1. lymphoid neoplasms lymphoid neoplasms Rasha M. Abd-Rabh lecturer of pathology faculty of medicine –Benha university

2. Histology Bean – shaped structure Bean – shaped structure Cortex Cortex paracortex paracortex Medulla Medulla

8. Lymph nodes are usually bean-shaped, with an indented region known as the hilum. Lymph nodes are usually bean-shaped, with an indented region known as the hilum. They are covered by a collagenous capsule that extends into the body of the node as trabeculae. The body of the lymph node is divided into an outer cortex and an inner medulla. They are covered by a collagenous capsule that extends into the body of the node as trabeculae. The body of the lymph node is divided into an outer cortex and an inner medulla. The cortex contains a high concentration of lymphocytes while the inner medulla is less cellular. The cortex contains a high concentration of lymphocytes while the inner medulla is less cellular.

9. In the cortex, B-lymphocytes are localized in lymphoid follicles just beneath the capsule. In absence of an active immune response, these follicles are known as. In the cortex, B-lymphocytes are localized in lymphoid follicles just beneath the capsule. In absence of an active immune response, these follicles are known as primary lymphoid follicles. When an immune response is underway, focal points of intense B-cell proliferation known as germinal centers can be found in some follicles. These follicles then become known as secondary lymphoid follicles. When an immune response is underway, focal points of intense B-cell proliferation known as germinal centers can be found in some follicles. These follicles then become known as secondary lymphoid follicles.

10. The T-lymphocytes are located deeper within the cortex and are diffusely distributed in the paracortical area. The T-lymphocytes are located deeper within the cortex and are diffusely distributed in the paracortical area. In the medulla, parts of the cortical cell mass extends as the medullary cords. This region contains macrophages and antibody-secreting plasma cells. In the medulla, parts of the cortical cell mass extends as the medullary cords. This region contains macrophages and antibody-secreting plasma cells.

11. Definition include a diverse group of tumors of B-cell, include a diverse group of tumors of B-cell, T-cell, and NK-cell origin. In many instances the phenotype of the In many instances the phenotype of the neoplastic cell closely resembles that of a particular stage of normal lymphocyte differentiation, a feature that is used in the diagnosis and classification of these disorders.

12. The vast majority (85% to 90%) of lymphoid neoplasms are of B-cell origin, with most of the remainder being T-cell tumors; only rarely are tumors of NK cell origin encountered.

13. Origin of lymphoid neoplasms

14. WHO Classifications The WHO 2008 classifications uses morphologic, immunophenotypic, genotypic, and clinical features to sort the lymphoid neoplasms into five broad categories,which are separated according to the cell of origin: The WHO 2008 classifications uses morphologic, immunophenotypic, genotypic, and clinical features to sort the lymphoid neoplasms into five broad categories,which are separated according to the cell of origin: 1. Precursor B-cell neoplasms (neoplasms of immature B cells) 1. Precursor B-cell neoplasms (neoplasms of immature B cells) 2. Peripheral B-cell neoplasms (neoplasms of mature B cells) 2. Peripheral B-cell neoplasms (neoplasms of mature B cells) 3. Precursor T-cell neoplasms (neoplasms of immature T cells) 3. Precursor T-cell neoplasms (neoplasms of immature T cells) 4. Peripheral T-cell and NK-cell neoplasms (neoplasms of mature T cells and NK cells) 4. Peripheral T-cell and NK-cell neoplasms (neoplasms of mature T cells and NK cells) 5. Hodgkin lymphoma (neoplasms of Reed-Sternberg cells and variants) 5. Hodgkin lymphoma (neoplasms of Reed-Sternberg cells and variants)

15. Pathogenesis Chromosomal translocations and other acquired mutations. Chromosomal translocations and other acquired mutations. Viruses. Viruses. Chronic Immune Stimulation. Chronic Immune Stimulation. Iatrogenic Factors. Iatrogenic Factors.

16. To diagnose Clinical dataGross examination Microscopic picture Immunophenotyping & cytogenetic

17. Clinical data: Age, Sex, Site and pattern of involvement, Blood picture. Clinical data: Age, Sex, Site and pattern of involvement, Blood picture. Gross examination: size of lymph node, homogenous, nodular. Gross examination: size of lymph node, homogenous, nodular.

