Multiple Myeloma

Overview

• Median age at diagnosis: 70 years
• More common in males
• Occurs more frequently in people of African descent in the US (reason unknown)
• Principally involves the bone marrow and is associated with lytic skeletal lesions

M Protein Production

• IgG — 60% (most common)
• IgA — 20–25%
• IgM, IgD, IgE — rare
• Remaining cases: only κ or λ free light chains (Bence Jones proteins)

Pathogenesis

Pathologic Effects (Morbidity & Mortality)

1. Skeletal Destruction

• Myeloma-derived factors upregulate RANKL on stromal cells → activates osteoclasts
• Tumor factors also inhibit osteoblast function
• Net result: increased bone resorption → hypercalcemia and pathologic fractures

2. Immune Defects

• Myeloma cells compromise normal B-cell function through uncertain mechanisms
• Despite elevated serum immunoglobulin (M protein), production of functional antibodies is profoundly depressed
• Result: high risk for bacterial infections

3. Renal Dysfunction ("Myeloma Kidney")

• Obstructive proteinaceous casts in distal convoluted tubules and collecting ducts (mostly Bence Jones proteins + albumin + tubular secretions)
• Light chain deposition in glomeruli/interstitium — as AL amyloid or linear deposits
• Hypercalcemia → dehydration, renal stones
• Increased incidence of bacterial pyelonephritis (from hypogammaglobulinemia)

Morphology

• Multifocal destructive lytic lesions involving vertebral column, ribs, skull, pelvis, femur, clavicle, scapula
• Arise in medullary cavity → erode cancellous bone → destroy cortex
• Appear as "punched-out" defects 1–4 cm in diameter on imaging (Fig. 10.28A)
• Pathologic fractures most frequent in vertebral column and femur

• Plasma cells typically >30% of marrow cellularity (required for diagnosis)
• Cells may resemble normal plasma cells or show abnormal features:
  • Prominent nucleoli
  • Russell bodies — cytoplasmic inclusions containing immunoglobulin (Fig. 10.28B)
• Late disease: spread to viscera and soft tissues; terminal stage may show a leukemic picture

• Proteinaceous Bence Jones casts in distal tubules and collecting ducts
• Casts surrounded by multinucleate giant cells (macrophage-derived)
• Adjacent tubular epithelium undergoes necrosis/atrophy from Bence Jones protein toxicity
• Other renal changes: metastatic calcification, AL amyloidosis (glomeruli/vessel walls), bacterial pyelonephritis, and rarely neoplastic plasma cell infiltrates in the interstitium

Laboratory Findings

Clinical Features

1. Plasma cell effects on skeleton — pathologic fractures, chronic bone pain
2. Excessive/abnormal immunoglobulins — hyperviscosity (with IgM/IgA particularly), amyloidosis
3. Suppression of humoral immunity — recurrent bacterial infections
4. Renal insufficiency — occurs in up to 50% of patients; second leading cause of death (after infections); correlated with degree of Bence Jones proteinuria

Diagnosis

• Imaging: typical punched-out lytic bone lesions
• Labs: M protein + Bence Jones protein quantification
• Definitive: bone marrow examination (plasma cells >30%)

Prognosis & Treatment

• Proteasome inhibitors (e.g., bortezomib) — myeloma cells accumulate misfolded Ig chains; proteasome inhibition exacerbates this, triggering apoptosis
• Thalidomide-like drugs (IMiDs) — stimulate degradation of pro-oncogenic proteins in myeloma cells
• Bisphosphonates — inhibit osteoclast-mediated bone resorption; reduce fractures and hypercalcemia
• Hematopoietic stem cell transplantation — prolongs life but not curative
• CAR-T cell therapy — cytotoxic T cells engineered to recognize plasma cell antigens (newer approach)

Note: There is no "Levinson" textbook in the available library. The content above is fully sourced from Robbins & Kumar Basic Pathology — the standard Robbins text for basic pathology. If you meant a different book (e.g., Jawetz, Melnick & Adelberg's Medical Microbiology by Levinson), please clarify and I'll look it up.

