Lymphoma Non-Hodgkins Lymphoma.pdf

Lymphoma II Non-Hodgkin’s Lymphoma (NHL) ILOs At the end of this session, the student will be able to: ▪ Identify various subtypes of NHL with their related epidemiology, etiology, immunophenotypic, and genetic bachground. ▪ List the etiological risk f...

Lymphoma II Non-Hodgkin’s Lymphoma (NHL) ILOs At the end of this session, the student will be able to: ▪ Identify various subtypes of NHL with their related epidemiology, etiology, immunophenotypic, and genetic bachground. ▪ List the etiological risk factors for non-hodgkin`s lymphoma. ▪ Summarize the histopathologic subtypes of non-hodgkin`s lymphoma. ▪ Outline WHO classification of NHL. ▪ Discuss the clinical picture of non-hodgkin`s lymphoma. ▪ Explain the diagnostic approach for NHL. ▪ List the differential diagnosis of NHL. ▪ Compare between Hodgkin`s and NHL. ▪ Recommend treatment of non-hodgkin`s lymphoma ▪ Summarize characteristics of Follicular and diffuse large B-cell lymphoma. Non-Hodgkin’s Lymphoma (NHL) NHL is a diagnosis applied to a group of histologically and biologically heterogenous clonal malignant diseases arising from the lymphoid system (mainly the lymph nodes). Non-Hodgkin lymphoma (NHL) may originate from B cell precursors, mature B cells, T cell precursors, and mature T cells. Non-Hodgkin lymphoma comprises various subtypes, each with different epidemiologies, etiologies, immunophenotypic, genetic, clinical features, and response to therapy. It can be divided into two groups, 'indolent' and 'aggressive,' based on the disease's prognosis. The most common mature B cell neoplasms are: 1. Follicular lymphoma, 2. Burkitt lymphoma, 3. Diffuse large B cell lymphoma, 4. Mantle cell lymphoma,  5. Marginal zone lymphoma, 6. Primary CNS lymphoma. The most common mature T cell lymphomas are: 1. Adult T cell lymphoma 2. Mycosis fungoides. Epidemiology NHL constitutes about 4% of all cancers, and its rate per annum has increased since the 1970’s. NHL is seen in patients of all ages, races, and socioeconomic status. Incidence increases with age (common in ages 65 to 74, the median age being 67 years). Male to female ratio is 3:2. The increased incidence is only part due to increased mean age of the population, improvement in diagnosis, the HIV pandemic and immunosuppressive therapy. Etiology Non-Hodgkin lymphomas (NHL) may be associated with various factors, including infections, environmental factors, immunodeficiency states, and chronic inflammation. Various infectious agents have been attributed to different types of NHL: o Epstein-Barr virus, is associated with certain types of NHL, including Burkitt lymphoma. o Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell lymphoma. o Hepatitis C virus (HCV) results in clonal B-cell expansions. o Human herpes virus 8 o Helicobacter pylori infection is associated with an increased risk of gastric mucosa-associated lymphoid tissue (MALT) lymphomas, a primary gastrointestinal lymphoma. Drugs: Phenytoin, digoxin, TNF antagonist, organic chemicals, pesticides, phenoxy- herbicides, wood preservatives, dust, hair dye, solvents, chemotherapy, and radiation exposure. Immunodeficiency states: Congenital, severe combined immunodeficiency disease (SCID), and induced immunodeficiency states like immunosuppressant medications. Patients with AIDS (Acquired immunodeficiency syndrome) can have primary CNS lymphoma. Autoimmune disorders: like Sjögren syndrome, rheumatoid arthritis, and Hashimoto thyroiditis are associated with an increased risk of NHL.  o Hashimoto's thyroiditis is associated with primary thyroid lymphomas. o Celiac disease is also associated with an increased risk of non-Hodgkin lymphoma. Pathological classification of NHL Some Subtypes of NHL: Follicular lymphoma Mantle cell lymphoma Diffuse large B cell lymphoma Primary cutaneous lymphoma Gastric marginal zone lymphoma of the mucosa-associated lymphatic tissue (MALT) type. WHO classification of the non-Hodgkin lymphomas (subclassified according to clinical aggressiveness*) Mantle cell