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Background

This is one of the most common primary bone tumors usually presenting within the first two decades of life. It presents in long bones during periods of the most active bone growth. It most commonly presents with pain and soft tissue swelling of 1-8 months duration. Surprisingly, pathologic fractures are present in only 5% of cases. With combination chemotherapy and surgery, cure rates as high as 70-80% have been obtained when prior to this, only 10-20% 5 year survival rates were achieved.

Conventional intramedullary osteosarcomas comprise 90% of all osteosarcomas but there are several important variants. These are listed below and described in detail in the outline.

Multifocal
Telangiectatic
Small cell
Intraosseous well-differentiated
Intracortical
Periosteal
Paraosteal
High-grade surface

OUTLINE

Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/
Other Diagnostic Testing
 
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/
Immunohistochemistry/
Electron Microscopy
 
Differential Diagnosis  
Prognosis  
Treatment  
Commonly Used Terms  
Internet Links  

 

EPIDEMIOLOGY CHARACTERIZATION
SYNONYMS Conventional intramedullary osteosarcoma
INCIDENCE

Most commonly biopsied primary bone tumor excluding multiple myeloma

16% of all primary bone tumors at the Mayo Clinic
19% of all malignant bone tumors

AGE RANGE-MEDIAN 85% develop <30 years
60% in second decade of life
SEX (M:F)
1.25:1
EPIDEMIOLOGIC ASSOCIATIONS CHARACTERIZATION
Radiation therapy  

 

DISEASE ASSOCIATIONS CHARACTERIZATION
Bone infarct  
Fibrous dysplasia  
Giant cell tumor  
Osteoblastoma  
Osteogenesis imperfecta  
Osteomyelitis, chronic  
Paget's disease of the bone  
Retinoblastoma, bilateral familial  

 

PATHOGENESIS CHARACTERIZATION
Familial cases

Deletion of chromosome 13 inactivating the retinoblastoma gene (RB gene)

Patients with familial disease inherit one inactive and one active RB gene-thus only one hit or mutation is required to develop cancers

Sporadic tumors require inactivation of both copies of the diploid chromosome 13 before a cancer may develop

ONCOGENES  


Molecular Analysis of p53, MDM2, and H-ras Genes in Osteosarcoma and Malignant Fibrous Histiocytoma of Bone in Patients Older than 40 Years.

Kawaguchi K, Oda Y, Sakamoto A, Saito T, Tamiya S, Iwamoto Y, Tsuneyoshi M.

Department of Anatomic Pathology (K-iK, YO, AS, TS, ST, MT), Pathological Sciences and Department of Orthopaedic Surgery (YI), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Mod Pathol 2002 Aug;15(8):878-88 Abstract quote

Some investigators have reported that the histological features of osteosarcoma (OS) arising in elderly patients are different from those in younger patients; however, a molecular biologic study of OS in elderly patients has not been documented. In this study, 23 cases of OS (15 osteoblastic and 8 MFH-like types) and 18 cases of MFH of bone in patients 40 years of age or older were analyzed for mutation of the p53 gene, amplification of the MDM2 gene, and mutation of the H-ras gene, using formalin-fixed paraffin-embedded materials.

We also examined the expression of p53, MDM2, and p21WAF1 protein immunohistochemically and assessed the proliferative activities using the monoclonal antibody MIB-1. p53 immunoreactivity was recognized in 5 of 23 OS cases (22%), whereas p53 gene mutations were also detected in 5 of 23 OS cases (22%; osteoblastic [4/15; 27%] and MFH-like [1/8; 18%] types) and in 4 of 18 cases of MFH of bone (22%). There was a statistically significant correlation between p53 immunoreactivity and p53 mutation status in OS (P =.0482). All those cases of osteoblastic OS and MFH of bone that had p53 mutations, with the exception of one case of MFH of bone that had a silent mutation, showed aggressive biologic behavior (dead of disease within 12 mo), in contrast to the MFH-like OS cases (alive without disease at 22 mo). Three cases of OS (13%) and three cases of MFH of bone (17%) showed immunoreactivity for MDM2. As for gene alteration, three cases of OS (13%) and 3 cases of MFH of bone (17%) demonstrated MDM2 amplification. MDM2 amplification showed a significant correlation with the expression of MDM2 protein in OS (P =.0344). p21WAF1 expression was detected in three cases of OS (13%) and in six cases of MFH of bone (33%). MDM2 alteration and p21WAF1 expression were not observed in any of the cases of MFH-like OS. MIB-1-LI showed a statistically significant correlation with p53 immunoreactivity and MDM2 immunoreactivity in OS (P =.0307 and P =.0358, respectively). H-ras mutation at Codons 12 and 13 was not recognized in any of the cases of OS or MFH of bone.

