Differential Diagnosis of Osteogenic Tumors in the Context of Osteosarcoma

Mulazim Hussain Bukhari, Samina Qamar and Farwa Batool

## Abstract

Primary bone tumors are rare, but osteosarcoma (OS) is the fourth commonest non-hematological primary neoplasm of the bone in the adolescence, and the other three commonest neoplasms, in descending order, are leukemia, brain tumors, and lymphoma. The commonest presenting complaints are swelling and aches. These tumors cannot be diagnosed without the help of radiology. There is a wide age range of these neoplasms commonly appearing in the second and third decade of life with a peak incidence in early teens. Males are affected more than females. The exact cause of osteosarcoma is unknown. However, a number of risk factors, like genetic predisposition, some existing bone diseases, environmental risk factors, and radiations, have been identified. If the bone tumors are viewed by clinical, radiological, and histopathological perspectives, the correct diagnosis can be made easily. Chemotherapy combined with surgery is the standard treatment modality with better 5-year survival rates. Elevated AKP is an important prognostic factor in this malignancy.

Keywords: aggressive osteoblastoma, osteogenic tumors, osteoma, osteoid osteoma, osteoblastoma, osteogenic sarcoma

## 1. Introduction

Primary neoplasm of the bones is relatively uncommon. Among these tumors, the osteosarcoma is the commonest primary malignant tumor, comprising of approximately 35% of all bone malignant tumors, followed by others like chondrosarcoma (25%), Ewing sarcoma (EWS) (16%), and chordomas (8%). This malignant tumor can arise from any bone, mainly usually in the metaphyseal (growth plates) long bones of the extremities, but the jaw, pelvis, and ribs may be the sites of origin [1].

The nomenclature of bone tumors are described in "the World Health Organization (WHO)" classification system [2]. We are adopting a table from this classification to review the pathological diagnostic criteria of these lesions. A number of variants of osteosarcoma exist, including conventional types (osteoblastic, chondroblastic, fibroblastic, telangiectatic, multifocal, parosteal, and periosteal) (Table 1) [3].

The histological pictures of bone tumors alone are not enough to make a differentiation between osteosarcoma and benign tumors or other malignancies of the bone; therefore, radiological and clinical help is needed to make the final diagnosis of osteogenic sarcoma. Therefore, the chapter will not only address osteosarcoma but will also discuss all osteogenic tumors stepwise [1].

## Osteosarcoma – Diagnosis, Mechanisms, and Translational Developments

#### Table 1. WHO-based classification of osteogenic tumors of the bone.

This chapter will mainly focus on general clinical, imaging, and histopathological characteristics, which will aid in diagnosis but may add a little to advances in tumor biology or treatment of the multitude of bone tumors described in this chapter.

The exact cause of osteosarcoma is unknown. However, a number of risk factors, like genetic predisposition, some existing (Paget disease, fibrous dysplasia, enchondromatosis, and hereditary multiple exostoses and retinoblastoma) bone diseases, environmental risk factors, and radiations, have been identified.

Keeping in mind the importance of this malignancy, it is therefore important to understand the other osteogenic tumors before reaching the importance of osteosarcoma; we will describe the differential diagnosis of osteogenic tumors in the context of osteosarcoma.

## 2. Osteoma

It is a benign neoplasm exclusively seen in flat bone of skull and face. Microscopically it consists of the mature lamellar bone. Multiple osteomas are associated with Gardner's syndrome (colonic polyposis). Sometimes it involves other than the skull and face, as surface lesions of parosteal type (Figure 1 and Tables 1 and 2) [4]. 3. Osteoid osteoma

Table 2.

Site and location

Age in years

Clinical symptoms

4. Osteoblastoma

13

It is a benign tumor of medullary metaphysis origin with a <2 cm lucent nidus, encompassed by the solid periosteal reaction. The characteristic features are its association with nocturnal pain (due to release of prostaglandin via Cox-1 and Cox-2 pathway) which can be relieved by aspirin, a salicylate analgesic. Histologically it comprised of three zones, nidus, fibrovascular stroma, and mineralized sclerotic bone. The nidus is composed of interconnected newly formed blood vessels and new bone-forming cells (osteoblasts and osteoid) [5–7] (Table 3, Figure 2).

Differential diagnosis of osteoma with osteoid osteoma, ossifying fibroma, and parosteal osteosarcoma.

It arises from the medullary metaphysis, but most cases arise from spongiosa of the bone. It is a rare benign tumor of the bone. These tumors are now considered in intermediated groups as they may be locally aggressive and tend to affect the axial skeleton more often than osteoid osteoma. They are less painful and have poor response with aspirin [10, 11]. These have many osteoclasts like giant cells and less

These tumors should be differentiated from osteomyelitis, stress fractures,

osteoblastoma, osteosarcoma, and other lesions [8, 9].

Features Osteoma Osteoid osteoma Ossifying

Differential Diagnosis of Osteogenic Tumors in the Context of Osteosarcoma

Cortex of metaphysis (skull, facial bone)

DOI: http://dx.doi.org/10.5772/intechopen.85190

40–60 more in males

Radiology Well-circumscribed radiodense and without destructive

features

Histology Nodular or dome-

bone

consists of hematopoietic or fibroadipose tissue Regular large ossicles of mature bone

shaped, dense cortical

Consists of dense lamellar bone with or without Haversian canals and usually without a medullary component Medullary component fibroma

Welldemarcated radiolucent in the early stages and then progressive calcification

The stroma is fibrous and more cellular Small ossicles and irregular bony trabeculae, much less mature bone Psammoma bodies

the same bones

range), and more in females

Metaphysis Metaphysis of

10–20 more in males 1–70 (wide

No pain With pain No pain Pain

A single <1.5 cm nidus

Lamellar bone with prominent osteoblastic

rimming Osteoma may have focal areas of reactive bone with similar features but not cellular as compard to OO, see also (Table 3)

that may be radiolucent or ossified and surrounded by a reactive bone

Parosteal osteosarcoma

Metaphysis of long bone

30–60 year (older age)

Continuity with the medullary component of the parent bone is not present. Appears to be attached to the surface of the parent none

Tumor osteoid is arranged in parallel arrays and separated by a bland fibroblastic stroma. With minimal atypia. Cartilage may be seen. Genetically, amplification of 12q13-15 seen with CDK4 and MDM2 genes. See also

(Table 9)

No other benign lesions seen (See Table 9)

#### Figure 1.

Radiological aspect of osteoma, (A) shows sharply radiodense lesions (black ring), (B) photomicrograph (H&E 40x) similar to normal cortex, revealing mature bone (arrow), with less stroma and no atypia.

Differential Diagnosis of Osteogenic Tumors in the Context of Osteosarcoma DOI: http://dx.doi.org/10.5772/intechopen.85190

Table 2.

This chapter will mainly focus on general clinical, imaging, and histopathological characteristics, which will aid in diagnosis but may add a little to advances in tumor biology or treatment of the multitude of bone tumors described in this chapter.

Osteoma Osteoblastoma Low-grade central osteosarcoma (OS)

Chondroblastic OS Fibroblastic OS Osteoblastic OS Telangiectatic OS Small cell OS Parosteal OS Periosteal OS

High-grade surface OS

Secondary OS

The exact cause of osteosarcoma is unknown. However, a number of risk factors,

Keeping in mind the importance of this malignancy, it is therefore important to understand the other osteogenic tumors before reaching the importance of osteosarcoma; we will describe the differential diagnosis of osteogenic tumors in the

It is a benign neoplasm exclusively seen in flat bone of skull and face. Microscopically it consists of the mature lamellar bone. Multiple osteomas are associated with Gardner's syndrome (colonic polyposis). Sometimes it involves other than the skull and face, as surface lesions of parosteal type (Figure 1 and Tables 1 and 2) [4].

Radiological aspect of osteoma, (A) shows sharply radiodense lesions (black ring), (B) photomicrograph (H&E 40x) similar to normal cortex, revealing mature bone (arrow), with less stroma and no atypia.

like genetic predisposition, some existing (Paget disease, fibrous dysplasia, enchondromatosis, and hereditary multiple exostoses and retinoblastoma) bone diseases, environmental risk factors, and radiations, have been identified.

Benign Intermediate Malignant

Osteosarcoma – Diagnosis, Mechanisms, and Translational Developments

Osteoid osteoma Conventional OS

context of osteosarcoma.

WHO-based classification of osteogenic tumors of the bone.

2. Osteoma

Figure 1.

12

Table 1.

Differential diagnosis of osteoma with osteoid osteoma, ossifying fibroma, and parosteal osteosarcoma.

## 3. Osteoid osteoma

It is a benign tumor of medullary metaphysis origin with a <2 cm lucent nidus, encompassed by the solid periosteal reaction. The characteristic features are its association with nocturnal pain (due to release of prostaglandin via Cox-1 and Cox-2 pathway) which can be relieved by aspirin, a salicylate analgesic. Histologically it comprised of three zones, nidus, fibrovascular stroma, and mineralized sclerotic bone. The nidus is composed of interconnected newly formed blood vessels and new bone-forming cells (osteoblasts and osteoid) [5–7] (Table 3, Figure 2). These tumors should be differentiated from osteomyelitis, stress fractures, osteoblastoma, osteosarcoma, and other lesions [8, 9].

### 4. Osteoblastoma

It arises from the medullary metaphysis, but most cases arise from spongiosa of the bone. It is a rare benign tumor of the bone. These tumors are now considered in intermediated groups as they may be locally aggressive and tend to affect the axial skeleton more often than osteoid osteoma. They are less painful and have poor response with aspirin [10, 11].

Site and location

Age in years

Clinical symptoms

Radiology of the osteoid osteoma (A) shows sharply radiodense lesions with nidus (black ring), similar to normal cortex, (B) photomicrograph (40X) of osteoid osteomas reveals irregular trabeculae of lamellar bone

Osteosarcoma Giant cell

Metaphysis Metaphysis

10–25 >20

Not severe pain Severe pain Pain No pain No pain

Radiographically, osteosarcoma is poorly circumscribed with cortical destruction and evidence of periosteal reactive bone Permeative pattern of growth at the periphery

Tumor osteoid is arranged in parallel arrays and separated by a hypocellular fibroblastic stroma.

Lacks the fibrovascular stroma and osteoblastic rimming of osteoid osteoma May show cartilage component

tumors

of epiphysis

Up to 40

Soap bubble appearance

Sheets of giant cells and more in number and contain more nuclei Giant cell tumors contain mononuclear stromal cells

Aneurysmal bone cyst (ABC)

Diaphysis

Younger 10–20

Lytic but demarcated Both processes may have similar presentations and radiographic findings and tend to involve the vertebra

Small foci of reactive osteoid may be present in aneurysmal bone cysts, which should not be confused with osteoblastoma

with prominent osteoblastic rimming and loose fibrovascular stroma (arrows).

Differential Diagnosis of Osteogenic Tumors in the Context of Osteosarcoma

DOI: http://dx.doi.org/10.5772/intechopen.85190

osteoma

metaphysis

A single < 1.5 cm nidus that may be radiolucent or ossified and surrounded by a reactive bone

Irregular trabeculae of lamellar bone with prominent osteoblastic rimming Loose fibrovascular stroma

5–30 More in males

Features Osteoblastoma Osteoid

Mean age 20 (10–70) More in females

Radiology Well-circumscribed nondestructive but sometimes with ABC

> changes Some have central nidus >2 cm. The lesions are predominantly lytic, with a rim of reactive

sclerosis

nidus Intralesional hemorrhages like ABC and numerous osteoclast-like giant

cells

in nidus

Table 4.

15

No peripheral rim of fibrovascular tissue like

Histology Irregular anastomosing trabeculae of osteoid and woven bone Variable mineralization and thickness of woven osteoid trabeculae. No central maturation like

Medulla of metaphysis Cortex of

Table

#### Figure 2.

Radiology of the osteoid osteoma (A) shows sharply radiodense lesions with nidus (black ring), similar to normal cortex, (B) photomicrograph (40X) of osteoid osteomas reveals irregular trabeculae of lamellar bone with prominent osteoblastic rimming and loose fibrovascular stroma (arrows).

#### Table 4.

Differential diagnosis of osteoblastoma with osteoid osteoma, osteosarcoma, giant cell tumors, and ABC.

