Timothy S. Fenske, MD April 5th, 2014 Lymphoma Overview Timothy S. Fenske, MD April 5th, 2014 Welcome!

Topics What is lymphoma? What causes lymphoma? How common is lymphoma? What are the different types of lymphoma? Hodgkin vs. non-Hodgkin lymphoma Staging and how lymphoma affects the body Brief overview of treatments for lymphoma How we monitor lymphoma (next presentation) “Remission” versus “cure”

What is lymphoma? A type of blood cancer which arises from lymphocytes Can be of B-cell origin or (less commonly) of T-cell origin and rarely of NK cell origin These cells normally fight viruses, bacteria, fungi and may also kill cancer cells Lymphocytes normally reside primarily within lymph nodes, blood, bone marrow, and spleen. However to a lesser extent they are found in every organ of the body. Lymphoma therefore most commonly involves lymph nodes, bone marrow and spleen, but can involve any part of the body. Normal lymphocytes in peripheral blood

The Lymphatic System: where the cells of the immune system work and travel We have a lot of “lymphoid tissue” in our bodies Lymph nodes are normal Lymph nodes normally enlarge and become painful with infection Lymphoma often grows in lymphoid tissues “nodal”= growing in a lymph node “extranodal”=growing outside of a lymph node

Grand Central Station, New York City (1954)

What causes lymphoma? In most cases, we cannot say In some cases risk factors can be identified, such as Immune suppression HIV, organ / bone marrow transplant Inherited immune deficiencies Toxins (agent orange, radiation, prior chemo, firemen) Infections (H. pylori, EBV, Hep C, HHV-8, HIV) Autoimmune conditions (RA, lupus, etc) Underlying condition Medications (MTX, anti-TNFs, others) Autoimmune (RA, Sjogren’s, lupus) In some cases, earlier detection now Patients living longer due to better treatment for other conditions H. Pylori in stomach biopspy Genetics? Environment? Diet/lifestyle?

How does a normal lymphocyte turn into a lymphoma cell ? Probably involves multiple steps Chromosome translocations “Overactivity” of certain signals inside the cell Cells then either proliferate more than normal, or don’t die when they are supposed to

How common is lymphoma? 6th most common cancer 9th leading cause of cancer death

How common is lymphoma? Women 679,510 Men 720,280 Total cancers/yr in US Prostate 33% Lung and bronchus 13% Colon and rectum 10% Urinary bladder 6% Melanoma of the skin 5% Non-Hodgkin’s lymphoma 4% Kidney 3% Oral cavity and pharynx Leukemia Pancreas 2% All other sites 18% 31% Breast 12% Lung and bronchus 11% Colon and rectum 6% Uterine corpus 4% Non-Hodgkin’s lymphoma Melanoma of the skin 3% Thyroid Ovary 2% Urinary bladder Pancreas 22% All other sites * Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Estimated for 2006. American Cancer Society. Cancer Facts & Figures 2006. Atlanta, GA: American Cancer Society; 2006.

Overall survival is improving: lots of patients living with lymphoma 662,789 people living with lymphoma in the US = Over 12,000 just in Wisconsin 20,620 people are expected to die from lymphoma each year www.lls.org (FACTS 2012)

80,321 capacity = 170 lymphoma survivors

Who is most likely to be affected by lymphoma? Hodgkin lymphoma mainly affects those 15-30, but there is a smaller peak in the 60s-70s too NHL primarily affects those 60 and older but can affect any age The age at diagnosis for Hodgkin’s lymphoma and NHL, measured in cases per 100,000 population, are compared with one another. The data, derived from the Surveillance, Epidemiology, and End Results (SEER) database, are for patients diagnosed between 1997 and 2001. There are approximately 58,870 new cases of NHL per year and 7,800 cases of Hodgkin’s lymphoma per year. NHL is a disease predominantly of the elderly, whereas Hodgkin’s lymphoma has a slightly bimodal distribution. Age at diagnosis (y) 1.Available at: http://seer.cancer.gov. Accessed March 23, 2005. 2.Adapted from Jemal et al. CA Cancer J Clin. 2006;56:106.

Non-Hodgkin Lymphoma Trends in Incidence, USA International Variation 83% increase in age-adjusted incidence between 1975-2008

General approach to patient with lymphoma What does the patient have? DIAGNOSIS How much disease does the patient have? STAGING How will the patient do? PROGNOSIS

What does the patient have? DIAGNOSIS

How does lymphoma affect the body? Enlargement of lymph nodes “B symptoms” Fevers, drenching night sweats, weight loss Lowering of blood counts Pain in some cases Cough / shortness of breath Swelling Rash / itching GI symptoms Many others possible: any organ can be affected, although lymph nodes, bone marrow and spleen are most common