In conclusion, although treatment differences during the time of study make it difficult to compare survival analysis, in the current study, p53 mutation in osteoblastic OS and MFH of bone in elderly patients seemed to be closely associated with the progression of the tumor, which was not the case in MFH-like OS. Furthermore, MDM2 alteration and p21WAF1 expression were demonstrated only in osteoblastic OS and MFH of bone, whereas they were not recognized in MFH-like OS. Although the number of patients in this analysis was small, it would appear that MFH-like OS may have some characteristic biologic aspects when compared with osteoblastic OS and MFH of bone in elderly patients.

von WILLEBRAND FACTOR  
von Willebrand factor expression in osteosarcoma metastasis.

Eppert K, Wunder JS, Aneliunas V, Kandel R, Andrulis IL.

[1] 1Fred A Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada [2] 2Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada.
Mod Pathol. 2005 Mar;18(3):388-97. Abstract quote  

A number of genes are implicated in the initiation and progression of osteosarcoma; however, cytogenetic and comparative genomic hybridization studies indicate the involvement of additional unidentified genes.

An examination of gene expression profiles in 22 high-grade osteosarcoma tumor specimens from 15 patients (including paired primary and metastatic samples from five patients) indicated that von Willebrand factor (vWF) mRNA expression may increase during tumor progression. vWF, a large glycoprotein previously considered to be expressed exclusively by endothelial cells and megakaryocytes, is involved in platelet aggregation and adhesion to the subendothelial matrix, processes critical to hematogenous tumor cell metastasis to the lung. Analysis of paired primary and metastatic osteosarcoma tumor samples from 10 patients revealed an increase in vWF gene expression in metastases (P=0.005).

Immunohistochemistry showed that, in addition to the endothelial cells, vWF protein was also detected in osteosarcoma cells in vivo in 13 of 29 tumor specimens as well as in SAOS2, an osteosarcoma cell line. The tumor cell staining correlated positively with high vWF expression in the sample (P=0.006). Although vascular endothelial cells contribute to the vWF mRNA detected in the tumor samples, there was neither any correlation between vascular density (VD) and vWF mRNA expression nor between VD and clinical outcome.

These findings suggest that vWF expression is deregulated in osteosarcoma tumors, potentially contributing to metastasis.

 

LABORATORY/
RADIOLOGIC
CHARACTERIZATION
Serum alkaline phosphatase Elevated
ARTERIOGRAPHY  
The value of serial arteriography in osteosarcoma: delivery of chemotherapy, determination of therapy duration, and prediction of necrosis.

Cullen JW, Jamroz BA, Stevens SL, Madsen W, Hinshaw I, Wilkins RM, Cullen P, Camozzi AB, Fink K, Peck SD, Kelly CM.

Childhood Hematology Oncology Associates, Presbyterian/St. Luke's Medical Center, 1601 East 19th Avenue, Suite 3250, Denver, CO 80218, USA.


J Vasc Interv Radiol. 2005 Aug;16(8):1107-19. Abstract quote  

PURPOSE: To investigate the value of serial arteriography to assess tumor response, predict necrosis, and individualize the duration of a combined intravenous (IV) and intraarterial (IA) neoadjuvant chemotherapy protocol in patients with biopsy-proven high-grade osteosarcoma or malignant fibrohistiocytoma of bone.

MATERIALS AND METHODS: Between July 1987 and March 2003, 109 patients completed a chemotherapy protocol of neoadjuvant IV doxorubicin and IA cisplatin. Patients were eligible regardless of age, disease stage, or disease site. A minimum of three IA cycles followed by definitive surgery was required for inclusion in the final analysis. IA dose and duration were increased for tumors larger than 10 cm. Initial arteriograms were scored as indicating mild, moderate, or marked tumor neovascularity (TNV). Subsequent arteriograms were prospectively compared with the baseline image for percent change in TNV. Treatment continued until a maximum of five cycles were administered or one of three criteria were met: (i) at least 90% decrease in TNV, (ii) plateau of effect, or (iii) no response.

RESULTS: Of 408 IA procedures, 42 patients underwent three cycles, 53 underwent four, and 14 required five cycles of neoadjuvant therapy. There was a 2.5% minor complication rate. Eighty-six percent of patients exhibited at least 90% decrease in TNV and 82% exhibited good histologic response (> or =90% tumor necrosis). Serial arteriography predicted a good histologic response with an accuracy of 90% and a sensitivity of 97%.

CONCLUSIONS: Serial arteriography was highly sensitive and accurately predicted good responses. This individually modified, dose-intensified neoadjuvant protocol yielded an excellent histologic response rate with minimal complications. Future endeavors should involve a multiinstitutional study of this unique approach.
RADIOGRAPHS

Lytic, sclerotic, or both

Classic finding of large infiltrating metaphyseal tumor arising in medullary bone and eroding through the cortex

Cumulus cloud densities form within the intramedullary and soft tissue components caused by mineralizing tumor osteoid

Codman triangles form in the overlying periosteal bone, associated with sunbursts and onionskins

 

GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION
Site Tubular bones, most common with the longer the bone growing in length and time, the greater the risk of cancer
Appearance

Usually deep penetration of the cortex with a large extraosseous tumor, often with proximal extensions and skip lesions

Osteoblastic elements are white-tan, yellow and firm
Chondroblastic elements are translucent lobules
Fibroblastic elements are tan, soft, and firm

