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Pathology of Lymph Nodes. Norman Levy, MD. Big Picture. As with other organs, lymph nodes, and more globally, the immune system, can be the site of infectious, immune and neoplastic disease, the latter either primary or metastatic

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big picture
Big Picture
  • As with other organs, lymph nodes, and more globally, the immune system, can be the site of infectious, immune and neoplastic disease, the latter either primary or metastatic
  • The clinical manifestations of diseases of the lymph nodes are:
    • Local enlargement, tender on nontender, +/_
    • Compression of adjacent structures +/_
    • Release of cytokines producing "systemic" symptoms of fever, weight loss and night sweats
  • Infectious organisms can stimulate the same acute, chronic or granulomatous reactions in the draining lymph nodes as they characteristically stimulate at other sites
big picture 2
Big Picture 2
  • Several types of immune stimuli can cause "reactive" enlargement of the entire lymph node, or selective expansion of cortical, paracortical or medullary regions
  • Metastatic tumors spread to the lymph nodes primarily via lymphatic drainage from adjacent solid organs
  • Primary neoplasms of the lymph nodes are all malignant
  • They are divided into malignant non-Hodgkin's lymphomas (NHL), and Hodgkin lymphoma
big picture 3
Big Picture 3
  • NHL's are more common, and can be simply divided into indolent, or slow growing types, and aggressive types
  • Malignant lymphomas represent clonal malignancies in which mutational events have caused the majority of progeny cells to freeze at a single stage of normal lymphocyte differentiation
    • Lymphomas frozen at a stage associated with high replication --> aggressive lymphomas;
    • Lymphomas frozen at stages associated with recirculation or final function --> indolent lymphomas
big picture 4
Big Picture 4
  • The diagnosis of malignant lymphomas is based on the microscopic recognition of the dominant cytologic cell type, supplemented by immunologic and molecular techniques
  • The treatment and prognosis of lymphomas are based on
    • The dominant cell type (and it's inherent biologic behavior),
    • The extent of spread (Stage)
    • The underlying health of the patient
  • All of the previous statements are complicated by the fact that indolent lymphomas can further mutate and transform to aggressive types
big picture 5
Big Picture 5
  • Hodgkin lymphoma is a less common nodal disease whose diagnosis is based on the detection of a characteristic cell, the Reed Sternberg cell, in the appropriate histologic setting
  • There are several (five) histologic subtypes, but prognosis is based primarily on extent of disease
  • Hodgkin lymphoma is a more curable disease than non-Hodgkin lymphomas
  • Now watch me confuse this relatively straightforward information with the details.
overview of the lymphoid immune system
Overview of the lymphoid immune system
  • Lymphocytes evolve from pluripotent stem cells --> two major functional cell types:
    • B lymphocytes, comprising the humoral immune --> production of antibodies
    • T lymphocytes, comprising the cellular immune system, -->
      • Direct killing of foreign or intracellularly infected cells, cytotoxic T cells
      • Fine control of the immune response through the secretion of cytokines, helper and suppressor T cells.
anatomical organization
  • The anatomic organization of the lymphoid immune system divided into two major functional regions:
    • The primary immune organs, sites of initial maturation --> immune competent cells:
      • B cells- bone marrow
      • T cells- thymus
    • The secondary immune organs, sites of antigen driven replication and differentiation into committed effector cells
      • Lymph nodes
      • Spleen
      • Mucosal Associated Lymphoid System (MALT)- lymphoid cells lining the respiratory and gastrointestinal tracts
      • Everywhere else
  • The lymph nodes, in their totality, represent the largest secondary organ, and the major site of lymphoid pathology
lymph node anatomy
Lymph node anatomy
  • To recognize lymph node pathology, one has to be familiar with normal lymph node anatomy and cytology
lymph node variation
Lymph node variation
  • Lymph node histology is dynamic: follicles
    • In the absence of immune stimulation, primary follicles
    • In the presence of immune stimulation, secondary follicles or germinal centers
lymphocyte homing
After initial maturation in the primary immune organs, "virgin" B and T lymphocytes --> peripheral blood --> home to specific sites within the lymph node (and the other secondary organs),

The sites of B cell homing include:

The primary and secondary follicles of cortex-the sites of

antigen presentation

proliferation and differentiation in response to same

The medullary cords -->plasma cells aggregate--> release their immunoglobulins into the efferent lymph

The site of T cell homing is the paracortex

The separation of B and T lymphocytes not absolute,

Both cell types present throughout lymph node, necessary for coordinated lymphoid immune response.

