hemangioma, aneurysmal bone cyst, unicameral bone cyst ... aneurysmal bone cyst.pdf · introduction...

Hemangioma, Aneurysmal Bone Cyst, Unicameral Bone Cyst, Giant Cell Tumor,

& Langerhan’s Cell Histiocytosis

Eric MascardNecker University Hospital, 75015 Paris

Institut Gustave Roussy Villejuif, 94805 CedexClinique Arago, 75014 Paris, France

Introduction

• Hemangioma, Aneurysmal Bone Cyst, Unicameral Bone Cyst, Giant Cell Tumor, Langerhan’s 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 what’s 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):

http://www.ncbi.nlm.nih.gov/pubmed/22993209

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 entityErrani 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


• 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


• 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


• 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 withspecial 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


• 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


• Solid component in the tumor ?• MRI, cystography


• 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 "bluereticulated chondroid-like material" in aneurysmal bone cysts: a classichistopathologic 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


• Telangiectatic osteosarcoma– Biopsy is mandatory– Very confusing– Atypical cells and mitoses– Irregular osteoid matrix– No USP6 mutation

• Differential diagnosis : giant cell tumor– Exceptional in children– More epiphyso metaphysal– High expression of P63 and H3F3 A mutation– Possibly associated

ABC or GCT ?

7 y ≠ GCT



• 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


• 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 preoperativelyAneurysmal 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.


• 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 à 94% healing but no more available• Polidocanol (Aetoxysclérol ®)

– 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


• 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.

Frédéric 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, Fröhlich 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, Brosjö O. Orthop Rev(Pavia). 2015 Dec 28;7(4):6182.

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 mesenchymalstromal 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, Höcker S, Bovée 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 CellTumor 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.

Langerhan’s Cell Histiocytosis• It is known that :

– Letterer-Siwe disease (multi organ involvement)– Hand-Schüller-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 : Langerhan’scell histiocytosis

• Histiocytosis X or Langerhans Cell Histiocytosis (LCH) is characterized by a proliferation in various tissues of dentriticcells of Langerhans type expressing several phenotypic markers including CD1a and protein S100.

Langerhan’s 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.


• 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)

Langerhan’s 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 : firstlybone (75%), then skin (34%) , lymph nodes, mastoids and ears,bone marrow, spleen and liver, lung, post-pituitary (diabetesinsipidus) 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

Langerhan’s 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


• 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

Langerhan’s 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.

Langerhan’s Cell Histiocytosis• Local treatment

– Sometimes biopsy is sufficient– No surgical treatment in mechanically solid lesions

(with chemotherapy) or vertebra plana


• 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 ?

hemangioma, aneurysmal bone cyst, unicameral bone cyst ... aneurysmal bone cyst.pdf · introduction...

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