Hemorrhage and necrosis is common

VARIANTS  
Multifocal Divided into synchronous and asynchronous
Synchronous

Lesions discovered within 6 months of each other

Often symmetric appearance with similar size and not a dominant lesion
Rarity of osseous metastasis
Usual absence of pulmonary metastasis

Childhood form is most common in 10 years of age with tumors confined to the medullary cavity with minimal extraosseous extension

Adult form less common with mean 37 years

Asynchronous
Develop less than 24 months after the initial lesion
Telangiectatic
0.4-12% of osteosarcomas
Pathologic fractures in 25%
Hemorrhagic and necrotic tumor
Small cell
1-4% of osteosarcomas
Similar presentation to conventional osteosarcomas
70% in first or second decades of life
90% have at least focal osteoblastic features
Intraosseous well-differentiated

1-2% of osteosarcomas
Peak incidence third decade
May affect older adults
Metaphyseal regions of long bones
85% central medullary lesions by radiographs

Intracortical
Very rare
Diaphyses of lower extremity long bone
Intracortical lucency surrounded by sclerosis
Periosteal
<2% of osteosarcomas
Subtype of surface osteoscaroma
Predilection for diaphyseal region of long bones
Located on the external surface of the cortex and extends into the surrounding soft tissue
May not invade the medullary cavity
  Ann Diagn Pathol 2000;4:300-302
Periosteal Osteosarcoma of the cranium
Paraosteal

5% of all osteosarcomas
Arises from the juxtacortical region of the long bones
Striking predilection for the distal femur, especially the posterior aspect
Dnese mushroom shaped mass attached to the outer metaphyeal cortex by broad base-as it grows it may encricule the involved bone-separated from the cortex by a narrow lucent zone

High-grade surface

Arises from the outer cortex of the bone with minimal or absent intramedullary expansion

Very rare
Median 20 years

Involves the diaphyseal or less commonly the diaphyseal-metaphyseal regions
Distal femur most common

Partially mineralized mass attached to the outer cortical surface with some cortical erosion

JAW  


Low-grade osteosarcoma of the jaw.

Zhao W, Cure J, Castro CY.

Departments of Pathology and Radiology, University of Alabama at Birmingham.

Ann Diagn Pathol 2002 Dec;6(6):373-7 Abstract quote

We describe a case of low-grade osteosarcoma of the jaw. The patient is a 25-year-old woman who presented with large, nontender, slowly progressive, expansile left mandibular mass. X-ray showed a predominantly hypodense mass with erosive growth pattern affecting the angle, posterior body, and ramus of the left mandible. The patient underwent left hemimandibulectomy. The tumor was a white-tan, well-circumscribed, multinodular, firm mass that measure 7.0 cm.

Microscopically, the tumor was composed of bland spindle cells, with minimal cellular atypia, absent mitotic figures, very focal osteoid formation with extensive bone destruction, and soft tissue infiltration. Immunhistochemical stains for a large panel of antibodies were noncontributory.

At present the patient is alive and well 7 months after surgery.

LARYNGEAL  

Laryngeal osteosarcoma: A clinicopathologic analysis of four cases and comparison with a carcinosarcoma


Fernando Martinez Madrigal
Luz Maria Ruiz Godoy
Keyla Pineda Daboin
Odile Casiraghi
Abelardo Meneses Garcia
Mario A. Luna, MD

Ann Diagn Pathol 6: 1-9, 2002. Abstract quote


We report the clinicopathologic findings of four cases of laryngeal osteosarcoma and one of carcinosarcoma with osteosarcoma components.

The tumors occurred in men ranging in age from 50 to 69 years within a median age of 63.3 years. The most common symptoms were hoarseness, dyspnea, and obstruction, or a combination of these. Biopsy material and intraoperative frozen sections usually showed a high-grade sarcoma, but the diagnosis of osteosarcoma was quite apparent on microscopic examination of the surgical specimen. The primary differential diagnosis is spindle cell carcinoma with osteoid formation. Pulmonary metastases and local recurrences were common.

Surgery is the treatment of choice, followed by adjuvant chemotherapy. Whether to use radiotherapy or not should be decided on an individual basis.

SKIN  
Primary cutaneous osteosarcoma of the scalp: a case report and review of the literature.

Department of Human Pathology and Oncology, University of Florence, Florence, Italy.

 

J Cutan Pathol. 2007 Jan;34(1):61-4. Abstract quote

We report on an 84-year-old man with a solitary, nodular lesion on the scalp. The patient had been previously submitted to electrodessications of the scalp due to multiple solar keratoses.

Histopathologically, the lesion showed features of a high-grade conventional osteoblastic osteosarcoma involving the dermis. Computed tomography showed no involvement of the underlying bone tissues. Clinical examination and extensive total body radiologic workup revealed absence of bone lesions in any body site, thus suggesting a final diagnosis of primary cutaneous extraskeletal osteosarcoma.

The clinico-pathological features of the case are discussed in light of the rare cases previously described in the literature.