Features

14

Site and

Cortex of metaphysis

location

Age in

5–30

Any age

Old age

Mean age 20 (10–73)

Wide range (1–70)

 Older age

> More in females

Not severe pain

No pain

Pain

years

Clinical

Severe pain

Pain, fever

Pain

symptoms

Radiology

 A single <1.5 cm nidus

Bone scan central area of reduced uptake

representing

of purulent material

 an avascular area

demonstrates

Positive findings include

Well-circumscribed

Well-demarcated

Continuity with the medullary

component of the parent bone is

not present. Appears to be

attached to the surface of the

parent none

Osteosarcoma – Diagnosis, Mechanisms, and Translational Developments

MRI and CT are more helpful

radiolucent in the early

stages and then

progressive

calcification

nondestructive

with secondary ABC changes Some have central nidus >2 cm

The lesions are

lytic, with a rim of reactive

sclerosis

Irregular trabeculae of osteoid and woven

bone

anastomosing

The stroma is fibrous

Tumor osteoid is arranged in

parallel arrays and separated by a

hypocellular

The spindle cells between bony

trabeculae instead of fat and

hematopoietic

Lacks the fibrovascular and osteoblastic rimming of

osteoid osteoma May show cartilage component.

See (Tables 4–8) for IHC

 tissue as seen in OS

 stroma

 fibroblastic stroma

and more cellular Small ossicles and

predominantly

 but sometimes

sclerosis, periosteal reaction/

elevation, cortical

thickening, and a fracture

line

that may be radiolucent or

ossified and surrounded

by a reactive bone

Histology

 Irregular trabeculae of

No central nidus

Zonal pattern with central,

more mature, denser bone

Presence of neutrophils,

lymphocytes,

etc. (acute or chronic

inflammatory

 cell infiltrate)

macrophages,

and peripheral woven bone

Cartilage with

ossification may be present

endochondral

Variable thickness of woven osteoid

trabeculae. No central maturation like nudus

Intralesional

ABC and numerous osteoclast-

like giant cells

No peripheral rim of

fibrovascular

Epithelioid aggressive variant

with large atypical epithelioid like osteoblasts may confuse with

OS, but take guidance from

radiology. See (Tables 2 and 4)

> Table 3.

Differential

 diagnosis of osteoid osteoma with

osteomyelitis,

 stress fracture,

osteoblastoma,

 ossifying fibroma, and

osteosarcoma.

 tissue like in nidus

 hemorrhages

 like

mineralization

 and

irregular bone

Trabeculae,

mature bone Psammoma bodies

 much less

lamellar bone with prominent osteoblastic

rimming

Loose fibrovascular

stroma

See also (Table 2)

More in males

 Osteoid osteoma

 Not site specific

Osteomyelitis

Stress fracture Not site specific

Osteoblastoma Medulla of metaphysis

Ossifying fibroma

Same bones

Metaphysis of long bone

Osteosarcoma

(60%). There is no gender difference, but males are affected more as compared to

Differential Diagnosis of Osteogenic Tumors in the Context of Osteosarcoma

association with underlying disease [12, 13, 16, 17].

5.1 Conventional intermedullary OS

DOI: http://dx.doi.org/10.5772/intechopen.85190

on radiology [18, 19].

[16, 20–23].

Figure 4.

17

There are many morphological variants of OS with anastomosing, reticular osteoid and oval, spindled to epithelioid stromal cells. The cells may form rosettes to small sheets in different patterns. There are several subtypes of OS, which can be, differentiated on the basis of the site, degree of histological differentiation, and

This type of OS shows the male predominance and bimodal age, pediatric and adult sarcoma. It has some association with hereditary effect, e.g., with mutation of RB gene, Li-Fraumeni syndrome, Ollier disease, fibrous dysplasia, and Paget disease (secondary OS). Radiation also plays a role in its pathogenesis. The long bones are commonly involved showing classical "Codman triangle" to moth-eaten picture due to permeation and destruction of medullary as well as cortical bone

It is composed of hyperchromatic cells forming sarcomatous component around the classical osteoid (Figure 4). This comprised of chondroblastic OS (25%), fibroblastic OS (25%), and osteoblastic OS (50%). Other subtypes are small cell-type OS, giant cell-rich OS, telengiactatic-type OS, surface-type OS, periosteal OS, and parosteal OS. Histologically it has two grades, low- and high-grade OS. Immunohistochemistry has some role in its differentiation from cartilage and other bone tumors, i.e., ALK, VIM, variable SMA, and desmin. The S100 is always negative except there is chondroid differentiation. EMA and keratin are negative in tumors

Radiological examination (A) showing intramedullary OS of left lower tibia with osteolytic and sclerotic lesion

in lower end above ankle joint (rings). There is a medullary and cortical destruction of bone. The photomicrograph of (B & C) (40X with H&E) based characteristic of conventional osteosarcoma, is the identification of osteoid (arrows), which is a dense, pink, amorphous extracellular material containing large amounts of collagen type I. (C) The tumor cells (atypical osteoblast) and cytoplasm are eosinophilic, are larger

than normal osteoblasts (arrows), and vary in size with nuclear atypia.

females [13].

#### Figure 3.

(A) Radiology (left ankle bone) shows osteoblastoma, with well-circumscribed nondestructive but sometimes with ABC changes (ring). The lesions are predominantly lytic, with a rim of reactive sclerosis. (B) Photomicrograph (H&E 40X) showing irregular anastomosing trabeculae of osteoid and woven bone, variable mineralization, and thickness of woven osteoid trabeculae (thick arrows). Numerous osteoclast-like giant cells (thin arrow). No peripheral rim of fibrovascular tissue like in nidus.

rimming with osteoblasts, osteoid, and rich vascularity as compared to osteoid osteoma (Table 4, Figure 3) [6, 12, 13]. This is also called giant osteoid osteoma more than 2 cm in size; it does not have the surrounding reactive bone as compared to osteoid osteoma and is not associated with nocturnal aches [13].

#### 4.1 Aggressive osteoblastoma

It is a rare variant of osteoblastoma, which commonly arises from the vertebrae, long bones, and bones of jaws; it is characterized by the presence of epithelioid osteoblasts in the stroma with aggressive behavior. The tumor has propensity for local invasion and recurrence, but still no metastasis has been seen in any case in the literature [14, 15].

## 5. Osteosarcoma (OS)

It is the most common primary bone tumors (20%) of mesenchymal origin second to multiple myeloma; the main histologic feature of this tumor is direct production of malignant osteoid from malignant cells without normal osteogenic process through fibrous and cartilage way; the cartilage or fibrous tissue may present elsewhere or in other osteogenic portions. Malignant osteoid is the characteristic finding of all types of OSs, and it is a eosinophilic, homogenous, glassy appearing lacelike material [16, 17].

Osteosarcoma is very rare in young children (0.5 cases per million per year in children <5 years). However, the incidence increases steadily with age [13].

It can affect all ages, but 75% appears in young age, it can affect all bones most commonly in metaphysis of long bones, and knee joint is commonly involved

Differential Diagnosis of Osteogenic Tumors in the Context of Osteosarcoma DOI: http://dx.doi.org/10.5772/intechopen.85190

(60%). There is no gender difference, but males are affected more as compared to females [13].

There are many morphological variants of OS with anastomosing, reticular osteoid and oval, spindled to epithelioid stromal cells. The cells may form rosettes to small sheets in different patterns. There are several subtypes of OS, which can be, differentiated on the basis of the site, degree of histological differentiation, and association with underlying disease [12, 13, 16, 17].

## 5.1 Conventional intermedullary OS

This type of OS shows the male predominance and bimodal age, pediatric and adult sarcoma. It has some association with hereditary effect, e.g., with mutation of RB gene, Li-Fraumeni syndrome, Ollier disease, fibrous dysplasia, and Paget disease (secondary OS). Radiation also plays a role in its pathogenesis. The long bones are commonly involved showing classical "Codman triangle" to moth-eaten picture due to permeation and destruction of medullary as well as cortical bone on radiology [18, 19].

It is composed of hyperchromatic cells forming sarcomatous component around the classical osteoid (Figure 4). This comprised of chondroblastic OS (25%), fibroblastic OS (25%), and osteoblastic OS (50%). Other subtypes are small cell-type OS, giant cell-rich OS, telengiactatic-type OS, surface-type OS, periosteal OS, and parosteal OS. Histologically it has two grades, low- and high-grade OS. Immunohistochemistry has some role in its differentiation from cartilage and other bone tumors, i.e., ALK, VIM, variable SMA, and desmin. The S100 is always negative except there is chondroid differentiation. EMA and keratin are negative in tumors [16, 20–23].

#### Figure 4.

rimming with osteoblasts, osteoid, and rich vascularity as compared to osteoid osteoma (Table 4, Figure 3) [6, 12, 13]. This is also called giant osteoid osteoma more than 2 cm in size; it does not have the surrounding reactive bone as compared

(A) Radiology (left ankle bone) shows osteoblastoma, with well-circumscribed nondestructive but sometimes with ABC changes (ring). The lesions are predominantly lytic, with a rim of reactive sclerosis. (B) Photomicrograph (H&E 40X) showing irregular anastomosing trabeculae of osteoid and woven bone, variable mineralization, and thickness of woven osteoid trabeculae (thick arrows). Numerous osteoclast-like

It is a rare variant of osteoblastoma, which commonly arises from the vertebrae,

long bones, and bones of jaws; it is characterized by the presence of epithelioid osteoblasts in the stroma with aggressive behavior. The tumor has propensity for local invasion and recurrence, but still no metastasis has been seen in any case in the

It is the most common primary bone tumors (20%) of mesenchymal origin second to multiple myeloma; the main histologic feature of this tumor is direct production of malignant osteoid from malignant cells without normal osteogenic process through fibrous and cartilage way; the cartilage or fibrous tissue may present elsewhere or in other osteogenic portions. Malignant osteoid is the characteristic finding of all types of OSs, and it is a eosinophilic, homogenous, glassy

Osteosarcoma is very rare in young children (0.5 cases per million per year in

It can affect all ages, but 75% appears in young age, it can affect all bones most

children <5 years). However, the incidence increases steadily with age [13].

commonly in metaphysis of long bones, and knee joint is commonly involved

to osteoid osteoma and is not associated with nocturnal aches [13].

giant cells (thin arrow). No peripheral rim of fibrovascular tissue like in nidus.

Osteosarcoma – Diagnosis, Mechanisms, and Translational Developments

4.1 Aggressive osteoblastoma

literature [14, 15].

16

Figure 3.

5. Osteosarcoma (OS)

appearing lacelike material [16, 17].

Radiological examination (A) showing intramedullary OS of left lower tibia with osteolytic and sclerotic lesion in lower end above ankle joint (rings). There is a medullary and cortical destruction of bone. The photomicrograph of (B & C) (40X with H&E) based characteristic of conventional osteosarcoma, is the identification of osteoid (arrows), which is a dense, pink, amorphous extracellular material containing large amounts of collagen type I. (C) The tumor cells (atypical osteoblast) and cytoplasm are eosinophilic, are larger than normal osteoblasts (arrows), and vary in size with nuclear atypia.

## 6. Differential diagnosis of conventional OS

## 6.1 Fracture callus and stress fracture

Sometime fracture callus may be confused with OS, because there is formation of spindle cells and cartilage with new bones, but all these elements are arranged with orderly maturation as compared to haphazard and abrupt arrangement in OS (Table 5). Postmenopausal women may have insufficiency fractures in the pelvis resembling metastatic carcinoma [24, 25].

two types of tumor osteoid, early-tumor osteoid, lacelike pattern around tumor cells, and late-tumor osteoid, a mineralized one having an appearance of a woven bone, but an important feature is that tumor osteoid is not rimmed by osteoblasts [16].

Osteomyelitis is an important cause of morbidity and mortality in children and adults due to acute and chronic bacterial infection. More common sites are the

Primary (hematogenous) osteomyelitis is associated with fever and local painful mass and may have fistula formation. A history of recent trauma with open fracture is significant for secondary osteomyelitis. The radiology and MRI are more helpful in the diagnosis of these lesions [26]. The C-reactive protein and erythrocyte sedimentation rate (ESR) are markedly elevated. Biopsy shows necrotic bone, fibrotic marrow, and chronic inflammation with or without an acute inflammatory component. Reactive bone is usually produced as part of an associated periosteal reaction,

It is a benign osteoid-producing tumor with roughly the same age and sex distribution as osteosarcoma. In conventional radiography, there is a well-defined round expansile mass with central radiolucent zone (>1.5 cm) and a peripheral rim of sclerosis (sclerosis may not be as extensive as in osteoid osteoma). On biopsy, there is an irregular interlacing network of osteoid with prominent osteoblastic rimming and features of woven bone; the differential diagnosis from OS is sometimes difficult when the OS is well differentiated and OB is showing bizarre

ABC has the same age range and location as osteosarcoma. It presents with pain and occasional pathological fracture. Secondary aneurysmal bone cysts can be seen in older patients, superimposed on other primary neoplasms. Conventional radiographs show radiolucent expansile bone lesion. MRI shows fluid levels on T2 weighted images. Biopsy can differentiate from telangiectatic osteosarcoma (TOS), which displays obvious histological features of malignancy (marked cellular pleomorphism, high and abnormal mitotic activity) (Figure 5) [24, 29] (Table 7).

