22.3 Lymphomas & Plasma Cell Dyscrasias

4. Lymphomas: Hodgkin vs. Non-Hodgkin

Hodgkin Lymphoma (HL)

• Epidemiology: Distinct bimodal age distribution, with a major peak in young adults aged 20–35 years and a second peak in adults >60 years.
• Clinical Presentation: Painless, non-tender, firm, rubbery, discrete lymphadenopathy, most commonly affecting the cervical (60–70%) and supraclavicular chains, or discovered as an asymptomatic widening of the mediastinum on chest radiograph. Systemic features:
  • B-Symptoms: Unexplained drenching night sweats, persistent fever (>38°C), and involuntary weight loss (>10% of body weight over 6 months). B-symptoms denote higher tumour burden and worse prognosis.
  • Alcohol-Induced Lymph Node Pain: Pathognomonic sensation of severe, aching pain localized to involved lymph nodes occurring within minutes of ingesting even small quantities of alcohol.
  • Pruritus: Severe, intractable generalized itching, often preceding lymphadenopathy by months.
• Histopathology & Architecture: The neoplastic population represents <1% of the cellular mass in the affected lymph node, consisting of pathognomonic giant Reed-Sternberg (RS) cells surrounded by a vast reactive cellular infiltrate of small lymphocytes, eosinophils, histiocytes, and plasma cells.
  • Reed-Sternberg Cells: Immature giant transformed B-cells, characteristically binucleated with symmetrical "mirror-image" nuclei containing prominent, inclusion-like, brightly eosinophilic nucleoli surrounded by a clear halo, creating the classic "owl-eyed" appearance.
  • Immunophenotype: Neoplastic RS cells are characteristically CD15+ and CD30+, and consistently negative for CD45 and CD20.
• Histological Subtypes (Classical HL, 95%):
  1. Nodular Sclerosis (65–70%): Most common subtype, especially in young women presenting with mediastinal lymphadenopathy. Characterized by broad, birefringent collagen bands circumscribing lymphoid nodules, and "lacunar" variant Reed-Sternberg cells.
  2. Mixed Cellularity (20–25%): More common in older patients and HIV-positive individuals; strongly associated with Epstein-Barr Virus (EBV) infection (>70%); rich in classic Reed-Sternberg cells and eosinophils.
  3. Lymphocyte-Rich (5%): Best prognosis among classical subtypes.
  4. Lymphocyte-Depleted (<1%): Abundant RS cells, sparse reactive lymphocytes, elderly patients; worst prognosis.
• Staging & Therapy: Ann Arbor staging system (Stages I–IV with A/B suffix). First-line chemotherapy is ABVD (Adriamycin/doxorubicin, Bleomycin, Vinblastine, Dacarbazine). Long-term treatment toxicities are critical for MRCP: Bleomycin-induced pulmonary fibrosis (monitored with transfer factor / DLCO) and anthracycline-induced cardiotoxicity, alongside secondary solid malignancies (especially breast cancer in young women following mantle field mediastinal irradiation).

Non-Hodgkin Lymphomas (NHL)

1. Diffuse Large B-cell Lymphoma (DLBCL):

   • Most common NHL overall (30–40% of adult lymphomas). Highly aggressive, presenting with rapidly enlarging, destructive nodal masses or extranodal disease (gastrointestinal tract, bone, central nervous system).
   • Curative-intent immunochemotherapy is standard: R-CHOP (Rituximab [anti-CD20], Cyclophosphamide, Hydroxydaunorubicin / doxorubicin, Oncovin / vincristine, and Prednisolone).

2. Follicular Lymphoma:

   • Most common indolent (low-grade) NHL (20–25%). Characterized by painless, generalized, fluctuating lymphadenopathy over many years.
   • Cytogenetics: Reciprocal translocation t(14;18)(q32;q21), placing the anti-apoptotic oncogene BCL-2 on chromosome 18 under the control of the immunoglobulin heavy chain (IGH) promoter on chromosome 14. This leads to constitutive over-expression of BCL-2 protein, which prevents physiological apoptosis of germinal-centre B-cells.
   • Histology: Nodular proliferation of cleaved centrocytes and centroblasts.

