A step-by-step diagnostic algorithm of bone tumors and pseudo-tumors

A step-by-step diagnostic algorithm of bone tumors and pseudo-tumors Poster No.: C-2043 Congress: ECR 2017 Type: Educational Exhibit Authors: C. G. Iacoban, S. Manole, G. Pervain, M. Mereuta ; Baia Mare/ 1 2 2 2 1 2 RO, Cluj-Napoca/RO Keywords: Neoplasia, Education, MR, CT, Conventional radiography, Musculoskeletal bone DOI: 10.1594/ecr2017/C-2043 Any information contained in this pdf file is automatically generated from digital material submitted to EPOS by third parties in the form of scientific presentations. References to any names, marks, products, or services of third parties or hypertext links to thirdparty sites or information are provided solely as a convenience to you and do not in any way constitute or imply ECR's endorsement, sponsorship or recommendation of the third party, information, product or service. ECR is not responsible for the content of these pages and does not make any representations regarding the content or accuracy of material in this file. As per copyright regulations, any unauthorised use of the material or parts thereof as well as commercial reproduction or multiple distribution by any traditional or electronically based reproduction/publication method ist strictly prohibited. You agree to defend, indemnify, and hold ECR harmless from and against any and all claims, damages, costs, and expenses, including attorneys' fees, arising from or related to your use of these pages. Please note: Links to movies, ppt slideshows and any other multimedia files are not available in the pdf version of presentations. www.myesr.org Page 1 of 67

Learning objectives 1. Review and reinforcement of the diagnostic algorythm of bone tumors and pseudotumors. 2. Appropriate discrimination of benign versus malignant bone entities via a radiographic checklist. 3. Assessment of the benefits of CT, MR, scintigraphy, SPECT-CT and PET-CT in the evaluation of skeletal neoplasms. Background Differentiation of benign and malignant bone entities requires a thorough analysis of the clinical setting and of the radiographic features, in a highly organized fashion that requires following certain steps. STEP 1 - AGE The AGE of the patient is of utmost importance. Bone tumors have a predilection for specific age groups, and while some are more often seen in younger individuals, others are more commonly encountered in older patients. However, ages should be regarded as approximate, as there can be exceptions. (Tab.1.) TUMOR/PSEUDOTUMOR AGE (years) Enchondroma 20-50 Chondrosarcoma >50 Osteochondroma 10-30 Osteoid osteoma 10-30 Osteosarcoma 10-14, >65 Ewing sarcoma 0-29 Nonossifying fibroma 20-30 Fibrous dysplasia 20-40 Simple bone cyst 10-20 Giant cell tumor 20-40 Page 2 of 67

Adamantinoma 20-30 Myeloma >40 Metastases >40 Paget disease >40 Tab.1. Age peaks of neoplastic and non-neoplastic bone diseases On conventional radiographs, tumor location, morphology and local extension should be regarded in detail. STEP 2 - LOCATION Propensity for the axial or appendicular skeleton, as well as for certain parts of the bone (epiphysis, metaphysis or diaphysis) further narrow down the differential diagnosis. (Tab.2. and Tab.3.) STEP 2.A - SKELETON PROPENSITY TUMOR/PSEUDOTUMOR SKELETAL DISTRIBUTION Enchondroma peripheral Chondrosarcoma axial Osteochondroma peripheral Osteoid osteoma peripheral Osteosarcoma peripheral Ewing sarcoma peripheral Nonossifying fibroma peripheral Fibrous dysplasia axial/peripheral Simple bone cyst peripheral Giant cell tumor peripheral Adamantinoma peripheral Myeloma axial/peripheral Metastases axial/peripheral Paget's Disease axial/peripheral Tab. 2. Distribution of bone tumors and pseudotumors throughout the skeleton Page 3 of 67

STEP 2.B - IN-BONE PROPENSITY TUMOR/PSEUDOTUMOR LOCATION WITHIN BONE Enchondroma Metaphysis Chondrosarcoma Metaphysis Osteochondroma Metaphysis Osteoid osteoma Diaphysis Osteosarcoma Metaphysis Ewing sarcoma Diaphysis Nonossifying fibroma Metaphysis Fibrous dysplasia Metadiaphysis Simple bone cyst Metadiaphysis Giant cell tumor Metaphysis Adamantinoma Diaphysis Myeloma Unspecific Metastases Unspecific Paget's Disease Epiphysis with metadiaphyseal extent Tab. 3. Intraosseous propensity of bone tumors and pseudotumors STEP 3 - RADIOGRAPHIC FEATURES The presence or absence of a marginal sclerotic rim, particular aspects of matrix mineralization (osteoid, chondral or fibrous) and the type of periosteal reaction (unilamellar, plurilamellar, spiculated) help us go for a specific diagnosis. STEP 3.A - PATTERN DESTRUCTION - DELINEATION - CONTOUR Tumor agressiveness and the likelihood of malignancy can be assessed by evaluating the tumor delineation/contour. The presence of a marginal sclerosis can be a marker of benignity. In slow growing neoplasms there is enough time for the host bone to create a sclerotic border surrounding the tumour, whereas in malignant neoplasms with fast doubling times, there is a poorly defined and visualised margin between cancerous and non-cancerous tissue.tumor delineation is therefore a reflection of the rate of growth. (Tab.4.) Page 4 of 67

TYPE OF DELINEATION GROWTH RATE 1A Well defined, sclerotic rim Indolent 1B Well defined, NO sclerotic Active tumor rim 1C Less sharp defined, NO Agressive tumor sclerotic rim 2 Moth-eaten Rapidly growing, malignant 3 Permeative Tab. 4. Lesion contour/delineation Rapidly growing, malignant STEP 3.B - TUMOR MATRIX Matrix mineralisation provides a prediction pattern for certain histologic cell types. Chondral calcification manifests as "rings-and-arcs", flocculent or "popcorn-like" calcifications. Osseous matrix has a "fluffy" or "cloud-like" aspect and is poorly defined. Fibrous tumours have a characteristic "ground glass appearance". (Tab.5.) MATRIX MINERALISATION APPEARANCE CHONDROID "Rings-and-arcs" OSTEOID "Cloud-like" FIBROID "Ground glass" Tab. 5. Matrix mineralisation patterns STEP 3.C - PERIOSTEAL REACTION Periosteal reactions, though non-specific, provide another discernment tool for cathegorizing tumor agressiveness.(tab.6.) TYPE OF PERIOSTEAL REACTION NEOPLASM CATHEGORY Solid layered Benign Single-layered Benign Multiple-lamellated Benign/malignant Spiculated "hair on end" Malignant Buttress Malignant transformation Page 5 of 67

