PATHOLOGY OF THE LYMPH NODES

PATHOLOGY OF THE LYMPH NODES AND LYMPHOMA

This is an excellent page on lymphoma and the lymph system. After studying this information, you may want to follow up with our page Lymph Nodes. I am a thirteen year survivor of lymphoma and was born with hereditary lymphedema (Milroy's Syndrome).

Pat O'Connor

June 18, 2008

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Related Terms: Non Hodgkin Lymphoma, Indolent lymphomas, Aggressive lymphomas, Immune system, B cell neoplasms, Classification of lymphoma, T Cell Lymphoma, Peripheral T cell lymphomas, Clinical staging of lymphomas, Hodgkins lymphoma, Follicular lymphoma, lymph node anatomy, arm swelling, leg swelling, lymphedema

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Arm and Leg Swelling After Lymphoma

With the advent of better and more effective cancer treatments, the survival rate for all cancers has risen dramatically. With this progress, a new and often misunderstood and misdiagnosed complication has arisen.

Many cancer survivors , having overcome cancer, find themselves with sudden and often unexplained swelling, usually of the arms or of the legs.

This swelling occurs because of one of several factors.

First, the swelling begins after lymph nodes have been removed for cancer biopsies.

Second, the swelling may start as a result of radiation damage to either the lymph nodes and/or the lymph system.

Due to either the removal of lymph nodes or damage to the lymph system, your body is no longer able to rid itself of excess fluids. The fluids collect in the limbs effected and swelling beings.

This swelling is called lymphedema. The swelling that occurs is permanent, and while it is not curable it is treatable.

Permanent Leg or Arm Swelling

****In the situation of any permanent leg swelling whether the cause is known or unknown, the diagnoses of lymphedema must be considered****

There are several groups of people who experience leg or arm swelling from known causes, but it doesn't go away or unknown causes where the swelling can actually get worse as time goes by.

Group One

This group includes those who have had the injuries, infections, insect bites, trauma to the leg, surgeries or reaction to a medication. When this swelling does not go away, and becomes permanent it is called secondary lymphedema.

Group Two

Another extremely large group that experiences permanent leg or arm swelling are cancer patients, people who are morbidly obese, or those with the condition called lepedema. What causes the swelling to remain permanent is that the lymph system has been so damaged that it can no longer operate normally in removing the body's waste fluid.

In cancer patients this is the result of either removal of the lymph nodes for cancer biopsy, radiation damage to the lymph system, or damage from tumor/cancer surgeries.

This is also referred to as secondary lymphedema.

Group Three

Group three consists of people who have leg or arm swelling from seemingly unknown reasons. There may be no injury, no cancer, no trauma, but for some reason the leg simply is swollen all the time.

The swelling may start at birth, it may begin at puberty, or may begin in the 3rd, 4th or even 5th decade of life or sometimes later.

This type of leg or arm swelling is called primary lymphedema. It can be caused by a genetic defect, malformation or damage to the lymph system while in the womb or at birth or be part of another birth condition that also effects the lymph system.

This is an extremely serious medical condition that must be diagnosed early, and treated quickly so as to avoid painful, debilitating and even life threatening complications. Treatment should NOT include the use of diuretics.

What is Lymphedema?

Lymphedema is defined simply as an accumulation of excessive protein rich fluid in the tissues of the leg. The accumulation of fluid causes the permanent swelling caused by a defective lymph system.

A conservative estimate is that there may be 1-2 million people in the United States with some form of primary lymphedema and two to three million with secondary lymphedema.

What are the symptoms of Lymphedema?

If you are an at risk person for arm lymphedema there are early warning signs you should be aware of. If you experience any or several of these symptoms, you should immediately make your physician aware of them.

1.) Unexplained aching, hurting or pain in the arm

2.) Experiencing "fleeting lymphedema." This is where the limb may swell, even slightly, then return to normal. This may be a precursor to full blown arm lymphedema.

3.) Localized swelling of any area. Sometimes lymphedema may start as swelling in one area, for example the hand, or between the elbow and hand. This is an indication of early lymphatic malfunction.

4.) Any arm inflammation, redness or infection.

5.) You may experience a feeling of tightness, heaviness or weakness of the arm.

How is Lymphedema Treated?

