HODGKINS LYMPHOMA

DR SWATHI R KRISHNA
• Are group of cancer which originates from reticuloendothelial System
• It was named after thomas hodgkin who first described it in 1832
• Classified- CHL and NLPHL
CLASSIFICATION
ANATOMIC DISTRIBUTION OF DISEASE

• HL almost always begins in the lymph nodes.

• 80% present with cervical lymph node involvement
• 50% have mediastinal disease.
• extend into extralymphatic sites- lung, pericardium, and soft tissue
• solitary extralymphatic involvement without nodal disease is rare
EPIDEMIOLOGY

• Bimodal age distribution : 20-35 and 70-80 years

• The median age of diagnosis is 26 years.
• It is rare in children younger than 10 yr
• most common diagnosed malignancy among 15- to 19-year-olds.
ETIOLOGY

• Epstein-Barr- risk of HL is 2.55 times higher with a history of infectious

mononucleosis-mixed cellularity HL (MCHL)
• Inherited risk - among first-degree relatives
• human immunodeficiency virus and AIDS
THE ROLE EPSTEIN-BARR VIRUS IN
PATHOGENESIS

• detected in HRS cells in 20% to 50% of CHLs

• mostly detected in cases of MCCHL and LDCHL
• found in HRS cells in nearly all cases of CHL occurring in patients infected with
HIV.
• MOA: EBV uses both activation of oncogenic pathways and immune escape
mechanisms.
• The EBV -LMP2A protein helps in triggering B-cell signaling .
• affects the microenvironment composition by increasing the production of
molecules involved in immune escape - PD-L147 and T-cell recruitment-IL-
10, CCL5, CCL20 and CXCL10
• transform antigen receptor–deficient GC B cells, which enables their escape
from apoptosis.allows their proliferation.
CLINICAL PRESENTATION
• painless lymphadenopathy
• Cervical -80%
• mediastinal adenopathy 50%- cough , chest pain, shortness of breath, vena cava
syndrome
• Abdominal- abdominal pain, bowel disturbances
• Three “B symptoms” - unexplained fevers- classic waxing-and-waning Pel-
Ebsteinpattern, drenching night -sweats, significant weight loss (10% of baseline
weight)
• One-third of patients present with 1 of these
• occur even in patients with relatively limited disease (stage II),
• Other symptoms:
• generalized pruritus,
• fatigue
• alcohol-induced pain in tissues involved by HL.
• Asymptomatic - detection of a mediastinal mass on a routine chest
radiograph
• NLPHL is often diagnosed in young people
• present with early-stage disease,
• usually in a solitary peripheral nodal site.
• Systemic symptoms are uncommon
 NATURAL HISTORY
• Sites of involvement are typically contiguous
• HL can extend from the lymph nodes to adjacent organs
• Hematogenous - liver or multiple bony sites.
• Involved bones can undergo blastic changes- “ivory
vertebra” on plain radiographs
• Rarely involves the Waldeyer lymphoid region or the
gut-associated lymphoid tissues such as Peyer patches.
• It also rarely involves the upper aerodigestive tract,
central nervous system, and skin.
• Contiguity’’ theory of kaplan and Rosenberg- hodgkins lymphoma appear to spread via
lymphatic channels to contiguous lymphatic structures in a predictable nonrandom pattern.
• suscepitibility’ theory of smithers-
• hematogenous distribution appeared more likely –
• When four or more lymph node regions were involved
• with increased splenic involvement
• in mixed cellularity and lymphocyte-depleted case
DIAGNOSTIC WORKUP
• History
• Physical Examination- Palpable nodes (note number, size, location, shape,
consistency, mobility) Palpable viscera
• pathologic documentation- excision biopssy
• Laboratory Studies
• Complete blood count
• ESR-
• lactate dehydrogenase and β2 microglobulin levels.
• liver function studies- ALP- Serum albumin-
• Blood urea nitrogen, creatinine
• If indicated:
• Pregnancy test in women of child-bearing age
• Pulmonary function studies
• Cardiac ejection fraction
• HIV testing
• Imaging
• Chest radiograph: posterior–anterior and lateral
• Contrast-enhanced CT scan of thorax, abdomen, and pelvis
• Contrast-enhanced CT scan of the neck (if neck irradiation is indicated)
• Integrated PET-CT scan (skull base to midthigh)
• chest radiographs - PA and lateral
• .Mediastinal adenopathy can be measured by dividing the
maximum width of the mediastinal mass by the maximum
intrathoracic diameter.
• bulky mediastinal adenopathy :
• When this ratio exceeds 1:3
• include a mass >10 cm and a ratio of mediastinal mass to
the chest diameter at T5-T6 exceeding 0.35
•  CT scans of the chest, abdomen, and pelvis - adenopathy or organ
involvement.
• Lymph nodes >1.5 cm are usually considered to be enlarged
• Spleen over 13-cm long is considered likely involved per the current staging
system.
• CT scan of the neck can help for treatment planning
PET SCAN