18. Microscpoic examination: Microscpoic examination: -L.N architecture. -L.N architecture. -Pattern of growth; diffuse, nodular, sinusal. -Pattern of growth; diffuse, nodular, sinusal. -monomorphic or pleomorphic cellular infiltrate. -monomorphic or pleomorphic cellular infiltrate. -Cellular feature -Cellular feature -cell size -cell size -cytoplasm -cytoplasm - Nucleus &chromatin - Nucleus &chromatin -Nucleoli -Nucleoli - mitosis - mitosis - characteristic feature - characteristic feature

19. Immunophenotping : Immunophenotping : -Monoclonal or polyconal. Clonal rearrangement of IG gene → B-cell lymphoma Clonal rearrangement of T –cell receptors→T – cell lymphoma

20. PRIMARILY T-CELL ASSOCIATED CD1 :Thymocytes and Langerhans cells CD1 :Thymocytes and Langerhans cells CD3 :Thymocytes, mature T cells CD3 :Thymocytes, mature T cells CD4 :Helper T cells, subset of thymocytes CD4 :Helper T cells, subset of thymocytes CD5 :T cells and a small subset of B cells CD5 :T cells and a small subset of B cells CD8 :Cytotoxic T cells, subset of thymocytes, and some NK cells CD8 :Cytotoxic T cells, subset of thymocytes, and some NK cells PRIMARILY B-CELL ASSOCIATED CD10: Pre-B cells and germinal-center B cells CD10: Pre-B cells and germinal-center B cells CD19: Pre-B cells and mature B cells but not plasma cells CD19: Pre-B cells and mature B cells but not plasma cells CD20 :Pre-B cells after CD19 and mature B cells but not plasma cells CD20 :Pre-B cells after CD19 and mature B cells but not plasma cells CD21:EBV receptor; mature B cells and follicular dendritic cells CD21:EBV receptor; mature B cells and follicular dendritic cells CD23:Activated mature B cells CD23:Activated mature B cells CD79aMarrow pre-B cells and mature B cells CD79aMarrow pre-B cells and mature B cells

21. 1-Acute Lymphoblastic Leukemia/Lymphoma

22. (ALLs) are neoplasms composed of immature B (pre-B) or T (pre-T) cells which are referred to as lymphoblasts children and adolescents, but it also occurs in adults (About 50% of the cases present as a mediastinal mass).

23. Morphology Diffuse &paracortical region. Diffuse &paracortical region. Scant basophilic cytoplasm. Scant basophilic cytoplasm. nuclei somewhat larger than those of small lymphocytes The nuclear chromatin is delicate and finely stippled. In many cases the nuclear membrane is deeply subdivided, imparting a convoluted appearance. nuclei somewhat larger than those of small lymphocytes The nuclear chromatin is delicate and finely stippled. In many cases the nuclear membrane is deeply subdivided, imparting a convoluted appearance. nucleoli are either absent or inconspicuous. nucleoli are either absent or inconspicuous. the mitotic rate is high. the mitotic rate is high. As with other rapidly growing lymphoid tumors, interspersed macrophages ingesting apoptotic tumor cells may impart a “ starry sky ” appearance As with other rapidly growing lymphoid tumors, interspersed macrophages ingesting apoptotic tumor cells may impart a “ starry sky ” appearance

26. Differential diagnosis 1- Burkitt lymphoma 2- blastoid variant of mantle cell lymphoma

27. Immunophenotyping All express TDT ( am marker of thymocytes) 80-85% show T – cell markers (CD1, CD2, CD7). 15-20% show B-cell markers (CD19, CD20,). CD99+ve CD34 +ve

28. 2-Small lymphocytic lymphoma

29. Low grade – B cell lymphoma. Affects middle aged and elderly individuals. It is the most common of the B – cell neoplasms to involve the spleen.