The preferred treatment today is decongestive therapy. The forms of therapy are complete decongestive therapy (CDT) or manual decongestive therapy (MDT), there are variances, but most involve these two type of treatment.

It is a form of massage therapy where the leg is very gently massaged to actually move the fluid out of the leg and into an area where the lymph system still functions normally.

With these massage treatments, swelling is reduced and then the patient is fitted with a pre-measured custom pressure garment to keep the swelling down and/or is taught to use compression wraps to maintain the leg size.

What are some of the complications of lymphedema?

1. Infections such as cellulitis, lymphangitis, erysipelas. This is due not only to the large accumulation of fluid, but it is well documented that lymphodemous limbs are localized immuno-deficient.

2. Draining wounds that leak lymphorrea which is very caustic to surrounding skin tissue and acts as a port of entry for infections.

3. Increased pain as a result of the compression of nerves usually caused by the development of fibrosis and increased build up of fluids.

4. Loss of Function due to the swelling and limb changes.

5. Depression - Psychological coping as a result of the disfigurement and debilitating effect of lymphedema.

6. Deep venous thrombosis again as a result of the pressure of the swelling and fibrosis against the vascular system. Also, can happen as a result of cellulitis, lymphangitis and infections.

7. Sepsis, Gangrene are possibilities as a result of the infections.

8. Possible amputation of the limb.

9. Pleural effusions may result if the lymphatics in the abdomen or chest are to overwhelmed to clear the lung cavity of fluids.

10. Skin complications such as splitting, plaques, susceptibility to fungus and bacterial infections.

11. Chronic localized inflammations.

Can lymphedema be cured?

No, at the present time there is no cure for lymphedema. But it can be treated and managed and most of the complications can be avoided. Life with lymphedema can still be active and full, with proper treatment, patient education, and patient life style adaptation.

For extensive information on lymphedema, please visit our home page:

Lymphedema People

http://www.lymphedemapeople.com

(c) Copyright 2005 by Pat O'Connor and Lymphedema People. Use of this information for educational purpose is encouraged and permitted. It must be available free and without charge and not used for financial renumeration or gain. Please include an acknowledgement to the author and a link to Lymphedema People.

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PATHOLOGY OF THE LYMPH NODES LYMPHOMA

Department of Pathology

Dartmouth Hitchcock Medical Center

http://www.dartmouth-hitchcock.org/

Author: N. Levy

VI. Big picture

(This is a difficult subject and lecture because of the accumulation of confusing historical terminology, subtle cytologic differences, and the current use of morphologic, immunologic and molecular tools in the diagnosis of these diseases. IT'S NOT MY FAULT! So I'm starting with some basic rules of the road. We will then discuss them in greater detail. Finally, you will have an opportunity to review and use this information in a later clinical seminar)

A. As with other organs, lymph nodes, and more globally, the immune system, can be the site of infectious, immune and neoplastic disease, the latter both primary and metastatic
B. The clinical manifestations of disease in the lymph nodes are
- 1. Local enlargement, tender or nontender, +/_
- 2. Compression/obstruction of adjacent structures +/_
- 3. "Systemic" symptoms of fever, weight loss and night sweats
C. Infectious organisms can stimulate the same acute, chronic or granulomatous reactions in the draining lymph nodes as they characteristically stimulate at other sites
D. Several types of immune stimuli can cause "reactive" enlargement of the entire lymph node, or selective expansion of cortical, paracortical or medullary regions
E. Metastatic tumors spread to the lymph nodes primarily via lymphatic drainage from adjacent solid organs
F. Primary neoplasms of the lymph nodes are all malignant
G. They are divided into malignant (non-Hodgkin's) lymphomas, and Hodgkin's lymphoma
H. Malignant lymphomas are more common, and can be simply divided into indolent, or slow growing, slowly progressive types, and rapidly growing aggressive types
I. Malignant lymphomas represent clonal malignancies in which the majority of cells are frozen at a single stage of normal lymphocyte differentiation
J. Lymphomas frozen at a stage associated with high replication rates yield aggressive lymphomas; lymphomas frozen at stages associated with recirculation or final function yield indolent lymphomas
K. The diagnosis of malignant lymphomas is based on
- 1. The microscopic loss of normal nodal histology and cytologic heterogeneity, and
- 2. Replacement by a dominant cytologic cell type,
- 3. Supplemented by immunologic and molecular techniques defining lineage, clonality, molecular pathogenesis
L. The prognosis and treatment of lymphomas is based on
- 1. Thedominant cell type (and it's inherent biologic behavior)
- 2. The extent of spread (Stage) and
- 3. The underlying health of the patient
M. All of the previous statements are complicated by the fact that indolent lymphomas can further mutate to aggressive types
N. Hodgkin's 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
O. There are five histologic subtypes, but prognosis is based primarily on extent of disease
P. Hodgkin's lymphoma is a more curable disease than malignant (non-Hodgkin's) lymphomas
Q. Now watch me confuse this relatively straightforward information with the details