Codman triangle Tab. 6. Periosteal reaction types Malignant STEP 3.D - SOFT TISSUE EVALUATION Local extension in the soft tissues further dichotomises lesions as probably benign or probably malignant. Cross-sectional imaging (CT and MR), scintigraphy, as well as hybrid imaging methods, such as PET-CT, play a significant role in the evaluation of the extent of the disease. STEP 4 - CROSS-SECTIONAL IMAGING Fine bone textural changes are better evaluated with CT, while local invasion and "skip metastasis" are better assessed with MRI. STEP 5 - FUNCTIONAL IMAGING Generally, functional nuclear medicine procedures have a limited role in evaluation of primary bone tumors, though they are substantially useful in detecting metastasis, following up the response to therapy and estimating prognosis. Nuclear medicine procedures that involve imaging of bone tumors utilize 99mTc-HDP, I-123 or I-131 MIBG, Ga-67, Thallium-201, 99mTc-MIBI, and PET imaging. (Tab. 7.) The nuclear medicine bone scan is a versatile tool because of its high sensitivity for different bone lesions, as well as its ability to image the entire skeleton in a single examination, at a reasonable cost. Bone scintigraphy remains popular despite technological advances in MRI, CT and PET. Because of the low specificity of bone scan, it is essential to make clinical and radiographic correlation, when needed. In addition, the development of single-photon emission computed tomography (SPECT) and hybrid SPECT/CT has improved sensitivity and specificity. (Tab.7.) UPTAKE HIGH UPTAKE MODERATE UPTAKE LOW UPTAKE DEGREE Aneurysmal cyst bone Enchondroma Simple bone cyst (donut sign pattern) Page 6 of 67

Giant cell tumour Nonossifying fibroma Fibrous dysplasia Osteoid osteoma Osteochondroma - variable uptake Tab. 7. Benign bone lesions on skeletal scintigraphy Findings and procedure details I. ENCHONDROMA Enchondroma is a hamartomatous, pseudo-tumorous lesion that is the result of the displacement of physis "reliques" into the metaphysis during embryonic and postembryonic development. It is usually an incidental finding, or revealed by pathologic fracture. DIAGNOSTIC ALGORYTHM STEP 1 - Age: 14 months - 90 years STEP 2 - Location 2A. Skeleton propensity in order of frequency:1. short tubular bones, 2. long tubular bones, 3. axial skeleton (only 4%); location complementary to chondrosarcoma (which in turn has a tendency to arise in the axial skeleton). 2B. Bone propensity: metaphysis (+/- diaphysis); centric location STEP 3 - Radiographic features: In short tubular bones the aspect is usually lytic, with a thin sclerotic rim and typical chondral calcifications; cortex destruction may be present. In long tubular bones enchondroma is characterised by the presence of dense chondrogenic calcifications, masking an underlying destructive process. Pathologic or insufficiency fracture can be present in both cases. Fig. 1 on page 20 STEP 4 - Cross-sectional imaging CT: improved assessment of the cortex and tumour matrix; usually not required Page 7 of 67

MR: lobular aspect; T2 hiperintensity, T1 iso/hypointensity; T1 C+ "rings and arcs" contrast uptake coresponding to fibrovascular septae between the cartilaginous lobules, T1 and T2 low signal if severe calcification is present; not required STEP 5 - Functional imaging: Increased radiotracer uptake can be seen, more intense in case of pathological fracture or oedostosis. Bone scan may help identify multiple lesions, but the role is otherwise very limited. Fig. 2 on page 22 Fig. 3 on page 24 II. OSTEOCHONDROMA Osteochondroma (syn. exostosis) is another hamartomatous bone lesion, resulting from bone surface displacement of physis rests during bone growth. Pathologically it is comprised of two components: a bony protusion (either pedunculated or sessile) having direct cortical and medullary continuity, crowned by a cartilaginous cap. DIAGNOSTIC ALGORYTHM STEP 1 - Age: 0-30 years STEP 2 - Location 2A. Skeleton propensity: 1. long tubular bones (more often around the knee), 2. flat bones (scapula, ileum) 2B. Bone propensity: metaphysis; the pedunculated type displays epiphysis to diaphysis growth direction STEP 3 - Radiographic features: bony protrusion directly cohesive to the cortex and medulla of the host bone. If present, matrix calcification evokes the cartilage cap Fig. 4 on page 24 STEP 4 - Cross-sectional imaging CT: shows linkage to parent bone in complex anatomical regions MR: depicts cartilaginous cap thickness (cut-off at 2 cm in skeletally mature patients), useful in the evalution of malignant transformation; it also shows bursitis and neobursa formation STEP 5 - Functional imaging: useful in detecting sarcomatous degeneration, particularly in osteochondromatosis (hereditary multiple exostosis - HME). Page 8 of 67

Osteochondromas may show variable uptake that decreases with advancing age. Although bone scan can exclude malignancy if no increased uptake is seen, the presence of increased activity does not differentiate benign from malignant lesions. Any new uptake in a lesion that previously had none, is suspicious. Fig. 5 on page 25 Fig. 6 on page 27 III. CHONDROSARCOMA Chondrosarcoma is the malignant counterpart of enchondroma/osteochondroma, being the third most common malignant bone tumour behind myeloma and osteosarcoma. It can be primary or secondary to a benign precursor lesion. DIAGNOSTIC ALGORYTHM STEP 1 - Age: > 50 years, peak in the 6th decade STEP 2 - Location 2A. Skeleton propensity: axial skeleton: 1. pelvis, 2. proximal femur, 3. proximal humerus, 4. distal femur, 5. ribs; peripheral skeleton: exceptional! short tubular bones of the hand and feet 2B. Bone propensity: metaphysis/metadiaphysis STEP 3 - Radiographic features: osteolytic to moth-eaten destruction pattern, showing chondroid calcification. Cortical scalloping, perforation or thickening, complete/ incomplete periosteal reaction as well as soft tissue involvement can be present. Pathological fracture is not infrequent. Fig. 7 on page 27 STEP 4 - Cross-sectional imaging CT: better assessment of matrix calcification, periostosis and architectural bone distorsions MR: T2 WI lobular hyperintensity, rings and arcs contrast uptake matching fibrovascular septae STEP 5 - Functional imaging: intense radiopharmaceutical uptake is seen with chondrosarcoma; differential diagnosis enchondroma vs. low-grade chondrosarcoma: the latter shows lower intensity uptake. Page 9 of 67

