Sarah Billmeier, HMS IIIGillian Lieberman, MD

Bone Disease in Plasma Cell Dyscrasias

Sarah BillmeierHarvard Medical School Year III

Gillian Lieberman, MD

July 2004

Courtesy of Dr. Ferris Hall

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Sarah Billmeier, HMS IIIGillian Lieberman, MD

Objectives

• Characterization of the plasma cell neoplasms

• Radiologic work up of Multiple Myeloma• A Visual Journey

Multiple Myeloma: LyticMultiple Myeloma: OsteopenicSclerotic Plasma Cell Neoplasms

Diffuse: Sclerotic Multiple MyelomaSolitary: Sclerotic PlasmacytomaMultifocal: POEMS

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Sarah Billmeier, HMS IIIGillian Lieberman, MD

Definitions• Multiple Myeloma (MM) = monoclonal malignant

proliferation of plasma cells

•

Plasmacytoma = discrete, solitary mass of neoplastic monoclonal plasma cells in either bone or soft tissue (extramedullary). Absence of multiple lesions, marrow plasmacytosis or other features of MM. Progresses to MM in 50-60%.

•

POEMS = syndrome of Polyneuropathy, Organomegally, Endocrinopathy, Monoclonal gammopathy & Skin problems

•

MGUS = Monoclonal Gammopathy of Undetermined Significance: Presence of M-protein in urine without evidence of multiple myeloma. With long term follow up 25% develop MM.

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Sarah Billmeier, HMS IIIGillian Lieberman, MD

Multiple Myeloma• Minimal diagnostic criteria:

Presence of >10% plasma cells in the BM or plasmacytoma

Serum or urine monoclonal protein

Related organ or tissue impairment (↑ calcium, renal insufficiency, anemia, lytic bone lesions, hyperviscosity, amyloidosis, recurrent infections)

• Epidemiology: MM represents 1-2% of all malignant disease & 10-33% hematologic malignancies. Incidence increases with age. Men > Women. Blacks >Whites

• Presentation: Bone pain precipitated by movement = most common. Other common symptoms include weakness, fatigue and weight loss.

http://radiology.uchc.edu/Code/1454.ht m

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Sarah Billmeier, HMS IIIGillian Lieberman, MD

Staging of MM – Durie & Salmon

Stage I – Low cell mass

All of the following Present:

• Hgb > 10 g/dl

• Serum IgG < 5 g/dl

• Serum IgA <3 g/dl

• Normal serum calcium

• Urine monoclonal prtn excretion <4 g/day

• No generalized lytic bone lesions

Stage III - High Cell Mass

>1 of the following:

• Hgb <8.5 g/dl

• Serum IgG > 7 g/dl

• Serum IgA > 5 g/dl

• Serum calcium >12 mg/dl

• Urine monoclonal prtn excretion >12 g/day

• Advanced lytic bone lesions

Stage II – Intermediate cell mass Fitting neither I nor III

Based on staging and other prognostic indicators median survival ranges from 5 years

to 15 months

Systemic tx is indicated for Stage II & III patients

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Sarah Billmeier, HMS IIIGillian Lieberman, MD

The Skeletal SurveyThe skeletal survey used at dx of MM to detect bone pathology for:

• Establishment of a baseline for future follow-up • Assessment of fracture risk• Staging

The skeletal survey in an adult consists of plain radiographs of the• skull (AP and lateral)• ribs (AP global, AP on the lower thoracic grid, two oblique views)• spine (AP and lateral of cervical, thoracic and lumbar areas)• pelvis (AP)• femurs (AP and lateral)• humerus (AP and lateral)

Bone scintigraphy is less sensitive than plain films in identifying lytic lesions. Most lesions of MM are not apparent unless a fracture occurred or the lesion is in a healing phase.

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Sarah Billmeier, HMS IIIGillian Lieberman, MD

MRI for lesion detection in MM?Several studies suggest

that MR is superior to radiographs for detection

of lesions in the spine.

The Durie and Salmon staging system was

developed in 1975 when only plain film was

available to image the skeleton.

Currently, MRI is not standardly used in MM

patients.Spine imaging of the same patient using

MRI and plain film

Baur A. et al. Cancer. 2002 Sep 15.

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Sarah Billmeier, HMS IIIGillian Lieberman, MD

Role for PET?

By directly imaging the increased metabolic activity of the bone

marrow PET may be able to:

• detect early lesions missed by skeletal

surveys or MRI

• may be useful to monitor response to

therapy

Currently PET is not commonly used for MM

imaging.PACS, BIDMC

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Sarah Billmeier, HMS IIIGillian Lieberman, MD

What Causes Lytic Lesions in MM?

