World health organization classification of bone tumors (fifth edition): What a radiologist needs to know?

Abstract

Since 1967, the World Health Organization (WHO) classification of tumors is regarded as a reference standard and practical guide and provides a precious resource not only for the histopathologists and oncosurgeons but also for the radiologists involved in cancer care. Primary bone tumors are a rare and heterogeneous group of neoplasms that have a broad spectrum of morphological, biological, genetic, and radiological features. Appropriate imaging workup and accurate histopathological diagnosis are crucial for appropriate management and prognostication. The fourth edition of the WHO classification of tumors of soft tissue and bone was introduced in 2013. In the past 7 years, there have been considerable advances in the understanding of this large and diverse group of tumors. With technological advances and the introduction of new molecular and genetic data about some bone tumors, there has been reorganization in the classification and introduction of a few new entities. The new WHO classification of soft tissue and bone tumors introduced in 2020 (fifth edition) has made essential refinements in the classification and has also introduced many new entities. Newly identified genetic alterations and corresponding immunohistochemical markers are included in the new classification, and this has helped in the reclassification of the existing tumor entities. These novel genetic alterations not only help in prognostication but are a target for potential therapeutic options which can bring a paradigm shift in the chemotherapeutic regimen for these entities in the future. The sole basis for the classification of bone tumors is histopathological. Although radiologists are not expected to know about the exquisite pathological details of bone tumors, a broad knowledge of the recent updates, including the reclassification of a few entities or the introduction of some, is vital for narrowing the differentials in imaging. A multidisciplinary approach including an orthopedic oncologist, radiologist, pathologist, surgical, and medical oncologist is required for accurate diagnosis and management of primary bone tumors. We hereby present a simplified review for the radiologists comprising the relevant details of the updates in bone tumors along with a simplified diagnostic algorithm to characterize these lesions.

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Review Article
World health organization classification of bone tumors
(h edition): What a radiologist needs to know?
Sonal Saran1, Ravi Hari Phulware2
Departments of 1Radiodiagnosis and 2Pathology and Laboratory Medicine, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India.
*Corresponding author:
Sonal Saran,
Assistant Professor, Department
of Radiodiagnosis, All India
Institute of Medical Sciences,
Rishikesh, Uttarakhand, India.
sonalsaranmalik@gmail.com
Received : 10October 2022
Accepted : 05November 2022
Published : 21 December 2022
DOI
10.25259/IJMSR_38_2022
Quick Response Code:
INTRODUCTION
Primary bone tumors are a rare and heterogeneous group of neoplasms that account for 0.2% of
all human neoplasms, and these neoplasms have a broad spectrum of morphological, biological,
genetic, and radiological features.[1] Primary bone tumors frequently aect younger age groups,
and oen the etiology is unknown. Benign tumors oen present as incidental ndings, whereas
malignant tumors are oen diagnosed at a late stage.[2] Appropriate imaging workup and accurate
histopathological diagnosis are crucial for appropriate management and prognostication. e
fourth edition of the World Health Organization (WHO) classification of tumors of so tissue
and bone was introduced in 2013.[3] In the past 7years, there have been considerable advances in
the understanding of this large and diverse group of tumors. e new WHO classification of so
ABSTRACT
Since 1967, the World Health Organization (WHO) classification of tumors is regarded as a reference standard and
practical guide and provides a precious resource not only for the histopathologists and oncosurgeons but also for
the radiologists involved in cancer care. Primary bone tumors are a rare and heterogeneous group of neoplasms
that have a broad spectrum of morphological, biological, genetic, and radiological features. Appropriate imaging
workup and accurate histopathological diagnosis are crucial for appropriate management and prognostication.
e fourth edition of the WHO classification of tumors of so tissue and bone was introduced in 2013. In
the past 7 years, there have been considerable advances in the understanding of this large and diverse group
of tumors. With technological advances and the introduction of new molecular and genetic data about some
bone tumors, there has been reorganization in the classication and introduction of a few new entities. e
new WHO classification of so tissue and bone tumors introduced in 2020 (h edition) has made essential
renements in the classication and has also introduced many new entities. Newly identied genetic alterations
and corresponding immunohistochemical markers are included in the new classication, and this has helped in
the reclassication of the existing tumor entities. ese novel genetic alterations not only help in prognostication
but are a target for potential therapeutic options which can bring a paradigm shi in the chemotherapeutic
regimen for these entities in the future. e sole basis for the classication of bone tumors is histopathological.
Although radiologists are not expected to know about the exquisite pathological details of bone tumors, a broad
knowledge of the recent updates, including the reclassication of a few entities or the introduction of some, is
vital for narrowing the dierentials in imaging. Amultidisciplinary approach including an orthopedic oncologist,
radiologist, pathologist, surgical, and medical oncologist is required for accurate diagnosis and management of
primary bone tumors. We hereby present a simplied review for the radiologists comprising the relevant details of
the updates in bone tumors along with a simplied diagnostic algorithm to characterize these lesions.
Keywords: World Health Organization classification of bone tumors, radiology, imaging
www.mss-ijmsr.com
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Radiology