Non-Hodgkin Lymphoma (NHL)

Overview

• Most arise in lymph nodes but extranodal presentations are common
• NHL is broadly divided into indolent (slow-growing, often incurable) and aggressive (fast-growing, but often curable) types
• Painless lymphadenopathy is the most common presentation

1. Follicular Lymphoma

Pathogenesis

• 85% have a (14;18) translocation — fuses the BCL2 gene (chr 18) to the IgH locus (chr 14)

• Results in overexpression of BCL2 protein → inhibition of apoptosis → cell survival
• Additional mutations in histone-modifying genes suggest epigenetic contributions

Morphology

FIG. 10.20 — Follicular lymphoma. (A) Nodular aggregates of lymphoma cells throughout the node. (B) Small cleaved centrocytes mixed with larger centroblasts; arrow indicates a prolymphocyte-like cell.

• Lymph nodes effaced by a distinctly nodular proliferation
• Predominantly centrocytes — slightly larger than resting lymphocytes with angular "cleaved" nuclei, coarse chromatin, indistinct nucleoli
• Mixed with variable centroblasts — larger cells with vesicular chromatin, several nucleoli
• Few mitoses, no apoptosis — distinguishes from follicular hyperplasia (where both are prominent)
• Occasional predominance of large cells = more aggressive histology

Immunophenotype

Clinical Features

• Adults >50 years; equal sex distribution
• Presents as painless, generalized lymphadenopathy
• Bone marrow involved at diagnosis in ~80% of cases
• Indolent but incurable — median survival ~10 years
• Transformation to aggressive DLBCL can occur (worsens prognosis)

2. Diffuse Large B-Cell Lymphoma (DLBCL)

Pathogenesis

Morphology

FIG. 10.21 — Diffuse Large B-Cell Lymphoma. Tumor cells are large (3–4× resting lymphocytes), with round/oval nuclei, dispersed chromatin, and distinct nucleoli.

• Large cells (3–4× resting lymphocyte size), variable morphology
• Round/oval nuclei with dispersed chromatin, several nucleoli, pale cytoplasm
• Some tumors have multilobate vesicular nuclei with prominent central nucleoli
• Occasionally highly anaplastic with Reed-Sternberg–like giant cells

Immunophenotype

• CD20 positive; variably express surface IgM/IgG, CD10, MYC, BCL2

Special Subtypes

• EBV-associated DLBCL — arises in AIDS, iatrogenic immunosuppression, elderly; posttransplant cases may be polyclonal initially and regress with restored immunity
• Primary effusion lymphoma — associated with HHV8/KSHV; arises in pleural, pericardial, or peritoneal cavities; HHV8 encodes oncoproteins including a cyclin D1 homolog
• Mediastinal large B-cell lymphoma — often involves thymus; young women; spreads to abdomen and CNS; frequently shows PD-L1 overexpression (immune evasion mechanism)

Clinical Features

• Median age ~60 years, but can occur at any age (~15% of childhood lymphomas)
• Rapidly enlarging symptomatic mass at one or more sites
• Extranodal presentations common — GI tract most frequent extranodal site
• Liver, spleen, and bone marrow involvement uncommon at diagnosis
• Aggressive and rapidly fatal if untreated
• With intensive chemotherapy + anti-CD20 immunotherapy (rituximab): complete remission in 60–80%; ~50% appear cured
• CAR-T cell therapy (anti-CD19) can be curative for relapsed/refractory cases

3. Mantle Cell Lymphoma

Pathogenesis

• (11;14) translocation — fuses cyclin D1 gene to the IgH locus
• Overexpression of cyclin D1 → promotes G1→S cell cycle progression (via Rb hyperphosphorylation) → uncontrolled proliferation

Morphology

Mantle cell lymphoma. (A) Vaguely nodular pattern, no proliferation centers. (B) Small cells with irregular nuclear contours.

