Bone tumors in children and adolescents

Benign childhood bone tumors

MALIGNANT BONE TUMORS

Incidence : 8.7/million children under 20years Comprises of about 6% of childhood cancer In the US, 650-700 children and adolescents younger than 20 years of age are diagnosed with bone tumors each year, of which approximately 400 are osteosarcoma and 200 are Ewings sarcoma. The two types of malignant bone cancer that predominated in children were osteosarcomas and Ewings sarcomas, about 56% and 34% of the malignant bone tumors, respectively

For all bone cancer combined, a steady rise in incidence rates occurred with increasing age between ages 5 and 10, and a steeper rise began at age 11 until age 15 coinciding with the adolescent growth spurt. The peak incidence of bone cancer (19/million) occurred at age 15, after which rates showed a decline ( see figure below).

Rates did not differ much by sex among younger children, but males had higher incidence than females during adolescence For osteosarcoma, black children had a higher overall rate than did white children . For Ewings sarcoma the racial variation in rates was dramatic: white children had an approximate 6-fold higher incidence rate than black children

The most frequent site of bone cancer development was the long bones of the lower limbs for osteosarcomas and the central axis for Ewings sarcomas

Current knowledge on causes of bone tumors

Known risk factors osteosarcoma
Prior treatment for childhood cancer with radiation therapy and/or chemotherapy Hereditary retinoblastoma,,Li-Fraumeni syndrome, and Rothmund-Thomson syndrome Radium :High doses

Known risk factors Ewings sarcoma

Race: ES is almost exclusively a disease of white children. Rates in whites are approximately 9 times those in blacks.

Benign childhood bone tumors

Static lesions :e.g. nonossifying fibromas locally aggressive lesions :e.g. aneurysmal
bone cysts

Most benign bone tumors have characteristic radiographic features and can be diagnosed with plain radiographs

Approach to Bone tumors

1.

Clues by appearance of lesion Clues by location of the lesion Clues by density of the lesion Other clues

2.

3.

4.

1. Clues by appearance of lesion

A. B. C.

D.

Patterns of bone destruction Periosteal reaction Tumor matrix Expansile lesion of bone

A. Patterns of bone destruction

I. Geographic : Destructive lesion with sharply defined border Implies a less aggressive,more slowgrowing, benign process Narrow transition zone
e.g. Non-ossifying fibroma Chondromyxoid fibroma Eosinophilic granuloma

I. Geographic.contd

Example: Non-ossifying fibroma

II. Moth-Eaten bone destruction

Areas of destruction with ragged borders Implies more rapid growth, probably malignancy e.g. Ewings sarcoma
Lymphoma Multiple myeloma Metastases

III. Permeative pattern:

Ill-defined lesion, with multiple worm-wholes Spreads through marrow space Wide transition zone Implies an aggressive malignancy e.g. Round cell lesions or tumors Lymphoma,Leukemia,Ewings sarcoma, Neuroblastoma,Oteomyelitis

Permeative pattern: contd e.g. Leukemia

Patterns of bone destruction (SUMMARY)

Geographic

Moth-eaten

Permeative

Less malignant

More malignant

B. Periosteal reaction

Benign
. Solid

.None

Non-ossifying fibroma

Chronic Osteomyelitis

B. Periosteal reaction.contd

More Aggressive or Malignant

Lamellated or onion peel

e.g. Ewings sarcoma

B. Periosteal reaction.contd

Sunburst

e.g. Osteosarcoma

Codmans trangle

e.g. Osteosarcoma

B.Periosteal reactioncontd

Solid

sunburst
Less malignant

onion peel

Codmans traingle

More malignant

C.Tumor Matrix

Osteoblastic
Fluffy, cotton-like or cloudy-like densities

e.g. Osteosarcoma

Cartileginous
Comma-shaped, punctate, annular, popcorn-like
e.g.Enchondroma, chondrosarcoma, chondromyxoid fibroma

C.Tumor matrix.contd
a.Oseoblastic

Cloud-like bone formation in Osteosarcoma (left)

C.Tumor matrix.contd

Cartileginous (Chondroid matrix )

Enchondroma

chondrosarcoma

Chondrosarcoma of the rib.

D.Expansile lesion of bone

Enchondroma Aneurysmal Bone cyst Fibrous dysplasia Multiple myeloma Metastasis Brown tumor

2. Clues by location of the lesion

In the transverse plane In the longitudinal plane Characteristic Locations by tumors Characteristic tumors by body site e.g. Pelvic lesion Expansive rib lesion Lesions of the spine

2.Clues by locationcontd

In the transverse plane

. .

