions among the two
chloride atoms that are present in its structure [07, 08]. These nucleophilic reactions take
place at the “N-7 positions of adenine and guanine” mostly replacing hydroxyl groups
present on DNA [08]. The reactions can also occur with the other two nitrogenous bases
[08]. This nucleophilic reaction causes cross-linking which inhibits DNA replication
among mammalian cells [08]. CDP is often used in conjugation with limb amputation and
three other drugs in canines [12]. The three other drugs include butophanol,
dexamethasone sodium phosphate, and mannitol. Butophanol and dexamethasone sodium
phosphate is used to reduce the risk of anaphylaxis and vomiting caused by the CDP [12].
The use of CDP requires a pretreatment evaluation to test for nephrotixity [12].

Adriamycin, 5,12-naphthacenedione,10-[(3-amino-2,3,6-trideoxy-α-L-lyoxy-
hexopyranosyl)oxy]-7,8,9,10-tetrohydro-6,8,11-trihydroxy-8-(hydroxylacetly)-1-
methoxy-,hydrochloride (8S-cis)-, has a chemical formula of C27H29NO11∙HCl with a
molecular weight of 579.99 [06]. ADA works by intercalation of nucleotide bases this
inhibits nucleotide replication [06]. This affects the way DNA and RNA polymerases
work [06]. ADA also interacts with topoisomerase II forming DNA cleavable complexes
[06]. Consequently, this cleaving results in cytocidal activity [06].

Ifosfamide, 3-(2-chloroethyl)-2-[(2-chloroethyl)amino)tetrahydro-2H-1,3,2-oxazaphorine
2-oxide, has a chemical formula of C7H15Cl2N2O2P with a molecular weight of 261.1
[09]. IF works by forming phosphotriesters with DNA forming DNA-DNA cross links
thus inhibiting DNA replication [09].

Staging

Staging is important in evaluating the severity and extent of one’s cancer progression
[10]. Another reason it is important is that it allows doctor’s to design a personal
treatment regimen [10]. There are two types of systems to access cancer progression; the
TNM system and staging system [10]. These two systems are generally used in
conjugation with one another [10]. The TNM system evaluates cancer based on the extent
of the primary tumor, metastatic progression to the lymph nodes, and metastatic
progression throughout the body [10]. The “staging system” is based on numbers rather
than letters. The numbers are numerically staged from 0-IV [10]. Stage 0 is the least
severe of all cancers while stage four is the most severe [10]. Both of these systems are
based of the results from physical exams, imaging studies, laboratory tests, pathology
tests, and surgical reports [10].

Etiology
The cause of osteosarcoma is not yet known [02]. However there is much speculation of
the causes. Some believe that has viral origins [02]. Yet others believe it could come from
radiation or genetic disposition; must likely from the mutation of p53 [02]. While some
also believe it may arise from famial retinoblastoma, or fimial Li-Fravmeni syndrome
[02]. Osteosarcoma generally metastasizes rapidly to the lungs of its victims [13].

Case Study
A 21-year old was diagnosed with synchronous multifocal osteosarcoma [11].
Synchronous multifocal osteosarcoma is much rarer than its predecessor osteosarcoma
[11]. It has a reported incidence of only 1% to 3%. His original diagnosis of
osteosarcoma was a diagnosis of sift tissue injury “bruised bone [11].” However six
months after the diagnosis the patient complained of swelling of his right proximal tibia.
A plain x-ray of swollen region indicated a pathological fracture “lesion.” A biopsy of the
lesion was performed confirming “the diagnosis of high-grade intramedullary
osteosarcoma [11].” Treatment of the tumor began with five cycles of the
chemotherapeutic agents doxorubicin and cisplatin [11]. Chemotherapy was followed by
a preoperative CT scan of the affected area [11]. This revealed lesions present on the
proximal femur that was confirmed as high-grade intramedullary osteosarcoma [11]. The
patient underwent resection of the proximal tibia and distal femur with prosthetic
replacement [11]. After surgery the patient underwent three months of postoperative
chemotherapy [11]. Nine months after the surgery plain x-ray and an MRI were taken
revealing no sign of osteosarcoma [11]. The patient remains clinically well [11].

Discussion
Osteosarcoma

Osteosarcoma is a disease that has a poor prognosis. However, this disease may be
conquered in the future. The case report by Currall and Dixon Synchronous Multifocal
Osteosarcoma: Case Report and Literature Review is just one example of the methods we
are using to conquer this disease.

Synchronous Multifocal Osteosarcoma

It is still debated on the cause of synchronous multifocal osteosarcoma [11]. Some

debates have argued p53 mutations, retinoblastoma, and bone-to-bone metastasis [11].
Currall and Dixon argue that it is almost proven the cause of synchronous multifocal
osteosarcoma is a metastatic process [11].

References
[01] Robert G. Mckinnel, Ralph E. Parchment, Alan O. Perantoni, and G. Barry Pierce. The Biological
Basis of Cancer. Cambridge University Press. 1998:294-297
[02] Piero Picci. Osteosarcoma (Osteogenic sarcoma). Orphanet Journal of Rare Diseases. 2007;2(6):1-4
[03] Victor P. Eroschchenko. Atlas of Histology with Functional Correlation Eighth Edition. Williams and
Wilkins. 1996:45-61.
[04] Trexall. http://www.rxlist/trexall-drug.htm. Accessed 11/18/2008.
[05] Gilomas: Effective Treatment. http://www.gliomas.com/new_page_3.htm. Accessed: 11/17/2008.
[06] Adriamycin. http://www.rxlist/adrimycin-drug.htm. Accessed 11/18/2008.
[07] Cisplatin. http://www.rxlist/cisplatin-drug.htm. Accessed 11/18/2008.
[08] K. Barabas, R. Milner, D. Lurie, and C. Adin. Cisplatin: a review of toxicities and therapeutic
applications. Veterinary and Comparative Oncology. 2008;6(1):1-18.
[09] Ifex. http://www.rxlist/ifex-drug.htm. Accessed 11/18/2008.
[10] National Cancer Institute. Staging: Questions and Answers. 2004:1-5
[11] Verity A. Currall and John H. Dixon. Synchronous Multifocal Osteosarcoma: Case Report and
Literature Review. Sarcoma.2006:1-3.
[12] Donald C. Plumb. Veterinary Drug Handbook Second Edition 1995:293
[13]