Hodgkin lymphomaBY Dr Maleeha

• 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 call Reed Sternberg cells.

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

• Hodgkin lymphoma (HL) is a aggressive B-cell lymphoma.

INTRODUCTION

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Hodgkin disease

Hodgkin lymphoma

Type of malignant lymphoma in which Reed-Sternberg cells are present in a characterstic background of reactive inflammatory cells of various types,

accompanied by fibrosis of variable degree. ( except NLPHL)

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Epidemiology

PathogenesisCell of origin

The malignant lymphocyte in cHL is known as the Hodgkin and Reed–Sternberg (HRS) cell.

• The demonstration of clonal rearrangements of the

immunoglobulin heavy- and light-chain loci has confirmed their B-cell origin.

• Furthermore, the presence of somatic hypermutation within the immunoglobulin heavy and light chain loci suggest that HRS cell are derived from B lymphocytes.

So why they do not have typical B cell marker???

• HRS cells have lost most of the normal B-cell lineage gene expression program through numerous aberrant genetic mechanisms, such as genetic silencing at B-cell gene promoter regions.

MOLECULAR PATHOGENESIS Genes involved in normal B-lymphocyte growth and

differentiation are suppressed in HRS cells. Signalling pathways contribute to the malignant

phenotype of HRS cells including the following:

1. HRS cells show constitutive activation of the NF-κB pathway, which is associated with apoptosis resistance.

2. The JAK-STAT signalling pathway is overactive in HRS

cells, resulting in uncontrolled growth and proliferation. Mechanisms of JAK-STAT over-activity include chromosomal gains.

3 HRS cells have been shown to have deacetylated histones (H3), increased H3K27 trimethylation and DNA methylation patterns, leading to silencing of tumor-suppressor genes and the extinction of the normal B-lymphocyte expression profile.

4 Mutations in β2M(house keeping gene)

ROLE OF EBV

This likely represents a mechanism by which the HRS cell bypasses the need for a functional B-cell receptor by using EBV-encoded proteins. EBV infection and expression of latent EBV-associated proteins (LMP1) is also associated with activation of NF-κB as well as JAK/STAT pathways.

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A possible model of pathogenesis

germinalcentreB cell

transformingevent(s)

loss of apoptosis

RS cellinflammatory

response

EBV?

cytokines

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Risk Factors• No clear risk factors, several implicated

• EBV (pathogen or passenger)• HIV • woodworking, farming• rare familial aggregations

• First degree relatives have five fold increase in risk for Hodgkin lymphoma.

• Associated with EBV infection mainly with mixed cellularity type. • High socio economic status. • Prolonged use of of human growth hormone. • men > women• whites > blacks > Asians

HISTOLOGICAL FEATURES

• An accurate histological diagnosis of cHL is made by recognizing the morphological and immuno phenotypic characteristics of the HRS cell within the appropriate cellular background.

• Systematic immuno histochemical evaluation of both the tumour cell compartment (HRS cells and its variants) and the associated cellular background is important

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Reed Sternberg cellCommon feature of ALL Hodgkin Lymphomas.• Large cells ( 20-50 um in diameter) with classically binucleate

or bilobed central nucleus each with a large acidophilic central nucleoli (mirror image) surrounded by a clear halo. “owl’s eye appearance”

• Variants: mononuclear (Hodgkin’s 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, EMAHigh level of circulating tumor DNA detected in most cases and

suggestive of higher proliferatiom rate of tumor cells

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Reed-Sternberg cell

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These reactive cells produce factors that support the growth and survival of the tumor cells and further modify the reactive cell response.

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

predominance)

RS Cell variants

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Lymph node, nodular-sclerosing Hodgkin lymphoma. (A) Clusters of Reed-Sternberg cells and variants react with anti-CD15. (B) Reed-Sternberg cells in the same case show negative results for CD45 (leukocyte common antigen), in contrast to positive surrounding small lymphocytes.

A

B

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2008 WHO Classification of Hodgkin Lymphoma

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Nodular Lymphocyte predominant Hodgkin lymphoma(NLPHL)

• <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

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•Small lymphocytes predominate in the reactive component in both types and are intermixed with varying numbers of histiocytes. Eosinophils, neutrophils, and “diagnostic” or “classic” RS cells are rare. In fact, the diagnosis of NLPHL is doubtful if diagnostic RS cells are found easily; the number of such cells should be fewer than one per histologic section.

