Bone or cartilage mass differential diagnosis

Jump to navigation Jump to search

Bone or Cartilage Mass Microchapters

Home

Patient Information

Overview

Classification

Causes

Differential Diagnosis

Epidemiology and Demographics

Screening

Diagnosis

Evaluation of Bone or Cartilage Mass

Staging

History and Symptoms

Physical Examination

Laboratory Studies

Imaging

Biopsy

Other Diagnostic Studies

Case Studies

Case #1

Bone or cartilage mass differential diagnosis On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Bone or cartilage mass differential diagnosis

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Bone or cartilage mass differential diagnosis

CDC on Bone or cartilage mass differential diagnosis

Bone or cartilage mass differential diagnosis in the news

Blogs on Bone or cartilage mass differential diagnosis

Directions to Hospitals Treating bone or soft tissue mass

Risk calculators and risk factors for Bone or cartilage mass differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]

Overview

Bone and cartilage tumors may be differentiated according to clinical features, laboratory findings, imaging features, histological features, and genetic studies, from other diseases that cause limited range of motion, limb deformity, bone pain, and local swelling.[1][2] Common differential diagnosis includes: osteoma, osteosarcoma, chondroma, chondrosarcoma, Ewing sarcoma, giant cell tumor, and metastases.

Common Differential Diagnosis

  • The table below summarizes common differential diagnosis of bone and cartilage tumors, that differentiate bone tumors according to type of tumor, age, location, histological features, imaging features, tissue of origin.
Type of tumor Age Location Histological features Imaging features Origin Bone/Cartilage
Osteoma 40-50 years Skull bones Matured lamellar bone Sclerotic Benign Bone
Osteoid osteoma 10-20 years Short and long bone diaphysis Osteiod outlined by osteoblasts, incorporated in a fibrous stroma Sclerotic Benign Bone
Osteosarcoma 11-40 years Long bones metaphysis Osteoid and bone formed of malignant osteoblasts and fibroblasts Sclerotic Malignant Bone
Chondroma 30-60 years Small tubular bones of the hands and feet Maturated hyaline cartilage (enchondroma/ecchondroma), preserving lobulation Well-defined Malignant Cartilage
Chondrosarcoma 30-60 years Long bones metaphysis, axial skeleton Immature cartilage, no preserving lobulation, cells arranged in groups of two or four, with atypia and mitosis Well-defined Malignant Cartilage
Ewing sarcoma 5-25 years Long bones diaphysis Small, round, undifferentiated cells, no stroma, a lot of capillary arrangement. Ill-defined Malignant Bone
Giant cell tumor 20-40 years Knee Multinucleated giant cells, fusiform cells, mononuclear cells. Well-defined Malignant Bone
Metastases 50-90 years No site predilection Frequently adenocarcinomas. Metastases can be blastic or lytic depending on the tumor origin Sclerotic Malignant Bone

