1. Lymphomas
Rowa’ Al-Ramahi

2. HODGKIN’S LYMPHOMA PATHOPHYSIOLOGY
Current hypotheses indicate that B-cell transcriptional processes are disrupted, which prevent expression of B-cell surface markers and production of immunoglobulin messenger RNA Alterations in the normal apoptotic pathways favor cell survival and proliferation.

3. HODGKIN’S LYMPHOMA PATHOPHYSIOLOGY
Malignant Reed-Sternberg cells overexpress nuclear factor- κ B, which is associated with cell proliferation and anti-apoptotic signals. Infections with viral and bacterial pathogens upregulate nuclear factor- κ B. Epstein- Barr virus is found in many, but not all, HL tumors.

4. CLINICAL PRESENTATION
Most patients with HL present with a painless, rubbery, enlarged lymph node in the supradiaphragmatic area and commonly have mediastinal nodal involvement. Less common asymptomatic adenopathy of the inguinal and axillary regions may be present at diagnosis.
Constitutional, or “B,” symptoms (e.g., fever, drenching night sweats, and weight loss) are present at diagnosis in ~25% of patients with HL.

5. DIAGNOSIS AND STAGING
Diagnosis requires the presence of Reed-Sternberg cells in the lymph node biopsy.
Staging is performed to provide prognostic information and to guide therapy. Clinical staging is based on noninvasive procedures such as history, physical examination, laboratory tests, and radiography including PET. Pathologic staging is based on biopsy findings of strategic sites (e.g., muscle, bone, skin, spleen, abdominal nodes) using an invasive procedure (e.g., laparoscopy).

6. DIAGNOSIS AND STAGING
Approximately half of the patients have localized disease (stages I, II, and IIE). The other half has advanced disease at diagnosis, of which 10% to 15% is stage IV.
Prognosis predominantly depends on age and stage; patients older than 65 to 70 years have a lower cure rate than younger patients. Patients with limited stage disease (stages I to II) have a 90% to 95% cure rate, whereas those with advanced disease (stages III to IV) have a 65% to 80% cure rate.

7. TREATMENT SUMMARY
The treatment goal for HL is to maximize curability while minimizing treatment-related complications.
Treatment options include radiation therapy, chemotherapy, or both (combined- modality therapy). The therapeutic role of surgery is limited, regardless of stage.
Combination chemotherapy is the primary treatment modality for most HL patients.

8. Radiation therapy is an integral part of treatment and can be used alone for selected patients with early-stage disease, although most patients will receive chemotherapy and radiation.
Involved-field radiation therapy targets a single field of HL. Extended-field or subtotal nodal radiation targets the involved field and an uninvolved area. Total nodal radiation therapy targets all areas.

9. Long-term complications of radiotherapy, chemotherapy, and chemoradiotherapy include gonadal dysfunction, secondary malignancies, and cardiac disease.
Patients treated for HL are at increased risk of developing secondary malignancies of the lung, breast, GI tract, and connective tissue, as well as leukemia.

10. Initial Chemotherapy
Two to 8 cycles of chemotherapy should be administered, depending on the stage of disease and presence of risk factors.
Salvage Chemotherapy
Response to salvage therapy depends on the extent and site of recurrence, previous therapy, and duration of first remission. Choice of salvage therapy should be guided by response to initial therapy and a patient’s ability to tolerate therapy.

11. Patients who relapse after an initial complete response can be treated with the same regimen, a non–cross-resistant regimen, radiation therapy, or high dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT).
Lack of complete remission after initial therapy or relapse within one year after completing initial therapy is associated with poor prognosis. Patients with these prognostic factors are candidates for high-dose chemotherapy and HSCT.

12. NON-HODGKIN’S LYMPHOMA
PATHOPHYSIOLOGY
NHLs are derived from monoclonal proliferation of malignant B or, less commonly, T lymphocytes and their precursors. The current classification schemes characterize NHLs according to cell of origin, clinical features, and morphologic features.

13. NON-HODGKIN’S LYMPHOMA
The World Health Organization (WHO) classification uses the term grade to refer to histologic parameters such as cell and nuclear size, density of chromatin, and proliferation fraction, and the term aggressiveness to denote clinical behavior of a tumor.

14. CLINICAL PRESENTATION
Patients present with a variety of symptoms, which depend on the site of involvement and whether it is nodal or extranodal.
Adenopathy can be localized or generalized. Involved nodes are painless, rubbery, and discrete and are usually located in the cervical and supraclavicular regions. Mesenteric or GI involvement can cause nausea, vomiting, obstruction, abdominal pain, palpable abdominal mass, or GI bleeding.