• integral component of initial staging, interim assessments and for response

evaluation after completion of treatment.
• Tissues affected by HL are intensely FDG-avid- FDG-PET is more sensitive
than CT for detecting disease.
• FDG’s uptake pattern in bone defines whether bone or bone marrow is
involved
• interim assessment after initial cycles of chemotherapy, - identification patients
who are cured and who need escalation of treatment
ANN ARBOR STAGING CLASSIFICATION
 LYMPH NODE REGIONS AS DEFINED IN THE ANN ARBOR
STAGING SYSTEM
EORTC:combine the hilar
and mediastinal regions &
subpectoral with axilla.
GHSG: combine the hilar and
mediastinal regions &
subpectoral with cervical
• The absence or presence of fever, night sweats, and/or unexplained loss of
10% or more body weight in the 6 mo before diagnosis is denoted by the
suffix letter A or B, respectively
• used since 1971
• was modified in the Cotswolds, England, in 1989 and in Lugano,
Switzerland, in 2014.
• The Cotswolds system - X to designate bulky disease,
• The Lugano system recommended deleting X and instead noting the size of
the largest node
PATHOLOGY OF HODGKIN LYMPHOMA

• Cell of Origin : CHL and NLPHL originate from mature B cells

• Histology
• neoplastic cells of CHL: Hodgkin/Reed-Sternberg (HRS) cells- : large cells with multiple
nuclei, prominent dense eosinophilic nucleus, and abundant pale cytoplasm,
• embedded in an inflammatory background
• account for less than 2% of the tumor mass.
• cytologic appearances of the neoplastic cells vary and include mononuclear Hodgkin cells,
lacunar cells, and mummified cell
FOUR HISTOLOGIC SUBTYPES

• NSCHL: most common histologic subtype -70%

• HRS-“lacunar” morphology
• surrounding inflammatory cellular infiltrate arranged into well-defined nodules that
are separated by thick sclerotic bands.
• Presents with mediastinal LNE
• Favourable prognosis
• LRCHL : 3% to 5% of all HLs
• Clinically mimics NLPHL.
• typically presents in peripheral lymph nodes without mediastinal involvement and as
early-stage disease
• MCCHLs
• frequently involve peripheral lymph nodes
• more common in elderly
• 80% -associated with EBV.
• LDCHL
• rare
• represents progression of NSCHL after therapy.
• Sheets of HRS cells without the background inflammatory milieu.
• Varying degrees of necrosis.
• neoplastic cells of Nodular lymphocyte predominant: “LP cells” or “popcorn
cells” large, multilobed, folded nucleus and is surrounded by small
lymphocytes arranged into nodules
• 6 different immunearchitectural patterns
IMMUNOPHENOTYPE

• HRS - express CD30 , PAX58 and interferon regulatory factor 4 IRF4 [MUM1]
and half of the cases also express CD15
• but other B-cell markers such as CD20, CD79a, and CD19 expressed sometimes
• immunoglobulins or transcription factors that are required for immunoglobulin
gene transcription such as OCT2 or BOB1 are not expressed
• loss of major histocompatibility complex (MHC) class I and II expression
• upregulation of immune escape molecules such PD-L1
• LP cells- express CD20, CD19, BCL6, CD45, PAX5, OCT2,BOB1 ,
IMMUNOGLOBULIN chains
• Negative for- CD15 & CD30
PATHOGENESIS

