references are 20 th EDITION OF Harrison's T.B. OF Internal Medicine & Dr Thomas Hodgkin's wikipedia page

1. Hodgkin's lymphoma
01-11-2022

3. • Thomas Hodgkin was an exceptional and compassionate physician
who first described the malignant lymphoma that bears his name.
• During his brief career at Guy's Hospital, England he made major
contributions to clinical medicine and pathology.
• In 1832 Hodgkin published his article
• Hodgkin thus recognized the disorder grossly . He pointed out that
the disease spread to contiguous lymph node groups in an orderly
manner and that splenic involvement was a late development

4. • Another well-known Guy's Hospital physician, Dr. Samuel Wilks in
1865 wrote a more detailed paper on the condition and for the
first time used the eponym “Hodgkin's disease,” thereby
immortalizing his predecessor.
• There was still no histologic description of the disorder. Soon,
however, many investigators used the microscope to examine the
tissues of Hodgkin's patients and recognized the characteristic
giant cells.
• The most thorough descriptions of the giant cells in Hodgkin's
disease were made by Sternberg in 1898 and then Dorothy
Reed in 1902

5. Gordon Museum at Guy's Hospital.
Hodgkin's disease watercolor drawing
by Robert Carswell in 1828. This was
case 7 in Hodgkin's report.
Abdominal lymph nodes (Hodgkin's
original case 2), Gordon Museum,
GKT, King's College London.
Histopathologic appearance of
Hodgkin's original case 2. Gordon
Museum, GKT, King's College
London.

6. Child with lymphadenopathy of the neck
(Dorothy Reed, ref. 21)
Patient with bull neck and axillary
lymphadenopathy.

7. the histopathologic appearance of Hodgkin's original case 2, which
was examined in 1968, nearly 140 years after the original
description.
Histologic appearance of a lymph node in
Hodgkin's disease.
Illustration by Dorothy Reed of the
characteristic giant cells in Hodgkin's
disease

8. Hodgkin's lymphoma

9. Discuss the pathological classification, clinical features , clinical staging,
investigations , diagnosis and treatment of Hodgkin’s lymphoma

10. • SAQ : Pathological classification , clinical staging , clinical features
• SAQ : evaluation , diagnosis & treatment
• Practical examination
Short case/ viva /
Pel–Eabstein fever ,classical features of lymphadenopathy , Reed
Sternberg cell , B –symptoms , Ann Arbor staging/ clinical staging

11. Hodgkin’s lymphoma (HL)
• 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 – 95%), but there is a second
subtype of HL, nodular lymphocyte predominant HL (NLPHL- 5%).
• While this NLPHL dose resemble cHL morphologically in certain respects, there
is some evidence that it is more related to the indolent B-cell NHLs biologically
than it is to cHL.

12. • Classical HL 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 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%.

13. New challenge in the treatment of HL
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.

14. EPIDEMIOLOGY AND ETIOLOGY
• HL is of B-cell origin.
• The incidence of HL appears fairly stable, with 8260 new cases diagnosed in 2017
in the United States.
• The lymphoma burden for India 2020 as estimated by the Globo con was 35,828
and 9,221 new cases of NHL and HL, with 20,390 and 3,513 deaths respectively.

15. • 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.

16. • There are four distinct subtypes of classical Hodgkin’s lymphoma (cHL) that are
differentiated based on their histopathologic features
• Patients in the younger age groups diagnosed 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
• Together, nodular sclerosis and mixed cellularity types account for nearly 95% of
cases.

17. Risk factors HL
• 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.

18. Reed-Sternberg (HRS) cells
• Reed-Sternberg (HRS) cells are the malignant cells in HL.
• 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.
• PAX-5 is transcription factor expressed throught B cell maturation, is detected in most B cell neoplasm

19. Reed-Sternberg (HRS) cells
• These cells, though, comprise 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

21. HRS cells,variant of HRS cells are Lacunar cells & Popcorn cells
can be called Hodgkin’s cells

23. Schematic of histopathologic features of sub-types of HL

24. histopathologic features of 4 sub-types of cHL

25. histopathologic features of sub-types of HL : NLPHL

26. APPROACH TO THE PATIENT
Classic Hodgkin’s Lymphoma:
Most patients with cHL present with palpable lymphadenopathy that is
nontender;
in most patients, these lymph nodes are in the neck - cervical ,
supraclavicular area, and axilla.
More than half of the patients will have mediastinal adenopathy at
diagnosis, and this is sometimes the initial manifestation.

