Non-Hodgkin’s Lymphoma Clinical Manifestations Mark D. Browning, M.D. February 22, 2016

New Left Chest Wall Mass February 2, 2015…79 yo female

Left Chest Mass…Feb, 2015

59 y.o female with Neck Swelling & Stridor Endocrinology Consult for enlarged thyroid Endocrinology Consult for enlarged thyroid Mass increased over prior 3 months Mass increased over prior 3 months Stridor Noticed Stridor Noticed ER…wheezes audible without stethoscope ER…wheezes audible without stethoscope ICU…pO2 = 76, LDH = 245 Increased ICU…pO2 = 76, LDH = 245 Increased Ct Showed thyroid mass with extension into mediastinum…CBC WNL Ct Showed thyroid mass with extension into mediastinum…CBC WNL Tracheostomy & Biopsy of Thyroid Tracheostomy & Biopsy of Thyroid

NHL 4.3% of All New Diagnosis of Cancer in 2014

% of Diagnosis of NHL by Age in 2014

NHL % of Deaths by Age

NHL Trends in Incidence Rate

Lifetime Risk/Prevalence of Non-Hodgkin’s Lymphoma 1 per 48 individuals are at risk in USA 1 January 2011 – –531,000 individuals alive with diagnosis of Non-Hodgkin’s Lymphoma

Non-Hodgkin’s Lymphoma Incidence.. for % of All Cancers 4.3% of All Cancers 70,800 people in USA (adults & children) 70,800 people in USA (adults & children) –38,160 men –31,970 female –95% are in adults…median age = 67 Deaths 18,990 or 3.2% of all Cancer Diagnoses Deaths 18,990 or 3.2% of all Cancer Diagnoses

*NHL -- Clinical Manifestations Epidemiology & Etiology Wide geographic variation in the world Wide geographic variation in the world –8 to 10 fold range Maximum rate in Western developed countries Maximum rate in Western developed countries No peak incidence like Hodgkin's Disease No peak incidence like Hodgkin's Disease Male > Female incidence in USA Male > Female incidence in USA Whites 2x incidence of Blacks Whites 2x incidence of Blacks

NHL Pathologic Manifestations Gross

Non-Hodgkin’s Lymphoma Does NOT Include Reed-Sternberg Cells

NHL…Biopsy Gross Description…not specific Gross Description…not specific Microscopic evaluation cornerstone of diagnosis for years…multiple classifications Microscopic evaluation cornerstone of diagnosis for years…multiple classifications Immunophenotype & Cytogenetics makes the diagnosis more specific and reproducible Immunophenotype & Cytogenetics makes the diagnosis more specific and reproducible

Lymph Node Regions – Clinically Relevant for Lymphoma Lymph Node Regions – Clinically Relevant for Lymphoma

*Immunologic & Cytogenetic Features of NHL

*Diffuse Large Cell Lymphoma Left Lower Slide (DLCL)

NHL Staging (identical for Hodgkin’s Disease) Ann Arbor is most popular Ann Arbor is most popular Rai or Binet can be used for CLL Rai or Binet can be used for CLL

NHL…Survival…Stage III/IV prior to Prognostic Index ( )

*International Non-Hodgkin’s Lymphoma Prognostic Project of >3000 patients—Aggressive Lymphomas (FILIP…1993) Age 60 =1 Age 60 =1 Stage >2 =1 Stage >2 =1 Serum LDH >1x abnormal =1 Serum LDH >1x abnormal =1 Performance status >1 =1 Performance status >1 =1 # of extranodal sites of disease >1 =1 # of extranodal sites of disease >1 =1

59 yo Female..FILIP Score =2 Age <60 (0 if < age 61) =0 Age <60 (0 if < age 61) =0 Stage 2AE (0 if <Stage 3) =0 Stage 2AE (0 if <Stage 3) =0 LDH 245 (0<1x abnormal) =1 LDH 245 (0<1x abnormal) =1 Performance Status ECOG(<2=0) =1 Performance Status ECOG(<2=0) =1 1# Extranodal sites (1 if >1) = 0 1# Extranodal sites (1 if >1) = 0 5year predicted Survival 46% 5year predicted Survival 46%

*Age Adjusted Prognostic Index for Aggressive NHL >3000 Pts

*Intermediate Grade Lymphoma Chemo & if Early Stage…Involved Field Radiation Therapy

NHL -- Clinical Manifestations Etiology Rare immunologic disorders or inherited disorders associated with increased incidence of NHL: Rare immunologic disorders or inherited disorders associated with increased incidence of NHL: –ataxia telangiectasia –Wiskott-Aldrich syndrome –common variable immunodeficiency syndrome –Bruton-type agammaglobulinemia –Chediak-Higashi syndrome –Impaired cellular immunity -- X-linked

