Hodgkin Lymphoma

Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy (neck most commonly involved), night sweats, weight loss, fever, and at times, splenomegaly and hepatomegaly. Diagnostic testing includes lymph node histologic analysis showing HRS cells, blood tests, and CT and PET scanning. HL is managed with chemotherapy and radiotherapy. The prognosis has improved significantly with the advent of chemotherapeutic regimens.

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Hodgkin lymphoma (HL) is a monoclonal B-cell lymphoma (neoplasm) originating in lymph nodes in which the malignant Hodgkin/Reed-Sternberg (HRS) cells are mixed with a heterogeneous population of nonneoplastic inflammatory cells.


  • Incidence in the United States: 2 to 3 cases per 100,000 population
  • Bimodal age peaks : young adults (15–34 years) and > 55 years of age 
  • Can be seen in children: 
    • Peak age of incidence: 12 years
    • Incidence: 1.1 cases per 100,000 children
    • Pediatric cases: 85% male
  • M > F (3:2) in adults
  • 30% of all lymphomas (remainder are non-Hodgkin)
  • Lowest incidence (United States):
    • American Indians
    • Alaska Natives
    • Asians/Pacific Islanders


  • Exact etiology unknown
  • Increased risk with:
    • EBV:
      • Responsible for infectious mononucleosis (IM)
      • Minority of patients infected with EBV will develop HL.
      • EBV DNA found in HRS cells in 50% of patients in North America and Europe.
      • EBV DNA found in HRS cells in 90% of patients in economically developing countries.
    • Immunodeficiency:
      • HIV: 5- to 25-fold increased risk of developing HL
      • Immunotherapy
      • Almost all cases of HL occurring in immunodeficiency conditions are EBV-positive.
    • Obesity
    • Diet high in meats and sweets
    • Physical inactivity
    • High birth weight
    • Cigarette smoking
  • Aspirin and breastfeeding seem to be protective.
  • Familial predisposition:
    • Unclear if genetic or environmental
    • Risk in close relatives: 3- to 5-fold greater than overall expected rate
    • Risk varies with subtype.
    • Risk stronger in siblings than in parents.


Based on WHO classification, HLs have the following types and subtypes according to immunophenotype and morphology.

Classic HL (95%):

  • Nodular sclerosis (NSHL):
    • 80% of HLs
    • Male = female
    • Young adults
    • Lacunar cells
    • Classic HRS cells
    • Background cells are mixed
    • Bands of fibrosis
    • Typically stage I or II (mediastinal)
  • Mixed cellularity:
    • 30% of HLs
    • Male > female
    • All ages
    • Histologic type most commonly observed in patients with HIV
    • Typically stage III or IV
    • Mononuclear and classic HRS cells
    • Background cells mixed
    • Eosinophilia present
  • Lymphocyte-rich:
    • 4% of HLs
    • Predominantly men in 30s
    • Mononuclear and classic HRS cells
    • Background cells: T lymphocytes
    • Best prognosis
  • Lymphocyte-depleted:
    • 2% of HLs
    • Associated with advanced age
    • Classic HRS cells along with variants
    • Few background cells
    • Some diffuse fibrosis
    • Typically older men
    • HIV association
    • Abdominal lymphadenopathy
    • Worst prognosis

Nodular lymphocyte–predominant HL (NLPHL):

  • 5% of HLs
  • Distinct clinical entity and not considered part of the classical HL type
  • Males > females: 3:1
  • Typical presentation is chronic asymptomatic peripheral lymphadenopathy.
  • Strong genetic component
  • Lymphocytic and histiocytic (L&H) (popcorn) neoplastic cells:
    • Express CD20 antigen
    • Negative for CD15 and CD30
  • Typical HRS cells are either infrequent or absent.
  • B cells and dendritic cells are the background cells.
  • More common in younger patients
  • Cervical and axillary involvement typical


Hodgkin/Reed-Sternberg cells

  • Neoplastic cells in classic Hodgkin lymphoma (cHL)
  • Bilobed nuclei with prominent nucleoli (owl’s-eye appearance)
  • cHL expresses CD15 (Leu-M1) and CD30 (Ki-1) antigens 
  • Comprise only 1%–2% of the total tumor cell mass
  • Produce cytokines (e.g., interleukins and tumor necrosis factor (TNF)), which stimulate cell proliferation
  • Result from clonal transformation of cells of B-cell origin:
    • Derived from germinal lymph node centers 
    • Origin cells acquire multiple mutations
  • Lose the ability to undergo apoptosis:
    • Latent membrane protein 1 (LMP-1), which is expressed by Epstein-Barr–infected cells, is responsible for activation of nuclear factor kappa-B (NF-kappaB) pathway, which is apoptotic.
    • NF-kappaB is translocated to the nucleus of RS cells.
    • NF-kappaB is also responsible for proliferation of the HRS cells and secretion of proinflammatory cytokines that are responsible for the systemic features of cHL.
  • No longer able to produce antibodies
  • Some HRS cells show evidence of EBV infection and frequent cytogenetic abnormalities:
    • EBV is an oncogenic virus associated with HL.
    • EBV is believed to be responsible for production of signals that render cells immortal (i.e., they no longer undergo apoptosis).
    • Detection of EBV in HRS cells varies with histologic subtype, geography, and immunocompetence.