30. - Diffuse effacement of the nodal architecure. - Diffuse effacement of the nodal architecure. -monotonous population. -monotonous population. - -small round mature – appearing lymphocytes -clumped chromatin. -clumped chromatin. -inconspicuous nucleoli. -inconspicuous nucleoli. -barely visible cytoplasm. -barely visible cytoplasm. -Scanty mitotic activity. -Scanty mitotic activity. as well as scattered pro-lymphocytes/paraimmunoblasts(large cell with vesicular nuclei and distinct nucleoli, singly or in small aggregates that simulate germinal centers. These formations (known as proliferative centers, growth centers, or pseudofollicles) have an increased number of Ki-67-positive

31. Diffuse Small sized Scanty cytoplasm Clumped chromatin Inconspicious nucleoli Low mitosis Scattered prolymphocytes

32. Immunohistochemistry -Pan – B- cell markers(CD20,CD19, Surface Ig) -CD23, CD5 +ve.

33. Differential diagnosis 1- mantle zone lymphoma.

34. 3-Follicular lymphoma

35. It is a low grade neoplasm composed of follicle center (germinal center) B cells (typically both centrocytes and centroblasts) The disease occurs with a median age of 60 years and with a slight female predominance. Pediatric cases are rare.

36. Microscopically : Microscopically : a predominantly nodular or nodular and diffuse growth pattern. Two principal cell types are present in varying proportions: (1) small cells with irregular or cleaved nuclear contours and scant cytoplasm, referred to as centrocytes (small cleaved cells); and (2) larger cells with open nuclear chromatin, several nucleoli, and modest amounts of cytoplasm, referred to as centroblasts 3) Absent or low mitosis.

37. Depending on the relative proportion of small and large cells, follicular lymphomas are subdivided into three categories, respectively designated in the WHO classification as follows : Depending on the relative proportion of small and large cells, follicular lymphomas are subdivided into three categories, respectively designated in the WHO classification as follows : Grade 1: with 0 – 5 centroblasts (large nucleolated cells) per high-power field. Grade 2: with 6 – 15 centroblasts per high-power field. Grade 1: with 0 – 5 centroblasts (large nucleolated cells) per high-power field. Grade 2: with 6 – 15 centroblasts per high-power field. Grade 3 : with more than 15 centroblasts per high- power field. G3a&G3b Grade 3 : with more than 15 centroblasts per high- power field. G3a&G3b

38. Immunohistochemistry: expressing CD19, CD20, and, surface Ig. expressing CD19, CD20, and, surface Ig. Germinal center B- cell markers: Cd10&Bcl-6 Germinal center B- cell markers: Cd10&Bcl-6 BCL2 is expressed in more than 90% of cases, in distinction to normal follicular center B cells, which are BCL2-negative BCL2 is expressed in more than 90% of cases, in distinction to normal follicular center B cells, which are BCL2-negative

39. Cytogenetic : Cytogenetic : The hallmark of follicular lymphoma is a (14;18) translocation that juxtaposes the IgH locus on chromosome 14 and the BCL2 locus on chromosome 18. leads to overexpression of BCL2. The hallmark of follicular lymphoma is a (14;18) translocation that juxtaposes the IgH locus on chromosome 14 and the BCL2 locus on chromosome 18. leads to overexpression of BCL2. BCL2 antagonizes apoptosis and promotes the survival of follicular lymphoma cells. BCL2 antagonizes apoptosis and promotes the survival of follicular lymphoma cells.

40. Nodular Closely packed follicles Two populations of cells Absent mitosis

43. Differential diagnosis 1- reactive follicular hyperplasia

44. 4- Mantle cell lymphoma

45. Mantle cell lymphoma is a low-grade B-cell neoplasm. Also known as intermediate lymphocytic, mantle zone, centrocytic, and diffuse small cleaved cell lymphoma.

46. it usually occurs in middle-aged and elderly individuals. Commonly affects male.

47. Microscopically 1Diffuse effacement by monomorphic small lymphocytes 2- irregular nuclear contours 3- clumped chromatin 4- inconspicuous nucleoli 5- minimal cytoplasm 6-no residual germinal centers formation 7-hyalinized blood vessels & scattered epithloid cells

50. Immunophenotyping Pan B cell markers Pan B cell markers Over expression of cyclin D1 Over expression of cyclin D1 +ve for CD5 +ve for CD5 _ve for CD23, CD10 and BCL-2. _ve for CD23, CD10 and BCL-2.

