Hodgkin’s Lymphoma

By-Dr Satyajeet RathModerator-Prof Kamal Sahni

INTRODUCTION

• Accounts for ~ 30% of all malignant lymphomas

• Are group of cancers which originates from Reticuloendothelial systems

• It was named after Thomas Hodgkin who first described it in 1832.

• Dorothy Reed and Carl Stenberg first described the malignant cells of Hodgkin’s lymphoma called Reed Stenberg cells.

• Hodgkins lymphoma was the first cancer which could be successfully treated by radiation therapy and also by combination chemotherapy.

Epidemiology

• Accounts for 0.58% of all cancers diagnosed and 0.23% of all cancer deaths in U.S each year.

• Incidence is less than 3 per 100,000

• It has a slightly male predominance (1.1:1)

• It is rare in children younger than 10 years

• Median age of patients at the time of diagnosis is 26 years

• It has Bimodal peak of distribution (25-30 yrs and >55 yrs)

Risk Factors

• First degree relatives have five fold increase in risk for Hodgkins Disease.

• Associated with EBV infection mainly with mixed cellularity type.

• Associated with Infectious Mononucleosis. Incidence is about 2.55 times higher

• High socio economic status.

• Prolonged uses of human growth hormone

Natural History• Hodgkins lymphoma arises in a single node or a chain of nodes and spreads first to

anatomically contiguous lymphoid tissue.

• If contiguity is assumed among the supraclavicular lymph nodes and upper para-aortic nodes/celiac axis/spleen, 90% of patients present with contiguous sites of involvement.9,10

• In addition, disease spread after treatment with limited irradiation also occurs in a contiguous fashion in most instances.9

• Visceral involvement by Hodgkins lymphoma may be secondary to extension from adjacent lymph nodes.

• Haematogenous spread occurs to liver or multiple bony sites

• It rarely involves the gut associated lymphoid tissue such as Waldeyer ring and Peyers patches.

• Mechanism of spleen involvement is unclear but almost all pts with hepatic and bone involvement are associated with splenic involvement.

6

Spread

• May have direct extension into perinodal tissue.

• 85% of Stage I/II disease are above diaphragm.

• Spleen: if >400g, almost always positive.

• Liver: if positive, spleen and retroperitoneal LN’s are also positive.

Clinical features

• Most common presentation is asymptomatic lymphnode enlargement typically in the neck i.e, painless,non-tender,rubbery lmphadenopathy

• Cervical lympnodes are involved in 80% cases .

• Mediastinal involvement is seen in about 50% cases .they produce symptoms like• Chest pain• Cough• Dyspnoea

• Infradiaphragmatic involvement is seen in 5% cases and usually seen with older patients.

Clinical features cont…

• B symptoms About 33% presents with B symptoms overall. Only 15-20% of stage I-II have B symptoms like

o Fever(>38oC) May first present as fever of unknown origin

Fever persists for days to weeks followed by afebrile intervals and then recurrence

Such type of pattern is called Pel Ebstein Fever

o Drenching night sweats

o Weight loss(> 10% in 6 mths)

Clinical features cont…• Other less frequently symptoms are

Pruritus

Alcohol induced pain over involved lymph nodes

Nephrotic syndrome

Erythema nodosum

Cerebellar degeneration

Immune hemolytic anaemia, Thrombocytopenia

Hypercalcaemia

Clinical Features

• Involvement of the spleen is dependent on histologic subtype.• It is involved in 60 percent of mixed cellularity and lymphocyte-depleted

cases compared with 34 percent of nodular lymphocyte-predominant and nodular sclerosis cases.

• Hepatic and marrow disease are invariably associated with splenic involvement

Symptom Percentage involved

Lymphadenopathy 90

Cervical Lmphadenopathy 70

Mediastinal mass 60

B symptoms 30

Axillary nodes 12

Inguinal nodes 9

Bone marrow involvement 5

Hepatosplenomegaly 25

Paediatric Hodgkin’s Lmphoma• Historically, children have had a particularly good prognosis

compared with adults• The nodular lymphocytepredominant subtype of the disease is

more frequent.• Overall, the incidence is highest in developed countries (North

America and Europe) and very rare in Asian populations• Histologic subtypes also vary by age at presentation. • Pathologic features of Hodgkin’s lymphoma are similar in adults

and children

• The childhood form, which presents in patients younger than 15 years of age, is associated with a marked male predominance, increasing family size, and decreasing socioeconomic status.• The young adult form, which

presents in patients ages 15 to 34 years, is associated with a higher socioeconomic

