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1. Plasma Cell Neoplasms - Classification and Multiple Myeloma

Classification of Plasma Cell Neoplasms

WHO Classification of Plasma Cell Neoplasms

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Multiple Myeloma - Detailed Discussion

Epidemiology

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Molecular Pathogenesis

Key Molecular Events

• del(17p13) - Loss of TP53: ~10% of newly diagnosed, increases to 30-40% at relapse; worst prognosis
• del(13q14) - Loss of RB1 and/or miR-15a/miR-16-1: seen in ~50% of myelomas
• Loss of CDKN2C (p18INK4c) leads to uncontrolled cyclin D-CDK4/6 activity

• Myeloma cells adhere to bone marrow stromal cells (BMSC) via VLA-4/VCAM-1 and syndecan-1 (CD138)
• Adhesion triggers IL-6 secretion by BMSCs → activates JAK/STAT3 pathway in myeloma cells (pro-survival, anti-apoptotic)
• RANKL (from myeloma cells and BMSCs) activates osteoclasts → bone destruction; simultaneously DKK-1 inhibits Wnt signaling → suppresses osteoblasts → net osteolysis
• VEGF promotes angiogenesis and tumor growth
• Immunosuppressive microenvironment: regulatory T cells, MDSCs, and PD-L1 expression facilitate immune evasion

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Morphology

• Plasma cells typically constitute >30% of marrow cellularity
• Cells have characteristic clock-face/cartwheel chromatin and perinuclear clearing (Golgi hof)
• Variants: Plasmablasts (vesicular chromatin, prominent nucleolus), Flame cells (fiery red cytoplasm), Mott cells (multiple grapelike cytoplasmic droplets containing Ig), Russell bodies (cytoplasmic Ig inclusions), Dutcher bodies (nuclear Ig inclusions)
• Multinucleated forms and bizarre cells may be seen

• Rouleaux formation - red cells stack in linear arrays due to elevated M protein (not specific; also seen in lupus, early HIV)
• Occasionally plasma cell leukemia when tumor cells flood peripheral blood

• CD138+ (syndecan-1) - most specific marker
• CD38+ (strong)
• Often CD56+ (unlike normal plasma cells) - helpful in identifying small tumor populations
• Cytoplasmic κ or λ light chain (clonal restriction)
• CD19-, CD20- (distinguishes from normal plasma cells and lymphoplasmacytic lymphoma)

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Diagnosis

• C - hyperCalcemia: serum calcium >0.25 mmol/L above upper normal or >2.75 mmol/L
• R - Renal insufficiency: creatinine >177 µmol/L or CrCl <40 mL/min
• A - Anemia: Hb <100 g/L or >20 g/L below lower normal
• B - Bone lesions: ≥1 osteolytic lesion on CT/PET-CT/skeletal survey

• S - ≥60% clonal plasma cells in marrow
• Li - serum free Light chain ratio ≥100 (involved:uninvolved)
• M - >1 focal lesion on MRI (≥5 mm)

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Differential Diagnosis

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Cytogenetics

• del(17p13) - TP53 loss - median OS ~24-26 months
• t(4;14)(p16;q32) - FGFR3/MMSET - median OS ~33 months
• t(14;16)(q32;q23) - MAF
• t(14;20) - MAFB
• Gain(1q21) - CKS1B amplification - adverse
• del(1p32) - CDKN2C loss

• Hyperdiploidy (trisomies of odd chromosomes) - best prognosis
• t(11;14)(q13;q32) - Cyclin D1 - standard risk (note: venetoclax-sensitive)
• del(13q) by itself - standard risk (when FISH-based)

• Stage I: β2M <3.5 mg/L + albumin ≥3.5 g/dL
• Stage II: Neither I nor III
• Stage III: β2M ≥5.5 mg/L

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Prognosis

• Hyperdiploid karyotype
• t(11;14) - standard risk
• Low β2-microglobulin
• Low LDH
• Normal creatinine and calcium
• MRD negativity after treatment
• Age <65 years
• Good performance status
• Response to initial therapy

• del(17p), t(4;14), t(14;16), t(14;20), gain(1q21)
• High β2-microglobulin (>5.5 mg/L)
• Low albumin
• Elevated LDH
• Renal failure
• Plasmablastic morphology
• Plasma cell leukemia
• MRD positivity post-treatment
• High plasma cell proliferation index

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Complications

1. Skeletal Complications

• Osteolytic bone lesions - the hallmark; due to uncoupled bone remodeling (increased osteoclast activity, suppressed osteoblast activity)
• Pathological fractures - vertebral compression fractures, long bone fractures
• Spinal cord compression - from vertebral collapse or epidural plasmacytoma
• Hypercalcemia - from osteoclast-mediated bone resorption → confusion, weakness, lethargy, constipation, polyuria; may precipitate renal failure