15. CLINICAL PRESENTATION
Bone marrow involvement can cause symptoms related to anemia, neutropenia, or thrombocytopenia.
Forty percent of patients with NHL present with B symptoms—fever, drenching night sweats, and weight loss.

16. DIAGNOSIS AND STAGING
Diagnosis is established by biopsy of an involved lymph node.
Diagnostic workup of NHL is generally similar to that of HL.
Systems for classifying NHLs continue to evolve. Lymphomas can be classified by degree of aggressiveness. Slow-growing or indolent lymphomas are favorable (untreated survival measured in years), whereas rapid-growing or aggressive lymphomas are unfavorable (untreated survival measured in weeks to months).

17. Prognosis depends on histologic subtype and clinical risk factors (e.g., age more than 60 years, performance status of 2 or more, abnormal lactic dehydrogenase, extranodal involvement, and stage III or IV disease). These risk factors are used to calculate the International Prognostic Index. It is most useful in patients with aggressive lymphomas.

18. A newer prognostic index for patients with indolent (follicular) lymphomas uses similar risk factors except that poor performance status is replaced with low hemoglobin (less than 12 g/dL). Current research is focused on the prognostic importance of phenotypic and molecular characteristics of NHL.

19. DESIRED OUTCOME
The primary treatment goals for NHL are to relieve symptoms and, whenever possible, cure the patient of disease while minimizing the risk of serious toxicity.

20. TREATMENT
General Principles
Appropriate therapy for NHL depends on many factors including patient age, histologic type, stage and site of disease, presence of adverse prognostic factors, and patient preference.
Treatment is divided into two categories: limited disease (e.g., localized disease; Ann Arbor stages I and II) and advanced disease (e.g., Ann Arbor stage III or IV and stage II patients with poor prognostic features).
Treatment options include radiation therapy, chemotherapy, and biologic agents.

21. Radiation therapy is rarely suitable for remission induction because NHL is rarely localized at diagnosis. Radiation therapy is used more commonly in advanced disease, mainly as a palliative measure.
Effective chemotherapy ranges from single-agent therapy for indolent lymphomas to aggressive, complex combination regimens for aggressive lymphomas.

22. Treatment strategies are summarized for the most common NHLs as examples of how to treat indolent (i.e., follicular) and aggressive (i.e., diffuse large B-cell) lymphomas.
Strategies are also summarized for acquired immune deficiency syndrome (AIDS)–related lymphoma.

23. Indolent Lymphomas
Follicular lymphomas occur in older adults with a majority having advanced disease at diagnosis. At diagnosis, most patients have the chromosomal translocation t (14:18). The clinical course is generally indolent, with median survival of 8 to 10 years. The natural history of follicular lymphoma is unpredictable with spontaneous regression of objective disease seen in 20% to 30% of patients.

24. Localized Follicular Lymphoma
Options for stage I and II follicular lymphoma include locoregional radiation therapy and immunotherapy (i.e., rituximab) with or without chemotherapy or radiation therapy.
Radiation therapy is the standard treatment and is usually curative.
Chemotherapy is not recommended, unless the patient has high-risk, stage II disease.

25. Advanced Follicular Lymphoma
Management of stages III and IV indolent lymphoma is controversial because standard approaches are not curative.
Median time to relapse is only 18 to 36 months. After relapse, response can be reinduced; however, response rates and durations decrease with each retreatment.

26. Advanced Follicular Lymphoma
Therapeutic options are diverse and include watchful waiting, radiation therapy, single-agent therapy, combination chemotherapy, biologic therapy, radioimmunotherapy, and combined-modality therapy.
Immediate aggressive therapy does not improve survival compared with conservative therapy (i.e., watchful waiting followed by single-agent chemotherapy, rituximab or radiation therapy, only when needed).

27. Oral alkylating agents chlorambucil or cyclophosphamide, used alone or in combination with prednisone, are the mainstay of treatment. These single agents are as effective as combination regimens and produce minimal toxicity, but secondary acute leukemia is a concern. Bendamustine is an IV alkylating agent approved for relapsed or refractory indolent NHL.

28. Two adenosine analogues, fludarabine and cladribine, produce high response rates in previously untreated and relapsed advanced follicular lymphoma. Their use is associated with prolonged myelosuppression and profound immunosuppression, increasing the risk of opportunistic infections.

29. Rituximab, a chimeric monoclonal antibody directed at the CD20 molecule on B cells, has become one of the most widely used therapies for follicular lymphoma. Rituximab is approved for first-line therapy either alone or combined with chemotherapy and as maintenance therapy for patients with stable disease or with partial or complete response following induction chemotherapy.

