Skip to content
Download PDF

Chapter 114: Hodgkin's Lymphoma

Oncology and Hematology · Part 4 – Oncology: Hematologic Malignancies

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. Hodgkin's lymphoma (HL) is a malignancy of mature B lymphocytes representing ~10% of all lymphomas.
  2. Classical Hodgkin's lymphoma (cHL) is the majority subtype; Nodular lymphocyte-predominant HL (NLPHL) is a second subtype related biologically to indolent B-cell NHLs.
  3. HL has a bimodal age distribution with peaks in the twenties and eighties.
  4. Reed-Sternberg (HRS) cells are the diagnostic malignant cells, large with bilobed nuclei, expressing CD15 and CD30, but comprising <1% of tumor cellularity.
  5. HRS cells harbor genetic aberrations in the PD-L1 locus, leading to overexpression of PD-L1 to avoid immune destruction.
  6. B symptoms (fever >38°C, night sweats, weight loss >10%) are prognostic factors in staging.
  7. Pain in lymph nodes on alcohol ingestion is a characteristic finding in HL.
  8. Early-stage disease (Stage I-II) is treated with ABVD chemotherapy (4-6 cycles) +/- radiation; 5-year OS is 97-100% with ABVD alone in low-risk.
  9. Advanced-stage disease (Stage III-IV) is treated with ABVD or AVD (brentuximab vedotin) +/- radiation; 5-year OS is excellent but late toxicity is a concern.
  10. Relapsed disease is treated with salvage chemotherapy (ICE, GND) followed by autologous stem cell transplantation.
  11. Immune checkpoint inhibitors (nivolumab, pembrolizumab) are effective in relapsed/refractory HL.
  12. The International Prognostic Score (IPS) predicts survival in advanced-stage disease based on 7 risk factors.
  13. EBV is detected in nearly all cases of HIV-associated cHL, suggesting a direct etiologic role.

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🖼 Figure Adult T-cell leukemia/lymphoma
2 🖼 Figure Hodgkin’s disease: A classic Reed-Sternberg (RS) cell is present near the center...

1. DEFINITION & OVERVIEW

Hodgkin's lymphoma (HL) is a malignancy of mature B lymphocytes. It represents approximately 10% of all lymphomas diagnosed each year. The majority of HL diagnoses are classical Hodgkin's lymphoma (cHL), but there is a second subtype, nodular lymphocyte-predominant HL (NLPHL). While NLPHL diagnosis resembles cHL morphologically in certain respects, there is evidence that it is more related to indolent B-cell non-Hodgkin's lymphomas (NHLs) biologically than it is to cHL. cHL is one of the success stories of modern oncology. Until the advent of extended-field radiotherapy in the mid-twentieth century, it was a highly fatal disease of young people. Radiation therapy cured some patients with early-stage disease, and the introduction of multiagent chemotherapy in the 1970s resulted in further improved cure rates. Cure rates now are >85%. The new challenge in the treatment of HL is late therapy-related toxicity, including a high rate of secondary malignancies and cardiovascular disease.

1.1 Subtypes of Hodgkin's Lymphoma

There are four distinct subtypes of cHL that are differentiated based on their histopathologic features. Patients in the younger age groups diagnosed in the United States largely have the nodular sclerosing subtype of HL. Elderly patients, patients infected with HIV, and patients in developing countries more commonly have mixed-cellularity HL or lymphocyte-depleted HL. Together, nodular sclerosis and mixed-cellularity types account for nearly 95% of cases.

Table 1 — Table 114-1 World Health Organization Classification of Hodgkin's Lymphoma

Classification Subtypes
Nodular lymphocyte-predominant Hodgkin's lymphoma Nodular lymphocyte-predominant Hodgkin's lymphoma
Classical Hodgkin's lymphoma Nodular sclerosis Lymphocyte-rich Mixed cellularity Lymphocyte-depleted

2. EPIDEMIOLOGY

The incidence of HL appears fairly stable, with an estimated 8830 new cases diagnosed in the United States in 2023. HL is more common in whites than in blacks and more common in males than in females. A bimodal distribution of age at diagnosis has been observed, with one peak incidence occurring in patients in their twenties and the other in those in their eighties. Some of the late age peak may be attributed to confusion among entities with similar appearance such as anaplastic large-cell lymphoma and T-cell/histiocyte-rich B-cell lymphoma. It usually presents with a mass and obstructive symptoms in the upper aerodigestive tract with occasional extranodal sites, but over two-thirds of patients will have localized disease. It is more common in men, and the median age at diagnosis is 60.