lymphoma can behave clinically as either an indolent or an aggressive disorder Classification of NHL (WHO) Clinical presentation The clinical presentation of NHL varies with the histologic subtype and sites of involvement. Some subtypes of NHL manifest variable lymphadenopathy for years, while others are highly aggressive and can cause death within weeks, if untreated. Even within a specific NHL subtype, the clinical presentation varies widely between individual patients. Patients present with complaints of fever, weight loss, or night sweats, also known as B symptoms. Systemic B symptoms are more common in patients with a high-grade variant of non- Hodgkin lymphoma. More than two-thirds of the patient present with painless peripheral lymphadenopathy. Waxing and waning episodes of lymphadenopathy, along with other symptoms, can be seen in low-grade lymphoma. Patients have different presentations and vary according to the site involved. Diagnosis Diagnosis and classification of NHL requires an adequate biopsy specimen and expert pathologic review because the clinical manifestations, prognosis, and management of lymphomas vary widely according to the type of lymphoma. Often present with painless lymphadenopathy. Diagnosis is made by tissue biopsy. Workup in Non-Hodgkin Lymphoma should include the following: 1. Complete blood count: May show anemia, thrombocytopenia, leukopenia, pancytopenia, lymphocytosis, and thrombocytosis. These changes in peripheral blood counts can be due to extensive bone marrow infiltration, hypersplenism from splenic involvement, or blood loss from gastrointestinal tract involvement. 2. Serum chemistry tests: Can help rule out tumor lysis syndrome, commonly in rapidly proliferative NHL such as Burkitt or lymphoblastic lymphoma. Lactate dehydrogenase levels can also be elevated due to high tumor burden or extensive infiltration of the liver. 3. Imaging: usually a CT scan of the neck, chest, abdomen, and pelvis or a PET scan. Dedicated imaging, such as an MRI of the brain and spinal cord or testicular ultrasound, might be needed. 4. Workup in Non-Hodgkin Lymphoma should include the following: 5. Lymph node and/or tissue biopsy: A lymph node should be considered for a biopsy if one or more of the following lymph node characteristics is present: significant enlargement, persistence for more than four to six weeks, progressive increase in size. 6. Lumbar puncture: usually reserved in those with a high risk of CNS involvement. 7. Immunophenotypic analysis of lymph node: peripheral blood, and bone marrow. 8. Bone marrow aspiration and biopsy: sometimes needed for the staging of the NHL. However, with the widespread use of PET scans, their utility is decreasing. Differential Diagnosis Medical conditions mimicking symptoms similar to Non-Hodgkin lymphoma are: 1. Hodgkin lymphoma 2. Epstein Barr virus infection 3. Systemic lupus erythematosus 4. Intussusception 5. Appendicitis 6. Toxoplasmosis 7. Metastasis from the primary tumor (e.g., nasopharyngeal carcinoma, soft tissue sarcoma) 8. Malignancies or lymphoproliferative disorders like granulocytic sarcoma and multicentric Castleman disease. 9. Mycobacterial and other bacterial infections cause benign lymph node infiltration and reactive follicular hyperplasia. ❖ Comparison of Non-Hodgkin’s Lymphoma and Hodgkin’s Lymphoma The treatment of NHL The treatment of NHL varies greatly, depending on tumor stage, grade, type of lymphoma, and various patient factors (e.g., symptoms, age, performance status). Treatment of Non-Hodgkin lymphoma is based on the type, stage, histopathological features, and symptoms. The most common treatment includes: ❑ Chemotherapy, ❑ Radiotherapy, ❑ Immunotherapy, ❑ Stem cell transplant, ❑ In rare cases, surgery. Chemoimmunotherapy, i.e., rituximab, in combination with chemotherapy, is most commonly used. Radiation is the main treatment for early-stage (I, II). Stage II with bulky disease, stage III, and IV are treated with chemotherapy along with immunotherapy, targeted therapy, and in some cases, radiation therapy. Complications 1. Hyperleukocytosis. 