Differential Diagnosis

  • The table below summarizes the findings that differentiate bone tumors according to clinical features, laboratory findings, imaging features, histological features, and genetic studies.
Disease Name History & Symptoms Physical Exam Lab Findings Imaging Findings Histologic Findings Genetic Studies
Adamantinoma
  • 20-30 yo males
  • Gradual dull bone pain at the tibial area
  • Leg swelling and tenderness
  • No specific lab findings
  • Well-demarcated, eccentric/epicenteric, expansile, osteolytic, cortical lesion on X ray
  • Located at the tibial diaphysis
  • Areas of lysis interspersed with areas of sclerosis
  • Lack of periosteal reaction
  • Biphasic tumor
  • Islands of epithelial cells found in a fibrous stroma
  • Fibro-osseous component includes spindle cells
  • Epithelial component includes nests of basaloid cells
  • p53 gene mutations
  • CK14 +ve
  • CK19 +ve
Ameloblastoma
  • 30-50 yo patients
  • Unerupted teeth
  • Oral ulcers
  • Painless mandibular mass
  • Lower jaw crepitus on palpation
  • Facial deformity
  • No specific lab findings
  • Multilocualted, expansile "soap-bubble" lesion, with well demarcated borders on X ray
  • Mixed solid and cystic pattern on MRI
  • Thick irregular wall, often with papillary solid structures projecting into the lesion on MRI
  • Tall columnar cells with a palisaded nuclei and reverse polarization
  • Subnuclear vacuolization
  • Giant cells
  • Subepithelial hyalinization
  • BRAF
  • V600E
Aneurysmal bone cyst
  • 10-20 yo patients
  • Gradual onset of bone pain
  • Limb swelling, tenderness, and warmth
  • Palpable lump
  • Restricted range of motion
  • No specific lab findings
  • Sharply defined, expansile osteolytic lesion on CT
  • Thin sclerotic margins
  • Air-fluid levels
  • Doughnut sign on bone scan
  • Bony trabeculae or osteoid tissue
  • Osteoclast giant cells
  • Benign spindle cells
  • Blood-filled spaces of variable sizes
  • Translocation t(16;17)(q22;p13)
Unicameral bone cyst
  • 10-20 yo patients
  • Asymptomatic
  • Pathologic fractures
  • Often unremarkable
  • No specific lab finding
  • Well defined geographic lucent lesions on Xray
  • Sclerotic margin
  • No periosteal reaction
  • Thinning of the endosteum and pseudotrabeculation
  • Cysts contain clear serosanguineous fluid
  • Fibrous membranous lining
  • TP53 mutations
Brown tumor
  • 40-50 yo females
  • History of hyperparathyroidism
  • Often unremarkable
  • Hyperparathyroidism
  • Well-defined, purely lytic lesions on X ray
  • Little reactive bone lesion
  • Solid, cystic, or mixed component on MRI
  • Fibrosis
  • Giant cells with round to oval nuclei and nucleoli
  • Elevated number of osteoblast and osteoclast
  • MEN1 gene
  • RET oncogene
Chondroblastoma
  • <20 yo males
  • Joint pain and muscle wasting
  • Bone tenderness and swelling
  • No specific lab finding
  • Well defined lucent lesions located at the epiphysis
  • Lobulated margins with a thin sclerotic rim
  • Internal calcifications
  • Joint effusion
  • Abundant extracellular material
  • Eosinophilic cytoplasm
  • Calcifications surround cells nests
  • Chickenwire appearance
  • S100+ve
  • Vimentin +ve
Chondromyxoid fibroma
  • Progressive bone pain
  • Bony swelling
  • Restricted range of movement in affected limb
  • Bone tenderness and swelling
  • No specific lab finding
  • Metaphyseal region of long bones
  • Lobulated, eccentric radiolucent lesion with a well defined sclerotic margin
  • No periosteal reaction
  • Presence of septations, pseudotrabeculation, and geographic bone destruction
  • Chondroid, myxoid, and fibrous tissue components
  • Spindle cells or stellate cells in a myxoid or chondroid stroma
  • Pseudolobulated architecture
  • Lobules with hypocellular centers and hypercellular peripheries
  • Scattered calcifications
  • SOX9 +ve
Chondrosarcoma
  • 50-70 yo males
  • Deep, achy, dull pain
  • Night time bone pain
  • Limited range of joints motion
  • Pathologic fracture
  • Palpable bony lump or local mass effect
  • No specific lab finding
  • Lytic intralesional calcification
  • Endosteal scalloping
  • Moth eaten appearance
  • Cortical remodelling, thickening and periosteal reaction
  • Bi-nucleation
  • Nuclear atypia with a hypochromatic enlarged nucleo
  • Infiltration of lamellar bone ("invasion")
  • Increased cellularity
  • S-100 +ve
  • Collagen II +ve
Desmoplastic fibroma
  • 20 yo patients
  • Painless, slowly growing mass
  • Palpable bony lump
  • No specific lab finding
  • Lytic bone lesions with geographic pattern of bone destruction on X ray
  • Located at metaphysis of long bones
  • Narrow zone of transition
  • Non-sclerotic margins
  • Internal pseudotrabeculation
  • Mature, bland fibroblasts
  • Little cellularity, no pleomorphism
  • Abundant collagenous stroma
  • Thin walled, dilated vascular channels
  • CD117
  • Beta-catenin
Enchondroma
  • 10-30 yo patients
  • Asymptomatic
  • Pathological fracture
  • Maffuci syndrome and Ollier disease
  • Widening of the bone
  • Limb-length discrepancy
  • Angular deformity
  • No specific lab finding
  • Located in the medullary cavity at the metaphyseal region of the hand bones
  • Small lytic lesions, sharply defined scalloped margin, and narrow zone of transition