2.1 Risk Factors

Infection by HIV is a risk factor for developing HL. In addition, an association between infection by Epstein-Barr virus (EBV) and HL has been suggested. Viral oncogenesis appears to play a greater role in HIV-related cHL: EBV can be detected in nearly all cases of HIV-associated cHL, compared to only one-third of cases of non-HIV-associated cHL.

3. ETIOLOGY & PATHOPHYSIOLOGY

HL is of B-cell origin. Reed-Sternberg (HRS) cells are the malignant cells in HL. HRS cells in HIV-associated cHL express the EBV-transforming protein latent membrane protein 1 (LMP-1), and the EBV genomes from multiple disease sites in the same HIV-associated cHL patient are episomal and clonal, suggesting that EBV is directly involved in early lymphomagenesis. Histologically, the HRS cell is diagnostic of cHL. These cells are large cells with abundant cytoplasm with bilobed and/or multiple nuclei. By immunohistochemistry, they are often PAX-5 positive but have low to no expression of other B-cell antigens like CD19 and CD20. They express CD15 and CD30 in 85 and 100% of cases, respectively. These cells, though, comprise <1% of the tumor cellularity, with the majority of the tumor made up of a surrounding inflammatory infiltrate of polyclonal lymphocytes, eosinophils, neutrophils, macrophages, plasma cells, fibroblasts, and collagen. The HRS cell interacts with its microenvironment via cell-cell contact and elaboration of growth factors and cytokines, which results in a surrounding cellular milieu that protects it from host immune attack. The surrounding environmental cells likewise support the HRS cells via cell-cell signaling and cytokine production, which provides signals that promote proliferation and survival of the HRS cell itself. Interestingly, 97% of HRS cells in cHL harbor genetic aberrations in the PD-L1 locus on chromosome 9p24.1, resulting in overexpression of PD-L1, the ligand for the inhibitory PD-1 receptor on immune cells. This is one mechanism whereby the HRS cell may be able to avoid immune destruction in its inflammatory microenvironment and may contribute to the generalized immune suppression in HL patients.

3.1 EBV and HIV Association

A monoclonal or oligoclonal proliferation of EBV-infected cells in 20–40% of the patients with HL has led to proposals for this virus having an etiologic role in HL. However, the matter is not settled definitively. Viral oncogenesis appears to play a greater role in HIV-related cHL: EBV can be detected in nearly all cases of HIV-associated cHL, compared to only one-third of cases of non-HIV-associated cHL.

4. CLINICAL FEATURES

Most patients with cHL present with palpable lymphadenopathy that is nontender; in most patients, these lymph nodes are in the neck, supraclavicular area, and axilla. More than half of the patients will have mediastinal adenopathy at diagnosis, and this is sometimes the initial manifestation. Subdiaphragmatic presentation of cHL is unusual and more common in older males. One-third of patients present with fevers, night sweats, and/or weight loss, or 'B' symptoms. Occasionally, HL can present as a fever of unknown origin. This is more common in older patients who are found to have mixed-cellularity HL in an abdominal site. Rarely, the fevers persist for days to weeks, followed by afebrile intervals and then recurrence of the fever. This pattern is known as Pel-Ebstein fever. This disease has its own prognostic score, which takes into account the presence or absence of 'B' symptoms, disease stage, whether LDH is elevated, and whether there is lymph node involvement. EBV viral load at diagnosis and at the end of therapy is also predictive. Together, nodular sclerosis and mixed-cellularity types account for nearly 95% of cases. Patients with early-stage disease do quite well, with 3-year OS of ~85%. Patients with more advanced-stage disease do poorly, with disseminated extranodal relapse occurring frequently, and the median OS is only 4.3 months.

