Hemangioma, Aneurysmal Bone Cyst,

Unicameral Bone Cyst, Giant Cell Tumor,

& Langerhans Cell Histiocytosis

Eric Mascard
Necker University Hospital, 75015 Paris
Institut Gustave Roussy Villejuif, 94805 Cedex
Clinique Arago, 75014 Paris, France
 Introduction
Hemangioma, Aneurysmal Bone Cyst,
Unicameral Bone Cyst, Giant Cell Tumor,
Langerhans Cell Histiocytosis :
What do they have in common ?
They are at the end of the pathology books
Most are of undefined nature
Impossible to treat in 15 minutes.
So whats new ????
 Hemangioma

Hemangioma of bone
Benign, extremely common, seldom symptomatic, found in
10% of subjects on spine autopsy
Any age, peak in the 50, slightly more female
Vertebra > skull > long bones > Others
Capillary, venous, cavernous, sclerotic hemangioma, or
angiomatosis
Made from well formed mature vessels of different calibers
Positive for vascular markers (CD31, CD34, ERG & FLI-1)
Usually not to be biopsied or resected
Vascular bone tumors: a proposal of a classification based on clinicopathological, radiographic and genetic features.
Errani C, Vanel D, Gambarotti M, Alberghini M, Picci P, Faldini C. Skeletal Radiol. 2012 Dec;41(12):
 Hemangioma
Hemangioma of bone
Some are painful
To distinguish from usual back pain
Embolization
Cementoplasty
Some look not like hemangiomas
Biopsy
Embolization
Cementoplasty
Surgery exceptionally
Decompression
Osteosynthesis (Fracture)
 Hemangioma
Epithelioid hemangioma
Occasional bone destruction with soft tissue involvement
Locally aggressive, 10% local recurrence rate, 3% lymph node
involvement. No distant metastases.
Male slightly > female, young adult
Capillary or venous sized vessels lined by epithelioid endothelial cells.
Positive for vascular markers (CD31, CD34, ERG, FLI-1) Keratin, EMA.
To be differentiated from epithelioid hemangioendothelioma
(malignant with a specific translocation WWTR1/CAMTA1 in FISH )
Surgical treatment is endolesional excision after embolization or
resection

Epithelioid hemangioma of bone and soft tissue: a reappraisal of a controversial entity

Errani C, Zhang L, Panicek DM, Healey JH, Antonescu CR. Clin Orthop Relat Res. 2012 May;470(5):
 Unicameral Bone Cyst
WHO 2013 :
Simple bone cyst or unicameral bone cyst (UBC) are lytic benign bone
lesions, of undetermined nature.
Intramedullary cavity filled with serous or sero-sanguineous fluid, usually
unilocular
UBC can involve all skeleton but usually the long bone metaphysis and
primarily proximal humerus and femur
Unique
Pathogenesis
More a dysplastic lesion than a real tumor
Impairment of venous blood circulation in cancellous bone
Bone resorption by increased blood pressure and high concentration of
inflammatory proteins
Epidemiology
Very frequent, male predominance
85% of patients are aged 10 to 20
 Unicameral Bone Cyst
Clinical presentation
Often asymptomatic
X-ray for other reason (Trauma, spine)
Pathological fracture
The most frequent
Pain, limping
Fissuring of the cyst
 Unicameral Bone Cyst
Imaging :
Nothing new.
Usually characteristic
The fallen fragment sign
The rising bubble sign
Cystography

But some look like ABC

 Unicameral Bone Cyst
Diagnosis :
Macroscopy
Usually characteristic
More difficult if fractured

