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Reed-Sternberg cell Hodgkin lymphoma histology

This histopathology image depicts a lymph node biopsy showing features diagnostic of lymphocyte-depleted classic Hodgkin lymphoma, reticular subtype. Using light microscopy on an H&E-stained paraffin section, the lymphoid architecture is markedly effaced by a cellular sheet of large, atypical mononuclear cells with prominent nucleoli. Occasional Reed-Sternberg cells are visible within the expansive background, including cells with multilobed or bilobed nuclei and prominent eosinophilic nucleoli, characteristic of Hodgkin lymphoma. The RS cells are scattered among numerous atypical mononuclear variants rather than forming a cohesive nodular structure. There is little-to-no fibrosis and only sparse non-neoplastic inflammatory cells, which is typical for the lymphocyte-depleted pattern. The background may show rimming by small lymphocytes and histiocytes in a reticular network, but overall cellularity is high. Immunophenotypic markers are not shown here, but in clinical practice RS cells typically express CD30 and CD15 with weaker PAX5 or B-cell markers. The diagnostic significance lies in recognizing the lymphocyte-depleted cHL morphology, which carries distinct clinical implications, often presenting with advanced stage disease and systemic symptoms. This image is useful for educational purposes, differential diagnosis conversation, and correlating histology with treatment planning (ABVD/BEACOPP regimens). Correlation with immunohistochemistry (CD30, CD15, PAX5) and EBV status further supports diagnosis in practice.

This histopathology image depicts a lymph node biopsy showing features diagnostic of lymphocyte-depleted classic Hodgkin lymphoma, reticular subtype. Using light microscopy on an H&E-stained paraffin section, the lymphoid architecture is markedly effaced by a cellular sheet of large, atypical mononuclear cells with prominent nucleoli. Occasional Reed-Sternberg cells are visible within the expansive background, including cells with multilobed or bilobed nuclei and prominent eosinophilic nucleoli, characteristic of Hodgkin lymphoma. The RS cells are scattered among numerous atypical mononuclear variants rather than forming a cohesive nodular structure. There is little-to-no fibrosis and only sparse non-neoplastic inflammatory cells, which is typical for the lymphocyte-depleted pattern. The background may show rimming by small lymphocytes and histiocytes in a reticular network, but overall cellularity is high. Immunophenotypic markers are not shown here, but in clinical practice RS cells typically express CD30 and CD15 with weaker PAX5 or B-cell markers. The diagnostic significance lies in recognizing the lymphocyte-depleted cHL morphology, which carries distinct clinical implications, often presenting with advanced stage disease and systemic symptoms. This image is useful for educational purposes, differential diagnosis conversation, and correlating histology with treatment planning (ABVD/BEACOPP regimens). Correlation with immunohistochemistry (CD30, CD15, PAX5) and EBV status further supports diagnosis in practice.

This brightfield histopathology image depicts a lymph node biopsy illustrating a histiocyte-rich variant of mixed cellularity classical Hodgkin lymphoma. The tissue is sectioned and stained with hematoxylin and eosin, viewed at low-to-intermediate magnification, revealing a densely cellular background with a prominent infiltrate of histiocytes and epithelioid macrophages forming aggregates, accompanied by scattered eosinophils, lymphocytes, plasma cells, and occasional neutrophils. The classic Reed-Sternberg cells are present but may be sparse within the abundant histiocytic milieu, with multilobed nuclei and prominent nucleoli. The architectural pattern is polymorphic rather than nodular, lacking prominent fibrous bands characteristic of nodular sclerosis. The histiocyte-rich variant features abundant macrophages mirroring granulomatous-like features, potentially mimicking inflammatory conditions; however, residual neoplastic Hodgkin cells in this setting bear the typical immunophenotype (CD30+, CD15+, PAX5 weak) in adjacent areas. Clinically, this histology correlates with mixed cellularity Hodgkin lymphoma, a B-cell origin neoplasm presenting with constitutional symptoms and lymphadenopathy. The image is relevant for educational demonstration of HL subtypes, differential diagnoses with non-Hodgkin lymphomas and granulomatous processes, and for training in histopathologic recognition, pattern recognition, and morphologic correlation with immunophenotype and clinical findings. Immunohistochemistry supports diagnosis by highlighting Reed-Sternberg cells (CD30+, CD15+, PAX5 weak) amid a histiocyte-rich background; EBV association may be variable; clinical staging and treatment follow Hodgkin lymphoma guidelines.