4.1 B Symptoms

  • Unexplained weight loss of >10% of the body weight during the 6 months before staging investigation.
  • Unexplained, persistent, or recurrent fever with temperatures >38°C during the previous month.
  • Recurrent drenching night sweats during the previous month.

4.2 Other Manifestations

  • Severe and unexplained itching.
  • Cutaneous disorders such as erythema nodosum and ichthyosiform atrophy.
  • Paraneoplastic cerebellar degeneration and other distant effects on the CNS.
  • Nephrotic syndrome.
  • Immune hemolytic anemia and thrombocytopenia.
  • Hypercalcemia.
  • Pain in lymph nodes on alcohol ingestion.

5. DIFFERENTIAL DIAGNOSIS

The differential diagnosis of a lymph node biopsy suspicious for HL includes inflammatory processes, mononucleosis, NHL, phenytoin-induced adenopathy, and nonlymphomatous malignancies.

5.1 Mimickers

  • Inflammatory processes.
  • Mononucleosis.
  • Non-Hodgkin's lymphoma (NHL).
  • Phenytoin-induced adenopathy.
  • Nonlymphomatous malignancies.

6. INVESTIGATIONS & DIAGNOSIS

The diagnosis of HL is established by review of an adequate biopsy specimen by an expert hematopathologist. HL is a tumor characterized by rare neoplastic cells of B-cell origin (immunoglobulin genes are rearranged but not expressed) in a tumor mass that is largely polyclonal inflammatory infiltrate, probably a reaction to cytokines produced by the tumor cells. Evaluation of patients with HL will typically begin with a careful history and physical examination. Patients should be asked about the presence or absence of 'B' symptoms. Comorbid diagnoses that may impact therapy should be reviewed, including a history of pulmonary disease and congestive heart failure given the use of chemotherapy drugs that can cause both lung and heart toxicity. A physical examination should pay attention to the peripherally accessible sites of lymph nodes and to the liver and spleen size. Laboratory evaluation should include a complete blood count with differential; erythrocyte sedimentation rate (ESR); chemistry studies reflecting major organ function including serum albumin; and HIV and hepatitis virus testing. A positron emission tomography (PET)/computed tomography (CT) scan is used for staging and is more accurate than a bone marrow biopsy for evaluation of bone marrow involvement as the bone marrow involvement in cHL tends to be patchy and therefore potentially missed on a unilateral bone marrow biopsy. Staging is done using the Ann Arbor staging system. Patients are stratified based on whether they have early-stage disease (stage I or II) or advanced-stage disease (stage III or IV). Patients with early-stage disease have a better prognosis overall but are further classified as favorable or unfavorable based on a variety of factors. These factors vary from study to study but include bulky disease, number of lymph node areas involved, an elevated ESR (>30 if 'B' symptoms are present; >50 if 'B' symptoms are absent), and age. Prognosis in advanced-stage disease is best predicted by the International Prognostic Score (IPS), which ascribes 1 point for male sex, older age (>45 years), stage IV disease, serum albumin <4 g/dL, hemoglobin <10.5 g/dL, white blood cell count ≥15,000/μL, and a lymphocyte count <600/μL and/or <8% of white blood cell count. Five-year progression-free survival ranges from 88% for patients with no risk factors to 62% for patients with four or more factors, but very few patients have multiple risk factors.

6.1 Staging System

Staging for cHL is anatomically based given the propensity of the disease to march from one lymph node group to the next group, often contiguous to the first. Staging is important for selecting therapy of appropriate duration and intensity, but the outcome of optimal therapy for all the stages is excellent.

