1. Lymphoma: Clinical Cases Tanya Repka, MD, FACP St. Luke’s Cancer Center trepka@slhduluth.com

2. Lymphomas   Predominant primary organ involvement is lymphatic tissues instead of bone marrow.   Clonal disorder--(provable by surface markers, Ig gene or T cell receptor gene rearrangement)   Two main types: Hodgkin's (HD) and Non-Hodgkin's (NHL).

3. Lymphoma Classification  Hodgkin’s Lymphoma Malignant Cell is Reed-Sternberg Cell Malignant Cell is Reed-Sternberg Cell Now recognized as a B-cell Now recognized as a B-cell Bulk of “tumor” is reactive tissue Bulk of “tumor” is reactive tissue Spreads contiguously from node to node Spreads contiguously from node to node  Non-Hodgkin's Localization depends on cell of origin Localization depends on cell of origin Spreads hematogenously Spreads hematogenously

4. B.S. Case Study  24 year old woman presented to primary care c/o enlarged node right neck and fevers  Placed on antibiotics x 2 weeks  On return to primary MD, no change in neck node  Referred to Oncology

5. B.S. Case Study  ROS 5 pound weight loss (125#), and night sweats 5 pound weight loss (125#), and night sweats  PE 2.5 cm rubbery right posterior cervical node and 2 cm right supraclavicular node, ?axillary node(s) 2.5 cm rubbery right posterior cervical node and 2 cm right supraclavicular node, ?axillary node(s) Skin: multiple excoriations on arms and legs Skin: multiple excoriations on arms and legs

6. B.S. Case Study  Referred to surgery  FNA done in surgeons office, path “suspicious for, but not diagnostic of, Hodgkin’s Disease”  Open biopsy “ classical nodular sclerosing Hodgkin’s Disease”

7. Lymphoma Staging Physical Exam Physical Exam Performance status Performance status B symptoms B symptoms 10% wt loss, night sweats, fever10% wt loss, night sweats, fever CBC, diff, plts, LDH, Uric acid, CMP CBC, diff, plts, LDH, Uric acid, CMP Chest/abd/pelvis CT (chest xray) Chest/abd/pelvis CT (chest xray) PET scan PET scan Bilateral BM bx or unilateral (1-2cm) + asp Bilateral BM bx or unilateral (1-2cm) + asp EF (MUGA or ECHO) EF (MUGA or ECHO)  2 microglobulin  2 microglobulin Hepatitis B testing Hepatitis B testing

8. Thomas Hodgkin, M.D 1798-1866

9. “…between thirty and forty years of age, stout made, and not lean, had been affected with swelling of the glands…….

10. “17 year old white boy, who presented with the Chief Complaint of swelling of the neck…..”

11. Age Distribution in Hodgkin’s Lymphoma

12. Classification of HL World Health Organization (WHO)  Nodular lymphocyte predominant  Classical HL Lymphocyte-rich classical Lymphocyte-rich classical Nodular sclerosis (grades I and II) Nodular sclerosis (grades I and II) Mixed cellularity Mixed cellularity Lymphocyte depleted Lymphocyte depleted

13. Therapy of HL  Highly curable with chemotherapy and/or radiation  Therapy determined principally by stage Localized disease can be treated with local therapy: XRT Localized disease can be treated with local therapy: XRT Widespread disease treated with systemic therapy: chemotherapy Widespread disease treated with systemic therapy: chemotherapy Bulky localized disease: chemotherapy f/b radiation therapy Bulky localized disease: chemotherapy f/b radiation therapy

14. Staging of lymphoma   Stage I Single nodal group   Stage II Multiple nodal groups   Stage III Nodal groups on both sides of diaphragm   Stage IV Marrow or CNS Involvement

15. Stages of HL A = asymptomatic B = symptoms (fever, night sweats, weight loss)

17. Long-term Follow-up of MOPP Treated Patients

18. B.S. Case study  CT/PET Uptake in right neck, right axilla Uptake in right neck, right axilla  Bone marrow: No involvement No involvement  Stage II Combination chemotherapy recommended Combination chemotherapy recommended

19. B.S. Case study  4 cycles of ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) (Adriamycin, bleomycin, vinblastine, dacarbazine)  CT/PET negative after 4 cycles  Pruritis resolves with first cycle  Additional 2 cycles  Observe vs IFRT (prognostic factors)

20. Late Effects of Therapy

21.  Second malignancy Solid tumors (risk continues to increase beyond 15 years) Solid tumors (risk continues to increase beyond 15 years) Lung cancer most common (1/3 of all second cancers)Lung cancer most common (1/3 of all second cancers) Breast cancerBreast cancer Secondary leukemia (rare beyond 10-15 years) Secondary leukemia (rare beyond 10-15 years)

22. Late Effects of Therapy  Cardiac mortality Distant third cause of death after HL and second malignancies Distant third cause of death after HL and second malignancies Most common is acute MI secondary to CAD Most common is acute MI secondary to CAD Associated with mediastinal XRT Associated with mediastinal XRT  Infectious mortality Hypogammaglobulinemia Hypogammaglobulinemia  Pulmonary Ranges from acute interstitial pneumonitis to chronic lung injury Ranges from acute interstitial pneumonitis to chronic lung injury May be gaining in significance in patients treated in recent years due to increasing use of bleomycin containing regimens, especially when combined with mediastinal XRT May be gaining in significance in patients treated in recent years due to increasing use of bleomycin containing regimens, especially when combined with mediastinal XRT Significant complication in transplant patients Significant complication in transplant patients

