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Lymphomas

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Overview of the lymphoid immune system Lymphocytes evolve from pluripotent stem cells located

in the bone marrow, and differentiate into two major functional cell types:

1. B lymphocytes, comprising the humoral immune system, whose ultimate function is the production of antibodies

2. T lymphocytes, comprising the cellular immune system, whose functions include

a. Direct killing of foreign or intracellularly infected cells, cytotoxic T cells

b. Fine control of the immune response through the secretion of cytokines, helper and suppressor T cells.

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The anatomical organization of the lymphoid immune system can also be divided into two major functional groups:

1. The primary immune organs, which are the sites of initial maturation from immature precursors into immune competent cells:

a. B cells- bone marrow b. T cells- thymus 2. The secondary immune organs, which are the sites of

antigen driven replication and differentiation into committed effector cells

a. Lymph nodes b. Spleen c. Mucosal Associated Lymphoid System (MALT)-

lymphoid cells lining the respiratory and gastrointestinal tracts

d. Everywhere else

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The lymph nodes, in their totality, are the largest of the secondary immune

organs, and the site of the majority of lymphoid pathology.

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Small lymphocytes

a. Small round dark blue dots. Round nucleus, clumped chromatin, small or absent nucleolus.

b. The dullest looking cells hiding the greatest level of functional heterogeneity. Can be T or B cell, virgin (unexposed to antigen) or differentiated effector/memory cell. Most likely lineage guessed by location within the node, but lineage and state of differentiation must be confirmed by immunologic/molecular techniques

c. Locations:

(1) B cells- primary follicles, mantle zone of secondary follicles, medullary cords

(2) T cells- paracortex, minor population within germinal center.

d. Kinetically, clumped chromatin tells us that the cell is nonproliferating- not activated to enter the cell cycle and replicate

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The lymph node is a dynamic organ, composed of transient B and T lymphocytes, antigen processing and presenting cells, replicating B and T lymphocytes (in response

to antigen), persistent and transient final effector cells. Some of these functional subgroups are

cytologically unique, and others are cytologically indistinguishable.

The ultimate microscopic impression, with practice, is one of cytologic heterogeneity, and histologic organization.

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Follicular (germinal) center cells (replicating and post-replicating

B cells)

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Pathology of lymph nodesA. Infections

1. Bacterial 2. Fungal, mycobacterial

B. Reactive hyperplasias 1. Exaggerations of normal histology. Expansion of all regions or

selective expansion of one. Some types characteristic of certain diseases, but most not

2. Follicular hyperplasia increase in number and size of germinal centers, spread into paracortex, medullary areas

a. Collagen vascular diseases, b. Systemic toxoplasmosis, c. Syphillis

3. Interfollicular hyperplasia- paracortex- a. Skin diseases b. Viral infections c. Drug reactions

4. Sinus histiocytosis- expansion of the medullary sinus histiocytes- a. Adjacent cancer b. Infections

C. Sarcoidosis D. Metastatic tumors E. Malignant lymphomas (Non-Hodgkins' lymphomas-NHLs) and

Hodgkin's lymphoma

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Pathology of Lymph NodesMalignant Lymphomas

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Pathology of lymph nodesA. Infections

1. Bacterial 2. Fungal, mycobacterial

B. Reactive hyperplasias 1. Exaggerations of normal histology. Expansion of all regions or

selective expansion of one. Some types characteristic of certain diseases, but most not

2. Follicular hyperplasia increase in number and size of germinal centers, spread into paracortex, medullary areas

a. Collagen vascular diseases, b. Systemic toxoplasmosis, c. Syphillis

3. Interfollicular hyperplasia- paracortex- a. Skin diseases b. Viral infections c. Drug reactions

4. Sinus histiocytosis- expansion of the medullary sinus histiocytes- a. Adjacent cancer b. Infections

C. Sarcoidosis D. Metastatic tumors E. Malignant lymphomas (Non-Hodgkins' lymphomas-NHLs) and

Hodgkin's lymphoma

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Classification Non-Hodgkin’s Lymphoma

T cell NHL B cell NHL Miscellaneous NHL

Hodgkin’s Lymphoma Lymphocyte predominant. Nodular Sclerosis. Mixed cellularity. Lymphocyte depleted Lymphocyte rich.