Table 2 — Table 114-2 The Ann Arbor Staging System for Hodgkin's Lymphoma

Stage Definition
I Involvement of a single lymph node region or lymphoid structure (e.g., spleen, thymus, Waldeyer's ring)
II Involvement of two or more lymph node regions on the same side of the diaphragm (the mediastinum is a single site; hilar lymph nodes should be considered 'lateralized' and, when involved on both sides, constitute stage II disease)
III Involvement of lymph node regions or lymphoid structures on both sides of the diaphragm
III1 Subdiaphragmatic involvement limited to spleen, splenic hilar nodes, celiac nodes, or portal nodes
III2 Subdiaphragmatic involvement includes paraaortic, iliac, or mesenteric nodes plus structures in III1
IV Involvement of extranodal site(s) beyond that designated as 'E'
More than one extranodal deposit at any location
Any involvement of liver or bone marrow

6.2 Diagnostic Criteria

  • Diagnosis requires review of an adequate biopsy specimen by an expert hematopathologist.
  • HRS cells are large cells with abundant cytoplasm with bilobed and/or multiple nuclei.
  • Immunohistochemistry: PAX-5 positive, CD19/CD20 low/negative, CD15 positive (85%), CD30 positive (100%).
  • HRS cells comprise <1% of tumor cellularity.
  • PET/CT is more accurate than bone marrow biopsy for bone marrow involvement.

7. MANAGEMENT & TREATMENT

The overwhelming majority of patients with HL will be cured with either chemotherapy alone or a combination of chemotherapy and radiation therapy. For early-stage disease, however, treatment with combined-modality therapy has been associated with a small decrease in risk of relapse but with an increased risk of late toxicity including secondary malignancies, thyroid disease, and premature cardiovascular disease and stroke resulting in minimal or no improvement in long-term survival. Much of this risk can be attributed to radiation therapy. Thus, investigation into the treatment of early-stage HL at present is aimed at trying to maximize treatment outcome without using radiotherapy. This is an area of controversy in the treatment of HL. For advanced-stage disease, patients do not benefit from the addition of radiation therapy to chemotherapy and are thus treated with chemotherapy alone. The most common regimens used in the United States include ABVD or brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (AVD) for six cycles. Brentuximab is an antibody-drug conjugate (ADC) that targets CD30 on the HRS cell and is conjugated to the microtubule inhibitor monomethyl auristatin E (MMAE). It was approved in the relapsed setting as a single agent and then was tested in phase 1 and 2 trials in combination with AVD chemotherapy for the upfront treatment of advanced-stage cHL. A phase 3 study, ESCHELON-1, randomized patients with advanced-stage cHL to either ABVD or brentuximab-AVD and demonstrated both a progression-free and overall survival benefit with brentuximab-AVD. Again, Stanford V and escalated BEACOPP have been evaluated in advanced-stage disease and are not associated with an improvement in overall survival but are associated with increased toxicity. The small fraction of patients who do not achieve complete remission with chemotherapy alone (partial responders with persistent PET scan positivity account for <10% of patients) may benefit from the addition of involved field radiotherapy. For early-stage disease, the most common chemotherapy regimen used to treat early-stage HL in the United States is ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). This regimen is given every other week, with each cycle including two treatments. In patients with low-risk, high, or favorable disease, the use of four to six cycles of ABVD alone, without radiation therapy, results in progression-free and overall survival rates of 88–92% and 97–100%, respectively, at 5–7 years. This may be associated with a slightly increased risk of relapse when compared with abbreviated chemotherapy (ABVD for four cycles) followed by involved field radiation therapy (30 Gy), but with no difference in overall survival owing to the excellent salvage strategies used for relapsed HL and to the late toxicities seen following radiation therapy to the chest. German studies have examined a very abbreviated chemotherapy regimen (ABVD for two cycles) and low-dose radiation (20 Gy) for particularly good-risk disease with two or fewer lymph node areas involved and found that this was equally effective to standard combined-modality therapy of ABVD for four cycles and 30 Gy of radiation. However, long-term follow-up is not yet available to assess the impact of the lower radiotherapy dose on late toxicities. Finally, the use of an early interim PET/CT scan can aid decisions regarding the duration and extent of therapy. In one study, a negative PET/CT scan after three cycles of ABVD predicted for excellent outcomes with no additional therapy; in another, a negative PET/CT scan after two cycles of ABVD predicted for good outcomes with two additional cycles of ABVD alone, without radiation therapy. For unfavorable-risk disease, the omission of radiation therapy following chemotherapy is associated with a more significant increased risk of relapse compared to favorable-risk disease, but again with no change in overall survival. For these patients, treatment options would include ABVD for four cycles followed by involved field radiation therapy or ABVD alone for six cycles. Treatment decisions are often based on the extent of the radiation field and the unfavorable risk factor, with patients with nonbulky disease being candidates for chemotherapy alone if radiation would be contraindicated for another reason. Combined modality therapy has typically been used for patients with bulky disease, although patients with bulky disease who have a negative PET/CT scan after chemotherapy may not benefit from additional radiation therapy. Alternative chemotherapy regimens to ABVD have been developed and include the Stanford V regimen and escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). Neither of these regimens has resulted in improved outcomes in patients with early-stage disease. Drugs that target the PD-1/PD-L1 axis have been developed for the treatment of relapsed HL based on the known genomic alterations leading to PD-L1 overexpression on the HRS cell (see 'Relapsed Disease,' below). In the setting of relapsed disease, these drugs, which include pembrolizumab and nivolumab, have very high response rates and are associated with durable responses. Phase 2 studies combining these drugs with either brentuximab (nivolumab) or ICE (nivolumab; ifosfamide, carboplatin, and etoposide) or GND (pembrolizumab; gemcitabine, vinorelbine, and doxorubicin) chemotherapy have demonstrated high complete response rates in order to get patients to autologous stem cell transplantation. A multicenter randomized trial comparing brentuximab-AVD to nivolumab-AVD in the upfront treatment of advanced-stage cHL has been presented, and there was a progression-free survival benefit with nivolumab-AVD and the regimen had an arguably more favorable toxicity profile. We await longer follow-up and U.S. Food and Drug Administration review of these results to determine if this study establishes a new standard of care for the upfront treatment of advanced-stage cHL. For patients with early-stage disease who do not respond sufficiently to salvage chemotherapy, radiation therapy can be very effective to achieve a remission; whether to consolidate such a remission with an autologous stem cell transplant is debated. Brentuximab is also used as a maintenance therapy following successful autologous stem cell transplantation based on results of the AETHERA study, a randomized trial of brentuximab maintenance versus observation. Finally, anti-CD30 chimeric antigen receptor (CAR) T-cell therapy has been tested in multiply relapsed cHL with promising early results; these products are now being tested in multicenter phase 2 clinical trials.