• Mediastinal lymphadenopathy occurs in up to 66%• Axillary or inguinal lymphadenopathy is less frequently seen

as the first presenting sign• Splenic involvement occurs in 30% to 40% of pediatric

patients with Hodgkin’s lymphoma, whereas hepatic involvement is exceedingly rare• pulmonary parenchyma, chest wall, pleura, and pericardium

are the most commonly involved extranodal sites of disease• Approximately 65% of children have stage I and II disease

and 35% have stage III and IV disease

Lymphnodes group

>10 cm

Bulky disease

Patient Evaluation and Staging

• A separate diagnostic CT scan is not necessary if it was done as part of an integrated PET/CT scan.

• The performance of bone marrow biopsy should be limited to patients with advanced-stage disease or those with constitutional symptoms given the low yield in patients with early-stage, favorable-prognosis disease of less than 1%.

Prognostic Factors

Prognostic factor for Early stage Hodgkins disease

Prognostic factors cont…

Advanced stage hodgkins lymphoma International prognostic score

• Hasenclever - data from over 5000 patients with advanced-stage Hodgkin’s lymphoma, mostly treated with doxorubicin-based combination chemotherapy

• Seven factors were found to have similar independent prognostic values in predicting freedom from progression (FFP) and overall survival (OS).

*Each of the following factors carries a score of 1: hypoalbuminemia, anemia, male sex, age ≥45 years, stage IV disease, leukocytosis, and lymphocytopenia.

PET SCAN

• PET Scan has become an integral component of initial staging.

• Information provided by PET has been recently incorporated in the lymphoma guidelines for response evaluation after completion of treatment.

• Useful for follow up study to evaluate residual masses , dx of early recurrence and predicting outcome.

• It has a specificity of 90-95%

Revised International Workshop Criteria With PET Scan

Bone Marrow Biopsy

• Less commonly put into practice

• Overall involvement of bone marrow in Hodgkins lymphoma is 5%.

• Indicated in pts withB symptomsClinical evidence of sub diaphragmatic diseaseStage iii-iv Recurrent disease

25

JACKSON AND PARKER(1947)

SMETANA AND COHEN’S ADDITION (1956)

LUKES(1963)

PARAGRANULOMA PARAGRANULOMA LYMPHOCYTIC AND HISTIOCYTIC, NODULAR LYMPHOCYTIC AND HISTIOCYTIC, DIFFUSE

GRANULOMA GRANULOMA

NODULAR SCLEROSIS

MIXED CELLULARITY

NODULAR SCLEROSIS

SARCOMA SARCOMA DIFFUSE FIBROSISRETICULAR

Early Classifications

26

Later Classifications

• The Lukes-Butler classification of HL, modified at the Rye Conference in 1966, described the criteria for the four familiar subtypes of HL: lymphocyte-predominant, nodular sclerosing, mixed cellularity, and lymphocyte-depleted.

• The REAL classification separated the nodular lymphocyte-predominant (NLP) subtype from so-called classic HL based on the immunophenotypic and genotypic differences

• The REAL classification of HL was carried forward to the 2001 WHO

classification of HL and the 2008 WHO classification.

Pathologic Classification

Reed Sternberg cell

Common feature of ALL Hodgkin Lymphomas.

• Large cells ( >45um in diameter) with classically binucleate or bilobed central nucleus each with a large acidophilic central nucleoli surrounded by a clear halo. “owl’s eye appearance”

• Variants: mononuclear (Hodgkin’s cell), mummified cell, lacunar cell, L/H cell.

• Requirement of Reed-Sternberg cell for initial diagnosis is “absolute”(less strict for LPHL or recurrent disease)

• Classic Reed-Sternberg cell: + CD15, CD30, CD25 – CD45, pan-B, S-100, keratin, EMA• Most current studies indicate the RS cells of HL are lymphocytic in

nature and, in the great majority of cases, are of B-cell origin.

Reed-Sternberg cell

lacunar cell(mixed cellularity) (nodular sclerosis) (lymphocyte

predominance)

RS Cell variants

Ann Arbor Staging Classification-1971• four-stage system formulated

to provide prognostic information and to guide therapeutic decisions

• The clinical stage (CS) denotes the stage as determined by all diagnostic examinations and a single biopsy only. If a second biopsy of any kind has been obtained,whether negative or positive, the term pathologic stage (PS) is used

• It does not reflect other important prognostic factors such as bulky disease or multiple sites of involvement, however

Cotswold’s Staging Classification for Hodgkin’s Lymphoma

• The availability of improved imaging techniques has also changed its applicability.