IV. OSTEOID OSTEOMA Osteoid osteoma is a benign osteoid-forming tumour, characterized by a radiotransparent nidus (the lesion itself), surrounded by a solid, fusiform, sclerotic cortical thickening in the shaft of a long bone, with "limited growth potential and disproportionate pain" that worsens at night. DIAGNOSTIC ALGORYTHM STEP 1 - Age: 5-40 years STEP 2 - Location 2A. Skeleton propensity: 1. long bones (femur, tibia), 2. spine, hand, foot 2B. Bone propensity: diaphyseal, metadiaphyseal STEP 3 - Radiographic features: a radiolucent/partially mineralised nidus (which represents the lesion itself) is usually present and is surrounded by a dense, reactive sclerosis. Solid periosteal reactional, or sometimes even lamellated periostosis may be present. Fig. 8 on page 29 STEP 4 - Cross-sectional imaging CT: useful in complex anatomical regions; the nidus presents as a low attenuating round lesion surrounded by intense osteosclerosis; matrix mineralisation is much better evaluated MR: T1 WI shows intermediate signal; fluid sensitive sequences show intermediate to high signal intensity; sclerosis appears hypointense, whereas surrounding bone marrow oedema appears as hyperintense STEP 5 - Functional imaging: has high sensitivity, presenting focal intense radiopharmaceutical uptake due to reactive hyperemia; it is particularly useful in atypical and symptom-free cases. An intraoperative gamma probe can be used to localize the lesion. Fig. 9 on page 29 Fig. 10 on page 31 V. CONVENTIONAL OSTEOSARCOMA Conventional osteosarcoma is the most common bone primary malignancy, behind multiple myeloma, composed of immature osteoid mesenchymal cells. Page 10 of 67

DIAGNOSTIC ALGORYTHM STEP 1 - Age: 2nd and 3rd decades, the majority within 15-25 years STEP 2 - Location 2A. Skeletal propensity: 1. long bones, usually about the knee (femur, tibia, humerus) 2. pelvis, fibula, facial bones, spine 2B. Bone propensity: metaphysis, later on, involvement of the entire width of the bone STEP 3 - Radiographic features: "fluffy, cloud-like cumulous" opacities within the lesion (osseous matrix calcification). In some cases, the appearance may be entirely lytic or sclerotic, but a mixture of both lysis and sclerosis is characteristic in the majority of the cases. Cortex penetration associated with different types of periosteal reaction (Codman triangle, lamellated, spiculated or sunburst) is the marker of high-grade agressiveness. Soft tissue-involvement is usually present. Fig. 11 on page 31 Fig. 12 on page 33 Fig. 13 on page 34 STEP 4 - Cross-sectional imaging CT: better assessment of matrix mineralisation and architectural changes; useful in complex anatomical regions MR: modality of choice for preoperative evaluation, T1 -intermediate signal, T2- high signal; hypointensity in both T1 and T2 is reflecting matrix mineralisation; hemorrhage - high signal in T1, necrosis (low T1/high T2 signal intensity); invasion of soft-tissues; Fig. 14 on page 35 STEP 5 - Functional imaging: marked radiopharmaceutical uptake is seen within the lesion. Scintigraphy also evaluates metastases. Fig. 15 on page 35 Fig. 16 on page 36 Fig. 17 on page 37 Fig. 18 on page 38 VI. EWING SARCOMA Ewing sarcoma is a malignant bone tumour of neuroectodermal origin usually found in the diaphysis of long bones. STEP 1 - Age: 5-25 years STEP 2 - Location Page 11 of 67

2A. Skeleton propensity: 1. long bones of the lower extremity (femur!), 2. ilium, spine, sacrum, scapula, ribs, clavicle 2B. Bone propensity: metadiaphysis, diaphysis STEP 3 - Radiographic features: usually a poorly defined, lytic, permeative lesion, with lamellated periosteal reaction (onion skin) or spiculated periostosis and soft-tissue involvement (the later is usually underestimated on plain radiographs). A sclerotic matrix mineralisation is usually found. Fig. 19 on page 39 Fig. 20 on page 40 STEP 4 - Cross-sectional imaging CT: is advantageous in complex anatomical regions such as the pelvis and spine, providing a better assessment of the structural changes and of the matrix. Fig. 21 on page 42 MR: preffered method of evaluating the local extension STEP 5 - Functional imaging: useful in evaluating metastatic disease, avid uptake of the boneseeking radiopharmaceuticals ( Fig. 22 on page 42 ). PET-CT is superior to scintigraphy due to increased spatial resolution and detection of non-osseous metastases. VII. NONOSSIFYING FIBROMA Nonossifying fibroma is a frequent benign tumour of fibrous origin. DIAGNOSTIC ALGORYTHM STEP 1 - Age: 2-20 years STEP 2 - Location 2A. Skeleton propensity: 1. long tubular bones (femur, tibia), 2. mandible (unusual) 2B. Bone propensity: metaphyseal STEP 3 - Radiographic features: metaphyseal well-defined, lytic lesion with sclerotic rim, involving the cortex and medulla, sometimes having a multiloculated/septated appearance Fig. 23 on page 44 STEP 4 - Cross-sectional imaging Page 12 of 67