 

HISTOLOGICAL TYPES CHARACTERIZATION
General

Must show malignant osteoid formed by malignant osteocytes

Stromal component may appear as fibrosarcomatous, chondroblastic, giant cell, small cell, telangiectatic, or malignant fibrous histiocytoma like

Stromal cells have high grade nuclei, numerous mitotic figures, and variable patterns of mineralization of the osteoid

Fibrosarcomatous  
Giant cell  
Chondroblastic  
Osteosarcoma
Anatomic and Histologic Variants


Michael J. Klein, MD, and Gene P. Siegal, MD, PhD

Am J Clin Pathol 2006;125:555-581
Abstract quote

Osteosarcoma is the most common primary tumor of bone, yet its absolute incidence among malignant tumors is low. Within its strict histologic definition, osteosarcoma comprises a family of lesions with considerable diversity in histologic features and grade. Its prognosis is dependent not only on these parameters but also on its anatomic site. It may occur inside the bones (in the intramedullary or intracortical compartment), on the surfaces of bones, and in extraosseous sites. Information of diagnostic or prognostic significance has not been elucidated from studies of its cytogenetics.

This review summarizes the anatomic and histologic variations of osteosarcoma and offers a schema for its subclassification.
VARIANTS  
Aneurysmal bone cyst variant
Low power appearance similar to ABC
Necrosis is usually sparse or absent
Cyst wall contains enlarged, densely hyperchromatic nuclei and atypical mitotic figures
Osteoid is focal
CENTRAL LOW GRADE  

Central low-grade osteosarcoma with pagetoid bone formation: a potential diagnostic pitfall.

Franchi A, Bacchini P, Rocca CD, Bertoni F.

1Department of Human Pathology and Oncology, University of Florence, Florence, Italy.

Mod Pathol. 2004 Feb 13 Abstract quote

Central low-grade osteosarcoma is an uncommon form of osteosarcoma, which is often difficult to distinguish from benign bone lesions.

We reviewed the radiographic studies, the histologic material and the clinical records of two patients with central low-grade osteosarcoma that closely simulated the histologic appearance of Paget's disease of bone. The patients were two women aged 46 and 53 years. Radiologically, they presented a large ill-defined densely sclerotic lesion involving the proximal tibia. Both lesions only focally presented the conventional histologic appearance of central low-grade osteosarcoma, with a proliferation of fibroblast-like cells embedded in a dense collagenous stroma and irregular anastomosing tumor bone trabeculae.

The most striking feature was the presence of extremely thickened irregular plates of bone with an irregular mosaic pattern of cement lines that closely resembled that of Paget's disease of bone. One patient, who had been initially treated for Paget's disease for 7 years, experienced disease progression. At resection of proximal tibia, there was evidence of dedifferentiation to high-grade osteosarcoma. After 2 months, she developed local recurrence that was treated with above-knee amputation, followed by chemotherapy. She died with multiple lung metastases 4 months later. The other patient is alive 9 months after wide tumor resection.

These cases further expand the spectrum of central low-grade osteosarcoma, and underscore the diagnostic difficulties in separating central low-grade osteosarcoma from benign bone diseases, which may lead to delay in diagnosis, inadequate treatment, and eventually to dedifferentiation. Recognition of this variant of central low-grade osteosarcoma is based on the aggressive radiologic appearance and on adequate tumor sampling for histologic examination.
Intraosseous well-differentiated

Well differentiated mature appearing bone with small central osteocytes within fibroblastic stroma with mild atypia

Mitotic figures 1-2/10 hpf

Intracortical
Osteoblastic sclerotic tumors
Multifocal-Synchronous

Usually osteoblastic with high grade histology
Adult forms usually better differentiated

PERIOSTEAL
Chondromatous foci predominate with focal malignant osteoid
Periosteal Osteosarcoma: Long-term Outcome and Risk of Late Recurrence.

Rose PS, Dickey ID, Wenger DE, Unni KK, Sim FH.

From the Departments of *Orthopedic Surgery, daggerRadiology, and double daggerPathology, Mayo Clinic, Rochester, MN.

Clin Orthop Relat Res. 2006 Jul 27 Abstract quote

The long-term outcome of periosteal osteosarcoma is not well defined.

We sought to examine the disease-specific survival and risk of late recurrence or dedifferentiation in a cohort of 29 patients with average of 15.8 years followup. Disease-free survival was 83%, with five patients dying of disease at an average of 26 months after presentation. Survival was similar with respect to anatomic location, pathologic grade, and limb-salvage resection. All instances of local recurrence, metastatic disease, and death occurred within 3 years after presentation. There were no instances of dedifferentiation.