NHL -- Clinical Manifestations Epidemiology & Etiology No common etiologic agent can be associated with NHL No common etiologic agent can be associated with NHL Family History of NHL or other lymphoproliferative disorders is associated with a markedly increased risk of NHL Family History of NHL or other lymphoproliferative disorders is associated with a markedly increased risk of NHL

NHL -- Clinical Manifestations Etiology -- Impaired Immunity -- Associated with increased risk of Lymphoma Rheumatoid arthritis Rheumatoid arthritis Sjogren's syndrome Sjogren's syndrome Hashimoto's thyroiditis Hashimoto's thyroiditis SLE SLE Celiac sprue Celiac sprue

NHL -- Clinical Manifestations Etiology -- Iatrogenic Previously treated for Hodgkin's Disease Previously treated for Hodgkin's Disease Immunosuppressive agents to prevent transplant rejection Immunosuppressive agents to prevent transplant rejection –Renal allografts (40-100x greater than expected) Heart transplant Heart transplant Allogeneic bone marrow transplant Allogeneic bone marrow transplant Immunotherapy for other reasons less pronounced Immunotherapy for other reasons less pronounced

NHL -- Clinical Manifestations Etiology -- Environmental Factors Farmers (2-8 fold) Farmers (2-8 fold) –herbicide 2,4 D –Risk directly correlated with duration of herbicide exposure Hair dye Hair dye –May account for as much as 20% of NHL in women

NHL -- Clinical Manifestations Etiology -- Environmental Factors Radiation therapy for ankylosing spondylitis Radiation therapy for ankylosing spondylitis Japanese atomic bomb survivors exposed >100cGy Japanese atomic bomb survivors exposed >100cGy Small risk from epidemiologic studies: Small risk from epidemiologic studies: –vinyl chloride workers –anesthesiologists –rubber production workers –leather workers –road transport workers – woodworkers

NHL -- Clinical Manifestations Etiology -- Viral Agents EBV -- Burkitt's in Africa but not USA EBV -- Burkitt's in Africa but not USA T-cell lymphoma -- SE USA, Caribbean, & SE Japan T-cell lymphoma -- SE USA, Caribbean, & SE Japan –Type C RNA retrovirus --- HTLV 1 HIV causative agent of AIDS -- associated with lymphoma HIV causative agent of AIDS -- associated with lymphoma

NHL Evaluation of patient Confirmation of histologic diagnosis Confirmation of histologic diagnosis Careful history & PE Careful history & PE Routine studies (CBC, chemistry profile, LDH, & CXR) Routine studies (CBC, chemistry profile, LDH, & CXR) Bone marrow aspirate & biopsy Bone marrow aspirate & biopsy Imaging studies to look for occult sites of disease Imaging studies to look for occult sites of disease –(CT Neck, chest, abdomen & pelvis), PET

Clinical History…Lymphoma 88 yo male noted right neck and parotid mass in May of 2001 Excission of right parotid mass and 2 lymph nodes revealed – –Nodular mixed small cleaved & large cell lymphoma Staging work up indicated left periaortic and mesenteric lymph nodes suspicious for lymphoma///marrow negative

Clinical History…Lymphoma Stage IIIA disease HIV negative & LDH 109 WNL Performance status 1 (ECOG 0-4) Prognostic variables – –LDH, performances status = 0, 0 – –Age 1, stage 1 & extranodal disease 0 = 2 FILIP Score =2 Prognosis 5yrs Rx …CNOP & Rituxin x 6 CR

Clinical History…Lymphoma 88 year old white male July 2006 left cervical lymph node noted Needle biopsy of node Diagnosis of low grade follicular center cell lymphoma Rx 2006 to 2015…watch and wait – –Options of Radiation Rx, Chemo, Rituxin or monitor only

Neck Lymph Node by PET/CT

Follicular Nodular Lymphoma

NHL Pathologic Manifestations Microscopic FollicularSmall Cells FollicularSmall Cells

Clinical History…Lymphoma 88 white male CT 8/2006 …borderline retroperitoneal and mesenteric lymph nodes ? Inflammatory 4/2007 nodes normalized PET/CT 2010…cervical & axillary lymph nodes- enlarged & active by PET PET/CT 12/2011…mild increase in Lymph Node Size & SUV…no major change 12/14

*Follicular Lymphoma International Prognostic Index (FLIPI) Parameters Parameter Parameter # of nodal sites # of nodal sites LDH level LDH level Age Age Stage Stage Hemoglobin level Hemoglobin level Adverse Factor >4Elevated>60III-IV<12