Lymphocyte homing
lymphocyte recirculation
Lymphocyte recirculation
  • Normal lymphocytes recirculate, passing from blood --> lymph nodes --> efferent lymphatics
    • Allows constant surveillance for the presence of the antigen for which the lymphocyte has a unique and specific receptor on it's surface.
  • If antigen not present, lymphocytes leave the node and recirculate
  • Virgin lymphocytes have a finite lifespan, numbered in weeks, unless they come in contact with antigen
cytology of the lymph node
Cytology of the lymph node
  • The normal or reactive lymph node is thus 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
    • Macrophages
  • Some of these functional subgroups are cytologically unique, others cytologically indistinguishable
  • The ultimate microscopic impression, with practice, is one of cytologic heterogeneity, and histologic organization
cell types i
Small lymphocytes

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

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, B or T, guessed by location within the node, but lineage and state of differentiation must be confirmed by immunologic/molecular techniques


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

T cells- paracortex, minor population within germinal center.

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

Cell types I
cell types 2 follicular germinal center cells
Replicating and post-replicating B cells

Noncleaved cells, small and large

Replicating populations- expanding antigen responsive cells.

Round nuclei but larger than resting small lymphocyte

Open or vesicular chromatin

Recognizable nucleoli.

Nucleus clear -->genetic material unwound for replication.

Size, large or small compared nucleus of macrophage.

Small cleaved cells-

Nonreplicating population

Post mitotic memory or plasma cell precursors

Clumped chromatin

Irregular folded and cleaved nuclear profiles

Cell types 2:Follicular (germinal) center cells
cytology of lymph node 3

Replicating large cells found outside the germinal centers.

