Lymphoma

• Heterogeneous group of lymphoid neoplasms with varied clinical courses and treatment responses.
• Classified by cell type of origin (B-cell vs. T-cell) and morphology (Hodgkin vs. non-Hodgkin).
• Over 100 discrete lymphomas identified based on genetic and morphologic characteristics.
• Recent classification systems emphasize genetic and pathologic markers for characterization and clinical management.

Comparison of Hodgkin and Non-Hodgkin Lymphoma

Aspect	Hodgkin Lymphoma malaise + fever/night sweats + pruritus → Hodgkin lymphoma	Non-Hodgkin Lymphoma malaise + fever/night sweats + lymphadenopathy → non-Hodgkin lymphoma
Classification	Malignant tumor of lymphoid tissue	Heterogeneous group of cancers of lymphocytes (B or T cells)
Lymphadenopathy	Painless, rubbery, especially cervical nodes	Painless, localized or widespread
Constitutional Symptoms	Malaise, weakness, weight loss	Possible, especially sweating
Fever and Night Sweats	Undulant (Pel–Ebstein) fever	Possible
Pruritus	Common	Uncommon
Alcohol-Induced Pain	Pain in enlarged lymph nodes after alcohol consumption	Not typical
Organ Enlargement	Possible enlarged spleen and liver	Possible enlarged liver and spleen
Extranodal Disease	Rare	Common (CNS, bone, skin, GIT)
Skin Infiltration	Not typical	Possible nodular infiltration (e.g., mycosis fungoides)
Diagnosis	Lymph node biopsy with histological confirmation	Lymph node biopsy
Additional Tests	FBE, CXR, CT/MRI (staging), bone marrow biopsy, isotopic scan	CXR, CT abdomen (staging)
Staging	Ann Arbor system (IA to IVB)	Based on CXR and CT abdomen findings
Treatment	Chemotherapy, immunotherapy, radiotherapy	Varies based on type and stage

• Clinical Presentation and Initial Management
  • Lymphoma typically managed by hematologists/oncologists but initial diagnosis often in primary care or general hospitals.
  • No classic presentation, standard workup, or single diagnostic test.
  • Common symptoms:
    • fatigue, pain
    • palpable lymphadenopathy
    • shortness of breath/cough.
  • Atypical presentations:
    • GI symptoms
    • CNS symptoms
    • cutaneous symptoms
    • other generalized or organ-specific symptoms.
  • Rare diagnosis: 2.6 cases per 100,000 for Hodgkin lymphoma, 19.6 cases per 100,000 for non-Hodgkin lymphoma (NHL).
  • Lymphadenopathy incidence in primary care:
    • 1.1% malignancy overall
      • ~4% in patients >40 years
      • <0.4% in patients <40 years.

Differential Diagnoses

1. Infectious Causes
   • Viral Infections (e.g., EBV, CMV, HIV)
     • Symptoms: fever, fatigue, lymphadenopathy, sore throat (EBV/mononucleosis)
     • Characteristics: Tender, mobile lymph nodes
   • Bacterial Infections (e.g., Streptococcal, Tuberculosis, Cat-Scratch Disease)
     • Symptoms: localized pain, fever, redness, warmth over lymph nodes
     • Characteristics: Tender, inflamed nodes, history of exposure (e.g., cat scratches for Cat-Scratch Disease)
   • Fungal Infections (e.g., Histoplasmosis)
     • Symptoms: respiratory symptoms, fever, weight loss
     • Characteristics: Generalized lymphadenopathy, particularly in endemic areas
2. Autoimmune Disorders
   • Systemic Lupus Erythematosus (SLE)
     • Symptoms: fatigue, fever, joint pain, skin rash
     • Characteristics: Generalized lymphadenopathy, positive ANA test
   • Rheumatoid Arthritis
     • Symptoms: joint pain, stiffness, fever
     • Characteristics: Symmetrical joint involvement, elevated rheumatoid factor
3. Metastatic Cancer
   • Solid Tumors (e.g., breast, lung, prostate)
     • Symptoms: depend on primary tumor location, e.g., breast mass, cough, hematuria
     • Characteristics: Fixed, hard, non-tender lymph nodes, history of primary malignancy
4. Benign Reactive Lymphadenopathy
   • Due to Local Infections or Inflammation
     • Symptoms: localized pain, fever, swelling
     • Characteristics: Tender, mobile nodes, improvement with treatment of underlying cause
5. Other Hematologic Malignancies
   • Leukemias (e.g., Acute Lymphoblastic Leukemia)
     • Symptoms: fatigue, fever, bleeding, bruising
     • Characteristics: Pancytopenia, abnormal blood smear, bone marrow involvement
6. Drug Reactions
   • COVID-19 vaccination
   • Drug-Induced Lymphadenopathy
     • Symptoms: history of new medication use, rash, fever
     • Characteristics: Generalized or localized lymphadenopathy, resolution after discontinuing the drug