Histology
Characteristic if a whitish
membrane is found on
curettage
Difficult in fractured UBC ,
showing aneurysmal changes
 Unicameral Bone Cyst
Prognosis
Spontaneous involution in adult
No malignant degeneration
Growth disturbance is rare
Fractures
Femoral neck (risk of necrosis)
In young children
If close to the physis, multi-locular
CT : evaluation of cortex thickness
 Unicameral Bone Cyst
Surveillance
In asymptomatic cases with no risk of fracture
Treatment :
Nothing will be effective in 100% of cases
Choose the less aggressive and less expensive methods
Corticosteroid injections : an old trick that still works
- Flont, P., M. Kolacinska-Flont, and K. Niedzielski, Factors predictive of positive response to steroid therapy in
simple bone cysts. Int Orthop, 2013. 37(8): p. 1519-25.
- Pavone, V., et al., Steroid injections in the treatment of humeral unicameral bone cysts: long-term follow-up
and review of the literature. Eur J Orthop Surg Traumatol, 2013.
- Wright, J.G., et al., A randomized clinical trial comparing intralesional bone marrow and steroid injections
for simple bone cysts. J Bone Joint Surg Am, 2008. 90(4): p. 722-30.
- Traub F, Eberhardt O, Fernandez FF, Wirth T., Solitary bone cyst: a comparison of treatment options with
special reference to their long-term outcome. BMC Musculoskelet Disord. 2016 Apr 14;17(1):162.
 Unicameral Bone Cyst
Methyl prednisolone injection
 Unicameral Bone Cyst
Surgery : when there is a risk of fracture...
 Unicameral Bone Cyst
Surgery :
Curetage, perforation, filling with bone substitute
Osteosynthesis according to localization and age
 Aneurysmal Bone Cyst
WHO 2013 : Benign bone lesion of undetermined
neoplastic nature, locally aggressive

There are several types of ABC :

The primitive ABC, or classic ABC :
Expansive and hemorrhagic tumor
Formerly considered as a reactive lesion
It is a true neoplastic lesion with a characteristic translocation
(USP6 rearrangement in chromosome 17)
The diagnosis must be assessed by a biopsy because a telangiectatic
sarcoma can mimic an ABC (no USP6 rearrangement)
 Aneurysmal Bone Cyst
The secondary ABC
Represents 30% of ABC and has no translocation.
It is developed in reaction to another lesion, usually benign to be looked
for on imaging for biopsy
GCT, chondroblastoma, osteoblastoma, fibrous dysplasia.
It should be called with the name of the lesion (for example GCT with
aneurysmal changes)
The solid ABC or giant cell reparative granuloma
Perhaps a healing classic ABC
Soft tissue ABC
Rare, characteristic USP6 translocation

Soft-tissue aneurysmal bone cyst with translocation t(17;17)(p13;q21) corresponding to COL1A1 and USP6
loci. Jacquot C, Szymanska J, Nemana LJ, & al., Skeletal Radiol. 2015 Nov;44(11):1695-9.

Aneurysmal bone cyst, in WHO classification of Tumours of Soft Tissue and Bone. Nielsen G.P., F.J.A.,
Oliveira A.M, B.J.A. Fletcher J.A., Hogendoorn P.C.W., Mertens F., Editor 2013, IARC: Lyon. p. 348-349.
 Aneurysmal Bone Cyst
Epidemiology
Quite rare (1.4 /1 000 000 per year)
Most patients are 10 to 20 year old
Rare after 30 and exceptional after 50
Usually unique
Localization
Long bones ( 67%), distal femur > tibia > humerus > fibula
Spine (15%) : posterior arch, lumbar > cervical > thoracic
Pelvis (9%).
Others bones...
 Aneurysmal Bone Cyst
Clinical presentation
Pain
Swelling
Rarely pathologic fracture
Spine
Wry neck
Stiff and painful scoliosis
Neurologic symptoms
 Aneurysmal Bone Cyst
Imaging : X-ray
ABC are metaphysal,
excentrated, bulging, containing
liquid
May develop in all bones of the
skeleton
Apparent multiple septa
ABC could be aggressive lesions
with a risk of bone destruction.
 Aneurysmal Bone Cyst
Imaging
In MRI, the liquid level image is
usual on axial in T2 sequence
after rest of the patient
Septa appear enhanced by
gadolinium injection
Characteristic in case of
multiple fluid levels filling
completely the lesion
 Aneurysmal Bone Cyst

Solid component in the tumor ?