  • Expansion of the overlying cortex with rings and arcs of calcifications
  • Lobules of hyaline cartilage
  • Surrounded by fibrous tissue and bone
  • Bony extension into the cartilage
  • Myxoid change, hypercellularity, and binucleation
  • Calcification, endochondral ossification, and necrosis
  • Ki-MCM6
Ewing sarcoma
  • 10-20 yo males
  • Extreme bone pain
  • Intermittent fever
  • Localized tenderness and swelling
  • Anemia and leukocytosis
  • Increased sedimentation rate
  • Large, poorly marginated tumor, located at the metaphysis
  • Destructive bone lesions on X ray
  • "Onion-skin" periosteal reaction
  • Sheets of round, uniform, PAS +ve, small cells with a scant clear cytoplasm
  • Round nuclei with indentations
  • Homer-Wright rosettes
  • Necrosis and hemorrhage
  • Prominent vasculature and variable mitotic figures
  • EWS/FLI-1 fusion gene
  • t(11;22)(q24;q12)
  • CD99 +ve
  • FLI-1 +ve
Fibrosarcoma
  • 30-60 yo males
  • Bone pain, progressive swelling, decreased range of motion
  • Pathologic fracture
  • Positive history of radiation exposure or bone infarct
  • Fixed, firm mass to a localized area of tenderness
  • Neurologic or vascular defect
  • No specific lab finding
  • Highly destructive with a wide zone of transition
  • Expansile large soft tissue mass extending from the bone
  • Periosteal reaction is uncommon
  • Elevated mitotic activity
  • Highly cellular fibroblastic proliferation
  • Herring bone pattern and spindle cell lesions
  • Long dark nuclei with increased granular chromatin
  • Scant cytoplasm
  • Vimentin +ve
Fibrous dysplasia
  • 10-20 yo patients
  • Asymptomatic
  • Incidental finding on imaging studies
  • Facial asymmetry, rib deformities, and leg-length discrepancy as late complication
  • No specific lab finding
  • Located at the craniofacial bones, ribs, and proximal femur
  • Ground-glass matrix
  • Completely lucent or bubbly cystic expansile benign lesion
  • Well circumscribed with no periosteal reaction
  • Fibrocellular matrix of immature collagen
  • Contains small irregularly shaped trabeculae of woven bone
  • "Chinese characters" appearance
  • Trabeculae not rimmed by osteoblasts
  • Cartilaginous islands
  • GNAS1 gene
Giant cell tumor
  • 20-30 yo female
  • Bone pain and swelling
  • Pathologic fracture
  • Paget disease of bone
  • Localised bone tenderness
  • No specific lab finding
  • Epiphyses of the femur
  • Solitary expansile eccentrically-placed lytic lesion
  • Intratumoral hemorrhage present
  • Tumor extends into the subchondral plate
  • Uniform and regular distribution of multinucleated giant cells and mononuclear stromal cells
  • Hemorrhage, necrosis, and hemosiderin deposition
  • Elevated mitotic figures
  • Acid phosphatase +ve
  • Alpha-1-antitrypsin +ve
  • Alpha-1-antichymotrypsin +ve
  • Ki-67 +ve
Ossifying fibroma
  • 1-5 yo children
  • Asymptomatic
  • Minority of cases may have bone pain, swelling, and pathological fractures
  • Painless, firm, swelling located at the anterior tibia
  • Anterior bowing of the tibia
  • No specific lab finding
  • Well-circumscribed lesion
  • Intracortical osteolysis
  • Sclerotic band (osteoblastic rimming)
  • Cortical expansion
  • Homogeneous lesion matrix
  • Fibrous proliferation of polyhedral, round, or spindle cells
  • Myxamatous matrix with calcifications
  • Psammomatoid growth patterns
  • Over expression of Runx2
Osteoblastoma
  • 20-30 yo males
  • Gradual, dull, and achy pain
  • Neurological deficit (cord compression)
  • Scoliosis and torticollis
  • No specific lab finding
  • Mainly located in the spine
  • Expansile lytic lesions with a rim of reactive sclerosis
  • Internal calcification
  • Cortical destruction, surrounding sclerosis, and periostitis
  • Secondary aneurysmal bone cyst
  • Trabeculae of woven and osteoid bones
  • Surrounded by a single layer of osteoblasts
  • Multiple osteoclasts
  • Loose fibrovascular stroma
  • Intralesional hemorrhage
  • p53 protein expression and high PCNA index.
Osteochondroma
  • < 20 yo males
  • Asymptomatic found incidentally on imaging
  • May have adjacent muscle soreness, pressure, or irritation with heavy exercising
  • Pathological fractures
  • Hard, immobile, painless palpable mass
  • Limited range of movements
  • No specific lab finding
  • Sessile or pedunculated lesion located at the metaphyseal region of the femur
  • Cartilage cap
  • Irregular subchondral bone
  • Projecting away from the epiphysis
  • Composed of bone, cartilage, and perichondrium
  • Pink fibrous capsule
  • Normal bony trabeculae
  • Absence of spindle cells
  • 8q24.1
  • 11p11-12
Osteoid osteoma
  • 10-35 yo males
  • Deep, constant, aching, localized bone pain
  • Pain worse at night
  • Pain relieved by aspirin
  • Restricted range of motion
  • No specific lab findings
  • Well circumscribed lucent cortical lesion located at the femur
  • Less than 2 cm in diameter with cortical thickening
  • Surrounded by reactive sclerosis
  • Ovoid central region of mineralisation
  • Anastomosing bony trabeculae
  • Sclerotic nidus of woven bone with variable mineralization
  • Osteoblast rimming
  • Highly vascularized, fibrous stroma
  • PTEN mutation