VII. Overview of the lymphoid immune system

A. 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.
B. 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
C. The lymph nodes, in their totality, are the largest of the secondary immune organs, and the site of the majority of lymphoid pathology.

VIII. Lymph node anatomy

To recognize lymph node pathology, one has to be familiar with normal lymph node anatomy and cytology

Figure 1: Picture of lymph node

A. The lymph node has 7 major subdivisions.
- 1. The lymph node capsule, which surrounds the lymph node
- 2. The subcapsular sinus- the initial entryway of lymphatic fluid into the node via afferent lymphatics
- 3. The lymph node cortex- beneath the subcortical sinus-the location of primary and secondary lymphoid follicles
  - a. In the absence of immune stimulation, the cortical lymphoid follicles are primary follices, composed of small B lymphocytes which may be virgin B lymphocytes or recirculating memory B cells. There is also a fine meshwork or dendritic reticulin cell cytoplasm, which is invisible without special immunolabelling techniques
  - b. With antigenic stimulation, antigen recognizing B cells are stimulated to replication and differentiation. This converts the primary follicle into a secondary follicle or germinal center, surrounded by a mantle zone of transient small lymphocytes, and a central area containing replicating "follicular center cells" and their differentiating progeny- see below.
- 4. The paracortex- the region surrounding and beneath the germinal centers
- 5. The medulla- deep to the cortex/paracortex, and composed of medullary cords and medullary sinuses
- 6. Medullary vessels- artery and vein
- 7. Afferent and efferent lymphatic vessels
B. After initial maturation in the primary immune organs, "virgin" B and T lymphocytes are released into the peripheralblood and home to specific sites within the lymph node (and theother secondary organs), controlled by incompletely understood homing receptors. Hence these regions are enriched for one type of lymphocyte, T or B. The separation of B and T lymphocytes is not absolute however, and both cell types are present throughout the lymph node, necessary for coordinated lymphoid immune response.
C. The sites of B cell homing include:
- 1. The primary and secondary follicles of the lymph node cortex-the sites of antigen presentation to B cells, and subsequent proliferation and differentiation in response to same
- 2. The medullary cords, where plasma cells aggregate, and release their immunoglobulins into the efferent lymph
D. The site of T cell homing is the paracortex.
E. Normal lymphocytes recirculate, passing from blood into and through the lymph nodes, and then into efferent lymphatics, surveilling for the presence of the antigen for which they have a unique and specific receptor on their surface. If this antigen is not present, the lymphocytes leave the node.
F. Virgin lymphocytes have a finite lifespan, numbered in weeks, unless they come in contact with antigen.

IX. Cytology of the lymph node

A. The 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. 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.
B. Cell types:
- 1. 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
  - Figure 2: Follicular center cell types
- 2. Follicular (germinal) center cells- replicating and post-replicating B cells.
  - a. Noncleaved cells, large and small
    - (1) Replicating populations within the germinal center-expanding the number of cellsreactive with entrapped antigen.
      - (a) Have round nuclei like small lymphocytes, but larger, with open or vesicular chromatin pattern, and recognizable nucleoli. Nucleus clear because genetic material unwound for replication. Size, large or small based on comparison with nucleus of macrophage.
  - b. Cleaved cells, small (and large))- post mitotic memory cell or plasma cell precursors
    - (1) Clumped chromatin like small lymphocytes, but irregular folded and cleaved nuclear profiles.
    - (2) Nonproliferating population
- 3. Immunoblasts- Proliferating large cells found outside the germinal centers. May be of B or T cell type. Again have characteristics of replicating lymphocytes- vesicular chromatin, nucleoli
- 4. Accessory cells
  - a. Antigen processing cells-process and present antigen to B and T lymphocytes- invisible innormal lymph node
    - (1) T cell paracortex- interdigitating reticulin cells
    - (2) B cell germinal centers- dendritic reticulin cells
  - b. Macrophages (histiocytes)-
    - (1) Tingible body macrophages of germinal centers
    - (2) Main cells of medullary sinuses- Abundant pale cytoplasm, oval nucleus, single small nucleolus