CT: soft tissue density is seen within the lytic lesion MR: T1 WI isointense with the muscle; T2 hyperintensity STEP 5 - Functional imaging: usually no uptake; mild uptake in lesions that already healed and moderate uptake in lesions during healing (filling with normal bone). VIII. FIBROUS DYSPLASIA Fibrous dysplasia is a benign fibroosseous lesion composed of woven bone and fibrous stroma. There are two types: monostotic and polyostotic. DIAGNOSTIC ALGORYTHM STEP 1 - Age < 30 years STEP 2 - Location 2A. Skeleton propensity - monostotic form: 1. Ribs; 2. Proximal femur; 3. Tibia, craniofacial bones, humerus; polyostotic form: unilateral and monomelic: 1. Femur; 2. Tibia; 3. Pelvis; 4. foot 2B. Bone propensity: metadiaphyseal STEP 3 - Radiographic features the lesions may be either transparent or sclerotic, are well circumscribed, sometimes surrounded by a sclerotic rim, having a ground glass matrix. No periosteal reaction is found. Fig. 24 on page 44 STEP 4 - Cross-sectional imaging CT: ground glass aspect, cystic or sclerotic, well defined, producing bone expansion, endosteal scalloping may be present MR: the aspect is highly heterogeneous and nonspecific STEP 5 - Functional imaging shows increased uptake that remains active during advancing in age. The degree of increased tracer uptake is typically high, resembling Paget disease. Distinguishing features are the age of the patients and different patterns of involvement. When Paget disease involves a long bone, it extends to at least one end of the bone, whereas fibrous dysplasia frequently does not involve the epiphysis. Fig. 25 on page 45 Fig. 26 on page 47 IX. SIMPLE BONE CYST Page 13 of 67

Simple bone cyst (unicameral bone cyst/essential bone cyst) is a common benign lesion of the bone. DIAGNOSTIC ALGORYTHM STEP 1 - Age: usually 9-20 years, can also be found in adults STEP 2 - Location 2A. Skeleton propensity: 1. proximal humerus, 2. proximal femur 3. pelvis, forearm, craniofacial skeleton, spine 4. calcaneum in adults 2B. Bone propensity: metaphysis, adjacent to the open physis STEP 3 - Radiographic features: centric osteolysis, well defined, with sclerotic margins, located within the metaphysis of proximal humerus and femur. A fallen fragment sign can be present due to pathological fracture and usually marks the inferior pole of the cyst. Endosteal scalloping can be present. No matrix mineralisation or periosteal reaction is found. Fig. 27 on page 47 STEP 4 - Cross-sectional imaging CT: more clearly defined radiographic features MR: T1: hypointensity (hyperintensity if proteinaceous content), T2 hyperintensity, T1 C+ peripheral rim enhancement STEP 5 - Functional imaging: mild peripheral tracer uptake, with central photopenia, increased uptake if fracture is present. Fig. 28 on page 49 Fig. 29 on page 51 X. GIANT CELL TUMOR Giant cell tumour is a frequent, locally agressive bone tumor composed predominantly of multinucleated giant cells that resemble osteoclasts. DIAGNOSTIC ALGORYTHM STEP 1 - Age: 20-50 years Page 14 of 67

STEP 2 - Location 2A. Skeleton propensity: 1. long bones (usually around the knee) - distal femur, proximal tibia, distal radius, proximal humerus, 2. sacrum, proximal humerus, proximal femur, innominate bone, vertebral bodies, distal tibia, proximal fibula, hand/wrist, foot 2B. Bone propensity: metaphysis with extension to subarticular bone STEP 3 - Radiographic features: the lesions are typically osteolytic, eccentric, welldefined, showing a geographic pattern of destruction, with a narrow zone of transition and no sclerotic rim; the lesion is expansile in most of the cases. The tumor may show cortex penetration, sometimes even periosteal reaction and soft tissue involvement; pathological fracture may be present; it may show pseudotrabecullation due to endosteal scalloping, resembling soap-bubbles. Fig. 30 on page 51 STEP 4 - Cross-sectional imaging CT: better assessment of tumor delineation, cortical thinning and penetration, periosteal reaction and absence of matrix calcification MR: better evaluation of soft tissue involvement STEP 5 - Functional imaging: scintigraphy shows peripheral radiopharmaceutical uptake, with photopenia in the center, creating the "doughnut sign", in the vast majority of cases. XI. ADAMANTINOMA Adamantinoma is an uncommon malignant bone tumor with low agressiveness, comprising both osteofibrous and epithelial components. DIAGNOSTIC ALGORYTHM STEP 1 - Age: average at 30 years STEP 2 - Location 2A. Skeleton propensity: 1. tibia, 2. fibula, 3. humerus, 4. femur 2B. Bone propensity: diaphysis, intracortical STEP 3 - Radiographic features: In the majority of cases the lesion is situated in the tibial diaphysis, is intracortical (involving the anterior cortex), is eccentric and expansile Page 15 of 67

and presents as a multilocular osteolytic lesion, creating a "soap bubble"appearance. Fig. 31 on page 52 STEP 4 - Cross-sectional imaging CT: better depicts the structural changes MR: T1 hypointensity, T2 hyperintensity, T1 C+ intense Gadolinium uptake STEP 5 - Functional imaging: shows increased tracer uptake in the lesion. XII. MYELOMA Multiple myeloma (plasma cell myeloma) is the most common primary bone neoplasm of haematopoetic origin having B-lymphocyte origin. The disease converges osteolytic lesions, bone pain, hypercalcemia, monoclonal immunoglobulins and amyloid deposition disease. The diagnosis is made by serum and urine immunoglobulin levels, bone marrow biopsy and lytic bone lesions integrated in adequate clinical context. DIAGNOSTIC ALGORYTHM STEP 1 - Age: 6th-7th decades STEP 2 - Location Skeletal and bone propensity:!bones containing red marrow: vertebrae, ribs, skull, pelvis, femur, clavicle, scapula STEP 3 - Radiographic features: include osteopenia, osteolytic lesions that are "punched-out" or expansile, mixed or even sclerotic lesions (POEMS), pathological fracture. Fig. 32 on page 53 STEP 4 - Cross-sectional imaging CT: better assessement of cortical thining and fractures MR: useful in evaluation of the extent of the disease STEP 5 - Functional imaging: scintigraphy has low sensitivity in the detection of myelomatous lesions. PET-CT detects bone involvement in 25% of newly diagnosed patients with negative skeletal surveys and extramedullary involvement in up to 25%. Page 16 of 67