Saran and Phulware: Radiological perspective of the 5th edition of WHO classication of bone tumor
Indian Journal of Musculoskeletal Radiology • Volume 4 • Issue 2 • July-December 2022 | 74 Indian Journal of Musculoskeletal Radiology • Volume 4 • Issue 2 • July-December 2022 | 75
tissue and bone tumors introduced in 2020 (h edition) has
made essential renements in the classication and has also
introduced many new entities [Table1].[4]
Since 1967, the WHO classification of tumors is regarded
as a reference standard and practical guide and provides
a precious resource not only for histopathologists and
Table1: 2020 WHO classication of bone tumors.
S. No. Category Sub-category Nature
1. Chondrogenic tumors Subungual exostosis
Bizarre parosteal osteochondromatous proliferation.
Periosteal chondroma
Enchondroma
Osteochondroma
Chondroblastoma NOS
Chondromyxoid broma
Osteochondromyxoma
Benign
Chondromatosis NOS
Atypical cartilaginous tumor
Intermediate
Chondrosarcoma, grades 1
Chondrosarcoma, grades 2
Chondrosarcoma, grades 3
Periosteal chondrosarcoma
Clear cell chondrosarcoma
Mesenchymal chondrosarcoma
Dedierentiated chondrosarcoma
Malignant
2. Osteogenic tumors Osteoma NOS
Osteoid osteoma NOS
Benign
Osteoblastoma NOS Intermediate
Low-grade central osteosarcoma
Osteosarcoma NOS
Parosteal osteosarcoma
Periosteal osteosarcoma
High-grade surface osteosarcoma
Secondary osteosarcoma
Malignant
3. Fibrogenic tumors Desmoplastic broma Intermediate
Fibrosarcoma NOS Malignant
4. Vascular tumors of bone Hemangioma NOS Benign
Epithelioid hemangioma Intermediate
Epithelioid hemangioendothelioma NOS
Angiosarcoma
Malignant
5. Osteoclastic giant cell-rich tumors Aneurysmal bone cyst
Non-ossifying broma
Benign
Giant cell tumor of bone NOS Intermediate
Giant cell tumor of bone, malignant Malignant
6. Notochordal Benign notochordal cell tumor Benign
Chordoma NOS (Chondroid chordoma)
Dedierentiated chordoma
Poorly dierentiated chordoma
Malignant
7. Other mesenchymal tumors of bone Chondromesenchymal hamartoma of the chest wall
Simple bone cyst
Fibrous dysplasia
Osteobrous dysplasia
Lipoma NOS
Hibernoma
Benign
Osteobrous dysplasia-like adamantinoma
Mesenchymoma NOS
Intermediate
(Contd...)

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Table1: (Continued)
S. No. Category Sub-category Nature
Adamantinoma of long bones (Dedierentiated adamantinoma)
Leiomyosarcoma NOS
Pleomorphic sarcoma, undierentiated
Bone metastases
Malignant
8. Hematopoietic neoplasms of bone Plasmacytoma of bone
Hodgkin disease NOS
Malignant lymphoma, non-Hodgkin, NOS; Diuse large B-cell
lymphoma NOS; Follicular lymphoma NOS; Marginal zone B-cell
lymphoma NOS; T-cell lymphoma NOS; Anaplastic large cell lymphoma
NOS; Malignant lymphoma, lymphoblastic, NOS: Burkitt lymphoma NOS
Langerhans cell histiocytosis NOS
Langerhans cell histiocytosis, disseminated
Erdheim-Chester disease
Rosai-Dorfman disease
9. Undierentiated small round cell
sarcomas of bone and so tissue
Ewing sarcoma
Round cell sarcoma with EWSR1–nonETS fusions
CIC‑rearranged sarcoma
Sarcoma with BCOR genetic alterations
Newly added entities are highlighted in bold and italics. NOS: Not otherwise specied
oncosurgeons but also for the radiologists involved in cancer
care. e sole basis for the classication of bone tumors is
histopathological. Although radiologists are not expected
to know about the exquisite pathological details of bone
tumors, a broad knowledge of the recent updates, including
the reclassication of a few entities or the introduction of
some, is vital for narrowing the dierentials in imaging.
A multidisciplinary approach including an orthopedic
oncologist, radiologist, pathologist, surgical, and medical
oncologist is required for accurate diagnosis and management
of primary bone tumors.
Aer the introduction of the h edition of the WHO
classification of tumors of so tissue and bone, a few articles
are published outlining the recent updates and comparison
with the previous edition, but these articles are dicult to
understand by the radiologists as these articles mainly focus
on the histopathological details, genetic alteration, and new
markers.[5] We hereby present a simplied review for the
radiologists comprising the relevant details of the updates in
bone tumors along with a simplied diagnostic algorithm to
characterize these lesions.
HOW TO APPROACH A BONE TUMOR?
Many factors come into play when we encounter and try
to diagnose a case of bone tumor. ese factors include
the age of the patient, location in the skeleton system
(axial or appendicular) and multiplicity. Whenever a
patient complains of bone pain and swelling pointing
toward a neoplastic pathology aecting bone, conventional
radiography (CR) is the rst imaging modality used
to evaluate the lesion because it is widely available and
aordable. Despite the advances in the imaging eld in
the form of multiplanar and functional imaging, the role
of CR cannot be neglected, and it is still the most relevant
rst investigation. Aradiograph gives us much information
about the bone tumor, including location within the long
bone (epiphyseal, diaphyseal, or metaphyseal), the pattern of
bone destruction (geographic, moth-eaten, or permeative),
zone of transition, type of periosteal reaction, matrix
mineralization, and adjacent so-tissue involvement. Most
bone tumors can be diagnosed, or at least we can narrow
down our dierentials on plain radiographs. By seeing
above mentioned criteria, bone tumors can be classied
into benign, intermediate, and malignant entities on
radiography.[6,7] However, there are some limitations of CR.
Lesions located in the region of complex anatomies such
as the pelvis, scapula, and spine are challenging to evaluate
on CR. e extent of marrow and so-tissue involvement,
including neurovascular bundles, joint involvement,
presence of skip lesions, and distant metastasis, is
challenging to assess on CR. ese factors are essential for
staging the disease, and ultimately deciding the treatment
and outcome. Computed tomography (CT) and magnetic
resonance imaging (MRI) help to cover all these aspects.[8]
An algorithm for the radiological diagnosis of bone tumors
is presented in [Figure1].
e role of radiologists does not end with the imaging
diagnosis and staging of the bone tumor, but he has a
signicant role to play in planning and performing image-
guided biopsies (ultrasound or CT guided), which helps to