It is a nonneoplastic intramedullary condition, associated with two forms, monostotic (seen in the ribs, femur, and tibia in young adults) and polyostotic (endocrine dysfunctions). The presentation of polyostotic fibrous dysplasia commonly includes bone deformity and pathological fracture. It has wide age range at

mass. There are generally no aggressive radiographical features. Pathological frac-

Microscopically, there are curved and irregularly shaped trabeculae-like fishhook configuration. These are interspersed in fibrous stroma of variable cellularity. These poorly moralized bony trabeculae have no rimming of osteoblasts, and carti-

presentation and no gender preference. The radiographs show a fusiform expanded swelling with thinning of cortex not associated soft with tissue

metaphysis and epiphysis of the lower limbs and vertebrae [26–28].

Differential Diagnosis of Osteogenic Tumors in the Context of Osteosarcoma

DOI: http://dx.doi.org/10.5772/intechopen.85190

readily differentiated using histological features [24] (Table 6).

osteoblasts due to degenerative activities [24] (Table 4).

6.4 Aneurysmal bone cyst (ABC)

6.5 Fibrous dysplasia (FD)

ture may be seen [24].

19

laginous islands are present in 10% of cases [30].

6.2 Osteomyelitis

6.3 Osteoblastoma

The osteoid and maturation level are the main difference between two lesions. The osteoid of the callus woven bone is mature and shows a parallel pattern with prominent osteoblastic rimming. Malignant osteoid is a eosinophilic, amorphous, fibrillary deposit between individual tumor cells or group of tumor cells. There are

#### Table 5.

Differential diagnosis of conventional osteosarcoma (NOS), fracture callus, Ewing's sarcoma, GCT, and chondroblastoma.

two types of tumor osteoid, early-tumor osteoid, lacelike pattern around tumor cells, and late-tumor osteoid, a mineralized one having an appearance of a woven bone, but an important feature is that tumor osteoid is not rimmed by osteoblasts [16].

## 6.2 Osteomyelitis

6. Differential diagnosis of conventional OS

Osteosarcoma – Diagnosis, Mechanisms, and Translational Developments

Sometime fracture callus may be confused with OS, because there is formation of spindle cells and cartilage with new bones, but all these elements are arranged with orderly maturation as compared to haphazard and abrupt arrangement in OS (Table 5). Postmenopausal women may have insufficiency fractures in the pelvis

The osteoid and maturation level are the main difference between two lesions. The osteoid of the callus woven bone is mature and shows a parallel pattern with prominent osteoblastic rimming. Malignant osteoid is a eosinophilic, amorphous, fibrillary deposit between individual tumor cells or group of tumor cells. There are

> Medulla of diaphysis and metaphysis

Pain May be pain No pain Pain

with a predominantly lytic appearance. No bone matrix is radiographically identified Onion skin appearance in ES on radiology

10–25 Any age Children 4–20 >20 up to 40 Younger age 10–30

Metaphyseal or diaphyseal tumor

Small round blue cells with regular size, primitiveappearing cells t(11;22)(q24;q12) chromosome rearrangement and CD99+ve

Differential diagnosis of conventional osteosarcoma (NOS), fracture callus, Ewing's sarcoma, GCT, and

Ewing's sarcoma Giant cell

tumors (GCT)

Metaphysis and epiphysis Rarely in vertebrae body

Soap bubble appearance

Sheets of giant cells and mononuclear stromal cells

Chondroblastoma

Epiphysis

Sharp and lytic lesions Fine calcification

Benign-appearing chondrocytes, without osteoid differentiation Nuclear grooves Chicken wire vascular stroma

6.1 Fracture callus and stress fracture

resembling metastatic carcinoma [24, 25].

Features Conventional

Radiology Radiographically, osteosarcoma is poorly circumscribed with cortical destruction and evidence of periosteal reactive bone Permeative pattern of growth at the periphery

Histology Tumor osteoid is arranged in parallel arrays and separated by a hypocellular osteoblastic stroma. Atypia and mitosis are common The small cells between bony osteoid. CD99, LCA, CK, and S-100 are negative

Site and location

Age in years

Clinical symptoms

Table 5.

18

chondroblastoma.

osteosarcoma (NOS)

Long bone Not specific

Fracture callus

Can be of any site and any bone

There may be increased translucency of the fracture during this stage, due to bone resorption

There is spindle cell proliferation with cartilage and bone, but orderly maturation is present in fracture callus and stress fractures

Osteomyelitis is an important cause of morbidity and mortality in children and adults due to acute and chronic bacterial infection. More common sites are the metaphysis and epiphysis of the lower limbs and vertebrae [26–28].

Primary (hematogenous) osteomyelitis is associated with fever and local painful mass and may have fistula formation. A history of recent trauma with open fracture is significant for secondary osteomyelitis. The radiology and MRI are more helpful in the diagnosis of these lesions [26]. The C-reactive protein and erythrocyte sedimentation rate (ESR) are markedly elevated. Biopsy shows necrotic bone, fibrotic marrow, and chronic inflammation with or without an acute inflammatory component. Reactive bone is usually produced as part of an associated periosteal reaction, readily differentiated using histological features [24] (Table 6).

## 6.3 Osteoblastoma

It is a benign osteoid-producing tumor with roughly the same age and sex distribution as osteosarcoma. In conventional radiography, there is a well-defined round expansile mass with central radiolucent zone (>1.5 cm) and a peripheral rim of sclerosis (sclerosis may not be as extensive as in osteoid osteoma). On biopsy, there is an irregular interlacing network of osteoid with prominent osteoblastic rimming and features of woven bone; the differential diagnosis from OS is sometimes difficult when the OS is well differentiated and OB is showing bizarre osteoblasts due to degenerative activities [24] (Table 4).

## 6.4 Aneurysmal bone cyst (ABC)

ABC has the same age range and location as osteosarcoma. It presents with pain and occasional pathological fracture. Secondary aneurysmal bone cysts can be seen in older patients, superimposed on other primary neoplasms. Conventional radiographs show radiolucent expansile bone lesion. MRI shows fluid levels on T2 weighted images. Biopsy can differentiate from telangiectatic osteosarcoma (TOS), which displays obvious histological features of malignancy (marked cellular pleomorphism, high and abnormal mitotic activity) (Figure 5) [24, 29] (Table 7).

## 6.5 Fibrous dysplasia (FD)

It is a nonneoplastic intramedullary condition, associated with two forms, monostotic (seen in the ribs, femur, and tibia in young adults) and polyostotic (endocrine dysfunctions). The presentation of polyostotic fibrous dysplasia commonly includes bone deformity and pathological fracture. It has wide age range at presentation and no gender preference. The radiographs show a fusiform expanded swelling with thinning of cortex not associated soft with tissue mass. There are generally no aggressive radiographical features. Pathological fracture may be seen [24].

Microscopically, there are curved and irregularly shaped trabeculae-like fishhook configuration. These are interspersed in fibrous stroma of variable cellularity. These poorly moralized bony trabeculae have no rimming of osteoblasts, and cartilaginous islands are present in 10% of cases [30].

6.6 Ewing's sarcoma

Figure 5.

up to 30% of cases [33].

6.7 Chondrosarcoma

CD 99 is positive in EWS [6, 33] (Table 5).

tissue mass.

21

It is the second commonest primary malignant bone tumor of the childhood after osteosarcoma. It typically arises from the medullary cavity and invades the Haversian system. Radiologically, It presents as moth-eaten and destructive permeated lucent lesions in the shaft of the long bones. It appears typical onionskin appendence due to periostitis. It may also involve flat bones and appears sclerotic in

(A) Radiological examination of telangiectatic osteosarcoma revealing a lytic/expansile, (ring) permeative lesion in the proximal fibula metaphysis with a wide zone of transition and cortical destruction, (B&C) histological examination of the photomicrographs (B; 5X and C; 400X, H&E) blood-filled spaces (thin

arrows), separated by septa containing highly malignant cells (small arrows).

Differential Diagnosis of Osteogenic Tumors in the Context of Osteosarcoma

DOI: http://dx.doi.org/10.5772/intechopen.85190

Same age range and predilection for males. Type II symptoms (e.g., fever, night sweats) are usually seen. Conventional radiographs show a metaphyseal or diaphyseal tumor with a predominantly lytic appearance. No bone matrix is radiographically identified. Onionskin appearance in ES on radiology. MRI shows a large soft

Biopsy shows small round blue cell tumor with no osteoid production. Cytogenetic and/or molecular studies show the typical translocations/molecular aberrations of Ewing sarcoma family of tumors and help rule out small cell

osteosarcoma (a rare subtype of osteosarcoma with very little osteoid production).

It is a cartilage-producing sarcoma with these differences with osteosarcoma. It is most common in patients between 50 and 60 years of age and not seen in less than 20 years. The tumor has a predilection for the pelvic bones and a slower growth rate. Conventional radiographs show a lytic lesion centered in the long bone metaphysis, with a permeative growth pattern scalloping the cortex and showing intra-tumoral calcifications, with a flocculent or ring-shaped appearance. The

#### Table 6.

Differential diagnosis of osteosarcoma, with osteomyelitis, Langerhans granuloma, and fibrous dysplasia.

It should be differentiated from other bony lesions, cemento-ossifying fibroma (rimming of osteoblast), chondrosarcoma (binucleation), Paget's disease (mosaic pattern bone histologically), non-ossifying fibroma (metaphyseal fibrous defect in tibia with the absence of osteoid), simple bony cyst, and osteofibrous dysplasia/ ossifying fibroma (exclusively seen in the tibia almost, with anterior bowing of the bone, in the cortex; rimming is seen around lamellar bony trabeculae) [30].

Some immunomarkers are helpful in the diagnosis of FD. Fibroblastic cells in FD and ossifying fibroma show strong Runx2 expression in the nucleus, while osteocalcin is seen in calcified regions in FD, and G protein genes (GNAS) are positive in extragnathic FD. FD shows GNAS (G protein gene) mutation not seen 15 in other lesions. FD is negative for osteocalcin [31, 32] (Table 6).

Differential Diagnosis of Osteogenic Tumors in the Context of Osteosarcoma DOI: http://dx.doi.org/10.5772/intechopen.85190

#### Figure 5.

(A) Radiological examination of telangiectatic osteosarcoma revealing a lytic/expansile, (ring) permeative lesion in the proximal fibula metaphysis with a wide zone of transition and cortical destruction, (B&C) histological examination of the photomicrographs (B; 5X and C; 400X, H&E) blood-filled spaces (thin arrows), separated by septa containing highly malignant cells (small arrows).

#### 6.6 Ewing's sarcoma

It is the second commonest primary malignant bone tumor of the childhood after osteosarcoma. It typically arises from the medullary cavity and invades the Haversian system. Radiologically, It presents as moth-eaten and destructive permeated lucent lesions in the shaft of the long bones. It appears typical onionskin appendence due to periostitis. It may also involve flat bones and appears sclerotic in up to 30% of cases [33].

Same age range and predilection for males. Type II symptoms (e.g., fever, night sweats) are usually seen. Conventional radiographs show a metaphyseal or diaphyseal tumor with a predominantly lytic appearance. No bone matrix is radiographically identified. Onionskin appearance in ES on radiology. MRI shows a large soft tissue mass.

Biopsy shows small round blue cell tumor with no osteoid production. Cytogenetic and/or molecular studies show the typical translocations/molecular aberrations of Ewing sarcoma family of tumors and help rule out small cell osteosarcoma (a rare subtype of osteosarcoma with very little osteoid production). CD 99 is positive in EWS [6, 33] (Table 5).

#### 6.7 Chondrosarcoma

It is a cartilage-producing sarcoma with these differences with osteosarcoma. It is most common in patients between 50 and 60 years of age and not seen in less than 20 years. The tumor has a predilection for the pelvic bones and a slower growth rate. Conventional radiographs show a lytic lesion centered in the long bone metaphysis, with a permeative growth pattern scalloping the cortex and showing intra-tumoral calcifications, with a flocculent or ring-shaped appearance. The

It should be differentiated from other bony lesions, cemento-ossifying fibroma (rimming of osteoblast), chondrosarcoma (binucleation), Paget's disease (mosaic pattern bone histologically), non-ossifying fibroma (metaphyseal fibrous defect in tibia with the absence of osteoid), simple bony cyst, and osteofibrous dysplasia/ ossifying fibroma (exclusively seen in the tibia almost, with anterior bowing of the bone, in the cortex; rimming is seen around lamellar bony trabeculae) [30].

Differential diagnosis of osteosarcoma, with osteomyelitis, Langerhans granuloma, and fibrous dysplasia.

Some immunomarkers are helpful in the diagnosis of FD. Fibroblastic cells in FD

and ossifying fibroma show strong Runx2 expression in the nucleus, while osteocalcin is seen in calcified regions in FD, and G protein genes (GNAS) are positive in extragnathic FD. FD shows GNAS (G protein gene) mutation not seen

15 in other lesions. FD is negative for osteocalcin [31, 32] (Table 6).

