Lymphoma in South East Asia

Transcription

1 Lymphoma in South East Asia

2 45-yo man presented with cervical LNs enlargement for 3 months He reported low grade fever in the evening with dry cough for 4 weeks He has no known medical history Positive findings Multiple cervical LNs enlargement (diameter 3-5 cm) Non-tender, movable, rubbery consistency

3 Lymphadenopathy in Lymphoma o Painless superficial lymphadenopathy is an initial presentation in 90% of patients o Neck 75% ; axillary and groin 25% o Firm and rubberry o Variation in size o Duration varied o o Indolent lymphoma : > 6months to years Aggressive lymphoma : 1-3 months o Maybe transient or wax and wane o Alcohol-inducing pain : HL

4 45-yo man presented with cervical LNs enlargement for 3 months CBC: Hb 11.4 g/dl WBC 9,800/uL N 69%, L 24%, M7%) Platelet 279,000/uL o 3T/1L o Thymoma o Substernal thyroid o Teratoma : germ cell tumors o Lymphoma

5 Diagnostic tests for lymphadenopathy Lymph node biopsy Open biopsy The best diagnostic test esp. lymphoma The biggest node (> 2 cm) If no single node predominates : prefer supraclavicular > neck > axilla > inguinal Persist for longer than 4-6 wks Progressively increasing in size Immunophenotypic studies is required for subclassification Core needle biopsy If an intact node is not easily accessible Fine needle aspiration (FNA) Cytology Reserved for established diagnosis or recurrence of cancer Not adequate for diagnosis of lymphoma Avoid FNA if suspected lymphoma since a repeat biopsy needs to be performed Infection : special stains, culture Abscess : bacteria TB

6 45-yo man presented with cervical LNs enlargement for 3 months Pathological report of lymph node Diffuse large cell lymphoma Further immunohistochemistry are recommended

7 Lymphoma Biologically and clinically heterogeneous group of lymphoproliferative disease Characterized by the clonal expansion of malignant cess of B-, T-, NK-cell origin Natural history, prognosis and therapeutic approach are dependent upon the specific subtype of NHL

8 How To Approach Patient With Lymphoma Presentation Lymphadenopathy vs. lymphocytosis FUO with cytopenia Diagnostic tools and classification: Clinical course Indolent vs. aggressive lymphoma B-symptoms WHO classification HL vs NHL B vs. T/NK cell lymphoma Staging (Ann Arbor) Prognostication IPI, FLIPI, MIPI, genetic and molecular profiling Plan of treatment (curative vs. palliative) Evaluation of response and follow-up

9 Lymphoma vs Leukemia Lymphoma Presentation with mass Mature lymphoid malignancy Example Small lymphocytic lymphoma (SLL) Lymphoblastic lymphoma Leukemia Presentation with abnormal circulating cells Either precursor (ALL) or mature lymphoid malignancy Example Chronic lymphocytic leukemia (CLL) Acute lymphoblastic leukemia (ALL)

10 Indolent vs Aggressive lymphoma Indolent Aggressive Age Elderly Any age Duration of symptoms Long > 6 months Short < 3 months Systemic symptoms Uncommon Common Stage I-II > III-IV Any Extranodal involvement Yes Yes Prognosis Limited stage : curable Advanced stage : incurable Treatment I-II : IFRT Symptomatic III-IV : systemic chemotherapy Curable Death would be inevitable In incurable cases Chemotherapy

11 Lymphoproliferative disorders LN or extranodal mass Clinical presentation Tumor doubling time Aggressive Indolent Immunophenotyping B-cell T-cell B-cell T-cell - Diffuse large B-cell lymphoma - Mantle cell lymphoma -- Burkitt lymphoma Peripheral T- cell lymphoma - CLL/SLL -Follicular lymphoma - MALT lymphoma - Lymphoplasmacytic lymphoma (WM) -LGL leukemia - Cutaneous T-cell lymphoma

12 Frequency of NHL Subtypes In Adults Peripheral T-cell (6%) Mantle cell (6%) Follicular lymphoma (22%) Other subtypes with a frequency 2% (9%) Composite lymphomas (13%) Small lymphocytic lymphoma (6%) Marginal zone B-cell lymphoma MALT type (5%) Diffuse large B-cell (31%) Marginal zone B-cell lymphoma nodal type (1%) Lymphoplasmacytic lymphoma (1%) Armitage JO, Weisenberger DD. J Clin Oncol. 1998;16:

13 Lymphoma subtypes in Thailand : TLSG (n=4,371) MF ALCL, ALK+ 0% 2% AITL 1% SPLTL 1% ENKTL 3% EATL 0% BL 2% HSTL 0% ALCL, ALK- 0% PTCL, NOS 4% HL 8% LBL SLL 1% 2% LPL 0% MZL 6% FL 6% MCL 3% DLBCL 61%