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NON-HODGKIN LYMPHOMAS Malignancies of the lymphoid system in which

the primary manifestations of disease occur outside the bone marrow, at the sites of normal lymphoid homing

1. Lymph nodes 2. Spleen 3. M.A.L.T. 4. Anywhere 5. (Lymphomas outside lymph nodes and spleen

are referred to as extranodal lymphomas)

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Approximately 40, 000 cases per year, 20,000 deaths

Composed of cells frozen at a single stage of normal lymphoid maturation/differentiation

Recapitulate the biologic behavior and immunophenotype of normal cell they mimic

Since there are several cytologically and immunologically recognizable stages of normal lymphoid maturation, there are several subtypes of lymphoma

All are clonal malignancies, derived from a single cell that has undergone a malignant transformation, mutation

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Definition: Tumors of the immune system; localized mass of

malignant, usually mature lymphocytes (not blasts) arising in lymph nodes or extranodal lymphoid sites (vs leukemia: based in the bone marrow).

Most NHLs are of B-cell origin (almost 85%); only 15% are derived from T/NK cells, and the small remainder stem from macrophages.

Clinical findings: Fever, anemia, infections Marked lymphadenopathy Hepatomegaly, Splenomegaly Skin lesions (cutaneous T-cell lymphoma (mycosis

fungoides), anaplastic large cell lymphoma, and angioimmunoblastic lymphoma).

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Clinical features of non-Hodgkin's lymphoma

Clinical presentation

1. Enlarging mass(es), typically painless, at sites of nodal tissue

2. Obstruction, ulceration of hollow organs- MALT- pain

3. Interference with normal organ function- solid organ infiltration- kidneys, liver, bone marrow

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Tumors of lymphoid tissue Lymphadenopathy:

firm (rubber-ball consistency), painless.

Eosinophilia Fever

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Clinical staging of lymphomas

1. Defines extent of disease; determines therapy and prognosis

2. Based on physical, radiologic examination, bone marrow biopsy and aspiration

3. Ann Arbor Staging system

4. B-symptoms: fever, weight loss > 10% body weight, night sweats

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Ann-Arbor Clinical Staging

Stage 1 Involvement of a single lymph node region (I) or involvement of a single extralymphatic organ or site (IE)

Stage 2 Involvement of two or more lymph node regions on the same side of the diaphragm alone (II) or with involvement of limited contiguous extralymphatic organ or tissue (IIE)

Stage 3 Involvement of lymph node regions on both sides of the diaphragm (III), which may include the spleen (IIIs) and/or limited contiguous

Stage 4 Multiple or disseminated foci of involvement of one or more extralymphatic organs or tissues with or without lymphatic involvement.

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Etiology: • Chromosomal translocations and molecular

rearrangements play an important role in the pathogenesis of many lymphomas and correlate with histology and immunophenotype

Examples:• Epstein-Barr virus (EBV)

• Burkitt lymphoma, Hodgkin disease, lymphomas in immunocompromised patients (HIV infection, organ transplantation), sinonasal lymphoma

• Human T-cell leukemia virus type 1 (HTLV-1)• Hepatitis C virus (HCV)

• lymphoplasmacytic lymphoma, Waldenström macroglobulinemia

• Kaposi sarcoma–associated herpesvirus (KSHV)

• body cavity–based lymphomas in patients with HIV infection and in patients with multicentric Castleman disease

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• Environmental factors • chemicals (pesticides, herbicides, solvents organic

chemicals, wood preservatives, dusts, hair dye) • chemotherapy • radiation exposure

• Congenital predisposition• severe combined immunodeficiency disease [SCID]• Wiskott-Aldrich syndrome

• The chronic inflammation (autoimmune disorders)

• Sjögren syndrome • Hashimoto thyroiditis

• Helicobacter pylori infection • GI lymphomas (particularly gastric MALT lymphomas).