• Patients taking bisphosphonates (which inhibit osteoclasts) do not have an increase in bone formation within lytic lesions

• Long search for a secreted factor that activates osteoclasts

• Myeloma cells secrete RANKL to increase osteoclast activity and DKKI to inhibit osteoblasts, creating a bias toward negative bone balanceGlass DA 2nd. Patel MS. Karsenty G. NEJM 2003 Dec

25.

• Formation of osteolytic lesions involves uncoupling of bone resorption and formation

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Sarah Billmeier, HMS IIIGillian Lieberman, MD

A Visual Journey by Case Series• Multiple Myeloma: Lytic

Patient 1: GWPatient 2: SL

• Multiple Myeloma: OsteopenicPatient 3: BV

• Sclerotic Plasma Cell NeoplasmsDiffuse: Sclerotic Multiple Myeloma

Patient 4: HMSolitary: Sclerotic PlasmacytomaMultifocal: POEMS

Patient 5: OJ (Plasmocytoma)Patient 6: BP (Mixed lytic-sclerotic)

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Sarah Billmeier, HMS IIIGillian Lieberman, MD Lytic Lesions of MM:

Patient 1 - GWGW is a 71 y.o. female who presents to the EW with mild pain and an inability to walk. Labs indicate M-protein by electrophoresis.

Pathologic fracture

Multiple lytic lesions without sclerotic margins

Courtesy of Dr. Ferris Hall

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Sarah Billmeier, HMS IIIGillian Lieberman, MD

Lytic MM: GW, Additional Radiographs

Lateral skull film with classic

punched out lytic lesions of various sizes

Courtesy of Dr. Ferris Hall

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Sarah Billmeier, HMS IIIGillian Lieberman, MD

DDx Multiple Punched-Out Lytic Lesions of Bone with Nonsclerotic Margins

Common:

• Arthritis (eg, gout, rheumatoid, osteoarthritis)

• Brown tumors of hyperparathyroidism

• Langerhans Cell Histiocytosis

• Metastases

• Multiple Myeloma

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Sarah Billmeier, HMS IIIGillian Lieberman, MD

Lytic MM Patient 2: Disease ProgressionSL was diagnosed in 1971 at age 28, initially with an isolated

plasmacytoma.

10% of MM patients have an indolent course.

June 1976 April 1985

All films this slide courtesy of Dr. Ferris Hall

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Sarah Billmeier, HMS IIIGillian Lieberman, MD

Complications of Bone Destruction

Pathologic Fracture

Additional Lesions

Courtesy of Dr. Ferris Hall

Lytic lesions may cause:

• hypercalcemia

• pathologic fractures

• loss of height

• cord compression

• osteoporosis

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Sarah Billmeier, HMS IIIGillian Lieberman, MD

Osteopenia in MM

• Evidence for diffuse bone loss in 60% of multiple myeloma patients

• In 5% of patients bone loss occurs without focal lytic lesions

• Bisphosphonates often used for treatment of bone disease in MM. Use of palmidronate is associated with:

↓ pathologic fractures↓ need for irradiation/surgery of bone↓ spinal cord compressionPrevention of hypercalcemia↓ bone pain.

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Sarah Billmeier, HMS IIIGillian Lieberman, MD

Osteopenic MM: Patient 3 - BV

Lateral thoracic spine illustrates diffuse osteopenia

PACS, BIDMC

History: BV is a 54 y.o. female diagnosed with MM following a fall onto her hip, which lead to the discovery of lytic lesions in the pubic bone, leukopenia, anemia, and an monoclonal IgG lambda spike. A confirming bone marrow biopsy showed greater than 30% plasma cells. Compression Fracture

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Sarah Billmeier, HMS IIIGillian Lieberman, MD

Osteosclerotic MM• 3-4% plasma cell neoplasms are sclerotic

• Sclerotic plasma cell neoplasms can be divided into:

Solitary: Sclerotic plasmacytoma

Diffuse: Sclerotic MM

Multifocal: POEMS

• 85% sclerotic myeloma patients present with polyneuropathy

• More indolent course

• Affects younger patients

• Lambda > Kappa chains

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Sarah Billmeier, HMS IIIGillian Lieberman, MD

Diffuse Osteosclerotic MM: Patient 4 - HM

Bone “superscan” with symmetrically diffuse increase of tracer uptake and diminished renal activity

Lateral spine radiograph of diffuse

sclerosisPACS, BIDMC

PACS, BIDMC

History: HM is 77 y.o. woman who presented with DOE and

pancytopenia. Initial work-up for lymphoproliferative disease prompted a CXR, CT, bone scan, skeletal survey and

electrophoresis.

