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Lecture 8 and 9

Lecture 8 and 9 Lymphomas; Multiple Myeloma, Plasma cell disorders; Lipid storage disease and Histiocytosis Abdulkarim Aldosari. O bjectives.

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Lecture 8 and 9

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  1. Lecture 8 and 9 Lymphomas; Multiple Myeloma, Plasma cell disorders; Lipid storage disease and Histiocytosis AbdulkarimAldosari

  2. Objectives List distinguishing features for nodular lymphocyte predominant, mixed cellularity, lymphocyte rich, lymphocyte depletion and nodular sclerosis Hodgkin lymphoma List distinguishing features for the four stages of Hodgkin lymphoma Describe classification criteria, differential diagnosis, prognosis and treatment for Hodgkin and non Hodgkin lymphomas Describe and compare multiple myeloma and monoclonal gammopathy Describe the workup of patients with plasma cell dyscrasia Define and describe amyloidosis Name and describe enzyme deficiencies seen in Gaucher’s disease, Niemann-Pick, and Tay-Sachs disease Describe clinical features and laboratory findings of Mucopolysaccharidoses and sea-blue histiocyte syndrome

  3. Lymphomas • http://blausen.com/?Topic=9562

  4. Lymphomas - Introduction Malignant lymphomas are a heterogeneous group of diseases From cells of the lymphoid tissue • Lymphocytes • Histiocytes • Reticulum cells Two categories • Hodgkin disease/ Hodgkin lymphoma • Lymphocytic lymphoma/non-Hodgkin lymphomas (NHLs)

  5. Introduction to the lymphomas Difficulties involved in lymphoma diagnosis due to the many subcategories Need to make distinction between: • Benign and malignant lymphoid proliferations • Hodgkin versus non-Hodgkin lymphoma • Subcategories of each type of lymphoma Definitive diagnosis may not be possible

  6. Introduction to Hodgkin Lymphoma First described by Thomas Hodgkin in 1832 Samuel Wilks in 1865 applied the term Hodgkin disease In 1898 Sternberg and in 1902 Reed described the histological features of Hodgkin disease, the unusual cell that is characteristic of Hodgkin disease = Reed-Sternberg cell Two distinct clinical and pathological disease • Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) • Classical Hodgkin lymphoma (CHL)

  7. Etiology and pathogenesis Possible viral etiology • Epstein-Barr virus (EBV) • EBV nucleic acids demonstrated in 80% of all cases of Hodgkin lymphoma (HL) • EBV antigens detected in 50% of the cases • CMV, Herpesvirus 6 also implicated • Mechanism is unclear • Possibly a preceding immunosuppression causing an abnormal immune response to the infections HL – malignant clonal proliferation • A small percentage of Reed-Sternberg cells and its variants • A larger percent of B cells

  8. Pathology Reed-Sternberg cell – cytological hallmark of HL • Large cell ( up to 45 µm ) with abundant acidophilic cytoplasm • Multinucleated or polylobed nucleus • Gigantic, inclusion like nucleoli • Halo effect around the nucleoli • Not necessarily diagnostic because seen in a variety of other conditions • Helpful in suggesting the possibility of HL or a subclassification of HL Reed-Sternberg cells in the proper cellular, stromal and clinical setting in conjunction with immunophenotyping → diagnosis of HL

  9. Nodular lymphocyte predominant HL • 5% of cases • Pathologically and clinically distinct from HL • Characterized by a nodular, and/or a diffuse proliferation of scattered large neoplastic cells knownas L&H , popcorn cell, or lymphocyte predominant cells (LP cells) • L&H = lymphocyte histiocyte RS variant • Popcorn cells are Reed Sternberg variants • Most of the lymphocytes found in the lymph nodes are normal (not cancerous)

  10. Nodular lymphocyte predominant HL • Occurs at any age with a peak incidence at 40yrs • Cervical and axillary lymph nodes are most frequently involved • Presents as an early stage disease; has slow progression and excellent outcome with standard therapy • Recurrence is common and occurs in 21% of cases • The immunophenotype of the L&H cells is distinct from the cells of the classic Hodgkin's lymphoma • Unlike classical Hodgkin Lymphoma, the LP cells show immunoreactivity with CD45 and CD20 and no staining with CD30 or CD15 • There is consistent staining with CD20, CD22, and CD79a • http://www.universitypathologists.com/education/case-of-the-month/february-2011