When to Suspect Lymphoma in a Patient

1. Persistent Lymphadenopathy
   • Lymph nodes >1 cm, firm/rubbery consistency, fixed, non-tender, matted nodes.
     • Less concerning features: nodes <1 cm, freely mobile, tender nodes (likely infectious).
   • Lymphadenopathy persisting for more than 4-6 weeks without signs of infection.
2. B-Symptoms
   • Unexplained fever >38°C, drenching night sweats
   • unexplained weight loss (>10% of body weight in 6 months)
   • Presence of B-symptoms corresponds with B staging in the Ann Arbor Staging System.
   • Isolated B-symptoms should prompt a comprehensive lymph node exam.

History and Physical Examination

• Detailed history of symptoms, exposure history, thorough physical exam including lymph node assessment.
• all accessible lymph nodes, liver, spleen, Waldeyer’s ring.

Laboratory Tests for Suspected Lymphoma

Lab test	Rationale	Abnormalities suggestive of lymphoma	Red flag results
Complete blood count (CBC)	Ensure trilineage normality, assess for gross abnormalities suggestive of bone marrow involvement	Anemia, thrombocytopenia, leukopenia/leukocytosis	Neutropenia, WBC > 100 K, severe anemia or thrombocytopenia
Comprehensive metabolic panel	Assess for the presence of hepatic or renal dysfunction suggestive of compressive or infiltrative disease	AKI, electrolyte abnormalities, hepatic or cholestatic injury patterns	Significant electrolyte abnormalities or evidence of significant organ injury
Phosphorus	Evaluate for evidence of tumor lysis. (Although phosphate levels in spontaneous TLS may be normal as opposed to phosphate levels in post-chemotherapy TLS)	Tumor lysis	Hyperphosphatemia with phosphorus levels >4.5 mg/dl in adults or > 25% increase from baseline. (In conjunction with elevated LDH, uric acid, potassium, ±AKI, as this is consistent with TLS)
LDH	Evaluate for evidence of rapid cellular turnover which may be associated with TLS.	Elevated LDH	In conjunction with elevated potassium, uric acid ± AKI, and hyperphosphatemia as this is consistent with TLS
Uric acid	To rule out tumor lysis syndrome	No clear association outside of TLS	Hyperuricemia with uric acid >8 mg/dl or 25% increase from baseline In conjunction with elevated LDH, potassium, ±AKI, and elevated phosphorus as this is consistent with TLS

Abbreviations: AKI, acute kidney injury; ED, emergency department; LDH, lactate dehydrogenase; MAHA, microangiopathic hemolytic anemia; TLS, tumor lysis syndrome.

Laboratory Tests for Suspected Lymphoma

1. Complete Blood Count (CBC)
   • Abnormalities may include anemia, thrombocytopenia, and leukopenia/lymphocytosis.
   • CBC abnormalities suggest complications like bone marrow infiltration, anemia of chronic disease, autoimmune hemolytic anemia, hypersplenism, or small lymphocytic lymphoma.
   • Presence of anemia in untreated lymphoma: 32%-45%; up to 57% of patients with anemia report symptoms.
2. Comprehensive Metabolic Panel (CMP)
   • Hypercalcemia (present in <15% of cases) is associated with decreased survival and may result from bone invasion, paraneoplastic syndromes, or tumor cells producing 1,25-dihydroxyvitamin D.
   • Renal injury can be due to compressive adenopathy, hypercalcemia, or monoclonal paraproteinemia (similar to multiple myeloma).
   • Hepatic dysfunction may occur due to compressive adenopathy, metastatic hepatic infiltration, or paraneoplastic syndromes.
3. Lactate Dehydrogenase (LDH), Uric Acid, and Phosphate
   • LDH commonly elevated in aggressive lymphoma and is an important prognostic factor.
   • Elevated LDH and uric acid levels indicate spontaneous tumor lysis syndrome (TLS), often without hyperphosphatemia.
4. Peripheral Blood Flow Cytometry (FC)
   • Identifies and quantifies specific cell types based on physical characteristics and surface antigen expression.
   • Diagnostic yield varies; FC detects malignant cells and their immunophenotype.
   • Limited utility in classical Hodgkin lymphoma (HL) and rare for circulating tumor cells.
   • Not recommended for screening hematologic malignancy in most cases.

