Non-Hodgkin lymphomas (NHLs) Hodgkin lymphoma )HL)

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1 Non-Hodgkin lymphomas (NHLs) Hodgkin lymphoma )HL)

2 Lymphoid Neoplasms: 1- non-hodgkin lymphomas (NHLs) 2- Hodgkin lymphoma 3- plasma cell neoplasms

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4 Non-Hodgkin lymphomas (NHLs)

5 Acute Lymphoblastic Leukemia/Lymphoma (ALL) Are neoplasms composed of immature B (pre-b) or T (pre-t) cells, which are referred to as lymphoblasts. ALL is the most common cancer of children. About 85% are B-ALLs, which typically manifest as childhood acute leukemias. The less common T-ALLs tend to present in adolescent males as thymic lymphomas.

6 Pathogenesis: Many of the chromosomal aberrations seen in ALL dysregulate the expression and function of transcription factors required for normal B- and T-cell development.

7 MORPHOLOGY: -In leukemic presentations: the marrow is hypercellular and packed with lymphoblasts Compared with myeloblasts, lymphoblasts have more condensed chromatin, less conspicuous nucleoli, and smaller amounts of cytoplasm that usually lacks granules. in contrast to myeloblasts, lymphoblasts are myeloperoxidase negative

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9 Clinical Features: - Symptoms related to depression of marrow function - generalized lymphadenopathy, splenomegaly, and hepatomegaly

10 Prognosis: - With aggressive chemotherapy about 95% of children with ALL obtain a complete remission, and 75% to 85% are cured. - only 35% to 40% of adults are cured.

11 Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma CLL is the most common leukemia of adults in the Western world. CLL : absolute lymphocyte count > 5000 per mm3

12 Pathogenesis: The most common genetic anomalies are deletions of 13q14.3, 11q, and 17p, and trisomy 12q. The cell of origin may be either a postgerminal center memory B cell or a naive B cell.

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14 proliferation centers are pathognomonic for CLL/SLL.

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16 Clinical Features: - Patients are often asymptomatic at diagnosis. When symptoms appear, they are nonspecific and include easy fatigability, weight loss, and anorexia - Generalized lymphadenopathy and hepatosplenomegaly - Overall median survival is 4 to 6 years, but is more than 10 years in individuals with minimal tumor burdens at diagnosis. - Large-cell transformation (Richter syndrome) is an ominous event, - with most patients surviving less than 1 year.

17 Treatment: - gentle chemotherapy - immunotherapy with antibodies against proteins found on the surface of CLL/SLL cells, particularly CD20. - Hematopoietic stem cell transplantation is being offered to the relatively young.

18 Follicular Lymphoma Follicular lymphoma is the most common form of indolent NHL in the United States It usually presents in middle age

19 Pathogenesis: Follicular lymphoma likely arises from germinal center B cells and is strongly associated with chromosomal translocations involving BCL2. Its hallmark is a (14;18) translocation that juxtaposes the IGH locus on chromosome 14 and the BCL2 locus on chromosome 18. The t(14;18) is seen in up to 90% of follicular lymphomas, and leads to overexpression of BCL2. BCL2 antagonizes apoptosis

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22 Clinical Features: - Follicular lymphoma tends to present with painless, generalized lymphadenopathy. Although incurable, it usually follows an indolent waxing and waning course. Survival (median, 7 to 9 years). Histologic transformation occurs in 30% to 50% of follicular lymphomas, most commonly to diffuse large B-cell lymphoma. The median survival is less than 1 year after transformation. Treatment: - low-dose chemotherapy - immunotherapy (e.g., anti-cd20 antibody)

23 Diffuse Large B-Cell Lymphoma Diffuse large B-cell lymphoma (DLBCL) is the most common form of NHL. The median patient age is about 60 years, but DLBCL also occurs in young adults and children.

24 Pathogenesis: One frequent pathogenic event is dysregulation of BCL6 BCL6 represses the expression of factors that normally serve to promote germinal center B- cell differentiation, growth arrest, and apoptosis,

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26 Clinical Features: DLBCL typically presents as a rapidly enlarging mass at a nodal or extranodal site. Bone marrow involvement is relatively uncommon and usually occurs late in the course.

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28 DLBCLs are aggressive tumors that are rapidly fatal without treatment. With intensive combination chemotherapy, 60% to 80% of patients achieve a complete remission, and 40% to 50% are cured. Adjuvant therapy with anti- CD20 antibody improves both the initial response and the overall outcome.

29 Burkitt Lymphoma (1) African (endemic) Burkitt lymphoma (2) sporadic (nonendemic) Burkitt lymphoma, (3) a subset of aggressive lymphomas occurring in individuals infected with HIV.

