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EHA-TSH Hematology Tutorial on Lymphoma

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EHA-TSH Hematology Tutorial on Lymphoma EHA-TSH Hematology Tutorial on Lymphoma Hodgkin Lymphoma: Diagnosis and Treatment (First Line and Relapsed Disease Speaker: Pervin Topcuoglu İzmir, Turkey April 6-7, 2019 I have no actual or potential conflict of interest in relation to this presentation Learning Objectives ‒ the morphological and clinical features ‒ the staging work-up and apply the Lugano classification to patients with Hodgkin lymphoma. ‒ the risk stratification prior to the treatment ‒ the treatment in patients with newly diagnosed HL and in those with relapse/refractory HL Content ‒ History ‒ Definition ‒ Epidemiology ‒ Subtypes ‒ Etiology ‒ Presentation ‒ Diagnosis ‒ Management ‒ Follow-up ‒ Summary and Future History History Definition ‒ A type of malignant lymphoma ‒ Germinal B center or Post-GBC ‒ Dorothy Reed and Carl Sternberg first described the malignant cells of HL-called as Reed Sternberg cells -Owl Eyes appearance ‒ The first cancer could be successfully treated by radiation therapy and also combination with chemotherapy (ChT) Epidemiology Median age at 40% diagnosis 30% 39 20% New cases 2.4.-2.5/100,000 persons 10% (EU and US data) 0% male, 2.9; female, 2.2 Percent o Deathso Percent HL most frequently diagnosed in <20 >84 35-44 45-54 55-64 65-74 75-84 20-34 patients 20-34 yrs of age, older Age than 55 yrs of age Increased incidence in industrialized Median age at death countries 67 Nodular sclerosis subtype associated with high standard of living Hodgkin Lymphoma Cancer Stat Facts. 2018. https://seer.cancer.gov/statfacts/html/hodg.html. Epidemiology Estimated New Cases in 2018 8,500 % of All New Cancer Cases 0.5% Percent Surviving 5 years Estimated Death in 2018 1,050 86.6 % % of All Cancer Deaths 0.2 % 2008-2014 3,00 2,50 2,00 1,50 1,00 Persons 0,50 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 0,00 1992 Number Per 100,000 100,000 Per Number Years New Cases Death-US Hodgkin Lymphoma Cancer Stat Facts. 2018. https://seer.cancer.gov/statfacts/html/hodg.html. Histological Subtypes as WHO classification Type Proportion of All HL Classical HL 95 % . Nodular sclerosis classical HL 70 % . Mixed cellularity classical HL 20-25 % . Lymphocyte rich classical HL 5 % . Lymphocyte depletion HL 1-2 % Lymphocyte predominant nodular, 5 % HL Swerdlow, SH IARC Press. 2008. Swerdlow, SH, et al. Blood. 2016;127(20):2375-2390 Teras. CA Cancer J Clin. 2016. Risk Factors ‒ High socioeconomical status: NS type ‒ Low socioeconomical status: MC and LD ‒ EBV: MC ve LD ‒ HIV and other immunosupresive situation ‒ Familial history: 3-5 fold Presentation Painless LAP: 70 % ‒ Supradiaphragmatic LAP • Cervical • Anterior mediastinal 60-80% • Supraclavicular • Axillary: 10-20 % ‒ Inguinal LAP (less) 6-12 % Presentation ‒ 1/3rd of the patients: B symptoms • Fever • Drenching night sweats • Weight loss (more than 10 % of BW within 6 months) ‒ Fatigue ‒ Chronic pruritus which may be early sign (15 %) ‒ Pain localized to the site of involved LAP that is precipitated by the consumption of alcohol. Presentation ‒ Most commonly EN involvement: • Spleen • Lungs • Liver • Bone marrow Other Presentations ‒ Skin lesions: • Ichthyosis, acrokeratosis, urticaria, erythema multiforme, erythema nodosum, necrotizing lesions, hyperpigmentation, skin infiltration ‒ CNS involvement is