•In NLPHL, RS cells are conspicuous with folded, multilobed nucleus and smaller nucleoli(“popcorn nuclei”).

•In the nodular subtype of LPHL, there is almost total obliteration of the nodal architecture by a vaguely nodular process.

•LPHL nodules are composed of small, round lymphocytes with varying numbers of epithelioid histiocytes which gives them a mottled appearance. L&H variants of RS cells may be numerous and are principally seen in the nodules.

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

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• An attenuated rim of residual normal node (top) is often present in nodular NLPHL. The vaguely nodular growth pattern and compressed adjacent normal node seen at low magnification are features highly suggestive of Nodular NLPHL.

Classical hodgkin

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1. Nodular Sclerosis• Most common type diagnosed• About 70%• Lacunar cells seen• CD15, 30 positive• EBV negative• Only subtype without a male predominance• Seen in younger patients with stage I-II disease. • Differential diagnosis: Large cell Non Hodgkin lymphoma, carcinoma,

germ cell tumour and thymoma.

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The classic histopathologic criteria for NSHL are

(a) prominent nodularity

(b) presence of lacunar RS cell variants, and

(c) birefringent broad collagen bands

• Nodal architecture is obliterated by relatively large nodules of tumor partly or totally encircled by dense connective tissue bands that are birefringent when viewed under polarized light.

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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)

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• Hodgkin lymphoma, nodular sclerosis type. A low-power view shows well-defined bands of pink, acellular collagen that subdivide the tumor into nodules

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2. Mixed Cellularity

• Constitutes about 20%• More than 50% present as stage III or IV disease• Biphasic incidence, peaking in young adults and again in adults

older than 55• CD15, 30, EBV positive• Presents in advanced stages• Tendency to involve spleen, bone marrow. • Differential diagnosis: Some cases of MCHL display an interfollicular

growth pattern. Such cases may be difficult to distinguish from peripheral T-cell lymphomas. Lennert’s lymphoma (diffuse mixed T-cell ML with excessive histiocytes). Diffuse follicular lymphoma.

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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,

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3. Lymphocyte Depleted• Constitutes <1%• 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

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4. Lymphocyte-Rich• RS cells CD15+, CD30+; 40% EBV+• App 5% of cases• 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” immuno phenotypic profile.

• Very good to excellent prognosis.

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Frequent mononuclear and diagnostic RS cells; background infiltrate rich in lymphocytes.

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CLINICAL FEATURES• 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.

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• Most common presentation is asymptomatic lymph node enlargement, typically in the neck.

• Cervical lymph nodes are involved in 80% cases. • Mediastinal involvement is seen in about 50% cases. They

produce symptoms like chest pain, cough and dyspnoea. • Infra diaphrgamatic involvement is seen in 5% cases and

usually seen with older patients. • Other less common symptoms are : Pruritis, alcohol induced pain over involved lymphnodes,

nephrotic syndrome, erythema nodosum, cerebellar degeneration, immune hemolytic anaemia, thrombocytopenia, hypercalcemia.

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B symptoms• About 33 % present with B symptoms overall• Only 15-20% of stage I-III have B symptoms like

1. Fever(>38^C)• May first present as fever of unknown origin• Fever persists for days to weeks followed by afebrile intervals and then

recurrence. • This pattern is called Pel Ebstein fever.

2. recurrent Drenching night sweats

3. Weight loss (>10% in 6 months)

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Diagnostic workup

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Peripheral Blood• The peripheral blood shows non -specific abnormalities.

• There may be anaemia, either normocytic normochromic or less often,

hypochromic microcytic.

• Rouleaux formation is often increased as is the erythrocyte

sedimentation rate.

• Some patients have neutrophilia, eosinophilia or thrombocytosis

• Occasional patients have lymphocytosis.

• Lymphopenia is common, with severe lymphopenia being seen in patients

with advanced disease or with unfavourable histological categories.