This brightfield histopathology image depicts a lymph node biopsy illustrating a histiocyte-rich variant of mixed cellularity classical Hodgkin lymphoma. The tissue is sectioned and stained with hematoxylin and eosin, viewed at low-to-intermediate magnification, revealing a densely cellular background with a prominent infiltrate of histiocytes and epithelioid macrophages forming aggregates, accompanied by scattered eosinophils, lymphocytes, plasma cells, and occasional neutrophils. The classic Reed-Sternberg cells are present but may be sparse within the abundant histiocytic milieu, with multilobed nuclei and prominent nucleoli. The architectural pattern is polymorphic rather than nodular, lacking prominent fibrous bands characteristic of nodular sclerosis. The histiocyte-rich variant features abundant macrophages mirroring granulomatous-like features, potentially mimicking inflammatory conditions; however, residual neoplastic Hodgkin cells in this setting bear the typical immunophenotype (CD30+, CD15+, PAX5 weak) in adjacent areas. Clinically, this histology correlates with mixed cellularity Hodgkin lymphoma, a B-cell origin neoplasm presenting with constitutional symptoms and lymphadenopathy. The image is relevant for educational demonstration of HL subtypes, differential diagnoses with non-Hodgkin lymphomas and granulomatous processes, and for training in histopathologic recognition, pattern recognition, and morphologic correlation with immunophenotype and clinical findings. Immunohistochemistry supports diagnosis by highlighting Reed-Sternberg cells (CD30+, CD15+, PAX5 weak) amid a histiocyte-rich background; EBV association may be variable; clinical staging and treatment follow Hodgkin lymphoma guidelines.

This high-power light micrograph of a lymph node biopsy, stained with Hematoxylin and Eosin, demonstrates classical Hodgkin lymphoma histology. The tissue is densely cellular with a polymorphic inflammatory background comprising small lymphocytes, eosinophils, plasma cells, and histiocytes. Scattered among the background are large binucleated Reed-Sternberg (RS) cells exhibiting prominent, mirror-image eosinophilic nucleoli and ample cytoplasm, giving an owl's eye appearance. Mononuclear RS variants with similar nuclear features are present, reflecting heterogeneity within the malignant cell population. The RS cells may appear with delicate nuclear membranes and occasional lobulation. The surrounding milieu often includes reactive T-lymphocytes and occasional eosinophils attracted by cytokines produced by RS cells. The overall architecture lacks well-formed nodules, and the background shows a mixed inflammatory infiltrate, characteristic of classical Hodgkin lymphoma subtypes such as mixed cellularity. Important differential considerations include infectious or benign reactive processes, but the presence of RS cells with classic morphology supports a diagnosis of classical HL. Clinically, these findings correlate with nodal enlargement and B symptoms in many patients, and histology guides staging and therapy decisions, including chemotherapeutic regimens such as ABVD and potential radiotherapy in select cases. Correlation with immunohistochemistry and clinical data improves diagnostic confidence and treatment planning for patient care.

This high-power light micrograph of a lymph node biopsy, stained with Hematoxylin and Eosin, demonstrates classical Hodgkin lymphoma histology. The tissue is densely cellular with a polymorphic inflammatory background comprising small lymphocytes, eosinophils, plasma cells, and histiocytes. Scattered among the background are large binucleated Reed-Sternberg (RS) cells exhibiting prominent, mirror-image eosinophilic nucleoli and ample cytoplasm, giving an owl's eye appearance. Mononuclear RS variants with similar nuclear features are present, reflecting heterogeneity within the malignant cell population. The RS cells may appear with delicate nuclear membranes and occasional lobulation. The surrounding milieu often includes reactive T-lymphocytes and occasional eosinophils attracted by cytokines produced by RS cells. The overall architecture lacks well-formed nodules, and the background shows a mixed inflammatory infiltrate, characteristic of classical Hodgkin lymphoma subtypes such as mixed cellularity. Important differential considerations include infectious or benign reactive processes, but the presence of RS cells with classic morphology supports a diagnosis of classical HL. Clinically, these findings correlate with nodal enlargement and B symptoms in many patients, and histology guides staging and therapy decisions, including chemotherapeutic regimens such as ABVD and potential radiotherapy in select cases. Correlation with immunohistochemistry and clinical data improves diagnostic confidence and treatment planning for patient care.