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draw the specimen from the most viable part of the tumor.
Histopathological evaluation of samples obtained under
image guidance is the nal step in diagnosing and grading
bone tumors. e biopsy track should always be planned
aer discussing with the surgeon so that the biopsy track is
excised with the tumor to avoid recurrence.[9]
WHAT’S NEW IN 2020 WHO CLASSIFICATION
OF BONE TUMORS?
With technological advances and the introduction of new
molecular and genetic data about some bone tumors, there
has been reorganization in the classication and introduction
of a few new entities. Newly identied genetic alterations
and corresponding immunohistochemical markers are
included in the new classication, and this has helped in the
reclassication of the existing tumor entities.[4] ese novel
genetic alterations not only help in prognostication but are
a target for potential therapeutic options which can bring a
paradigm shi in the chemotherapeutic regimen for these
entities in the future. Radiologists play an essential role in the
multidisciplinary team involved in the care of bone tumor
patients, and therefore they need to be aware of important
new development in the latest WHO classication. Major
changes in the categories of the tumor, their biological
potential and summary of newly added and recategorized
entities in the 2020 WHO Classication of Bone Tumors with
their Clinical and Imaging characteristics are summarized
in [Tables 2 and 3]. In the upcoming sections, we will be
discussing various categories of bone tumors and the updates
in the new classication with an emphasis on their imaging
appearance.
Chondrogenic tumors
e latest classication has recategorized chondroblastoma
and chondromyxoid fibroma from the intermediate to
benign category. Previously, enchondroma and periosteal
chondroma [Figure 2] were listed together under the
term chondroma, but now they are reclassied as separate
benign entities. Synovial chondromatosis (SC), which has
a high recurrence aer excision, is recategorized from
benign to intermediate category. e SC has recurrence
rates varying from 10% to 15%. It can undergo malignant
transformation into synovial chondrosarcoma in 1–5%
of cases in the long run. ere is a signicant overlap
between SC and synovial chondrosarcoma in terms of
clinical behavior and radiological appearance, however
cortical destruction and marrow invasion in the setting
of multiple recurrences raise the suspicion of malignant
transformation.[4]
e previous classication used the terms “atypical
cartilaginous tumor (ACT)” and “Chondrosarcoma
Grade 1 (CS1)” interchangeably and classied them in
the intermediate category.[3] In the appendicular skeleton,
these lesions behave in a locally aggressive fashion and do
not metastasize. erefore, in the current classication,
the term ACT is used when the lesion is located in the
appendicular skeleton, whereas CS1 is used when the
lesion is located in the axial skeleton even though both
lesions are identical in histomorphology. Reclassifying
CS1 in the malignant category benets understanding
that these lesions need more extensive surgery than the
benign lesion. e radiologist needs to understand another
critical dierence in the terminology, that is, between
Figure1: An algorithm for the radiological diagnosis of bone tumors.