  11. Nodular lymphocyte predominant HL • Slightly higher incidence in the U.S. among blacks than whites, and a lower incidence among Asians • 3:1 male predominance • Shows a propensity toward peripheral (neck and/or axilla) • Nodal spread is dis-contiguous, compared with the contiguous nodal spread of classical HL. • In 50%–60% of NLPHL cases, the time between the initial presentation of lymphadenopathy and the diagnosis of NLPHL is 6–12 months or longer http://theoncologist.alphamedpress.org/content/14/7/739.long

  12. Nodular lymphocyte predominant HL • Prognosis is good - 90-100% remission rate with primary therapy • Relapse seen in 10-15% of patients and occurs on average 3-6 years after diagnosis • Overall 10 year survival rates are >90% in limited stage disease

  13. Classic Hodgkin Lymphoma Defined by the observation of classic Reed-Sternberg cells in the appropriate cellular and stromal background Background of the lesion determines the subclassification of CHL: Nodular sclerosis HL • Most common subtype of HL; 60-80% of all cases of HL • The involved lymph nodes contain • R-S cells • Normal WBCs • Lacunar cells (grouped lacunars)- type of RS cells • Scar tissue (birefringent collagenous sclerosis) • The disease is more common in women than men • Usually affects adolescents and adults under 50 • Most patients are cured with current treatments

  14. Classic Hodgkin Lymphoma Mixed-cellularity HL • Accounts for about 15-30% of all cases of HL • Found more commonly in men than women • Lymph nodes contain heterogeneous mix of cells; R-S cells in addition to several other cell types • Primarily affects older adults • More advanced disease is usually present by the time this subtype is diagnosed

  15. Classic Hodgkin Lymphoma Lymphocyte-rich HL • < 5% of HL cases • The disease may be diffuse (spread out) or nodular (knot-like) in form • Characterized by the presence of numerous normal-appearing lymphocytes and classical R-S cells. • Usually diagnosed at an early stage in adults and has a low relapse (returns after treatment) rate Lymphocyte depletion HL • Rarely diagnosed • Abundant R-S cells and few normal lymphocytes are present in the lymph nodes of patients with this subtype • Aggressive and usually not diagnosed until it is widespread through the body

  16. Classic Hodgkin Lymphoma

  17. Classic Hodgkin Lymphoma Histologic progression HL progresses from: Lymphocyte rich → mixed cellularity → lymphocyte depletion lymphoma Clinical features: • ~9,000 new cases of HL are projected each year • Most commonly diagnosed in young adults 15-35yrs and in adults over 50 • Most patients with HL present with swelling of the lymph nodes (which is often but not always painless) • Fever, night sweats, unexplained weight loss, and lack of energy

  18. Diagnosis and staging of HL Clinical staging for patients with Hodgkin lymphoma (HL) includes • Careful history • Detailed physical examination • Laboratory studies (CBC, sedimentation rate, chemistry panel; liver, kidney, bone profile) • Thoracic and abdominal/pelvic computerized tomographic (CT) scans • Positron emission tomography (PET) scans, gallium scans • Bone marrow biopsy if symptomatic, Cytopenia or advanced stage

  19. Diagnosis and staging of HL Most widely used staging scheme - Cotswold’s revision of the Ann Harbor classification Stage I - Involvement of a single lymph node region (cervical, axillary, inguinal, mediastinal) or lymphoid structure (spleen, thymus, or Waldeyer's ring) Stage II - Involvement of two or more lymph node regions or structures on the same side of the diaphragm. Hilar nodes should be considered to be "lateralized“. All nodal disease within the mediastinum is considered to be a single lymph node region. The number of anatomic regions should be indicated by a subscript (II-3). Stage III – Involvement of lymph node regions or lymphoid structures on both sides of the diaphragm. III-1 with or without the involvement of the spleen, hilar, celiac or portal nodes; and stage III-2 with involvement of the paraaortic, iliac, inguinal, or mesenteric nodes Stage IV - Involvement of one or more extranodal organs or tissue beyond that designated E, with or without associated lymph node involvement