Long-term disease-free survival is possible after resection of the local recurrence. Limb-salvage therapy seems to offer survival equivalent to amputation, and there does not seem to be a substantial risk of late recurrence, dedifferentiation, or disease progression.
Paraosteal

Pathol Case Rev 2001;6:28-32

Long narrow trabeculae or ill-defined islands of osteoid and woven bone separated by a fibrous stroma

Trabeculae may undergo a maturation resulting in the formation of lamellar bone

Spaces between bony trabeculae filled with spindled cells with minimal cytolgica atypia

May contain foci of dedifferentiation and these tumors have a very poor prognosis-May occur in 16% of cases

Small cell

Small round cells with at least focal osteoid
Focal hemangiopericytoma-like pattern may be common

May have a Ewing's sarcoma-like pattern 2/3 of cases
Lymphoma-like pattern 1/3 of cases

High-grade surface
High grade neoplasms with microscopic foci of intramedullary extension in 60% of cases

 

SPECIAL STAINS CHARACTERIZATION
PAS positive with diastase sensitivity Glycogen present

 

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
Osteoblastoma  
Osteoid osteoma  

 

PROGNOSIS AND TREATMENT CHARACTERIZATION
PROGNOSIS

Assessment of preoperative chemotherapy is most important prognostic factor

Histology does not appear to have as an important prognostic effect

Poor factors
Flat bones, except for jaws
Invasion of two or more structures adjacent to the involved bone
Follow-up study of long-term survivors of osteosarcoma in the prechemotherapy era.

Division of Anatomic Pathology, Mayo Clinic, Rochester, MN 55905, USA.

 

Hum Pathol. 2006 Aug;37(8):1009-14. Abstract quote

Osteosarcoma is the most common primary bone sarcoma. Several studies published in the 1960s established that approximately one fifth of patients survive when treated with surgery alone. There is no information, however, about the long-term consequences of osteosarcoma. It is especially relevant to know if these patients are at risk for a second malignancy.

We reviewed all clinical records from long-term (defined as more than 10 years) osteosarcoma survivors treated at Mayo Clinic in the prechemotherapeutic era from 1900 to 1960. We re-reviewed histological sections for most cases. Patients or next of kin provided follow-up information during telephone interviews. Rates of second malignancy were compared with expected rates in the population at large. We identified 465 patients treated for osteosarcoma. Of these patients, 83 (17.8%) were long-term survivors, including 19 who were alive up to 65 years after treatment. Of the 7 patients with pulmonary metastases, 3 died. A second malignancy developed in 26 patients, 15 of whom died of the malignancy.

Although long-term survivors of osteosarcoma have a higher incidence of a second malignant tumor than a normal population, this increase was not statistically significant. No demographic or histological variables predicted long-term survival.
Survival after recurrence of osteosarcoma: A 20-year experience at a single institution.

Crompton BD, Goldsby RE, Weinberg VK, Feren R, O'donnell RJ, Ablin AR.

Department of Pediatrics, UCSF Children's Hospital, San Francisco, California.

Pediatr Blood Cancer. 2005 Aug 25; [Epub ahead of print] Abstract quote  

BACKGROUND: Approximately one-third of patients with osteosarcoma who have a complete response to their initial treatment can be expected to relapse. It is important to define what host, tumor, or treatment characteristics determine outcome after relapse. We present findings in 59 patients treated at our institution from 1974 to 1996 who have relapsed one or more times after their initial response.

METHODS: Host and tumor characteristics at diagnosis and relapse, therapeutic interventions and survival outcomes were determined from examination of medical records and a follow-up questionnaire.

RESULTS: Of the 59 patients, 37 initially presented with localized disease of the extremity, 11 with localized non-extremity disease, and 11 with metastatic disease. This report focuses on those with localized disease of the extremity. For these patients, median time from original diagnosis to first recurrence was 14 months. Median survival after first recurrence was 31 months. The median post initial relapse survival was the same for patients whose first relapse occurred before or after 14 months from original diagnosis. Seventeen of 29 patients with systemic metastasis at first recurrence had complete removal of their disease and had a median post-op survival of 2.5 years, while the remaining 12 patients with no surgery, had a median survival of 2 years. Of the 37 patients who presented with primary disease only in the extremities and relapsed: 31 died (2 more than 6 years from first recurrence) and 6 are alive from 6 to 24 years from first recurrence (5 without disease and 1 with disease). Three of the five disease-free survivors had three or more relapses.

CONCLUSION: With a long follow-up time, we found 15% of patients with relapsed osteosarcoma who originally presented with localized disease in the extremity are alive with no evidence of disease at 10 years from first recurrence (Kaplan-Meier estimate). Even patients with multiple relapses may have long-term disease-free survival after salvage therapy. Chemotherapy and time to first recurrence were unrelated to survival after relapse in this study. Complete surgical removal of metastatic disease may be important for long-term survival.
SURVIVAL  
90%>chemotherapy induced tumor necrosis
91% disease free survival
90%<chemotherapy induced tumor necrosis
14% disease free survival
Advent of adjuvant chemotherapy added after this histologic finding has significantly improved survival
Variants  
Synchronous multifocal
Childhood form almost always fatal within 6-8 months
Adult form almost always fatal within 29 months
Asynchronous multifocal
Not as uniformly fatal as synchronous type
Telangiectatic
May have prognosis similar to conventional osteosarcoma
Small cell
Hematogenous mets very common, especially to lungs, central nervous system, and bones
Intraosseous well-differentiated
Similar to conventional osteosarcoma
Intracortical
Similar to conventional osteosarcoma
Periosteal
Similar to conventional osteosarcoma
Paraosteal