Surrounding inflammatory stroma

  • Benign reactive cells that are attracted to and proliferate with the expression of cytokines by HRS cells.
  • Comprise the bulk of the tumor
  • Mixture of macrophages, lymphocytes, mast cells, neutrophils, eosinophils, and plasma cells
  • HRS cells also activate fibroblasts and collagen deposition.

Genetic mutations

  • Affect proliferation and survival of malignant cells
  • Mutations producing abnormalities of intracellular signaling:
    • NF-kappaB
    • JAK-STAT 
    • NOTCH
  • Mutations producing immune evasion: PD-1 related genes


  • Proceeds from a single lymph node to adjacent nodes via lymphatic channels
  • Distant spread later

Clinical Presentation

Time course:

  • cHL generally progresses slowly.
  • Some variability 

Most common presentations:

  • Asymptomatic lymphadenopathy:
    • 66% of cHL cases
    • Nontender
    • Firm
    • Rubbery consistency
    • Neck most common site
    • Axillary and inguinal nodes less common
    • Retroperitoneal node involvement in 30% of patients
  • Chest mass on imaging:
    • Mediastinal nodes involved in over 50% of patients.
    • Not detectable on physical exam
Prominent cervical lymphadenopathy

Hodgkin lymphoma:
Prominent cervical lymphadenopathy

Image: “Hodgkin’s Disease (Essentials of Medicine)” by Charles Phillips Emerson, Nellie Gates Brown. License: Public Domain

“B” symptoms (constitutional) present in 40% of cases:

  • Fever
  • Night sweats
  • Unintended weight loss
  • Fatigue

Other symptoms:

  • Pruritus (10%–15%)
  • Alcohol-associated pain (rare): alcohol consumption induces pain in lymph nodes (pathognomonic).
  • Skin lesions (ichthyosis, acrokeratosis, erythema nodosum, urticaria, erythema multiforme)
  • Bone pain (if there is bone involvement)
  • Paraneoplastic syndromes:
    • Neurologic
    • Nephrotic

Diagnosis and Staging


  • Lymphadenopathy:
    • Painless
    • Most common symptom
    • Contiguous spread or single node
    • Unilateral 
    • Cervical/supraclavicular → axillary → inguinal
    • Nontender, rubbery 
  • Constitutional B symptoms:
    • Low-grade fever
    • Night sweats
    • Weight loss
  • Pruritus
  • Back or bone pain
  • Pel-Ebstein fever: waves of fever for weeks 
  • Alcohol pain
  • Family history: particularly helpful in NSHL

Physical exam

  • Lymph nodes:
    • Palpable nodes
    • Painless
    • Neck: 60%–80%
    • Axilla: 6%–20%
    • Inguinal: 6%–20%
  • Superior vena cava (SVC) syndrome:
    • If sufficient physical obstruction of SVC by mediastinal node infiltration
    • Venous distention of the upper limbs and neck 
    • Facial swelling and congestion
    • Pleural effusion: shortness of breath
    • Cough
  • Rare, extranodal manifestations:
    • Hepatomegaly
    • Splenomegaly
    • Diminished breath sounds and tachypnea (pleural effusion)
    • Bony tenderness 

Diagnostic testing

Laboratory studies:

  • CBC with differential:
    • Anemia
    • Lymphopenia
    • Neutrophilia
    • Eosinophilia
  • Erythrocyte sedimentation rate (ESR):
    • General marker for inflammation
    • May be elevated
    • Associated with worse prognosis
  • Serum chemistries:
    • Serum calcium elevation
    • Serum sodium elevation
    • Serum creatinine increased in nephrotic syndrome
  • Liver function tests:
    • Alkaline phosphatase (ALP) may be increased with involvement of:
      • Liver
      • Bone
    • LDH increased
    • May correlate with disease extent and bulk
  • Albumin
  • HIV testing
  • Hepatitis B and C testing


  • Chest X-ray (masses or mediastinal widening)
  • CT scanning to evaluate:
    • Lymph node enlargement
    • Hepatomegaly
    • Splenomegaly
    • Lung:
      • Nodules
      • Effusions
      • Infiltrates
  • PET scanning:
    • Considered essential to the initial staging of HL:
    • Injection of fluorodeoxyglucose (FDG), which is an analogue of glucose:
      • Taken up by tumor cells
      • Emits gamma rays
      • Gamma rays are detected by scanner.
    • Ability to distinguish between viable tumor and necrosis or fibrosis
    • Often performed in conjunction with CT scanning
    • Guides the need for further treatment
Chest X-ray showing mediastinal lymphadenopathy in Hodgin lymphoma

Chest X-ray showing mediastinal lymphadenopathy in Hodgin lymphoma

Image: “Hodgkin’s lymphoma presenting with markedly elevated IgE: a case report” by Ellis AK, Waserman S. License: CC BY 2.0


  • Excisional biopsy of a peripheral lymph node (preferred):
    • Mandatory testing
    • Microscopy: 
      • RS cells
      • Pleomorphic inflammatory cell infiltrate
      • Fibrosis
    • Immunophenotype: 
      • CD30 (classical HL)
      • CD15 (classical HL)
      • CD20 (NLPHL)
      • Absence of CD45 and CD3
  • Bone marrow biopsy: to determine extent of disease


Staging is based on the Ann Arbor classification.