• Diffuse or vaguely nodular pattern in lymph nodes
• No proliferation centers (distinguishes from CLL/SLL)
• Cells slightly larger than normal lymphocytes; irregular nucleus, inconspicuous nucleoli, scant cytoplasm
• Occasional blastoid variant (larger, lymphoblast-like cells)
• Bone marrow involved in most cases; peripheral blood in ~20%
• GI involvement: lymphomatoid polyposis (multifocal submucosal nodules resembling polyps)

Immunophenotype

• Surface IgM, IgD; CD20+; CD5+ (shared with CLL/SLL); Cyclin D1+ (distinguishing marker)

Clinical Features

• Fatigue, lymphadenopathy, generalized disease (bone marrow, spleen, liver, GI tract)
• Moderately aggressive, incurable
• Median survival: 6–7 years
• Treatment includes BTK inhibitors (tumor cells depend on B-cell receptor signaling for survival)

4. Extranodal Marginal Zone Lymphoma (MALToma)

Pathogenesis

• Arises within sites of chronic inflammation:
  • Autoimmune: salivary glands (Sjögren syndrome), thyroid (Hashimoto thyroiditis)
  • Infection: H. pylori gastritis (most common)
• Tumor cells depend on inflammatory cytokines from H. pylori–specific T cells for growth
• Key insight: H. pylori eradication with antibiotics often causes tumor regression — a unique cancer therapy

5. Burkitt Lymphoma

Pathogenesis

• Translocations involving MYC gene (chromosome 8):
  • Most common: t(8;14) — MYC fused to IgH locus (chr 14)
  • Variants: t(8;2) and t(8;22) — MYC fused to κ or λ light chain loci
• MYC = master regulator of Warburg metabolism (aerobic glycolysis) → drives rapid cell growth
• Burkitt lymphoma is among the fastest growing human tumors
• EBV association: most endemic (African) cases + ~20% of sporadic cases

Morphology

FIG. 10.22 — Burkitt lymphoma. Uniform intermediate-sized cells, high mitotic rate, and classic "starry sky" pattern.

• Intermediate-sized tumor cells with round/oval nuclei, 2–5 distinct nucleoli
• Moderate basophilic/amphophilic cytoplasm with lipid vacuoles (on smears)
• Very high proliferation AND apoptosis rates → tissue macrophages ingesting nuclear debris → "starry sky" pattern (macrophages = stars; dark tumor cells = sky)

Immunophenotype

• Surface IgM; CD20+; CD10+; BCL6+ (germinal center B-cell markers)

Clinical Features

• Affects children and young adults
• Usually arises at extranodal sites:
  • Endemic (African): maxillary/mandibular jaw masses
  • Sporadic (North America): abdominal tumors — bowel, retroperitoneum, ovaries
• Leukemic presentations: must distinguish from B-ALL (different treatment)
• Highly aggressive but majority cured with very intensive chemotherapy

6. Other Notable NHL Entities

Hairy Cell Leukemia

• Uncommon, indolent B-cell neoplasm
• Nearly all cases have activating BRAF mutations (also mutated in melanoma, colon cancer)
• Morphology: fine hairlike cytoplasmic projections
• Markers: CD20+, surface Ig+, CD11c+, CD103+ (distinctive)
• Treated with purine analogues (e.g., cladribine) — induces prolonged remissions

Peripheral T-Cell Lymphomas

• Uncommon, heterogeneous group
• Most are aggressive with a poor prognosis
• Example: Anaplastic large cell lymphoma (ALCL) — characterized by ALK kinase fusions (e.g., t(2;5) → NPM-ALK); responds to ALK inhibitors

Comparison Summary Table

Note on "Levinson": No textbook by Levinson exists in the available library. The content above is entirely from Robbins & Kumar Basic Pathology. If you meant a specific microbiology or immunology text, please clarify the full title.