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Indian Journal of Musculoskeletal Radiology • Volume 4 • Issue 2 • July-December 2022 | 76 Indian Journal of Musculoskeletal Radiology • Volume 4 • Issue 2 • July-December 2022 | 77
central and peripheral ACT/CS1. e term “central ACT/
CS1” is used when the tumor is located in the medulla
of the bone, whereas the term “peripheral ACT/CS1” is
used when the tumor arises from the cartilaginous cap of
a pre-existing osteochondroma. Central ACT/CS1 can
further be classied into primary (de novo) and secondary
(arising from preexisting enchondroma) categories. About
50% of high-grade chondrosarcoma share IHD1 or IHD2
mutations with enchondroma/ACT/CS1 suggesting the
genetic connection between these entities. e location of
high-grade chondrosarcoma is similar to that of ACT/CS1.[4]
It is challenging to dierentiate between enchondroma and
ACT/CS1 radiologically. Some imaging features which can
help to dierentiate enchondroma from ACT/CS1 are listed
in [Table4].
Osteochondromas are benign bony outgrowths covered
by a cartilaginous cap with clear continuity of cortex
and medulla. e lesions can be sessile or pedunculated,
and these lesions generally point away from the joint.
e growth of osteochondroma ceases aer the fusion
of physis. Some clinical and radiological criteria predict
the development of malignancy in the cartilaginous cap.
Clinical features include syndromic association, an increase
in the size of mass, pain, and the development of symptoms
due to compression of the adjacent neurovascular bundle
[Figure 3]. Radiological criteria are very objective and
include the thickness of the cap of more than 20 mm,
altered appearance on sequential studies, and development
of so-tissue mass. MRI has a clear advantage over any
other modality for visualization of the cartilaginous cap.
MRI sequences such as diusion-weighted imaging (DWI)
and dynamic contrast-enhanced MRI (DCE-MRI) also
help distinguish between benign cartilaginous cap and
malignancy developing within it. Imaging helps to obtain
a biopsy sample from the most viable (enhancing and with
restricted diusion) part of the cap to increase diagnostic
yield. Progression to malignancy occurs in 1% of cases of
solitary osteochondroma and 20% of cases of hereditary
multiple exostoses. ACT/CS1 constitutes more than 90%
of cases of malignancies in osteochondroma, and CS 2–3
constitutes the rest of the cases.[10]
Table2: Major changes in the categories of tumor and their biological potential in the latest classication of bone tumors.
Tumor entities 2013 WHO Classication 2020 WHO Classication
Chondroblastoma Intermediate (rarely metastasizing) Benign
Chondromyxoid broma Intermediate (locally aggressive) Benign
Synovial chondromatosis Benign Intermediate (locally aggressive)
Chondrosarcoma grade 1 Intermediate (locally aggressive) Malignant
Epithelioid hemangioma Intermediate (locally aggressive and rarely
metastasizing) tumor
Intermediate (locally aggressive) tumor
Aneurysmal bone cyst Tumor of undened neoplastic nature;
Intermediate (locally aggressive)
Osteoclastic giant cell-rich tumor;
Benign
Non-ossifying broma Fibrohistiocytic tumor Osteoclastic giant cell-rich tumor
Chondromesenchymal hamartoma of
the chest wall
Tumor of undened neoplastic nature Other mesenchymal tumor of bone
Simple bone cyst Tumor of undened neoplastic nature Other mesenchymal tumor of bone
Fibrous dysplasia Tumor of undened neoplastic nature Other mesenchymal tumor of bone
Osteobrous dysplasia Tumor of undened neoplastic nature Other mesenchymal tumor of bone
Osteobrous dysplasia like
Adamantinoma
Tumor of undened neoplastic nature;
Malignant tumor
Other mesenchymal tumor of bone;
Intermediate (locally aggressive)
Adamantinoma Miscellaneous tumor Other mesenchymal tumor of bone
Pleomorphic undierentiated sarcoma Miscellaneous tumor Other mesenchymal tumor of bone
Langerhans cell histiocytosis Tumor of undened neoplastic nature Hematopoietic neoplasm of bone
Erdheim-Chester disease Tumor of undened neoplastic nature;
Intermediate (locally aggressive)
Hematopoietic neoplasm of bone;
Malignant
Rosai-Dorfman disease Tumor of undened neoplastic nature Hematopoietic neoplasm of bone
Ewing sarcoma Miscellaneous tumor Undierentiated small round cell sarcoma
Leiomyosarcoma Myogenic tumor Other mesenchymal tumor of bone
Leiomyoma Myogenic tumor Removed
Lipoma Lipogenic tumor Other mesenchymal tumor of bone
Liposarcoma Lipogenic tumor Removed
Benign brous histiocytoma Fibrohistiocytic tumor Removed
Giant cell lesions of the small bones Osteoclastic giant cell rich tumor Removed
WHO: World Health Organization

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Tab l e 3 : Summary of newly added and recategorized entities in 2020 WHO classication of bone tumors with their clinical and imaging
characteristics.
Category Sub-category Common locations in the skeleton system; Most common age group
aected; Radiographic features
Chondrogenic tumors Periosteal chondroma Proximal humerus and distal femur; 3rd–5th decade; Arise from the
periosteum of long bones and shows saucerisation of the adjacent bony cortex
with a sclerotic periosteal reaction and ring and arc pattern of calcication.
Enchondroma Small tubular bones of hand/feet and long bones; 1st–3rd decade; small
osteolytic lesions with no/mild endosteal scalloping and ring and arc pattern
of calcication. No cortical destruction and periosteal reaction. Multiple
lesions can be seen in Ollier disease and Maucci syndrome
Chondroblastoma NOS Epiphysis or apophysis of a long bone; 1st–3rd decade; well-dened lytic
lesion (<5 cm) with geographical bone destruction and thin sclerotic
margins. Rings and arcs calcication can be seen. Intense adjacent marrow
edema is oen seen on MRI. Might be associated with joint eusion.
Chondromyxoid broma Metaphyseal region of long bones; 2nd and 3rd decade; well-dened lytic
lesion with geographical bone destruction and sclerotic margins. No cortical
destruction and periosteal reaction. Pseudotrabeculation can be seen.
Chondromatosis NOS Knee and hip; 4th–5th decade; so-tissue mass surrounding the joint with numerous
uniform-sized calcied loose bodies demonstrating rings and arcs calcication.
Atypical cartilaginous tumor Appendicular skeleton (femur, humerus, tibia, ribs); 3rd–6th decades;
osteolytic lesions with no/mild endosteal scalloping and ring and arc pattern
of calcication. No cortical destruction and periosteal reaction.
Chondrosarcoma, grades 1 Axial skeleton (pelvis, scapula, skull base); 3rd–6th decades; osteolytic lesions
with no/mild endosteal scalloping and ring and arc pattern of calcication.
No cortical destruction and periosteal reaction.
Vascular tumors of bone Epithelioid hemangioma Multifocal regional distribution (long and at bones); all age groups;
expansile radiolucent, lytic or cystic-appearing lesions with narrow
transition zone and endosteal scalloping.
Osteoclastic giant
cell-rich tumors
Aneurysmal bone cyst Metaphysis of long bones, posterior elements of the spine; 1st and 2nd decade;
a sharply dened, eccentric expansile multicystic lucent bone lesion, with
uid-uid levels on MRI
Non-ossifying broma Metaphysis of a long bone; 1st and 2nd decade; multiloculated, lucent lesion
eccentrically located in the metaphysis near the physis of a long bone with a
thin sclerotic rim.
Notochordal Poorly dierentiated chordoma Clivus, skull base, and cervical spine; children and young adults; destructive
lytic lesion with expansile so-tissue mass. Calcication is uncommon.
Other mesenchymal
tumors of bone
Chondromesenchymal
hamartoma of the chest wall
Ribs; neonate; or infants; well-dened, expansile, partly calcied mass
involving one or more ribs with uid-uid levels on MRI.
Simple bone cyst Metaphysis of long bones (humerus>femur); 1st and 2nd decades; centrally
located well dened geographic lytic lesion with a narrow zone of transition,
thin sclerotic margin with no periosteal reaction or so-tissue component.
Sometimes they are associated with a pathologic fracture. Fallen fragment
sign and trap door sign can be seen.
Fibrous dysplasia Long bones, craniofacial bones, and ribs (monostotic or polyostotic); 1st–3rd decade;
expansile or non-expansile lytic lesion with usually smooth and homogenous
appearance, with endosteal scalloping and cortical thinning. Ground glass matrix is
generally seen. No periosteal reaction. Rind sign at the margins is seen.
Osteobrous dysplasia Mid-diaphysis of tibia; 1st decade; a bubbly lytic lesion centered in the tibial
cortex, sclerotic margins, no periosteal reaction, pseudo trabeculation, and
anterior bowing can be seen.
Lipoma NOS Calcaneum, femur; 4th–5th decade; benign-appearing osteolytic bone lesion with
well-dened margins and occasional central calcication giving cockade sign.
Hibernoma Spine and pelvis; 5th–7th decade; sclerotic (most commonly) or osteolytic
with peripheral sclerosis.
Osteobrous dysplasia-like
adamantinoma
Mid-diaphysis of tibia; 3rd decade; a bubbly lytic lesion centered in the tibial
cortex, with sclerotic margins, cortical destruction with so tissue extension,
no periosteal reaction, intramedullary extension common.
(Contd...)