7.1 Early-Stage Disease Treatment

  • Most common regimen: ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine).
  • Frequency: Every other week, with each cycle including two treatments.
  • Low-risk/Favorable disease: 4-6 cycles of ABVD alone (no radiation).
  • Outcomes: Progression-free survival 88-92%, Overall survival 97-100% at 5-7 years.
  • Abbreviated regimen: ABVD for 2 cycles + low-dose radiation (20 Gy) for good-risk disease.
  • Bulky disease: Combined modality therapy (chemotherapy + radiation) typically used.
  • PET/CT role: Negative PET/CT after 2-3 cycles may predict excellent outcomes with no additional therapy or reduced therapy.

Table 3 — Table 7.1 Early-Stage HL Treatment Options

Risk Category Regimen Radiation Cycles
Low-risk/Favorable ABVD None (or IFRT 30 Gy) 4-6
Good-risk ABVD Low-dose (20 Gy) 2
Bulky Disease ABVD Involved Field 6+

7.2 Advanced-Stage Disease Treatment

  • Do not benefit from addition of radiation therapy after complete response to chemotherapy.
  • Treat with chemotherapy alone.
  • Common regimens: ABVD or AVD (brentuximab vedotin + doxorubicin, vinblastine, dacarbazine).
  • AVD: 6 cycles.
  • Brentuximab: Antibody-drug conjugate targeting CD30.
  • Alternative regimens: Stanford V, escalated BEACOPP (not associated with improved overall survival).
  • Relapsed/Refractory: Salvage chemotherapy (ICE, GND) + Autologous Stem Cell Transplantation.
  • Immune Checkpoint Inhibitors: Nivolumab, Pembrolizumab (high response rates, durable responses).