Osteosarcoma
  • 10-20 yo males
  • Bone pain and swelling
  • Pathologic fracture
  • History of Paget disease of bone or irradiation
  • Tender, warm, palpable mass
  • Limited range of motion
  • No specific lab findings
  • Metaphyseal regions of femur and tibia
  • Medullary and cortical bone destruction
  • Wide zone of transition with a moth-eaten appearance
  • Sunburst and codman triangle
  • Tumor matrix ossification/calcification
  • Hemorrhage, fibrosis and cystic degeneration
  • Areas of bone formation
  • Poorly formed trabecular bone
  • Cellular pleomorphism and mitoses
  • RB1 tumor suppressor gene
Plasmacytoma
  • 55-60 yo males
  • Back pain
  • Pathological fracture
  • Palpable vertebral mass
  • Palpable bony lump
  • Elevated monoclonal antibodies
  • Well-defined, “punched-out” lytic lesions
  • Marked erosion, expansion, and destruction of bone cortex
  • Thick ridging around the periphery
  • “Soap bubble” appearance
  • Atypical plasma cells
  • Unregulated expression of cMYC with KRAS12V in T2 B cells
Eosinophilic Granuloma
  • 5-10 yo males
  • Local bone pain
  • Failure to thrive
  • Spontenously resolve
  • Localized swelling and tenderness
  • ESR may be elevated
  • Ill-defined border, cortical destruction with aggressive periostitis
  • Punched out lytic lesions without sclerotic rim
  • "Hole within a hole" sign
  • Common locations include femur, skull, iliac bone, rib, vertebra
  • Langerhans cells histiocytes - key feature.
  • Elevated expression of p53, c-myc, and H-ras
Brodie abscess
  • 5-15 yo males
  • Nocturnal pain
  • Rapid response to analgesics
  • Mimics osteoid osteoma
  • Tender, localized and painful mass
  • Limited range of motion
  • Leukocytosis
  • Increased sedimentation rate
  • Lytic lesion often in an oval configuration
  • Surrounded by thick dense rim of reactive sclerosis
  • Lucent tortuous channel extending toward growth plate prior to physeal closure (pathognomonic)
  • Common location is the epiphysis long axis of long bones
  • Neutrophils, lymphocytes and plasma cells with bone necrosis and reactive new bone formation
  • There are no genetic studies associated
Osteoma
  • 20-35 yo females
  • Facial pain and headache
  • Related to familial syndromes (eg. Gardner syndrome)
  • Facial tenderness and cosmetic deformity
  • No specific lab findings
  • Well-defined, circumscribed mass with varying amounts of central lucency
  • Lobulated mass occupying frontal or maxillary sinus
  • Common location is facial skeletal bones
  • Presence of dense compact mature bone in paucicellular fibrous stroma.
  • APC gene mutation, present in multiple forms
Intraosseous lipoma
  • 5-85yo, males
  • Bone pain
  • Incidental finding
  • Localized tender mass in affected limb
  • No specific lab findings
  • Benign-appearing osteolytic bone lesion with well-defined margins.
  • Common location is the calcaneal bone, if found in long bones is located in the metaphysis
  • Mature adipocytes without admixed hematopoietic tissue or bony trabeculae
  • Translocation t(3;12)(q28;q14)
Enostosis
  • No age or gender predilection
  • Asymptomatic
  • Incidental finding
  • Often unremarkable
  • No specific lab findings
  • Bone-islands, typically less than 1 cm, "fingers" at the margins that blend with the surrounding trabeculae is a classic finding
  • Common predilection for diaphysis of long bones, pelvis, spine and ribs
  • Dense cortical like bone complete with haversian canals located within the spongiosa
  • Associated mutation is LEMD3 gene
Chordoma
  • 30-70 yo, no gender predilection
  • Slow growing tumor, commonly found in caucasians
  • Originate from embryonic remnants of the primitive notochord
  • Often unremarkable
  • No specific lab findings
  • Well-circumcised, lytic lesion with marginal sclerosis.
  • Intratumoral calfications
  • Distrubtion is along the axial skeleton
  • Common locations, include: sacrococcygeal, spheno-occipital: 30-35% vertebral bodies
  • Cords and lobules of physaliferous (having bubbles or vacuoles) cells separated by fibrous septa with extensive myxoid stroma
  • Associated with the duplication of T gene
Bone metastasis
  • No age or gender predilection
  • Often asymptomatic
  • Initial presentation may be a pathological fracture
  • Often unremarkable
  • Increased serum calcium and alkaline phosphatase
  • Increase in hydroxyproline excretion may also be present
  • Three-patterns may be observed: lytic, sclerotic, and mixed
  • Morphological characteristics may vary: expansile, focal or diffuse
  • Common locations, include: axial skeleton, and long bones
  • Stromal bone formation, descruction and ostoclast activation
  • Associated mutation will vary depending on primary tumor
Intraosseous ganglion
  • 30-50, no gender predilection
  • Mild localized pain
  • Origin due to a synovial herniation
  • Can be multiple or single
  • Often unremarkable
  • No specific lab findings
  • Subchondral radiolucent lesion without degenerative arthritis, often localized in the epiphyses of long bones (medial malleolus, femoral head, proximal tibia, carpal bones)
  • Uni-/multilocular cysts surrounded by a fibrous lining, containing gelatinous material
  • There are no genetic studies associated

