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Home , Bone metastasis

1/24/2020

METASTASES AND MYELOMA METASTASES AND MYELOMA

Alberto Bazzocchi, MD, PhD THE MOST FREQUENT CAUSES FOR The Rizzoli Orthopaedic Institute, Bologna, Italy MALIGNANCY IN

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PROBLEM

IMAGING APPEARANCES ARE VERY SIMILAR…!

HOW WILL WE DIAGNOSE ONE OR THE OTHER…? MYELOMA OR …?

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A new bone lesion? Multiple bone lesions? When to suspect hemato or bone mets Hemato OR bone mets?

1° Oncologic history 1° You already know what it is 2° Age of the patient (and of radiologist) 2° exams and look for other organs 3° Multiple lesions 3° How many and how big lesions?

If in trouble: If in trouble: … Call Dr. R. Lalam, Oswestry, UK (mobile: +44 345 3456678) … Call Prof. G. Guglielmi, Foggia, Italy (mobile: +39 347 6789678)

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20% of bone is TRABECULAR RED BONE MARROW HEMATOPOIETICALLY ACTIVE “PARENCHYMA” Bone marrow 40% WATER Red cells, Lymphocytes, (PARTITIONS) 40% FAT Megakariocytes, BLOOD CELLS precursors, 20% PROTEIN Platelets… PRIMARY - MYELOMA YELLOW BONE MARROW HEMATOPOIETICALLY INACTIVE 15% WATER FILLED BY BONE MARROW H-E x10 80% FAT 5% PROTEIN STROMA RED MARROW TRABECULAE YELLOW MARROW OSSEOUS COMPONENTS SUPPORTING SYSTEM Science Photo Library/Getty Images SUPPORTING SYSTEM BLOOD VESSELS SECONDARY - METASTASES H-E x40

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MYELOMA MYELOMA - epidemiology

• MOST COMMON PRIMARY MALIGNANT BONE NEOPLASM in adults • Common malignancy in patients above 40 • (70% of cases between ages 50 and 70 / Median age 69 years) • Arises from RED MARROW due to the monoclonal proliferation of plasma • Male predilection (M:F 2:1) cells (MONOCLONAL GAMMOPATHY)

• 1% of all malignancies and 10% of all hematological disease • WIDE RANGE OF RADIOLOGICAL ABNORMALITIES

• and combined account for • INCURABLE (progressive renal problems) approximately 50% of all PRIMARY BONE MALIGNANCIES

Alipio et al Radiographics 2019

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MYELOMA – CLINICAL SYMPTOMS MYELOMA – TYPES / TERMINOLOGY • Bone • initially intermittent, but becomes constant • Four main patterns are recognized: • worse with activity/weight-bearing, and thus is worse during the day • Disseminated form: • • multiple well-defined "punched out" lytic lesions: predominantly affecting the • axial skeleton typically normochromic/normocytic • diffuse skeletal osteopenia • Renal failure • Solitary PLASMOCYTOMA - a single large/expansile lesion most • Proteinuria …COMPLICATION! commonly in a vertebral body or in the pelvis • Hypercalcemia • OSTEOSCLEROSING MYELOMA (rare) – linked to POEMS syndrome • Bone lesion PATHOLOGICAL FRACTURE (vertebral, long bone) SMOULDERING MULTIPLE MYELOMA AMYLOIDOSIS (Asymptomatic. Between MGUS and active myeloma) RECURRENT INFECTION (pneumonia) Dispenzieri et al Blood 2013

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MYELOMA - LABORATORY MYELOMA - DISTRIBUTION

• Reverse albumin/globulin ratio (LOW albumin, HIGH globulin) Has the distribution of RED MARROW (axial skeleton and proximal appendicular skeleton): • Monoclonal gammopathy (IgA and/or IgG peak) • Bence Jones protein (Ig light chain) proteinuria • vertebrae (most common) • Hypercalcemia • ribs • Decreased or normal alkaline phosphatase unless there is a • skull pathological fracture due to impaired osteoblastic function • shoulder girdle • Approximately 1% of cases will have negative serum electrophoresis • pelvis and negative Bence Jones protein • long • extraskeletal structures: rare

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MYELOMA – DIAGNOSIS RADIOGRAPHS

diagnosis of multiple myeloma • CAN BE DIAGNOSED CLINICALLY... SKELETAL SURVEY potential complications (e.g. pathological fracture) assessing response to therapy • RADIOLOGICALLY - BONE LESIONS ~40% bone destruction is required for lesion detection, thus giving the skeletal survey a high false-negative rate of ~50% (range 30-70%).