27. • 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(>10%), 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

28. Rare presentations in HL
• 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.
HL can occasionally present with unusual manifestations.
These include severe and unexplained itching,
cutaneous disorders such as erythema nodosum and ichthyosis form 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

29. Evaluation
• 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.

30. Laboratory evaluation
Laboratory evaluation should include
 CBC - complete blood count with differential;
ESR - erythrocyte sedimentation rate;
chemistry studies reflecting major organ function including serum albumin;
 and HIV and hepatitis virus testing.
A PET/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.

32. The initial evaluation of a patient with HL or NHL is similar.
• In both situations, the determination of an accurate anatomic stage is an
important part of the evaluation.
• Staging is done using the Ann Arbor staging system

37. Diagnosis of HL
• 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.

38. Differential Diagnosis of HL
The differential diagnosis of a lymph node biopsy suspicious for HL includes
inflammatory processes,
mononucleosis,
NHL,
phenytoin-induced adenopathy,
and non lymphomatous malignancies.

39. • 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.
• Patients are stratified based on whether they have
early stage, stage I or II,
Or
 advanced stage, stage III or IV, disease.

40. 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.

41. Prognosis
Prognosis in advanced stage disease is best predicted by the International
Prognostic Score (IPS), 0-4 points
, 0/1 –low risk ; 2- intermediate ; 3-high intermediate ; 4- high risk
which ascribes a point
for male sex,
older age (>45 years),
stage IV disease,
Low serum albumin

42. TREATMENT : Classic Hodgkin’s Lymphoma
• The overwhelming majority of patients with HL will be cured with either
chemotherapy alone, or a combination of chemotherapy and radiation therapy.
• It has long been appreciated that patients with advanced stage disease do not
benefit from the addition of radiation therapy to chemotherapy and are thus
treated with chemotherapy alone..

44. • 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.

45. Early Stage Disease
• The most common chemotherapy regimen used to treat HL in the USA 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.

46. Table below shows the optimal management strategy for HL
depending on the stage and prognostic factors at diagnosis.

50. Recent advances in the treatment of HL include
the use of
• antibody drug conjugates such as brentuximab
and
• Immune checkpoint inhibitors nivolumab/pembrolizumab.

51. Newer drugs: antibody drug conjugate
• Newer drugs have been developed for the treatment of relapsed HL
• These include the antibody drug conjugate brentuximab, which is an antibody
against CD30 conjugated to the microtubule inhibitor MMAE.
• This drug has been combined with adriamycin, bleomycin, and dacarbazine in
early phase studies for advanced stage HL with favorable efficacy compared to
historical controls.
• We await the data from the randomized trial of AVD+brentuximab compared to
ABVD.

52. antibody drug conjugates : Brentuximab
• Brentuximab is a monoclonal antibody directed against the CD30
antigen present on the surface of the Reed Sternberg cell.
• It is conjugated to MMAE (monomethyl auristatin E) which is toxic to the
neoplastic cell.
• Brentuximab is used upfront to reduce the toxicity of conventional
chemotherapy regimens by omitting bleomycin (causes pulmonary
fibrosis)
• and it has been efficacious in the relapsed/refractory setting, as well.

54. Newer drugs:anti-PD-1 immune checkpoint inhibitors
• Drugs that target the PD-1/PD-L1 axis have been developed in an attempt to
boost the host immune recognition of tumors.
• This was particularly attractive in HL given the overexpression of PD-L1 on the
HRS cell surface.
• In the setting of relapsed disease, these drugs, which include pembrolizumab
and nivolumab, have very high response rates and are associated with durable
responses.
• These are now being tested in conjunction with chemotherapy both as salvage
therapy for relapsed disease and in previously untreated patients.