• The genetic changes in CHL affect two broad biologic mechanisms important
for oncogenesis.
• immune escape – Mechanisms of Immune Escape
• Under physiologic conditions, PD-1 expressed on activated T cells and PD-
L1and PD-L2 expressed on antigen-presenting cells such as dendritic cells
and macrophages  suppressing T-cell–mediated immunity controlling
immune-mediated collateral tissue damage and autoimmunity
• In CHL, most of the lymphoid cells express PD-1, and the PD-L1 expression
is directly upregulated in the neoplastic HRS cells
• This provides an immunologic shield that isolates HRS cells from tumor-
infiltrating T lymphocytes (TILs).
• HRS cells lack expression of MHC class I and II molecules and, therefore,
are unable to present tumor neoantigens to the TILs
• enhancement of cell survival signals.
• alterations in JAK/STAT
• deregulate the nuclear factor kappa B (NF-κB) pathway
• Pathogenesis of NLPHL remains poorly understood.
• The most important recurrent genetic feature - BCL6 gene rearrangements
DIFFERENTIAL DIAGNOSIS
• CHL:
• gray zone lymphomas (GZLs) (based on
cytologic and immunophenotypic features of the
neoplastic cells)
• Primary EBV infection (infectious
mononucleosis)
• EBV reactivation syndromes. ( the polymorphic
nature of the B-cell proliferation and EBV
serology )
• HRS-like cells can be seen in other NHLs.
(absence of background inflammatory infiltrate)
DIFFERENTIAL DIAGNOSIS

• NLPHL:
• DLBCL - environmental characteristics discriminate (detection of one nodule
showing the typical features of NLPHL )
• HRS cells in LRCHL can resemble LP cells - HRS cells- positive for CD30 and
CD15, and OCT2 negative.
• disease progresses  infiltrate becomes more diffuse and T-cell rich  may
mimic T-cell/histiocyte-rich large B-cell lymphoma
PROGNOSTIC FACTORS

• EARLY-STAGE HODGKIN LYMPHOMA

• defined by involvement of nodal groups on one side of the diaphragm only,
• high initial cure rates, up to 95% with the first line of therapy, and good overall survival at
>95% after 5 years
• early-stage disease - favorable and unfavorable categories.
• common features include the presence of bulky disease , more advanced age, elevated
erythrocyte sedimentation rate, systemic symptoms, and multiple or extranodal sites of
involvemen
• Patients with three or more adverse risk factors are often considered
to be in an unfavorable prognostic group for advanced HL.
MANAGEMENT
• early-stage HL :abbreviated chemotherapy combined with irradiation of all
initially involved sites
• NLPHL: RT alone
• advanced-stage disease : definitive chemotherapy with rt to high-risk areas,
such as bulky disease, slowly responding disease, or incompletely responding
disease
FAVOURABLE STAGE I TO II
CLASSIC HODGKIN LYMPHOMA
• Historically, patients with favourable presentations of stage I to II Hodgkin
lymphoma were candidates for treatment with radiation therapy alone, with
curative intent and expectations.
• The treatment volume generally included the mantle and para-aortic fields, as well
as the spleen.
• results were excellent, but the appearance of late risks of radiation therapy,
including secondary neoplasia and cardiovascular disease,resulted in a shift of
management to the use of combined-modality therapy
• The current treatment of choice for these patients is abbreviated chemotherapy
plus ISRT.
UNFAVOURABLE STAGE I TO II
CLASSIC HODGKIN LYMPHOMA
STAGE III TO IV DISEASE

• EORTC trial –
• patients in complete remission after MOPP–ABV to IFRT or no RT, showed
no significant differences in FFS or OS between the two groups. However,
patients with partial remission after chemotherapy benefited from
consolidation RT,
• Retrospective analysis of data from the UK suggested that CMT improved
PFS and OS.
• irradiation is often added on a selected basis, especially for bulky disease
STAGE I TO II A NODULAR LYMPHOCYTE-
PREDOMINANT
HODGKIN LYMPHOMA
• Patients with limited presentations of nLPHD may achieve long-term
disease-free survival after treatment with irradiation alone.
• The retrospective review of experience with nLPHD in the GHSG, there was
no significant difference in response induction, freedom from treatment
failure, or overall survival for irradiation versus combined-modality therapy
• ISRT alone, dose 30 to36 Gy Is the standard treatment for these patients,
CHEMOTHERAPY