May be of B or T cell type

Have nuclear characteristics of replicating lymphocytes-

Vesicular chromatin


Accessory cells

Antigen processing cells

Interdigitating reticulin cells- T cell paracortex

Dendritic reticulin cells- B cell germinal centers

Process and present antigen to B and T lymphocytes

Invisible in normal lymph node

Macrophages (histiocytes)-

Phagoctytic cells of lymph node

Tingible body macrophages of germinal centers

Medullary and subcapsular sinus macrophages-

Abundant pale cytoplasm

Oval nucleus, single small nucleolus

Cytology of lymph node 3
pathology of lymph nodes 1
Pathology of lymph nodes 1
  • Infections
  • Reactive hyperplasias
  • Sarcoidosis
  • Metastatic tumors
  • Malignant lymphomas
    • Non-Hodgkin’s lymphoma-NHL
    • Hodgkin’s lymphoma
pathology of lymph nodes 2
Pathology of lymph nodes 2
  • Infections
    • Bacterial
      • Acute inflammation, abscess formation
    • Granulomatous, caseous and noncaseous
    • Diagnosis by culture, serologies, and/or special stains
reactive hyperplasias
Reactive hyperplasias
  • Exaggerations of normal histology.
    • Expansion of all regions or selective expansion
    • Some types characteristic of certain diseases, but most not
  • Follicular hyperplasia- increase in number and size of germinal centers, spread into paracortex, medullary areas
    • Collagen vascular diseases
    • Systemic toxoplasmosis
    • Syphillis
  • Interfollicular hyperplasia- paracortex
    • Skin diseases
    • Viral infections
    • Drug reactions
  • Sinus histiocytosis- expansion of the medullary sinus histiocytes-
    • Adjacent cancer
    • Infections
malignant lymphomas non hodgkin s lymphomas nhls
Malignant lymphomas (Non-Hodgkin's lymphomas-NHLs)
  • Malignancies of the lymphoid system which primarily manifest themselves outside the bone marrow, at the sites of normal lymphoid homing
    • Lymph nodes
    • Spleen
    • M.A.L.T.
    • Anywhere(Lymphomas outside lymph nodes and spleen are referred to as extranodal lymphomas)
  • Approximately 40, 000 cases per year, 20,000 deaths
clinical presentation
Clinical presentation
  • Enlarging mass(es), typically painless, at sites of nodal tissue
  • Compression, infiltration of hollow organs
    • Pain, obstruction, perforation
  • Interference with normal organ function-
    • Solid organ infiltration- kidneys, liver, bone marrow
  • Systemic symptoms
    • Fever
    • Night sweats
    • Weight loss
  • If marrow infiltrated, can have leukemic component
nhl 2
  • Composed of cells that have lost the ability to pursue the full range of lymphoid differentiation, and are frozen at a single stage of the normal maturation/differentiation sequence
  • Recapitulate the biology and immunophenotype of normal cell counterpart
  • Several cytologically and immunologically recognizable stages of normal lymphoid maturation --> several subtypes of lymphoma
  • Clonal malignancies, derived from a single cell that has undergone a malignant transformation, mutation
  • Best initially conceptualized as two major clinical types
    • Indolent lymphomas
    • Aggressive lymphomas
nhl 3 indolent lymphomas
NHL 3 Indolent lymphomas
  • Lymphomas frozen at stages not normally replicating, but may be circulating
  • Diseases of slow accumulation, due to defective apoptosis
  • Often widespread at diagnosis
  • Prolonged natural history, median survivals >5 years
  • Will usually respond to chemo- or radiation therapy
  • Will usually relapse, but respond to same or alternative tx
  • Currently incurable unless
    • Localized disease or
    • Marrow ablation with some type of stem cell transplant
  • Classification of indolent lymphomas- later
aggressive lymphomas
Aggressive lymphomas
  • Lymphomas frozen at stages characterized by replication and accelerated growth
  • Diseases of defective cell cycle control
  • More often localized at presentation than indolent lymphomas
  • More often extranodal
  • Shorter natural history; median survival </= 2 years
  • Require more aggressive therapy to achieve "clinical remission"- disappearance of all detectable disease
  • Despite short natural history, curable disease in some with aggressive therapy
    • Approximately 30-40% of adults
    • 50-80% children
  • All childhood lymphomas of this type
classification of lymphomas
Classification of lymphomas
  • Subtyping or classification within the two groupings necessary, because different subtypes have
    • Distinct clinical presentations
    • Can require different therapy
    • Have differing prognoses, reflecting different mechanisms of molecular pathogenesis.
  • Unfortunately, rarely unanimous acceptance of any one classification scheme.
  • Intermittent upgrading of classification, with new terminology, reflecting new information and classifier bias
  • Classification often lags behind advances in immunology, research pathology
  • Final result:
    • Difficult area to teach
    • Difficult to remember
    • Job security for me
workingformulation for clinical usage
From 1982-1994, the classification used in the United States

Based on:

The observed clinical history of 1200 patients classified according to the terminology to right

Microsopic examination alone, utilizing

Loss of normal nodal architecture

The dominant cytologic cell type observed under the microscope

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

Low grade

ML, small lymphocytic

ML, follicular small cleaved cell

ML, follicular, mixed small and large cell

Intermediate grade:

ML, follicular, large cell

ML, diffuse, small cleaved cell

ML, diffuse, mixed small and large cell

ML, diffuse, large cell

High grade

ML, immunoblastic

ML, lymphoblastic

ML, small non-cleaved cell (Burkitt's vs non-Burkitt's)

Miscellaneous (mycosis fungoides, true histiocytic, etc.)

WorkingFormulation for Clinical Usage
working formulation
Working Formulation
  • Divided into three "grades" of lymphoma- low, intermediate and high. As stated above,
    • Low grade = indolent
    • Intermediate and high = aggressive
  • Limitations
    • Purely morphologic classification mixed T and B cell lymphomas together
    • Lumped distinct subtypes of B cell lymphomas together
    • Obscured the biologic, clinical and therapeutic differences
    • Distorted interpretation of clinical trials
r e a l w h o classification
R.E.A.L./W.H.O. Classification
  • WF replaced in 1994 by the Revised European American Lymphoma (REAL) classification, now being modified by the World Health Organization (WHO)
  • REAL/WHO is a "disease” oriented rather than purely morphology oriented classification, based on:
    • Cell lineage: B v T v NK v Histiocytic
    • Stage of maturation of the presumed normal counterpart.
    • Includes immunologic and molecular criteria in addition to purely morphologic criteria of WF
    • Each disease entity may have differing grades of aggressiveness
    • Greatly expanded the list of entities; includes leukemias of lymphoid origin
    • Made teaching to medical students (and in fact all physicians) even more difficult than WF
  • REAL contained a number of “provisional entities” which have been clarified in the upcoming W.H.O. revision.
real who classification backbone
REAL/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
indolent versus aggressive

