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Hodgkins Lymphoma

Hodgkins lymphoma


30% of all lymphomas


Characteristic features

1.      Preferentially occur in cervical lymph nodes

2.      Young adults

3.      Contain a small number of scattered mononucleated and multinucleated tumour cells (Hodgkin and Reed-Sternberg cells HRS)

4.      Tumour cells are usually ringed by T-lymphocytes in a rosette like manner





1. Nodular lymphocyte predominant

2. Classical Hodgkins

a)     Nodular sclerosing

b)     Lymphocyte predominant

c)      Mixed cellularity

d)     Lymphocyte depleted


Nodular lymphocyte predominant

5% of all cases of Hodgkins


Usually localised (5-20% present with advanced stage disease)


Lymph node architecture replaced by a nodular with or without a diffuse infiltrate predominantly consisting of small lymphocytes, histiocytes and intermingled L&H cells (lymphocytic and or histocytic Reed-Sternberg cell variants).

L&H cells often have multilobated nuclei and are often termed popcorn cells

Immunophenotype CD20, CD 79a, BCL6, CD45, J chain and CD75 in most instances


Pathology of Reed Sternberg Cells

§   Have VDJ gene rearrangement

§   Post germinal centre immunophenotype and genotype

§   In classical Hodgkin’s mature B-cell antigen expression may be low or absent and there is no immunoblobulin production despite gene rearrangements. (due to crippling mutations in the Ig genes or dysregulation of transcription factors)

§   Would expect to be prone to apoptosis since normal B-cells are dependent on Ig expression

§   Express C-FLIP, a downregulator of Fas may prevent apoptosis

§   May also escape apoptosis via the NF-KB pathway

§   Classical Hodgkin’s do not express the transcription factor Oct2 or its coactivator BOB1/OBF1

§   EBV may also be important in Hodgkins (EBV associated proteins detected in 40% of cases of classical Hodgkin’s – higher rates in the very young and old)

§   Nearly all cases in HIV are associated with EBV



Classical Hodgkin’s






Usually +ve






Occasionally +ve


CD 45



Ig expression



Other B antigens

Usually -ve

Usually +ve




Nodular Lymphocyte predominant (5%)

Men 30-50

Cervival, axillary, inguinal lymphadenopathy

Mediastinal, splenic and marrow involvement rare

Nodular pattern

Typical Reed-Sternberg cells infrequent

Popcorn cells

Prominent proliferation of lymphocytes

Nodular sclerosing (70%)

Median age 28 M=F

Usually presents with stage II disease

Mediastinal involvement in 80%

Bulky disease 54%

Spleen / lung 10%

Nodular pattern of lymph node involvement with collagen bands

Typical Reed-Sternberg cells often infrequent

Lymphocyte rich (5%)

Male (70%) – older than other subtypes

Stage II disease with peripheral lymphadenopathy (10%) mediastinal disease

Similar prognosis to NLPHL

Nodular pattern (occasionally diffuse)

Small numbers of typical Reed-Sternberg cells present with a background of small lymphocytes

Mixed cellularity (20%)

Men (70%) Median age 37

Associated with HIV

Often presents with stage III/IV disease

Peripheral lymphadenopathy common

Mediastinal involvement uncommon

Moderately frequent Reed-Sternberg cells with extensive disorderly fibrosis, reactive cells infrequent

Lymphocyte depleted (<5%)

Men (75%) Median age 37


Most cases now reclassified as NHL (anaplastic or pleormorphic large cell)

Highly variable morphological appearances



Clinical features

§   Asymtomatic lymphadenopathy often cervical or supraclavicular

§   Mediastinal mass

§   Systemic symptoms 25% (fatigue, fever, weight loss, night sweats, itching)

§   Splenomegaly can occur without disease involvement (hepatomegaly cant)

§   Eosinophila frequently seen



Ann Arbor 



Involvement of a single LN or structure (spleen, thymus, Waldeyer’s ring)


> LN regions on the same side of the diaphragm


LNs on both sides of the diaphragm


+ spleninc, hilar, celiac or portal nodes


+ para-aortic, iliac or mesenteric nodes


Extranodal involvement (beyond E)

Modifying factors


No symptoms


Fever, drenching night sweats, weight loss >10% in 6 months


Bulky disease > 1/3 widening of mediastinum


Involvement of a single, continuous extranodal site


Clinical stage


Pathological stage



EORTC risk factors - used for early stage disease



Clinical stage I or II (max 3 nodal areas)

Age <50

ESR <50 or <30 with B symptoms

Mediastinal ratio <0.35

Clinical stage II with >4 nodal areas




Hasenclever index – late stage disease

Age >45

Male gender

Serum albumin <40 g/L

Hb <10.5

Stage IV disease

WC >15

Lymphopenia <0.6 or 8% of WC



Response assessment

§   PET scanning more sensitive and specific for disease free survival than CT scanning