Similar to conventional osteosarcoma

Foci of dedifferentiation indicates a poorer prognosis, these patients are best managed with chemotherapy and surgery rather than surgery alone

High-grade surface
Similar to conventional osteosarcoma
HER-2/NEU  

Clinicopathologic Analysis of HER-2/neu Immunoexpression among Various Histologic Subtypes and Grades of Osteosarcoma

Scott E. Kilpatrick, M.D., Kim R. Geisinger, M.D., Tonya S. King, Ph.D., Janiece Sciarrotta, B.S., William G. Ward, M.D., Stuart H. Gold, M.D. and Gary D. Bos, M.D.

Departments of Pathology and Laboratory Medicine (SEK, JS), Pediatrics-Hematology/Oncology (SHG), and Orthopedics (GDB), University of North Carolina, Chapel Hill, North Carolina; Departments of Pathology (KRG) and Orthopedics (WGW), Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina; and Department of Health Evaluation Sciences (TSK), Pennsylvania State University College of Medicine, Hershey, Pennsylvania

Mod Pathol 2001;14:1277-1283 Abstract quote

Overexpression of the HER-2/neu oncogene appears to have prognostic significance in breast cancer. Recently, some have reported a relationship between increased immunohistochemical expression in osteosarcoma and poor clinical outcome. Despite limited data, a pilot trial of Herceptin, which targets the oncogene product, has been initiated for the therapy of some metastatic osteosarcomas (CCG-P9852).

Archival formalin-fixed, paraffin-embedded tissue obtained from 41 patients diagnosed with osteosarcoma was examined immunohistochemically by 2 antibodies against the HER-2/neu oncogene product: CB-11 (monoclonal, 1/100) and Oncor (polyclonal, 1/200). All but one tumor (case of recurrent dedifferentiated parosteal osteosarcoma) represented primary tumor samples; when applicable, only prechemotherapy biopsies were analyzed.

The study sample included the full spectrum of histologic subtypes and grades of osteosarcoma (25 conventional high grade; 3 telangiectatic; 1 small cell; 6 parosteal; 1 periosteal; and 5 low-grade intramedullary). A case of metastatic breast cancer with known overexpression of the HER-2/neu oncogene served as the positive control. Complete membranous positivity, considered prognostically significant in breast cancer, was not seen in any of our osteosarcoma cases. At least focal cytoplasmic positivity was documented in 40 (98%) tumors using the CB11 antibody and in 34 (83%) using the Oncor antibody.

The intensity of the cytoplasmic staining (0, 13+) did not correlate with histologic subtype/grade, response to chemotherapy (<90% versus 90% necrosis), metastasis, or survival. Immunohistochemical overexpression of the HER-2/neu oncogene, defined as complete membranous positivity, is not present in our series of osteosarcomas. Cytoplasmic positivity is observed in most osteosarcomas, irrespective of histologic subtype/grade, and is not associated with response to preoperative chemotherapy or disease progression.

METASTASIS-GENERAL  


Patterns of recurrence after resection of osteosarcoma of the extremity. Strategies for treatment of metastases.

Huth JF, Eilber FR.

Department of Surgery, UCLA School of Medicine.

 

Arch Surg 1989 Jan;124(1):122-6 Abstract quote

We studied recurrence patterns in 255 patients with high-grade osteosarcoma of the extremity and the efficacy of the treatment of these recurrences.

One hundred seven patients developed metastatic disease: 77 had isolated pulmonary metastases, 17 had simultaneous metastases to lung and elsewhere, and 13 had metastases to other sites. Of the 77 patients with metastases confined to the lung, 51 (66%) underwent thoracotomy for resection of the metastases, and 13 (17%) are long-term disease-free survivors. Patients with simultaneous metastases to lung and other sites, and patients with metastases to sites other than lung, have a poor prognosis with only one long-term disease-free survivor in these groups.

Thoracotomy has a limited role in the treatment of metastatic disease. Improvements in aggressive, systemic chemotherapy are essential for improving the prognosis in these patients.

METASTASIS-BRAIN Lung metastasis, if surgically resectable, and combined with adjuvant chemotherapy, may lead to 5 year survival of 37%


Brain metastases in osteosarcoma: incidence, clinical and neuroradiological findings and management options.

Baram TZ, van Tassel P, Jaffe NA.

Department of Pediatrics, University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston 77030.

J Neurooncol 1988;6(1):47-52 Abstract quote

Brain metastasis is uncommon in osteosarcoma, but this may be changing with prolonged patient survival in the modern chemotherapy era.

We present 5 patients with brain metastases out of 39 with lung metastasis (13%) in a total of 87 osteosarcoma patients. The clinical manifestations of brain metastases were catastrophic: massive hemorrhage in 2 and status epilepticus in 3. Metastases were single or multiple, and some were osteoblastic.