Imaging for Lymphoma

1. Computed Tomography (CT) Scan
   • Historically used in Ann Arbor staging system.
   • Provides anatomical details and helps identify lymph node involvement.
2. Positron Emission Tomography-Computed Tomography (PET-CT)
   • Preferred imaging modality for staging and monitoring treatment response.
   • Superior accuracy for staging and specificity for extranodal disease.
   • Useful in diagnosing indolent lymphomas and guiding biopsy.
   • Not all lymphomas are FDG avid; lack of FDG uptake does not rule out lymphoma.
   • PET-CT may spare bone marrow biopsy in aggressive lymphomas with focal FDG uptake in bone marrow.
   • MRI preferred for suspected CNS involvement due to high physiologic FDG uptake in the brain.

Biopsy for Lymphoma

1. Fine Needle Aspiration (FNA)
   • Unlikely to yield an accurate or complete diagnosis of lymphoma; not recommended for targeted workup.
   • Recommended for head and neck masses with high accuracy for non-lymphoma diagnoses.
   • Low sensitivity and NPV for lymphoma; combined with FC and immunohistochemistry (IHC) for differential diagnosis when other causes are suspected.
2. Core Needle Biopsy (CNB)
   • More tissue obtained compared to FNA; used with ancillary tests (FC, IHC, FISH/cytogenetics).
   • Diagnostic efficacy varies (79%-97%); superior in certain cases compared to excisional biopsy.
   • ASCP and CAP guidelines recommend CNB with careful patient selection and technique consideration.
3. Incisional/Excisional Biopsy
   • Gold standard for suspected lymphomas.
   • Recommended when HL is suspected due to lower diagnostic sensitivity of CNB for HL.
   • High false negative rates for HL with CNB; surgical biopsy preferred for comprehensive tissue sampling.

Tissue studies/biopsy for probable lymphoma

Diagnostic study	Description	Limitations	Notes
Peripheral blood flow cytometry	Method of identifying and quantifying specific cell types by physical characteristics and surface antigen expression	Lymphoma cells are rarely detected in peripheral blood	Not recommended for screening for lymphoma under most circumstances, and unlikely to be diagnostic even in cases where blasts or lymphoma cells are seen on peripheral smear
Fine needle aspiration	Least invasive sampling technique, can be combined with ancillary testing such as IHC, FC, and cytogenetic tests to improve diagnostic sensitivity	Extremely high false negative rate, especially for HL. High rate of incorrect or incomplete subclassification	Reasonable to consider in combination with ancillary testing if lymphoma is not the most likely diagnosis or if the biopsy site is difficult to safely access by more invasive techniques, though unlikely to provide subclassification/actionable lymphoma diagnosis and low NPV
Core needle biopsy	Less invasive and more readily available diagnostic technique than excisional biopsy and non-inferior or superior in some circumstances when combined with ancillary testing	Not recommended for diagnosis of HL due to exceptionally high false negative rate. Risk of insufficient sample for complete subclassification/actionable diagnosis, or insufficient sample for follow-up tests for research/clinical trial eligibility.	Reasonable to consider in cases where NHL is suspected and robust ancillary testing is available, though subsequent surgical biopsy may be needed.
Surgical (excisional) biopsy	Gold standard sampling technique	Most invasive and least available technique, NPV < 100	Recommended in all cases where HL is highly suspected or ancillary testing capabilities are limited

Abbreviations: FC, flow cytometry; HL, Hodgkin lymphoma; IHC, immunohistochemistry; NPV, negative predictive value.

Lymphoma emergencies

Hematologic emergency	Suggestive signs/symptoms	Initial management
Tumor lysis syndrome	Elevated lactate dehydrogenase (LDH), uric Acid, Potassium, ±phosphorus. AKI	Aggressive fluid resuscitation with isotonic fluids, management of hyperkalemia if indicated, immediate emergency room evaluation and hospitalization
Venous thromboembolism	Unilateral lower extremity swelling, erythema, pain. Sudden onset dyspnea/hypoxia.	If stable for outpatient management, low molecular weight heparin (LMWH), apixaban, rivaroxaban have the most evidence for anticoagulation in patients with malignancy
Paraneoplastic processes	Neurologic symptoms, dermatologic changes, fever, hematologic abnormalities, arthralgias, renal dysfunction, angioedema	Commensurate with the severity of presentation. Evidence of MAHA, severe neurologic involvement, rash and fever, severe AKI should be referred to the ED
Compressive or infiltrative tumor effects	Hepatic or renal dysfunction Evidence of neurovascular compromise including claudication, bowel or bladder dysfunction, saddle anesthesia, motor or sensory dysfunction.	Commensurate with the severity of presentation Severe hepatic or renal dysfunction, evidence of cauda equina syndrome, or rapidly progressive motor/sensory changes should be referred to the ED