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(1) Destruction or distortion of normal lymph node architecture;

(2) Morphologically, predominance of one lymphocyte cell type (Cell uniformity; monotony);

(3) Presence of macrophages laden with nuclear debris;

(4) Pattern of involvement: nodular or diffuse (5) Invasion of surrounding tissue (capsular); (6) Necrosis (apart from apoptosis) is common

in some lymphomas, and of course in necrotizing infections.

Microscopic criteria

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Microscopic features of malignant lymphomas

1) In low power:

a) Loss of normal architectural organization

b) Presence of absence of aberrant follicle formation

2) In high power:

a) Replacement of cellular heterogeneity by a dominant cell type

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General Diagnostic studies in lymphomas Use of immunologic techniques: 1. Malignant lymphomas reproduce the

immunobiology of their benign counterparts 2. This reproduction may be aberrant, and hence

distinguishable from normal 3. Normal lymphoid maturation (within the

primary lymphoid organs) requires: The production of a unique antigenic receptor on

it's surface, through the process of genetic rearrangement of discontinuous segments of the antigen receptor genes

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Immunologic signals can be detected by a. Flow cytometry-automated fluorescent

microscopy b. Immunohistochemistry- in situ

detection through the use of enzyme substrate color deposition.

Examples a. B cell small lymphocytic lymphoma- monoclonal light

chain, CD19, CD20, CD5 positive, CD10 negative

b. B cell marginal zone lymphoma- monoclonal light chain, CD19, CD20, CD10 positive, CD5 negative

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Molecular techniques 1. Detection of antigen receptor clonality 2. Detection of unique cytogenetic

rearrangements Examples; a. T(14;18) and follicular small cleaved lymphoma-

involves immunoglobulin heavy chain gene, ch.14, and bcl2, chr. 18, an "oncogene" normally controlling programmed cell death

b. T(8;14) and Burkitt's lymphoma- involves Ig heavy chain gene and myc oncogene, chr.8, which normally controls entry into cell cycle

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General Complications of LymphomasDisease-related complications

• Cytopenias (neutropenia, anemia, thrombocytopenia secondary to bone marrow infiltration)

• Anemia (secondary to autoimmune hemolytic anemia, in some).

• Bleeding (secondary to thrombocytopenia, DIC, or vascular invasion by the tumor)

• Infection (secondary to leukopenia, especially neutropenia) • Cardiac problems (pericardial effusion or arrhythmias) • Respiratory problems (pleural effusion and/or parenchymal

lesions)• SVC syndrome (secondary to a large mediastinal tumor) • Spinal cord compression (secondary to vertebral metastases) • Neurologic problems (secondary to primary CNS lymphoma or

lymphomatous meningitis) • GI obstruction, perforation, and bleeding in a patient with GI

lymphoma (may also be caused by chemotherapy) • Pain secondary to tumor invasion • Leukocytosis (lymphocytosis) in leukemic phase of disease.

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Chemotherapy and other treatment-related complications• Cytopenias (ie, neutropenia, anemia,

thrombocytopenia)• Infection• Neuropathy • Dehydration after diarrhea or vomiting • Cardiac toxicity from doxorubicin • Catheter-related sepsis • Catheter-related thrombosis • Secondary malignancies• Tumor lysis syndrome ()

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o Tumor lysis syndrome

Commonly occurs after treatment of high-grade bulky NHLs because of their exquisite sensitivity to therapy:

- Hyperuricemia, - Hyperkalemia (death from cardiac asystole), - Hyperphosphatemia, - Hypocalcemia, - Renal failure.