Small lymphocytic lymphoma/CLL

Follicular lymphoma, Grades 1/2

Extranodal Marginal zone lymphoma of MALT type

Nodal marginal zone lymphoma

Splenic marginal zone lymphoma

Hairy cell leukemia

Lymphoplasmacytic lymphoma

Plasma cell myeloma


Cutaneous T cell lymphoma

Cutaneous CD30+ anaplastic large cell lymphoma


Prolymphocytic leukemia

Large B cell lymphoma

Burkitt lymphoma

Mantle cell lymphoma

Anaplastic large cell lymphoma

All peripheral T cell lymphomas

Indolent versus aggressive

Divides B and T

b cell neoplasms precursor b
B cell neoplasms- Precursor B
  • 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
    • Treated as acute leukemia
      • 80% cure rate in children
      • 20-30% in adults because of "bad" cytogenetics: frequent presence of Philadelphia chromosome t(9;22)
peripheral b cell lymphomas
Peripheral B-cell lymphomas
  • Lymphomas frozen at various stages of antigen dependent B cell maturation and differentiation
peripheral b cell neoplasms
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- grades 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
example indolent lymphoma follicular lymphoma grade i

Most common type of indolent lymphoma in US; second most common type lymphoma overall

Disease of adults >40 (median age 59)

Usually widely disseminated at diagnosis, incl. bone marrow

Will respond to “gentle chemotherapy” but will relapse

Incurable short of bone marrow transplant unless rare limited disease

Overall 5 yr survival 72%

Over time, additional mutations --> progression (“transformation”) to large cell lymphoma --> aggressive clinical course

Although Gr.1 is most common presentation, some patients present with predominance of large cells within follicles -->more aggressive clinical course


Due to t(14;18)(q32, q21)

Upregulates expression of an anti-apoptotic protein Bcl2

Immortalizes lymphoma cells

Example Indolent Lymphoma:Follicular lymphoma Grade I
follicular lymphoma grade i
Follicular lymphoma Grade I
  • Pathology/diagnosis
    • Benign equivalent: small cleaved cell of germinal center
    • Clumped chromatin and infrequent nucleolus like small lymphocyte
    • Irregular nuclear profile, with nuclear folds or "cleavages"
    • Retain follicular structure, but monotonous accumulation of single cell type
    • Characteristic immunophenotype:
      • Positive:Monoclonal light chain, CD19, CD10, Bcl2
      • Negative: CD5, Cyclin D1/Bcl1
    • Can also detect translocation by cytogenetics and/or polymerase chain reaction
examples aggressive b cell lymphoma diffuse large b cell lymphoma
Examples: aggressive B cell lymphoma-Diffuse large B cell lymphoma
  • Clinical
    • Most common lymphoma- 30% NHL
    • Disease of adults and children, but median age 64
    • Limited versus widespread disease ~1:1
    • Presents with rapidly enlarging masses
    • Approximately 40% curable with aggressive chemotherapy/ stem cell transplant
      • Partially predictable by International Prognostic Index (later)
  • Pathogenesis
    • Not as clearly defined as previous examples- several cytogenetic abnormalities associated with large cell lymphoma, but no defining one
diffuse large b cell lymphoma
Diffuse Large B cell lymphoma
  • Pathology
    • Benign equivalent- large replicating B cells of germinal center and paracortex
    • Diffuse infiltration of lymph node
    • Often necrosis; increased mitotic rate
    • Cytology: Oval or cleaved nucleus with vesicular chromatin and 1-3 nucleolus
    • Nucleus larger than that of reactive macrophage
    • Several cytologic subtypes initially felt to have differing clinical behavior.
    • Yielded division into intermediate versus high grade types- now not felt valid or significant without immunologic/molecular evidence
    • Immunophenotype characterized by monoclonal light chain, CD19 expression,with variable expression of other B cell associated antigens
burkitt s lymphoma