How does lymphoma affect the body? There is a very WIDE RANGE of how lymphoma can affect people In part this is because there are so many types of lymphoma, with variable behavior However even within one type of lymphoma there is a lot of variation One end of the spectrum: no symptoms, and discovered “accidently” Other end: extremely ill, hospitalized, with multiple organs affected

What is the difference between Hodgkin and non-Hodgkin lymphoma? HL NHL Subtypes 2 >50 Peak age 20s over age 60 Cases / yr 8,000 70,000 Common sites Neck, mediastinum Various S/Sx Usually mild Often severe 5 yr OS 80+ % Varies Treatment ABVD +/- RT Wide range of options

Normal lymph node Benign, “reactive” lymph node Follicular lymphoma Diffuse large B-cell lymphoma

Diffuse Large B Cell Lymphoma (Aggressive) In addition to morphology, other special protein stains (immunohistochemistry and flow cytometry) as well as chromosome tests (FISH) or (less commonly) molecular tests (PCR) may be important to establish an accurate diagnosis.

Lymphoma in the bone marrow Normal bone marrow Bone marrow involved by lymphoma Paratrabecular aggregates

There are more than 60 types of lymphoma T and NK cell (12%) Other subtypes (9%) Burkitt (2.5%) Mantle cell (6%) Diffuse large B cell (DLBCL) (30%) Follicular (25%) Small lymphocytic (7%) MALT-type marginal-zone B cell (7.5%) Nodal-type marginal-zone B cell (<2%) Lymphoplasmacytic (<2%)

Why so many lymphomas? Type of B cell lymphoma depends on: Pre-B Early B Mature B Plasmacytoid B Type of B cell lymphoma depends on: Where the cell was in development/maturation when it went “bad” What type of chromosome rearrangement or mutation occurred Plasma Activated B Stem cell Burkitts, FL, DLBCL WM MM MCL, CLL ALL Germinal center Individual stages of B-cell differentiation are identified by characteristic morphology and expression patterns of cell-surface antigens (CDs). CD19 is a marker of B-cell commitment, and its expression is first detected during the pre–B-cell stage.1 Changes in morphology and antigen expression during B-cell differentiation are reflected in the malignant counterparts of individual B cells. Detection of specific subsets of antigens has become an important method for identifying leukemia and lymphoma subtypes. For example, chronic lymphocytic leukemia (CLL) is a malignancy of intermediate B cells characterized by expression of CD19, CD20, CD23, and CD5 antigens.2 The malignant clone of follicular lymphoma (FL) is a more mature B cell, expressing CD19, CD20, and CD22, but not CD5. Several CD20, CD22, and CD52 monoclonal antibodies (mAbs) are currently being investigated for the treatment of B-cell malignancies. With the advent of mAb therapy, understanding of specific patterns of antigen expression will be critical for successful treatments. The hashed lines on the bars depict lower or variable expression levels. ALL = acute lymphoblastic leukemia; MCL = mantle cell lymphoma; PLL = prolymphocytic leukemia; DLBCL = diffuse large B-cell lymphoma; HCL = hairy cell leukemia; WM = Waldenström’s macroglobulinemia; MM = multiple myeloma. Jaffe. In: Non-Hodgkin’s Lymphoma. 1997:84. Ginaldi et al. J Clin Pathol. 1998;51:364.

Why so many lymphomas? Pre-B Early B Mature B Plasmacytoid B Plasma Activated B Stem cell Burkitts, FL, DLBCL WM MM MCL, CLL ALL Germinal center Just like people, the problem that results depends on the stage of development when things went wrong. Individual stages of B-cell differentiation are identified by characteristic morphology and expression patterns of cell-surface antigens (CDs). CD19 is a marker of B-cell commitment, and its expression is first detected during the pre–B-cell stage.1 Changes in morphology and antigen expression during B-cell differentiation are reflected in the malignant counterparts of individual B cells. Detection of specific subsets of antigens has become an important method for identifying leukemia and lymphoma subtypes. For example, chronic lymphocytic leukemia (CLL) is a malignancy of intermediate B cells characterized by expression of CD19, CD20, CD23, and CD5 antigens.2 The malignant clone of follicular lymphoma (FL) is a more mature B cell, expressing CD19, CD20, and CD22, but not CD5. Several CD20, CD22, and CD52 monoclonal antibodies (mAbs) are currently being investigated for the treatment of B-cell malignancies. With the advent of mAb therapy, understanding of specific patterns of antigen expression will be critical for successful treatments. The hashed lines on the bars depict lower or variable expression levels. ALL = acute lymphoblastic leukemia; MCL = mantle cell lymphoma; PLL = prolymphocytic leukemia; DLBCL = diffuse large B-cell lymphoma; HCL = hairy cell leukemia; WM = Waldenström’s macroglobulinemia; MM = multiple myeloma. How you address these problems will vary . . . Jaffe. In: Non-Hodgkin’s Lymphoma. 1997:84. Ginaldi et al. J Clin Pathol. 1998;51:364.

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