XIII. METASTASES Skeletal metastases comprise the spread of malignant cells from one site to another within the body. Most common primary tumors that metastasize to the bone are lung cancer, breast cancer, nephrocarcinoma and prostate cancer. DIAGNOSTIC ALGORYTHM STEP 1 - Age: any STEP 2 - Location Skeletal propensity:!red marrow involvement: vertebrae, pelvis, proximal femur, proximal humerus, skull STEP 3 - Radiographic features: depending on the predominant process (bone resorption or bone formation) they can be classified as lytic, sclerotic or mixed. (Tab. 1) In order to be visible on plain radiographs, bone mineral loss of aproximately 50% is required. Fig. 33 on page 54 LYTIC LESIONS SCLEROTIC LESIONS MIXED LESIONS Tthyroid carcinoma Prostate Breast carcinoma Nephrocarcicoma Breast cancer Lung carcinoma Pheocromocytoma Transitional cell carcinoma Cervical cancer Endometrial carcinoma Carcinoid Testicular tumors Gatrointestinal carcinomas Medulloblastoma Prostate carcinoma Ewing sarcoma Neuroblastoma After treatment Melanoma Mucinous tumors HCC Lymphoma gastrointestinal Squamocellular carcinoma Tab. 1. Metastatic lesion types STEP 4 - Cross-sectional imaging Page 17 of 67

CT: best for evaluating bone involvement and for identifying pathological fractures Fig. 34 on page 55 MR: not widely used STEP 5 - Functional imaging: scintigraphy is a highly sensitive routine imaging for the detection of both lytic and sclerotic metastases. They can appear as increased uptake foci, isointense or even as photopenic defects (Tab. 2). Other problematic scintigraphic patterns are the so-called "superscan" appearance when the involvement is extensive and diffuse and the "flare phenomenon" in patients undergoing cyclical chemotherapy (the bone scan may paradoxically worsen in cases with good response to therapy) (Tab. 3). Fig. 35 on page 57 Fig. 36 on page 57 Fig. 37 Fig. 38 "HOT" METASTASES "COLD" METASTASES ISOINTENSE METASTASES Breast cancer Renal cell carcinoma Renal cell carcinoma Lung cancer Thyroid carcinoma Thyroid carcinoma Prostate cancer Anaplastic neoplasms Anaplastic neoplasms Transitional cell carcinoma Neuroblastoma Neuroblastoma Colorectal cancer Multiple myeloma Medulloblastoma Reticulum cell sarcoma Osteosarcoma Langerhans cell histiocytosis Carcinoid Lymphoproliferative disease (lymphoma, leukemia) Lymphoma Tab. 2. Skeletal metastases uptake on bone scans Unique focal lesions Multiple focal lesions Diffuse metastatic process - the so-called "superscan" Photon-deficient metastases - cold lesions Normal (false negative) Flare reaction (on follow-up scans) Soft tissue lesions (radiopharmaceutical uptake in tumor) Tab. 3. Scintigraphic patterns in bone metastases Page 18 of 67

XIV. PAGET'S DISEASE OF THE BONE Paget's disease of the bone is a chronic bone disease due to hyperactivity of osteoclasts and osteoblasts resulting in abnormal bone remodelling (syn. osteitis deformans) DIAGNOSTIC ALGORYTHM STEP 1 - Age: over 40 years STEP 2 - Location 2A. Skeletal propensity: 1. spine, 2. pelvis 3. skull, 4. tibia, femur, humerus 2B. Bone propensity: epiphyseal with metadiaphyseal extension in long bones STEP 3 - Radiographic features: the aspect of the disease is highly dependent on whether the lesion is in the incipient active phase (usually lytic aspect), active (mixed aspect) or late inactive (sclerotic or blastic aspect) phase. In the skull the aspect is of lytic well defined lesions - osteoporosis circumscripta (I phase), mixed sclerotic/lytic lesions - "cotton wool" appearance (II+III phase). Diploic space widening has also been reported and also the Tam o'shanter sign (= platybasia + enlargement of the cranium). In the vertebrae the aspect can be of a picture frame vertebra with hyperostosis due to marginal sclerosis and later on, Paget's disease cand be a cause of ivory vertebra. In the pelvis, thickening of the iliopectineal and iliopubic lines is characteristic. In the long bones the lytic lesion begins in the subchondral space developing toward the diaphysis where it is very well separated from adjacent healthy bone in the form of letter V - the so-called "blade of grass" or "candle flame" sign. Hyperostosis due to cortical thickening and thickening of bone trabeculae results in bowing of the long bones (lateral curvature of the femur, anterior curvature of the tibia). Fig. 39 on page 60 STEP 4 - Cross-sectional imaging CT: better depicts architectural changes in the bone MR: fatty signal in early phase, T1 WI hypointesity + T2 hyperintensity in the middle phase, low T1+T2 in the end phase corresponding to blastic changes. T1 C+ foci of increased uptake are characteristic and are a marker of disease activity. STEP 5 - Functional imaging: The scintigraphic appearance is striking, with intensely increased radiotracer uptake, seen in all phases of the disease. The bone expansion is Page 19 of 67

also suggested on bone scans. As a characteristic feature, when Paget disease involves a long bone, it extends to at least one end of the structure. Bone scan is also useful to evaluate the extent of disease. Fig. 40 on page 61 Fig. 41 on page 62 Images for this section: Page 20 of 67

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Fig. 1: a,b. enchondroma of the distal phalanx in the 4th finger of the left hand showing an expansile lytic lesion, showing no matrix mineralisation; c,d. same aspect of an enchondroma of the middle phalanx; e. enchondroma of the proximal left humerus displaying chondrogenic matrix calcifications, masking the subjacent lytic lesion. Department of Radiology, Orthopedics and Trauma Hospital, Cluj-Napoca; Department of Radiology, Cluj-Napoca County Hospital, Cluj-Napoca/Romania Page 22 of 67

Fig. 2: 99mTc-HDP whole body bone scan - multiple focal areas of increased radiotracer uptake corresponding to inflammatory poliarticular lesions, located at the costovertebral joints - dorsal spine, joints of the hands, knees, tibiotarsal joints bilateral and left tarsal Page 23 of 67

joints; suspicious high radiotracer focal uptake at the right femural neck - lesser trochanter area. SPECT/CT was performed at this level (Fig. 3). A case of enchondroma. Nuclear Medicine Laboratory - Cluj-Napoca County Hospital, Cluj-Napoca/Romania Fig. 3: SPECT/CT of the pelvis showing a litical bone lesion with interior septae and calcifications, sclerotic contour, periostal reaction, measuring 4,5 cm in long axis, with partial high uptake of the radiotracer, extending from the right femoral neck to the right lesser trochanter, suggestive for enchondroma. Nuclear Medicine Laboratory - Cluj-Napoca County Hospital, Cluj-Napoca/Romania Page 24 of 67