• Suggest the diagnosis / exclude other causes Hanrahan et al Radiographics 2010 • Assess possible mechanical COMPLICATIONS (fractures) Times are changing… • Assess disease PROGRESSION

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RADIOGRAPHS – TYPICAL FEATURES RX

• Lytic (”raindrop skull”) • Sharply defined/punched out • Endosteal scalloping • Generalised osteopenia (less common) associated with fractures! • Sclerotic in only 3% of patients (osteosclerosing myeloma)

Delorme et al Eur J Radiol 2009

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BONE SCINTIGRAPHY BS CT - Whole-body low dose (WBLD) CT

• Bone scintigraphy • More accurate than a skeletal survey • Variable due to the potential lack of Sensitivity of ~70% and specificity of ~90% CT osteoblastic activity • Dose only 1x - 2x compared with skeletal • Larger lesions may be either hyperactive survey (hot) or photopenic (cold) • Bone scans may also be normal • Sensitivity of detecting lesions is less than • WBLD CT is also better: that of a plain film skeletal survey! • To assess pathological fractures in severely affected bones • To detect the presence of extramedullary lesions Alipio et al Radiographics 2019 Candas et al J Med Cases 2011 Eur J Radiol 2012 19 20

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MRI • More sensitive in detecting multiple lesions compared to skeletal survey and CT MRI

• Five patterns have been described: • normal bone marrow signal (!) • diffuse involvement • focal involvement • combined diffuse and focal involvement • variegated ("salt and pepper")

Alipio et al Radiographics 2019 Dutoit et al Insights into imaging 2016 23 24

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MRI MRI Most frequently used MR sequences • T1 C+ (Gd) T1 spin-echo • • T1 ENHANCES T2 spin-echo • Several enhancement curves may be seen: • Typically low signal • type 4 curve: steep wash-in of contrast medium, due to the high vascularization and • high-grade / diffuse involvement may become isointense to perfusion with leakage through the highly permeable capillaries, followed by an early adjacent marrow wash-out back into the intravascular space because of the small interstitial space with closely packed plasma cells • type 3 and type 5 curves may also be seen • T2 (with fat-suppression) • DWI/ADC • high signal • Usually exhibit restricted diffusion, with higher signal on high b-value DWI • infiltration of the ribs is probably best appreciated on T2 compared to the very low signal of normal background marrow images with fat suppression, appearing bright (“white ribs sign”) Baur-Melnyk A et al Eur J Radiol 2005 Dutoit et al Insights into imaging 2016 Dutoit et al Insights into imaging 2016 25 26

FOCAL INVOLVEMENT

T1 + Gd

T2 T2 Fat Sat T1 T2 T1 T2 T2 Fat Sat T1 + Gd

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FOCAL INVOLVEMENT FOCAL INVOLVEMENT

T2 Fat Sat T1 T1 + Gd T2 Fat Sat T1 T1 + Gd

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FOCAL PATTERN MAY BE ASSOCIATED WITH POORER SURVIVAL…

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VARIEGATED

DIFFUSE

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FOCAL

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NUCLEAR MEDICINE

FDG PET-CT • FDG PET-CT F-18 FDG uptake by the myeloma lesions corresponds to lytic bone lesions or soft tissue plasmacytomas seen on CT.

Focal high FDG uptake in the bone may be considered a positive lesion even in the absence of on CT. Oops…

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Eur J Radiol 2012 Eur J Radiol 2012 39 40

STILL HARD SOMETIMES…

… BREAST

… MYELOMA Eur J Radiol 2012 41 42

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WHICH METHOD…?

comparable WB MRI superior to WBLD CT

WB DWI intramedullary more sensitive, extramedullary equal DECT similar to MRI

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WHAT IS NEW…? CURRENT EVIDENCE:

RADIOMICS

SKELETAL SURVEY – SHOULD NOT LONGER BE USED UNLESS IT IS THE ONLY OPTION TEXTURE ANALYSIS WHOLE BODY LOW DOSE CT – COST EFFECTIVE INITIAL APPROACH