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Table3: (Continued)
Category Sub-category Common locations in the skeleton system; Most common age group
aected; Radiographic features
Mesenchymoma NOS Long bones (metaphysis), pelvic bones; 1st and 2nd decade; lytic expansile
lesions with sclerotic rim, internal ring-like calcications, and features of
cortical thinning and/or destruction with so tissue mass.
Adamantinoma of long
bones (Dedierentiated
adamantinoma)
Mid-diaphysis of tibia; 2nd–3rd decades; a bubbly lytic lesion centered in the
tibial cortex, with sclerotic margins, cortical destruction with so tissue
extension, no periosteal reaction, intramedullary extension common. It has
a propensity to metastasize to distant locations.
Leiomyosarcoma NOS Long bones and at bones; 7th–8th decades; osteolytic lesion with an
aggressive pattern of bone destruction.
Pleomorphic sarcoma,
undierentiated
Femur, humerus and tibia; 3rd–5th decade; highly destructive with a wide
zone of transition (occasionally expansile). Periosteal reaction is uncommon.
e lesion usually has no matrix mineralization.
Hematopoietic
neoplasms of bone
Langerhans cell histiocytosis
NOS
Skull, pelvis and femur; 1st decade; solitary or multiple punched out lytic
lesions without sclerotic rim. Hole within a hole sign, button sequestrum
and geographic destruction is seen in the skull. A oating tooth is seen in
the mandible and vertebra plana are seen in the spine.
Langerhans cell histiocytosis,
disseminated
Skull, pelvis and femur; 1st decade; multiple organ systems with multiple lesions
are seen. Skeletal lesions are similar to Langerhans cell histiocytosis NOS.
Erdheim-Chester disease Femur and tibia (Multifocal involvement); middle age; bilaterally
symmetrical cortical sclerosis obliterating the cortico-medullary
dierentiation. Cardiac involvement and retroperitoneal brosis can be seen
leading to arrhythmias and hydronephrosis.
Rosai-Dorfman disease Femur, tibia, skull; 2nd decade; skeletal lesions are typically lytic and
intramedullary, sometimes with surrounding sclerosis. Permeative
destruction, Cortical thinning, and focal breakthrough can also be seen. It
was previously termed “sinus histiocytosis with massive lymphadenopathy.”
Bone involvement is seen in 5–10% of cases.
Undierentiated small
round cell sarcomas of
bone and so tissue
Ewing sarcoma e diaphysis of long bones, at bones; 1st and 2nd decade; large osteolytic lesion
with a permeative pattern of destruction and wide zone of transition extending
into adjacent so tissues. Lamellated (onion skin) periosteal reaction is common.
Round cell sarcoma with
EWSR1–nonETS fusions
Long bones and at bone; broad age range; large osteolytic lesion with the
permeative pattern of destruction and wide zone of transition extending into
adjacent so tissues.
CIC-rearranged sarcoma Predominantly involve so tissue with rare involvement of bones; broad age
range; lytic or mixed lytic-sclerotic lesion with an aggressive periosteal reaction.
Sarcoma with BCOR genetic
alterations
Pelvis and long bones; 1st and 2nd decade; lytic or mixed lytic-sclerotic lesion
with an aggressive periosteal reaction.
WHO: World Health Organization, NOS: Not otherwise specied
Table4: Imaging features that dierentiate Enchondroma from ACT/CS1.
Enchondroma ACT/CS1
Appearance Clustered cartilage deposits Conuent mass
Tumor size Less than 5 cm More than 5 cm
Endosteal scalloping Less than 2/3 of cortical thickness More than 2/3 of cortical thickness
Expansile bony remodeling Generally Absent May be present
So tissue extension Absent May be present
Radiotracer uptake on bone scan Less or no More
Presence of marrow fat signal on MRI Present Present/absent
CS1: Chondrosarcoma grade 1, ACT: Atypical cartilaginous tumor