rare, but paraneoplastic neurological syndroms such as cerebellar degeneration ‒ Nephrotic syndrome ‒ Hypercalcemia ‒ Anemia, thrombocytopenia, leukocytosis ‒ Chest pain, bronchial obstruction, abdominal pain, spinal cord compression, and peripheral edema Diagnosis ‒ Excisional LN biopsy ‒ If excision not feasible core-needle biopsy may suffice ‒ FNA is inadequate for initial diagnosis Histological and IHC ‒ HL originated from GCB or Features post-GBC cells ‒ Classical HL includes Reed- Sternberg Cells(RS) (CD30+, CD15+ variable, PAX5+) • RS cells: Large binucleated or multinucleated cells with pale chromatin, distinct nuclear membrane, single prominent eosinophilic, inclusion-like nucleolus in each nuclear lobe, and abundant amphophilic cytoplasm ‒ Surrounding inflammatory RS cells 0.1-2% of total tumor cells cells Nodular Lymphocyte-Predominant Hodgkin ‒ Macronodular proliferation are Lymphoma composed of scattered neoplastic cells: lymphocyte- predominant (LP) cells. ‒ IHC pattern: CD20+, PAX-5+, and CD79a+ ‒ In contrast to RS cells, CD15- and CD30-, but OCT-2+ and BOB.1+ . ‒ The origin is GBC: BCL-6+ but usually CD10neg ‒ 50% of the pts are EMA+, variably express IRF4/MUM1. ‒ EBERneg and LMP-1neg Evaluation and Staging ‒ WBC ‒ RFT, albumin and LFT ‒ ESR and C-RP ‒ PA X-Ray ‒ Hepatitis tests (B and C) and HIV screening ‒ PET/CT* ‒ BM biopsy is no longer indicated in PET/CT available ‒ MRI and PET/MRI in selected patients *Prior to ChT or surgery, gross tumor volume and planning target volume should be defined. tRoutine BM bx is not required if the PET scan (-) or displays homogenous pattern of BM uptake. BM may be assumed to be involved if the PET scan displays multifocal (≥3) skeletal lesions Evaluation and Staging ‒ Prior to treatment: • Cardiac evaluation (ECO or MUGA) • If necessary, Pulmonary function tests • Thyroid tests • Reproductive counseling, and serum pregnancy testing How can we stage a patient with lymphoma? 1971 Ann Arbor 1988 Cotswolds modification Classification 1999 NCI criteria 2007 IWG revised guidelines 2011 workshop at 11-ICML 2013 2nd workshop at 12-ICML 2014 Lugano classification Lugano Classification (Derived from Ann-Arbor Staging with Cotswolds- Modification) Stage I Involvement of a single lymph node ((LN) region (eg, cervical, axillary, inguinal, mediastinal) or lymphoid structure such as the spleen, thymus, or Waldeyer's ring. Stage II Involvement of two or more LN regions or LN structures on the same side of the diaphragm. Hilar nodes should be considered to be "lateralized" and when involved on both sides, constitute stage II disease. For the purpose of defining the number of anatomic regions, all nodal disease within the mediastinum is considered to be a single LN region, and hilar involvement constitutes an additional site of involvement. The number of anatomic regions should be indicated by a subscript (eg, II-3). Stage III Involvement of LN regions or lymphoid structures on both sides of the diaphragm. This may be subdivided stage III-1 or III-2: stage III-1 is used for patients with involvement of the spleen or splenic hilar, celiac, or portal nodes; and stage III-2 is used for patients with involvement of the paraaortic, iliac, inguinal, or mesenteric nodes. Stage IV Diffuse or disseminated involvement of one or more extranodal organs or tissue beyond that designated E, with or without associated lymph node involvement. Cheson BD, et al. J Clin Oncol 2014; 32: 3059-3068 