X. Pathology of lymph nodes

A. Infections
- 1. Bacterial
  - a. Acute inflammation, abscess formation
- 2. Fungal, mycobacterial
  - a. Granulomatous, caseous and noncaseous
- 3. Diagnosis by culture, serologies, and/or special stains
  - a. Some typical histologic patterns
    - 1. Necrotizing granulomatous reactions in cat scratch disease, tularemia
    - 2. Sinusoidal and perisinusoidal monocytoid B cells, intrafollicular granulomas in toxoplasmic lymphadenitis
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

XI. Non- Hodgkin's Lymphomas

A. 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)
B. Approximately 40, 000 cases per year, 20,000 deaths
C. Composed of cells frozen at a single stage of normal lymphoid maturation/differentiation
D. Recapitulate the biologic behavior and immunophenotype of normal cell they mimic
E. Since there are several cytologically and immunologically recognizable stages of normal lymphoid maturation, there are several subtypes of lymphoma
F. All are clonal malignancies, derived from a single cell that has undergone a malignant transformation, mutation
G. Best initially conceptualized as two major clinical types
- 1. Indolent lymphomas
- 2. Aggressive lymphomas
H. Indolent lymphomas
- 1. Lymphomas frozen at stages which are not normally replicating, but may be circulating
- 2. Often widespread throughout the body at diagnosis
- 3. Prolonged natural history, median survivals greater than 5 years
- 4. Will usually respond very well to chemo- or radiation therapy
- 5. Will usually relapse, and currently incurable unless
  - a. Localized disease (see below) or
  - b. Marrow ablation with some type of stem cell transplant
- 6. Classification of indolent lymphomas- see below
I. Aggressive lymphomas
- 1. Lymphomas frozen at stages normally characterized by replication and accelerated growth
- 2. More often localized at presentation than indolent lymphomas; more often extranodal
- 3. Short natural history; median survival </= 2 years
- 4. Require more aggressive forms of chemotherapy to achieve "clinical remission"- disappearance of all detectable disease
- 5. Despite aggressive natural history, approximately 30-40% of adults curable with aggressive therapy, 50-80% children
J. Subtyping within these two common clusters is necessary, because they have distinct clinical presentations, can require different therapy, and have differing prognoses, reflecting different mechanisms of molecular pathogenesis.
K. 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
- 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
  - c. The observed clinical history of 1200 patients classified according to the terminology below

Table 1: Working Formulation for Clinical Usage

Miscellaneous
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, large cell, immunoblastic
ML, lymphoblastic
ML, small non-cleaved cell (Burkitt's vs non-Burkitt's)

Miscellaneous (mycosis fungoides, true histiocytic, etc.)

d. Divided into three "grades" of lymphoma-low, intermediate and high
- 1). Low grade = indolent
- 2). Intermediate and high = aggressive
e. Microscopic features of malignant lymphomas
- 1) Low power
  - a) Loss of normal architectural organization
  - b) Presence of absence of aberrant follicle formation
- 2) High power
  - a) Replacement of cellular heterogeneity by a dominant cell type

XI. Non- Hodgkin's lymphoma cont'd

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 being modified by the World Health Organization (WHO)
- a. Necessary because purely morphologic Working Formulation classification mixed T and B cell lymphomas together, obscuring the biologic, clinical and therapeutic differences between them, and distorting clinical trials
- b. REAL/WHO is a "disease" oriented classsification based on cell lineage and stage of maturation of the presumed normal counterpart. Each entity may have differing grades of aggressiveness
- c. Includes immunologic and molecular criteria in addition to purely morphologic criteria of the Working Formulation
- d. Greatly expanded the list of entities,and includes leukemias of lymphoid origin
- e. Made teaching to medical students (and in fact all physicians) even more difficult than previously
- f. Finally, REAL contained a number of "provisional entities" which have undergone further clarification in the upcoming World Health Organization revision.