30 Pathogenesis. All forms of Burkitt lymphoma are highly associated with translocations of the MYC gene on chromosome 8 that lead to increased MYC protein levels. The translocation partner for MYC is usually the IgH locus [t(8;14)]

31 Essentially all endemic Burkitt lymphomas are latently infected with EBV, which is also present in about 25% of HIV-associated tumors and 15% to 20% of sporadic cases.

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33 Clinical Features. Both endemic and sporadic Burkitt lymphomas are found mainly in children or young adults; Most tumors manifest at extranodal sites. (Mass involving the mandible) Involvement of the bone marrow and peripheral blood is uncommon

34 Burkitt lymphoma is very aggressive but responds well to intensive chemotherapy Most children and young adults can be cured. The outcome is more guarded in older adults

35 Mantle cell lymphoma: Tumor of naive B cells that pursues a moderately aggressive course and is highly associated with translocations involving the cyclin D1 gene Marginal zone lymphoma: Indolent tumors of antigen-primed B cells that arise at sites of chronic immune stimulation and often remain localized for long periods of time Mycosis fungoides /Sézary syndrome :are different manifestations of a tumor of CD4+ helper T cells that home to the skin.

36 Hodgkin lymphoma (HL)

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38 It is characterized by the presence of neoplastic giant cells called Reed-Sternberg cells. These cells release factors that induce the accumulation of reactive lymphocytes, macrophages, and granulocytes, which typically make up greater than 90% of the tumor cellularity. the neoplastic Reed-Sternberg cells are derived from germinal center or postgerminal center B cells.

39 The average age at diagnosis is 32 years. It was the first human cancer to be successfully treated with radiation therapy and chemotherapy, and is curable in most cases.

40 Classification. The WHO classification recognizes five subtypes of HL: 1. Nodular sclerosis 2. Mixed cellularity 3. Lymphocyte-rich 4. Lymphocyte depletion 1,2,3, Classical HL Classical RS cells 5. Lymphocyte predominance

41 Identification of Reed-Sternberg cells and their variants is essential for the diagnosis. Diagnostic Reed-Sternberg cells are large cells (45 μm in diameter) with multiple nuclei or a single nucleus with multiple nuclear lobes, each with a large inclusionlike nucleolus about the size of a small lymphocyte (5 to 7 μm in diameter). The cytoplasm is abundant. Variants of RS cells: - Mononuclear variants contain a single nucleus with a large inclusion-like nucleolus - Lacunar cells have more delicate, folded, or multilobate nuclei and abundant pale cytoplasm that is often disrupted during the cutting of sections, leaving the nucleus sitting in an empty hole (a lacuna) - Lymphohistiocytic variants (L&H cells) with polypoid nuclei, inconspicuous nucleoli, and moderately abundant cytoplasm are characteristic of the lymphocyte predominance subtype

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43 Nodular Sclerosis Type: - This is the most common form of HL - deposition of collagen in bands that divide involved lymph nodes into circumscribed nodules - uncommonly associated with EBV - The prognosis is excellent

44 Mixed-Cellularity Type: - The Reed-Sternberg cells are infected with EBV in about 70% of cases. - it is more likely to be associated with older age - the overall prognosis is very good.

45 Lymphocyte-Rich Type: -It is associated with EBV in about 40% of cases - has a very good to excellent prognosis.

46 Lymphocyte Depletion Type: - This is the least common form of HL - The Reed-Sternberg cells are infected with EBV in over 90% of cases - occurs predominantly in older adults, in HIV+ individuals of any age - the overall outcome is somewhat less favorable than in the other subtypes.

47 Lymphocyte Predominance Type: - uncommon nonclassical variant of HL accounts for about 5% of cases - contains so-called L&H (lymphocytic and histiocytic) variants RS - EBV is not associated with this subtype - Patients younger than 35 years of age - the prognosis is excellent

48 Clinical Features. - HL most commonly present as painless lymphadenopathy. - Patients with the nodular sclerosis or lymphocyte predominance types tend to have stage I-II disease and are usually free of systemic manifestations. - Patients with disseminated disease (stages III-IV) or the mixed-cellularity or lymphocyte depletion subtypes are more likely to have constitutional symptoms, such as fever, night sweats, and weight loss.

49 The spread of HL is remarkably stereotyped: nodal disease first, then splenic disease, hepatic disease, and finally involvement of the marrow and other tissues. Staging involves physical examination, radiologic imaging of the abdomen, pelvis, and chest, and biopsy of the bone marrow With current treatment protocols, tumor stage rather than histologic type is the most important prognostic variable.

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51 The cure rate of patients with stages I and IIA is close to 90%. Even with advanced disease (stages IVA and IVB), disease-free survival at 5 years is 60% to 70%. long-term survivors treated with radiotherapy had a much higher incidence of certain malignancies, including lung cancer, melanoma, and breast cancer. Patients treated with early chemotherapy regimens containing alkylating agents also had a high incidence of secondary tumors, particularly acute myeloid leukemia.

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