Bone mass must be differentiated from other diseases that cause bone pain, edema, and erythema.

Disease Findings
Soft tissue infection
(Commonly cellulitis)
History of skin warmness, swelling and erythema. Bone probing is the definite way to differentiate them.[3][4]
Osteonecrosis
(Avascular necrosis of bone)
Previous history of trauma, radiation, use of steroids or biphosphonates are suggestive to differentiate osteonecrosis from ostemyelitis.[5][6]
MRI is diagnostic.[7][8]
Charcot joint Patients with Charcot joint commonly develop skin ulcerations that can in turn lead to secondary osteomyelitis.
Contrast-enhanced MRI may be diagnostically useful if it shows a sinus tract, replacement of soft tissue fat, a fluid collection, or extensive marrow abnormalities. Bone biopsy is the definitive diagnostic modality.[9]
Bone tumors May present with local pain and radiographic changes consistent with osteomyelitis.
Tumors most likely to mimic osteomyelitis are osteoid osteomas and chondroblastomas that produce small, round, radiolucent lesions on radiographs.[10]
Gout Gout presents with joint pain and swelling. Joint aspiration and crystals in synovial fluid is diagnostic for gout.[11]
SAPHO syndrome
(Synovitis, acne, pustulosis, hyperostosis, and osteitis)
SAPHO syndrome consists of a wide spectrum of neutrophilic dermatosis associated with aseptic osteoarticular lesions.
It can mimic osteomyelitis in patients who lack the characteristic findings of pustulosis and synovitis.
The diagnosis is established via clinical manifestations; bone culture is sterile in the setting of osteitis.
Sarcoidosis It involves most frequently the pulmonary parenchyma and mediastinal lymph nodes, but any organ system can be affected.
Bone involvement is often bilateral and bones commonly affected include the middle and distal phalanges (producing “sausage finger”), wrist, skull, vertebral column, and long bones.
Langerhans' cell histiocytosis The disease usually manifests in the skeleton and solitary bone lesions are encountered twice as often as multiple bone lesions.
The tumours can develop in any bone, but most commonly originate in the skull and jaw, followed by vertebral bodies, ribs, pelvis, and long bones.[12]

