Suspecting Tumors, or Could it be cancer? Donna E. Reece, M.D. Princess Margaret Cancer Centre University Health Network Toronto, ON CANADA 07 February 2018

Background Low back pain is common However, <1% have a serious cause (cancer, infection, fracture)1 1Henschke N et al. Arthritis Rhematol 2009; 60: 3072-3080.

Case: 50 year old woman Long-standing osteoporosis since age 32 with known compression fracture of T7 after moving furniture Found to have light chain myeloma in 2006 CT scan of abdomen and pelvis performed for flank pain showed numerous small lytic lesions throughout the skeleton Normal hemoglobin, creatinine, calcium Normal serum protein electrophoresis Serum free kappa level of 759 mg/L (normal 3.3-19.4 mg/L ) Skeletal survey showed compression at T7, pathologic fracture and lytic lesion in L4; multiple "punched out“ lesions in the skull Bone marrow biopsy showed sheets of malignant plasma cells

Multiple Myeloma What is it? Cancer of bone marrow plasma cells (cells that make antibodies) Intact or light chain component used as a “tumor marker” Found in serum and/or urine Serum or urine (24 hour) EP Serum free light chain assay* Second most common hematological malignancy Median age 65 years Key signs and symptoms Anemia Lytic bone damage Renal failure High serum calcium Recurrent infections *Not funded in outside labs in Ontario; must be ordered under hospital budget.

Multiple Myeloma What is it? Tests to order for suspected myeloma: Total serum protein and albumin Serum protein electrophoresis (SPEP) –will detect a intact monoclonal Ab if over 1 g/L (80% of patients) Serum immunofixation (IFE)- will identify the MoAb and can detect it if over 0.5 g/L 24 hour urine for total protein, electrophoresis (UPEP), and immunofixation –Will detect a monoclonal light chain (20%) Serum free light chain assay—picks up excess kappa or lambda light chain if over 0.005 g/L Cancer of bone marrow plasma cells (cells that make antibodies) Intact or light chain component used as a “tumor marker” Found in serum and/or urine Serum or urine (24 hour) EP Serum free light chain assay* Second most common hematological malignancy Median age 65 years Key signs and symptoms Anemia Lytic bone damage Renal failure High serum calcium Recurrent infections *Not funded in outside labs in Ontario; must be ordered under hospital budget.

Multiple Myeloma What is it? Tests to order for suspected myeloma: Total serum protein and albumin Serum protein electrophoresis (SPEP) –will detect a intact monoclonal Ab if over 1 g/L (80% of patients) Serum immunofixation (IFE)- will identify the MoAb and can detect it if over 0.5 g/L 24 hour urine for total protein, electrophoresis (UPEP), and immunofixation –Will detect a monoclonal light chain (20%) Serum free light chain assay—picks up excess kappa or lambda light chain if over 0.005 g/L Electrophoresis Cancer of bone marrow plasma cells (cells that make antibodies) Intact or light chain component used as a “tumor marker” Found in serum and/or urine Serum or urine (24 hour) EP Serum free light chain assay* Second most common hematological malignancy Median age 65 years Key signs and symptoms Anemia Lytic bone damage Renal failure High serum calcium Recurrent infections *Not funded in outside labs in Ontario; must be ordered under hospital budget.

Multiple Myeloma What is it? Tests to order for suspected myeloma: Total serum protein and albumin Serum protein electrophoresis (SPEP) –will detect a intact monoclonal Ab if over 1 g/L (80% of patients) Serum immunofixation (IFE)- will identify the MoAb and can detect it if over 0.5 g/L 24 hour urine for total protein, electrophoresis (UPEP), and immunofixation –will detect a monoclonal light chain (20%) Serum free light chain assay—picks up excess kappa or lambda light chain if over 0.005 g/L Cancer of bone marrow plasma cells (cells that make antibodies) Intact or light chain component used as a “tumor marker” Found in serum and/or urine Serum or urine (24 hour) EP Serum free light chain assay* Second most common hematological malignancy Median age 65 years Key signs and symptoms Anemia Lytic bone damage Renal failure High serum calcium Recurrent infections Free Kappa 3.3-19.6 mg/L Free Lambda 5.6-26.3mg/L Kappa/Lambda: 0.26-1.65 Serum free light chain (Freelite®) assay* Antibody target *Not funded in outside labs in Ontario; must be ordered under hospital budget.

Case: Imaging

Case: 50 year old woman, continued She received induction chemotherapy and a stem cell transplant and entered a complete remission Monthly IV pamidronate was given for 2 years, then q 3 months She was monitored every 3 months with serum free light chain levels Skeletal survey annually She relapsed in 2014 and was treated with oral chemotherapy followed by a second stem cell transplant In May 2016, she developed radicular pain down her right leg and an MRI of the spine was ordered She was driving back to Sault Ste Marie when the MRI results were phoned to the MD

Case: Imaging New compression fracture at T6 with impending spinal cord compression

Key Points She had the main risk factor for aggressively evaluating low back pain →prior hx of cancer However, her cancer-related problem was not reflected by her symptoms In this setting, the whole spine should be imaged, not just the area of concern (lumbosacral spine) Her lumbar symptoms were related to degenerative disease Immediate referral to neurosurgical facility important to maintain function Patients with myeloma live many years now, and aggressive management of skeletal damage is critical to maintain quality of life

Background Suspecting tumors… Tumors of the spine are more frequently metastatic (97%) rather than primary1 50-70% of cancer patients found to have spinal metastasis before death Sources: prostate, breast, kidney, thyroid, lung Acronym = “PBKTL” GI cancers and melanoma as well Hematologic malignancies are also potential causes Multiple myeloma is a hematologic malignancy characterized by bone destruction and anemia Lymphoma may occasionally present in bone Thoracic/thoracolumbar (70%) and lumbosacral spine (20%) most common sites 1Lewandrowski KU, et al. Tumors of the Spine. Philadelphia: Elsevier Saunders; 2011;1480-1512.

