Hodgkin Lymphom.pptx

hodgkin lymphoma

1. Hodgkin Lymphoma By NUWAYEZU JEAN BOSCO

2. Introduction Hodgkin lymphoma (HL) is an aggressive B-cell lymphoma, and one of the most curable of all haematological malignancies. Today more than 80% of patients with newly diagnosed HL can now expect to be cured of their disease.

3. The incidence of HL varies with economic status and geographic location. It can affect all age groups but is most common in young adults . In developed countries it is associated with a bimodal age of onset distribution, with an early, larger, peak occurring in young adults aged between 20 and 40 years and a second, smaller, peak occurring in those over 55 years . In developing countries, the disease predominantly occurs in childhood, with the incidence decreasing with age. Overall, men are affected slightly more frequently than women (1.3 : 1).

4. Classification

5. Classical Hodgkin Lymphoma Classic owl’s eye appearance ( binucleate HRS cell with two mirror-image nuclei) The malignant cell in cHL , the Hodgkin Reed- Sternberg (HRS) cell, is a large (20–50 μ m ), bi- lobed cell with two or more nuclei with eosinophilic nucleoli. HRS cells are derived from germinal center B lymphocytes, but lack a B- cell receptor and several B- cell associated genes and proteins. HRS express CD30, CD15 and PAX-5 . Other B- cell markers are typically reduced or absent including CD20, CD19 , and transcription factors OCT-2 and BOB1 HRS cells account for the minority of cells in affected lymph nodes and are surrounded by a background of mixed inflammatory cells including B- and T- cells, plasma cells, eosinophils, neutrophils, macrophages, and fibroblasts.

6. Classic Hodgkin lymphoma is further subdivided into 4 histopathological subtype: Nodular sclerosis, 70% M ixed cellularity 20-25% L ymphocyte-rich, 5% Lymphocyte-depleted < 1%

7. Popcorn cell or LP cell The malignant cells in NLPHL are large with folded nuclei and multiple nucleoli (also known as “popcorn” cells) in a nodular background consisting of expanded follicular dendritic cell meshworks and small B-lymphocytes. LP cells are typically CD30 and CD15 negative , with CD19+,CD20+,CD45+,and CD79a+ Nodular Lymphocyte Predominant Hodgkin lymphoma

8. Malignant cell in Classic hodgkin lymphoma ( cHL ) Malignant cell in Nodular Lymphocyte Predominant Hodgkin lymphoma ( NLPHL) Pathogenesis

9. Molecular pathogenesis HRS cells show constitutive activation of the NF- κ B pathway, which is associated with apoptosis resistance. The basis for constitutive NF- κ B activation in at least a proportion of cases is the result of inactivating mutations in TNFAIP3 and NFKBIA , which encode inhibitors of the NF- κ B pathway. Other mechanisms of NF- κ B over-activity include genomic amplification of REL, expression and stimulation of CD40 by HRS cells and EBV infection of HRS cells (resulting in LMP-1 expression, which can mimic activation of CD40). Epstein-Barr virus (EBV) − positive Reed-Sternberg (RS) cells are found in approximately 40% of patients with HL ,mostly in cases of mixed cellularity classic HL (MCCHL) and lymphocyte-depleted classic HL (LDCHL),

10. 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 at 9p24 (which includes the JAK2 locus) and inactivating mutations in PTPN1 (leading to increased phosphorylation of JAK-STAT pathway members). HRS cells have been shown to have deacetylated histones (H3), increased H3K27 trimethylation and DNA methylation patterns, leading to silencing of tumour-suppressor genes and the extinction of the normal B-lymphocyte expression profile. HRS cells escape antitumor immune responses via inhibition of PD-1-expressing immune cells, such as cytotoxic T cells, due to overexpression of the PD-1 ligands PD-L1 and PD-L2.

11. Molecular Pathogenesis of cHL

12. Risk factors EBV infection(mixed cellularity and LD subtypes ) Immunocompromised status : HIV , immunosuppression due to solid organ or hematopoietic stem cell transplantation (SCT), or who are treated with immunosuppressive medications( EBV associated disease) Autoimmune diseases: SLE, RA, sarcoidosis The risk of developing cHL is higher among relatives of patients with cHL , and specific HLA haplotypes (HLA-A1) are associated with a higher risk. In identical twins, the risk of HL is increased approximately 100-fold. NS subtype, is associated with factors indicative of a high standard of living, including small family size

13. Clinical presentation Lymphadenopathy that commonly shows a slow progressive growth over months The most frequent site of lymphadenopathy is in the cervical and supraclavicular nodal regions but other sites may be involved too Lymphadenopathy can cause compression to vital organ and may present as Cough, chest pain and superior vena cava syndrome ( mediastinal) cHL is a highly inflammatory tumour and may be associated with numerous systemic symptoms including classic B symptoms, itch and alcohol-induced lymph node pain