2. Renal Complications (Myeloma Kidney)

• Cast nephropathy (myeloma kidney) - the most common; Bence Jones proteins (free light chains) form casts in distal tubules and collecting ducts → tubular obstruction + giant cell reaction → tubulointerstitial nephritis
• Light chain deposition disease (LCDD) - non-fibrillar deposits of κ light chains in glomeruli and tubules → nephrotic syndrome
• AL amyloidosis - fibrillar λ light chain deposits; Congo red positive; glomerulonephritis/nephrotic syndrome
• Hypercalcemic nephropathy
• Hyperuricemic nephropathy
• Infections contributing to AKI

3. Hematologic Complications

• Anemia - normocytic normochromic; due to marrow replacement, renal EPO deficiency, cytokine suppression (IL-6, TNF-α)
• Leukopenia and thrombocytopenia - from marrow infiltration
• Hyperviscosity - particularly with IgA and IgM myelomas; causes visual disturbances, neurological symptoms, cardiac failure

4. Immunologic Complications

• Immunoparesis - suppression of normal (polyclonal) immunoglobulins → recurrent bacterial infections (especially encapsulated organisms: Streptococcus pneumoniae, Haemophilus influenzae)
• This is one of the leading causes of death in myeloma

5. Amyloidosis (AL)

• Primary AL amyloidosis in ~10% of myeloma patients
• Periorbital purpura ("raccoon eyes"), macroglossia, cardiomyopathy, hepatomegaly, peripheral neuropathy, nephrotic syndrome

6. Neurological Complications

• Hypercalcemia → encephalopathy
• Spinal cord/nerve root compression
• Peripheral neuropathy (from amyloid, myeloma infiltration, or treatment-related)
• Hyperviscosity → central neurological symptoms
• POEMS syndrome (rare variant): Polyneuropathy, Organomegaly, Endocrinopathy, M protein, Skin changes

7. Coagulation Abnormalities

• M proteins may interfere with coagulation factors, causing bleeding tendency
• Increased risk of thrombosis (especially with lenalidomide + dexamethasone)

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2. Plasmacytoma - Short Note

Types

• ~3-5% of plasma cell neoplasms
• Most commonly affects axial skeleton (vertebrae, pelvis, ribs, skull)
• Same age and sex distribution as myeloma (older males)
• Clinically: bone pain, pathological fracture; no CRAB features
• Serum/urine M protein may be mildly elevated in some
• Bone marrow elsewhere is normal (<5% plasma cells)
• Radiographically: solitary lytic lesion
• Histology: sheets of plasma cells replacing normal bone
• Natural history: virtually all SPB eventually progress to overt multiple myeloma, but this may take 10-20 years or longer
• Treatment: local radiation therapy; monitor for progression

• Arises in soft tissues without involvement of bone or marrow
• Preferential sites: upper respiratory tract (nasal cavity, paranasal sinuses, nasopharynx, oropharynx) - accounts for ~80%
• Also: lungs, GI tract, thyroid, testes
• Older males predominantly
• M protein rarely elevated
• Prognosis is much more favorable than SPB: extraosseous plasmacytomas, particularly in the upper respiratory tract, are frequently cured by local resection or radiation
• Only ~15% progress to multiple myeloma (vs. nearly 100% for SPB)

Diagnosis

• Biopsy showing clonal plasma cells at single site
• Normal bone marrow biopsy (confirms it is not myeloma)
• No CRAB criteria
• Skeletal survey/PET-CT to exclude other lesions
• Serum and urine immunofixation, free light chains

Differential Diagnosis

• Multiple myeloma (multiple lesions, CRAB features, >10% marrow plasma cells)
• Metastatic carcinoma
• Giant cell tumor / Ewing sarcoma (in bone)
• Lymphoma (extraosseous sites)
• Reactive plasmacytosis

Source: Robbins & Kumar Pathologic Basis of Disease; Cummings Otolaryngology Head and Neck Surgery

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3. Minimal Residual Disease (MRD) - Short Note

Definition

Detection Methods

Clinical Significance

• MRD status after induction is the most important independent prognostic factor for disease-free and overall survival in both pediatric and adult ALL
• MRD-negative patients post-induction: disease-free survival ~70%
• MRD-positive patients: disease-free survival <40%
• MRD-positive patients should receive targeted therapy to reduce tumor burden, followed by allogeneic stem cell transplantation (SCT) if possible
• Phenotypic aberrations are unique to each patient and can be detected in up to 95% of individuals
• Bone marrow collection at diagnosis is essential for identifying individual markers

• Achieved via flow cytometry (EuroFlow panel) or NGS (clonoSEQ)
• MRD negativity is associated with significantly improved progression-free and overall survival
• Now considered a surrogate endpoint in clinical trials

• ctDNA-based MRD after surgery shows high positive predictive value for relapse in colon, rectum, lung, bladder, and breast cancers
• Limitation: modest clinical sensitivity - substantial false-negative rate
• Coverage approved by CMS for colorectal cancer (Signatera MRD test, Natera)
• Active clinical trials testing MRD-guided adjuvant therapy