• Anaemia, leucopenia and pancytopenia are common in patients

with bone marrow infiltration

• The neoplastic cells of classical Hodgkin lymphoma rarely if ever

circulate in the peripheral blood; occasional instances of this

phenomenon have been reported but not in recent decades and the

diagnosis of the cases reported might therefore be doubted.

• In multivariate analysis an increased WBC and a reduced

lymphocyte count are of prognostic significance

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Bone Marrow Biopsy

• The demonstration of infiltration requires trephine biopsy

• Detection rate is higher with bilateral biopsy or single large biopsy

• Diagnostic cells are rarely present in films of aspirate.

• BM infiltration is more likely with B symptoms, stage 3 & 4,anemai.

Bone marrow trephine biopsy from a patient with stage IV classical Hodgkin lymphoma demonstrates diagnostic

Reed-Sternberg and Hodgkin cells

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PET SCAN

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Spread

• Generally a well behaved spread of disease through contiguous LN groups, (especially NS and LP); <5% show non-contiguous 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.

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Ann Arbor Staging System• Stage I: Single lymph node region (I) or single extralymphatic organ or

site (IE)

• Stage II: > 2 lymph node regions on same side of diaphragm (II) or with limited, contiguous extra lymphatic tissue involvement (IIE)

• Stage III: both sides of diaphragm involved, may include spleen (IIIS) or local tissue involvement (IIIE)

• Stage IV: multiple/disseminated foci involved with > 1 extra lymphatic organs (i.e. bone marrow)

(A) or (B) designates absence/presence of “B” symptoms*(E) Localized, solitary involvement of extra lymphatic tissue, excluding

liver and bone marrow

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Stage I Stage II Stage III Stage IV

Staging of lymphoma

A: absence of B symptomsB: fever, night sweats, weight loss

Management

chemotherapy Radiotherapy

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Chemotherapy Regimen Medication Regimen Medication

1. ABVD(US)

•ADRIAMYCIN•BLEOMYCIN•VINBLASTINE•DACARBAZINE

2. STANFORD V(NEW)

•ADRIAMYCIN•BLEOMYCIN•VINBLASTINE•VINCRISTINE•PREDNISONE•MECHLORETHAMINEETOPOSIDE

3. MOPP •Mechlorethamine• Vincristine•Procarbazine• Prednisone

4. BEACOPP(EUROPE)

•BLEOMYCIN•ETOPOSIDE•ADRIAMYCIN•CYCLOPHOSPHAMIDE•ONCOVIN•PROCARBAZINE•PREDNISONE

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Radiotherapy • Radiation therapy is the most effective single thrapeutic agent for treating

Hodgkin lymphoma.

• The main objective of radiation in Hodgkin lymphoma is to treat involved and contiguous field.

• Radiotherapy can be given by 1. 2D planning2. 3D planning 3. IFRT(involved field radio therapy)

• Involved field radiotherapy is the most commonly used technique at present. It targets a smaller area rather than a classical extended field.

Novel agents• One of the single most effective new anti-HL therapies emerge is

brentuximab vedotin (BV)

• BV is an antibody–drug conjugate, which consists of an anti-CD30

antibody conjugated to an antimicrotubule agent (monomethyl auristatin

E (MMAE)). .

• Other agents that have shown promise in cHL include the

immunomodulatory drug lenalidomide, the histone deacetylase inhibitors

(e.g. panobinostat) and the anti-PD-1 antibody nivolumab.

LATE EFFECTS/COMPLICATIONS• Due to the high cure rates achieved by the treatment of both early stage and advanced stage

cHL, patients treated for cHL are at risk of numerous late toxicities related to treatment.

• During the first 10 years after diagnosis, most deaths are the result of relapse, however, after

this period most deaths are a result of late effects of treatment.

• For early-stage disease, the cause of death for the majority of patients overall is related to

treatment rather than cHL.

• The chronic toxicity profile of cHL treatment depends on numerous factors, including the

intensity of chemotherapy regimen, types of chemotherapeutic agents to which the patient is

exposed, site of radiotherapy fields and age of patient at treatment.