  • Stage I:
    • 1 group of lymph nodes (I): primarily cervical or
    • A single extralymphatic site (Ie)
  • Stage II:
    • ≥ 2 lymph nodes on 1 side of diaphragm (II) or
    • Localized extranodal foci and infestation of ≥ 1 lymph nodes on 1 side of diaphragm (IIe)
  • Stage III:
    • Lymph node involvement on both sides of the diaphragm (III), which may include the spleen (IIIs) or
    • Limited contiguous extralymphatic organ or site (IIIe, IIIes)
  • Stage IV: disseminated involvement of ≥ 1 extralymphatic organs without lymph node involvement
  • “A” indicates the absence of systemic symptoms.
  • “B” indicates the presence of systemic symptoms.

Management and Prognosis


  • Goals of therapy:
    • Maximize cure for all stages.
    • Minimize both short- and long-term complications.
    • Minimize risks of toxicity.
  • Primarily guided by clinical stage
  • Stage IA:
    • Chemotherapy with ABVD (doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine)
    • Followed by localized or regional radiotherapy
  • Stage IB/II:
    • 4–6 courses of ABVD
    • Radiotherapy to bulky nodes
  • Stages III and IV: 
    • 6–8 courses of ABVD
    • Radiotherapy for residual bulky lymphadenopathy
  • Refractory cases: 
    • Autologous stem cell transplantation
    • Different chemotherapeutics
    • Antibodies to block PD-L1
    • Antibodies against CD30


  • International Prognostic Score (IPS): based on 7 unfavorable features at diagnosis:
    • Male sex
    • Age > 45 years
    • Stage IV disease
    • Hypoalbuminemia: serum albumin < 4 g/dL
    • Hemoglobin < 10.5 g/dL
    • Lymphocyte count < 600/µL and/or < 8% of the WBC
    • WBC ≥ 15,000/µL
  • Freedom of progression at 5 years:
    • 0 factors: 84% (7% of patients)
    • 1 factors: 77% (22% of patients)
    • 2 factors: 67% (29% of patients)
    • 3 factors: 60% (23% of patients)
    • 4 factors: 51% (12% of patients)
    • 5 or more factors: 42% (7% of patients)


  • Radiotherapy complications:
    • Myelodysplasia 
    • Acute leukemia 
    • Sarcoma
    • Increased risk of lung cancer or fibrotic lung disease, particularly in smokers
  • Chemotherapy complications: 
    • Adriamycin is cardiotoxic.
    • Bleomycin causes pneumonitis.
    • Congestive heart failure and increased risk of coronary artery disease
    • Long-term immunodeficiency
    • Neuropathy and muscle atrophy

Differential Diagnosis

  • Reactive processes: infectious, autoimmune, and other inflammatory processes may result in lymphadenopathy, organomegaly, fever, and other systemic symptoms. Reactive processes have a polymorphous infiltrate but lack Reed-Sternberg cells. Diagnosis is by histologic analysis, blood tests, and imaging studies. Treatment is tailored to the underlying disease.
  • Non-Hodgkin lymphoma (NHL): composes all forms of lymphocyte malignancies that do not have the HRS cells histologically. Signs and symptoms include lymphadenopathy, and constitutional symptoms. Diagnosis is by histologic examinations of lymphoid tissue or bone marrow. Imaging is performed to assist with staging. Management is with chemotherapy, radiation therapy, and stem cell transplantation. 
  • Anaplastic large cell lymphoma: neoplasm of T-cell origin that produces inflammatory responses and tissue fibrosis (a subtype of NHL). Signs and symptoms include lymphadenopathy, but constitutional symptoms are rare. Anaplastic large cell lymphoma has an aggressive course. Diagnosis is made by a combination of morphologic and immunophenotypic evaluations. Management is with chemotherapy and stem cell transplantation.
  • EBV-positive mucocutaneous ulcer: disorder characterized by isolated circumscribed ulcerative lesions that occur in older patients or in the setting of immunosuppression. Lesions are commonly in the oropharynx, but skin or GI sites can be involved. The lesions contain polymorphous inflammatory infiltrates with scattered EBV-infected B cells that resemble HRS cells. EBV-positive mucocutaneous ulcer has an extranodal presentation, benign course, and frequent spontaneous regressions, and it is responsive to conservative treatment.


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  2. Canellos, G., Ng, A. (2021). Overview of the treatment of classic Hodgkin Lymphoma in adults. In Freedman, A. (Ed.), UpToDate. Retrieved April 18, 2021, from https://www.uptodate.com/contents/overview-of-the-treatment-of-classic-hodgkin-lymphoma-in-adults
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