3. Burkitt Lymphoma:

   • Highly aggressive, rapidly dividing B-cell malignancy with the shortest doubling time of any human tumour (~24 hours).
   • Variants: Endemic (equatorial Africa; jaw/facial bone mass, tightly linked to EBV in >95%), Sporadic (Western world; presents as an ileocaecal abdominal mass causing obstruction or intussusception), and Immunodeficiency-associated (HIV).
   • Cytogenetics: Reciprocal translocation t(8;14)(q24;q32), juxtaposing the c-MYC proto-oncogene on chromosome 8 with the IGH enhancer on chromosome 14, driving massive, deregulated transcriptional activation of cell-cycle progression.
   • Histology: Pathognomonic "starry sky" appearance: Sheets of uniform, medium-sized, deeply basophilic blast cells with lipid vacuoles ("dark sky") punctuated by pale, lipid-laden tingible-body macrophages phagocytosing apoptotic debris ("stars").
   • Oncological Emergency: Extremely high risk of spontaneous or chemotherapy-induced Tumour Lysis Syndrome (TLS) (massive release of intracellular contents: hyperuricaemia, hyperkalaemia, hyperphosphataemia, secondary hypocalcaemia, and acute urate nephropathy). Prophylaxis with intravenous rasburicase (recombinant urate oxidase) or allopurinol and aggressive IV hydration is mandatory.

4. Mantle Cell Lymphoma:

   • Moderately aggressive B-cell NHL characterized by the translocation t(11;14)(q13;q32), juxtaposing the cyclin D1 (CCND1) gene with the IGH locus. This causes cyclin D1 over-expression, forcing continuous cell-cycle progression through the G1-to-S phase checkpoint.
   • Immunophenotype: CD5+, CD19+, CD20+, and CD23- (crucial discriminator from CLL, which is CD23+).

5. Plasma Cell Dyscrasias: Myeloma, MGUS & Amyloidosis

Multiple Myeloma

• Definition: Neoplastic, clonal proliferation of terminally differentiated plasma cells within the bone marrow, producing a monoclonal paraprotein in serum and/or urine.
• Diagnostic Criteria (IMWG): Requires >=10% clonal plasma cells on bone marrow examination (or biopsy-proven plasmacytoma) PLUS at least one feature of end-organ damage attributed to the plasma cell disorder, remembered by the classic CRAB acronym:
  • C = HyperCalcaemia: Corrected serum calcium >2.75 mmol/L (or >0.25 mmol/L above upper limit). Driven by myeloma cell secretion of osteoclast-activating factors (RANKL, MIP-1a) and inhibition of osteoblasts via Dickkopf-1 (DKK1).
  • R = Renal Insufficiency: Serum creatinine >177 umol/L (>2.0 mg/dL) or eGFR <40 mL/min. The predominant pathological mechanism is myeloma cast nephropathy ("light chain nephropathy"): excessive monoclonal serum free light chains (kappa or lambda) overwhelm proximal tubular endocytic reabsorption, pass into distal collecting tubules, and coprecipitate with Tamm-Horsfall mucoprotein (uromodulin). This forms dense, rigid, crystalline intratubular casts surrounded by multinucleated giant cells, causing extensive tubular rupture, interstitial nephritis, and progressive renal failure.
  • A = Anaemia: Normocytic, normochromic anaemia (haemoglobin >20 g/L below normal or <100 g/L), resulting from marrow plasma cell infiltration and cytokine-mediated suppression of erythropoiesis.
  • B = Bone Lytic Lesions: >=1 osteolytic bone lesion on skeletal radiography, whole-body low-dose CT, or MRI. Bone destruction produces severe, localized back pain, pathological fractures, and vertebral collapse. Skull radiographs show classic "punched-out" lytic lesions without reactive osteoblastic rimming. Crucial Exam Pearl: Radionuclide bone scans (99mTc-phosphonate) rely on osteoblastic activity and are falsely negative (cold) in >50% of multiple myeloma; whole-body low-dose CT is the UK imaging investigation of choice.
• Biochemical & Laboratory Investigation:
  • Serum Protein Electrophoresis (SPEP): Demonstrates a discrete, narrow monoclonal band ("M-protein" / paraprotein) in the gamma or beta globulin region, most commonly IgG (55%), followed by IgA (20%), with light chain only in 15–20%.
  • CRITICAL EXAM TRAP - Urinalysis: Standard hospital urine dipsticks detect albumin via tetrabromophenol dye-binding and DO NOT DETECT monoclonal free light chains (Bence-Jones proteins)! A patient with severe myeloma cast nephropathy producing massive light-chain proteinuria can have a completely negative protein dipstick. Detection of Bence-Jones protein requires urine protein electrophoresis (UPEP) with immunofixation or automated serum free light chain (sFLC) ratio assay.
• Treatment Approach: Induction with triplet therapy: a proteasome inhibitor (bortezomib), an immunomodulatory drug (lenalidomide), and dexamethasone (VRd regimen), followed by high-dose melphalan conditioning and autologous haematopoietic stem cell transplantation (ASCT) in eligible, fit patients. Skeletal events are prevented with monthly intravenous zoledronic acid (requires dental review to prevent osteonecrosis of the jaw).