Secondary solid organ malignancy• Patients treated for HL have an approximately 3 fold increased risk of solid organ malignancy

• The most common secondary malignancies are ;

breast

lung

gastrointestinal tract cancers

• Radiotherapy increases the risk of secondary solid organ malignancy at exposed sites, whereas

chemotherapy has a more complex association with secondary solid organ malignancy, resulting in an

increased risk of some types (e.g. colorectal carcinoma associated with procarbazine use), but also acting

to abrogate the risk of others (e.g. reduction of breast cancer risk in patients receiving radiotherapy

through reducing ovarian function and inducing premature menopause).

• One of the most potent determinants of the risk of developing a secondary solid organ malignancy is the

age at which the patient received treatment

Secondary myeloid malignancy

• The risk of secondary MDS/AML is approximately 1% or less with ABVD, but may be

up to 4% with escalated BEACOPP.

Cardiovascular disease

• Patients treated for cHL are at an increased risk of late cardiovascular disease. This

is contributed to by exposure of the heart to radiotherapy, as well as treatment with

anthracycline based chemotherapy regimens. The latency of coronary artery

disease as a result of radiotherapy is approximately 10 years. Importantly,

concomitant cardiovascular risk factors including hypertension,

hypercholesterolemia and smoking all compound this risk and should be

aggressively managed.

Infertility• Women (regardless of age) receiving escalated BEACOPP have severely reduced ovarian

reserve and significantly higher rates of sustained amenorrhea post treatment.

• Women over the age of 30 treated with BEACOPP regimens have a 50% rate of sustained

amenorrhea (4 years) post treatment and those over 35 treated with escalated BEACOPP

have a less than 5% rate of return to a regular menstrual cycle.

• For male patients,sperm storage can usually be offered before treatment.

CASE PRESENTATION OF

HODGKIN’S LYMPHOMA

History

• • Female patient, 12years old, presented on 10/2009 .

• • The condition started 2 weeks ago with sever diffuse abdominal pain, abdominal distention ,

absolute constipation so patient sought medical advice and was diagnosed as acute intestinal

obstruction.

• Urgent exploration done with intestinal mass found and completely excised moderate to high grade

fever mainly by night, partially responding to medical treatment.

• • The condition was associated with small right neck swelling of lemon size surgical removal of which

showed a non malignant nature.

• On 5/2010, patient developed multiple painless neck swellings with gradual onset progressive course

associated with night fever and weight loss - no drenching night sweating.

• • Surgical removal of cervical swelling was done and patient was referred to us.

• • No manifestation of other system affection was apparent.

Examination & Workup Lymphatic system: • Right upper deep cervical LN about 3*2 cm• Multiple small left upper deep cervical LNs the largest one about 1 cm in diameter • RT axillary LN about 1,5 cm in diameter in the apical group• All of the above described lymph nodes are firm to rubbery in consistency, non tender, freely

mobile and with normal overlying skin• No other enlarged LN groups Laboratory workup: ESR: 1st hr 25

Imaging Workup: CT neck : Multiple bilateral upper and lower deep cervical LNs the largest one on RT side about

3*2.5 cm, the largest one on the left side about 1 *1 cmUS axillae: Multiple bilateral axillary LNs the largest one on the RT side about 1.6*0.8 cm most of

them show loss of the central hilum mostly pathological LNs Echo: FS 36 with MR grade1 Pulmonary Function Test : Free Pathology report Suggestive of Hodgkin lymphoma, nodular lymphocytic predominant type with tumor cells

positive for CD20 Bone marrow biopsy Free

ManagementFinal Diagnosis :

Hodgkin lymphoma, nodular lymphocytic predominant type stage 2B, non bulky disease

Treatment plan:

4 courses of ABVD /COEP then IFRTH 25 gy/17 settings on neck and axillae

Evaluation after 2 courses:

CT neck : multiple enlarged cervical LNs the largest one about 1cm

Axillae US: RT LN with eccenteric hilum largest 1cm

Evaluation after another 2 courses and IFRTH:

CT neck : multiple enlarged cervical LNs the largest one about 1cm.

Axillae US: RT LN with eccenteric hilum largest one about 1 cm.

Other imaging investigations, Echo, PFT, BMB were free

Prospective Approach

• What is the current situation? • - Patient finished treatment on 11-2010 -

Patient is in CR up till now and on follow up for 2,5 years now

• What is the future plan ?• - Patient is under regular follow up in our

outpatient clinic