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Classification of lymphomas

1. Rarely unanimous acceptance of any one classification scheme.

2. Often changing terminology, reflecting classifier bias and new information

3. Often lags behind advances in immunology, research pathology

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According to cell type T cell, B cell, Histiocytic

According to Clinical grade Low grade, Intermediate, High grade

Histopathological Diffuse/Follicular Small, Intermediate, Large cell.

Classifications

39Small Intermediate Large

Histologic typesHistologic types

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Histologic typesHistologic types

Diffuse Follicular

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4. From 1982-1994, the classification used in the United States was called the Working Formulation for Clinical Usage.

a. Based on the dominant cytologic cell type observed under the microscope

b. Presence or absence of "follicularity" - mimicking of normal lymphoid follicle formation

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5. Working Formulation was replaced in 1994 with the Revised European American Lymphoma project (REAL) classification, proposed by the International Lymphoma Study Group.

6. This is now modified by the World Health Organization (WHO) first in 2004 and in 2008.

WHO is a "disease" oriented classification based on cell lineage and stage of maturation of the presumed normal counterpart. Each entity may have differing grades of aggressiveness

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WHO classification- backbone

B cell neoplasms Precursor B cells-related to acute

leukemia Peripheral B cell lymphomas- the majority

of B cell lymphomas

T cell and Natural Killer cell neoplasms Precursor T cells Peripheral T cell and NK neoplasms

Hodgkin's lymphoma

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B cell neoplasms

Precursor B cell lymphoblastic leukemia/lymphoma Frozen at lymphoblast cell stage of antigen independent B cell differentiation- normally

restricted to bone marrow Usually present as acute leukemia+/- lymph node involvement Can initially present as node or skin disease, with later progression to bone marrow Peripheral B-cell neoplasms- frozen at various stages of antigen dependent B cell

maturation and differentiation Small lymphocytic/CLL- the virgin B cell fresh from the marrow Prolymphocytic leukemia- a more clinically aggressive variant of above Lymphoplasmacytic lymphoma- the primary immune response Mantle cell lymphoma- the mantle region surrounding the follicle Follicular lymphoma- the follicle- grade 1-3 Extranodal marginal zone lymphoma- cells at the periphery of the follicle in extranodal

sites of lymphoid tissue- Mucosal Associated Lymphoid Tissue- such as G.I. tract Nodal marginal zone lymphoma Splenic marginal zone lymphoma- immunologically distinct Hairy cell leukemia- pre-plasma cell Diffuse large B-cell lymphoma- this breaks the ideal of specific cell stage, but all represent

lymphomas with high replication rate Burkitt lymphoma- very aggressive Plasma cell myeloma- diffuse bone marrow proliferation of plasma cells Plasmacytoma- solitary focus of monoclonal plasma cells, with variable risk of progression

to myeloma, depending on site

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Why list separately, if most B-cell neoplasms are indolent? Because;

They differ in clinical presentation, immunology, therapy, prognosis, molecular pathogenesis, even if all crudely categorized by median survival > two years

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Small lymphocytic lymphoma(SLL/CLL)

Well-differentiated lymphocytic lymphoma, The solid phase of chronic lymphocytic leukemia

B-cell lymphoma Composed of cells that look like never-

stimulated, resting lymphocytes (they look normal but don't work).

Around 30% of these patients eventually develop a more aggressive B-cell lymphoma (including 1% who get a very aggressive one, i.e., Richter's syndrome).

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Follicular lymphoma most common type of indolent lymphoma in US, and second most

common type lymphoma overall Disease of adults >40 (median age 59) Usually widely disseminated at diagnosis, with bone marrow

involvement Will respond to "gentle chemotherapy" but will relapse-cannot be

cured short of bone marrow transplant, but overall 5 yr survival 72% Benign equivalent is small cleaved cell of germinal center Cytology: clumped chromatin and infrequent nucleolus like small

lymphocyte, but irregular nuclear profile, with nuclear folds or "cleavages"

Retain follicular structure, but monotonous accumulation of single cell type

Over time, additional mutations can occur, producing progression ("transformation") to large cell lymphoma and more aggressive clinical course

Pathogenesis: due to t(14;18), which upregulates expression of an anti-apoptotic protein Bcl2

Has characteristic immunophenotype: monoclonal light chain, CD19, CD10, Bcl2 positive, CD5, Bcl1/Cyclin D1 negative

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Mantle cell lymphoma

B-cell tumor It's a disease of older men, Often arises extranodally. It grows wrapped around normal germinal

centers.