30. The most common chemotherapy regimen used with rituximab is the CHOP regimen. Several different maintenance rituximab schedules have been studied. No consistent overall survival benefit has been observed with maintenance rituximab. Practice guidelines list rituximab maintenance as an option in both first- and second-line therapy, but the strength of the recommendation depends on the treatment setting.

31. Adverse effects are usually infusion related, especially after the first infusion of rituximab, & consist of fever, chills, respiratory symptoms, fatigue, headache, pruritus, and angioedema. Patients should receive acetaminophen , 650 mg, and diphenhydramine , 50 mg, 30 minutes before the infusion.

32. Anti-CD20 radioimmunoconjugates are mouse antibodies linked to radioisotopes (e.g., 131 I-tositumomab and 90 Y-ibritumomab tiuxetan). They have the advantage of delivering radiation to tumor cells expressing the CD20 antigen and to adjacent tumor cells that do not express it. They have the disadvantage of damaging adjacent normal tissue (e.g., bone marrow).
Radioimmunotherapy was initially used as salvage therapy and is being evaluated as first-line therapy in combination with CHOP (cyclophosphamids, doxorubicin, vincristine, and prednisone).

33. Radioimmunotherapy is generally well tolerated
Radioimmunotherapy is generally well tolerated. Toxicities include infusion- related reactions, myelosuppression, and possibly myelodysplastic syndrome or AML. 131 I-tositumomab can cause thyroid dysfunction.
The decision to use radioimmunotherapy requires consideration of the complexity, risks, and cost. The ideal candidate has limited bone marrow involvement and adequate blood cell counts.

34. High-dose chemotherapy followed by HSCT is an option for relapsed follicular lymphoma.
The recurrence rate is lower after allogeneic than after autologous HSCT, but the benefit is offset by increased treatmentrelated mortality.

35. Aggressive Lymphomas
Diffuse large B-cell lymphomas are the most common lymphoma in patients of all ages but most commonly seen in the seventh decade.
Extranodal disease is present at diagnosis in 30% to 40% of patients. The International Prognostic Index score correlates with prognosis. Diffuse aggressive lymphomas are sensitive to chemotherapy with cure achieved in some patients.

36. Aggressive Lymphomas
Treatment of localized disease
Stage I and nonbulky stage II should be treated with three to four cycles of rituximab and CHOP (R-CHOP) followed by locoregional radiation therapy.
Patients with at least one adverse risk factor should receive six to eight cycles of R-CHOP followed by locoregional radiation therapy.

37. Advanced Disease
Bulky stage II and stages III and IV lymphoma should be treated with RCHOP or rituximab and CHOP-like chemotherapy until achieving complete response (usually four cycles). Two or more additional cycles should be given following complete response for a total of six to eight cycles. Maintenance therapy following a complete response does not improve survival.

38. Advanced Disease
High-dose chemotherapy with autologous HSCT should be considered in high-risk patients who respond to standard chemotherapy and are candidates for autologous HSCT.
Although historically, elderly adults have lower complete response and survival rates than younger patients, full dose R-CHOP is recommended as initial treatment for aggressive lymphoma in the elderly.

39. Treatment of refractory or relapsed disease
Approximately one-third of patients with aggressive lymphoma will require salvage therapy at some point. Salvage therapy is more likely to induce response if the response to initial chemotherapy was complete (chemosensitivity) than if it was primarily or partially resistant to chemotherapy.
High-dose chemotherapy with autologous HSCT is the therapy of choice for younger patients with chemosensitive relapse.

40. Salvage regimens incorporate drugs not used as initial therapy
Salvage regimens incorporate drugs not used as initial therapy. Commonly used regimens include DHAP (dexamethasone, cytarabine, and cisplatin), ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin), and MINE (mesna, ifosfamide, mitoxantrone, and etoposide). None is clearly superior to the others.
ICE (ifosfamide, carboplatin, and etoposide) appears to be better tolerated than cisplatin-containing regimens, especially in elderly adults.
Rituximab is being evaluated in combination with many salvage regimens.

41. EVALUATION OF THERAPEUTIC OUTCOMES
The primary outcome to be identified is tumor response, which is based on physical examination, radiologic evidence, PET/CT and other baseline findings. Complete response is desirable because it yields the only chance for cure.
Patients are evaluated for response at the end of four cycles or, if treatment is shorter, at the end of treatment.

42. Optimal outcomes for most types of lymphoma may require delivery of full doses on time. Hematopoietic growth factors and other supportive care measures are often needed to achieve this goal.
To optimize chemotherapy administration, the clinician must identify, monitor, treat, and prevent or minimize treatment-related toxicity. Pertinent laboratory data and other procedures should be reviewed to establish a baseline for monitoring purposes.