3% lymphomas

Disease of adults and children- median age 31

Initially recognized in Africa by Thomas Burkitt

Association with Epstein Barr virus infection

Localization in jaw

In US, usually presents in ileocecal region of children

1/3 of all childhood lymphomas

Earlier eras, very aggressive and rapidly fatal

Now, ~70-80% children curable

40% of adults


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

Burkitt's lymphoma
burkitt s lymphoma46
Burkitt's lymphoma
  • Pathology
    • Benign equivalent is replicating small noncleaved cell of germinal center:
    • Diffuse infiltration of lymph node
    • Very high mitotic rate, lot of ineffective proliferation;
    • Attracts macrophages to phagocytize> starry sky pattern at low power
    • Cytology: round nucleus, smaller than that of reactive macrophage
    • Vesicular chromatin and 2-5 nucleoli
    • Immunophenotype:
      • Positive: Monoclonal light chain, CD19, CD10
      • Negative: CD5
mantle cell lymphoma
Mantle cell lymphoma
  • Clinical
    • 6% lymphomas
    • Disease of adults (median age 63)
    • Usually widely disseminated
    • Poor response to all attempted therapies,
    • ? curable with transplant
    • 5yr survival 27%
  • Pathogenesis
    • Due to t(11;14)
    • Upregulates Bcl1 (cyclin D1), a cell cycle regulator
mantle cell lymphoma48
Mantle cell lymphoma
  • Pathology/Diagnosis
    • Benign equivalent is lymphocyte of inner mantle zone
    • Cytology similar to cleaved cell, but nuclear irregularities not as prominent
    • Nodal infiltration diffuse, vaguely nodular or "mantle zone" around residual benign follicles
    • Large cell progression infrequent
    • Immunophenotype:
      • Positive: monoclonal light chain, CD19, CD5, Bcl1 (and Bcl2)
      • Negative CD10, CD23

Follicular lymphoma

Mantle cell lymphoma



t cell lymphomas precursor t
T cell lymphomas-Precursor T
  • Clinical
    • Disease of teenagers; boys>girls
    • Can present as acute leukemia or mediastinal mass+/- marrow involvement
    • Aggressive lymphoma/leukemia, but curable: ~70% with appropriate multiagent chemotherapy
  • Pathogenesis
    • No single gene culprit, but frequently involve translocation of (onco)genes to site of T cell receptor genes, --> upregulation of proteins
t cell lymphomas precursor t52
T cell lymphomas-Precursor T
  • Pathology
    • Benign equivalent immature T cells of thymus
    • Histology: Diffuse infiltration of thymus/adjacent lymph nodes
    • Cytology: “Blast cells” of intermediate size with oval to “convoluted” nuclear profiles, fine chromatin and 0-1 nucleolus
    • Again need immunology to distinguish from pre-B
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

Peripheral T cell lymphomas
key points regarding t cell lymphomas

Represent 20% all lymphomas

More often extranodal than B

Can involve skin, midline facial area, liver

Very characteristic clinical presentations

Most diseases bad: high stage, and poorer response to therapy than B cell lymphomas of all grades


Characteristic cytogenetic findings associated with several types

Anaplastic large cell lymphoma- t(2;5): ALK1 gene

Hepatosplenic T cell lymphoma- Isochromosome 7


Cytologic features not as predictive of behavior as B cell lymphomas

Anaplastic large cell lymphoma --> better prognosis than most indolent B cell lymphomas- 77% 5 year survival

Mycosis fungoides, indolent cutaneous lymphoma, incurable, but with long clinical course

Immunophenotypic studies frequently demonstrate

Loss of normal T cell associated antigens

Antigens associated with Natural Killer cell function

Immunology absolutely necessary to recognize

Key points regarding T cell lymphomas
ancillary diagnostic studies
Ancillary diagnostic studies
  • Use of immunologic/molecular techniques
  • Malignant lymphomas reproduce the immunobiology of their benign counterparts
  • This reproduction may be aberrant, and hence distinguishable from normal
  • Expression, normal and aberrant can be used to:
    • Determine lineage, B versus T versus NK
    • Detect clonality
    • Suspect malignancy- loss or aberrant expression of expected antigens
    • Recognize characteristic patterns of antigenic expression associated with certain subtypes of lymphoma
normal lymphoid maturation
Requires two major activities

The production of a unique antigenic receptor on it's surface

The expression of several surface proteins necessary for antigen recognition, cell activation, cell-cell communication.