MRI, cystography
 Aneurysmal Bone Cyst
Biopsy
Mandatory to eliminate a telangiectatic sarcoma or an
associated tumor (oriented by imaging)

Percutaneous (Core biopsy) or preferably surgical

curopsy
Supposed to formally differentiate ABC and UBC
Blood on aspiration could be a bleeding UBC
Histology is very difficult in case of fractured UBC (showing
aneurysmal changes)
In spine could be very hemorrhagic (embolization ?)
 Aneurysmal Bone Cyst
Histopathology
Blood filled spaces with no endothelium, no muscular or
elastic fibers
Connective tissue septa with osteoclast-like giant cells and
reactive woven bone
Characteristic fibrochondroid matrix, deeply calcified and
blue

Differential diagnostic value of "blue

reticulated chondroid-like material" in
aneurysmal bone cysts: a classic
histopathologic analysis of 215 cases. Bahk WJ,
Mirra JM. Am J Clin Pathol. 2015
Jun;143(6):823-9.
 Aneurysmal Bone Cyst
Differential diagnosis : unicameral bone cyst
Same population, same localization, same X ray.
Curopsy could be useful
 Aneurysmal Bone Cyst

Telangiectatic osteosarcoma
Biopsy is mandatory
Very confusing
Atypical cells and mitoses
Irregular osteoid matrix
No USP6 mutation
 Aneurysmal Bone Cyst
Differential diagnosis : giant cell tumor
Exceptional in children
More epiphyso metaphysal
High expression of P63 and H3F3 A mutation
Possibly associated

7 y GCT

ABC or GCT ?
 Aneurysmal Bone Cyst

Evolution
3 groups of variable evolution :
Quiet, active and aggressive
No malignant transformation
(excepted after radiotherapy)
Some will heal spontaneously
Possible growth disturbance or severe
bone destruction
Need for quick diagnosis and therapy
 Aneurysmal Bone Cyst
Treatment
Observation
After biopsy (4 to 8 weeks)
If the diagnosis is certain
Not potentially complicated lesions (spine, or fracture)
Spontaneous healing is possible.
Other treatments
15 to 44 % local recurrence
Less aggressive techniques if possible
 Aneurysmal Bone Cyst
Treatment
Methyl prednisolone injection
Contra indicated = possible stimulation of the lesion
Radiotherapy
It works.
Risk of malignant transformation
Contra indicated (excepted in some inoperable spine tumors)
Radiation Therapy for Aneurysmal Bone Cysts. Zhu S1, Hitchcock KE, Mendenhall WM. Am J Clin
Oncol. 2015 Jul 9.

Selective embolization
In spine & sacral lesions curative (alone) or preoperatively
Aneurysmal bone cysts of the spine: treatment options and considerations. Boriani S et al. ; J
Neurooncol. 2014 Oct;120(1):171-8.
Selective arterial Embolisation of Aneurysmal Bone Cysts of the Sacrum: a promising Alternative to
Surgery. Henrichs MP, Beck L, Gosheger G and al. Rofo. 2016 Jan;188(1):53-9.
 Aneurysmal Bone Cyst
Treatment
Intra lesional injections
Demineralized bone matrix, calcitonin, bone substitutes,
bone marrow etc..
Nothing widely accepted and proven
Doxycyclin
Many injection (up to 10) could be necessary
Useful in ABC close to physis, spinal cord, nerves

Percutaneous Doxycycline Treatment of Juxtaphyseal Aneurysmal Bone Cyst.

Shiels WE 2nd, Beebe AC, Mayerson JL. J Pediatr Orthop. 2016 Mar;36(2):205-12.
 Aneurysmal Bone Cyst
Treatment
Intra lesional sclerotherapy
Ethibloc
70 94% healing but no more available
Polidocanol (Aetoxysclrol )
3 injections in average
Same efficiency than intralesional surgery with adjuvants
Less complications than Ethibloc
Sclerotherapy with alcohol
Few complications, efficient, simple and cheap
Possible in sacrum
1 to 4 injections, 10% failures

Primary aneurysmal bone cysts in children: percutaneous sclerotherapy with absolute alcohol and
proposal of a vascular classification. Lambot-Juhan K, et al. Pediatr Radiol, 2012. 42(5): p. 599-605.