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Hodgkin lymphoma nodular sclerosis histology

This histopathology image depicts recurrent nodular sclerosis classical Hodgkin lymphoma (cHL) on a hematoxylin and eosin stained lymph node biopsy. The tissue is examined under brightfield light microscopy at high-power fields; the nodular architecture is demonstrated by fibrous bands creating discrete nodules with collagenous sclerosis. Within the nodules, numerous classic Reed-Sternberg (RS) cells are present, frequently bi- or multinucleated with prominent eosinophilic nucleoli and ample cytoplasm; lacunar variants may be observed. The background shows a mixed inflammatory milieu including lymphocytes, plasma cells, neutrophils, eosinophils, and histiocytes; eosinophil-rich infiltrate is characteristic of cHL. Immunophenotype typical of RS cells is implied but not shown here: CD30 and CD15 positivity with PAX5 dim/weak positivity and variable CD20 negativity, helping distinguish cHL from other lymphoproliferative disorders. The sclerosis pattern and RS cell morphology, in the appropriate clinical context, support a relapse rather than a de novo lymphoma; however, post-therapy changes can alter cellular composition. This image underlines the importance of correlating histology with prior treatment history and immunohistochemistry to confirm relapse, guide staging, and inform therapy decisions, including salvage regimens or autologous stem cell transplantation considerations. Correlating morphology with immunophenotype and clinical history is essential for accurate relapse assessment. This informs prognosis and therapeutic strategy.

This histopathology image depicts recurrent nodular sclerosis classical Hodgkin lymphoma (cHL) on a hematoxylin and eosin stained lymph node biopsy. The tissue is examined under brightfield light microscopy at high-power fields; the nodular architecture is demonstrated by fibrous bands creating discrete nodules with collagenous sclerosis. Within the nodules, numerous classic Reed-Sternberg (RS) cells are present, frequently bi- or multinucleated with prominent eosinophilic nucleoli and ample cytoplasm; lacunar variants may be observed. The background shows a mixed inflammatory milieu including lymphocytes, plasma cells, neutrophils, eosinophils, and histiocytes; eosinophil-rich infiltrate is characteristic of cHL. Immunophenotype typical of RS cells is implied but not shown here: CD30 and CD15 positivity with PAX5 dim/weak positivity and variable CD20 negativity, helping distinguish cHL from other lymphoproliferative disorders. The sclerosis pattern and RS cell morphology, in the appropriate clinical context, support a relapse rather than a de novo lymphoma; however, post-therapy changes can alter cellular composition. This image underlines the importance of correlating histology with prior treatment history and immunohistochemistry to confirm relapse, guide staging, and inform therapy decisions, including salvage regimens or autologous stem cell transplantation considerations. Correlating morphology with immunophenotype and clinical history is essential for accurate relapse assessment. This informs prognosis and therapeutic strategy.

Imaging modality: bright-field light microscopy of a hematoxylin and eosin stained lymph node biopsy section viewed at high magnification. The tissue displays nodular sclerosis—nodules of lymphoid cells separated by thick bands of collagen—typical of classic Hodgkin lymphoma. The background comprises a mixed inflammatory infiltrate including eosinophils, neutrophils, small lymphocytes, plasma cells, and histiocytes. Fibroblasts are present within the fibrous bands and contribute to sclerosis. Notable features include multinucleated Reed–Sternberg cells, often with prominent nucleoli, located centrally in nodules; occasional lacunar variants may be seen in deeper sections. Eosinophilic and sometimes neutrophilic microabscesses are common in the nodular background and can obscure or mimic necrotizing granulomas at low magnification. The cellular composition varies between nodules, producing a heterogeneous appearance. This histology supports a diagnosis of nodular sclerosis type of classic Hodgkin lymphoma when combined with immunophenotypic data (CD15+, CD30+, PAX5 weak). Diagnostic significance lies in identifying RS cells within a reactive milieu; differential diagnoses include granulomatous inflammation and other lymphomas. Clinically, this pattern often correlates with mediastinal or peripheral lymphadenopathy in young adults and informs staging, prognosis, and chemotherapy decisions. In sum, lymphoid nodules with fibrous septa and RS cells characterize nodular sclerosis HL.