Technical Considerations

• Collection of bone marrow at diagnosis is essential to identify patient-specific markers
• 20-30% of adult ALL patients who are MRD-negative after induction still relapse (loss of sensitivity, clonal evolution, extramedullary disease)
• NGS and ddPCR offer superior sensitivity (parts-per-million range with multiplex bespoke assays)
• Liquid biopsies face challenges from biological background (clonal hematopoiesis) and technical noise

Source: Harrison's Principles of Internal Medicine 22E; Henry's Clinical Diagnosis and Management by Laboratory Methods

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4. Mast Cell Disorders - Short Note

Definition

WHO Classification

Molecular Pathogenesis

• KIT D816V mutation is the hallmark: present in >90% of mastocytosis cases
• KIT (CD117) encodes a transmembrane receptor tyrosine kinase for stem cell factor (SCF)
• The D816V point mutation in exon 17 produces constitutive (ligand-independent) activation of KIT → growth factor-independent cell proliferation
• Important: KIT D816V is NOT specific to mastocytosis; also found in a subset of CBF-AML, GI stromal tumors, and melanomas
• Non-D816V KIT mutations also occur but are less common
• A subset with PDGFRA rearrangements also shows mast cell expansion but lacks KIT D816V - these cases are sensitive to imatinib
• SM frequently co-presents with other hematologic neoplasms (SM-AHN): chronic myelomonocytic leukemia (CMML) is most common, also MDS, MPN, AML

Clinical Features

• Pruritus, urticaria, flushing, dermatographism
• Abdominal pain, diarrhea, nausea (GI histamine release)
• Anaphylaxis (often triggered by insect stings, NSAIDs, contrast media, alcohol)
• Hypotension, syncope

• Bone pain, arthralgia, osteoporosis, pathological fractures
• Hepatomegaly, splenomegaly, lymphadenopathy
• Cytopenias from marrow infiltration
• Malabsorption

• Tan/brown maculopapular lesions with urtication on stroking (Darier's sign)
• In children: often large, papular/bullous lesions; may spontaneously regress

Morphology

• Aggregates of spindle-shaped mast cells in the papillary dermis, extending into reticular dermis

• Multifocal, sharply demarcated compact aggregates of mast cells (key feature)
• Cells may be spindle-shaped and hypogranular on H&E
• Mixed infiltrates: mast cells + lymphocytes + eosinophils + histiocytes + fibroblasts, often with peripheral rim or central core of lymphocytes
• Associated fibrosis
• Tryptase-positive round cell infiltrates (TROCI) = compact infiltrates of hypergranular mast cells
• Reactive mast cells do NOT form compact aggregates (important distinction)

Immunophenotype / Markers

• Mast cell tryptase - most specific marker
• CD117 (KIT/c-kit) - strong expression
• CD25 and CD2 - aberrant expression (normal mast cells lack CD25/CD2) - used in diagnosis
• CD45, CD33, CD68 positive
• Myeloperoxidase negative
• Chloroacetate esterase positive
• Special stains: Giemsa, Toluidine blue (for granules in tissue)

Diagnostic Criteria for Systemic Mastocytosis

• Multifocal, dense infiltrates of mast cells (≥15 mast cells in aggregates) in BM or other extracutaneous organs

1. 25% of mast cells in BM biopsy are spindle-shaped or have atypical morphology

2. Activating KIT D816V mutation
3. Mast cells in BM express CD25 and/or CD2 (aberrant)
4. Serum total tryptase persistently >20 ng/mL

Differential Diagnosis

• Reactive mast cell hyperplasia (no compact aggregates; seen in HCL, lymphoplasmacytic lymphoma, myeloid neoplasms)
• Basophilic leukemia (TROCI overlap)
• AML with abnormal mast cells
• Lymphoma with mast cell-rich stroma

Prognosis

• Cutaneous mastocytosis in children: excellent; often spontaneously resolves
• Indolent SM: near-normal life expectancy; main morbidity from mediator release
• SM-AHN: prognosis determined largely by the associated hematologic neoplasm
• Aggressive SM and Mast Cell Leukemia: median survival <1-2 years

Treatment Highlights

• Avoidance of triggers; H1/H2 antihistamines; mast cell stabilizers (cromolyn sodium)
• Epinephrine for anaphylaxis
• Bisphosphonates for osteoporosis
• Midostaurin (multi-kinase inhibitor including KIT): FDA-approved for advanced SM
• Avapritinib (selective KIT D816V inhibitor): approved for aggressive SM; highly effective against D816V mutation
• Imatinib: only effective in KIT D816V-negative cases (e.g., PDGFRA-rearranged)
• Cladribine, IFN-α: for cytoreduction in advanced SM
• Allogeneic SCT: for eligible patients with aggressive SM or MCL

Sources: Henry's Clinical Diagnosis and Management by Laboratory Methods; Harrison's Principles of Internal Medicine 22E; Robbins & Kumar Pathologic Basis of Disease

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Summary Table: All Four Entities at a Glance