Aneurysmal bone cyst: A 19-case series managed by percutaneous sclerotherapy. Batisse F, Schmitt A,
Vendeuvre T, Herbreteau D, Bonnard C, Orthop Traumatol Surg Res. 2016 Apr;102(2):

Is sclerotherapy better than intralesional excision for treating aneurysmal bone cysts ? Varshney MK,
et al. Clin Orthop Relat Res, 2010. 468(6): p. 1649-59
 Aneurysmal Bone Cyst
Alcohol sclerotherapy

2012
and
2013 2014
 Aneurysmal Bone Cyst
Alcohol sclerotherapy
Pr Brunelle. Necker hospital, Paris
 Aneurysmal Bone Cyst
Treatment
Cryoablation
Per cutaneous, interventional radiology
Spine lesions
Cementoplasty after cryoablation
Or cryoablation after selective embolization

Treatment of a spinal aneurysmal bone cyst using combined image-guided cryoablation and
cementoplasty. Tsoumakidou G1, Too CW, Garnon J, Steib JP, Gangi A. Skeletal Radiol. 2014 Aug 5.

Successful treatment of a Musculoskeletal Tumor Society grade 3 aneurysmal bone cyst with N-
butyl cyanoacrylate embolization and percutaneous cryoablation. Griauzde J, Gemmete JJ, Farley
F. J Vasc Interv Radiol. 2015 Jun;26(6):905-9.
Frdric Deschamps IGR
 Aneurysmal Bone Cyst
Medical treatment
Zolendronic acid
Successful treatment of a sacral aneurysmal bone cyst with zoledronic acid. Simm PJ, M O'Sullivan, MR
Zacharin. J Pediatr Orthop, 2013. 33(5): p. 61-4.

Denosumab
Denosumab: a potential new and innovative treatment option for aneurysmal bone cysts. Lange T,
Stehling C, Frhlich B, & al. Eur Spine J. 2013 Jun;22(6):1417-22.

Response of Aneurysmal Bone Cyst to Denosumab. Skubitz KM, Peltola JC, Santos ER, Cheng EY. Spine
(Phila Pa 1976). 2015 Nov;40(22):E1201-4.

Targeting receptor-activator of nuclear kappaB ligand in aneurysmal bone cysts: verification of target and
therapeutic response. Pelle DW, Ringler JW, Peacock JD & al. Transl Res. 2014 Aug;164(2):139-48.

In spine and sacral lesions : can avoid dangerous surgery

In case of recurrence after treatment
Still in evaluation but definitive healing published ( GCT)
 Aneurysmal Bone Cyst
Treatment : Is there still a place for surgery ?
Large resection
Few local recurrence
Complications not justified in a benign condition
Marginal or subperiosteal resection
In very aggressive lesions ?
Less recurrences than curettage
After failure of sclerotherapy
Curettage ???
If curopsy
Otherwise better to do sclerotherapy (Polidocanol or alcohol)
Large spinal and sacral lesions : Denosumab or surgery in
case of fracture after pre operative embolization.
Current Strategies for the Treatment of Aneurysmal Bone Cysts. Tsagozis P, Brosj O. Orthop Rev
(Pavia). 2015 Dec 28;7(4):6182.
Aneurysmal Bone Cyst
 Aneurysmal Bone Cyst
Acute paraplegia in a pregnant woman :
Ceasarean section
Decompression + fixation in emergency
Denosumab post operatively