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Osteogenic tumors
Osteoid osteoma (OO) and osteoblastoma are dierentiated
based on size and location in the skeleton system
[Figure 4]. OOs are more predominantly seen in the
diaphyseal or metadiaphyseal region of long bones, whereas
osteoblastomas are more prevalent in posterior elements of
the spine. Osteoblastoma can sometimes become aggressive
and is classied in an intermediate category. Lesions <2cm
are classied as OO and lesions ≥2 cm osteoblastoma in
the presence of classic clinical and radiological features.
Nevertheless, both OO and osteoblastoma share the same
molecular genetic alteration.[11,12]
e previous classication included secondary osteosarcoma
in the conventional osteosarcoma (COS) subtype, but now,
the recent classication has described it in a separate category.
Now osteosarcoma not otherwise specied (NOS) includes
only three subtypes: COS, telangiectatic osteosarcoma, and
small cell osteosarcoma. COS accounts for the majority
of osteosarcoma [Figure 5]. Osteosarcoma NOS can also
be subdivided into dierent types based on the dominant
matrix: Osteoblastic, chondroblastic, and broblastic;
However, this subdivision has no role in predicting
prognosis. COS and telangiectatic osteosarcoma are more
commonly encountered in the metaphyseal region of long
bones whereas small cell osteosarcoma is predominantly seen
in the diaphysis. Recent classication has also removed Clear
cell and chondroblastoma-like osteosarcoma subtypes from
the osteogenic tumors.[4]
In the latest classication, secondary osteosarcoma is divided
into six subtypes:[4]
a) Osteosarcoma in Paget’s disease of bone,
b) Radiation-induced osteosarcoma
c) Infarct related osteosarcoma
d) Chronic osteomyelitis related
e) Implant-related osteosarcoma
f) Osteosarcoma secondary to brous dysplasia.
e prognosis of secondary osteosarcoma occurring as a
result of Paget’s disease of bone and radiation treatment is
poorer than COS.
Figure 2: A40-year-old male presented with swelling in the
proximal le arm which on radiography (a) demonstrated well
dened calcied mass lesion centered over the humeral cortex (solid
arrow). Axial T2 W Magnetic resonance imaging (MRI) image
(b) shows the lesion (solid arrow) is centered over the periosteum
and appears hyperintense as compared to adjacent muscles with
internal areas of hypointensities. Axial T1 W post-contrast MRI
image (c) shows heterogeneous enhancement in the lesion (solid
arrow), (d) hematoxylin and eosin section shows hyaline lobules of
bland chondrocytes with periosteal rimming. e diagnosis of this
case was periosteal chondroma.
Figure 3: A20-year-old male patient with diaphyseal aclasis
presented with rm swelling in the le popliteal region,
(a)  Radiograph of the bilateral knee joint showing multiple
sessile and pedunculated bony outgrowth arising from femur,
tibia, and bula pointing away from the joint suggesting multiple
osteochondromas, (b) lateral radiograph of the le knee shows
a so-tissue density mass (solid arrow) in the popliteal region,
(c) ultrasound with Doppler examination revealed popliteal artery
(Pop A) in the periphery of the mass lesion with no color ow in
the rest of the lesion, and (d) computed tomography angiography
image shows large popliteal artery pseudoaneurysm with peripheral
thrombosis. e cause of popliteal artery pseudoaneurysm could
be irritation of the vessel wall by an underlying osteochondroma.
Endovascular repair of the aneurysm was performed.
d
c
b
a
d
c
b
a

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Fibrogenic tumors
e 2020 WHO classication has not updated this category
of bone tumors. It includes the desmoplastic fibroma of bone
in the intermediate grade and brosarcoma in the malignant
grade. ese tumors are composed of spindle cells with
variable collagen.[4]
Desmoplastic fibroma is an extremely rare tumor of bone
(<0.1% of all bone tumors) that is locally aggressive but
does not metastasize. It is considered the bony counterpart
of desmoid tumors found in the so tissues and is a
diagnosis of exclusion. Both desmoplastic broma and
desmoid tumors are histologically identical. Low-to-
intermediate signal intensity is characteristic of MRI.[13]
Transition to brosarcoma or osteosarcoma is extremely
rare. e recurrence rate aer curettage is generally more
than 70%, so the preferred management is resection with
wide margins.
Fibrosarcoma is a sporadic malignant brogenic tumor
of bone that occurs in the middle and old age groups.[14]
Initially, malignant brous histiocytoma and brosarcoma of
bone were considered as a single entity, but these lesions are
distinct entities.[4]
Vascular tumors
In 2020 WHO classification, epithelioid hemangioma of bone
is moved from an intermediate locally aggressive and rarely
metastasizing tumor to the intermediate locally aggressive
tumor category.[4] Epithelioid hemangioma, epithelioid
hemangioendothelioma, and angiosarcoma can be multifocal
and involve multiple bones. Angiosarcoma accounts for <1%
of malignant bone tumors. Angiosarcoma has the propensity
to metastasize to other skeletal sites.[15]
Osteoclastic giant cell-rich tumors
It comprises a heterogeneous group of tumors and tumor-
like lesions rich in osteoclast type multinucleate giant cells.
ere has been a recategorization of the aneurysmal bone
cyst (ABC) and non-ossifying fibroma (NOF) into this group
in the latest classication. In the present classication, the
term “benign fibrous histiocytoma” is no longer in use.[4]
Figure 4: A16-year-old male patient with osteoid osteoma
presented with pain in the le hip joint which was more at night and
relieved by aspirin, (a and b) magnetic resonance imaging of the
patient revealed a well-dened osteolytic lesion (circle) measuring
6–7mm in size, located in the le acetabulum with adjacent marrow
edema (arrow), a hypointense nidus can also be visualized in the
area, computed tomography (CT) in bone window setting shows
a well-dened osteolytic lesion (circle) in the le acetabulum with
adjacent reactive sclerosis, (d) CT-guided radiofrequency ablation
of the lesion was performed.
Figure 5: A17-year-old female patient presented with a mass in
the right upper leg for 2months. e lesion was slowly increasing
in size. Radiographic (a and b) evaluation revealed an ill-dened
osteolytic and sclerotic mass lesion involving proximal tibial
metaphysis and diaphysis with the permeative pattern of bone
destruction, wide zone of transition, osseous matrix (arrow), and
so-tissue extension. A radiographic diagnosis of osteosarcoma
was established and a biopsy of the lesion conrmed the same.
Hematoxylin and eosin sections (c and d) show blood-lled spaces
along with atypical spindle cells producing immature and neoplastic
bone formation.
d
c
b
a
d
c
b
a