Lugano Classification (Derived from Ann-Arbor Staging with Cotswolds- Modification) Addendum A B symptoms are absent. Addendum B B symptoms are present: fever (temperature >38ºC), drenching night sweats, and/or unexplained loss of >10% of body weight within the preceding 6 months. Addendum E The designation "E" refers to extranodal contiguous extension (ie, proximal or contiguous extranodal disease) that can be encompassed within an irradiation field appropriate for nodal disease of the same anatomic extent. More extensive extranodal disease is designated stage IV. Bulky disease A single nodal mass, in contrast to multiple smaller nodes, of 10 cm or ≥⅓ of the transthoracic diameter at any level of thoracic vertebrae as determined by CT; record the longest measurement by CT scan. The term "X" (used in the Ann Arbor staging system) is no longer necessary. Subscript "RS" is used to designate the stage at the time of relapse. Patients can be clinically or pathologically staged. Splenectomy, liver biopsy, lymph node biopsy, and/or bone marrow biopsy are mandatory for the establishment of pathological stage. The pathologic stage at a given site is denoted by a subscript (eg, M = bone marrow, H = liver, L = lung, O = bone, P = pleura, and D = skin). Cheson BD, et al. J Clin Oncol 2014; 32: 3059-3068 Lymph Node Regions Ann Arbor EORTC GHSG R Cervical/SCL R ICL/Subpec R axilla Supra L Cervical/SCL L ICL/Subpec L axilla Diaphragm Mediastinum R Hilum L Hilum Total 9 5 5 Infra EORTC includes to combine the ICL/subpec area with axilla: GHSG includes to combine the cervical/SCL and subpec GHSG combined the mediastinum and bilaterally hila Practical Staging Criteria of Involvement Sites Tissue site Clinical Type Test Positive finding FDG-avid PET-CT Increased FDG uptake Lymph nodes Palpable Non-avid CT Unexplained node enlargement FDG-avid PET-CT Diffuse uptake, solitary mass, military lesion, nodules Spleen Palpable Non-avid CT > 13 cm in vertical length, mass, nodules Liver Palpable FDG-avid PET-CT Diffuse uptake, mass, nodules Non-avid CT Mass, nodules Cheson BD, et al. J Clin Oncol 2014; 32: 3059-3067 Criteria of Involvement Sites Tissue site Clinical Type Test Positive finding CT scan Mass lesion(s) Sign, MRI Leptomeningeal infiltration, CNS symptom mass lesions CSF Cytology, flow cytometry assessment PET/CT, Lymphoma involvement Other biopsy (e.g., skin, Site lung, GI tract, dependent bone, BM) Cheson BD, et al. J Clin Oncol 2014; 32: 3059-3067 Treatment of Classical Hodgkin Lymphoma Prognostic Factor, Risk Stratification, and Treatment Groups Treatment Group EORTC/LYSA GHSG Early Stage CSI-II without risk factors CI-II without risk factors Early stage (supradiaphragmatic) IntermediateFavorable stage CSI-II with ≥1 risk factors CSI, IIa with ≥ risk factors; Unfavorable (supradiaphragmatic) CSIIB with risk factors C and/or D, but not A/B Advanced Stage CSIII-IV CSIIB with risk factors A and/or B, CS III/IV A. Large Mediastinal mass: mediastinum-thorax ratio ≥0.35 (EORTC/LYSA), mediastinal larger than 1/3 of the maximum thoracic width (GHSG) B. EN disease C. Elevated ESR: > 50 mm/h wo B symptoms, > 30 mm/h w (B symptoms; fever, night sweat, unexplained weight loss > 10 % over 6 months D. Nodal areas: Involvement of 4 out 5 supradiaphragmatic nodal areas (EROTC/LYSA), involvement of 3 out of 11 nodal areas on both sides of the diaphragm (GHSG) Eichenauer DA, et al.
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