Dr Gilles Missenard et Pr Charles Court

 Giant Cell Tumor
WHO 2013 : Benign bone tumor, locally aggressive
Less than 2 % become malignant and some gives lung mets
Relatively frequent
5% of all bone tumor and 20% of all benign bone tumors
(but 20 % of all bone tumors in India and China)
Arises in patient with closed physis
Very rare in children
Developed from the metaphyseal side of the growth
cartilage then comes to the epiphysis
Distal femur, proximal tibia, pelvis, proximal humerus,
sacrum, distal radius (very rare in skull scapula & diaphysis)
 Giant Cell Tumor
Pathogenesis remains unclear
Reactive response to vascular insufficiency : deep
hypoxia and acute hemorrhage
Stimulation of osteoblast like cells, monocytes
recruitment and osteoclast differentiation then
inducing tumor formation.
High percentage of GCT cells have chromosomal
changes(without loss of genetic material)
GCT with complex clonal karyotypes have highest
risk for aggressive behavior
 Giant Cell Tumor
Clinical features
Pain, pathological fracture, swelling
Young adult
Radiology
Lytic bone lesion, usually characteristic
Growing to the epiphysis
To differentiate from other epiphyseal
lesions
Chondroblastoma
Clear cell chondrosarcoma
Subchondral degenerative cysts
Biopsy is mandatory
 Giant Cell Tumor
Histology :
Mononuclear cell
proliferation of
primitive mesenchymal
stromal cells
RANKL expression in
tumor cells
Macrophages and
osteoclastic giant cells
P63 expression
 Giant Cell Tumor
New diagnostic tool
Molecular biology : Histone 3.3 mutation
H3F3 A gene in osteoblastic tumors
GCT (49/53 = 92 %) => Mutations G34W/L
H3F3 B gene in cartilaginous tumors
Chondroblastoma (73/77 =95 %) =>Mutations K36M
No H3F3 mutation in Chondromyxoid fibroma and
chordoma

Mutation Analysis of H3F3A and H3F3B as a Diagnostic Tool for Giant Cell Tumor of Bone and
Chondroblastoma. Cleven AH, Hcker S, Bove JV & al. Am J Surg Pathol. 2015 Nov;39(11):1576-83.
 Giant Cell Tumor
Prognosis
Local recurrence in 10 to 30%
Lung metastases or implants
In 2 % , 3-4 years after diagnosis
Mainly with distal radius
CGT with intravascular growth or emboli
Some will disappear, some will kill the patient
Malignant transformation
After radiotherapy
Role of denosumab ?
Or misdiagnosis (giant cell
osteosarcoma, malignant GCT) ?
 Giant Cell Tumor
Local treatment
Surgery
Aggressive curettage, high speed burr, pulsed
lavage
Adjuvant therapy have no proven efficiency
(phenol, liquid nitrogen, argon laser)
Thermic effect of PMMA cement used in filling
Osteosynthesis only if needed
En bloc resection in recurrent lesions or
expendable bones such as rib, fibula, iliac wing)
Radiation therapy
In some spinal recurrent lesions ?
Resection of lungs mets
 Giant Cell Tumor
Medical therapy
Based on the TCG biology
(RANKL activation of osteoclasts)
Osteoclasts Inhibition
Diphosphonates (Zometa)
Anti RANKL antibody = Denosumab
Indication for Denozumab to be discussed in MDT
When surgical treatment is not possible
When surgical treatment would be mutilating
In metastatic GC tumor
Locally aggressive and recurrent tumors (very effective)
With Ca and D Vitamin supplementation, Phosphorus and Ca
Monitoring, and dental panoramic radiograph
Giant cell tumors of the spine: has denosumab changed the treatment paradigm?
Goldschlager T, Dea N, Boyd M and al. J Neurosurg Spine. 2015 May;22(5):526-33.

GSF-Geto Groupos recommandations (Chevreau C, Dumaine V, Brouchet A, Missenard G) 2016

 Giant Cell Tumor
Many concerns with Denosumab
Recurrence after end of treatment
When to stop ?
General complications
Difficult to perform a curettage after
Denosumab
Could help to perform en bloc resection ?
Induction of malignant transformation ?
Some teams are already using it less

A High-grade Sarcoma Arising in a Patient With Recurrent Benign Giant Cell

Tumor of the Proximal Tibia While Receiving Treatment With Denosumab.
Aponte-Tinao LA, Piuzzi NS, Roitman P, Farfalli GL. Clin Orthop Relat Res. 2015
Sep;473(9):3050-5.
 Langerhans Cell Histiocytosis
It is known that :
Letterer-Siwe disease (multi organ involvement)
Hand-Schller-Christian (rash, bone lysis, diabetes insipidus)
Eosinophilic granuloma
Have the same histology : histiocytosis X (Lichtenstein 1953)
Have common features with the epidermal Langerhans cells
as the Birbeck granules in electron microscopy : Langerhans
cell histiocytosis