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Extranodal Marginal zone Lymphoma (MALT

lymphoma) Mucosal tumor Helicobacter infection

if the mutation is present lymphoid proliferation.

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Examples aggressive B cell lymphomas: Diffuse large B cell lymphoma: 30% NHL Disease of adults and children- median

age 64 Limited versus widespread disease 1:1 Approximately 40% curable with

aggressive chemotherapy/ stem cell transplant- partially predictable by

International Prognostic Index Benign equivalent- large replicating cells

of germinal center and paracortex

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Cytology: Oval or cleaved nucleus with vesicular chromatin and 1-3 nucleoli.

Nucleus larger than that of reactive macrophage, often necrosis; increased mitotic rate

Diffuse infiltration of lymph node Several cytologic subtypes initially felt to have differing

clinical behavior. Yielded division into intermediate versus high grade types- now not felt valid or significant.

Pathogenesis not as clearly defined- several cytogenetic abnormalities associated with large cell lymphoma, but no defining one

Immunophenotype characterized by monoclonal light chain, CD19 expression, with variable expression of other B cell associated antigens

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B-cell autoimmune disorders: Sjögren's syndrome Hashimoto's disease Angioimmunoblastic lymphadenopathy.

Epstein-Barr induced lymphomas in immunosuppressed patients: AIDS victims, Transplant patients.

Lymphomas of the body cavities: Without a solid phase Usually seen in immunosuppressed people Always are caused by KSHV (herpes 8).

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Burkitt's lymphoma- 3% lymphomas Disease of adults and children- median

age 31 Initially recognized in Africa by Thomas

Burkitt- noted association with Epstein Barr

virus infection and localization in jaw In US, usually presents in ileocecal region

of children- 1/3 of all childhood lymphomas Approximately 40% of adults curable with

very aggressive therapy; 70-80% children

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Benign equivalent is replicating small noncleaved cell of germinal center:

cytology: round to oval nucleus, smaller than that of reactive macrophages with vesicular chromatin and 2-5 nucleoli

Diffuse infiltration of lymph node Very high mitotic rate, lot of ineffective

proliferation; attracts macrophages to phagocytize and produces a “starry sky” pattern at low power

Pathogenesis: t(8;14), producing upregulation of myc oncogene, a cell cycle regulation gene

Immunophenotype: Monoclonal light chain, CD19, CD10 positive, CD5 negative

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Starry sky;

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Burkitt’s Lymphoma- Bcell immunostain (CD20 +)

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T cell lymphomas Precursor T cell lymphoblastic lymphoma/leukemia Peripheral T cell lymphomas Predominantly leukemic/disseminated T-cell prolymphocytic leukemia T-cell large granular lymphocytic (LGL) leukemia NK cell leukemia Adult T-cell leukemia/lymphoma Predominantly nodal Angioimmunoblastic T-cell lymphoma Peripheral T-cell lymphoma unspecified Anaplastic large cell lymphoma, T/null-cell Predominantly extranodal Mycosis fungoides Sezary syndrome Primary cutaneous CD30+ T-cell lymphoproliferative disorders Subcutaneous panniculitis-like T-cell lymphoma NK/T cell lymphoma, nasal and nasal-type Enteropathy-type intestinal T-cell lymphoma Hepatosplenic T-cell lymphoma

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Key points regarding T cell lymphomas Represent 20% of all lymphomas Tend to involve extra-nodal sites like skin,

midline facial area, liver more than B cell, with very characteristic clinical presentations Cytologic features not as predictive of behavior

as B cell lymphomas One of most aggressive looking, anaplastic large

cell lymphoma, actually has better prognosis than most indolent B cell lymphomas-77% 5 year survival