Antigen receptors are generated through the process of "genetic rearrangement"- the random selection and juxtaposition of discontinuous genetic segments encoding the antigen receptor genes

B cells

Immunoglobulin receptor composed of two heavy and two light chains

Select specific heavy chain antigen recognition sequence

Select only one of two light chains, kappa or lambda

T cells

Select one of two heterodimeric receptors

Alpha/Beta heterodimer T cell receptor

Gamma/Delta heterodimer T cell receptor

Normal lymphoid maturation
normal lymphoid maturation57
Normal lymphoid maturation
  • Requires two major activities
    • The production of a unique antigenic receptor on it's surface
    • The expression of several surface proteins necessary for antigen recognition, cell activation, cell-cell communication.
  • Antigen receptors are generated through the process of "genetic rearrangement"- the random selection and then juxtaposition of discontinuous genetic segments encoding the antigen receptor genes
    • B cells
      • Immunoglobulin receptor composed of two heavy chains and two light chains
        • Select specific heavy chain gene sequences
        • Select only one of two light chains, kappa or lambda
    • T cells
      • Select one of two heterodimeric receptors
        • Alpha/Beta heterodimer T cell receptor
        • Gamma/Delta heterodimer T cell receptor
surface antigen production
Surface antigen production
  • Immune cells require numerous surface molecules for effective immune response, cell-cell communication and regulation
  • Classified into B cell associated, T cell associated, activation associated, cytokine receptors
  • Expression occurs in an orderly sequence in lymphoid maturation
  • Antibodies to these molecules cataloged thru the CD - clusters of differentiation - numerical system
    • Initially developed to characterize monoclonal antibodies detecting proteins whose function was unknown .
    • Now up to CD166. You'll only be tested on 1-130 though (- a joke for you paranoid types.)
immunologic techniques
Immunologic Techniques
  • Flow cytometry-automated fluorescent microscopy
  • Immunohistochemistry- in situ immunologic detection through the use of enzyme substrate color deposition
  • Both utilize monoclonal antibodies to detect clonality and unique antigenic patterns
immunologic techniques63
Immunologic Techniques
  • Flow cytometry-automated fluorescent microscopy
  • Immunohistochemistry- in situ detection through the use of enzyme substrate color deposition
  • Examples
    • B cell small lymphocytic lymphoma-
      • Monoclonal light chain, CD19, CD20, CD5, CD23 positive, CD10 negative
    • B cell follicular lymphoma-
      • Monoclonal light chain, CD19, CD20, CD10 positive, CD5 negative
molecular techniques
Molecular techniques
  • Detection of antigen receptor clonality
  • Detection of unique cytogenetic rearrangements/translocations
  • Examples
    • Clonal gene rearrangement by Southern blot
    • Bcl2/JH rearrangement by polymerase chain reaction
clinical presentation67
Clinical presentation
  • Enlarging mass(es), typically painless, at sites of nodal tissue
  • Obstruction, ulceration of hollow organs- pain, perforation
  • Interference with normal organ function-
    • Solid organ infiltration- kidneys, liver, bone marrow
  • Systemic symptoms
    • Fever
    • Night sweats
    • Weight loss
  • If marrow infiltrated, can have leukemic component
clinical staging of lymphomas
Clinical staging of lymphomas
  • Defines extent of disease; determines therapy and prognosis
  • Based on physical, radiologic examination, bone marrow biopsy and aspiration
  • Ann Arbor Staging system
  • B symptoms- fever, weight loss > 10% body weight, night sweats
  • International prognostic index
    • Aggressive lymphomas
  • Cytogenetics
  • Oncogenes
international prognostic index 1
International Prognostic Index 1
  • Clinical features identifying prognostic subsets of diffuse large cell lymphoma
  • Identified through retrospective statistical analysis of large set patients
  • Assigned 1 point for each bad feature
therapy i indolent lymphomas
Seminar cases will also discuss

Limited stage (5-10% cases)

Radiation therapy

Can be curative

Disseminated indolent/low grade lymphomas (90%)

No therapy

Low morbidity limited chemotherapy

Older patients

No expectation of cure

Most will respond totally or partially, with months to years of disease free survival, but will relapse