WHOLE BODY MRI – MOST SENTITIVE TECHNIQUE FOR BONE INVOLVEMENT AND PAIN Nuclear Medicine PET/CT – BEST TOOL TO EVALUATE TREATMENT RESPONSE

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MYELOMA –TREATMENT MYELOMA – RESPONSE TO TREATMENT • International Myeloma Working Group response criteria • INCURABLE • thalidomide, lenalidomide, and bortezomib (proteasome inhibitor) Kumar et al Lancet 2016 have provided significant survival gains. • These are typically used in combination with older agents such as Imaging assessment of bone lesions and extramedullary cyclophosphamide, melphalan, prednisolone and doxorubicin. plasmocytomas: optional component of the response criteria • Treatment response is usually assessed by measuring serum markers and bone marrow sampling. • Stem-cell harvest and autologous stem cell transplant post- chemotherapeutic/radiotherapy bone marrow ablation are also used, ***except FDG PET: required for reporting although relapse is inevitable. imaging minimal residual disease (MRD)-negative status.

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DIFFERENTIAL DIAGNOSIS IMPORTANT ROLE FOR RADIOLOGY BONY METASTASES Findings that favor the diagnosis of BONE METASTASES • Vertebral pedicles rather than vertebral bodies • Rarely involve mandible, distal axial skeleton • Extensive bony metastases rarely have a normal appearance on bone scan

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METASTASES METASTASES

• Bone is the third most frequent site of metastasis, behind lung and TYPE OF TUMOR RELATIVE INCIDENCE MEDIAN SURVIVAL PERCENTAGE OF BONE METS PATHOLOGICAL FRACTURES liver IN ONCOLOGIC PATIENTS • Prostate and are responsible for the majority of the Breast 65-75% 19 –25 months 60% skeletal metastases (up to 70%) Prostate 65-75% 12 –53 months - • high incidence Thyroid 60% 48 months - • relatively long clinical course Lung 30-40% 6 –7 months 10% Bladder 40% 6 –9 months - Renal cell carcinoma 20-25% 12 months - • Overall incidence of bone metastasis is not known 14-45% 6 months -

Coleman R et al Cancer Treat Rev 2001 Macedo et al Oncol Rev 2017 Cecchini M et al EAU Update Series 2005 51 52

METASTASES – CLINICAL SYMPTOMS METASTASES – CLINICAL SYMPTOMS

• Severe pain - poorly localized, worse at night, not necessarily relieve • Spinal cord compression with sleep or lying down. breast (20 - 30%) • Impaired mobility (15%) • Pathologic fractures • Bone marrow aplasia (displacement due to infiltration) • 10-30% of all cancer patients • Hypercalcemia - constipation, polyuria, polydipsia and fatigue. In final • proximal parts of the long bones being the most frequent fracture site stages, hypercalcemia can leads to cardiac arrhythmias and acute • (femur accounting for over half of all cases) renal failure. Also increases osteoclastic bone resorption. • Rib fractures and vertebral collapses are also very common, which can lead Poor prognosis with a median survival of 10-12 weeks to kyphoscoliosis and a degree of restrictive lung disease

Coleman R et al Cancer Treat Rev 2001 Selvaggi et al Clin Rev Oncol Hematol 2005

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METASTASES - TYPES (According to mechanism of interference with bone remodeling) DIAGNOSIS TYPE Tumors LYTIC Renal cell carcinoma Melanoma • CLINICAL ONLY SUSPICION…. Non-small cell lung cancer Non- BREAST: predominantly osteolytic Langerhans-cell histiocytosis 15-20% of women have • RADIOLOGICALLY - BONE LESIONS Great majority of breast cancer osteoblastic lesions, or both BLASTIC types of lesions • Suggest the diagnosis / exclude other causes Small cell lung cancer Hodgkin lymphoma or • Assess possible mechanical COMPLICATIONS (fractures) Medulloblastoma MIXED Breast • Assess disease PROGRESSION Gastrointestinal Squamous .

Selvaggi et al Clin Rev Oncol Hematol 2005 55 56

RADIOGRAPHS RX

• Fast, cheap, and readily available technique ? • First test in the evaluation of . • VERY SPECIFIC but sensitivity is low (44-50%) • UNDETECTABLE at initial stages. • Lesions up to 1 cm might go undetected. • More than 50% of trabecular bone must be destroyed before it will be evident on film. • Medullary lesions are more difficult to detect than lesions in cortical bone because of the limited contrast in trabecular bone.