14 Infection and lymphoma Infectious agent EBV Helicobacter pylori Chlamydia psitaci Borrelia burgdorferi Campylobacter jejuni HCV HHV-8 HTLV-1 Lymphoma subtypes HL, HIV associated DLBCL Burkitt lymphoma Nasal NK/T-cell lymphoma Gastric MALT lymphoma Orbital adnexal lymphoma (MALT type) Cutaneous MALT lymphoma Immunoproliferative small intestinal disease (alpha-heavy chain disease Splenic marginal zone lymphoma Lymphoplasmacytic lymphoma Primary effusion lymphoma (HIV) Adult T-cell leukemia/lymphoma

15 Orbital adnexal lymphoma

16 Cutaneous marginal B-cell lymphoma

17 MALT lymphoma of small intestine (IPSID, alpha heavy chain disease) Small bowell infiltrative lesion : duodenum & jejunum H&E CD20+ LELs Alpha heavy chain Gamma heavy chain Kappa Lambda

18 Splenic Marginal Zone Lymphoma Splenic MZL : HCV infection Circulating villous lymphocytes

19 Primary Effusion Lymphoma Body cavity effusion : pleural effusion, ascites without lymphadenopathy Presence of abnormal bizarre immunoblastic like cells in body fluid Evidence of HHV8 infection (100%) Most cases are also coinfected by EBV (90%) Cabone A, et al. Br J Haematol. 2005; 130,

20 Adult T-cell leukemia/lymphoma: Flower cells of leukemia

21 Unusual Presentation of lymphoma Brain tumor Stroke like Prolonged fever without nodal disease Lymphoma subtype Paraventricular lesion - DLBCL Intravascular lymphoma (DLBCL) Primary BM lymphoma Intravascular lymphoma Hepatosplenomegaly Hemophagocytic syndrome Hypercalcemia Metabolic disturbance of high tumor burden - Hypoglycemia - Lactic acidosis Body cavity effusion Hepatosplenic T-cell lymphoma DLBCL, MCL CLL, Splenic MZL DLBCL, T-cell lymphoma Any aggressive lymphoma Any aggressive lymphoma - BL - DLBCL Pyro thorax associated lymphoma Primary effusion lymphoma (HIV), MALT lymphoma, Small bowel lesion (polyp, bowel wall infiltration) Presented with chronic diarrhea or mid abdominal pain DLBCL, MCL MALT lymphoma EATL

22 Lugano modified Ann Arbor Staging No A, B, X, S Spleen and Waldeyer s ring are nodal diseases Cheson, et al. J Clin Oncol 2014;32:

23 Diffuse large B- cell lymphoma

24 Diffuse large B-cell lymphoma The most prevalent subtype of lymphoma in Asia Although curable,, relatively short survival in the absence of therapy induced remission DLBCL can present with nodal or extranodal diseases

25 Primar y sites among limited stage DLBCL Norasetthada, et al. Blood 2015; 126 (23): 2676a

26 T h e K a p l a n - M e i e r p l o t s o f P F S and O S o f l i m i t e d s t a g e D L B C L a c c o r d i n g t o s i t e s o f o r i g i n P= year PFS 57.6% p = year OS = 74.9% 4 year OS = 65.1% 4-year PFS 56.5% Norasetthada, et al. Blood 2015; 126 (23): 2676a

27 Survival of limited stage DLBCL according to site of origin LN Intestine Pancreas Lung&Pluera Norasetthada, et al. Blood 2015; 126 (23): 2676a

28 IPI Prognosis for aggressive lymphoma has been developed before rituximab era International Prognosis Index Risk Score CR (%) 5-year OS(%) - Age > 60 years - LDH > normal - Performance status > 2 - Ann Arbor stage III/IV - Number of extranodal disease sites > 1 Low Lowintermediate Highintermediate High

29 Role of Rituximab and RT in limited stage DLBCL in Thailand Norasetthada, et al. Blood 2015; 126 (23): 2712a

30 CHOP-like chemotherapy with or without rituximab in young patients with good -prognosis diffuse large -B-cell lymphoma: 6-year results of MInT Trial 6-year event-free survival was 55 8% vs 74.3% Pfreundschuh, et al.lancet Oncol 2011; 12: 1013

31 10-year follow-up of the GELA LNH-98.5 study in Low Risk patients Coiffier B, et al. BLOOD. 2010; 116:

32 DLBCL vs PMBL DLBL and PMBL Savage, et al. Blood. 2003;102:

33 Dose-Adjusted EPOCH-Rituximab Therapy in Primary Mediastinal B-Cell Lymphoma Dunleavy, et al. N Engl J Med 2013;368:

34 Treatment plan for diffuse large B -cell lymphoma Newly diagnosed DLBCL Subtype of DLBCL DLBCL PMBCL Stage I-II III-IV Tumor burden Treatment IPI = 0, No bulky disease R-CHOP x 3 + IFRT IPI > 1 Bulky disease R-CHOP x 6 + IFRT at bulky disease No bulky disease R-CHOP x 6 Bulky disease R-CHOP x 6 + IFRT at bulky disease No bulky disease R-CHOP/DA- R-EPOCH x 6 Bulky disease R- CHOP/DA- R-EPOCH x 6 + IFRT

35 Hodgkin lymphoma

36 Lymphoma subtypes in Thailand : TLSG (n=4,371) SPLTL 1% MF 0% HSTL 0% EATL 0% ENKTL 3% BL 2% ALCL, ALK+ 2% AITL 1% ALCL, ALK- 0% PTCL, NOS 4% HL 8% LBL SLL 1% 2% LPL 0% MZL 6% FL 6% MCL 3% DLBCL 61%

37 Epidermiology: HL US. Incidence 3.2 (100,000 population) In Thailand has lower incidence and much lower incidence than NHL Age : Bimodal distribution Male > Female High economic status Genetic predisposing Infection : EBV

38 Lymphoma: HL vs NHL HL (< 10%) NHL (> 90%) Origin B-cell B or T or NK-cell Clinical course Aggressive (except NLPHL) Vary Age Bimodal distribution Incidence increases with age LN involvement Axial LNs Any LNs Extranodal involvemnt Uncommon Common Treatment ABVD CHOP based regimens

39 Diagnosis: HL Hx and PE LN BX ( Not FNA) Pathologic Finding: Reed- Sternberg cell

40 WHO histological classification of HL Nodular lymphocyte predominant HL Classical HL Nodular Sclerosis classical HL Mixed cellularity classical HL Lymphocyte-rich classical HL Lymphocyte depleted classical HL

41 Treatment: classical HL St I-II favorable: ABVD 3 cycles + IFRT Number of cycles depending on the response after 2 cycles St I-II unfavorable (bulky disease, B-symptoms, ESR > 50, >3 sites of involvement) ABVD 6 cycles IFRT If bulky disease or achieving PR after chemotherapy St III-IV ABVD 6 cycles escalated BEACOPP IFRT If bulky disease or achieving PR after chemotherapy

42 Indolent B-cell lymphoma

43 Marginal zone lymphoma

44 Lymphoma subtypes in Thailand : TLSG (n=4,371) SPLTL 1% HSTL 0% EATL 0% MF 0% AITL ALCL, ALCL, PTCL, NOS ALK+ ALK- 4% 1% 2% 0% HL 8% LBL SLL 1% 2% LPL 0% MZL 6% FL 6% MCL 3% ENKTL 3% BL 2% DLBCL 61%

45 Marginal zone lymphoma MALT lymphoma 50-70% of MZLs Occurring in mucosal and glandular tissue These sites are oftenly affected by chronic infection/inflammation Stomach (HP) Oculoadnexal tisue (C. psitaci) Intestine (C. jejuni) Skin (B. burdoferri) Salivary gland (Sjogren syndrome) Thyroid (Hashimoto thyroiditis) Nodal MZL Splenic MZL : HCV infection

46 Gastric MALT lymphoma Lymphoepithelial lesions are characteristic of lymphoma and are not commonly seen in reactive infiltrates Staining for CD43 frequently seen in MALT, may be helpful in determining the neoplastic nature of the infiltrate Normal B-cells are negative It also present on cells of B- cell CLL/SLL and MCL

47 Scenarios of multistep development of gastric MZBCL. Chronic H. pylori (HP) infection induces lymphoid tissue neogenesis Bende, et al. Haematologica 2009;94:

48 Eradication Therapy for H. pylori in Patients With Gastric MALT Lymphoma: A Pooled Data Analysis Data from 32 studies with 1, 480 treated patients The MALT lymphoma remission rate was 77.5% Higher RR in Patients with stage I than stage II lymphoma (78.4% vs 55.6%; P =.0003) Patients in Asian than in Western groups (84.1% vs 73.8%; P =.0001) Patients without the API2 MALT1 translocation than in those with this translocation (78% vs 22.2%; P =.0001) Neoplasia confined to the submucosa than that with deeper invasion (82.2% vs 54.5%; P =.0001) Lymphoma localized to the distal stomach than those with disease involving proximal stomach (91.8% vs 75.7%; P =.0037) Zullo, et al. Clin Gastroenterol Hepatol 2010;8:

49 Predictive factors for gastric lymphoma remission following H pylori eradication Zullo, et al. Clin Gastroenterol Hepatol 2010;8:

50 EGILS consensus report: Gastric Malt lymphoma H pylori eradication cures gastric MALT lymphoma only in stage IE and, to a much lesser percentage, in stage IIE It is preferable to eradicate H pylori in all cases as it is a trigger of the immune response Treatment of H pylori infection is the first step in the management of gastric MALT lymphoma independent of the stage of disease Ruskone-Fourmestraux, et al. Gut 2011;60:747e758

51 Treatment plan for gastric MALT lymphoma Newly diagnosed Gastric MALT lymphoma Stage IE-IIE II-IV H.Pylori H.Pylori + H.Pylori - Regardless of H.Pylori status Treatment HP eradication IFRT Rituximab if IFRT is not applicable Rx as follicular lymphoma 3 months evaluation after HP eradication Response without residual disease Residual disease or no response Further treatment IFRT

52 ocular adnexal MALT lymphoma (OaML) Site of involvement Orbit (40%) Conjunctiva (35%-40%) Lacrimal gland (10%- 15%) Eyelid (10%) Bilaterality occurs in 10% to 15% of cases 90% with localized disease Stefanovic, et al. Blood. 2009; 114:

53 the Association Between C.psittaci and OAML Husain, et al. Cancer. 2007;110: Positive for Cps in 23% of ocular adnexal lymphoma 25% Other MALT lymphoma specimens

54 Regression of OAML after Chlamydia psittaci-eradicating antibiotic therapy A prospective phase 2 clinical trial of 27 patients with OAML Using doxycycline 100 mg orally twice daily for 3 weeks Partial or complete lymphoma regression (48%) after antibiotic therapy was observed 63% Cp-positive 37% Cp-negative patients The 2-year FFS: 66% Ferrari, et al. Ann Oncol. 2006;17:

55 Six-month oral clarithromycin regimen is safe and active in relapsed OAML Clarithromycin 500 mg orally, twice daily, for 6 months ORR of 100% in patients with conjunctival lymphoma who had evidence of C.psittaci infection 3-year progressionfree survival of 58% Govi, et al. Br J Haematol. 2010; 150:

56 Rx for ocular adnexal MALT lymphoma Given the variable prevalence of Cp infection in patients with OAML, empiric antibiotic therapy without prior testing for Chlamydial infection cannot generally be recommended Radiation therapy continues to be the treatment of choice for the majority of patients with localized OAML

57 Splenic marginal zone lymphoma A relatively rare neoplasm accounting for 1-3% of all NHLs It represents the most frequent lymphoma presenting in the spleen The peak of incidence of SMZL is in the seventh decade of life A true indolent course allowing a median survival time ranging from 9-13 years Presentation Bone marrow infiltration (83-100%) An overt leukemic component (29-75%)

58 Splenic marginal zone lymphoma It represents the most frequent lymphoma presenting in the spleen The peak of incidence of SMZL is in the seventh decade of life A true indolent course allowing a median survival time ranging from 9-13 years Presentation Bone marrow infiltration (83-100%) An overt leukemic component (29-75%)

59 Therapy for Splenic MCL The first-line management of asymptomatic patients consists of a watchful-waiting approach Splenectomy is an effective treatment in both nai ve or relapsed/refractory MZL patients, Producing complete resolution of splenomegaly-related symptoms Amelioration of peripheral cytopenias Prolonged treatment-free interval (12-94 months) in most patients Orchard J, et al. Blood 2003;101: ; Ruchlemer R, et al. Br J Haematol 2002;118:952-8

60 HCV and SMZL HCV infection, who are candidates to receive upfront antiviral therapy with pegylated Interferon-alpha and Ribavirin In up to 78% of HCV+ SMZL patients achieving clearance of HCV RNA following antiviral treatment The sustained virological response are paralleled by the clinical remission of the lymphoproliferative disease Valissa, et al. J Clin Oncol 2005;23:468-73

61 MZL: Treatment Gastric MALT lymphoma St IE-IIE HP eradication EGD reevaluate in 3 months If not response : IFRT Oribital adnexal lymphoma St IE-IIE Doxycycline x 2 weeks Reevaluation If not response : IFRT Splenic MZL HCV treatment MALT lymphoma of small intestine (IPSID, alpha heavy chain disease) Tetracyclin for C. jejuni eradication For other type of MZL St I-II IFRT St III-IV Rx in symptomatic case only CD20 monoclonal Ab + CVP Chlorambucil

62 Conclusion Lymphoma consists of various subgroups Correct lymphoma classification would lead to a better prognostication and treatment approach Treatment should be tailored made according to each patients Patient status (Age, PS, underlying disease) Disease status (Stage, aggressiveness, organ involvement) Though curable disease in some patients, lymphoma can not be cured in patients with multiple relapse or refractory cases. Knowing the right time to stop treatment and giving the best palliative care

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