Histiocytosis X or Langerhans Cell Histiocytosis (LCH) is

characterized by a proliferation in various tissues of dentritic
cells of Langerhans type expressing several phenotypic markers
including CD1a and protein S100.
 Langerhans Cell Histiocytosis
Formerly considered as a reactive process

Now considered as a neoplastic proliferation

Recurrent BRAF (V600E) mutations are found in 60% of
LCH (also found in melanoma)
The LCH is due to a mutation in a myeloid precursor cell.
The more immature the cell at time of the mutation, the
greater chance for a more extensive disease :
Misguided myeloid differentiation hypothesis

BRAF and MAP2K1 mutations in Langerhans cell histiocytosis: a study of 50 cases.

Alayed K, Medeiros LJ, Patel KP and al. Hum Pathol. 2016 Feb 1.
 Langerhans Cell Histiocytosis
Epidemiology
LCH affects 4 to 8 children per million and 1 to 2
adults per million each year
Less cases in black, more in Hispanic population
Higher risk of LCH in poor socio-economic
circumstances and in crowded conditions
Most are diagnosed between September and
February (Sweden)
 Langerhans Cell Histiocytosis
Clinical presentation
Highly variable from a self-healing bone lesion to a severe life-
threatening multi-organ disease with 10 to 20% mortality.
In children the organs that are frequently involved are : firstly
bone (75%), then skin (34%) , lymph nodes, mastoids and ears,
bone marrow, spleen and liver, lung, post-pituitary (diabetes
insipidus) and lastly the gastro-intestinal tract.
In adults bone and lung (mainly in smokers)
Different risk groups :
Low risk : Skin and bone (and lung)
High risk : Risk organs (spleen, liver, bone marrow)
Central nervous system : LCH neurodegenerative disease
 Langerhans Cell Histiocytosis
Orthopedic lesions
Pain, soft tissue mass, pathologic
fracture (Vertebra plana)
Lytic bone lesions (Skull, femur,
maxillary, pelvis, ribs)
May mimic malignant bone tumors
Biopsy is mandatory (at the first
onset)
Ewing sarcoma
 Langerhans Cell Histiocytosis
Initial Staging : patient referral
Pediatric oncology team
Specialized adult department (national experts)
Physical examination
Skin, mucosae, lung, spleen and liver
Laboratory
Complete blood cell count, liver function tests
Bone marrow biopsy and aspiration in young patients
Imaging
Skeletal survey or PET
CT of the head
MRI of the brain in case of neurologic involvement
 Langerhans Cell Histiocytosis
Treatment
Stratified on the extent of the disease.
MDT discussion (national experts)
Single system diseases in which the prognostic is usually
excellent, require a minimal treatment (either no treatment or
only local therapy)
The multi-organ diseases are usually treated with
chemotherapy (weekly Vinblastine and steroids)
Mutation-specific targeted therapy is in development (BRAF
inhibitors in tumors with mutation)
Langerhans Cell Histiocytosis Treatment (PDQ): Health Professional Version. PDQ Pediatric Treatment Editorial
Board. PDQ Cancer Information Summaries . Bethesda (MD): National Cancer Institute (US); 2002-2016 Mar 30.
 Langerhans Cell Histiocytosis
Local treatment
Sometimes biopsy is sufficient
No surgical treatment in mechanically solid lesions
(with chemotherapy) or vertebra plana
 Langerhans Cell
Histiocytosis

Local treatment
Steroids injection
Curettage with or without grafting
Osteosynthesis
No radiation therapy
 Conclusion
In many of these lesions why do surgery ?
Medical treatments and interventional radiology
have so much progressed that surgery could be
avoided in many of the above conditions....
Surgical complications could be devastating for
the patient (and the surgeon)
Even in benign condition the approach
becomes multidisciplinary
 Conclusion
What would you prefer for your child ?