Table 2: International Lymphoma Study Group Classification (including provisional WHO categories)

B-Cell Neoplasms	T/NK-Cell Lymphoma	Hodgkin's Lymphoma
Precursor B-cell lymphoblastic leukemia/lymphoma	Precursor T cell lymphoblastic leukemia/lymphoma	Lymphocyte predominance, nodular

Peripheral B-cell neoplasms	Peripheral T-cell and NK-cell neoplasms	Classical HL
B-cell CLL/SLL	Predominantly leukemic/disseminated	Lymphocyte rich classical HL
B-cell prolymphocytic leukemia	T-cell prolymphocytic leukemia	Nodular sclerosis
Lymphoplasmacytic lymphoma	T-cell large granular lymphocytic (LGL)	Mixed cellularity
Mantle cell lymphoma	leukemia	Lymphocyte depletion
Follicular lymphoma	NK cell leukemia	Unclassifiable classical HL
Extranodal marginal zone B-cell lymphoma, MALT type (+/- monocytoid B cells)	Adult T-cell leukemia/lymphoma
Splenic marginal zone B-cell lymphoma (+/-villous lymphocytes)	Predominantly nodal
Hairy cell leukemia	Angioimmunoblastic T-cell lymphoma
Diffuse large B-cell lymphoma	Peripheral T-cell lymphoma unspecified
Burkitt lymphoma	Anaplastic large cell lymphoma, T/null-cell
Plasma cell myeloma	Predominantly extranodal
Plasmacytoma	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
	gd (gamma/delta)
	ab (alpha/beta)

7. REAL/WHO classification- backbone
- a. B cell neoplasms
  - 1) Precursor B cells-related to acute leukemia
  - 2) Peripheral B cell lymphomas- the majority of B cell lymphomas
- b T cell and Natural Killer cell neoplasms
  - 1) Precursor T cells
  - 2) Peripheral T cell and NK neoplasms
- c Hodgkin's lymphoma
8. B cell neoplasms
- a. Precursor B cell lymphoblastic leukemia/lymphoma
  - 1) Frozen at lymphoblast cell stage of antigen independent B cell differentiation- normally restricted to bone marrow
  - 2) Usually present as acute leukemia+/- lymph node involvement
  - 3) Can initially present as node or skin disease, with later progression to bone marrow
- b. Peripheral B-cell neoplasms- frozen at various stages of antigen dependent B cell maturation and differentiation
  - 1) Small lymphocytic/CLL- the virgin B cell fresh from the marrow
  - 2) Prolymphocytic leukemia- a more clinically aggressive variant of above
  - 3) Lymphoplasmacytic lymphoma- the primary immune response
  - 4) Mantle cell lymphoma- the mantle region surrounding the follicle
  - 5) Follicular lymphoma- the follicle- grade 1-3
  - 6) 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
  - 7) Nodal marginal zone lymphoma
  - 8) Splenic marginal zone lymphoma- immunologically distinct
  - 9) Hairy cell leukemia- pre-plasma cell
  - 10) Diffuse large B-cell lymphoma- this breaks the ideal of specific cell stage, but all represent lymphomas with high replication rate
  - 11) Burkitt lymphoma- very aggressive
  - 12) Plasma cell myeloma- diffuse bone marrow proliferation of plasma cells
  - 13) Plasmacytoma- solitary focus of monoclonal plasma cells, with variable risk of progression to myeloma, depending on site
- c. Why list separately, if most indolent?
  - 1) Differ in clinical presentation, immunology, therapy, prognosis, molecular pathogenesis, even if all crudely categorized by median survival > two years
  - 2) Examples "indolent" peripheral B
    - (a). follicular lymphoma- most common type of indolent lymphoma in US, and second most common type lymphoma overall
      - (1.) Disease of adults >40 (median age 59)
      - (2.) Usually widely disseminated at diagnosis, with bone marrow involvement
      - (3.) Will respond to "gentle chemotherapy" but will relapse-cannot be cured short of bone marrow transplant, but overall 5 yr survival 72%
      - (4.) Benign equivalent is small cleaved cell of germinal center
      - (5.) Cytology: clumped chromatin and infrequent nucleolus like small lymphocyte, but irregular nuclear profile, with nuclear folds or "cleavages"
      - (6.) Retain follicular structure, but monotonous accumulation of single cell type
      - (7.) Over time, additional mutations can occur, producing progression ("transformation") to large cell lymphoma and more aggressive clinical course
      - (8.) Pathogenesis: due to t(14;18), which upregulates expression of an anti-apoptotic protein Bcl2
      - (9.) Has characteristic immunophenotype: monoclonal light chain, CD19, CD10, Bcl2 positive, CD5, Bcl1/Cyclin D1 negative
    - (b). Mantle cell lymphoma- 6% lymphomas
      - (1.) Disease of adults (median age 63)
      - (2.) Usually widely disseminated
      - (3.) Poor response to all attempted therapies, ? curable with transplant-overall 5yr survival 27%
      - (4.) Benign equivalent is lymphocyte of inner mantle zone
      - (5.) Cytology similar to cleaved cell, but nuclear irregularities not as prominent
      - (6.) Nodal infiltration diffuse, or expansion of mantle zone around residual benign follicles
      - (7.) Large cell progression not frequent
      - (8.) Pathogenesis due to t(11;14), which upregulates, Bcl1, a cell cycle effector
      - (9.) Immunophenotype: monoclonal light chain, CD19, CD5, Bcl1 (and Bcl2) positive, CD10 negative