2.Clues by locationcontd

In the longitudinal plane Epiphyseal e.g. GCT, Chondroblastoma Metaphyseal e.g.Osteosarcoma, Chondrosarcoma Diaphyseal e.g. Round cell lesions, enchondroma

2.Clues by locationcontd

Characteristic locations by tumors

Simple bone cyst
Chondroblastoma

Proximal humerus
Epiphyses Epiphyses Tibia Sacrum, clivus Spine, posterior Adamantinoma,Tibia

Giant Cell tumor

Adamantinoma

Chordoma
Osteoblastoma

3.Clues by density of the lesion

Sclerotic cortical lesions Lytic lesions Blastic lesions

3.Clues by density of the lesion..contd

Sclerotic cortical lesions

e.g. Osteoid osteoma :a benign bone lesion with a small nidus surrounded

by a zone of reactive sclerosis.

3.Clues by density of the lesion..contd

Lytic lesions

e.g. Fibrous Dysplasia

3. Clues by density of the lesion..contd

Blastic lesions

e.g. lymphoma

4.Other clues

Soft tissue extension

Usually implies malignancy

More likely to form discrete soft tissue mass

Benign conditions with soft tissue extension

Osteomyelitis

Usually infiltration of fat

4.Other cluescontd
Benign vs. Malignant

Clinical cases n explanation

Case#1

A 17-year-old male presented with increasing pain in the right upper arm of approximately 3 months' duration and a recent onset of low-grade fever. On physical examination, there was some local tenderness and soft tissue swelling over the distal and mid thirds of the right humerus. Shown below is the radiographic finding and histopathology of the lesion.

Thank You!

case

Case #
1. Describe both the x-ray finding and the histopathology 2. What are your DDx and most likely diagnosis

3. How common is this lesion in children and what is the c/p

4. The parents asked you to explain to them what it will be like the next step in terms of managing the condition and its long term outcome

Diagnosis: Ewing's Sarcoma (ES)

ES and PNET are "small round blue cell " tumors of children and young adults occurring in 80% of cases between the ages of 5 and 20 years Most common skeletal sites include diaphyses of femur, tibia and humerus, and also pelvis and ribs (Askin tumor of the chest). Associated soft tissue mass is a common finding.

Key facts Most common presentation: ill-defined osteolytic lesion with multiple small holes in the diaphysis of a long bone in a child with a large soft tissue mass. Presentation with pain, mass, fever, anemia and leukocytosis. Most common location: femur, iliac bone, fibula, rib, tibia. Differential diagnosis: Osteosarcoma, lymphoma, infection and EG. Frequently aggressive type of periosteal reaction, but never a benign type.

Ewing's Sarcoma (ES)contd

The following studies are required to support the diagnosis of ES and PNET: Demonstration of t(11;22) or EWS-FLI-1 fusion transcript (present in both ES and PNET) Immunostains(both ES and PNET are positive for CD99/O13. In addition, PNET shows positive staining with neural markers) EM (ES cells are undifferentiated and show prominent glycogen deposits; PNET shows neural differentiation)

Ewing's Sarcoma (ES)contd

Treatment
Surgery : Local for control Chemotherapy Radiation therapy

Prognostic Factors for Ewing Sarcoma Pretreatment Treatment response factors.

Ewing's Sarcoma (ES)contd

Pretreatment Site : distal ext > prox. Ext > centeral/pelvic sites Size : Cutoffs of either 100 mL or 200 mL are used to define larger tumors. Large trs- portend bad Px Age :Infants and younger patients (<15 years) have a better prognosis than adolescents aged 15 years or older, young adults, or adults Gender : Girls with Ewing sarcoma have a better prognosis than boys Metastases: (15-20% ): poor Px

Serum LDH : Standard cytogenetics :

Ewing's Sarcoma (ES)contd

Treatment response factors to preoperative therapy

No or minimal Residual tr after surgery or decreased PET uptake following CTx

Good Px or event free survival

Histopathology , Molecular pathology and Pathologic fracture

NB. The ff have no Pxc importance

Case # 3

An 11-year-old male was seen in consultation for an increasingly painful proximal humeral lesion associated with a soft tissue mass since the last 3 1/2 months. Has a h/o trauma while playing football 4 months ago
Radiological findings:

Plain radiograph shows an ill-defined destructive tumor in the proximal humerus(see below)
Laboratory results:

On admission, the patient's temperature was 37.5C. His WBC was 8.5 (4.5 - 9.5) with a normal differential. His electrolytes and liver function tests were normal, and the alkaline Phosphatase was 1020 (up to 740). The erythrocyte sedimentation rate was 52 (up to 15) and the protein C was 0.72 (up to 0.5). On examination, his left proximal armand shoulder joint was enlarged and slightly tender. There were no neurovascular or cutaneous abnormalities, except for some distended superficial veins. The ROM of the extremity was unimpaired.