Patterns of Bone Metastasis Bone lesions may be lytic, blastic or mixed Primarily blastic Primarily lytic Mixed Prostate Small cell lung Hodgkin’s disease Carcinoid Medulloblastoma POEMS syndrome Multiple myeloma Renal cell cancer Non-small cell cancer Thyroid cancer Melanoma Non-Hodgkin’s lymphoma Langerhans cell histiocytosis Breast cancer GI cancers Most squamous cell

Patterns of Bone Metastasis Imaging of the Spine Lytic lesion Blastic lesion

Bone is a dynamic organ…… Seeman E, et al. N Engl J Med. 2006;354:2250-61. van Bezooijen RL, et al. Cytokine Growth Factor Rev. 2005;16:319-27.

Bone is a dynamic organ…… Osteoclasts mediate bone destruction, not tumor cells directly, in osteolytic metastasis Seeman E, et al. N Engl J Med. 2006;354:2250-61. van Bezooijen RL, et al. Cytokine Growth Factor Rev. 2005;16:319-27.

Bone is a dynamic organ…… New bone formation involved in osteoblastic metastasis Seeman E, et al. N Engl J Med. 2006;354:2250-61. van Bezooijen RL, et al. Cytokine Growth Factor Rev. 2005;16:319-27.

Suspecting malignancy…. Bone metastasis to the spine can cause Pain Pathologic fractures Epidural spinal cord compression, including cauda equina syndrome Cauda equina syndrome -- compression of nerve roots below spinal cord (i.e. L2) causing low back pain +/- radiation down legs, weakness of plantar flexion of the feet, bladder and rectal sphincter paralysis, impotence, sensory loss in dermatomal distribution of affected nerve roots Hypercalcemia

Suspecting malignancy… Pain Use of “red flag” symptoms suggested in some guidelines in the past The goal was to identify patients at a higher risk of a dangerous cause of back pain Could serve as indications for earlier imaging exams Examples included: age ≥50, history of cancer, failure to improve by 1 month of therapy, unexplained weight loss, no relief with recumbency, insidious onset, sensory level, pain worse at night, fever, thoracic pain

Diagnostic Accuracy of ACP “Red Flags” for Spinal Malignancy: Meta-analysis Only a prior history of cancer informative: Post-test probability of 7% in primary care Post-test probability of 33% in ER Downie A, et al. BMJ 2013; 347:f7095.

Diagnostic Accuracy of Other “Red Flags” for Spinal Malignancy: Meta-analysis Prevalence of spinal malignancy: Primary care 0.5% Secondary or tertiary setting 1.5% Downie A, et al. BMJ 2013; 347:f7095.

Suggested Evaluation for Acute Low Back Pain No hx of significant trauma Signs or symptoms of cauda equina syndrome (new urinary retention, fecal incontinence or saddle anesthesia) Significant motor deficits (progressive motor weakness or significant motor deficits not localized to a single unilateral nerve root) Yes Emergent MRI and consultation No Yes Discuss choice of imaging with patient’s oncologist Current or recent cancer history (particularly breast, prostate, lung, thyroid, kidney, myeloma) No Moderate to high risk of cancer (multiple risk factors/symptoms, remote history of cancer, strong clinical suspicion) Yes Plain films and ESR (or CRP) Plain film suggests possible cancer Plain film (-) but ESR high Evaluate for malignancy MRI Adapted from Wheeler SG et al. Evaluation of back pain in adults. UpToDate 2018.

Spine Imaging in Malignancy Plain films Poor sensitivity as screen for bone metastasis (at least 30% loss of bone density needed to see lytic lesion) Can evaluate mechanical alignment of vertebra and screen for severe compression fracture Also, bone survey remains the standard for screening for multiple myeloma CT scans Superior bony detail; can show lytic and blastic lesions before apparent on plain films Good for diagnosing fracture or impending fracture Can show soft tissue involvement Can be helpful before surgery or XRT

Spine Imaging in Malignancy MRI More sensitive than CT for small lesions Can show extent of tumor within bone Useful to define extent of medullary and extraspinal disease of spine Can distinguish benign and malignant causes of lesions Gold standard for spinal cord compression, epidural disease or nerve root impingement Disadvantages: sensitive to movement and metal artifact, not permitted with many implantable devices, can be problematic with claustrophobia Bone scan Skeletal scintigraphy with 99m-Tc MDP Accumulates in areas of increased osteoblastic activity Reasonably sensitive (79-86%) and specific (81-88%) ] for bone metastases NOT good for lytic lesions like myeloma or aggressive lesions with rapid bone destruction

Other Indications for Imaging No improvement in pain after 4-6 weeks of conservative therapy and risk factors for cancer Plain films and ESR Suspected compression fractures Signs and symptoms Sudden onset of pain with minimal or no trauma Point tenderness Girdle/belt/band-like pain Muscle spasms Can be osteoporotic or tumor-related MRI can help distinguish these two possibilities

When to move beyond conservative approaches in a patient with back pain…. Should be based on: Combination of clinical features Strength of clinical suspicion Consequences of delayed diagnosis

Thank you! The PM Myeloma physicians, scientists, nurses and support staff The PM Myeloma Research program nurses, coordinators, managers The Myeloma Canada Research Network (MCRN) Myeloma Canada Bloom Chair for Myeloma Research CCTG TFRI collaboration with Dr. T. Reiman Our myeloma patients and families