Imaging modality: bright-field light microscopy of a hematoxylin and eosin stained lymph node biopsy section viewed at high magnification. The tissue displays nodular sclerosis—nodules of lymphoid cells separated by thick bands of collagen—typical of classic Hodgkin lymphoma. The background comprises a mixed inflammatory infiltrate including eosinophils, neutrophils, small lymphocytes, plasma cells, and histiocytes. Fibroblasts are present within the fibrous bands and contribute to sclerosis. Notable features include multinucleated Reed–Sternberg cells, often with prominent nucleoli, located centrally in nodules; occasional lacunar variants may be seen in deeper sections. Eosinophilic and sometimes neutrophilic microabscesses are common in the nodular background and can obscure or mimic necrotizing granulomas at low magnification. The cellular composition varies between nodules, producing a heterogeneous appearance. This histology supports a diagnosis of nodular sclerosis type of classic Hodgkin lymphoma when combined with immunophenotypic data (CD15+, CD30+, PAX5 weak). Diagnostic significance lies in identifying RS cells within a reactive milieu; differential diagnoses include granulomatous inflammation and other lymphomas. Clinically, this pattern often correlates with mediastinal or peripheral lymphadenopathy in young adults and informs staging, prognosis, and chemotherapy decisions. In sum, lymphoid nodules with fibrous septa and RS cells characterize nodular sclerosis HL.

This light microscopic histopathology image depicts lymph node tissue stained with Hematoxylin and Eosin, examined at low magnification to emphasize nodular architecture characteristic of nodular sclerosis classical Hodgkin lymphoma. The sample reveals prominent nodularity with broad, concentric bands of hyalinized collagen that enclose discrete cellular nodules. Within these nodules, clusters of lacunar variant Reed-Sternberg cells are evident, accompanied by a sparsely cellular inflammatory background. The nodules display a mottled or moth-eaten appearance due to variable density of malignant RS cells and associated microabscesses or small foci of necrosis. The thick fibrous bands give the lymph node a fibrotic, polarized halo around nodules; in polarized light, the collagen may appear birefringent, highlighting the sclerosis. Overall the image demonstrates hallmarks of NSCHL: nodular sclerosis pattern, lacunar RS cells, and a desmoplastic stroma with dense collagen bands. Clinically, this pattern is associated with mediastinal involvement in younger patients and a favorable prognosis when treated appropriately. This histology is essential for differential diagnosis against other Hodgkin lymphoma subtypes (mixed cellularity, lymphocyte-rich) and against non-Hodgkin lymphomas. The image is relevant for pathology education, diagnostic pathology practice, and tumor biology research. Correlation with immunohistochemical profile and clinical staging enhances diagnostic confidence. Useful for teaching and research applications.

This light microscopic histopathology image depicts lymph node tissue stained with Hematoxylin and Eosin, examined at low magnification to emphasize nodular architecture characteristic of nodular sclerosis classical Hodgkin lymphoma. The sample reveals prominent nodularity with broad, concentric bands of hyalinized collagen that enclose discrete cellular nodules. Within these nodules, clusters of lacunar variant Reed-Sternberg cells are evident, accompanied by a sparsely cellular inflammatory background. The nodules display a mottled or moth-eaten appearance due to variable density of malignant RS cells and associated microabscesses or small foci of necrosis. The thick fibrous bands give the lymph node a fibrotic, polarized halo around nodules; in polarized light, the collagen may appear birefringent, highlighting the sclerosis. Overall the image demonstrates hallmarks of NSCHL: nodular sclerosis pattern, lacunar RS cells, and a desmoplastic stroma with dense collagen bands. Clinically, this pattern is associated with mediastinal involvement in younger patients and a favorable prognosis when treated appropriately. This histology is essential for differential diagnosis against other Hodgkin lymphoma subtypes (mixed cellularity, lymphocyte-rich) and against non-Hodgkin lymphomas. The image is relevant for pathology education, diagnostic pathology practice, and tumor biology research. Correlation with immunohistochemical profile and clinical staging enhances diagnostic confidence. Useful for teaching and research applications.

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Important note on the source: Davidson's Principles and Practice of Medicine is not in the textbook library. The content above is sourced from the three most authoritative equivalent references available: Harrison's Principles of Internal Medicine (22nd Ed, 2025), Goldman-Cecil Medicine, and Robbins & Cotran Pathologic Basis of Disease. These texts cover Hodgkin lymphoma at the same depth or greater than Davidson's, and the clinical content is virtually identical.

