This document provides an overview of Hodgkin lymphoma (HL), including: - HL is a malignancy of mature B lymphocytes that represents 10% of lymphomas diagnosed annually. - Classical HL has high cure rates of over 85% with radiation and chemotherapy. However, late therapy-related toxicities are a new challenge. - Staging is important for selecting appropriate therapy intensity, with early stage patients having a better prognosis than advanced stage. - Treatment depends on stage and risk factors, and may involve chemotherapy alone or with radiation for early stage disease. Advanced stage is treated with chemotherapy only. - Late effects of therapy include secondary cancers and heart disease, so reducing radiation exposure is a focus of research.

1. Dr. Shivaom Chaurasia
Resident
Internal Medicine

2.  Hodgkin’s lymphoma (HL) is a malignancy of
mature B lymphocytes.
 It represents ~10% of all lymphomas diagnosed
each year. The majority of HL diagnoses are
classical HL (cHL).
 It was named after Thomas Hodgkin who first
described it in 1832.
 Dorothy Reed and Carl Sternberg first described
the malignant cells of Hodgkin lymphoma called
Reed Sternberg cells.

3.  Classical HL is one of the success stories of
modern oncology.
 Radiation therapy cured some patients with early
stage disease, and the introduction of multi-agent
chemotherapy in the 1970s resulted in further
improved cure rates, both for patients with early
and advanced stage disease.
 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.

4.  Hodgkin lymphoma arises in a single node or chain of
nodes and spreads first to anatomically contiguous
lymphoid tissue.
 Visceral involvement by hodgkin lymphoma may be
secondary to extension from adjacent lymph nodes.
 Hematogenous spread occurs to liver or multiple
bony sites.
 Mechanism of spleen involvement is unclear but all
patients with hepatic and bone involvement are
associated with splenic involvement.

5.  Made up of organs, such as the tonsils, spleen, liver,
bone marrow and a network of lymphatic vessels
that connect to lymph nodes
 Lymph nodes located throughout the body
 Lymph nodes filter foreign particles out of the
lymphatic fluid
 Contain B and T lymphocytes
Immature lymphocytes that travel to the thymus
differentiate into T-Cells
Immature lymphocytes that travel to the spleen
or lymph nodes differentiate into B cells

10.  HL is of B-cell origin.
 Race: HL is more common in whites than in blacks and
more common in males than in females.
 Age: 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.
 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 Third World countries more commonly have
mixed-cellularity HL or lymphocyte-depleted HL.

12.  Reed-Sternberg (HRS) cells are the malignant cells
in HL.
 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.

13.  Histologically,
the HRS cell is
diagnostic of
cHL
 These cells
are large cells
with abundant
cytoplasm
with bilobed
and/or
multiple
nuclei.

14. Popcorn cellLacunar cellClassic RS cell
(mixed cellularity) (Nodular sclerosis)
(Lymphocyte
predominance)

15.  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.
 The HRS cell interacts with its microenvironment
via cell-cell contact and elaboration of growth
factors and cytokines, 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.

18. Evaluation of patients with HL will typically begin
with a careful history and physical examination.
Lymphadenopathy
 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.

19.  One third of patients present with “B” symptoms
 Fever
 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.
 night sweats, and/or
 weight loss
 >10% of body weight in 6 months.

20.  HL can occasionally present with unusual manifestations.
 These include 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, and
 pain in lymph nodes on alcohol ingestion.
 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.

21.  Treatment of HL depends on the stage at presentation; investigations
therefore aim not only to diagnose lymphoma but also to determine the
extent of disease.
 FBC may be normal.
 If a normochromic, normocytic anaemia or lymphopenia is present,
 this is a poor prognostic factor. An eosinophilia or a neutrophilia may be present.
 ESR may be raised.
 Renal function tests are required to ensure function is normal prior to
treatment.
 Liver function may be abnormal in the absence of disease or may reflect
hepatic infiltration. An obstructive pattern may be caused by nodes at the
porta hepatis.
 LDH measurements showing raised levels are an adverse prognostic factor.
 HIV and hepatitis virus testing.

22.  Chest X-ray may show a mediastinal mass.
 CT scan of chest, abdomen and pelvis permits staging.
 Bulky disease (> 10 cm in a single node mass) is an
adverse prognostic feature.
 Positron emission tomography (PET) scanning identifies
nodes involved with HL, which are
18fluorodeoxyglucose (FDG)-avid, and this allows more
accurate staging and monitoring of response .
 Lymph node biopsy may be undertaken surgically or by
percutaneous needle biopsy under radiological
guidance

24.  The differential diagnosis of a lymph node biopsy
suspicious for HL includes
 inflammatory processes,
 mononucleosis,
 NHL,
 phenytoin-induced adenopathy, and
 nonlymphomatous malignancies.
 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 intensity, but the outcome of optimal
therapy for all the stages is excellent.

25.  Patients are stratified based on whether they
have early stage, stage I or II, or advanced
stage, stage III or IV, disease.
 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.

28.  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.

29.  The most common chemotherapy regimen used to treat HL in the United
States is ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine).
 This regimen is given every other week, with each cycle including two
treatments.
 In patients with low-risk, or favorable disease, the use of 4–6 cycles of
ABVD alone, without radiation therapy, results in progression-free and
overall survivals of 88–92% and 97–100% at 5–7 years.
 This may be associated with a slightly increased risk of relapse when
compared with abbreviated chemotherapy (ABVD x4 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.
 Finally, the use of an early interim PET/CT scan can aid decisions on the
duration and extent of therapy.