2. Adult T-cell leukemia-lymphoma can cause hypercalcemia. 3. Pericardial tamponade. 4. Lymphoplasmacytic lymphoma with Waldenstrom macroglobulinemia can cause hyperviscosity syndrome. 5. Hepatic dysfunction. 6. Venous thromboembolic disease. 7. Autoimmune hemolytic anemia and thrombocytopenia - can be observed with small lymphocytic lymphoma. Prognosis The prognosis of non-Hodgkin lymphoma mainly depends on histopathology, the extent of involvement, and patient factors. One point is given for each factor, a total score from (0 to 5), which determines the degree of risk. These are classified as:  1. Low risk (0-1 adverse factor), 2. Intermediate risk (2 adverse factors), 3. Poor risk (≥ 3 adverse factors). Congenital or acquired immunodeficiency states are associated with an increased risk of lymphoma, and response to therapy is poor. Some Specific Common Subtypes of non-Hodgkin’s Lymphoma Follicular Lymphoma Low-grade non-Hodgkin’s Lymphoma (Indolent Lymphoma). This is the most common form of indolent NHL and is associated with t (14;18) translocation and constitutive BCL-2 expression in the great majority of cases. Patients are likely to be middle-aged or elderly. The disease is characterized by a benign course for many years (around 10 years) presenting with painless lymphadenopathy; which is characterized by being of follicular or nodular pattern showing small cleaved B-cell lymphocytes. The majority of patients will have stage III or IV disease. However, sudden transformation may occur to aggressive diffuse tumors which are sometimes associated with a Leukaemic phase. Treatment is usually with single oral agents i.e. Chlorambucil or Cyclophosphamide, Vincristine and Predisolone (CVP) combination. Fludarabine alone or in combination with Cyclophosphamide or Mitozantrone could be used. Rituximab (Anti CD20) is also effective alone or in combination with chemotherapy. Diffuse Large B-Cell Lymphoma It is a rapidly progressive lymphadenopathy (high–grade Lymphoma). It is aggressive but potentially curable. Histologically, the disorder is characterized by the presence of Large cells of B-cell origin (centroblasts or immunoblasts). Cases associated with 3q27 translocation showing BCL-6 over expression, have a relative good prognosis. DNA micro array analysis can give prognostic information. The disorder occurs at all ages but becomes commoner in later life. It represents one-third of all Lymphomas. Patients may present with night sweats, fever, weight loss and lymphadenopathy or with extranodal involved sites such as GIT, testis, brain or bone.  Treatment is with combination chemotherapy of (CHOP): o Cyclophosphamide, o Doxorubicin (Hydroxydaunorubicin) o Vincristine (Oncovin) o Predisolone. This CHOP combination has been considered the gold standard regimen for Large B- cell Lymphoma. Recently, the addition of CD20 antibody (Rituximab) to CHOP has improved survival rates. The treatment is administered every 3 weeks for a total of 6 – 8 courses. Radiotherapy is usually given to sites of bulky or residual masses after completion of chemotherapy. Complications Life-threatening emergent complications of NHL should be considered during the initial workup and evaluation. Early recognition and prompt therapy are critical for these situations, which may interfere with and delay treatment of the underlying NHL. These can include: 1. Febrile neutropenia 2. Hyperuricemia and tumor lysis syndrome - Presents with fatigue, nausea, vomiting, decreased urination, numbness, tingling of legs, and joint pain. Laboratory findings include an increase in uric acid, potassium, creatinine, and phosphate and a decrease in calcium levels. This can be prevented with vigorous hydration and allopurinol. 3. Spinal cord or brain compression 4. Focal compression depending on the location and type of NHL - airway obstruction (mediastinal lymphoma), intestinal obstruction and intussusception, ureteral obstruction 5. Superior or inferior vena cava obstruction