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Most common type in skin, mycosis fungoides, is an indolent lymphoma, similarly incurable, but with long clinical course

Most nodal disease is bad, high stage, and poorer response to therapy than B cell lymphomas of all grades

Immunophenotypic studies frequently demonstrate

Loss of normal T cell associated antigens Antigens associated with Natural Killer cell

function

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Pathogenesis in T-cell lymphomas Characteristic cytogenetic findings

associated with several types Anaplastic large cell lymphoma- t(2;5):

ALK1 gene Hepatosplenic T cell lymphoma-

Isochromosome 7

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Precursor T cell lymphoblastic lymphoma/leukemia

Disease of young teenagers; boys>girls Can present as acute leukemia or mediastinal

mass+/- marrow involvement Aggressive lymphoma/leukemia, but curable

~70% with appropriate multiagent chemotherapy Benign equivalent immature T cells of thymus Cytologic features: "Blast cells" of intermediate

size with oval to "convoluted" nuclear profiles, fine chromatin and 0-1 nucleolus

Histology: Diffuse infiltration of thymus/adjacent lymph nodes

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Pathogenesis: unclear, but frequently involves

translocation of oncogenes to site of T cell receptor genes, and upregulation of protein production

It is the solid counterpart to T-cell acute lymphoblastic leukemia.

T-cells have convoluted (i.e., more than one cleft) nuclei

similarities with baby, intra-thymic T-cells it typically presents itself in the anterior

mediastinum (i.e., thymus area).

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T-cell lymphoblastic lymphoma

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T-cell lymphoblastic Lymphoma

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Mycosis fungoides (Sézary syndrome) Lymphomas of the epidermis and upper dermis, Composed of large T4-cells with very elaborately

infolded ("cerebriform") nuclear membranes. The distinctive "Pautrier microabscesses" are

clusters of these T-cells within the epidermis. In "mycosis fungoides", patients suffer from red,

peeling skin for some years, then enter a plaque and eventually a tumor phase, in which the patient looks horrible and has lymphoma throughout the body.

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Mycosis fungoides early skin lesions & skin plaques

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Pautrier Microabscesses

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Multiple Myeloma Syn.:Plasma cell myeloma, plasmocytoma,

myelomatosis. Mean age: 62 years (M=F) Lytic bone lesions with bone pain

fractures and hypercalcemia, X-ray: multiple punched out, osteoporotic bony

lesions Renal failure Very high ESR >100 (Rouleaux formation) Immunodeficiency infections (especially

encapsulated bacteria).

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Rouleaux formation

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Plasma cell neoplasmCancer of B-cells that are differentiated

enough to secrete an immunoglobulin and/or a light chain (kappa or lambda - never both), monoclonal Ig paraprotein (Bence-Jones protein)

Hypergammaglobulinemia Hyperviscosity syndrome• bleedings (purpura), • neuropathy, • heart failure, • visual failure&blindness, etc.

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 IgG  50%

   IgA  20%

   IgD  < 1%

   IgE  rarely

   light chain only  25%

   non-secretor  1 to 2%

Hypergammaglobulinemia in MM(monoclonal)

Remaining, normal immunoglobulins are decreased because residual, normal plasma cells are suppressed from making antibodies by the malignant plasma cell clone.

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Bone lesions

Tendency to make multiple holes ("lytic lesions") in the bone marrow ("myelo-") and nearby cortex.

The effect is mediated, at least in part, by lymphotoxin (TNF-beta).

Cancer of plasma cells always involves bone, but only about half of cases feature good "punched-out" x-ray lesions.

The remaining patients have diffuse disease and suffer precocious osteoporosis.

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Bence-Jones protein

The monoclonal protein (immunoglobulin or chain) produced by an abnormal clone of multiple myeloma cells is called the M-protein.