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Giant cell tumors (GCT) can be categorized into benign or
malignant [Figure 6]. Malignant GCTs represent 5–10%
of GCT. Radiographs are not very helpful in dierentiating
benign from malignant GCTs. DWI and DCE MRI can help
identify highly cellular components within the lesion, which
can further be biopsied to obtain representable samples for
histopathological evaluation.[16] Malignant GCTs can be
categorized into primary (more favorable prognosis) and
secondary (more common). Denosumab-treated GCT is now
recognized as a distinct variant of GCT. Giant cell lesions of
the small bones are now considered a true solid variant of
ABC. Terminologies such as “giant cell lesion of small bones”
and “giant cell reparative granuloma of small bone” are
obsolete. ABC can be categorized into primary (de novo) and
secondary (developing in preexistent tumors such as GCT,
chondroblastoma, brous dysplasia, and NOF) [Figure 7].
Distinguishing primary from secondary ABC is important
as the treatment for the two is completely dierent. [Table5]
summarizes features that help to distinguish primary from
secondary ABC.[4]
Notochordal tumors
Poorly dierentiated chordoma (PDC) is a new entity that
is added to the recent classication of bone tumors. Like
conventional chordoma, PDC also has a predilection for
the axial skeleton but it predominantly aects the clivus
and skull base. It is generally seen in children, and young
adults, with females aected slightly more than males.
PDC is more aggressive than conventional chordoma. It
generally demonstrates intermediate T2 signal intensity
unlike conventional chordoma and shows avid contrast
enhancement.[17]
Dedierentiated chordoma is characterized by the presence
of sarcomatous elements in addition to the chordoma
(biphasic).[4] Biomorphic appearance can be visualized even
on MRI.
Figure 7: A10-year-old male with an aneurysmal bone cyst of
radius showing a well-dened expansile osteolytic lesion (solid
arrow) with multiple thin internal bony septae giving soap bubble
appearance on radiography (a), (b) axial T2 W Magnetic resonance
imaging image showing multiple uid-uid levels within the lesion
(arrow), (c) Hematoxylin and eosin sections show blood-lled
cystic spaces separated by brous septa with osteoclast type giant
cells, broblasts in their walls.
Figure6: A35-year-old female patient presented with swelling in
the right anterior chest wall. Radiograph of the chest (a) revealed a
well-dened lesion in the right upper thorax (arrow), and magnetic
resonance imaging (b and c) revealed a well-dened expansile
osteolytic lesion in the right second rib anteriorly with hyperintense
signal intensity on T2 W images and hypointense signal intensity
on T1 W images, Computed tomography (d) of the chest shows a
well-dened expansile osteolytic lesion in the right 2ndrib anteriorly
with cortical thinning and few internal bony septae, (e  and f)
hematoxylin and eosin sections show areas of hemorrhage with
numerous osteoclasts like giant cells scattered in between the
mononuclear round and spindle cells proliferation suggestive of
giant cell tumor.
c
b
a
d
c
b
f
a
e

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Other mesenchymal tumors
is is the new category of bone tumor introduced in the
2020 WHO classication. Tumors included in this category
in the present classication were previously categorized as
tumors of undened neoplastic nature or Miscellaneous
tumors. Hibernoma of bone, mesenchymoma, and
dedierentiated adamantinoma are newly recognized
entities. PUS was previously termed as “undierentiated
high-grade pleomorphic sarcoma.” PUS can be primary or
secondary. Secondary PUS may arise in pre-existent bone
infarcts, Paget’s disease and radiation necrosis.[18]
Hibernoma (tumor of brown adipose tissue) is a very
rare benign tumor seen in the spine or pelvis of elderly
patients (female>male). Mesenchymoma, also known as
Fibrocartilaginous mesenchymoma, is a very rare, locally
aggressive neoplasm seen in children and aects the
metaphyseal region of long bones, most commonly followed
by pelvic bones, vertebrae, and ribs.[4]
Adamantinoma is divided into three types in the recent
classification: Classic adamantinoma (malignant), OFD-
like adamantinoma, and dedierentiated adamantinoma
(newly introduced). OFD-like adamantinoma was previously
categorized as a malignant tumor, but in recent classication,
it is placed in the Intermediate (locally aggressive) category.
Dedierentiated adamantinoma is the rarest subtype and has
an aggressive clinical course with metastasis seen in 2/3rdof
the patients. is subtype may be associated with sarcomatoid
dedierentiation. In contrast classic adamantinoma displays
a low rate of metastasis and longer survival. OFD and
OFD like adamantinoma are more commonly seen in the
young age group with females aected more than males,
whereas classic and dedierentiated adamantinoma is more
commonly seen in males of the middle age group. OFD
and all types of adamantinoma are typically located in the
tibial cortex. Anterior bowing is more common in OFD and
OFD like adamantinoma whereas marrow involvement and
extraosseous extension are more commonly seen in classic
and dedierentiated adamantinoma.[19]
Hematopoietic neoplasms of bone
Multiple myeloma is the most common malignant
bone tumor in adults [Figure 8]. It can present in either
disseminated form (more common and poor prognosis) or
as solitary plasmacytoma. e disseminated form presents as
multiple punched-out lytic lesions predominantly involving
the axial skeleton. Sometimes disseminated form presents
as mere diuse osteopenia with no identiable lytic lesion.
Solitary plasmacytoma in the majority of patients has latent
systemic involvement at the time of presentation. e term
“Plasma cell myeloma” is no longer in use. Multiple myeloma
is removed from the h edition of the WHO classication
of bone tumors and is included in the fourth edition of the
Figure 8: A55-year-old female with multiple myeloma showing
multiple osteolytic lesions in pelvic bones and bilateral femur
(arrows) on the radiograph (a), follow-up radiograph aer
2 weeks shows pathological fracture in the right iliac bone
(arrow), hematoxylin and eosin sections from bone marrow
show nodules/sheets of plasma cells (c), these plasma cells show
diuse immunopositivity for CD138 (d) and kappa (e), while
Immunonegative for lambda (f).
Table5: Features that dierentiate primary from secondary ABC.
Primary ABC Secondary ABC
Age 1st–2nd decade 3rd decade
Location Metaphysis with or without
epiphyseal extension
Epiphysis (preexistent GCT or chondroblastoma)
Diaphysis (preexistent NOF and FD)
Cortex Intact Breached with a so tissue mass
USP6 gene rearrangement Present in 70% of cases Absent
ABC: Aneurysmal bone cyst, GCT: Giant cell tumors, NOF: Non-ossifying fibroma
d
c
b
f
a
e