14. Diagnosis An accurate histological diagnosis of cHL is made by recognizing the morphological and immunophenotypic characteristics of the HRS cell within the appropriate cellular background Excision biopsy( prefered) or image guided core niddle biopsy if no accessible peripheral lymphadenopathy for adequate tissue diagnosis

15. WORK UP CBC Renal and liver function tests – usually performed as a baseline before chemotherapy and as a screen for hepatic dysfunction as a result of cHL Erythrocyte sedimentation rate (ESR) commonly is elevated and is prognostic in early stage disease. Lactate dehydrogenase (LDH) is rarely elevated except in patients with extensive, advanced-stage disease HIV serology Echocardiogram/nuclear medicine assessment of cardiac function

16. Staging and risk stratification Staging should be performed with [18F]fluorodeoxyglucose (FDG) positron emission tomography/computerized tomography (PET/CT) scanning. PET/CT improves the accuracy of staging compared with CT scans alone and is the preferred imaging modality in cHL. Recent studies have demonstrated a high sensitivity of PET/CT for bony involvement. Therefore, bone marrow biopsies are not necessary as part of the initial staging procedures for most patients with cHL younger than 60 years.

17. Cotswold-Modified Ann Arbor Staging System for Hodgkin Lymphoma

18. HL patients have traditionally been divided into two distinct prognostic groups according to clinical stage at diagnosis: Early-stage disease , accounting for 45% of newly diagnosed patients, Advanced-stage disease , accounting for 55% of newly diagnosed patients. Early stage disease refers to Ann Arbor stage I or II. Advanced stage Disease refers to any patient with Ann Arbor stage III or IV.

19. Early stage I or II HL is considered “ favorable ” if it is limited to an area above the diaphragm and is not associated with other risk factors. Early stage I or II HL is considered “ unfavorable ” in the presence of other risk factors related to age, tumor burden, ESR, and number of involved nodal areas

20. Prognostic Factors in Early and Advanced-Stage Hodgkin Lymphoma

21. RISK STRATIFICATION FOR ADVANCED DISEASE IPS of 0, 1 or 2 :low-risk IPS 3–7 : high-risk

22. Management of classical HL cHL is treated with chemotherapy with or without radiotherapy Chemotherapy alone is associated with a higher risk of relapse (4% to 8%) but likely has less long-term toxicity compared with combined modality treatment. Most widely used initial chemotherapy regimens are: ABVD ( adriamycin , bleomycin, vinblastine, and dacarbazine) BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone)

23. Treatment Approach According to Prognostic Group

24. PET-adapted therapy In addition to stratifying therapy based on early- or advanced stage disease and the presence or absence of baseline risk factors, patients may also be stratified by their early response to therapy. This is based on the fact that the prognosis is worse for those with residual disease on PET scan after 2 cycles of Chemotherapy

25. Deauville score for the standardized reporting of PET scans in lymphoma.

26. Early-stage disease PET scan is performed after 2 to 3 cycles of ABVD, decision for further cycles of chemotherapy and/or radiotherapy depending on the response This aim to offer escalated therapy to those patients with suboptimal initial disease response, whilst sparing those patients with good early disease control to potentially unnecessary further treatment/toxicity

27. Advanced disease Commence treatment with ABVD in all patients and then intensify treatment to escalated BEACOPP if interim PET appearance is unfavourable. Or, Commence treatment with escalated BEACOPP and subsequently de-intensify treatment to ABVD (or a reduced number of cycles of escalated BEACOPP) if interim PET is favourable . Or, Stratify patients based on IPS upfront to decide between ABVD or escalated BEACOPP as frontline therapy. Treatment is then intensified or de-intensified to the alternative regimen, based on interim PET scan.

28. Treatment of Relapse/refractory disease Salvage chemtherapy followed by Autologous stem cell transplantation Commonly used Salvage chemotherapy regimen include: ICE ( ifosfamide , carboplatin, etoposide)( most common) ESHAP (etoposide, methylprednisolone, cytarabine and cisplatin) DHAP (dexamethasone, cytarabine, cisplatin). Brentuximab vedotin: anti CD 30 Nivolumab and Pembrolizumab: anti PD1 Allogenic stem cell transplantation for relapsed cases post ASCT

29. Treatment of NLPHL Early stage(I or II) Radiotherapy alone is associated with excellent outcomes. Observation may be considered after complete surgical excision of single node. Combined modality therapy (chemoradiotherapy) is often used in those with B-symptoms or risk factors for poorer outcomes Treatment – advanced stage (III–IV) Chemotherapy with a variety of regimens is used including “ cHL -type” (e.g. ABVD) as well as “NHL-type” (e.g. CVP/CHOP). Rituximab is usually incorporated into these regimens (due to CD20 expression on tumour cells and its observed activity as a single-agent)

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