They pass easily through the glomerular basement membrane to the bloodstream (if the kidneys are working). in the urine, Bence-Jones protein. about 2/3 of myeloma patients produce

Bence-Jones protein, later on, Bence-Jones protein plugs up the

renal tubules, and contributes to myeloma kidney.

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Renal lesions in MM

The kidney develops myeloma nephropathy in 60 - 80% of cases of myeloma, manifested as interstitial fibrosis around the distal tubules.

It is caused by light chain toxicity to the tubules. Infection, hypercalcemia, and amyloid are

contributory.

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Problems in MM Osteoporosis pathologic fractures hypercalcemia (several mechanisms) infections (myeloma cells suppress normal plasma

cells) anemia and neutropenia (crowding out of normal cells) kidney failure (Bence-Jones and/or amyloid) myeloma neuropathy (infiltration, compression,

vincristine) amyloidosis B (10% of myeloma patients; cardiac

problems) plasma cell leukemia (a terminal stage).

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Bone lesions in MM

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Pathology of MM

The bone marrow is infiltrated by malignant plasma cells (which will comprise at least 10% of the cell population), with a range of morphologic dysplasia The plasma cell infiltrate is spotty and does not diffusely

obliterate normal hemaopoiesis (like acute leukemia) The plasma cell aggregates will correspond to the bony lesions

seen on x-ray (typically, vertebral column, ribs, skull, pelvis, etc.), in which case the disease is called "multiple myeloma."

Rarely, only a single bony lesion is seen, in which case the disease is called "solitary myeloma." This almost always progresses to multiple myeloma.

Occasionally, the collections of malignant plasma cells can occur in an extramedullary location, usually soft tissue of the upper respiratory tract, and the disease is called "plasmacytoma"; these are usually cured by surgical excision.

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Multiple Myeloma

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LANGERHANS CELL HISTIOCYTOSIS Langerhans-type histiocytes, a class of

dendritic macrophages. Lesions:

a range of cells from "blasts" to well-differentiated Langerhans cells.

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Letterer-Siwe disease ("acute disseminated histiocytosis") affects small children involves most of the body's organs.

Eosinophilic granuloma solitary bone lesions in young people. the histiocytes have coffee-bean nuclei and are

admixed with eosinophils. Hand-Schüller-Christian disease

affects the skull bones and other body parts. intermediate between the other two in severity.

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SUMMARY:

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Rules for non-Hodgkin’s lymphomas RULE: All monoclonal proliferations of lymphocytes

are best considered malignant. RULE: Most lymphomas are somewhat more common

in men. RULE: Lymphoma tissue feels like "fish flesh" or "firm

rubber" (some fibrosis). RULE: Fatigue, malaise, night-sweats, fever, and

weight loss are the usual symptoms (if any) of these diseases.

RULE: Some lymphomas have one or more special risk factors: helicobacter in the stomach previous irradiation immunosuppression ataxia-telangiectasia .

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RULE: A majority of lymphomas arise in the lymph nodes (one or more groups).

RULE: A large minority arise in extra-nodal lymphoid tissue, i.e., Waldeyer's ring, stomach, terminal ileum, skin, marrow.

RULE: When lymphomas arise in lymph nodes, they present as non-tender enlargement.

RULE: Lymphomas metastasize to other lymphoid tissues (nodes, spleen, etc.), and eventually to the marrow, blood.

RULE: Lymphomas tend to spread to sites according to their B-cell or T-cell origin. Skin lymphomas are usually of T-cell origin.

RULE: The malignant cells of lymphomas are more uniform.

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(1) Destruction or distortion of normal lymph node architecture;

(2) Morphologically, predominance of one lymphocyte cell type (Cell uniformity; monotony);

(3) Presence of macrophages laden with nuclear debris;

(4) Pattern of involvement: nodular or diffuse (5) Invasion of surrounding tissue (capsular); (6) Necrosis (apart from apoptosis) is common

in some lymphomas, and of course in necrotizing infections.

Microscopical criteria