55. Immune checkpoint inhibitors: Nivolumab / Pembrolizumab.
• These drug have made a huge impact in the treatment of refractory HL.
• The Programmed Death 1 (PD-1) pathway serves as a checkpoint to
curtail T-cell-mediated immune responses, and by expressing PD-1
ligands on the cell surface (engaging PD-1 receptor–positive immune
effector cells), tumors can evade an immune response.
• PD-1-blocking antibodies (pembrolizumab and nivolumab) have been used
to enhance immunity in refractory solid tumors and lymphomas.

56. PD-1 blockade in Hodgkin lymphoma. (A) PD-L1 and PD-L2 are
upregulated in Hodgkin Reed-Sternberg (HRS) cells through
several mechanisms,

57. Recent Advance in the Management of Refractory Lymphomas
• CAR-T cell therapy (chimeric antigen receptor–T cells):
• In this strategy, a patient's own T cells are genetically
engineered to express a synthetic receptor that binds a tumor
antigen.
• CAR-T cells are then expanded for clinical use and infused
back into the patient's body to attack and destroy
chemotherapy-resistant cancer.

59. Allogeneic CAR-T Cell Therapy
Allogeneic-derived chimeric antigen receptor (CAR) cells mean the cells are
taken from a nonrelated healthy donor rather than the patient themselves
may have several advantages including:
•The potential to be manufactured in advance and stored for off-the-shelf
immediate use which is in contrast to most available CAR-T cells which
require the use of a patient's own genetically modified T cells, created
through a multiweek manufacturing process.
•Avoidance of CAR-T cell cytokine release syndrome and neurotoxicity.
• Lower cost

60. SURVIVORSHIP
• 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.

61. • 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

62. • The development of carcinomas as a complication of treatment for HL is a major
problem.
• These tumors usually occur ≥10 years after treatment and are associated with
use of radiotherapy.
• For this reason, young women treated with thoracic radiotherapy for HL should
institute screening mammograms 5–10 years after treatment,
• and all patients who receive thoracic radiotherapy for HL should be discouraged
from smoking.

63. • 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

64. Late side effects from the treatment of HL
• A number of other late side effects from the treatment of HL are well
known.
• Patients who receive thoracic radiotherapy are at very high risk for
the eventual development of hypothyroidism and should be
observed for this complication; intermittent measurement of
thyrotropin should be made to identify the condition before it
becomes symptomatic.
• 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.

65. Late side effects from the treatment of HL : infertility
• Because of the young age at which HL is often diagnosed, infertility is a concern
for patients undergoing treatment for HL.
• Chemotherapy regimens containing alkylating agents induce permanent
infertility in nearly all men.
• The risk of permanent infertility in women treated with alkylating agent-
containing chemotherapy is age-related, with younger women more likely to
recover fertility.
• Infertility is very rare after treatment with ABVD.

66. NODULAR LYMPHOCYTE-PREDOMINANT HODGKIN LYMPHOMA

67. • NLPHL has a number of characteristics that suggest its relationship to NHL,
rather than cHL, however.
• 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.

68. • This lymphoma tends to have a chronic, relapsing course
• and sometimes transforms to diffuse large B-cell lymphoma, including a specific
subtype of diffuse large B-cell lymphoma known as T cell/histiocyte-rich B-cell
lymphoma, which shares an immunophenotype with the L&H cell.
•
• This natural history most closely resembles that of the indolent B cell NHLs.

69. • Patients with NLPHL are 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

70. • 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.
• Some clinicians favor no treatment of asymptomatic disease and merely close
follow-up, akin to the indolent B cell NHLs

71. HL NHL
Reed Sternberg cell /variant cell
present
R.S. /variant cells absent
Mostly initial involvement is of Lymph
nodes
In 1/3 rd cases extranodal disease initiate
first
axial LN Peripheral LN
Spread from one node to another
contagiously through efferent
lymphatics
Spread from one site to another non
contagiously through haematogenous
route
Prognosis over all good
Variant cells lacunar cell / popcorn cell

72. Thank you

73. Thank you