Features Osteosarcoma Osteomyelitis Langerhans

Osteosarcoma – Diagnosis, Mechanisms, and Translational Developments

Long bone Epiphysis (neonates)

10–25 Any age, more in

Pain Pain, fever,

Metaphysis (children)

children

discharges

The earliest radiological changes are seen in adjacent soft tissues +/ muscle outlines with swelling and loss or blurring of normal fat planes. An effusion may be seen in an adjacent joint. MRI is more

helpful

In acute cases, neutrophils and necrotic bony trabeculae, in TB, granulomas, and in chronic nonspecific cases, lymphocytes and macrophages are more common

Site and location

Age in years

Clinical symptoms

Radiology Radiographically, osteosarcoma is poorly

bone

Histology Tumor osteoid is

fat and

osteoma

Table 6.

20

circumscribed with cortical destruction and evidence of periosteal reactive

Permeative pattern of growth at the periphery

arranged in parallel arrays and separated by a hypocellular fibroblastic stroma. Atypia is common The spindle cells between bony trabeculae instead of

hematopoietic tissue as seen in OS Lacks the

fibrovascular stroma and osteoblastic rimming of osteoid

May show cartilage component

granuloma

Metaphysis or diaphysis

More common in children 5–15 years

Multiple lytic lesions with significant periosteal reaction

There is monoclonal proliferation of Langerhans cells (distinctive cells of monocyte– macrophage lineage) and should be considered a malignancy although its biological behavior is very variable. EM shows Birbeck granules. Express CD1a, S100,

HLA-DR

Local pain No pain

Fibrous dysplasia

Medulla of diaphysis

1–30 years > males

The conventional radiographs show ground glass appearance with no associated soft tissue mass. There are generally no aggressive radiographical features

There is large fibrous matrix with scattered curvilinear irregularly shaped trabeculae of immature, inadequately mineralized bone. There is no rimming by osteoblasts GNAS +ve, osteoclastin +ve Run-X-2 +ve, see also

(Table 9)

overexpression of a tumor necrosis factor receptor (RANK/RANKL) which results in a hyper-proliferation of osteoclasts [16]. Histologically, the GCTs are characterized by the presence of osteoclast-like, giant cells and round-to-oval polygonal mononuclear cells. Frequent mitotic figures in the mononuclear cells may be seen, especially in pregnant women or those on the oral contraceptive pill (due to increased hormone levels) [16, 35]. Important features are given below (Table 5). This lesion is most common in skeletally mature women with closed epiphysis which usually presents with bone pain and sometimes pathological fractures. It involves epiphysis and extends to joint articular cartilage. Conventional radiographs show tumor with an osteolytic appearance located in the epiphysis of long bones, with the distal femur and proximal tibia being the most commonly affected. No doubt it is benign but is locally aggressive. This translates radiographically into the absence of an osteosclerotic rim at its periphery as well as the presence of a soft tissue mass. No bone/osteoid formation is identified. Radiology is soap bubble appearance. Biopsy shows typical appearance of evenly distributed giant cells in a mononuclear stroma. The nuclei of the giant cells resemble the nuclei of the histiocytes. There is atypia or mitosis, potentially malignant with 50% recurrence rate

Differential Diagnosis of Osteogenic Tumors in the Context of Osteosarcoma

DOI: http://dx.doi.org/10.5772/intechopen.85190

These are rare manifestation than secondary lymphoma involving the bone. It is rare, accounting for <5% of bone tumors and <1% of non-Hodgkin lymphoma. It is more common in old age males as compared to OS. The patient presents with type II general symptoms like night sweatings, fever, and weight loss. The conventional radiographs may be normal (tumor cells tend to grow between patient's bony trabeculae with little bone destruction). There may be multiple or single bone involvement. MRI shows focal change in the marrow signal. Bone marrow biopsy is usually the confirmatory test. Flow cytometric studies should be considered in patients suspected of having lymphoma. Leukocyte common antigen (LCA) is positive in lymphomas while negative in OS [24, 36]. Usually it should be differentiated from infections, small cell OS, Ewing's sarcoma, eosinophilic granuloma, and

It is a multisystem but rare disease. It is associated with a wide and heterogeneous clinical spectrum and extent of multisystem involvement. The age range is 5–15 years, more common in the children and early teens. The males are more affected than females (M/F ratio is 3:2) [38, 39]. It has a predilection for the bones of the skull, the calvarium, but any other bone like the humerus, femur, and ribs can be involved. There is local pain and swelling. Radiographically there are multiple lytic lesions with significant periosteal reaction. Biopsy shows a proliferation of neoplastic Langerhans cells in an inflammatory background [24] (Table 6).

Generally it occurs in older age group than osteosarcoma. There is usual history of a primary malignancy known to metastasis to bone, such as breast, lung, thyroid, kidney, and prostate. Conventional radiographs and radionuclide scans usually show osteolytic lesions (rarely osteoblastic) involving multiple bones. CT imaging may reveal other organs affected by metastatic disease. Biopsy usually confirms the

and 10% metastasis [32].

metastatic lesions [36, 37].

diagnosis [35].

23

6.10 Langerhans cell histiocytosis

6.11 Metastases from other malignancies

6.9 Primary lymphoma of the bones

#### Table 7.

Differential diagnosis of telangiectatic osteosarcoma (TOS) and, conventional osteosarcoma, angiosarcoma, ABC, and GCT.

cortex is usually thickened with a slightly expanded fusiform appearance, mainly due to the slow permeative growth of the tumor (chronic periosteal reaction). Scalloping of the inner cortex is a radiographic sign worrisome for malignancy. Biopsy is the confirmatory test. Low-grade CS with ossification may mimic OS, but the cartilaginous component in OS, if seen, is always high-grade and malignant osteoids are essential for its diagnosis. Dedifferentiated CS has a well-differentiated benign chondral lesion or chondrosarcoma and sharply juxtaposed with a highgrade non-cartilaginous component; typically, there is an abrupt transition between the two tissue types. The non-cartilaginous component of dedifferentiated chondrosarcoma is generally osteosarcoma, a fibrosarcoma, or a malignant fibrous histiocytoma. Dedifferentiation to leiomyosarcoma, giant cell tumor, and, rarely, clear-cell chondrosarcoma or rhabdomyosarcoma has been reported. Always look the age, site and radiology for help. The S-100 is negative in OS [34].

#### 6.8 Giant cell tumor (GCT) of the bone

The GCT is usually benign and arises from long bone epiphysis and metaphysis. It is rare in vertebrae, but when they occur in a vertebra, the body and not the arch is usually involved [35]. The pathogenesis of GCT is accredited due to

### Differential Diagnosis of Osteogenic Tumors in the Context of Osteosarcoma DOI: http://dx.doi.org/10.5772/intechopen.85190

overexpression of a tumor necrosis factor receptor (RANK/RANKL) which results in a hyper-proliferation of osteoclasts [16]. Histologically, the GCTs are characterized by the presence of osteoclast-like, giant cells and round-to-oval polygonal mononuclear cells. Frequent mitotic figures in the mononuclear cells may be seen, especially in pregnant women or those on the oral contraceptive pill (due to increased hormone levels) [16, 35]. Important features are given below (Table 5).

This lesion is most common in skeletally mature women with closed epiphysis which usually presents with bone pain and sometimes pathological fractures. It involves epiphysis and extends to joint articular cartilage. Conventional radiographs show tumor with an osteolytic appearance located in the epiphysis of long bones, with the distal femur and proximal tibia being the most commonly affected. No doubt it is benign but is locally aggressive. This translates radiographically into the absence of an osteosclerotic rim at its periphery as well as the presence of a soft tissue mass. No bone/osteoid formation is identified. Radiology is soap bubble appearance. Biopsy shows typical appearance of evenly distributed giant cells in a mononuclear stroma. The nuclei of the giant cells resemble the nuclei of the histiocytes. There is atypia or mitosis, potentially malignant with 50% recurrence rate and 10% metastasis [32].

## 6.9 Primary lymphoma of the bones

These are rare manifestation than secondary lymphoma involving the bone. It is rare, accounting for <5% of bone tumors and <1% of non-Hodgkin lymphoma. It is more common in old age males as compared to OS. The patient presents with type II general symptoms like night sweatings, fever, and weight loss. The conventional radiographs may be normal (tumor cells tend to grow between patient's bony trabeculae with little bone destruction). There may be multiple or single bone involvement. MRI shows focal change in the marrow signal. Bone marrow biopsy is usually the confirmatory test. Flow cytometric studies should be considered in patients suspected of having lymphoma. Leukocyte common antigen (LCA) is positive in lymphomas while negative in OS [24, 36]. Usually it should be differentiated from infections, small cell OS, Ewing's sarcoma, eosinophilic granuloma, and metastatic lesions [36, 37].

#### 6.10 Langerhans cell histiocytosis

It is a multisystem but rare disease. It is associated with a wide and heterogeneous clinical spectrum and extent of multisystem involvement. The age range is 5–15 years, more common in the children and early teens. The males are more affected than females (M/F ratio is 3:2) [38, 39]. It has a predilection for the bones of the skull, the calvarium, but any other bone like the humerus, femur, and ribs can be involved. There is local pain and swelling. Radiographically there are multiple lytic lesions with significant periosteal reaction. Biopsy shows a proliferation of neoplastic Langerhans cells in an inflammatory background [24] (Table 6).

#### 6.11 Metastases from other malignancies

Generally it occurs in older age group than osteosarcoma. There is usual history of a primary malignancy known to metastasis to bone, such as breast, lung, thyroid, kidney, and prostate. Conventional radiographs and radionuclide scans usually show osteolytic lesions (rarely osteoblastic) involving multiple bones. CT imaging may reveal other organs affected by metastatic disease. Biopsy usually confirms the diagnosis [35].

cortex is usually thickened with a slightly expanded fusiform appearance, mainly due to the slow permeative growth of the tumor (chronic periosteal reaction). Scalloping of the inner cortex is a radiographic sign worrisome for malignancy. Biopsy is the confirmatory test. Low-grade CS with ossification may mimic OS, but the cartilaginous component in OS, if seen, is always high-grade and malignant osteoids are essential for its diagnosis. Dedifferentiated CS has a well-differentiated benign chondral lesion or chondrosarcoma and sharply juxtaposed with a highgrade non-cartilaginous component; typically, there is an abrupt transition between

Differential diagnosis of telangiectatic osteosarcoma (TOS) and, conventional osteosarcoma, angiosarcoma,

Note: ABC; Aneurysmal bone cyst, GCT; Giant cell tumors, OS; Osteosarcoma, IHC; Immunohistochemistry, Ch; chromosome.

the two tissue types. The non-cartilaginous component of dedifferentiated

the age, site and radiology for help. The S-100 is negative in OS [34].

is usually involved [35]. The pathogenesis of GCT is accredited due to

6.8 Giant cell tumor (GCT) of the bone

Features Telangiectatic

Radiology Lytic bony lesions, geographic bony destruction with wide zone of transition tends to be more common than permeative bony destruction

Histology It is consist of

vascular sinusoids surrounded by thin septae, osteoid matrix and cells with significant pleomorphism and high mitotic rate

Site and location

Age in years

Clinical symptoms

Table 7.

22

ABC, and GCT.

osteosarcoma (TOS)

Conventional OS

Osteosarcoma – Diagnosis, Mechanisms, and Translational Developments

Sclerotic lesions and cortical destruction

Malignant osteoblasts and malignant osteoids IHC:SATB2 and AKP are positive, TP53 alteration and MDM2 amplification

Metaphysis Metaphysis Not specific Metaphysis

Mean age 20 years 10–25 Old age Younger 10–20, slightly

Dull pain Dull pain No pain No pain No pain

Soft tissue mass

Blood vessels are lined by malignant endothelial cells

Angiosarcoma ABC Giant cell

Flat bones, vertebrae, long bones

Lytic but demarcated Both processes may have similar presentations and radiographic findings and tend to involve the

CT and MRI show fluid

Small foci of reactive osteoid may be present in aneurysmal bone cysts, which should not be confused with osteoblastoma IHC shows rearrangement of USP6, gene present of

more in females

vertebra

level

Ch 17,

CDH11

t(16;17)(q22;p13). Fusion of USP6 with tumors

Metaphysis of epiphysis

>20 up to 40

Soap bubble appearance

Sheets of giant cells and mononuclear stromal cells. Sometimes, may appear with bloodfilled spaces

chondrosarcoma is generally osteosarcoma, a fibrosarcoma, or a malignant fibrous histiocytoma. Dedifferentiation to leiomyosarcoma, giant cell tumor, and, rarely, clear-cell chondrosarcoma or rhabdomyosarcoma has been reported. Always look

The GCT is usually benign and arises from long bone epiphysis and metaphysis. It is rare in vertebrae, but when they occur in a vertebra, the body and not the arch

## 7. Special variants of OS with differential diagnosis

#### 7.1 Telangiectatic OS

It is an uncommon variant of OS in the second decade with a mean age of 20 years. It comprises of 2.5–12% of all osteosarcomas. Almost all osteosarcomas have telangiectatic component. In order to diagnose telangiectatic osteosarcoma, there should be more than 90% component with telangiectatic features. It is more common in males like conventional OS (with a ratio of 2:1 for male to female) [24] better than conventional OS [13].