Table X: Indolent B cell lymphomas

	Follicular Lymphoma (Grade I)	Mantle cell Lymphoma	Marginal zone Lymphoma	Small lymphocytic lymphoma/CLL
Frequency (% all lymphomas)	22%	6	8	7
Age of onset-median	59	63	61	65
Stage at Presentation	Stage III/IV (Disseminated)	Stage III/IV	Stage I	Stage IV
Response to Therapy	Good to most treatments, but incurable short of transplant	Poor response to all therapies to date	Frequently curable	Similar to Follicular lymphoma
5 yr survival	72%	27	74	51
Predominant site presentation	Nodal	Nodal	Extranodal	Marrow/nodal
Pattern of nodal Infiltration	Follicular	Diffuse or "mantle zone"	Diffuse	Diffuse
Benign cell Equivalent	Germinal center small cleaved cell	Mantle cell	Marginal zone Lymphocyte	Virgin B cell
Dominant cell type	Small cleaved cell in most cases, but can be large cell	Small cell with irregular nucleus, similar to cleaved	Mix of small lymphocytes, plasma cells	Small lymphocytes with round nucleus
Immuno phenotype	Positive: CD19 CD10, Bcl2+ Negative: CD5-	Positive:CD19 CD5, Bcl2 Negative: CD10	Positive: CD19 Bcl2 Negative: CD10, CD5	Positive: CD19 CD5,CD23 Negative: CD10
Molecular Pathogenesis	t(14;18) Bcl2/JH	t(11;14) Bcl1/JH	Trisomy 3	Trisomy 12

3) Examples aggressive B cell lymphoma
- (a.) diffuse large B cell lymphoma-30% NHL
  - (1.) Disease of adults and children- median age 64
  - (2.) Limited versus widespread disease 1:1
  - (3.) Approximately 40% curable with aggressive chemotherapy/ stem cell
  - transplant- partially predictable by International Prognostic Index
  - (4.) Benign equivalent- large replicating cells of germinal center and paracortex
  - (5.) Cytology: Oval or cleaved nucleus with vesicular chromatin and 1-3 nucleoli.
  - Nucleus larger than that of reactive macrophage, often necrosis; increased mitotic rate
  - (6.) Diffuse infiltration of lymph node
  - (7.) Several cytologic subtypes initially felt to have differing clinical behavior. Yielded division into intermediate versus high grade types- now not felt valid or significant.
  - (8.) Pathogenesis not as clearly defined- several cytogenetic abnormalities associated with large cell lymphoma, but no defining one
  - (9.) Immunophenotype characterized by monoclonal light chain, CD19 expression, with variable expression of other B cell associated antigens
- (b) Burkitt's lymphoma- 3% lymphomas
  - (1) Disease of adults and children- median age 31
  - (2) Initially recognized in Africa by Thomas Burkitt- noted association with Epstein Barr
  - virus infection and localization in jaw
  - (3) In US, usually presents in ileocecal region of children- 1/3 of all childhood lymphomas
  - (4) Approximately 40% of adults curable with very aggressive therapy; 70-80% children
  - (5) 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
  - (6) Diffuse infiltration of lymph node
  - (7) Very high mitotic rate, lot of ineffective proliferation; attracts macrophages to phagocytize and produces a "starry sky" pattern at low power
  - (8) Pathogenesis: t(8;14), producing upregulation of myc oncogene, a cell cytcle regulation gene
  - (9) Immunophenotype: Monoclonal light chain, CD19, CD10 positive, CD5 negative