Hodgkin Lymphoma - Complete Reference


1. Definition

Hodgkin lymphoma (HL) is a malignancy of mature B lymphocytes characterized by the presence of pathognomonic neoplastic giant cells called Reed-Sternberg (RS) cells within a reactive inflammatory background (lymphocytes, eosinophils, macrophages, plasma cells - comprising >90% of tumor cellularity).
Two major types:
  • Classical Hodgkin Lymphoma (cHL) - ~90% of cases
  • Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL) - ~10%
It was the first human cancer to be successfully cured with radiation and chemotherapy.

2. Epidemiology

FeatureDetail
Incidence (USA)~8,830-9,000 new cases/year
Age distributionBimodal - peak 1: young adults (25-30 yrs); peak 2: adults >50-55 yrs
SexSlightly more common in males
RaceMore common in Whites than Blacks; rare in Asians
GeographyHighest: USA, Canada, Switzerland, northern Europe; Lowest: East Asia
IndiaAge distribution shifted strongly into childhood
HIVIncreases HL risk 5-10 fold
Cure rate>85% overall

3. Etiology and Pathobiology

Epstein-Barr Virus (EBV)

  • Leading etiologic suspect - no definitive proof yet
  • 2-3 fold elevated risk follows infectious mononucleosis
  • EBV in RS cells: 20-40% of non-HIV HL; ~100% of HIV-associated HL
  • RS cells in HIV-HL express LMP-1 (EBV latent membrane protein-1 - transforming oncoprotein)
  • Clonal EBV genomes at multiple disease sites = direct early lymphomagenesis role

Genetic Factors

  • Siblings: 3-7 fold increased risk
  • Identical twins: high concordance
  • HLA alleles confer susceptibility/protection

Reed-Sternberg Cell - Molecular Origin

  • Clonal IGH gene rearrangements + somatic hypermutation signs
  • Origin: germinal center or post-germinal center B cells
  • Most B-cell gene expression is silenced (loss of PAX5, OCT2, BOB.1, PU.1)
  • NF-kB aberrantly activated - promotes RS cell survival and proliferation
  • RS cells secrete cytokines (IL-10, IL-5, CCL5, etc.) that recruit the reactive milieu and suppress anti-tumor immunity

4. WHO Classification

Classical HL (cHL) - all share RS cell immunophenotype: CD15+, CD30+, PAX5 weak+, CD20-, CD45-

SubtypeFrequencyKey FeaturesEBV Association
Nodular Sclerosis60-70%Young adults, female preponderance, mediastinal mass, collagen bands, lacunar RS cells~25%
Mixed Cellularity20-30%Older adults, HIV, developing countries, diffuse infiltrate, classic RS cells~75%
Lymphocyte-Rich~5%Best prognosis, few RS cells, abundant lymphocytes~40%
Lymphocyte-DepletedRarestElderly, HIV, advanced stage, sheets of RS cells or diffuse fibrosis~100% (HIV-assoc)

NLPHL (Nodular Lymphocyte-Predominant)

  • Popcorn cells (L&H cells): multilobed nuclei like popcorn kernels
  • Immunophenotype: CD20+, BCL6+, CD15-, CD30- (opposite of cHL!)
  • Ongoing somatic hypermutation = true germinal center B cells
  • Males <35 years, cervical/axillary LN; mediastinal + BM involvement rare
  • EBV: rarely associated
  • 3-5% risk transformation to diffuse large B-cell lymphoma
  • Prognosis: excellent

5. Histopathology - Reed-Sternberg Cells

Classic RS Cell (cHL):

  • Large cell, abundant pale cytoplasm
  • Bilobed/multilobed nucleus with prominent eosinophilic "owl's eye" nucleoli
  • Mirror-image nuclei when binucleated - the hallmark

Variants:

  • Lacunar cells (nodular sclerosis) - cytoplasm retraction artifact in formalin
  • Mononuclear Hodgkin cells - single large nucleus/nucleolus
  • Popcorn/L&H cells (NLPHL) - multilobed, popcorn-like nuclei
RS cells with owl-eye nucleoli - classical cHL
Classic RS cells with eosinophilic "owl's eye" nucleoli in mixed cellularity cHL
Nodular sclerosis - fibrous bands with lacunar RS cells
Nodular sclerosis cHL: thick collagen bands creating discrete nodules with lacunar RS cells