Fig. 4: a. AP radiograph of the right knee showing a bony projection on the lateral aspect of the fibula that shows cortical and medullary coherence with the parent bone corresponding to an osteochondroma (exostosis). b. postoperative radiograph showing complete resection of the tumour. Department of Radiology, Orthopedics and Trauma Hospital, Cluj-Napoca/Romania Page 25 of 67

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Fig. 5: 99mTc-HDP whole body bone scan - area of increased radiotracer uptake in the right proximal humerus. SPECT/CT of the thorax was performed (Fig. 6). Right humerus osteochondroma. Nuclear Medicine Laboratory - Cluj-Napoca County Hospital, Cluj-Napoca/Romania Fig. 6: SPECT-CT of the upper thorax, showing an osteolytic bone tumor, with extraosseous growth, inhomogeneous, with increased radiotracer uptake in the inferior and in the extra-osseous areas, localised at the level of the right humeral metaphysis. Mild reactive radiotracer uptake at the level of the right humeral head and the right scapulohumeral joint. Right humerus osteochondroma. Nuclear Medicine Laboratory - Cluj-Napoca County Hospital, Cluj-Napoca/Romania Page 27 of 67

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Fig. 7: a,b. Left proximal humerus chondrosarcoma - radiograph showing a metaphyseal lytic lesion with marked chondral calcifications and associated pathological fracture Department of Radiology, Orthopedics and Trauma Hospital, Cluj-Napoca/Romania Fig. 8: a,b. AP and axial radiographs showing an osteoid osteoma of the left proximal femur as a metaphyseal lesion with radiolucent nidus and intense peripheral sclerosis; c. AP radiograph showing an osteoid osteoma of the right distal femur - only an intense sclerosis is visible (no nidus is discernable) Department of Radiology, Orthopedics and Trauma Hospital, Cluj-Napoca/Romania Page 29 of 67

Fig. 9: 99mTc-HDP whole body bone scan, showing a suspicious increased focal uptake of the radiotracer in the area of the left proximal femur. SPECT/CT was performed (Fig. 10). Osteoid osteoma. Page 30 of 67

Nuclear Medicine Laboratory - Cluj-Napoca County Hospital, Cluj-Napoca/Romania Fig. 10: SPECT/CT of the pelvis showing a hyperdense bone lesion with hypodense center, presenting increased radiopharmaceutical uptake, localised in the intertrochanteric area of the left femur. Osteoid osteoma of the left proximal femur. Nuclear Medicine Laboratory - Cluj-Napoca County Hospital, Cluj-Napoca/Romania Page 31 of 67

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Fig. 11: AP radiograph showing a lytic-type osteosarcoma of the proximal left humerus showing intense destruction and marked involvement of the soft tissues Department of Radiology, Orthopedics and Trauma Hospital, Cluj-Napoca/Romania Fig. 12: a,b. AP and lateral radiograph of the left knee showing an osteoblastic-type osteosarcoma of the distal femur with intense "cloud-like" amorphous matrix calcification. Page 33 of 67

Department of Radiology, Orthopedics and Trauma Hospital, Cluj-Napoca/Romania Page 34 of 67

Fig. 13: a,b. AP and lateral knee radiograph showing a mixed-type (lytic/sclerotic) osteosarcoma of the distal femur; c,d. postoperative aspect after insertion of a knee replacement implant Department of Radiology, Orthopedics and Trauma Hospital, Cluj-Napoca/Romania Fig. 14: Osteosarcoma of the right femur a. T1 WI shows an inhomogeneous, predominantly hypointense diaphyseal tumour with extension in the soft tissues; b. on STIR WI the lesion appears in high signal; c,d,e. T1 C+ FAT-SAT WI upon administration of Gadolinium, the lesion shows intense inhomogeneous enhancement; e.post-operative CT after insertion of osteosynthesis device. Department of Radiology, Orthopedics and Trauma Hospital, Cluj-Napoca/Romania Page 35 of 67

Fig. 15: 99mTc-HDP blood flow and blood pool images of the distal third of the right femur, where a primary unclassified bone tumor was suspected, showing high uptake in both early phases. At 3 hours postinjection, whole body images were acquired (Fig. 16). Osteosarcoma. Nuclear Medicine Laboratory - Cluj-Napoca County Hospital, Cluj-Napoca/Romania Page 36 of 67

Fig. 16: 99mTc-HDP whole body bone scan shows an inhomogeneous high uptake area in the distal third of the right femur, corresponding to the aspects described on the early phases aquisitions (Fig. 15) and multiple focal areas of high uptake in the skeleton, aspect that pleads for multiple bone metastasis. SPECT/CT was performed (Fig. 17, 18). Osteosarcoma of the femur. Nuclear Medicine Laboratory - Cluj-Napoca County Hospital, Cluj-Napoca/Romania Page 37 of 67

Fig. 17: Distal femur SPECT/CT shows a tumor with cortical bone destruction and soft tissue invasion in the area of high radiotracer uptake seen on previous aquisitions. Osteosarcoma of the distal third of the right femur. Nuclear Medicine Laboratory - Cluj-Napoca County Hospital, Cluj-Napoca/Romania Page 38 of 67

Fig. 18: SPECT/CT of the spine. Multiple bone metastasis at this level in the case of an osteosarcoma of the distal third of the right femur. Nuclear Medicine Laboratory - Cluj-Napoca County Hospital, Cluj-Napoca/Romania Page 39 of 67

Fig. 19: a,b. Ewing sarcoma of the left distal femur showing a metaphyseal mixed (lytic/ sclerotic) lesion with unilamellar periosteal reaction Department of Radiology, Orthopedics and Trauma Hospital, Cluj-Napoca/Romania Page 40 of 67

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Fig. 20: Ewing sarcoma of the femur appearing as a lytic diaphyseal lesion displaying a typical onion-skin plurilamellar periosteal reaction Department of Radiology, Cluj-Napoca Clinic County Hospital, Cluj-Napoca/Romania Fig. 21: Ewing sarcoma of the left iliac wing appearing as a mixed, lytic-sclerotic lesion, with lamellar periosteal reaction Department of Radiology, Cluj-Napoca Clinic County Hospital, Cluj-Napoca/Romania Page 42 of 67