23. M.F. Case Study  50 year old man referred to Oncology by primary care  Clinical presentation: C/o abdominal problems x several years C/o abdominal problems x several years Sought attention of 1° care in 10/05 with c/o epigastric pain, Rx: Protonix Sought attention of 1° care in 10/05 with c/o epigastric pain, Rx: Protonix May ‘06: Continued pain and burping, gallbladder u/s revealed an abdominal mass May ‘06: Continued pain and burping, gallbladder u/s revealed an abdominal mass CT scan several very large masses in abdomen, felt to be adenopathy, left hydronephrosis/hydroureter CT scan several very large masses in abdomen, felt to be adenopathy, left hydronephrosis/hydroureter

24. M.F. Case Study  ROS MF……….. MF……….. 20-25% weight loss over the past year, night sweats x 6 months, no fever (but does not take temps), nausea x 6 months 20-25% weight loss over the past year, night sweats x 6 months, no fever (but does not take temps), nausea x 6 months  Social history: works at grain elevator for many years, at least 25 pack year history, drinks 4-5 beers/day

25. M.F. Case Study  5/24/06, CT guided FNA of retroperitoneal mass  Path: malignant lymphoma B cell type, most were small lymphocytes c/w low grade lymphoma, but non-specific. Flow cytometry not helpful: B cell lymphoma  ? Treatment

26. M.F. Case Study  6/9/06 Laparascopic intraabdominal small bowel mesenteric mass biopsy  Path: Malignant lymphoma, B-cell phenotype (comprising about 35-40%) arising in a background of follicular lymphoma, grade 1 (comprising approximately 60-65%)

27. Non-Hodgkin’s Lymphoma (NHL)  Classified by morphologic/molecular features Dozens of specific types (blame the pathologists) Dozens of specific types (blame the pathologists) Scheme revised every few years (ditto) Scheme revised every few years (ditto)  Most commonly of B-cell origin, but may be from T-cell origin

28. Non-Hodgkin’s Lymphoma (NHL)  Traditionally classified in a few broad clinical categories (by “treating physicians” Low grade; eg, follicular lymphomas Low grade; eg, follicular lymphomas Intermediate grade; e.g., diffuse large cell Intermediate grade; e.g., diffuse large cell Aggressive; e.g., Burkitt’s Aggressive; e.g., Burkitt’s  Spread hematogenously Usually widespread at diagnosis Usually widespread at diagnosis

29. Classification of NHL World Health Organization (WHO)  Mature B-cell neoplasms Follicular Follicular Mantle cell Mantle cell Diffuse large cell Diffuse large cell Burkitt’s Burkitt’s  Mature T-cell neoplasms Mycosis fungoides Mycosis fungoides Peripheral T-cell Peripheral T-cell Anaplastic large cell Anaplastic large cell

30. Histologic Subtypes of NHL Sandlund JT et al. NEJM 1996;334:1288.

31. NHL Outcomes  Determined by cell type Low grade-indolent but incurable Low grade-indolent but incurable Follicular/small lymphocyticFollicular/small lymphocytic Intermediate/aggressive-rapidly lethal but curable Intermediate/aggressive-rapidly lethal but curable Diffuse large cell/Burkitt’sDiffuse large cell/Burkitt’s  Therapy determined by cell type Indolent gets indolent therapy Indolent gets indolent therapy Intermediate/aggressive gets aggressive therapy Intermediate/aggressive gets aggressive therapy

32. Therapy of Indolent NHL Therapy of Indolent NHL Don’t treat unless forced to Don’t treat unless forced to -Cytopenias, “B”-symptoms As little therapy as possible As little therapy as possible -Monoclonal antibody therapy (Rituximab – anti CD20) or mild alkylators often achieve remissions Survival measured in years to decades Survival measured in years to decades -Some never need therapy

33. Non-Hodgkin's Therapy   Aggressive lymphoma therapy Treat at diagnosis for cure Combination cytotoxics Previously *multiple agents* (PromaceCytobom, COPBLAM, mBACOD, MBACOD, VACOP-B, etc)Previously *multiple agents* (PromaceCytobom, COPBLAM, mBACOD, MBACOD, VACOP-B, etc) Now R-CHOP XRT if localized   Targeted therapies Rituximab: anti-CD-20   Stem cell transplant (auto/allo) Allows more aggressive therapy If allogeneic get immune attack as well

34. M.F. Case Study  Combination chemotherapy R-CHOP x 3 cycles R-CHOP x 3 cycles  CT scan: Dramatic decrease in the size of the retrocrural mass, also significant decrease in the size of the retroperitoneal mass, initially over 12 cm, now 6 cm  Combination chemotherapy R-CHOP x 3 cycles R-CHOP x 3 cycles

35. M.F. Case Study  CT/PET after 6 cycles: Improvement but still with PET showing minimal hyperactivity  2 additional cycles of R-CHOP  Referral to University for consideration of stem cell transplant  U recommended allogeneic sibling hematopoietic stem cell transplant, U felt auto transplant had less chance of relapse but with higher morbidity/mortality  MF has 7 siblings, 3 were HLA compatible

36. M.F. Case Study  During BMT w/u he was found to have decreased renal function (bulky NHL) and moderately reduced EF (Adria)  Non-myeloablative peripheral blood (G- CSF primed) stem cell sibling transplant recommended

37. M.F. Case Study  After preparatory regimen received his brother’s stem cells on 2/22 and 2/23/07  Post-transplant course complicated by CMV viremia, renal insufficiency 2° CSA, acute skin GVHD, laparoscopic cholecystectomy, and chronic gut GVHD

38. Key Difference Between HD and NHL   Hodgkin's spreads through lymphatics. Therapy determined by stage   Non-Hodgkin's spreads through blood. Therapy determined by cell type