Multiple cyst-like spaces resemble an aneurysmal bone cyst, except that the septa of the cysts contain stromal cells (mononuclear and multinucleated) with cytologically malignant changes. Mitotic figures are present, including atypical forms. Sometimes the malignant stromal cells are floating in the center of the large hemorrhagic cysts; identification of the stromal cells may be difficult, requiring multiple sections. The TOS may arise in other bony diseases like fibrous dysplasia, Paget's disease, or postradiation therapy. Malignant osteoid can be difficult to identify, usually focal and found in a delicate lacelike pattern [24, 40] (Figure 5 and Table 7).

Advice: If the diagnosis of aneurysmal bone cyst is being considered, all tissue should be evaluated histologically for evidence of malignant stroma to rule out telangiectatic osteosarcoma radiological correlation.

#### 7.2 Differential diagnosis of TOS

#### 7.2.1 Aneurysmal bone cyst

The aneurysmal bone cysts are usually seen in young age with slight female preponderance in flat and vertebral areas but may involve long bones. Radiology shows a lucent expansile lesion in the metaphysis of long bones with thin reactive covering of periosteal bone. CT and MRI show some fluid levels in the ABC. Microscopically, thin blood filled spaces. These spaces are not lined by endothelium but only fibroblastic cells are there. The stroma of the ABC may be cellular but typically lacks cytological atypia and atypical mitoses and may contain reactive bone with atypical osteoblasts. Cytologic malignant features and atypical mitoses are absent (Figure 6, Table 7).

7.4 Differential diagnosis of well-differentiated OS

Differential Diagnosis of Osteogenic Tumors in the Context of Osteosarcoma

DOI: http://dx.doi.org/10.5772/intechopen.85190

myofibroblasts, and histiocytes but not endothelium (C).

osteoid production on histologic examination (Table 5).

Chondroblastoma is a rare primary bone tumor of young people that typically

(A) Radiological examination reveals (ring) homogenous cystic areas (aneurysmal bone cyst) without cortical destructions. (B) Photomicrograph (H&E 10X) revealing cystic lesions (arrow), with giant cells (red arrow) separated by fibrous septa (black arrows), alternating with solid areas and septa lined by fibroblasts,

A rare variant of osteosarcoma with CB features may be seen and can be difficult to distinguish from CB, as both tumors can present in young patients as a lytic lesion in an epiphyseal location. Histologically, this OS may reveal small round-oval cells with eosinophilic cytoplasm and scattered giant cells and therefore may cause confusion with CB, especially on a small biopsy specimen. Clues to the appropriate malignant diagnosis include a more aggressive, infiltrative lesion on radiological studies, and the presence of nuclear atypia, atypical mitoses, and/or malignant

It is usually seen in young ages (10–30 years) and more common in males. It is commonly found in metaphysis, diaphysis of ribs, jaw, skull, tibia, and femur. It is locally aggressive tumor and may be monostotic or polyostotic and associated with

arises at the ends of the long bones. Radiologic investigations show a small, circumscribed, lytic lesion. The tumor is characterized histologically by the proliferation of chondroblasts along with areas of mature cartilage, giant cells, and, occasionally, secondary aneurysmal bone cyst formation. Chondroblastoma, however, may also present with atypical features, such as prominent hemosiderin deposition, numerous giant cells, or the presence of a large aneurysmal bone cyst

7.4.1 Chondroblastoma

component.

Figure 6.

7.4.2 Fibrous dysplasia

25

#### 7.2.2 Conventional osteosarcoma

Radiographically, these tumors are not purely lytic. Intramedullary osteosarcoma may contain focal telangiectatic areas, which should not be overinterpreted (Table 8).

#### 7.3 Well-differentiated intraosseous low-grade osteosarcoma

The low-grade OS is a rare subtype of osteosarcoma, usually occurring in young adults in their tibia and femur. Microscopically, there may be components of heavy osteoid and fibrocollagenous stroma, and the cells appear benign but with invasion of cortex and surrounding soft tissue. The spindle cells are with mild atypia, marked collagen production, scant atypia, and abundant osteoid production (Figure 9). The patients present with pain and swelling in older people. It arises from metaphysis of long bone of lower extremity, while other sites are uncommon. Radiologically, there are irregularly sclerotic lesions with poorly defined sclerotic margins, and mineralized matrix is common (Figure 7A–C).

Differential Diagnosis of Osteogenic Tumors in the Context of Osteosarcoma DOI: http://dx.doi.org/10.5772/intechopen.85190

#### Figure 6.

7. Special variants of OS with differential diagnosis

Osteosarcoma – Diagnosis, Mechanisms, and Translational Developments

found in a delicate lacelike pattern [24, 40] (Figure 5 and Table 7).

telangiectatic osteosarcoma radiological correlation.

It is an uncommon variant of OS in the second decade with a mean age of 20 years. It comprises of 2.5–12% of all osteosarcomas. Almost all osteosarcomas have telangiectatic component. In order to diagnose telangiectatic osteosarcoma, there should be more than 90% component with telangiectatic features. It is more common in males like conventional OS (with a ratio of 2:1 for male to female) [24]

Multiple cyst-like spaces resemble an aneurysmal bone cyst, except that the septa of the cysts contain stromal cells (mononuclear and multinucleated) with cytologically malignant changes. Mitotic figures are present, including atypical forms. Sometimes the malignant stromal cells are floating in the center of the large hemorrhagic cysts; identification of the stromal cells may be difficult, requiring multiple sections. The TOS may arise in other bony diseases like fibrous dysplasia, Paget's disease, or postradiation therapy. Malignant osteoid can be difficult to identify, usually focal and

Advice: If the diagnosis of aneurysmal bone cyst is being considered, all tissue should be evaluated histologically for evidence of malignant stroma to rule out

The aneurysmal bone cysts are usually seen in young age with slight female preponderance in flat and vertebral areas but may involve long bones. Radiology shows a lucent expansile lesion in the metaphysis of long bones with thin reactive covering of periosteal bone. CT and MRI show some fluid levels in the ABC. Microscopically, thin blood filled spaces. These spaces are not lined by endothelium but only fibroblastic cells are there. The stroma of the ABC may be cellular but typically lacks cytological atypia and atypical mitoses and may contain reactive bone with atypical osteoblasts. Cytologic malignant features and atypical mitoses

Radiographically, these tumors are not purely lytic. Intramedullary osteosarcoma may contain focal telangiectatic areas, which should not be overinterpreted (Table 8).

The low-grade OS is a rare subtype of osteosarcoma, usually occurring in young adults in their tibia and femur. Microscopically, there may be components of heavy osteoid and fibrocollagenous stroma, and the cells appear benign but with invasion of cortex and surrounding soft tissue. The spindle cells are with mild atypia, marked collagen production, scant atypia, and abundant osteoid production (Figure 9). The patients present with pain and swelling in older people. It arises from metaphysis of long bone of lower extremity, while other sites are uncommon. Radiologically, there are irregularly sclerotic lesions with poorly defined sclerotic margins, and mineral-

7.3 Well-differentiated intraosseous low-grade osteosarcoma

7.1 Telangiectatic OS

better than conventional OS [13].

7.2 Differential diagnosis of TOS

are absent (Figure 6, Table 7).

7.2.2 Conventional osteosarcoma

ized matrix is common (Figure 7A–C).

24

7.2.1 Aneurysmal bone cyst

(A) Radiological examination reveals (ring) homogenous cystic areas (aneurysmal bone cyst) without cortical destructions. (B) Photomicrograph (H&E 10X) revealing cystic lesions (arrow), with giant cells (red arrow) separated by fibrous septa (black arrows), alternating with solid areas and septa lined by fibroblasts, myofibroblasts, and histiocytes but not endothelium (C).

### 7.4 Differential diagnosis of well-differentiated OS

#### 7.4.1 Chondroblastoma

Chondroblastoma is a rare primary bone tumor of young people that typically arises at the ends of the long bones. Radiologic investigations show a small, circumscribed, lytic lesion. The tumor is characterized histologically by the proliferation of chondroblasts along with areas of mature cartilage, giant cells, and, occasionally, secondary aneurysmal bone cyst formation. Chondroblastoma, however, may also present with atypical features, such as prominent hemosiderin deposition, numerous giant cells, or the presence of a large aneurysmal bone cyst component.

A rare variant of osteosarcoma with CB features may be seen and can be difficult to distinguish from CB, as both tumors can present in young patients as a lytic lesion in an epiphyseal location. Histologically, this OS may reveal small round-oval cells with eosinophilic cytoplasm and scattered giant cells and therefore may cause confusion with CB, especially on a small biopsy specimen. Clues to the appropriate malignant diagnosis include a more aggressive, infiltrative lesion on radiological studies, and the presence of nuclear atypia, atypical mitoses, and/or malignant osteoid production on histologic examination (Table 5).

#### 7.4.2 Fibrous dysplasia

It is usually seen in young ages (10–30 years) and more common in males. It is commonly found in metaphysis, diaphysis of ribs, jaw, skull, tibia, and femur. It is locally aggressive tumor and may be monostotic or polyostotic and associated with

endocrine disorders. Radiologically, it is circumscribed radiolucent lesions, within

Differential Diagnosis of Osteogenic Tumors in the Context of Osteosarcoma

There are irregularly shaped bony trabeculae without rimming of osteoblasts. The osteoids are of mature woven bones, and irregular in FD, while mature osteoids are present in WDIOS. There is no cortical destruction on X-rays seen in

(A) Radiological examination showing medullary and cortical bone destruction wide zone of transition (ring and arrow), permeative or moth-eaten appearance. (B) Photomicrograph of (10X H&E) of conventional intramedullary osteosarcoma and bony osteoid (thick arrow) surrounded by pleomorphic stroma and mitoses

X-ray of parosteal osteosarcoma (ring) showing surface-attached mass (A). Photomicrograph (H&E 20X) revealing continuously branching bony trabeculae (thick arrow) with spindle cell proliferation of malignant

the medullary cavity.

DOI: http://dx.doi.org/10.5772/intechopen.85190

Figure 7.

Figure 8.

27

cells (thin arrow) (B and C).

(thin arrows) (20X H&E) (C).

DLBCL; Diffuse large B cell lymphoma, MFH; Malignant Fibrous Histiocytoma.

#### Table 8.

Differential diagnosis of osteosarcoma with malignant fibrous histiocytoma, lymphoma, and osteoblastoma.

Differential Diagnosis of Osteogenic Tumors in the Context of Osteosarcoma DOI: http://dx.doi.org/10.5772/intechopen.85190

endocrine disorders. Radiologically, it is circumscribed radiolucent lesions, within the medullary cavity.

There are irregularly shaped bony trabeculae without rimming of osteoblasts. The osteoids are of mature woven bones, and irregular in FD, while mature osteoids are present in WDIOS. There is no cortical destruction on X-rays seen in

#### Figure 7.

Features Osteosarcoma MFH Lymphoma Osteoblastoma

Metaphysis Metaphysis

Localized pain and swelling

The most common is a lytic pattern with permeative bone destruction and a wide zone of transition

DLBCL is the most common subtype. The bony pelvis and femur are the most common locations

50–60 Younger age and

Pain

more in females 10–30

Well-defined lytic

They manufacture abundant osteoid, but they are not composed of atypical and pleomorphic osteoblasts

lesions

Metaphysis of the long bones

seen in the second

associated when arising from other primary bone lesions, like Paget's disease, radiation, giant cell tumor, and bone infarction

Purely osteolytic permeative lesions without a periosteal reaction and without mineralization

No extensive osteoid formation. Some osteoid osteogenic sarcomas may have a predominant histologic pattern of malignant fibrous histiocytoma; the presence of osteoid formation requires the diagnosis of osteosarcoma They are heterogeneous fibroblastic tumors formed by poorly differentiated fibroblasts, myofibroblasts, histiocyte-like cells with high degree of pleomorphism and characteristic storiform pattern and also demonstrating

decade

Osteosarcoma – Diagnosis, Mechanisms, and Translational Developments

10–25 10 to 60, commonly

Pain Dull pain but may be

Site and location

Age in years

Clinical symptoms Metaphysis of long

bone

Radiology Radiographically, osteosarcoma is poorly circumscribed with cortical destruction and evidence of periosteal reactive

bone

Histology Tumor osteoid is

fat and

osteoma

Table 8.