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Fig. 22: 99mTc-HDP whole body bone scan showing a single high radiotracer uptake area, at the level of the left tibial metaphysis, corresponding to an Ewing sarcoma. Nuclear Medicine Laboratory - Cluj-Napoca County Hospital, Cluj-Napoca/Romania Fig. 23: a. metaphyseal lytic lesion plated on the lateral cortex of the distal tibia, surrounded by a sclerotic rim, with internal sclerotic septations, creating the so-called "soap-bubble" appearance, highly sugestive of a nonossifying fibroma. b. same aspect of a distal femoral nonossifying fibroma. Department of Radiology, Orthopedics and Trauma Hospital, Cluj-Napoca/Romania Page 44 of 67

Fig. 24: a. fibrous dysplasia of the right femur and ischio-pubic rami, showing mixed, lyticsclerotic lesions, creating a hazy, ground-glass aspect, with no periosteal reaction or softtissue involvement and associated pathological fracture. b. post-operative radiograph upon insertion of osteosynthetic material c. fibrous dysplasia of the right femur appearing as a mixed lytic-sclerotic expansile lesion of the right femur, with ground glass fibrous matrix mineralisation and Sheperd's crook deformity Department of Radiology, Orthopedics and Trauma Hospital, Cluj-Napoca/Romania Page 45 of 67

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Fig. 25: 99mTc-HDP whole body bone scan, showing a suspicious high radiotracer uptake in the left scapulohumeral area. There were identified also smaller areas of high uptake on the right proximal and left distal tibial epiphysis. SPECT/CT was performed at the level of the first lesion (Fig. 26). Fibrous dysplasia. Nuclear Medicine Laboratory - Cluj-Napoca County Hospital, Cluj-Napoca/Romania Fig. 26: SPECT/CT of the upper thorax. Multiple osteolytic multicystic lesions at the level of the humeral head bilateral (with marked increased radiotracer uptake on the left side) and acromion bilateral, lateral extremity of the right clavicle, with loss of left acromiohumeral articular space (arthrosis). A case of fibrous dysplasia. Nuclear Medicine Laboratory - Cluj-Napoca County Hospital, Cluj-Napoca/Romania Page 47 of 67

Fig. 27: a. lytic, well-circumscribed, mildly expansile lesion of the fibula - simple bone cyst; b. lytic, well-defined lesion of the proximal femural metaphysis showing an intense Page 48 of 67

sclerotic rim and mild endosteal scalloping characteristic of a bone cyst c. lytic, wellcircumscribed lesion of the calcaneus suggestive of an essential bone cyst Department of Radiology, Orthopedics and Trauma Hospital, Cluj-Napoca/Romania Page 49 of 67

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Fig. 28: 99mTc-HDP whole body bone scan showing a high focal uptake in the area corresponding to the first metatarsal bones of the left leg. SPECT/CT of this area was performed (Fig. 29). Simple bone cyst. Nuclear Medicine Laboratory - Cluj-Napoca County Hospital, Cluj-Napoca/Romania Fig. 29: Bone SPECT/CT of the left foot, revealing a simple bone cyst of the second left metatarsal bone, having very low/ no radiotracer uptake. The high uptake lesion proved to be located between the first and the second metatarsal bones of the left foot - most probable determined by an inflammatory process. Nuclear Medicine Laboratory - Cluj-Napoca County Hospital, Cluj-Napoca/Romania Page 51 of 67

Fig. 30: Large lytic expansile lesion of the proximal tibia suggestive of a giant cell tumour. Department of Radiology, Orthopedics and Trauma Hospital, Cluj-Napoca/Romania Page 52 of 67

Fig. 31: Lytic expansile lesion located in the anterior diaphyseal cortex of the tibia with multiple "soap-bubble" lucencies - typical of an adamantinoma. Department of Radiology, Orthopedics and Trauma Hospital, Cluj-Napoca/Romania Page 53 of 67

Fig. 32: a. multiple lucencies, relatively well-defined, with no sclerotic border diseminated throughout the left humerus,with associated pathological fracture, sugestive of multiple myeloma. b. multiple coalescing lytic lesions in the tibial diaphysis in a patient with multiple myeloma. Department of Radiology, Orthopedics and Trauma Hospital, Cluj-Napoca/Romania Page 54 of 67

Fig. 33: a. intensely sclerotic metastases in the left iliac wing in a patient with metastatic prostate carcinoma b. marked lysis of the right humeral head in a patient with metastatic nephrocarcinoma Department of Radiology, Orthopedics and Trauma Hospital, Cluj-Napoca; Department of Radiology, Cluj-Napoca Clinic County Hospital, Cluj-Napoca/Romania Page 55 of 67

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Fig. 34: a,b. CT scan showing mixed lytic-sclerotic metastases of the left iliac wing and vertebrae in a patient treated for Ewing sarcoma CT Clinic, Cluj-Napoca/Romania Fig. 35: CT and 18F-FDG PET-CT images in a patient with metastatic disease showing lytic lesions with increased 18F-FDG uptake suggesting intense metabolic activity. a,b. clavicle metastasis; c,d. right iliac wing metastasis; e,f. vertebrae metastasis CT Clinic, Cluj-Napoca/Romania Page 57 of 67

Fig. 36: 99mTc-HDP whole body bone scan, performed in the case of a patient with prostate andenocarcinoma, shows multiple focal areas of high radiotracer uptake, at the level of the skull, spine, clavicles, ribs, pelvis and femur bilateral, suggestive for multiple bone metastases. Nuclear Medicine Laboratory - Cluj-Napoca County Hospital, Cluj-Napoca/Romania Page 58 of 67

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Fig. 37: 99mTc-HDP whole body bone scan showing multiple focal areas of suspicious high radiotracer uptake, at the levels of the spine, 6th left rib (anterior side) and right posterior iliac crest. SPECT/CT was performed (Fig. 38). Multiple bone metastases. Nuclear Medicine Laboratory - Cluj-Napoca County Hospital, Cluj-Napoca/Romania Fig. 38: Bone SPECT/CT showing multiple osteolytic lesions with high perilesional radiotracer uptake, at the level of the spine (D8, D12, L4 vertebrae) suggesting multiple bone metastases. Nuclear Medicine Laboratory - Cluj-Napoca County Hospital, Cluj-Napoca/Romania Page 60 of 67