FILIPI Index One Point for Each >60 years of age >60 years of age Stage III or IV Stage III or IV Greater than 4 lymph node groups involved Greater than 4 lymph node groups involved Serum Hgb <12 Serum Hgb <12 Elevated LDH Elevated LDH

Overall Survival According to FLIPI Prognosis#factors 5yrOS 10yrOS Prognosis#factors 5yrOS 10yrOS Good0-1 91% 71% Intermediate2 78%51% Poor>3 53%36%

*NHL Survival…Prognostic Variables…Low-Grade Lymphoma 5 years 0-1 Risk 89% 0-1 Risk 89% 2-3 Risk factors 71% 2-3 Risk factors 71% >3 Risk factors 47% >3 Risk factors 47% 10 years70%49% 8% 8%

Patient’s FILIPI Score >60 = 1 >60 = 1 Stage III =1 Stage III =1 > 4 lymph nodes no =0 > 4 lymph nodes no =0 Serum Hgb <12 no=0 Serum Hgb <12 no=0 Elevated LDH no=0 Elevated LDH no=0 Total Score of 2 = 71% at 5 Total Score of 2 = 71% at 5

NHL -- Low Grade Therapy Localized Disease Localized Disease –radiation alone Advanced Disease Advanced Disease –watch and wait* –treat when symptoms present –treat with non-aggressive therapy – Four doses of Rituxin improves disease free survival….2011 data

Patients Non-Hodgkin’s Lymphoma Prognosis depends on the Grade///Stage…e.g...III/IV Patients Non-Hodgkin’s Lymphoma Prognosis depends on the Grade///Stage…e.g...III/IV

NHL -- Clinical Manifestations New insights into the origins of these malignancies New insights into the origins of these malignancies Excellent palliation and curative therapy with combination chemotherapy &/or radiation therapy > 40 years ago Excellent palliation and curative therapy with combination chemotherapy &/or radiation therapy > 40 years ago Goal Goal –Correct tissue diagnosis & staging –Curative – Aggressive Lymphoma –Palliative – Indolent Lymphoma

Hematopoiesis

*Characteristic Phenotype of B & T-Cell Lymphomas

*Normal Histology & Phenotype of Lymph Node

Morphology

Revised European American Lymphoma & WHO Classification Shows defects in the Working Formulation from 1982 – –B cells   Marginal zone ( MALT)   Mantle Cell   Follicular grades 1 & 2   Lymphoplasmocytic – –T cells….multiple listed

*Lymphomas -- Staging Ann Arbor system Clinical Staging: Clinical Staging: –examination, laboratory & imaging studies Pathologic Staging: Pathologic Staging: If exploratory laparotomy is performed. Common for Hodgkin’s …none since 1990 Rarely used in Non-Hodgkin’s lymphoma

Abdominal CT…NHL…8/07

CLL/NHL Lymph Node

CLL/NHL…WDLL

CLL/NHL Lymph Node 40X

NHL -- Clinical Manifestations Low Grade Histologies…Indolent "good or favorable prognosis" "good or favorable prognosis" 23-43% of newly diagnosed NHL 23-43% of newly diagnosed NHL median age of years median age of years bone marrow involvement common bone marrow involvement common >50-80% present with stage III or IV >50-80% present with stage III or IV 75+% have circulating B lymphocytes 75+% have circulating B lymphocytes Numerous primary & secondary cytogenetic abnormalities Numerous primary & secondary cytogenetic abnormalities specific t(14;18)(q32;q21) in most pts specific t(14;18)(q32;q21) in most pts

NHL -- Clinical Manifestations Low Grade Histologies…Indolent Median survival >7-8 years Median survival >7-8 years Considered a fatal malignancy Considered a fatal malignancy 28-44% of these patients on repeat biopsy during their course may show evidence of transformation 28-44% of these patients on repeat biopsy during their course may show evidence of transformation Rates of transformation at autopsy have been >70% Rates of transformation at autopsy have been >70% Transformed lymphomas may be quite aggressive & poorly responsive to Rx Transformed lymphomas may be quite aggressive & poorly responsive to Rx

NHL…Low Grade…Survival…Stage III/IV

*NHL -- High Grade Lymphoblastic -- Clinical Characteristics 50-75% mediastinal mass at presentation 50-75% mediastinal mass at presentation –emergent symptoms related to:  SVC syndrome  tracheal obstruction Appears localized at diagnosis Appears localized at diagnosis Evolves rapidly & characterized by disseminated disease Evolves rapidly & characterized by disseminated disease

NHL -- High Grade Lymphoblastic -- Clinical Characteristics <25% blasts in bone marrow to separate from T-cell ALL <25% blasts in bone marrow to separate from T-cell ALL bone marrow involvement is common bone marrow involvement is common CNS detected 33% time during clinical course CNS detected 33% time during clinical course