• In 1988, a meeting was held in the Cotswolds, England, where revisions to the Ann Arbor staging system were made

• The following main changes were made: • (1) The use of computed tomography (CT) scanning is allowed to assess disease

involvement below the diaphragm. • (2) For stage II disease, the number of anatomic nodal sites is indicated by a

subscript (e.g., stage II3)• (3) For stage III disease, upper and lower abdominal involvement was subdivided

as III1 and III2, respectively• (4) Bulky disease is denoted by X, defined as more than one-third widening of

the mediastinum at the T5 to T6 level or more than 10 cm maximum dimension of the nodal mass

• (5) Unconfirmed/uncertain complete remission (CRu) was introduced to denote the presence of a residual imaging abnormality but the absence of pathologically confirmed residual disease.

Cotswolds Staging Classification for Hodgkin’s Lymphoma

Pathological ClassificationHistologic Subtypes

Nodular lymphocyte predominant Hodgkins lymphoma(NLPHL)

Classical Hodgkins lymphoma(CHL)

1 Nodular sclerosis Hodgkins lymphoma

2 Lymphocyte rich classical Hodgkins lymphoma

3 Mixed cellularity Hodgkins lymphoma

4 Lymphocyte depletion Hodgkin lymphoma

Lymphocyte predominant Hodgkin lymphoma

• <5% of Hodgkin lymphoma• Mainly involves cervical, axillary or mediastinal• L&H cells or Popcorn cells are seen

• Positive for CD20, 45, CD79a, Bcl-6, J-chain, and PAX-5. EMA positive in 50% cases.

• Negative for CD15, 30.

• Differential Diagnosis: Well differentiated lymphocytic lymphoma, mononucleosis, malignant melanoma,, progressive transformation of germinal centers

• Hodgkin lymphoma, lymphocyte predominance type. Numerous mature-looking lymphocytes surround scattered, large, pale-staining lymphohistiocytic variants (“popcorn” cells).

Nodular Sclerosis

• Most common type diagnosed. About 70%

• Lacunar ceells are seen

• CD 15 and 30 positive

• EBV negative

• Only subtype without a male predominance

• Seen in younger pts with stage I –II disease

LACUNAR VARIANT RS CELL : These variants possess large, multilobated, or irregular nuclei with finely dispersed chromatin; nucleoli are usually small. The cytoplasm of lacunar cells retracts when fixed in formalin, so the nuclei gives the appearance of cells that lie with empty spaces between them. (lacunae)This retraction in absent in tissues fixed in Zenker and B5.

Mixed Cellularity

• Constitutes about 20%

• More common in young children

• CD 15,30 EBV positive

• Presents in advanced stages

• Tendency to involve spleen,bone marrow

Lymph node, mixed-cellularity Hodgkin lymphoma disease. Diagnostic Reed-Sternberg cells are usually found without difficulty in mixed-cellularity Hodgkin lymphoma. The reactive component consists of small, round lymphocytes, histiocytes, plasma cells, and eosinophils,

Lymphocyte Depleted• Constitutes <5%• Worst prognosis of all subtypes• Older males, rare in children• Present as febrile illness with

pancytopenia, hepatomegaly, and no peripheral lymphadenopathy

• Advanced stage, Stage IV• The biologic hallmark of LDHL is a

collapse of cell-mediated immunity, HIV infection

• RS cells CD15+, CD30+; most EBV+• Differential Diagnosis: Large cell Non-

Hodgkin’s lymphoma. Nodular sclerosis HL

Lymphocyte-Rich• RS cells CD15+, CD30+; 40% EBV+• Uncommon• M > F• Tends to be seen in older adults• This is an uncommon form of classical HL• Reactive lymphocytes make up the vast majority of the cellular infiltrate. In

most cases, involved lymph nodes are diffusely effaced, but vague nodularity due to the presence of residual B-cell follicles is sometimes seen.

• Differential Diagnosis: This entity is distinguished from the lymphocyte predominance type by the presence of frequent mononuclear variants and diagnostic Reed-Sternberg cells with a “classical” immunophenotypic profile.

• Very good to excellent prognosis.

Thank You