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BONE SCINTIGRAPHY BS • Provides information on osteoblastic activity and skeletal vascularity • Bone scintigraphy is highly sensitive but usually has a low specificity Neoplastic…? Traumatic…? Inflammatory…? • Sensitivity ranges from 62 to 89%, with a false-positive rate as high as 40%. • It is more sensitive and more specific than plain films and CT but less than MRI in the spine.

CT T1 T2 T2 Fat Sat T1 + Gd Algra et al Radiographics 1991

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CT • Sensitivity for diagnosis ranges from 71-100% CT • Soft tissue extension of bone metastases • Biopsy – guidance Rosenthal et al Cancer 1997 NEW…

CT

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MRI • Sensitivity ranges from 82-100% MRI • Specificity ranges from 73-100%.

• Bonus! ”Halo” sign T2 • Spinal cord compression • Imaging bone marrow

T1WI T2WI

INCREASES CONSPICUITY… Schweitzer et al Radiology 1993 65 66

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”Bull’s eye” sign (high on T1) = normal hematopoietic marrow Fat saturation gadolinium-enhanced T1WI 53 yo woman. Lumbalgia. Breast cancer.

USE FAT SUPRESSION ! ? CONSPICUITY OF LESIONS SENSITIVITY NOT INCREASED Meyer JS et al. 2005 Pediatr Radiol

EXTRAMEDULLARY / SOFT TISSUES

STIR T1WI Schweitzer et al Radiology 1993 Case courtesy of Dr Pilar Aparisi Gómez T1WI T1WI + Gd 67 68

NON-ROUTINE SEQUENCES - I NON-ROUTINE SEQUENCES - II

T1 fluid-attenuated inversion recovery (T1W FLAIR) Melhem ER et al. 1997 AJNR • Diffusion-weighted imaging Herneth AM et al. 2000 Radiologe Optimizes tissue contrast between fatty marrow / abnormal tissue Lesions with higher cellular density show restricted diffusion (improving the conspicuity of edema and metastatic lesions) bright on diffusion-weighted imaging. low signal intensity on apparent diffusion coefficient imaging. This property helps in identifying small primary neoplastic or metastatic disease.

T1WI T1W FLAIR b 0b 400 b 800 ADC T1WI T1W FLAIR Lavdas E et al. 2010 Acta Radiologica Case courtesy of Dr Pilar Aparisi Gómez 69 70

NON-ROUTINE SEQUENCES - III NON-ROUTINE SEQUENCES - IV

In-phase and out-of-phase imaging sequences Disler DG et al. 1997 AJR • Dynamic contrast-enhanced MRI Neoplastic conditions replacing normal marrow will not have signal dropout on out-of-phase image Assessment of response to Prediction progression of vertebral collapse Kanchiku T et al. 2003 Spine

• Proton MR spectroscopy DROP-OUT > 20% Based on measurement of lipid-water ratio BENIGN • Whole body MRI (coronal T1WI / STIR) Myeloma, Metastases, Lymphoma (Low definition - targeted study may be necessary) IN-PHASE OUT-OF-PHASE

HEPATOCARCINOMA Case courtesy of Dr Catherine Phan ESSR 2018

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Prostatic NUCLEAR MEDICINE adenocarcinoma • LUNG CANCER (sensitivity 92%, specificity 99%) • BREAST (sensitivity 95%, specificity 94%) • LOWER accuracy in renal and prostate cancer bone metastasis because they are slow growing (uptake of 18-fluorodeoxyglucose is low)

• Reveal metastatic spread to sites other than bone

Could substitute bone scan and MRI 11C-Choline 73 74

18F-Dopa Prostatic adenocarcinoma Pre

Post

11C-Choline

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68Ga-DOTA-NOC HCC NET 11C-Acetate

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WHAT IS NEW…? TREATMENT

• Biphosphonates New MRI sequences • • Radiotherapy • • Ablation (different types) • Surgery • Stereotatic radiosurgery Development PET / CT and PET / MRI

MOLECULAR IMAGING

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ARTIFICAL INTELLIGENCE CONCLUSIONS

RADIOMICS METASTASIS MYELOMA

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Thank You!

Alberto Bazzocchi, MD, PhD

Diagnostic and Interventional Radiology The Rizzoli Orthopaedic Institute Italy a [email protected] 83

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