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
Classification
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 M>F Usually localised (5-20% present with advanced stage disease) Morphology 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
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
Staging
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
Therapy
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
PET
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
Staging § 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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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