§   CT PET allows PET to be overlayed onto a CT image

§   Optimal timing of PET uncertain as may be positive due to residual macrophage activity




Nodular lymphocyte predominant NLPHL

§   Disease usually localised

§   Most often treated with involved field radiotherapy (although if surgical excision is complete this may be unnecessary)

§   CR 96% with 8 year survival of 99% and 98% for stage I and II disease respectively

§   NLPHL tends to relapse as large cell lymphoma up to 10-15 years after diagnosis

§   Groups from the US and Germany have started to use rituximab in the treatment in NLPHL


Classical Hodgkin’s

§   Unlike many forms of cancer it is often possible to cure even if first line therapy fails

§   Creates dilemma as to whether to try and maximise cure with first line treatment or to use less toxic regimes and then use higher dose treatment at relapse in a greater proportion of individuals.


1. Localised disease (Stage I and IIA)

§   Studies difficult to interpret as different entry criteria used (EORTC rule on max 3 nodal areas) – in UK tend to divide at IIA v IIB

§   Historically used radiotherapy

§   Now standard therapy is three cycles of ABVD plus involved field radiotherapy

§   Several different regimes of radiotherapy and chemotherapy trialled

§   Some debate as to whether radiotherapy should be avoided due to risk of secondary malignancies current Canadian HD6 phase III study randomises patients with I-IIA to ABVD chemo or STNI

§   May be that shorter courses of chemotherapy alone adequate especially if guided by PET scanning (to be investigated by forthcoming UK NCRI trial)


2. Advanced disease

§   ABVD shown to be superior to MOPP in the seminal CALGB trial in 1992 (despite the less long toxicity)

§   New regime BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisolone) developed by German Hodgkin’s study group

§   ABVD / COPP arm closed early due to reduced freedom from treatment failure (76 v 69%) BEACOPP also had improved survival

§   Escalated BEACOPP had a lower rate of early disease progression than normal BEACOPP

§   However, greater chance of infertility

§   ChlVPP/PABLOE is an alternative high dose regime widely used in the UK

§   Early stem cell transplant shown not to be beneficial


Radiotherapy in advanced Hodgkin’s




18F – fluorodeoxyglucose PET scanning

§        Most widely used functional imaging modality for aggressive NHL and HL

§        Has been most widely used for response assessment after completion of therapy

§        Increasingly used for staging and assessment of response during therapy



§        Provides complementary information to BM and CT resulting in modification of disease stage

§        Usually upstaging in about 20%

§        Post treatment assessment

§        More accurate than CT because of its ability to distinguish between viable tumour and necrosis or fibrosis in residual mass, which are present in about 2/3 with HL

§        Therapy monitoring

§        Still evolving

§        2 current UKCRN trials

§        evaluating prognostic role of PET in DLBCL after 2 cycles of treatment

§        phase III trial to determine role of PET in stage Ia/IIa HL


Hodgkins Lymphoma

§        Pretreatment staging

§        Sensitive to nodal and extranodal disease

§        It is able to detect sites that would otherwise have been missed by CT

§        Due to the increasing reliance on systemic treatment , PET is increasingly unlikely to a change in treatment approach

§        Restaging

§        Assessment of patients with known relapse is similar to initial staging

§        Accuracy when base on vague symptoms is probably lower because of potential for false positives caused by benign processes

§        Response assessment after treatment

§        Consistently shown a high negative predictive value of about 90%

§        NPV of CT is also high

§        PPV for PET is much lower  (60%), but still better than CT (20%)

§        Because of residual masses

§        2/3 of residual masses by CT are PET negative

§        30% with PET positive residual masses do not progress/ relapse highlighting the importane of histological confirmation

§        PPV for PET in aggressive NHL is much higher (85%)

§        Probably because HL patients commonly receive radiotherapy and thus get false positives from post irradiation inflammatory changes. Also get more thymic hyperplasia because patients younger

§        Delay imaging until 3 weeks post chemotherapy and 8-12 weeks after radiotherapy

§        New definitions on PET positive residual masses

§        Study reviewing 50 patients with HL or aggressive NHL

§        1 year EFS of 96% in PET negative RMs

§        1 year EFS of 0% in PET positive RMs

§        1 year EFS of 90% without RMs

§        Postchemotherapy PET to assess need for radiotherapy

§        May save some patients from unnecessary radiotherapy, but this has not been evaluated in a trial yet

§        PET for therapy monitoring

§        Potentially high impact on patient management and outcome if treatment can be tailored

§        Currently being performed for prognostic information, but the role of risk-adapted treatment based on mid-therapy PET is being addressed in a number of trials

§        PET for post therapy surveillance

§        Concerns re high false positive rates