  20. Diagnosis and staging of HL Subclassification of stage Stages I, II, III, and IV adult HL can be sub classified into A and B categories: B for those with defined general symptoms A for those without B symptoms The B designation is given to patients with any of the following symptoms: • Unexplained loss of more than 10% of body weight in the 6 months before diagnosis • Unexplained fever with temperatures above 38°C • Drenching night sweats http://www.cancer.gov/cancertopics/pdq/treatment/adulthodgkins/HealthProfessional/page3

  21. Stage1 of HL Stage I adult non-Hodgkin lymphoma. Cancer is found in one lymphatic area (lymph nodes, tonsils, thymus, or spleen). In stage IE (not shown), cancer is found in one organ or area outside the lymph nodes. E: is used if the disease is "extranodal" (not in the lymph nodes) or has spread from lymph nodes to adjacent tissue

  22. Stage 11 of HL Stage II: Cancer in two or more lymph node groups, and both are either above (a) or below (b) the diaphragm Stage IIE Cancer in one or more lymph node groups either above or below the diaphragm and outside the lymph nodes in an organ or area on the same side of the diaphragm as the lymph nodes with cancer (a).

  23. Stage 111 of HL Stage III - in one or more lymph node groups above and below the diaphragm (a). Stage IIIE - in lymph node groups above and below the diaphragm and outside the lymph nodes in a nearby organ or area (b). Stage IIIS - in lymph node groups above and below the diaphragm (a) and in the spleen (c). Stage IIIE plus S,- in lymph node groups above and below the diaphragm, outside the lymph nodes in a nearby organ or area (b), and in the spleen (c).

  24. Stage 1V of HL Stage IV: Cancer found throughout one or more organs that are not part of a lymphatic area (lymph nodes, tonsils, thymus, or spleen) (a); or in one organ that is not part of a lymphatic area and has spread to lymph nodes far away from that organ (b); or cerebrospinal fluid (not shown), the liver, bone marrow, or lungs.

  25. Treatment and prognosis • Based on staging evaluation • Multiagent chemotherapy • 10 year survival for stage 1 and 11 > 80% • 10 year survival for stages 111 and 1V improved with aggressive chemotherapy ~70%

  26. Non-Hodgkin Lymphoma • Any of a large group of cancers of lymphocytes • Can occur at any age • Marked by lymph nodes that are larger than normal, fever, and weight loss • Many different types divided into aggressive (fast-growing) and indolent (slow-growing) types • Can be formed from either B-cells or T-cells • Estimated new cases and deaths from non-Hodgkin lymphoma in the United States in 2013: • New cases: 69,740 • Deaths: 19,020 http://www.cancer.gov/cancertopics/types/non-hodgkin

  27. Non-Hodgkin Lymphoma B-cell non-Hodgkin lymphomas • Burkitt lymphoma • Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) • Diffuse large B-cell lymphoma • Follicular lymphoma • Immunoblastic large cell lymphoma • Precursor B-lymphoblastic lymphoma • Mantle cell lymphoma

  28. Non-Hodgkin Lymphoma T-cell non-Hodgkin lymphomas • Mycosis fungoides • Anaplastic large cell lymphoma • Precursor T-lymphoblastic lymphoma Lymphomas that occur after bone marrow or stem cell transplantation are usually B-cell non-Hodgkin lymphomas Prognosis and treatment depend on the stage and type of disease.