26

Permeative pattern of growth at the periphery

arranged in parallel arrays and separated by a hypocellular fibroblastic stroma. Atypia is common The spindle cells between bony trabeculae instead of

hematopoietic tissue as seen in OS Lacks the

fibrovascular stroma and osteoblastic rimming of osteoid

May show cartilage component

bizarre

cells

DLBCL; Diffuse large B cell lymphoma, MFH; Malignant Fibrous Histiocytoma.

multinucleated giant

Differential diagnosis of osteosarcoma with malignant fibrous histiocytoma, lymphoma, and osteoblastoma.

Run-X-2 negative

(A) Radiological examination showing medullary and cortical bone destruction wide zone of transition (ring and arrow), permeative or moth-eaten appearance. (B) Photomicrograph of (10X H&E) of conventional intramedullary osteosarcoma and bony osteoid (thick arrow) surrounded by pleomorphic stroma and mitoses (thin arrows) (20X H&E) (C).

#### Figure 8.

X-ray of parosteal osteosarcoma (ring) showing surface-attached mass (A). Photomicrograph (H&E 20X) revealing continuously branching bony trabeculae (thick arrow) with spindle cell proliferation of malignant cells (thin arrow) (B and C).

FD, while there are irregularly sclerotic lesions with poorly defined sclerotic margins. The mineralized matrix is common in WDIOS while lacking in FD (Tables 6 and 9).

osteoid, variable cartilage, and highly fibrous spindle cell stroma in disorganized manner. In some cases there may be hypocellularity, but there is always mild atypia in the stroma. These tumors have a slight female predominance, with a male-tofemale ratio of 1:1.5, and occur predominantly in the third decade. About three fourths of cases involve the distal posterior femur, with the proximal tibia as the second most common site. Clinically it presents as a painless mass of long

Differential Diagnosis of Osteogenic Tumors in the Context of Osteosarcoma

DOI: http://dx.doi.org/10.5772/intechopen.85190

duration; pain may occur late in the course of this tumor but is not evident initially. Microscopically, there is disorderly arrangement of well-formed bony trabeculae and osteoid and exceptionally osteoclast-like giant cells. There are spindle-shaped stroma with mild atypia and variable amount of cartilage (Table 9) compared to conventional OS (Figure 8 and Table 9). Radiodense, bosselated, or mushroomshaped mass arises on the surface of a bone; in long-term lesions, tumor may

It is a benign disorder where the medullary spaces contain adipose tissue or marrow hematopoietic tissue with cartilaginous cap. The bony trabeculae are nor-

The myositis ossificans (MO) is distinguished from PAOS by its orderly pattern

of maturation. Radiologically, things appear inverse in the MO as compared to PAOS. There is the dense ossification in the center in MO and opaque bone at the periphery, making it eggshell in appearance. Histologically there is zonal arrange-

X-ray of periosteal osteosarcoma (ring) showing broad-based lesion thickening of cortical areas of the femur (A). Photomicrograph (H&E 40X) revealing bony trabeculae with spindle cell proliferation (arrow) of

malignant cells and cartilage (red arrow) differentiation (B and C).

ment. Maturation toward lamellar bone and marrow adipose tissue begins

encircle the bone [41].

7.5.1 Osteochondroma

7.5.2 Myositis ossificans

Figure 9.

29

7.5 Differential diagnosis PAOS

mally arranged as compared to the PAOS.

## 7.4.3 Non-ossifying fibroma (cortical fibrous defect)

Usually seen in young persons, it is a benign lesion. Microscopically, no osteoid and bony trabeculae but only storiform spindle stroma, giant cells, and hemosiderin-laden microphages are seen. Radiologically, these are eccentric sharply defined lytic lesions in metaphyseal cortex in young people.

## 7.4.4 Parosteal osteosarcoma (PAOS)

This infrequent variant occurs in a juxtacortical position in the metaphyses of long bones and grows very slowly. It grows, as a lobulated mass around the bone shafts as a low-grade malignant bone tumor with well-formed bony trabeculae,

Note: Well-differentiated intramedullary osteosarcoma (WDIOS), parosteal osteosarcoma (PAOS), fibrous dysplasia (FD), conventional osteosarcoma (COS).

#### Table 9.

Differential diagnosis of WD intramedullary osteosarcoma, parosteal osteosarcoma, conventional OS, periosteal osteosarcoma, and fibrous dysplasia.

Differential Diagnosis of Osteogenic Tumors in the Context of Osteosarcoma DOI: http://dx.doi.org/10.5772/intechopen.85190

osteoid, variable cartilage, and highly fibrous spindle cell stroma in disorganized manner. In some cases there may be hypocellularity, but there is always mild atypia in the stroma. These tumors have a slight female predominance, with a male-tofemale ratio of 1:1.5, and occur predominantly in the third decade. About three fourths of cases involve the distal posterior femur, with the proximal tibia as the second most common site. Clinically it presents as a painless mass of long duration; pain may occur late in the course of this tumor but is not evident initially. Microscopically, there is disorderly arrangement of well-formed bony trabeculae and osteoid and exceptionally osteoclast-like giant cells. There are spindle-shaped stroma with mild atypia and variable amount of cartilage (Table 9) compared to conventional OS (Figure 8 and Table 9). Radiodense, bosselated, or mushroomshaped mass arises on the surface of a bone; in long-term lesions, tumor may encircle the bone [41].

## 7.5 Differential diagnosis PAOS

## 7.5.1 Osteochondroma

FD, while there are irregularly sclerotic lesions with poorly defined sclerotic mar-

Usually seen in young persons, it is a benign lesion. Microscopically, no osteoid and bony trabeculae but only storiform spindle stroma, giant cells, and hemosiderin-laden microphages are seen. Radiologically, these are eccentric sharply defined

This infrequent variant occurs in a juxtacortical position in the metaphyses of long bones and grows very slowly. It grows, as a lobulated mass around the bone shafts as a low-grade malignant bone tumor with well-formed bony trabeculae,

Metaphysis Metaphysis Metaphysis Metaphysis Medulla of diaphysis.

10–20 10–25 10–25 10–25 1–30 years > males

Diffuse cortical destruction like Codman's triangle, osteoblastic features

This is a higher-grade osteosarcoma involving the medullary cavity.  The cartilage in lobules with peripheral spindling and central bone formation. Malignant osteoid/ bone is present but may be focal

The conventional radiographs show ground glass appearance with no associated soft tissue mass. There are generally no aggressive radiographical features

There is large fibrous matrix with scattered curvilinear irregularly shaped trabeculae of immature, inadequately mineralized bone. There is no rimming by

osteoblasts differentiating feature from cement-ossifying fibroma. Cartilaginous islands are present in 10%, differentiating feature from chondroblastoma

PAOS COS PEOS Fibrous dysplasia

gins. The mineralized matrix is common in WDIOS while lacking in FD

Osteosarcoma – Diagnosis, Mechanisms, and Translational Developments

7.4.3 Non-ossifying fibroma (cortical fibrous defect)

lytic lesions in metaphyseal cortex in young people.

7.4.4 Parosteal osteosarcoma (PAOS)

intramedullary

(Tables 6 and 9).

Features WD

Site and location

Age in years

Clinical symptoms OS

Pain and swelling, patients older

sclerotic lesions with poorly defined sclerotic margins, mineralized matrix common

Radiodense, bosselated, or mushroomshaped mass arising on the surface of a bone; in longterm lesions, tumor may encircle the bone

Tumor osteoid is arranged in parallel arrays and separated by a hypocellular fibroblastic stroma that exhibits minimal cytologic atypia and minimal mitotic activity without atypical forms

Radiology Irregularly

Histology Heavy osteoid component, fibrocollagenous stroma with minimal atypia

conventional osteosarcoma (COS).

periosteal osteosarcoma, and fibrous dysplasia.

Table 9.

28

It is a benign disorder where the medullary spaces contain adipose tissue or marrow hematopoietic tissue with cartilaginous cap. The bony trabeculae are normally arranged as compared to the PAOS.

## 7.5.2 Myositis ossificans

The myositis ossificans (MO) is distinguished from PAOS by its orderly pattern of maturation. Radiologically, things appear inverse in the MO as compared to PAOS. There is the dense ossification in the center in MO and opaque bone at the periphery, making it eggshell in appearance. Histologically there is zonal arrangement. Maturation toward lamellar bone and marrow adipose tissue begins

#### Figure 9.

X-ray of periosteal osteosarcoma (ring) showing broad-based lesion thickening of cortical areas of the femur (A). Photomicrograph (H&E 40X) revealing bony trabeculae with spindle cell proliferation (arrow) of malignant cells and cartilage (red arrow) differentiation (B and C).

peripherally and extends centrally in this proliferative process, which is the reverse in parosteal osteosarcoma [41].

## 7.5.3 Osteochondroma

The osteochondroma shows continuity of corticomedullary areas of the tumor and the underlying medullary canal, but these features are lacking in PAOS. Medullary spaces contain adipose tissue or marrow hematopoietic tissue, cartilaginous cap.

## 7.5.4 Periosteal osteosarcoma

Abundant cartilage is present. Higher-grade osseous component and evidence of periosteal reaction.

## 7.5.5 Periosteal osteosarcoma (PEOS)

This malignant bone tumor is commonly seen in routine biopsies, entirely different from PAOS (juxtacortical OS) despite its similarity with terminology. It arises on surface of long bones (upper tibia and femur). The PEOS affects a slightly older age group (10–20 years) as compared to conventional osteosarcoma. Malignant osteoid must be present, but the predominant pattern of tumor is represented by lobulated chondromatous tissue with cytologic features of grade 2 or 3 chondrosarcoma. Tumor is located on the surface of the bone and may extend into soft tissue. The lesions are limited to the cortex and rarely invade the medullary cavity. The tumor appears perpendicular to the shaft. Sometimes high-grade anaplastic sarcomatous spindle cell component may separate lobules of the malignant chondroid component [24] (Figure 9 and Table 10) [20, 42].

## 7.6 Differential diagnosis of PEOS

#### 7.6.1 Periosteal chondroma

It is usually smaller and better defined and composed of benign chondroid tissue and does not contain malignant tumor osteoid [24].

## 7.6.2 Periosteal chondrosarcoma

Radiographically, it contains "popcorn" calcifications, and histologically, it is a low-grade chondrosarcoma containing no tumor osteoid [20, 24].

#### 7.6.3 Parosteal osteosarcoma

Radiographically, this tumor is more radiodense, and histologically this is a low-grade malignant fibro-osseous tumor without chondroid differentiation [20, 24].

### 7.6.4 Conventional intramedullary osteosarcoma

This is a higher-grade osteosarcoma involving the medullary cavity. Periosteal osteosarcoma does not involve the medullary cavity [24].

Features

31

Site and

Metaphysis

Metaphysis

Metaphysis

Metaphyseal

NOS

location

Age in

10–25

10–25

10–25

10–30

Any age

Any age

DOI: http://dx.doi.org/10.5772/intechopen.85190

years

Clinical

Dull pain

Dull pain

Dull pain

No pain

Pain

No pain Lytic lesions

without

Differential Diagnosis of Osteogenic Tumors in the Context of Osteosarcoma

bony

destructions

symptoms

Radiology

 Radiodense,

 bosselated,

mushroom-shaped

on the surface of a bone; in long-

term lesions, tumor may encircle

the bone

Histology

 Tumor osteoid is arranged in

This is a osteosarcoma

medullary cavity. Periosteal

osteosarcoma

the medullary cavity

 does not involve

 involving the

higher-grade

parallel arrays and separated by

a hypocellular

stroma that exhibits minimal cytologic atypia and minimal

mitotic activity without atypical

forms

Note: Parosteal

Table 10. Differential

 diagnosis of parosteal

osteosarcoma,

conventional

osteosarcoma,

 periosteal

osteosarcoma,

osteochondroma,

 myositis ossificans, and parosteal lipoma.

Osteosarcoma,

 PAOS;

Conventional

Osteosarcoma,

 COS; Periosteal

 fibroblastic

 mass arising

 or

Diffuse cortical destruction

Broad-based

mass causing extrinsic erosion

of thickened underlying

diaphyseal cortex and

perpendicular

reaction extending into the

soft-tissue

Osteosarcoma

cartilaginous

cartilage in lobules with

peripheral spindling and

central bone formation. Little

no. of mitosis

Malignant

present but may be focal

osteosarcoma,

 PEOS.

osteoid/bone

 is

 component.