Case #3.contd

Case #3.contd
Q1. What is your diagnosis? 1. Osteosarcoma, 2. GCT 3. Aggressive osteoblastoma 4. MFH Q2. What is the distinguishing and diagnostic feature of this tumor? 1. Highly pleomorphic mesenchymal cells 2. Tumor osteoid 3. Characteristic immunophenotype 4. Characteristic chromosomal abnormality

Case #3.contd
Q3. How would you manage this patient? Q4. Prognosis depends on 1.Tumor response to pre-operative chemotherapy 2. Surgical stage 3. Skeletal site of involvement 4. All of the above

Osteosarcoma

The most common primary malignant neoplasm of bone that occurs in children and young adults Accounts for 60% of malignant bone lesions in the first two decades of life

Statistics
On average, 400 cases are diagnosed per year. The overall survival rate for patients diagnosed between 1974 and 1994 is 63%. Occurrence is slightly higher in AA than in Whites and higher in males than in females. The highest occurrence in adolescence is 15 to 19 years old.

Symptoms
Pain and swelling of the affected area are the most common clinical findings On rare occasions, fever and night sweats may occur,but more so in Ewings sarcoma than osteosarcoma

Diagnostic Imaging
Radiographic appearance (plain x-ray) of proximal humeral Osteosarcoma.

Diagnostic Imaging
MRI appearance (T1weighted image) of Osteosarcoma of the proximal humerus. Note dramatic tumor extension into adjacent soft tissue regions

Treatment
Preoperative and/or postoperative chemotherapy Resection - A procedure performed for the specific purpose of removal Allograft replacement - the process of transplanting tissues and organs

Prognosis
Factors that seem to negatively impact prognosis are:
Site (axial locations fare worse), Larger tumor size, Poor response to chemotherapy and Presence of metastatic disease .

The most consistent and clinically relevant of these is presence of detectable metastases

Case #4

A 15-year-old female was seen in consultation for a lesion in the proximal femur. She complained of chronic mild to moderate pain in her right hip and was walking with a noticeable limp. Physical examination revealed hip deformity and minimal limb length discrepancy.She also c/o of pain in the left lower leg.
Plain film shows a large, elongated, well-defined intramedullary lesion of the proximal femur with "shepherd's crook" deformity (lateral bowing) due to a healed pathologic fracture. The lesion is partially surrounded by a sclerotic rim and has a complex appearance with lytic areas, multiple foci of "ground glass" density, and radiopaque areas. Curettage specimen consisted of pieces of firm, white-gray, gritty tissue,with a thin, wavy spicules of woven bone ("Chinese characters" ) Following is the plain film,histopathology and picture taken of the patient :

Case #4..contd

Case #4.contd
Q.1 What is your diagnosis? 1. Enchondroma 2. Fibrous dysplasia 3. Osteosarcoma, Grade II 4. Simple Bone cyst Q2. What other complications is this patient at risk for ?

Q3. What is the mode of inheritance and the molecular defect of these problem?

Diagnosis: Fibrous Dysplasia

Fibrous dysplasia is a common benign fibro-osseous lesion, which occurs sporadically during the period of skeletal growth (ages 10 to 25). It is a hamartoma and is characterized by the intramedullary location. There are two forms of the disease: monostotic (80% of cases) and polyostotic.

Fibrous dysplasiacontd

Polyostotic involvement may be a part of McCuneAlbright syndrome (fibrous dysplasia, patchy cutaneous pigmentation, and precocious puberty),
Most common locations include the long bones (femur, tibia and humerus), the ribs, cranio-facial bones and pelvis. In the long bones, the lesion is found in the metaphysis or diaphysis.

Molecular Genetics
McCune Albright syndrome is a rare, sporadically occurring genetic disorder McCune Albright syndrome is the result of a postzygotic somatic mutation in the GNAS complex locus. This locus, located on chromosome 20, codes for multiple proteins, one of which is the Gs-alpha, the alpha subunit of the heterotrimeric stimulatory G protein

Case #5

A bone lesion, in the distal tibial meta-diaphysis of the right leg ,was discovered incidentally in a 13-year-old boy. The lesion was totally asymptomatic. Plain radiograph shows a sharply demarcated, lucent, loculated, meta-diaphyseal lesion surrounded by a rim of sclerotic bone (see below).