  29. Etiology and pathogenesis • Damage to region of the genetic code that regulate growth and reproduction of immune cells • May be due to chemicals, ionizing radiation, viruses (EBV) • Genetic damage associated with numeric and/or structural alterations in chromosomes • Chromosomal abnormalities demonstrated in 60% of NHL cases • Mainly translocations in chromosomes 2,8,14,22 • Chromosomal regions relates to function of the genetic material • t(11;14) = BCL1-IgH; t(14;18) = IgH- BCL2; t(3;14) = BCL6-IgH

  30. Etiology and pathogenesis Best example • Burkitt’s lymphoma – in 90% of cases – c-myc proto-oncogene located at region q24 of chr 8 translocated to IgH chain 14q32 • Also in 40% of large-cell lymphomas

  31. Pathology of NHL Classification schemes based on: • Growth pattern: nodular or diffuse • Cytological features of malignant cells Historically the most widely used in USA: Working formulation for clinical usage Working Formulation has become outdated and less useful to clinicians and pathologists European and American pathologists proposed a new classification • The Revised European American Lymphoma (REAL) classification

  32. Pathology of NHL Since 1995, members of the European and American Hematopathology societies have been collaborating on a new World Health Organization (WHO) classification • Represents an updated version of the REAL system • Utilizes clinical, morphological, immunophenotypic and genotypic features • Requires an understanding of the morphology of the lymph nodes and the maturation of normal lymphocytes

  33. Pathology of NHL The WHO modification of the REAL classification identifies three major categories of lymphoid malignancies based on morphology and cell lineage: • B-cell neoplasms • T-cell/natural killer (NK)-cell neoplasms • Hodgkin lymphoma Both lymphomas and lymphoid leukemias are included in this classification because both solid and circulating phases are present in many lymphoid neoplasms and distinction between them is artificial. • B-cell chronic lymphocytic leukemia and B-cell small lymphocytic lymphoma are different manifestations of the same neoplasm • Also lymphoblastic lymphomas and acute lymphocytic leukemias Within B-cell and T-cell categories, two subdivisions: • Precursor neoplasms= earliest stages of differentiation • Mature neoplasms

  34. Lymph nodes Three major anatomical regions Cortex – populated by B cells, plasma cells, reticular cells B cell organized into nodules - 1o or 2o follicles 1o follicles → 2o follicles containing a germinal center Germinal center surrounded by mantle zone (crescent of B cells) Germinal center contains – centrocytes, centroblasts, dendritic cells, histiocytes/macrophages

  35. Lymph nodes Paracortex – occupied by T-cells Medulla – contains T cells, B cells, macrophages, plasma cells NHL arise from any of these normal cellular counterparts B cell – most common 85-90% T/NK – 10-15% Histiocytes and dendritic cells - < 1%

  36. Follicular B-cell lymphoma • The most common of the indolent non-Hodgkin's lymphomas = 40% of adult NHL • The second-most-common form of non-Hodgkin's lymphomas overall • It is a lymphoma of follicle center B-cells (centrocytes and centroblasts) with at least partial follicular growth pattern • Follicular growth should be included in the pathologic assessment • Positive for the B-cell markers CD10, CD19, CD20, and CD22 but almost always negative for CD5 • A translocation between chromosome 14 and 18 results in the overexpression of the bcl-2 gene

  37. Follicular B-cell lymphoma According to the WHO criteria, the disease is morphologically graded into • grade 1 (<5 centroblasts per high-power field (hpf)) • grade 2 (6–15 centroblasts/hpf) • grade 3 (>15 centroblasts/hpf) • grade 3A (centrocytes still present) • grade 3B (the follicles consist almost entirely of centroblasts • More aggressive than grades 1 and 2 Progression from follicular to more aggressive diffuse large cell lymphoma – 40% of cases Male: female – 1:1 Survival rate at 5yrs >60%

  38. Mantle cell lymphoma Characterized by • small-to-medium sized lymphocytes with pale staining cytoplasm • Irregular nucleus • Inconspicuous nucleoli • Cells express CD5, Cd34 • t(11;l4) • A disease of older adults • Male: female – 3:1 • Disease widespread at diagnosis • Lymph nodes and spleen as most common sites of involvement • One of the rarest of the NHL

  39. Mucosal-associated lymphoid tissue • Marginal zone- poorly defined anatomical compartment of the lymph nodes • Small cleaved cell (centrocytes-like) • Lymphomas related to marginal zone cells – referred to as lymphomas of the mucosa-associated lymphoid tissue (MALT) • Frequently of the stomach, but virtually any mucosal site can be afflicted. • Originate from B cells in the marginal zone of the MALT • Also called extranodal marginal zone B cell lymphoma