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Indian Journal of Musculoskeletal Radiology • Volume 4 • Issue 2 • July-December 2022 | 84 Indian Journal of Musculoskeletal Radiology • Volume 4 • Issue 2 • July-December 2022 | 85
Figure 10: A9-year-old male with Ewing sarcoma of right bular diaphysis
showing an ill-dened osteolytic lesion in the bular diaphysis with the poor zone
of demarcation, the permeative pattern of bone destruction and onion skin type of
periosteal reaction (arrow in a), magnetic resonance imaging images show diuse
inltration of marrow (b) with enhancement on the post-contrast image (c),
hematoxylin and eosin sections show a malignant small round cell tumor (d), higher
magnication demonstrating monomorphic round cells with ne granular chromatin
with the absence of nucleoli (e), these tumor cells are diusely immunopositive for
CD99 (f), FLI-1 (g) and NKX2-2 (h) with increased Ki67 labeling index (i).
d
hi
c
g
b
f
a
e
Figure9: A2-year-old child with disseminated Langerhans cell histiocytosis showing multiple well dened osteolytic lesions involving
the skull with beveled edges (arrows in a and b), similar lesions can also be seen in the appendicular skeleton (arrows in c and d).
d
c
b
a

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Indian Journal of Musculoskeletal Radiology • Volume 4 • Issue 2 • July-December 2022 | 84 Indian Journal of Musculoskeletal Radiology • Volume 4 • Issue 2 • July-December 2022 | 85
WHO classication of hematopoitic and lymphoid tissues
published in 2017.[20]
Langerhans cell histiocytosis [Figure 9], Erdheim-Chester
disease, and Rosai-Dorfman disease were classied previously
in the category of tumors of undefined neoplastic nature, but
in the recent classication, these tumors are classied in the
category of hematopoietic neoplasms of bone.[4]
Primary bone lymphoma (PBL) can be unifocal or multifocal
involvement of the skeletal system without evidence of
systemic disease for 6 months. PBL is less common than
secondary involvement from disseminated lymphoma.
More than 80% of PBL are diuse large B-cell lymphomas.
Dierent types of bone lymphomas are indistinguishable
from Imaging studies.[21]
Undierentiated small round cell sarcomas of bone and
so tissue
A new chapter on undierentiated small round cell sarcomas
of bone and so-tissue tumors is introduced in the 2020
WHO classification, which includes Ewing’s sarcoma
(EWS), round cell sarcoma with EWSR1–non-ETS fusions,
CIC-rearranged sarcoma, and sarcoma with BCOR genetic
alterations. ese tumors are dierent from each other
based on clinical features and molecular proles. EWS is
dierent from the other three because of the unique gene
fusion involving the FET family of genes and a member of
ETS transcription factors. EWS is the second most common
malignant bone tumor aer osteosarcoma in the pediatric
and adolescent age group [Figure10].[4]
CONCLUSION
In this review, we have summarized major changes in the
2020 WHO classication of bone tumors with relevant
points for the information and knowledge of the radiologist.
Radiologists play a crucial role in the team of physicians
and surgeons involved in the care of bone tumor patients;
erefore, the radiologist needs to stay updated with the
latest development and advances even if the basis of these
developments is majorly molecular, genetic, and pathological.
We have also summarized the imaging approach and
parameters used for the evaluation of patients presenting
with clinical features of bone tumors. Imaging features of
many new entities are yet to be discovered, and with time,
we may be able to understand these entities better with the
help of further research and enhancement in the available
literature.
Declaration of patient consent
Patient’s consent not required as patients identity is not
disclosed or compromised.
Financial support and sponsorship
Nil.
Conicts of interest
ere are no conicts of interest.
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How to cite this article: Saran S, Phulware RH. World Health Organization
classification of bone tumors (h edition): What a radiologist needs to
know? Indian J Musculoskelet Radiol 2022;4:73-86.