 The

 with prominent

Bony trabeculae appear normal Orderly maturation,

 not

Lipocytes,

no osteoid

attached to underlying

bone; more active

histologically

 periosteal

 surface soft-tissue

Metaphyseal

direction opposite to adjacent

joint. Cortex and medulla are

continuous

bone

 with underlying

 lesions grow in

> like Codman's triangle,

osteoblastic

 features

 PAOS

COS

PEOS

Osteochondroma

Myositis ossificans

 Parosteal

lipoma

NOS

Differential Diagnosis of Osteogenic Tumors in the Context of Osteosarcoma DOI: http://dx.doi.org/10.5772/intechopen.85190

peripherally and extends centrally in this proliferative process, which is the reverse

The osteochondroma shows continuity of corticomedullary areas of the tumor and the underlying medullary canal, but these features are lacking in PAOS. Med-

Abundant cartilage is present. Higher-grade osseous component and evidence of

This malignant bone tumor is commonly seen in routine biopsies, entirely different from PAOS (juxtacortical OS) despite its similarity with terminology. It arises on surface of long bones (upper tibia and femur). The PEOS affects a slightly older age group (10–20 years) as compared to conventional osteosarcoma. Malignant osteoid must be present, but the predominant pattern of tumor is represented

chondrosarcoma. Tumor is located on the surface of the bone and may extend into soft tissue. The lesions are limited to the cortex and rarely invade the medullary cavity. The tumor appears perpendicular to the shaft. Sometimes high-grade anaplastic sarcomatous spindle cell component may separate lobules of the malignant

It is usually smaller and better defined and composed of benign chondroid tissue

Radiographically, it contains "popcorn" calcifications, and histologically, it is a

This is a higher-grade osteosarcoma involving the medullary cavity. Periosteal

Radiographically, this tumor is more radiodense, and histologically this is a low-grade malignant fibro-osseous tumor without chondroid differentiation [20, 24].

by lobulated chondromatous tissue with cytologic features of grade 2 or 3

chondroid component [24] (Figure 9 and Table 10) [20, 42].

low-grade chondrosarcoma containing no tumor osteoid [20, 24].

and does not contain malignant tumor osteoid [24].

7.6.4 Conventional intramedullary osteosarcoma

osteosarcoma does not involve the medullary cavity [24].

ullary spaces contain adipose tissue or marrow hematopoietic tissue,

Osteosarcoma – Diagnosis, Mechanisms, and Translational Developments

in parosteal osteosarcoma [41].

7.5.3 Osteochondroma

cartilaginous cap.

periosteal reaction.

7.5.4 Periosteal osteosarcoma

7.5.5 Periosteal osteosarcoma (PEOS)

7.6 Differential diagnosis of PEOS

7.6.1 Periosteal chondroma

7.6.2 Periosteal chondrosarcoma

7.6.3 Parosteal osteosarcoma

30

Table 10.

 Differential diagnosis of parosteal osteosarcoma, conventional osteosarcoma, periosteal osteosarcoma, osteochondroma, myositis ossificans, and parosteal lipoma.

#### 7.6.5 High-grade surface osteosarcoma

It lacks cartilaginous differentiation. Osteoid component is pleomorphic and high grade [12, 13].

examination. To approach the remedy of patient, grading and staging with good

\*, Samina Qamar<sup>2</sup> and Farwa Batool<sup>3</sup>

1 Head of Pathology Department, UCMD, University of Lahore, Pakistan

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 King Edward Medical University, Lahore, Pakistan

provided the original work is properly cited.

3 Faisal Abad Medical University, Faisal Abad, Pakistan

\*Address all correspondence to<EMAIL_ADDRESS>
differential diagnosis are very important to save the life of the patient.

Differential Diagnosis of Osteogenic Tumors in the Context of Osteosarcoma

DOI: http://dx.doi.org/10.5772/intechopen.85190

Conflict of interest

Source of support

Author details

33

Mulazim Hussain Bukhari<sup>1</sup>

None.

Nil.

## 8. High-grade surface osteosarcoma

This is a high-grade osteosarcoma with similar histological features to those of conventional intramedullary osteosarcoma. The tumor grows on the surface and lacks significant medullary involvement. Radiographically it mimics periosteal osteosarcoma, except it has cumulus cloud-like patterns of mineralization. It is a large, lobulated surface mass with variable consistency ranging from soft to firm and may contain hemorrhagic areas. It should not significantly involve the medullary region [13, 24].

#### 8.1 Differential diagnosis of high-grade OS

#### 8.1.1 Dedifferentiated parosteal osteosarcoma

It usually has residual low-grade malignant fibroblastic stromal component. Parosteal osteosarcoma lacks high-grade anaplastic appearance [12, 24].

### 8.1.2 Conventional intramedullary osteosarcoma

Significant medullary component (minimal medullary component in a high-grade surface osteosarcoma) [24].

#### 8.1.3 Low-grade central osteosarcoma

It is a large, poorly marginated intramedullary mass that either is sclerotic or exhibits trabeculations and histologically similar to parosteal osteosarcoma [12, 24].

### 9. Summary

Osteosarcoma (OS) is a high-grade malignancy of the bone with high-mortality rate. The exact cause of the condition is unknown, and presently, it is not possible to prevent an osteosarcoma occurrence. It is mainly divided into two types, primary and secondary, based on etiology, while based on where they occur, osteosarcoma is classified as medullary osteosarcoma (occurring in the bone cavity) and surface osteosarcoma (occurring on the bone surface). OS has a bimodal age distribution, having the first peak during adolescence and the second peak in older adulthood, while a little bit more common in males. Some genetic mutations, like mutation of RB and P53 genes, are associated with osteosarcoma. Radiation affected persons, patients of Paget's disease of the bone, fibrous dysplasia, osteoblastoma, Ollier disease, and chemotherapy, are other conditions and disorders that are thought to be associated with Osteosarcomas. The tumor grows slowly in the initial phase of the tumors and may be asymptomatic. Then tumors grow at a moderate rate, and then they suddenly start to rapidly progress. Pathological fractures are commonly seen in long bones.

Three parameters are used for its diagnosis, physical examination with medical history, radiological support (X-rays, CT, MRI), and biopsy for microscopic

Differential Diagnosis of Osteogenic Tumors in the Context of Osteosarcoma DOI: http://dx.doi.org/10.5772/intechopen.85190

examination. To approach the remedy of patient, grading and staging with good differential diagnosis are very important to save the life of the patient.

## Conflict of interest

None.

7.6.5 High-grade surface osteosarcoma

8. High-grade surface osteosarcoma

8.1 Differential diagnosis of high-grade OS

8.1.2 Conventional intramedullary osteosarcoma

high-grade surface osteosarcoma) [24].

8.1.3 Low-grade central osteosarcoma

8.1.1 Dedifferentiated parosteal osteosarcoma

high grade [12, 13].

region [13, 24].

9. Summary

seen in long bones.

32

It lacks cartilaginous differentiation. Osteoid component is pleomorphic and

Osteosarcoma – Diagnosis, Mechanisms, and Translational Developments

This is a high-grade osteosarcoma with similar histological features to those of conventional intramedullary osteosarcoma. The tumor grows on the surface and lacks significant medullary involvement. Radiographically it mimics periosteal

osteosarcoma, except it has cumulus cloud-like patterns of mineralization. It is a large, lobulated surface mass with variable consistency ranging from soft to firm and may contain hemorrhagic areas. It should not significantly involve the medullary

It usually has residual low-grade malignant fibroblastic stromal component.

Parosteal osteosarcoma lacks high-grade anaplastic appearance [12, 24].

Significant medullary component (minimal medullary component in a

It is a large, poorly marginated intramedullary mass that either is sclerotic or exhibits trabeculations and histologically similar to parosteal osteosarcoma [12, 24].

Osteosarcoma (OS) is a high-grade malignancy of the bone with high-mortality rate. The exact cause of the condition is unknown, and presently, it is not possible to prevent an osteosarcoma occurrence. It is mainly divided into two types, primary and secondary, based on etiology, while based on where they occur, osteosarcoma is classified as medullary osteosarcoma (occurring in the bone cavity) and surface osteosarcoma (occurring on the bone surface). OS has a bimodal age distribution, having the first peak during adolescence and the second peak in older adulthood, while a little bit more common in males. Some genetic mutations, like mutation of RB and P53 genes, are associated with osteosarcoma. Radiation affected persons, patients of Paget's disease of the bone, fibrous dysplasia, osteoblastoma, Ollier disease, and chemotherapy, are other conditions and disorders that are thought to be associated with Osteosarcomas. The tumor grows slowly in the initial phase of the tumors and may be asymptomatic. Then tumors grow at a moderate rate, and then they suddenly start to rapidly progress. Pathological fractures are commonly

Three parameters are used for its diagnosis, physical examination with medical

history, radiological support (X-rays, CT, MRI), and biopsy for microscopic

## Source of support

Nil.

## Author details

Mulazim Hussain Bukhari<sup>1</sup> \*, Samina Qamar<sup>2</sup> and Farwa Batool<sup>3</sup>

1 Head of Pathology Department, UCMD, University of Lahore, Pakistan

2 King Edward Medical University, Lahore, Pakistan

3 Faisal Abad Medical University, Faisal Abad, Pakistan

\*Address all correspondence to<EMAIL_ADDRESS>
© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## References

[1] Dorfman H, Vanel D, Czerniak B, Park Y, Kotz R, Unni K. WHO Classification of Tumours of Bone: Introduction. 2013 [226]. Available from: https://www.iarc.fr/en/publica tions/pdfs-online/pat-gen/bb5/bb5-cla ssifbone.pdf

[2] Ghadah Al Saanna G, Bovée J, Hornick J, Alexander Lazar A. A review of the WHO classification of tumours of soft tissue and bone. In: Bruce S, Beverly S, editors. The Electronic Sarcoma Update Newsletter (ESUN). NY;USA: Liddy Shriver; 2013

[3] Murphey MD. World Health Organization classification of bone and soft tissue tumors: Modifications and implications for radiologists. Seminars in Musculoskeletal Radiology. 2007; 11(3):201-214

[4] Chaudhry J, Rawal SY, Anderson KM, Rawal YB. Cancellous osteoma of the maxillary tuberosity: Case report. General Dentistry. 2009;57(4): 427-429

[5] Mannava S, Sundaram M. Fibrous dysplasia, osteofibrous dysplasia, and adamantinoma. In: Davies A, Sundaram M, James S, editors. Imaging of Bone Tumors and Tumor-Like Lesions. Medical Radiology. Berlin, Heidelberg: Springer; 2007. pp. 411-424

[6] Greenspan A, Jundt G, Remagen W. Differential Diagnosis in Orthopaedic Oncology. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2007

[7] Kaiser MS, Rahman W, Hossain M, Siddiquee TH, Hossain MT, Das KP, et al. Evaluation of outcome of surgical excision of the nidus of osteoid osteoma of long bone. Mymensingh Medical Journal: MMJ. 2014;23(4): 686-694

[8] Burgener FA, Kormano M, Pudas T. Bone and Joint Disorders: Differential

Diagnosis in Conventional Radiology. New York: Thieme Publishers; 2006. pp. 872

future perspectives of molecular targeted therapy for osteosarcoma. International Journal of Molecular Sciences. 2016;17(4):506-511

[18] Greenspan A. Orthopedic Imaging: A Practical Approach. NY: Lippincott Williams & Wilkins; 2004. pp. 982

DOI: http://dx.doi.org/10.5772/intechopen.85190

Differential Diagnosis of Osteogenic Tumors in the Context of Osteosarcoma

delivery. Srpski Arhiv za Celokupno Lekarstvo. 2013;141(7–8):528-531

[26] Lee YJ, Sadigh S, Mankad K, Kapse N, Rajeswaran G. The imaging of osteomyelitis. Quantitative Imaging in Medicine and Surgery. 2016;6(2):

[27] Lew DP, Waldvogel FA. Osteomyelitis. Lancet (London, England). 2004;364(9431):369-379

[28] Jaramillo D. Infection:

2011;41(Suppl 1):S127-S134

2015;5(4):85-87

2004;182(6):1389-1398

402-406

145764

D, Singh S. Primary epiphyseal aneurysmal bone cyst of distal ulna. Journal of Orthopaedic Case Reports.

[30] Fitzpatrick KA, Taljanovic MS, Speer DP, Graham AR, Jacobson JA, Barnes GR, et al. Imaging findings of fibrous dysplasia with histopathologic and intraoperative correlation. AJR American Journal of Roentgenology.

[31] Iida S, Kishino M, Sakai T, Ishida H, Okura M, Toyosawa S, et al. Multiple osseous dysplasia arising from impacted teeth: Report of a case associated with odontogenic lesions. Journal of Oral Pathology & Medicine. 2006;35(7):

[32] Toyosawa S, Yuki M, Kishino M, Ogawa Y, Ueda T, Murakami S, et al. Ossifying fibroma vs fibrous dysplasia

[33] Chen C, Borker R, Ewing J, Tseng WY, Hackshaw MD, Saravanan S, et al. Epidemiology, treatment patterns, and outcomes of metastatic soft tissue sarcoma in a community-based

oncology network. Sarcoma. 2014;2014:

of the jaw: Molecular and immunological characterization. Modern Pathology. 2007;20(3):389-396

Musculoskeletal. Pediatric Radiology.