Fig. 39: a,b. Second stage Paget's disease of the proximal tibia showing a mixed sclerotic-lytic lesion, with thickened trabeculae and cortex resulting in hyperostosis and anterior bowing of the tibia. Department of Radiology, Orthopedics and Trauma Hospital, Cluj-Napoca/Romania Page 61 of 67

Fig. 40: 99mTc-HDP whole body bone scan, showing intense high uptake areas with coarse expansion at the level of the right humerus and right femoral diaphysis, aspect corresponding to a polyostotic Paget's disease. Left acromioclavicular high focal uptake area, possibly inflammatory lesion. Nuclear Medicine Laboratory - Cluj-Napoca County Hospital, Cluj-Napoca/Romania Page 62 of 67

Fig. 41: Middle stage Paget's disease of the left proximal humerus. a. radiograph revealing a mixed lytic-sclerotic lesion involving the epiphysis, metaphysis as well as the Page 63 of 67

diaphysis of the bone, where it is sharply delineated in the form of a "blade of grass", with hyperostosis due to endostosis and thickened cortical trabeculae; b. CT shows a suplimentary round intracortical low-attenuating lesion. c,d,e. T1, STIR and T1 C+ FATSAT weighted images showing a focal round intracortical lesion (hypointense on T1, hyperintense on STIR), and showing marked Gadolinium enhancement), typical for a metabolically active focus. f. 99mTc-HDP whole body bone scan and static segmental images of the thorax show increased uptake at the site of the lesion. Department of Radiology, Cluj-Napoca Clinic County Hospital, Cluj-Napoca/Romania ; Nuclear Medicine Laboratory - Cluj-Napoca County Hospital, Cluj-Napoca/ Romania ; Hyperdia Clinic, Cluj-Napoca/Romania Page 64 of 67

Conclusion Radiographic findings in conjunction with cross-sectional and nuclear imaging methods, complementing and interconnecting structural and functional information, via a focused diagnostic algorithm help the radiologist in the recognition of benign, malignant and pseudo-tumorous bone lesions. Personal information References 1.Davies AM, Sundaram M, James SJ. Imaging of Bone Tumors and Tumor-Like Lesions: Techniques and Applications. Springer Science & Business Media; 2009. 694 p. 2.Grainger A. Grainger and Allison's Diagnostic Radiology: Musculoskeletal System. Elsevier Health Sciences; 2015. 269 p. 3.Bennett PA, Oza UD. Diagnostic Imaging: Nuclear Medicine. Elsevier Health Sciences; 2015. 602 p. 4.Miller TT. Bone Tumors and Tumorlike Conditions: Analysis with Conventional Radiography. Radiology. 2008 Mar 1;246(3):662-74. 5.Lu Y, Villalobos C, Zamora R, Cornejo MC, Wittig JC. Radiographic and Scintigraphic Evaluation of Bone Tumors and Diseases. JBJS Rev. 2014 Jun 24;2(6):e5. 6.Elgazzar AH. A Concise Guide to Nuclear Medicine. Springer Science & Business Media; 2011. 167 p. 7.Ziessman HA, O'Malley JP, Thrall JH. Nuclear Medicine: The Requisites. Elsevier Health Sciences; 2013. 466 p. 8.Littrell LA, Wenger DE, Wold LE, Bertoni F, Unni KK, White LM, et al. Radiographic, CT, and MR Imaging Features of Dedifferentiated Chondrosarcomas: A Retrospective Review of 174 De Novo Cases. RadioGraphics. 2004 Sep 1;24(5):1397-409. Page 65 of 67

9.Kransdorf MJ, Stull MA, Gilkey FW, Moser RP. Osteoid osteoma. RadioGraphics. 1991 Jul 1;11(4):671-96. 10.Liu PT, Chivers FS, Roberts CC, Schultz CJ, Beauchamp CP. Imaging of Osteoid Osteoma with Dynamic Gadolinium-enhanced MR Imaging. Radiology. 2003 Jun 1;227(3):691-700. 11.Murphey MD, Jelinek JS, Temple HT, Flemming DJ, Gannon FH. Imaging of Periosteal Osteosarcoma: Radiologic-Pathologic Comparison. Radiology. 2004 Oct 1;233(1):129-38. 12.Reynolds J. The "Fallen Fragment Sign" in the Diagnosis of Unicameral Bone Cysts. Radiology. 1969 Apr 1;92(5):949-53. 13.Chakarun CJ, Forrester DM, Gottsegen CJ, Patel DB, White EA, Matcuk GR. Giant Cell Tumor of Bone: Review, Mimics, and New Developments in Treatment. RadioGraphics. 2013 Jan 1;33(1):197-211. 14.Jee WH, Choe BY, Kang HS, Suh KJ, Suh JS, Ryu KN, et al. Nonossifying fibroma: characteristics at MR imaging with pathologic correlation. Radiology. 1998 Oct 1;209(1):197-202. 15.Kransdorf MJ, Moser RP, Gilkey FW. Fibrous dysplasia. RadioGraphics. 1990 May 1;10(3):519-37. 16.Camp MD, Tompkins RK, Spanier SS, Bridge JA, Bush CH. Adamantinoma of the Tibia and Fibula with Cytogenetic Analysis. RadioGraphics. 2008 Jul 1;28(4):1215-20. 17.Ferraro R, Agarwal A, Martin-Macintosh EL, Peller PJ, Subramaniam RM. MR Imaging and PET/CT in Diagnosis and Management of Multiple Myeloma. RadioGraphics. 2015 Mar 1;35(2):438-54. 18.Abrams HL. Skeletal Metastases in Carcinoma. Radiology. 1950 Oct 1;55(4):534-8. 19.Smith H. Paget's Disease of the Bone. Radiology. 1931 May 1;16(5):694-6. Page 66 of 67

20.Radiopaedia.org, the wiki-based collaborative Radiology resource [Internet]. Radiopaedia. [cited Dec 19]. Available from: https://radiopaedia.org/ Page 67 of 67