Case #5..contd

The parents got worried so much after you showed them the x-ray and wanted you to tell them what it is and how commonly this thing occurs.They also wanted to know what will be done next.What would you tell them? Late at night(the same day) they called at your cell phone to hear your opinion.They tell you that from what they have read on the internet, they think ,what their son has is a GCTwhat would be your response? Would you confirm to them that their suspicion is indeed right ? If not,how would you convince them otherwise ? They also want to hear your opinion about the chance of his lesion transforming in to a cancer? Please explain

Diagnosis: Non-Ossifying Fibroma (NOF)

NOF is a common, non-neoplastic, self-healing lesion occuring in skeletally immature individuals, usually between the ages of 5 and 20 years
Small lesions are usually incidental radiological findings. The larger lesions may present with a pathologic fracture.

In most cases, NOF presents as a solitary lesion in the metaphysis or meta-diaphysis of the long bone at the knee (distal femur, proximal tibia or fibula), distal tibia and proximal humerus

X-ray characteristics of NOF:

*Geographic

* Lytic * Multilobulated * Metaphyseal * Usually intramedullary * Eccentric * Well-marginated * Sclerotic rim

Management considerations NOF The following considerations should be kept in mind:

Does the lesion involve more than 50% of the transverse diameter of the bone? Prophylactic surgery may be indicated, as the risk of fracture is higher in this circumstance.
Is the lesion becoming larger and more symptomatic? A more aggressive therapy may be considered.

Management considerations NOF Is the location of the lesion particularly associated with high risk for pathologic fracture (eg, femoral neck)? Localization around the femoral neck is associated with an increased risk of pathologic fracture, producing avascular necrosis of the femoral head. Therefore, stabilization may be indicated.

Case #6

A 16-year-old boy was seen in consultation for increasing pain in the mid upper arm. Characteristically, the pain intensified at night and subsided with aspirin after 20 to 30 minutes. Plain radiograph shows the a small, intracortical, radiolucent focus (nidus), surrounded by dense reactive periosteal bone

Histopathologic specimen:

Case#6

Case#6

Which of the following is the most likely lesion in this patient?

GCT Osteosarcoma Osteoid Osteoma Enchodroma

1) 2) 3) 4)

Discuss the treatment plan and prognosis

Osteoid Osteoma is a benign bone lesion with a nidus of less than 2 cm surrounded by a zone of reactive bone.
Osteoid osteoma has a distinct clinical picture of dull pain that is worse at night and disappears within 20 to 30 minutes of treatment with NSAIDs medication. Most frequently (50% of cases), arise in the femur and tibia 4 diagnostic features include: (1) a sharp round or oval lesion (2) less than 2 cm in diameter, (3) has a homogeneous dense center (4) a 1-2 mm peripheral radiolucent zone.

Case#7
14-year-old female presented with a 3 months history of increasing pain in her elbow , proptosis of the left eye and a dandruff like scalp lesion. Shown Below is the patients picture and skull radiograph. Also included is the histology of a sample of tissue from the affected site

Case#7
1) What are your differentials? 2) The parents asked you the prognosis. What would be your response

3) What would be most diagnostic of this patients lesion?

Diagnosis: Eosinophilic Granuloma (EG)

Eosinophilic granuloma (EG) is the benign form of the 3 clinical variants of Langerhans cell histiocytosis
1) Eosinophilic granuloma (localized form of disease at single skeletal sites) 2) Hand-Schuller-Christian disease (extensive, multifocal, symptomatic disease with predominantly skeletal involvement) 3) Letterer-Siwe disease (aggressive systemic form of disease that involves multiple organs and systems and leads to functional impairment of the affected sites).

Eosinophilic Granuloma..contd EG commonly occurs in individuals younger than 30 years and has the highest incidence in the first decade of life. Location.. Any bone can be involved, but the most common sites include the skull, mandible, spine, ribs, and long bones Extraskeletal lesions most commonly arise in the lungs and lymph nodes. Clinical behavior. EG is a benign, self-limited disorder. Progression to systemic disease occurs exclusively in the first two years of life. Lesions usually begin to regress after approximately 3 months, but they may take as long as 2 years to resolve. The prognosis is usually excellent, with spontaneous resolution by fibrosis occurring within 1-2 years.

Eosinophilic Granuloma..contd

The Langerhans cells are pathognomonic and clonal. They are characterized by histiocyte-like appearance and indented or grooved nuclei. Unlike histiocytes, these cells show strong positivity for S-100 and CD1a, and contain Birbeck granules (rod-shaped and tennis racquetshaped cytoplasmic inclusions), which can be demonstrated by electron microscopy.
DDx include osteomyelitis, granulomatous inflammation, Hodgkin's and non-Hodgkin's lymphoma, neuroblastoma