6. Clinical Features

Lymphadenopathy

  • Painless, nontender enlarged lymph nodes
  • Distribution: cervical > supraclavicular > axillary (upper body predominance)
  • Mediastinal adenopathy in >50% at diagnosis (may be the presenting feature)
  • Spread: orderly and contiguous (unlike NHL's non-contiguous spread)
  • Rarely involves mesenteric nodes or Waldeyer's ring (unlike NHL)
  • Subdiaphragmatic presentation: unusual, more common in older males

B Symptoms (~1/3 of patients)

  • Fever >38°C (unexplained, persistent, or recurrent)
  • Drenching night sweats
  • Weight loss >10% of body weight over 6 months

Special Features

  • Pel-Ebstein fever: cyclical pattern of days-weeks of fever alternating with afebrile intervals (classic for HL)
  • Alcohol-induced lymph node pain - characteristic (rare but highly specific)
  • Severe unexplained pruritus
  • Cutaneous anergy (depressed cell-mediated immunity due to IL-10 from RS cells)
  • Paraneoplastic cerebellar degeneration
  • Nephrotic syndrome (minimal change disease association)
  • Immune hemolytic anemia / thrombocytopenia
  • Hypercalcemia
  • Erythema nodosum, ichthyosiform skin changes

7. Ann Arbor Staging System

StageDefinition
ISingle lymph node region OR one extralymphatic site (Ie)
II≥2 node regions, same side of diaphragm; IIe = + local extralymphatic extension
IIINode regions on both sides of diaphragm; III₁ = spleen/celiac/portal; III₂ = paraaortic/iliac/mesenteric
IVDiffuse extranodal organ involvement; liver or bone marrow involvement
ANo B symptoms
BFever >38°C, night sweats, or weight loss >10%
EContiguous extranodal extension from a nodal site
XBulky disease (mediastinal mass >1/3 chest diameter, or any mass >10 cm)
Stage is the most important prognostic variable in current practice.

8. Investigations

Mandatory Workup

  • History + physical exam (all lymph node groups, liver, spleen)
  • CBC with differential (lymphopenia, eosinophilia, anemia possible)
  • ESR (elevated; prognostic value)
  • Serum chemistry: LDH, albumin, alkaline phosphatase, bilirubin, creatinine
  • Serum protein electrophoresis
  • HIV serology (mandatory)
  • Hepatitis B + C serology
  • Chest X-ray (PA + lateral)
  • Contrast CT of neck, thorax, abdomen, pelvis (slices ≤1 cm)
  • FDG-PET/CT - now mandatory for staging, mid-treatment assessment, end-of-treatment assessment

Tissue Diagnosis

  • Excisional lymph node biopsy (gold standard)
  • FNA alone is inadequate - core or excisional biopsy required
  • IHC panel: CD15, CD30, CD20, CD45, PAX5, EBV (LMP-1)

Bone Marrow Biopsy

  • Largely replaced by PET/CT in cHL (BM involvement tends to be patchy, may be missed on unilateral biopsy)
  • Still considered in unexplained cytopenias

9. International Prognostic Score (IPS) - Advanced HL

7 adverse factors (1 point each):
  1. Serum albumin <4 g/dL
  2. Hemoglobin <10.5 g/dL
  3. Male sex
  4. Age ≥45 years
  5. Stage IV disease
  6. WBC ≥15,000/µL
  7. Lymphocytes <600/µL OR <8% of WBC
  • Score 0-1 → ~80% 5-year freedom from progression
  • Score ≥5 → ~55% 5-year freedom from progression

10. Treatment

ABVD Regimen (Cornerstone)

DrugClass
A - Doxorubicin (Adriamycin)Anthracycline - topoisomerase II inhibitor
B - BleomycinDNA strand break agent (lung toxicity risk)
V - VinblastineVinca alkaloid - microtubule inhibitor
D - DacarbazineAlkylating agent
Given every 28 days.