• The initial successful drug combination for treating Hodgkin lymphoma was nitrogen mustard,
vincristine, procarbazine, and prednisone (MOPP),. The acute toxicities of treatment at that time
were significant.
• ABVD replaced MOPP as the gold standard of chemotherapy for Hodgkin lymphoma. This is
based largely on the results of an intergroup trial that compared MOPP, ABVD, and MOPP/ABVD
• in an effort to reduce toxicity, the Stanford V regimen which almost always includes a component of
radiation, was developed as an alternative to ABVD.
• to enhance efficacy of CT, GHSG developed the BEACOPP regimen, which may be administered in
a baseline, escalated, or 14-day scheduling.
The most successful of
these is ABVD
Given as D1 and D15
repeated every 28 days
NEWER DRUGS

• BRENTUXIMAB VEDOTIN is an anti-CD30 monoclonal antibody linked to

• an antitubulin agent.
• BV has demonstrated efficacy in CD30+ lymphomas, including Hodgkin lymphoma and
anaplastic large-cell lymphoma.
• It is approved for patients who have had disease recurrence after stem cell transplantation
• NEVOLUMAB- anti PD1 immunomodulatory agent used in disease refractory to HSCT
and BV
 TOXICITIES

• Emesis ,fatigue
• Anorexia
• BM suppression – more with intense regimens
• Infertility MOPP- 86-100% ,BEACOPP-87-93% ,ABVD- <5%
• Neuropathy •
• Cardiomyopathy- adriamycin: >450mg/m2
• Pulmonary- bleomycin : >200mg/m2
• Second malignancy –alkylating agents- leukemia : AML, MDS, NHL, lung cancer,
RADIOTHERAPY

• Radiation therapy is the most effective single therapeutic agent for treating Hodgkins
lymphoma
• The main objective of radiation in Hodgkins lymphoma is to treat involved and
contiguous field to a dose associated with a high likelihood of tumor eradication,
meanwhile keeping the dose to adjacent tissues and organs ALARA.
• For many years wide field RT alone was treatment of choice for early favorable HL. •
CR were high but OS was not satisfying.
• CMT were superior to RT alone.
• Presently indications of RT
• RT alone: stage 1, IIA NLPHL
• Part of CMT – early stage d/s with abbreviated chemotherapy and in
advanced d/s along with full course chemotherapy
• Palliative RT
RADIATION DELIVERY

• Radiotherapy can be given by

• 2D Planning
• 3D Planning
• IMRT
• proton-based systems (3-D and intensity modulated proton therapy [IMPT])
FIELD DESIGN : OLD TECHNIQUES

• Extended field RT
• Supradiaphragmatic: Mantle ,Mini mantle ,Modified mantle, Extended
mantle
• Infradiaphragmatic: Paraaortic ,Spleen ,Pelvic ,Inverted Y
THE MANTLE

• The target volume for mantle field includes All of the major lymph node regions above the diaphragm
•  Occipital
•  Submental
•  Submandibular
•  Ant and Post cervical
•  Infraclavicular
•  Axillary
•  Medial pectoral
•  Paratracheal
•  Mediastinal and hilar nodes
• Position: Supine, head fully extended •
Arms : At side , Above head
• UB: bisected the mandible and passes
through the mastid process.
• lateral margins: to flash the axillae
• The inferior axillary margins: at the level
of the inferior tips of the scapulae.
• LB: T10-11 interspace
• Shielding
• Lung blocks
The upper border of lung block curves centrally to include infraclavicular nodes
The medial borders are shaped so as to treat the hilar nodes.
A gap of 8-10 cm is left in midline between blocks to treat mediastinal nodes.
• Larynx – anteriorly at 20Gy
• Humeral head
• Spinal cord shielding dose>40Gy
• Heart after 30 Gy
•  The full mantle is rarely treated.
INVERTED “Y” FIELD

• The classical subdiaphragmatic field.