  40. T-cell and NK cell lymphomas • T-cell lymphomas account for ~15% of all NHLs in the USA • NK cell shares many features with T-cells • When NK cells become cancerous, the cancer is called NK or NK/T-cell lymphoma • Many different forms of T-cell lymphomas, some of which are extremely rare • T-cell lymphomas can be aggressive (fast-growing) or indolent (slow-growing)

  41. T-cell and NK cell lymphomas • Peripheral T-cell lymphoma (PTCL) - entire group of mature or "post-thymic" T-cell lymphomas (arise from mature T-cells) • distinguishes them from the immature T-cell lymphomas such as acute lymphocytic leukemia (ALL) or lymphoblastic lymphoma. • Under this broad meaning, almost all types of T-cell lymphoma fall under the category of PTCL • Cells characteristically express CD3, the T-cell receptor (TCR) αβ or γδ chains, and either CD4 or CD8 • Natural killer (NK) cells share the same ontogeny with T cells • + NK-cell markers CD56

  42. T-cell and NK cell lymphomas Because of morphological phenotypic and genotypic complexity of T/NK cells clinical features are necessary in classification of the lymphomas Three patterns of clinical presentation of mature T/NK cell lymphoma • Nodal • Extranodal • Leukemic/disseminated

  43. T-cell and NK cell lymphomas Nodal group most common in western countries • Peripheral T-cell lymphoma, unspecified • Anaplastic large cell lymphoma • Angioimmunoblastic T-cell lymphoma Peripheral T-cell lymphoma, unspecified (PTCL) • Most common of all the T-cell lymphomas • Involves the lymph nodes, other sites such as the liver, bone marrow, gastrointestinal tract, and skin, may also be involved. • PTCLs is aggressive and requires combination chemotherapy upon diagnosis • Usually Tdt-, CD3+, CD4+, CD8-

  44. T-cell and NK cell lymphomas Anaplastic large cell lymphoma • Accounts for ~12-15% of all T-cell lymphomas in adults and 10-30% of all lymphomas in children. • Can be divided into three types: • 2 systemic (presents in lymph nodes or organs) subtypes • 1 non-systemic subtype – appears only on the skin - not to be confused with primary cutaneous anaplastic large cell lymphoma • The systemic types are usually fast-growing, while the skin-only type is usually more slow-growing • Characterized by large cell with kidney-shaped nuclei and eosinophilic inclusion-like region adjacent to the nucleus Unusual in that it responds to therapy Overall survival – 80% at 5yrs

  45. T-cell and NK cell lymphomas Angioimmunoblastic T-cell lymphoma • Fast-growing; accounting for 1-2% of all T-cell lymphomas in the United States • Initial symptoms often include swollen lymph nodes and systemic symptoms such as fever and rash. • It is generally treated like other fast-growing T-cell lymphomas, but can be managed with milder therapies in certain circumstances • Affected lymph nodes contain mixture of atypical lymphoid cells, follicular dendritic cells, thick-walled high endothelial venules • CD4+, CD21+ • Usually follows an aggressive clinical course

  46. T-cell and NK cell lymphomas Primary Cutaneous T-cell Lymphoma (PCTL) • Extranodal presentation • Accounts for 2-3% of all NHL cases and usually affects adults. • Agroup of typically slow-growing cancers that appear on and are most often confined to the skin • Mycosis fungoides, which appears as skin patches or plaques, is the most common type of cutaneous T-cell lymphoma • Less common forms include: Sézary syndrome • Primary cutaneous anaplastic large cell lymphoma • Lymphomatoid papulosis

  47. T-cell and NK cell lymphomas Require thin sections of fixed paraffin-embedded material to observe the peculiar cerebriform nucleus of malignant T-cells 90% exhibit pan-T+, CD4+, CD8- 10% exhibit pan-T+, CD4-, CD8+ Different from systemic anaplastic large-cell lymphoma • Both CD30+, but PCTLs are epithelial membrane antigen (EMA)- negative; • T(2;5) translocation (+) for systemic anaplastic large-cell lymphoma (-) for PCTL PCTL is indolent, incurable versus the aggressive curable systemic anaplastic lymphoma

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