30.  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 x 4 cycles followed by involved field radiation therapy or
 ABVD alone for 6 cycles.
 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.
 Neither of these regimens has resulted in improved outcomes
inpatients with early stage disease.

32.  Patients with advanced stage disease do not benefit from the addition of
radiation therapy after a complete response to chemotherapy alone and
should be treated with chemotherapy alone.
 The most common regimen used in the United States is ABVD x6 cycles.
 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.
 Newer drugs-
 antibody drug conjugate brentuximab (an antibody against CD30 conjugated to
the microtubule inhibitor MMAE)
 pembrolizumab and nivolumab (Drugs that target the PD-1/PD-L1 )
 In case of relapse

33.  Patients who relapse after primary therapy of
Hodgkin’s lymphoma can frequently still be cured.
 Patients who relapse after an effective
chemotherapy regimen are usually not curable
with subsequent chemotherapy administered at
standard doses.
 For patients who respond completely or nearly so,
autologous bone marrow transplantation can cure
over half of patients.
 Standard salvage chemotherapy regimens include
ICE (ifosfamide, carboplatin, etoposide) or GND
(gemcitabine, navelbine, doxil).

34.  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.
 For patients with advanced stage disease in
whom salvage chemotherapy fails, the antibody
drug conjugate brentuximab vedotin, a CD30-
directed antibody linked to the microtubule toxin
MMAE, is active and can be tried as a bridge to
allogeneic transplant.
 The anti-PD-1 immune checkpoint inhibitors,
nivolumab and pembrolizumab, have efficacy in
relapsed HL, and many responses are durable.

35.  Because of the very high cure rate in patients with HL, long-term
complications have become a major focus for clinical research.
 In fact, in some series of patients with early-stage disease, more
patients died from late complications of therapy than from HL itself.
 This is particularly true in patients with localized disease.
 The most serious late side effects include second malignancies and
cardiac injury.
 Patients are at risk for the development of acute leukemia in the first
10 years after treatment with combination chemotherapy regimens
that contain alkylating agents plus radiation therapy.
 The risk of development of acute leukemia after treatment for HL is
also related to the number of exposures to potentially leukemogenic
agents (i.e., multiple treatments after relapse) and the age of the
patient being treated, with those aged >60 years at particularly high
risk.

36.  The development of carcinomas as a complication of
treatment for HL is a major problem. (≥10 years after
treatment)
 For this reason, young women treated with thoracic
radiotherapy for HL should institute screening
mammograms 5–10 years after treatment.
 Mediastinal radiation also accelerates coronary artery
disease, and patients should be encouraged to
minimize risk factors for coronary artery disease such
as smoking and elevated cholesterol levels.
 Cervical radiation therapy increases the risk of
carotid atherosclerosis and stroke and thyroid
disease, including cancer.

37.  Patients who receive thoracic radiotherapy are at
very high risk for the eventual development of
hypothyroidism.
 Lhermitte’s syndrome occurs in ~15% of patients
who receive thoracic radiotherapy. This syndrome
is manifested by an “electric shock” sensation into
the lower extremities on flexion of the neck.
 Because of the young age at which HL is often
diagnosed, infertility is a concern for patients
undergoing treatment for HL.

39.  NLPHL is now recognized as an entity distinct from cHL.
 Previous classification systems recognized that biopsies
from a small subset of patients diagnosed as having HL
contained a predominance of small lymphocytes and
rare Reed-Sternberg-like cells; tumors have a nodular
growth pattern and a clinical course that varied from
that of patients with cHL.
 This is an unusual clinical entity and represents <5% of
cases of HL and defines NLPHL.
 NLPHL has a number of characteristics that suggest its
relationship to NHL, rather than cHL.

40.  The HRS-like cell, or L&H (lymphocyte and
histiocyte) or “popcorn” cell, is a clonal
proliferation of B cells that are positive for B cell
markers CD45, CD79a, CD20, CD19, and BCL2.
 They do not express two markers normally found
on HRS cells, CD30 and CD15.
 This lymphoma tends to have a chronic, relapsing
course and sometimes transforms to diffuse large
B-cell lymphoma.

41.  More commonly male (75%).
 Like cHL, the age distribution of patients with this
disease has two peaks, but unlike cHL these peaks
include children and adults ages 30–40 years,
respectively.
 The majority of patients diagnosed have stage I or
II disease (75%), with a minority having advanced
stage disease at diagnosis.
 B symptoms are uncommon.

42.  Patients with early stage disease at diagnosis should
be treated with definitive radiotherapy.
 This is associated with a 15-year non-relapse survival
of 82%.
 The treatment of patients with advanced stage
NLPHL is controversial.
 For patients who need therapy due to symptoms or
signs of organ function impairment, both cHL
regimens and B-cell NHL regimens have been used,
including ABVD and R-CHOP. (R) rituximab
(C) cyclophosphamide (H) doxorubicin hydrochloride
(O) vincristine (P) prednisolone

44.  Harrison’s Principles of Internal Medicine
Twentieth Edition
 Davidsons Principles and Practice of
Medicine 23rd ed