• • Target Volume:
•  Para aortic
•  Pelvic
•  Inguinal nodes(b/l)
•  Spleen
• Treatment Fields:
•  For Paraaortic
•  Superiorly:The T10-11 vertebrae
•  Inferiorly:The lower limit of L4
•  Laterally:width of transverse process.
•  Pelvic Field:
•  Laterally:1.5-2 cm lat to the widest point in pelvis
•  Inferiorly:Lesser trochanter.
• BLOCKS:
• Central midline block for
•  Bladder
•  Small bowel
• Oophoropexy if performed
• Testicular shielding
TOTAL NODAL IRRADIATION

Mantle+ inverted Y
+ spleen
 IFRT

• Targets a smaller area rather

than a classical extended field.
 IFRT encompasses region and
not an individual lymph node.
 Initially involved Pre chemo
sites and volume are treated
3DCRT

• GTV: Original prechemo volume of involved lymphnodes clinically and

radiologically
• CTV: GTV with whole nodal regions that contains the involved lymphnodes.
• PTV: Depends on immobilization, reproducibility, organ motion- usually 10
mm margin is added to CTV
INRT

• INRT - EORTC-GELA Lymphoma Group

• fields are designed to treat only the initially involved nodes with some modifications to
avoid OARs.
• This gross tumor volume (GTV) then becomes the CTV, and a 1-cm expansion of the
CTV defines the planning target volume (PTV).
• requires prechemotherapy diagnostic CT and PET-CT imaging with the patient in the
treatment position, postchemotherapy contrast-enhanced CT simulation, and fusion of
the prechemotherapy and postchemotherapy images.
ISRT

• ISRT volumes - vary depending on the clinical situation and treatment protocol.
• patients with favorable early-stage HL receive ISRT to all initial sites of disease
after completing chemotherapy.
• For patients treated with radiotherapy alone (i.e., NLPHL), the ISRT CTV should be
increased to include sites of potential subclinical disease. - additional 2- to 5-cm
margin within the lymphatic stations superior and inferior to the initially involved
disease on PET-CT imaging, taking into account the OARs
• with unfavorable early-stage HL, ISRT to all sites of disease should be used
when abbreviated chemotherapy has been delivered ; but for those who
receive more intensive chemotherapy, certain complete responding areas that
could result in an unacceptable dose to an OAR could be omitted
• Patients with stage III/IV disease are more likely to receive ISRT to sites of
initially bulky disease or sites of slow or incomplete response to
chemotherapy.
RADIATION DOSE (NCCN GUIDELINES )

• radiation therapy alone (NLPHL- 30 to 36 Gy to involved sites and 25 to 30 Gy

to sites of potential subclinical involvement, delivered in 1.5- to 2-Gy fractions
• component of a combined modality approach-
• for nonbulky 30 Gy
• for bulky site 30 to 36 Gy
• incomplete metabolic response (Deauville 4, 5) - 36 to 45 Gy. delivered 1.5 to
2 Gy per
• Palliative- 4- 30Gy
TOXICITY RADIOTHERAPY

• depend on the field treated

• Acute- sore throat, skin reaction dysphagia, Vomiting, diarrhea, BM suppression,
Herpes zoster
• Chronic: pneumonitis , cardiac toxicities, peptic ulcer, diarrhea, intestinal obstruction
Infertility Endocrine dysfunctions Hyposplenism Dental caries
• Second malignancy: lymphoma: DLBCL , solid tumors - Lung, and breast ( stomach,
colon, pancreas, cervix, ovary, vulva, prostate, testis, kidney, bladder & NHL •)
FOLLOW-UP

• After therapy- CR to be documented including PET neg – in 3 mo and initially abn/l lab test
should be done and documented
• f/u at 3-6 mo 1-2yr, 6-12 mo-upto 5yr, Annually after 5yr
• H & P at each visit
• ESR, s albumin, LDH, ALP to be repeated as indicated
• TSH, FBS annually and lipid profile biannually
• Imaging- max upto 3 CT scans if indicated in 2yr, PET only if clinically indicated
• Cancer screening
RELAPSED OR REFRACTORY DISEASE

• 10% of patients with early-stage disease

• •20–30% with advanced disease will be refractory to, or relapse after, initial
treatment.
• Outlook of patients with relapsed disease depends on
• time to relapse(TTR)
• stage at time of relapse
• performance status.
STEM CELL TRANSPLANTATION

• use autologous bone marrow or peripheral blood stem cells (PBSC) to

support intensification of chemotherapy
• Autologous transplantation involves the replacement of hematopoietic stem
cells that have been irreversibly injured by HDCT or radiotherapy.
• This can be accomplished, either with bone marrow cells obtained by
multiple aspirations from the posterior iliac crest under anesthesia or with
PBS collected by apheresis
• thankyou