2nd year bds pathology multiple myeloma

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Multiple Myeloma - 2nd Year BDS Pathology

Sources: Robbins & Kumar Basic Pathology; Robbins, Cotran & Kumar Pathologic Basis of Disease

Definition

Multiple myeloma is a malignant neoplasm of plasma cells (terminally differentiated B lymphocytes), characterized by:

Bone marrow infiltration by clonal plasma cells
Production of a monoclonal immunoglobulin (M protein)
Extensive skeletal destruction
Systemic effects on kidneys, immune system, and blood

Epidemiology

Feature	Detail
Incidence	~30,000 new cases/year in the USA; 1% of all cancer deaths in Western countries
Age	Peak at 65-70 years; rare under 40
Sex	More common in males
Race	Higher incidence in people of African descent

Pathogenesis

Genetic basis:

Frequent chromosomal translocations involving the IGH locus on chromosome 14q32 fused to proto-oncogenes (cyclin D1, cyclin D3)
Deletions of chromosome 17p (TP53 locus) - associated with poor prognosis
Late-stage translocations involving MYC - seen in aggressive disease / plasma cell leukemia
Mutations in NF-κB pathway genes support B-cell survival

Key cytokine - Interleukin-6 (IL-6):

Produced by bone marrow stromal cells AND tumor cells themselves
Major growth and survival factor for myeloma cells
High serum IL-6 = poor prognosis

Bone destruction mechanism:

Myeloma cells release MIP1α (CCL3) - a chemokine that activates osteoclasts
Myeloma-derived factors upregulate RANKL on stromal cells → osteoclast activation
Other tumor factors inhibit osteoblasts (via Wnt pathway inhibition)
Net result: uncoupled bone resorption → hypercalcemia + pathologic fractures

M Protein (Monoclonal Protein)

Type	Frequency
IgG	60% (most common)
IgA	20-25%
Light chains only (κ or λ)	~20%
IgM, IgD, IgE	Rare
Nonsecretory	~1%

Excess free light chains are small enough to pass through the glomerulus and appear in urine as Bence Jones proteins
Free and complete M proteins are present together in 60-70% of cases

Morphology

Gross / Radiologic

Multiple "punched-out" lytic bone lesions, 1-4 cm in diameter
Lesions begin in medullary cavity, erode cancellous bone, then destroy cortex
Pathologic fractures - most common in vertebral column and femur
Bones most commonly affected (in order): vertebral column, ribs, skull, pelvis, femur, clavicle, scapula
Less commonly: diffuse demineralization (osteopenia) rather than focal defects

Skull X-ray - classic "pepper-pot" or punched-out appearance:

Multiple myeloma of the skull (lateral X-ray) - punched-out lytic lesions in the calvaria

Fig. 13.21 - Multiple myeloma of the skull. Sharply punched-out bone lesions are most obvious in the calvaria. (Robbins, Cotran & Kumar)

Bone Marrow Histology

Plasma cells constitute > 30% of marrow cellularity (diagnostic threshold)
Normal marrow elements are partially or completely replaced

Key cytologic features of myeloma cells:

Variant	Feature
Plasmablasts	Vesicular chromatin, prominent single nucleolus
Russell bodies	Cytoplasmic globular immunoglobulin inclusions
Dutcher bodies	Nuclear immunoglobulin inclusions
Flame cells	Fiery red cytoplasm
Mott cells	Multiple grapelike cytoplasmic droplets
Multinucleated cells	Seen in advanced disease

Bone marrow aspirate - myeloma cells with prominent nucleoli and cytoplasmic droplets:

Bone marrow aspirate in multiple myeloma showing plasma cells with multiple nuclei, prominent nucleoli, and cytoplasmic Ig droplets (Mott cells)

Fig. 13.22 - Bone marrow aspirate. Normal marrow largely replaced by plasma cells including forms with multiple nuclei and cytoplasmic droplets. (Robbins, Cotran & Kumar)

Peripheral Blood - Rouleaux Formation

High levels of M protein in blood cause red cells to stack in linear arrays (rouleaux)
Characteristic but not specific (also seen in lupus, early HIV)

Myeloma Kidney (Renal Morphology)

Proteinaceous casts in distal convoluted tubules and collecting ducts (mainly Bence Jones proteins + albumin)
Multinucleate giant cells (macrophages) surround the casts
Adjacent tubular epithelial cells become necrotic/atrophic (toxic effect of Bence Jones proteins)
Additional renal lesions: metastatic calcification, AL amyloidosis in glomeruli and vessel walls, bacterial pyelonephritis