Monoclonal Gammopathy of Undetermined Significance (MGUS)

• Definition & Diagnostic Triad:
  1. Serum monoclonal paraprotein band <30 g/L;
  2. Clonal bone marrow plasma cells <10%; AND
  3. Strict absence of CRAB end-organ damage or myeloma-defining biomarkers.
• Natural History: Exceptionally common in older populations (present in >3% of adults >50 years and >5% of adults >70 years). Carries a constant, lifelong risk of progression to symptomatic multiple myeloma, Waldenström's macroglobulinaemia, or AL amyloidosis of approximately 1% per year.
• Management: Watchful waiting with annual clinical review, FBC, calcium, renal function, and paraprotein quantification. No active medical therapy is indicated.

AL (Primary Systemic) Amyloidosis

• Pathophysiology: Clonal plasma cell dyscrasia (often small clone) that synthesizes abnormal, unstable monoclonal immunoglobulin light chains (lambda in 75–80% of cases). These light chains misfold into insoluble fibrils arranged in a cross-beta-sheet conformation, which deposit irreversibly within extracellular tissues, causing progressive organ disruption.
• Clinical Manifestations:
  • Renal: Severe non-selective proteinuria and full-blown nephrotic syndrome with preserved or declining renal function.
  • Cardiac: Infiltrative, restrictive cardiomyopathy with symmetrical ventricular wall thickening, diastolic dysfunction, low-voltage QRS complexes on ECG (striking mismatch: thick ventricular walls on echo but tiny QRS voltages on ECG), and a classic granular, "sparkling" myocardial appearance on echocardiography.
  • Pathognomonic Physical Signs:* Macroglossia (enlarged, indurated tongue with lateral scalloping from dental impressions, seen in 15%) and periorbital ecchymosis / purpura ("raccoon eyes") triggered by minor trauma or coughing, resulting from amyloid infiltration and fragility of the periorbital microvasculature.
  • Coagulation Defect: Acquired Factor X deficiency (caused by rapid adsorption and clearance of circulating factor X onto extensive amyloid fibrils in the liver and spleen), presenting with severe spontaneous bleeding with a prolonged PT and aPTT.
• Diagnosis: Tissue biopsy (subcutaneous abdominal fat pad aspirate [80% sensitive], labial salivary gland, or affected organ) stained with Congo red, which displays pathognomonic apple-green birefringence under cross-polarized light microscopy.