Surgical intervention in 2 cases resulted in dramatic, though transient, clinical improvement. We advocate periodic neuroradiology screening in osteosarcoma patients with lung metastases, for early detection of brain involvement.


Brain metastases in osteosarcoma. Report of a long-term survivor and review of the St. Jude Children's Research Hospital experience.

Marina NM, Pratt CB, Shema SJ, Brooks T, Rao B, Meyer WH.

Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, TN 38101-0318.

Cancer 1993 Jun 1;71(11):3656-60 Abstract quote

BACKGROUND. Brain metastasis has been considered a rare event in osteosarcoma, although with prolonged survival an increasing incidence has been suggested. There have been no prior reports of long-term survivors among patients with this complication.

METHODS. The authors describe a child treated for osteosarcoma who is alive and free of disease 8 years after the detection of brain metastases. Of 254 patients with primary osteosarcoma referred to St. Jude Children's Hospital between 1962 and 1989, 13 developed brain metastases, all after relapse or recurrence in another site. Concomitant active lung metastases were present in all of the patients except the one long-term survivor, whose pulmonary disease had responded to treatment with cisplatin and doxorubicin. Log-rank analyses were used to compare survival duration and the frequency of brain metastases among patients treated before and after 1982, when effective multiagent therapy was initiated.

RESULTS. Log-rank analyses comparing patients treated before and after 1982 showed that the introduction of effective modern therapy improved survival among patients at risk for brain metastases (i.e., those with recurrent and progressive disease, P = 0.007) but was not associated with a statistically significant increase in the frequency of brain metastases (15.5% versus 4.5%, P = 0.125).

CONCLUSIONS. Although the outlook for patients with this complication remains bleak, the resolution of brain metastases after eight courses of ifosfamide in the patient described in this article suggests that enrollment of selected patients in Phase II trials is merited.


Isolated brain metastases of osteosarcoma in a patient presenting with a patent foramen ovale.

Menassa L, Haddad S, Aoun N, Slaba S, Atallah N.

Department of Radiology, Hotel-Dieu de France, Beirut, Lebanon.

Eur Radiol 1997;7(3):365-7 Abstract quote

We report the case of a patient in whom brain MR imaging was requested for initial symptoms of intracranial hypertension. The presence of multiple intracranial hemorrhagic lesions suggested brain metastases. Body screening showed periosteal osteosarcoma of the left fibula with no lung metastases, but with a patent foramen ovale which probably allowed neoplastic cells to reach the brain without being filtered through the lungs.

The conclusion of this study was that a left-right cardiac communication is to be considered in cases of isolated brain metastases from osteosarcoma.

PLATELET-DERIVED GROWTH FACTOR AA  


Expression of Platelet-Derived Growth Factor-AA is Associated with Tumor Progression in Osteosarcoma.

Sulzbacher I, Birner P, Trieb K, Traxler M, Lang S, Chott A.

Clinical Institute of Pathology (IS, PB, MT, SL, AC) and Department of Orthopedics (KT), University of Vienna Medical School, Vienna, Austria.

Mod Pathol 2003 Jan;16(1):66-71 Abstract quote

Platelet-derived growth factors are secreted by mesenchymal cells. The homodimer platelet-derived growth factor-AA especially stimulates bone cells through interaction with the platelet-derived growth factor-alpha receptor homodimer.

In this study we wanted to determine the expression of the receptor and its ligand in human osteosarcomas and to correlate the expression of platelet-derived growth factor-AA and -alpha receptor with clinicopathological parameters. Fifty-seven osteosarcomas were immunohistochemically analyzed for expression of platelet-derived growth factor-AA and platelet-derived growth factor-alpha receptor.

Spearman's correlation coefficient revealed a strong correlation between the expression of platelet-derived growth factor-AA and platelet-derived growth factor-alpha receptor (r = 0.867). No differences were observed relative to gender, age, tumor stage, tumor location, and response to neoadjuvant chemotherapy between high or low platelet-derived growth factor-AA and platelet-derived growth factor-alpha receptor expression. High platelet-derived growth factor-AA expression correlated with tumor progression in univariate analysis (P =.0415; log-rank test), whereas platelet-derived growth factor-alpha receptor expression showed a trend toward a shorter disease-free survival, which failed to reach significance (P =.0627, log-rank test).

In multivariate analysis, platelet-derived growth factor-AA expression remained a significant independent predictor of tumor progression (P =.021, Cox regression). Immunohistochemical analysis of platelet-derived growth factor-AA expression in osteosarcoma may be a useful marker of prognosis and may be considered as a possible target for novel therapeutic strategies.

TREATMENT Usually preoperative chemotherapy with surgical resection and radiotherapy
CHEMOTHERAPY  
Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate.

Meyers PA, Schwartz CL, Krailo M, Kleinerman ES, Betcher D, Bernstein ML, Conrad E, Ferguson W, Gebhardt M, Goorin AM, Harris MB, Healey J, Huvos A, Link M, Montebello J, Nadel H, Nieder M, Sato J, Siegal G, Weiner M, Wells R, Wold L, Womer R, Grier H.

Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA.
J Clin Oncol. 2005 Mar 20;23(9):2004-11. Abstract quote  

PURPOSE: To determine whether the addition of ifosfamide and/or muramyl tripeptide (MTP) encapsulated in liposomes to cisplatin, doxorubicin, and high-dose methotrexate (HDMTX) could improve the probability for event-free survival (EFS) in newly diagnosed patients with osteosarcoma (OS).

PATIENTS AND METHODS: Six hundred seventy-seven patients with OS without clinically detectable metastatic disease were treated with one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and HDMTX and underwent definitive surgical resection of the primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 double dagger 2 factorial design. The primary end point for analysis was EFS.

RESULTS: Patients treated with the standard arm of therapy had a 3-year EFS of 71%. We could not analyze the results by factorial design because we observed an interaction between the addition of ifosfamide and the addition of MTP. The addition of MTP to standard chemotherapy achieved a 3-year EFS rate of 68%. The addition of ifosfamide to standard chemotherapy achieved a 3-year EFS rate of 61%. The addition of both ifosfamide and MTP resulted in a 3-year EFS rate of 78%.

CONCLUSION: The addition of ifosfamide in this dose schedule to standard chemotherapy did not enhance EFS. The addition of MTP to chemotherapy might improve EFS, but additional clinical and laboratory investigation will be necessary to explain the interaction between ifosfamide and MTP.
INTERFERON  
Interferon-alpha as the only adjuvant treatment in high-grade osteosarcoma: Long term results of the Karolinska Hospital series.

Muller CR, Smeland S, Bauer HC, Saeter G, Strander H.

Department of Tumour Biology, The Norwegian Radiumhospital, Oslo, Norway.

Acta Oncol. 2005 Jul;44(5):475-480. Abstract quote  

This experience of single agent interferon-alpha treatment in high-grade osteosarcoma was based on observed anti-osteosarcoma activity in laboratory models and was started before introduction of aggressive combination chemotherapy.

From 1971 to 1990, 89 consecutive patients with non-metastatic high-grade osteosarcoma received semi-purified, leukocyte interferon-alpha as adjuvant treatment. From 1971 to 1984, 70 patients were given a dose of 3 MIU daily for one month followed by 3 times weekly for an additional 17 months. For 19 patients treated from 1985 to 1990 the dose was increased to 3 MIU daily and the treatment duration extended to 3-5 years.

All patients underwent surgery prior to interferon treatment. The toxicity was mainly constitutional and long-term toxicity was virtually absent. With a median follow-up of 12 years the observed 10-year metastases-free and sarcoma specific survival rates were 39% and 43%, respectively. Only one of seven survivors after relapse received chemotherapy.

This work suggests activity of interferon-alpha as adjuvant treatment in high-grade osteosarcoma. The efficacy of interferon in combination with standard therapy should be explored in randomized trials.
RADIATION  
[Standards and Options for the use of radiation therapy in the management of patients with osteosarcoma. Update 2004]

[Article in French]

Claude L, Rousmans S, Carrie C, Breteau N, Dijoud F, Gentet JC, Giammarile F, Jouve JL, Kind M, Marec-Berard P, Mascard E, Bataillard A, Philip T; Federation nationale des centres de lutte contre le cancer (FNCLCC); Federation hospitaliere de France (FHF); Federation nationale de cancerologie des CHRU (FNCCHRU); Federation francaise de cancerologie des CHG (FFCCHG); centres regionaux de lutte contre le cancer (CRLCC); Societe francaise de lutte contre les cancers de l'enfant et de l'adolescent (SFCE).

Centre Leon-Berard, Lyon, France.


Cancer Radiother. 2005 Mar;9(2):174-91. Abstract quote  

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of French Cancer Centres (FNCLCC), the 20 French regional cancer centres, and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients. The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery.

OBJECTIVE: To update the SOR recommendations for the use of radiation therapy in the management of patients with osteosarcoma. This work was performed in collaboration with the French society against cancers in children and adolescent (SFCE).

METHODS: Data have been identified by literature search using Medline (from January 1992 to October 2003). In addition several Internet sites were searched in October 2003.

RESULTS: The 3 mains standards are: 1) local and exclusive curative irradiation is not indicated as primary treatment for osteosarcoma or for local and operable recurrence, except for lesion in inaccessible sites or if the patient refuses surgery; 2) local and prophylactic adjuvant irradiation is not indicated for the treatment of osteosarcoma after chemotherapy (neoadjuvant and/or adjuvant) and complete macro or microscopic surgery, except for non-operable R1 or R2 surgical resection; 3) whole-lung prophylactic irradiation is not indicated in non-metastatic osteosarcoma. Systemic metabolic radiotherapy for pain treatment, using samarium-153 ethylenediaminetetramethylene phosphonic acid (Sm-153-EDTMP) can be offered to patients with painful metastatic osteosarcoma or in case of recurrent bone sites inaccessible to local therapies (surgery, external irradiation).

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Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.


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