Table 4 — Table 7.2 Advanced-Stage HL Regimens

Regimen Components Notes
ABVD Doxorubicin, Bleomycin, Vinblastine, Dacarbazine Standard of care
AVD Brentuximab vedotin, Doxorubicin, Vinblastine, Dacarbazine Phase 3 study (ESCHELON-1) showed PFS/OS benefit
Stanford V Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, Prednisone Not associated with improved overall survival
Escalated BEACOPP Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, Prednisone Increased toxicity

7.3 Relapsed Disease Treatment

  • Patients who relapse after primary therapy can frequently still be cured.
  • Patients who relapse after effective chemotherapy are usually not curable with subsequent chemotherapy administered at standard doses.
  • Alternative salvage chemotherapy administered at standard doses to document sensitivity and achieve maximum reduction of tumor mass.
  • Standard salvage regimens: ICE, GND.
  • Newer combinations: Brentuximab with immune checkpoint inhibitors (nivolumab).
  • Combinations of ICE or GND with nivolumab or pembrolizumab: Highly effective, lead to high complete remission rates.
  • Autologous stem cell transplantation: Can cure over half of patients who respond completely or nearly so.
  • Maintenance: Brentuximab used as maintenance therapy following successful autologous stem cell transplantation (AETHERA study).
  • CAR T-cell therapy: Tested in multiply relapsed cHL with promising early results.

8. PROGNOSIS & COMPLICATIONS

Patients with early-stage disease have a better prognosis overall but are further classified as favorable or unfavorable based on a variety of factors. These factors vary from study to study but include bulky disease, number of lymph node areas involved, an elevated ESR (>30 if 'B' symptoms are present; >50 if 'B' symptoms are absent), and age. Prognosis in advanced-stage disease is best predicted by the International Prognostic Score (IPS), which ascribes 1 point for male sex, older age (>45 years), stage IV disease, serum albumin <4 g/dL, hemoglobin <10.5 g/dL, white blood cell count ≥15,000/μL, and a lymphocyte count <600/μL and/or <8% of white blood cell count. Five-year progression-free survival ranges from 88% for patients with no risk factors to 62% for patients with four or more factors, but very few patients have multiple risk factors. The new challenge in the treatment of HL is late therapy-related toxicity, including a high rate of secondary malignancies and cardiovascular disease. Current clinical trials are aimed at minimizing this risk while preserving efficacy.

8.1 International Prognostic Score (IPS)

  • Ascribes 1 point for each of the following risk factors:
  • Male sex.
  • Older age (>45 years).
  • Stage IV disease.
  • Serum albumin <4 g/dL.
  • Hemoglobin <10.5 g/dL.
  • White blood cell count ≥15,000/μL.
  • Lymphocyte count <600/μL and/or <8% of white blood cell count.
  • Five-year progression-free survival: 88% (no risk factors) to 62% (four or more factors).

Table 5 — Table 8.1 International Prognostic Score (IPS) Criteria

Risk Factor Criteria Points
Sex Male 1
Age > 45 years 1
Stage Stage IV 1
Albumin < 4 g/dL 1
Hemoglobin < 10.5 g/dL 1
WBC ≥ 15,000/μL 1
Lymphocytes < 600/μL or < 8% 1

8.2 Late Toxicity

  • Secondary malignancies.
  • Cardiovascular disease.
  • Premature cardiovascular disease and stroke.
  • Thyroid disease.
  • Premature cardiovascular disease and stroke resulting in minimal or no improvement in long-term survival.