Many will respond to additional rounds of similar or alternative regimens

Pts will die of disease, or interceding disease of elderly

Death from disease due to

Immune suppression- infections

Progression to aggressive lymphoma

"Bone marrow transplant"-

Effort at cure

Reserved for younger patients <60

High dose chemotherapy and allogeneic transplantation

High dose chemotherapy and autologous peripheral stem cell collection/reinfusion

Increased morbidity

Therapy I Indolent lymphomas
therapy ii aggressive lymphoma
Therapy II- Aggressive lymphoma
  • Limited disease localized disease treated with irradiation plus limited cycles multiagent chemotherapy
  • More extensive disease with more cycles multiagent (>/= 4 drugs) chemotherapy
    • Complete remission rates 60-80%
    • 30-40% cured
  • Newer therapies and their roles still being established
    • Bone marrow transplantation
      • Allogeneic
      • Autologous
    • Immunotherapy
hodgkin s lymphoma
Hodgkin's lymphoma
  • Less common than NHL; ~ 10,000 cases per year
  • Age incidence bimodal, with one peak in late adolescence, young adulthood, second peak beginning in sixth decade
    • Bimodal curve shifts to younger ages in poorer countries
  • Unlike NHL, HL diagnosed by the presence of a minor cellular component, the Reed-Sternberg cell, found in the appropriate microscopic cellular background
hodgkin s histologic subtypes
Hodgkin's Histologic subtypes
  • Are characteristic patterns of involvement, and characteristic variants of Reed Sternberg cell associated with different subtypes
  • Nodular sclerosing HL
    • Most common type Hodgkin's lymphoma in US/Europe
    • Usually presents in the anterior mediastinum and neck of young adult females
    • Characterized by fibrotic capsule and bands subdividing tissue and
    • Lacunar variant Reed Sternberg cell
histologic subtypes 2
Histologic subtypes 2
  • Lymphocyte predominant
    • Usually presents with limited disease in the neck of young adults
    • Associated with L and H (lymphocytic and histiocytic) or "popcorn cell" variant RS cell
  • Mixed cellularity
    • More extensive disease
    • Older patients than NS and LP
    • More R-S cells, eosinophils, plasma cells
    • Mononuclear variant R-S cells
    • Inherently more aggressive disease
  • Lymphocyte depleted
    • Often presents in retroperitoneum, older patients
    • Accompanied by loss lymphocytes, sclerosis and pleomorphic RS cell variants
    • Also more aggressive disease
ancillary studies
Ancillary studies
  • Ancillary immunologic studies assist the dx of Hodgkins' lymphoma
  • Distinguish HL from
    • Immunoblast reactions
    • Unusual variants of NHL
  • CD15 and CD30 antigens in golgi and on cell membrane of R-S cells most useful
patterns of spread
Patterns of spread
  • Hodgkin's lymphoma spreads contiguously via lymphatics
  • Staging as in NHL- may or may not include laparotomy/splenectomy
  • Limited stage, low bulk disease treated with radiation therapy
  • Higher stage, B symptoms (IIB-IV) treated with multi-agent chemotherapy+/- radiation therapy
  • Complications of therapy
    • Radiation effects to lungs, heart, bone marrow
    • Sterility
    • Splenectomy associated sepsis
    • Therapy associated second malignancies
  • Hodgkin's lymphoma is a curable malignancy
  • Overall cure rate approximately 80%
  • With modern therapy, prognosis based more on staging, bulk of disease, than morphologic subtype
  • Not true in earlier era, where prognosis decreased with number of lymphocytes; lymph depleted HL had a terrible prognosis
  • The etiology of HL is still unknown
  • The lineage of the R-S cell was also obscure until recently
  • The mixed cellular infiltrate, unusual large cells, clustered familial cases, and early evidence of immune dysfunction suggest an infectious etiology+/- an inherited predisposition
  • In approximately 30% of cases, Epstein Barr virus found within the RS cells
  • Molecular studies, utilizing single cell dissection and PCR based sequencing of the antigen receptor genes indicate that the R-S cell in the majority of cases is an altered B cell.
  • Thus HL is a type of B cell lymphoma, but with a very different biology from the other types of B cell lymphoma
  • Still deserves a separate category in the classification system
molecular information
Molecular information
  • The molecular abnormalities within the different types of

R-S variants effect the expression of lineage associated antigens

    • L and H cells of lymphocyte predominant HL express B cell antigens, and are clonal proliferations of this cell type
    • RS cells of other types may express T cell, B cell and macrophage associated antigens, but usually fail to express antigen receptors
      • At the molecular level, show B cell gene rearrangements with out of frame mutations or.
      • Mutations in transcription/translation systems so no antigen receptor proteins transported to surface