References

  1. Alina Maria Sisu. On the Bone Tumours: Overview, Classification, Incidence, Histopathological Issues, Behavior and Review Using Literature Data. http://www.intechopen.com/books/histopathology-reviews-and-recent-advances/on-the-bone-tumours-overview-classification-incidence-histopathological-issues-behavior-and-review Accessed on February 2, 2016
  2. Bone tumors. https://en.wikipedia.org/wiki/Bone_tumor Accessed on February 2, 2016
  3. Bisno AL, Stevens DL (1996). "Streptococcal infections of skin and soft tissues". N. Engl. J. Med. 334 (4): 240–5. doi:10.1056/NEJM199601253340407. PMID 8532002.
  4. Stevens DL, Bisno AL, Chambers HF, Dellinger EP, Goldstein EJ, Gorbach SL, Hirschmann JV, Kaplan SL, Montoya JG, Wade JC (2014). "Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America". Clin. Infect. Dis. 59 (2): 147–59. doi:10.1093/cid/ciu296. PMID 24947530.
  5. Shigemura T, Nakamura J, Kishida S, Harada Y, Ohtori S, Kamikawa K, Ochiai N, Takahashi K (2011). "Incidence of osteonecrosis associated with corticosteroid therapy among different underlying diseases: prospective MRI study". Rheumatology (Oxford). 50 (11): 2023–8. doi:10.1093/rheumatology/ker277. PMID 21865285.
  6. Slobogean GP, Sprague SA, Scott T, Bhandari M (2015). "Complications following young femoral neck fractures". Injury. 46 (3): 484–91. doi:10.1016/j.injury.2014.10.010. PMID 25480307.
  7. Amanatullah DF, Strauss EJ, Di Cesare PE (2011). "Current management options for osteonecrosis of the femoral head: part 1, diagnosis and nonoperative management". Am J. Orthop. 40 (9): E186–92. PMID 22022684.
  8. Etienne G, Mont MA, Ragland PS (2004). "The diagnosis and treatment of nontraumatic osteonecrosis of the femoral head". Instr Course Lect. 53: 67–85. PMID 15116601.
  9. Ahmadi ME, Morrison WB, Carrino JA, Schweitzer ME, Raikin SM, Ledermann HP (2006). "Neuropathic arthropathy of the foot with and without superimposed osteomyelitis: MR imaging characteristics". Radiology. 238 (2): 622–31. doi:10.1148/radiol.2382041393. PMID 16436821.
  10. Lovell, Wood (2014). Lovell and Winter's pediatric orthopaedics. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. ISBN 978-1605478142.
  11. Joosten LA, Netea MG, Mylona E, Koenders MI, Malireddi RK, Oosting M, Stienstra R, van de Veerdonk FL, Stalenhoef AF, Giamarellos-Bourboulis EJ, Kanneganti TD, van der Meer JW (2010). "Engagement of fatty acids with Toll-like receptor 2 drives interleukin-1β production via the ASC/caspase 1 pathway in monosodium urate monohydrate crystal-induced gouty arthritis". Arthritis Rheum. 62 (11): 3237–48. doi:10.1002/art.27667. PMC 2970687. PMID 20662061.
  12. Picarsic J, Jaffe R (2015). "Nosology and Pathology of Langerhans Cell Histiocytosis". Hematol. Oncol. Clin. North Am. 29 (5): 799–823. doi:10.1016/j.hoc.2015.06.001. PMID 26461144.