[29] Kapila R, Sharma R, Sohal YS, Singh

184-198

[19] Knipe H, Gaillard F. Osteosarcoma: Radiopaedia.org. Available from: http:// radiopaedia.org/articles/osteosarcoma

[20] Yarmish G, Klein MJ, Landa J, Lefkowitz RA, Hwang S. Imaging characteristics of primary osteosarcoma:

Radiographics. 2010;30(6):1653-1672

[21] Xie GP, Song HJ, Jiang N, Qin CH, Wang L, Xu SY, et al. Periosteal

osteosarcoma and Marfan's syndrome: A case report and literature review. Oncology Letters. 2016;11(1):311-315

[22] Siddiqui YS, Sherwani M, Khan AQ, Zahid M, Abbas M, Asif N. Neglected

[23] Limmahakhun S, Pothacharoen P, Theera-Umpon N, Arpornchayanon O, Leerapun T, Luevitoonvechkij S, et al. Relationships between serum biomarker levels and clinical presentation of human osteosarcomas. Asian Pacific Journal of Cancer Prevention: APJCP.

[24] Gattuso G, Reddy V, David O, Spitz D, Meryl H, Haber. Bone tumors. In: Differential Diagnosis in Surgical Pathology. 2nd ed. Pheladelphia; PA, USA: Saunders; Elsevier; 2009. p. 336

Bogdanovic Z, Petronijevic M, Opalic J, Plecas D. Diagnosis and treatment of rib fracture during spontaneous vaginal

[25] Jovanovic N, Ristovska N,

orthopedic oncology—causes, epidemiology and challenges for management in developing countries. Indian Journal of Cancer. 2015;52(3):

325-329

35

2011;12(7):1717-1722

Nonconventional subtypes.

[9] Elstrom JA, Virkus WW, Pankovich A. Handbook of Fractures. 3rd ed. McGraw-Hill Education; 2006

[10] Atesok KI, Alman BA, Schemitsch EH, Peyser A, Mankin H. Osteoid osteoma and osteoblastoma. The Journal of the American Academy of Orthopaedic Surgeons. 2011;19(11): 678-689

[11] Jambhekar NA, Desai S, Khapake D. Osteoblastoma: A study of 12 cases. Indian Journal of Pathology & Microbiology. 2006;49(4):487-490

[12] Mills S, Greenson J, Hornick J, Longacre T, Reuter V. Sternberg's Diagnostic Surgical Pathology. 6th ed. NY; USA: Wolters Kluwer; 2012

[13] Roasi J. Ackerman's Surgical Pathology. 10th ed. NY; USA: Mosby; 2011. p. 1703

[14] Baker AC, Rezeanu L, Klein MJ, Pitt MJ, Buecker P, Hersh JH, et al. Aggressive osteoblastoma: A case report involving a unique chromosomal aberration. International Journal of Surgical Pathology. 2010;18(3):219-224

[15] Harrington C, Accurso BT, Kalmar JR, Iwenofu OH, Agrawal A, Allen CM, et al. Aggressive osteoblastoma of the maxilla: A case report and review of the literature. Head and Neck Pathology. 2011;5(2):165-170

[16] Kumar V, Abbas AK, Fausto N. Robbins and Cotran Pathologic Basis of Disease. 9th ed. NY: Elsevier Saunders; 2016. p. 776

[17] Shaikh AB, Li F, Li M, He B, He X, Chen G, et al. Present advances and

Differential Diagnosis of Osteogenic Tumors in the Context of Osteosarcoma DOI: http://dx.doi.org/10.5772/intechopen.85190

future perspectives of molecular targeted therapy for osteosarcoma. International Journal of Molecular Sciences. 2016;17(4):506-511

References

ssifbone.pdf

Liddy Shriver; 2013

11(3):201-214

427-429

686-694

34

[1] Dorfman H, Vanel D, Czerniak B, Park Y, Kotz R, Unni K. WHO Classification of Tumours of Bone: Introduction. 2013 [226]. Available from: https://www.iarc.fr/en/publica tions/pdfs-online/pat-gen/bb5/bb5-cla

Osteosarcoma – Diagnosis, Mechanisms, and Translational Developments

Diagnosis in Conventional Radiology. New York: Thieme Publishers; 2006.

[9] Elstrom JA, Virkus WW, Pankovich A.

[10] Atesok KI, Alman BA, Schemitsch EH, Peyser A, Mankin H. Osteoid osteoma and osteoblastoma. The Journal

[11] Jambhekar NA, Desai S, Khapake D. Osteoblastoma: A study of 12 cases. Indian Journal of Pathology & Microbiology. 2006;49(4):487-490

[12] Mills S, Greenson J, Hornick J, Longacre T, Reuter V. Sternberg's Diagnostic Surgical Pathology. 6th ed. NY; USA: Wolters Kluwer; 2012

[13] Roasi J. Ackerman's Surgical Pathology. 10th ed. NY; USA: Mosby;

[14] Baker AC, Rezeanu L, Klein MJ, Pitt MJ, Buecker P, Hersh JH, et al. Aggressive osteoblastoma: A case report involving a unique chromosomal aberration. International Journal of Surgical Pathology. 2010;18(3):219-224

[15] Harrington C, Accurso BT, Kalmar JR, Iwenofu OH, Agrawal A, Allen CM, et al. Aggressive osteoblastoma of the maxilla: A case report and review of the literature. Head and Neck Pathology.

[16] Kumar V, Abbas AK, Fausto N. Robbins and Cotran Pathologic Basis of Disease. 9th ed. NY: Elsevier Saunders;

[17] Shaikh AB, Li F, Li M, He B, He X, Chen G, et al. Present advances and

Handbook of Fractures. 3rd ed. McGraw-Hill Education; 2006

of the American Academy of Orthopaedic Surgeons. 2011;19(11):

pp. 872

678-689

2011. p. 1703

2011;5(2):165-170

2016. p. 776

[2] Ghadah Al Saanna G, Bovée J, Hornick J, Alexander Lazar A. A review of the WHO classification of tumours of soft tissue and bone. In: Bruce S, Beverly S, editors. The Electronic Sarcoma Update Newsletter (ESUN). NY;USA:

[3] Murphey MD. World Health Organization classification of bone and soft tissue tumors: Modifications and implications for radiologists. Seminars in Musculoskeletal Radiology. 2007;

[4] Chaudhry J, Rawal SY, Anderson KM, Rawal YB. Cancellous osteoma of

report. General Dentistry. 2009;57(4):

[5] Mannava S, Sundaram M. Fibrous dysplasia, osteofibrous dysplasia, and adamantinoma. In: Davies A, Sundaram M, James S, editors. Imaging of Bone Tumors and Tumor-Like Lesions. Medical Radiology. Berlin, Heidelberg:

[6] Greenspan A, Jundt G, Remagen W. Differential Diagnosis in Orthopaedic Oncology. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2007

[7] Kaiser MS, Rahman W, Hossain M, Siddiquee TH, Hossain MT, Das KP, et al. Evaluation of outcome of surgical

[8] Burgener FA, Kormano M, Pudas T. Bone and Joint Disorders: Differential

excision of the nidus of osteoid osteoma of long bone. Mymensingh Medical Journal: MMJ. 2014;23(4):

the maxillary tuberosity: Case

Springer; 2007. pp. 411-424

[18] Greenspan A. Orthopedic Imaging: A Practical Approach. NY: Lippincott Williams & Wilkins; 2004. pp. 982

[19] Knipe H, Gaillard F. Osteosarcoma: Radiopaedia.org. Available from: http:// radiopaedia.org/articles/osteosarcoma

[20] Yarmish G, Klein MJ, Landa J, Lefkowitz RA, Hwang S. Imaging characteristics of primary osteosarcoma: Nonconventional subtypes. Radiographics. 2010;30(6):1653-1672

[21] Xie GP, Song HJ, Jiang N, Qin CH, Wang L, Xu SY, et al. Periosteal osteosarcoma and Marfan's syndrome: A case report and literature review. Oncology Letters. 2016;11(1):311-315

[22] Siddiqui YS, Sherwani M, Khan AQ, Zahid M, Abbas M, Asif N. Neglected orthopedic oncology—causes, epidemiology and challenges for management in developing countries. Indian Journal of Cancer. 2015;52(3): 325-329

[23] Limmahakhun S, Pothacharoen P, Theera-Umpon N, Arpornchayanon O, Leerapun T, Luevitoonvechkij S, et al. Relationships between serum biomarker levels and clinical presentation of human osteosarcomas. Asian Pacific Journal of Cancer Prevention: APJCP. 2011;12(7):1717-1722

[24] Gattuso G, Reddy V, David O, Spitz D, Meryl H, Haber. Bone tumors. In: Differential Diagnosis in Surgical Pathology. 2nd ed. Pheladelphia; PA, USA: Saunders; Elsevier; 2009. p. 336

[25] Jovanovic N, Ristovska N, Bogdanovic Z, Petronijevic M, Opalic J, Plecas D. Diagnosis and treatment of rib fracture during spontaneous vaginal

delivery. Srpski Arhiv za Celokupno Lekarstvo. 2013;141(7–8):528-531

[26] Lee YJ, Sadigh S, Mankad K, Kapse N, Rajeswaran G. The imaging of osteomyelitis. Quantitative Imaging in Medicine and Surgery. 2016;6(2): 184-198

[27] Lew DP, Waldvogel FA. Osteomyelitis. Lancet (London, England). 2004;364(9431):369-379

[28] Jaramillo D. Infection: Musculoskeletal. Pediatric Radiology. 2011;41(Suppl 1):S127-S134

[29] Kapila R, Sharma R, Sohal YS, Singh D, Singh S. Primary epiphyseal aneurysmal bone cyst of distal ulna. Journal of Orthopaedic Case Reports. 2015;5(4):85-87

[30] Fitzpatrick KA, Taljanovic MS, Speer DP, Graham AR, Jacobson JA, Barnes GR, et al. Imaging findings of fibrous dysplasia with histopathologic and intraoperative correlation. AJR American Journal of Roentgenology. 2004;182(6):1389-1398

[31] Iida S, Kishino M, Sakai T, Ishida H, Okura M, Toyosawa S, et al. Multiple osseous dysplasia arising from impacted teeth: Report of a case associated with odontogenic lesions. Journal of Oral Pathology & Medicine. 2006;35(7): 402-406

[32] Toyosawa S, Yuki M, Kishino M, Ogawa Y, Ueda T, Murakami S, et al. Ossifying fibroma vs fibrous dysplasia of the jaw: Molecular and immunological characterization. Modern Pathology. 2007;20(3):389-396

[33] Chen C, Borker R, Ewing J, Tseng WY, Hackshaw MD, Saravanan S, et al. Epidemiology, treatment patterns, and outcomes of metastatic soft tissue sarcoma in a community-based oncology network. Sarcoma. 2014;2014: 145764

[34] Schneiderman BA, Kliethermes SA, Nystrom LM. Survival in Mesenchymal Chondrosarcoma varies based on age and tumor location: A survival analysis of the SEER database. Clinical Orthopaedics and Related Research. 2017;475(3):799-805

[35] Murphey MD, Nomikos GC, Flemming DJ, Gannon FH, Temple HT, Kransdorf MJ. From the archives of AFIP. Imaging of giant cell tumor and giant cell reparative granuloma of bone: Radiologic-pathologic correlation. Radiographics. 2001;21(5):1283-1309

[36] Lim CY, Ong KO. Imaging of musculoskeletal lymphoma. Cancer Imaging. 2013;13(4):448-457

[37] Maruyama D, Watanabe T, Beppu Y, Kobayashi Y, Kim SW, Tanimoto K, et al. Primary bone lymphoma: A new and detailed characterization of 28 patients in a single-institution study. Japanese Journal of Clinical Oncology. 2007;37(3):216-223

[38] Arceci RJ, Hann IM, Smith OP, Hoffbrand AV. Pediatric Hematology. Wiley; 2006

[39] Gianfreda D, Musetti C, Nicastro M, Maritati F, Cobelli R, Corradi D, et al. Erdheim-Chester disease as a mimic of IgG4-related disease: A case report and a review of a single-center cohort. Medicine. 2016;95(21):e3625

[40] Weiss A, Khoury JD, Hoffer FA, Wu J, Billups CA, Heck RK, et al. Telangiectatic osteosarcoma: The St. Jude Children's Research Hospital's experience. Cancer. 2007;109(8): 1627-1637

[41] Donmez FY, Tuzun U, Basaran C, Tunaci M, Bilgic B, Acunas G. MRI findings in parosteal osteosarcoma: Correlation with histopathology. Diagnostic and Interventional Radiology (Ankara, Turkey). 2008;14(3):142-152

[42] Murphey MD, Jelinek JS, Temple HT, Flemming DJ, Gannon FH. Imaging of periosteal osteosarcoma: Radiologicpathologic comparison. Radiology. 2004;233(1):129-138

Section 3

Basic Science and

Translational Treatments

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Section 3