Stage-Based Treatment Summary

StageTreatment
Early favorable (I-II, no bulk, no B symptoms)ABVD x2 + IFRT 20-30 Gy; or ABVD x2-4 (if interim PET negative, RT may be omitted)
Early unfavorable (I-II with bulk or B symptoms)ABVD x4 + IFRT 30 Gy
Advanced (III-IV)ABVD x6 OR BV-AVD (A+AVD) x6 - superior PFS by ECHELON-1 trial
High-risk advancedEscalated BEACOPP (more toxic, reserved for very high-risk)

Brentuximab Vedotin (BV)

  • Anti-CD30 antibody-drug conjugate (ADC) delivering monomethyl auristatin E (MMAE)
  • Replaces bleomycin in A+AVD (BV-AVD) regimen
  • Improved PFS vs. ABVD in advanced HL (ECHELON-1 trial)
  • Also used as consolidation post-ASCT in high-risk relapsed/refractory disease

PET-Guided Therapy

  • Interim PET after cycle 2 - guides escalation or de-escalation
  • Negative interim PET = excellent prognosis; radiation may be safely omitted in early favorable disease
  • Positive interim PET = consider treatment intensification

11. Relapsed/Refractory Disease

  1. Salvage chemotherapy (ICE, DHAP, ESHAP, GDP)
  2. Autologous HSCT (high-dose chemoradiation + stem cell rescue) - potentially curative in ~50%
  3. Brentuximab vedotin - maintenance post-ASCT in high-risk cases
  4. Anti-PD-1 checkpoint inhibitors:
    • Nivolumab and Pembrolizumab - ORR 65-80%
    • HL RS cells overexpress PD-L1 (due to 9p24.1 amplification + JAK2 amplification) = highly susceptible to PD-1 blockade
  5. Allogeneic HSCT - for select relapsed cases post-autologous transplant

12. Late Treatment Complications

ComplicationAgentNotes
Secondary malignanciesRadiation + alkylating agentsBreast cancer (young women), lung cancer, AML/MDS
Cardiovascular diseaseDoxorubicin + chest RTCardiomyopathy, premature CAD, valve disease
Pulmonary fibrosisBleomycin5-10%; minimized by PFT monitoring and dose limits
HypothyroidismNeck radiationCommon; requires lifelong monitoring
InfertilityAlkylating agentsBEACOPP >> ABVD for gonadotoxicity
Peripheral neuropathyVinblastine, BVDose-dependent; dose reduction if needed
The challenge now is curing HL while minimizing these late toxicities - hence the shift toward less radiation, PET-guided therapy, and replacing bleomycin with BV.

13. Special Situations

HL in Pregnancy

  • Minimize radiation imaging; use ultrasound + single PA chest X-ray with shielding
  • Often can continue pregnancy to term without treatment
  • If treatment required: ABVD safe in 2nd and 3rd trimester
  • Alternative: single-agent vinblastine until delivery, then full chemotherapy

HL in HIV

  • 5-10x increased risk; virtually always EBV-associated
  • Usually mixed cellularity or lymphocyte-depleted histology
  • 80% present with advanced stage + B symptoms + extranodal involvement
  • Treatment: HAART + ABVD + G-CSF + antimicrobial prophylaxis
  • With proper support, cure rates now comparable to HIV-negative patients

HL in the Elderly (>65 years)

  • 5-year OS <50% vs. ~80% in younger patients
  • Worse outcomes due to comorbidities, inability to receive full chemotherapy doses
  • Target: full staging + full-dose chemotherapy (with G-CSF support)
  • In >70 years or pre-existing pulmonary/cardiac disease: reduce bleomycin dose or omit doxorubicin

14. Prognosis

ScenarioOutcome
Overall cure rate>85%
Stage I-IIACure ~90%
Stage IVA/IVB (5-yr DFS)60-70%
Relapsed post-ASCT~50% still curable
Favorable factors: early stage, no B symptoms, no bulky disease, female sex, low IPS, negative interim PET
Unfavorable factors: advanced stage, B symptoms, bulky disease, high IPS, lymphocyte-depleted subtype

15. HL vs. NHL Quick Comparison

FeatureHodgkin LymphomaNon-Hodgkin Lymphoma
Node patternSingle axial group, contiguous spreadMultiple peripheral nodes, non-contiguous
Mediastinal involvementVery commonLess common (except some subtypes)
Mesenteric/Waldeyer's ringRarely involvedCommonly involved
Extranodal diseaseRare at presentationCommon
Hallmark cellReed-Sternberg cell (CD15+, CD30+)Varies by subtype
PrognosisExcellent, >85% curableHighly variable

Sources: Harrison's Principles of Internal Medicine 22nd Ed (2025), Ch. 114 | Goldman-Cecil Medicine, Ch. 172 | Robbins & Cotran Pathologic Basis of Disease, Ch. 13
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