9. SPECIAL CONSIDERATIONS

Comorbid diagnoses that may impact therapy should be reviewed, including a history of pulmonary disease and congestive heart failure given the use of chemotherapy drugs that can cause both lung and heart toxicity. HIV and hepatitis virus testing is included in the initial evaluation. Infection by HIV is a risk factor for developing HL. Viral oncogenesis appears to play a greater role in HIV-related cHL: EBV can be detected in nearly all cases of HIV-associated cHL, compared to only one-third of cases of non-HIV-associated cHL. HRS cells in HIV-associated cHL express the EBV-transforming protein latent membrane protein 1 (LMP-1), and the EBV genomes from multiple disease sites in the same HIV-associated cHL patient are episomal and clonal, suggesting that EBV is directly involved in early lymphomagenesis.

9.1 HIV-Associated HL

  • Infection by HIV is a risk factor for developing HL.
  • EBV detected in nearly all cases of HIV-associated cHL.
  • HRS cells express EBV-transforming protein latent membrane protein 1 (LMP-1).
  • EBV genomes are episomal and clonal.

10. KEY PEARLS & CLINICAL TRAPS

  • HL is one of the success stories of modern oncology with cure rates now >85%.
  • The new challenge is late therapy-related toxicity, including a high rate of secondary malignancies and cardiovascular disease.
  • Pain in lymph nodes on alcohol ingestion is a characteristic finding in HL.
  • B symptoms (fever >38°C, night sweats, weight loss >10%) are prognostic factors.
  • HRS cells comprise <1% of tumor cellularity but are diagnostic.
  • PET/CT is more accurate than bone marrow biopsy for bone marrow involvement.
  • Immune checkpoint inhibitors (nivolumab, pembrolizumab) have very high response rates in relapsed disease.
  • Brentuximab is an antibody-drug conjugate that targets CD30 on the HRS cell.

10.1 Board Exam Favorites

  • Bimodal age distribution (twenties and eighties).
  • Nodular sclerosis and mixed-cellularity types account for nearly 95% of cases.
  • PD-L1 overexpression on HRS cells allows immune evasion.
  • EBV viral load at diagnosis and at the end of therapy is predictive.

11. WHAT TO LOOK FOR — DIAGNOSTIC CLUES

  • Pain in lymph nodes on alcohol ingestion.
  • Pel-Ebstein fever pattern (fevers persist for days to weeks, followed by afebrile intervals and then recurrence).
  • B symptoms (fever >38°C, night sweats, weight loss >10%).
  • Mediastinal adenopathy is sometimes the initial manifestation.
  • Subdiaphragmatic presentation is unusual and more common in older males.
  • Severe and unexplained itching.
  • Cutaneous disorders such as erythema nodosum and ichthyosiform atrophy.

11.1 Specific Findings

  • Pathognomonic signs: Reed-Sternberg (HRS) cells with bilobed nuclei.
  • Red flags: B symptoms, bulky disease, elevated ESR.
  • Named eponymous signs: Pel-Ebstein fever.
  • Lab/imaging signatures: PET/CT positivity, elevated LDH.

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

Adult T-cell leukemia/lymphoma

Caption: FIGURE 113-7 Adult T-cell leukemia/lymphoma. Peripheral blood smear showing leukemia cells with typical “flower-shaped” nucleus. — Figure 114-1: Histology of Hodgkin's disease showing a classic Reed-Sternberg (RS) cell near the center of the field. RS cells are large cells with a bilobed nucleus and prominent nucleoli surrounded by a pleomorphic cellular infiltrate.

Figure 2

Hodgkin’s disease: A classic Reed-Sternberg (RS) cell is present near...

Caption: FIGURE 114-1 Hodgkin’s disease: A classic Reed-Sternberg (RS) cell is present near the center of the field. RS cells are large cells with a bilobed nucleus and prominent nucleoli surrounded by a pleiomorphic cellular infiltrate. (From DL Kasper: Harrison’s Principles of Internal Medicine, 16th ed. New York, NY: McGraw-Hill; 2005, Fig. 97-11, p. 654.) — Figure 113-7: Peripheral blood smear showing leukemia cells with typical 'flower-shaped' nucleus (Adult T-cell leukemia/lymphoma), referenced in the text context of differential diagnosis or related lymphoid malignancies.

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.