Lymphoblasts

*NHL -- High Grade Small noncleaved cell Lymphomas Burkitt vs. non-Burkitt Burkitt vs. non-Burkitt –degree of cellular pleomorphism –proportion of cells with single large nucleolus 8/14 Translocation 8/14 Translocation

*NHL -- Small noncleaved lymphomas Endemic in Africa & New Guinea 5-10 cases per 100,000 children 5-10 cases per 100,000 children few in adult population few in adult population associated with elevated aby titer to EBV antigens associated with elevated aby titer to EBV antigens 85% of tumors have multiple copies of EBV DNA genome 85% of tumors have multiple copies of EBV DNA genome

NHL – Small Non-cleaved Lymphomas USA & Europe 2-3 cases per 1,000,000 in children 2-3 cases per 1,000,000 in children sporadic regions sporadic regions 1-2% of NHL in all age groups 1-2% of NHL in all age groups association of EBV is not as clear as in endemic cases association of EBV is not as clear as in endemic cases

NHL…Burkitt’s Lymphoma Appears like stars in the sky Appears like stars in the sky

Small noncleaved lymphomas Chromosome abnormalities 75% have t(8:14) 75% have t(8:14) 20% have t(8;2) 20% have t(8;2) common translocation is of the c-myc on chromosome 8 common translocation is of the c-myc on chromosome 8

*Small noncleaved cell lymphomas Sporadic Clinical Presentation Bowel obstruction or perforation is common Bowel obstruction or perforation is common Remainder present as: tumors of ovaries, kidneys, retroperitoneum, peripheral lymph nodes or diffuse marrow involvement Remainder present as: tumors of ovaries, kidneys, retroperitoneum, peripheral lymph nodes or diffuse marrow involvement Mean age is > 11 with males = females Mean age is > 11 with males = females

*Small noncleaved cell lymphomas Endemic vs. Sporadic African Endemic African Endemic –bones of jaw –abdominal viscera Sporadic Sporadic –intra-abdominal tumors from:  Peyer's patches or mesenteric lymph nodes

High Grade Lymphomas Lymphoblastic lymphoma Lymphoblastic lymphoma –LSA2-L2 protocol similar to ALL regimen Small noncleaved cell lymphoma Small noncleaved cell lymphoma –Very aggressive chemotherapy with CNS Rx

*NHL Salvage Therapy Bone marrow transplant Bone marrow transplant –Failed intermediate grade & high grade lymphomas that are responsive to pre- transplant therapy

*Autologous Transplant for Relapsed Hodgkin’s & Non-Hodgkin’s (Intermediate & High Grade)

*Non-Hodgkin’s Lymphoma Mantle Cell Lymphoma No counterpart in the working formulation No counterpart in the working formulation specific clinicopathologic entity specific clinicopathologic entity

*Non-Hodgkin’s Lymphoma Mantle Cell Lymphoma Malignant expansion of the mantle zone surrounding lymph node germinal centers with small lymphoid cells Malignant expansion of the mantle zone surrounding lymph node germinal centers with small lymphoid cells –irregular nuclear borders, small nucleoli –scant cytoplasm –very few large cells (vs follicular lymphoma with large cells) Intermediate between SLL and follicular small cleaved cells Intermediate between SLL and follicular small cleaved cells

Mantle Zone Lymphoma Pattern Progression Expansion Expansion –surrounds normal germinal centers  appearance nodular -- nodular variant –germinal centers are effaced  diffuse pattern –blastoid or lymphoblastoid variant

Mantle Cell Lymphoma Clinical Features Male predominance Male predominance median age of 6th decade median age of 6th decade widespread at diagnosis widespread at diagnosis –marrow, liver and spleen leukemic phase with lymphocytosis is not unusual leukemic phase with lymphocytosis is not unusual –differentiated from CLL Usually aggressive course Usually aggressive course –median survival of 3-5 years with some indolent

*Non-Hodgkin’s Lymphoma Mantle Cell Lymphoma -- Immunophenotype Expresses surface IgM and IgD Expresses surface IgM and IgD + CD5, 19, 20, 22, 43 + CD5, 19, 20, 22, 43 Lack CD23 (most useful differential feature from SLL & CLL) Lack CD23 (most useful differential feature from SLL & CLL) (CD5 is negative in SLL) (CD5 is negative in SLL)

*Mantle Cell Lymphoma Therapy Survival not improved with doxorubicin Survival not improved with doxorubicin CVP for slowly progressive disease CVP for slowly progressive disease Hyper CVAD vs CHOP + Rituxin Hyper CVAD vs CHOP + Rituxin Young patients with poor responses Young patients with poor responses –consider transplant