Immunophenotype

Marker	Status
CD138 (Syndecan-1)	Positive - hallmark of plasma cells
CD56	Often positive - useful for identifying small tumor populations
Cytoplasmic κ or λ	Present (light chain restriction = clonality)

Related Entities (Plasma Cell Neoplasms)

Entity	Key Feature
Smoldering myeloma	High M component, no symptoms - may not require treatment for years
Solitary plasmacytoma	Single bony or soft-tissue mass; can progress to myeloma
MGUS (Monoclonal Gammopathy of Undetermined Significance)	Common asymptomatic precursor; ~1%/year risk of progression to myeloma
Waldenström macroglobulinemia	IgM excess → hyperviscosity; associated with lymphoplasmacytic lymphoma
AL amyloidosis	λ light chains deposit as amyloid; 15% of myeloma patients

Laboratory Findings

Serum protein electrophoresis (SPEP):

Normal serum: broad, diffuse band in γ-globulin region
Myeloma: single, sharp, tall M-spike (narrow spike = monoclonal protein)

Immunofixation electrophoresis (IFE):

Characterizes the M protein by heavy chain class (G, A, M) and light chain type (κ or λ)

Serum protein electrophoresis comparing normal serum (broad band) vs patient serum (sharp M-protein spike), with immunofixation showing IgG-kappa M protein

Fig. 13.23 - M protein detection. Normal serum shows a broad band (arrow); myeloma serum shows a single sharp spike (arrowhead) confirmed as IgG-κ by immunofixation. (Robbins, Cotran & Kumar)

Other lab findings:

↑ Serum immunoglobulins (M protein)
Bence Jones proteinuria (urine light chains) - heat test: precipitates at 40-60°C, re-dissolves at 100°C
Normocytic normochromic anemia (marrow replacement)
↑ ESR, ↑ serum calcium
Renal failure (elevated creatinine)
Moderate leukopenia and thrombocytopenia

Clinical Features (Mnemonic: CRAB)

Letter	Feature	Mechanism
C - Hypercalcemia	Confusion, weakness, lethargy, constipation, polyuria	Bone resorption
R - Renal failure	Up to 50% of patients	Bence Jones toxicity, casts, amyloid, hypercalcemia
A - Anemia	Normocytic normochromic	Marrow replacement
B - Bone lesions	Pain, pathologic fractures	Osteoclast activation

Additional features:

Recurrent bacterial infections - most common cause of death. Myeloma cells suppress normal B-cell function → profound hypogammaglobulinemia despite high total Ig
Cellular immunity is relatively preserved
Hyperviscosity (less common than Waldenström)
AL amyloidosis causing multi-organ deposits

Oral/Dental Relevance (BDS Focus)

Jaw (mandible) can be involved with lytic bone lesions - may present as unexplained tooth mobility, jaw pain, or a "punched-out" appearance on dental X-rays
Rare cases present as gingival swelling as the primary oral manifestation
Solitary plasmacytoma of the jaw has been reported
Bisphosphonate therapy used for myeloma bone disease carries risk of medication-related osteonecrosis of the jaw (MRONJ), especially with IV zoledronic acid/pamidronate
Always include multiple myeloma in differential diagnosis of radiolucent jaw lesions in elderly patients

Diagnosis

Imaging - skeletal survey (skull, spine, pelvis) showing punched-out lytic lesions
Bone marrow biopsy - > 10% clonal plasma cells (symptomatic myeloma requires ≥ 10% plus organ damage, or ≥ 60%)
Serum/urine protein electrophoresis - M protein detection
Immunofixation - characterize M protein class
Complete blood count - anemia, leukopenia, thrombocytopenia
Serum calcium, creatinine, β2-microglobulin, LDH - for staging and prognosis

Prognosis

Patients with multiple bony lesions, if untreated: survival < 6-12 months
Smoldering myeloma: may not require treatment for years
Median survival with treatment: ~5 years
Cures remain rare, but modern agents (proteasome inhibitors, IMiDs, monoclonal antibodies) have significantly improved outcomes

Key exam points for 2nd year BDS:

Multiple myeloma = plasma cell malignancy - NOT a B-cell lymphoma
Classic lesion = punched-out lytic bone lesions (no osteoblastic reaction = no increase in serum alkaline phosphatase, unlike metastatic carcinoma)
Bence Jones protein = free immunoglobulin light chains in urine - hallmark
M protein/M spike on electrophoresis
IL-6 = key growth factor
Russell bodies = cytoplasmic Ig inclusions
CRAB criteria for diagnosis
Most common M protein = IgG

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