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Sarah Billmeier, HMS IIIGillian Lieberman, MD

POEMS• Polyneuropathy – predominantly sensorimotor

• Organomegally – liver, spleen or lymph nodes

• Endocrinopathy – impotence, amenorrhea, gynecomastia, IGT

• Monoclonal gammopathy – myeloma in >50%, MGUS or others

• Skin Changes – hyperpigmentation, thickening, hirsutism

• Rare! • Affected patients may not have all findings• Pathogenesis remains unknown• Skeletal findings usually on axial and proximal appedicular skeleton and are usually sclerotic or infrequently mixed lytic-sclerotic

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Sarah Billmeier, HMS IIIGillian Lieberman, MD

Sclerotic Plasmacytoma POEMS Pt. 5: OJHistory: OJ is a 42 y.o. male who presented with back pain,

endocrinopathy, parasthesias & leg weakness. IgG was slightly ↑, Bx diagnosed a plasmacytoma. MRI was performed to evaluate

CC.

PACS, BIDMC PACS, BIDMC

CT: well defined lytic lesion with

sclerotic rim. No cortical

destruction or bony

expansion.

PET fusion: Homogenous

focus of intense FDG uptake

T2W fat suppressed MRI: lesion with dark

signal margin & high

intensity central aspect.

T1W MRI: lesion with a dark margin

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Sarah Billmeier, HMS IIIGillian Lieberman, MD

Mixed Lytic-sclerotic POEMS Patient 6: BP

Plain film of the pelvis: multiple foci of sclerosis

Round lytic lesion within

sclerotic focus

BP is a 27 y.o. male

who presents with

gynecomasti a, impotence

& papilledema

Courtesy of Dr. Ferris Hall

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Sarah Billmeier, HMS IIIGillian Lieberman, MD

Mixed Lyic-sclerotic POEMS

Patient PB’s Axial CT of the pelvis at the level of

the lytic lesion seen on plain film

Courtesy of Dr. Ferris Hall

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Sarah Billmeier, HMS IIIGillian Lieberman, MD

SummaryPlasma cell neoplasms are often first diagnosed radiologically

Plain film & potentially MRI or PET findings influence tumor prognosis and therapy decisions

Skeletal surveys may be supplemented by additional imaging modalities in the future for lesion detection and follow-up

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Sarah Billmeier, HMS IIIGillian Lieberman, MD References

• Aggarwal S. Goulatia RK. Sood A. Prasad K. Ahuja GK. Mitchell MJ. Kumar A. POEMS syndrome: a rare variety of plasma cell dyscrasia. AJR. American Journal of Roentgenology. 155(2):339-41, 1990 Aug.

• Baur A. Stabler A. Nagel D. Lamerz R. Bartl R. Hiller E. Wendtner C. Bachner F. Reiser M. Magnetic resonance imaging as a supplement for the clinical staging system of Durie and Salmon?. Cancer. 95(6):1334-45, 2002 Sep 15.

• Croucher PI. Apperley JF. Bone disease in multiple myeloma. British Journal of Haematology. 103(4):902-10, 1998 Dec.

• Edelman RR. Kaufman H. Kolodny GM. Case report 350: Multiple myeloma--blastic type. Skeletal Radiology. 15(2):160-3, 1986.

• Glass DA 2nd. Patel MS. Karsenty G. A new insight into the formation of osteolytic lesions in multiple myeloma. New England Journal of Medicine. 349(26):2479-80, 2003 Dec 25.

• Jadvar H. Conti PS. Diagnostic utility of FDG PET in multiple myeloma. Skeletal Radiology. 31(12):690-4, 2002 Dec.

• Hall FM. Gore SM. Osteosclerotic myeloma variants. Skeletal Radiology. 17(2):101-5, 1988.• Kyle, RA. Clinical and laboratory manifestations of multiple myeloma. UpToDate. 2004, Jan

24.• Lecouvet FE. Malghem J. Michaux L. Maldague B. Ferrant A. Michaux JL. Vande Berg BC.

Skeletal survey in advanced multiple myeloma: radiographic versus MR imaging survey. British Journal of Haematology. 106(1):35-9, 1999 Jul.

• Longo, DL. Plasma Cell Disorders. Harrisons Online. www.harrisonsonline.com accessed 2004, July 20.

• Pathweb. Diseases of Bone, Multiple Myeloma. http://radiology.uchc.edu/Code/1454.htm•

Reeder, Maurice M. Reeder and Felson's Gamuts in Radiology: Comprehensive Lists of Roentgen differential diagnosis, 3rd ed. Springer-Verlag, New York, 1993.

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Sarah Billmeier, HMS IIIGillian Lieberman, MD

Acknowledgements

• Ferris Hall, MD• Mary Hochman, MD• Stephanie DiPerna, MD• Gillian Lieberman, MD• Pamela Lepkowski• Larry Barbaras our Webmaster