51. 5- marginal zone lymphoma

52. An uncommon and indolent B-cell lymphoma. Affect eldelry patients & slight female predominance.

53. Microscopically the nodules are formed of medium -sized lymphocytes with irregular nuclear contours, moderate abundant clear cytoplasm, and condensed nuclear chromatin. The pattern of involvement is predominantly sinusal and interfollicular.

55. Immunophenotyping Pan B-cell markers(CD19, CD20) Pan B-cell markers(CD19, CD20) _ve for CD5, CD23 and cyclin D1,CD10 _ve for CD5, CD23 and cyclin D1,CD10 No Bcl-2 or Bcl-6 genes rearrangement. No Bcl-2 or Bcl-6 genes rearrangement.

56. 4- small lymphocytic lymphoma 3-Marginal zone lymphoma 2-Follicular lymphoma 1-Mantle cell lymphoma Immuno Histochemical markers +ve +ve+ve-ve-ve+ve-ve-ve-ve-ve+ve+ve-ve-ve-ve+ve+ve+ve -ve +ve Pan-B-cell markers CD10CD5CD23 Cyclin D1 Bcl-2

57. 6-Burkitt lymphoma

58. Is a highly aggressive B-cell neoplasm that occurs in three major clinical forms: occurs in three major clinical forms: endemic, sporadic, and immunodeficiency endemic, sporadic, and immunodeficiency associated. associated. All three types present primarily in extranodal sites, including the GI tract. in extranodal sites, including the GI tract.

59. There are three variants of BL: the endemic form occurs in Africa, is caused by infection with the Epstein Barr virus (EBV), and affects children between 4 and 7 years of age. the endemic form occurs in Africa, is caused by infection with the Epstein Barr virus (EBV), and affects children between 4 and 7 years of age. the sporadic form occurs throughout the word in children and young adults. the sporadic form occurs throughout the word in children and young adults. immunodeficiency-associated form is related to HIV infection. immunodeficiency-associated form is related to HIV infection.

60. Nodal architecture is effaced with a diffuse or nodular infiltrate Nodal architecture is effaced with a diffuse or nodular infiltrate The cells are medium sized and uniform. The cells are medium sized and uniform. Large vesicular nuclei. Large vesicular nuclei. scant cytoplasm, clumpy chromatin, scant cytoplasm, clumpy chromatin, multiple small nucleoli. multiple small nucleoli. numerous mitotic figures. numerous mitotic figures. Many apoptotic bodies and tingible body macrophages with phagocytosed nuclear debris create a starry-sky pattern. Many apoptotic bodies and tingible body macrophages with phagocytosed nuclear debris create a starry-sky pattern. Microscopically

61. Diffuse or nodular Medium – sized Clumped chromatin Vesicular nulcei Multiple prominent nucleoli Increased mitosis Starry sky appearance

62. Immunohistochemistry: B-cell phenotype (positive for CD10, CD19, CD20, PAX5, and bcl-6); expresses sIg. B-cell phenotype (positive for CD10, CD19, CD20, PAX5, and bcl-6); expresses sIg. High Ki67 High Ki67 Negative for CD23, Cd30, TdT Negative for CD23, Cd30, TdT

63. Cytogenetic : -all three forms are linked with Myc translocation (t8,14) in about 90% of cases.

66. 7-Diffuse large B cell lymphoma

67. Diffuse large B-cell lymphoma (DLBCL) is the most common form of NHL Diffuse large B-cell lymphoma (DLBCL) is the most common form of NHL Predominantly affects females; peak incidence between 20 and 40 years of age Predominantly affects females; peak incidence between 20 and 40 years of age

68. Microscopically Diffuse growth pattern composed of large atypical lymphoid cells with reniform or multilobated nuclei, vesicular chromatin, and distinct nucleoli Large amounts of pale or clear cytoplasm

69. Diffuse Large – sized Vesicular nuclei Prominent nucleoli

71. Immunohistochemistry: These mature B-cell tumors express CD19 and CD20 and show variable expression of germinal center B-cell markers such as CD10 and BCL6. Most have surface Ig These mature B-cell tumors express CD19 and CD20 and show variable expression of germinal center B-cell markers such as CD10 and BCL6. Most have surface Ig