9. T cell lymphomas
- a. Precursor T cell lymphoblastic lymphoma/leukemia
  - 1) Disease of young teenagers; boys>girls
  - 2) Can present as acute leukemia or mediastinal mass+/- marrow involvement
  - 3) Aggressive lymphoma/leukemia, but curable ~70% with appropriate multiagent chemotherapy
  - 4) Benign equivalent immature T cells of thymus
  - 5) Cytologic features: "Blast cells" of intermediate size with oval to "convoluted" nuclear profiles, fine chromatin and 0-1 nucleolus
  - (a) Histology: Diffuse infiltration of thymus/adjacent lymph nodes
  - (b) Pathogenesis unclear, but frequently involves translocation of oncogenes to site of T cell receptor genes, and upregulation of protein production
- b. Peripheral T cell lymphomas
  - 1) Predominantly leukemic/disseminated
    - a) T-cell prolymphocytic leukemia
    - b) T-cell large granular lymphocytic (LGL) leukemia
    - c) NK cell leukemia
    - d) Adult T-cell leukemia/lymphoma
  - 2) Predominantly nodal
    - a) Angioimmunoblastic T-cell lymphoma
    - b) Peripheral T-cell lymphoma unspccified
    - c) Anaplastic large cell lymphoma, T/null-cell
  - 3) Predominantly extranodal
    - a) Mycosis fungoides
    - b) Sezary syndrome
    - c) Primary cutaneous CD30+ T-cell lymphoproliferative disorders
    - d) Subcutaneous panniculitis-like T-cell lymphoma
    - e) NK/T cell lymphoma, nasal and nasal-type
    - f) Enteropathy-type intestinal T-cell lymphoma
    - g) Hepatosplenic T-cell lymphoma
- c. Key points regarding T cell lymphomas
  - 1) Represent 20% all lymphomas
  - 2) Tend to involve extranodal sites like skin, midline facial area, liver more than B cell,
  - with very characteristic clinical presentations
  - 3) Cytologic features not as predictive of behavior as B cell lymphomas
    - (a) One of most aggressive looking, anaplastic large cell lymphoma,actually has better prognosis than most indolent B cell lymphomas-77% 5 year survival
  - 4) Most common type in skin, mycosis fungoides, is an indolent lymphoma, similarly incurable, but with long clinical course
  - 5) Most nodal disease is bad, high stage, and poorer response to therapy than B cell lymphomas of all grades
  - 6) Immunophenotypic studies frequently demonstrate
    - (a) Loss of normal T cell associated antigens
    - (b) Antigens associated with Natural Killer cell function
  - 7) Pathogenesis: Characteristic cytogenetic findings associated with several types
    - (a) Anaplastic large cell lymphoma- t(2;5): ALK1 gene
    - (b) Hepatosplenic T cell lymphoma- Isochromosome 7

XII. Ancillary diagnostic studies

A. 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:
  - a. 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
    - 1.) B cells
      - a.) immunoglobulin receptor composed of two heavy and two light chains
      - b.) Selection of only one of two light chains, kappa or lambda
    - 2.) T cells
      - a.) Alpha/Beta heterodimer T cell receptor
      - b.) Gamma/Delta heterodimer T cell receptor
  - b. The expression of several surface proteins necessary for antigen recognition, cell activation, cell-cell communication.
    - 1.) Classified into B, T, activation associated, cytokine receptor thru the CD, clusters of differentiation, numerical system. Now up to CD166. (You'll only be tested on 1-130 though - a joke for you paranoid types.)
- 4. Expression, normal and aberrant can be used to:
  - a. Determine lineage, B versus T
  - b. Detect clonality- light chain disproportion (normal ratio kappa/lambda light chain expression in B cells= 2/1)
  - c. Suspect malignancy- loss of expression, aberrant expression
  - d. Recognize characteristic patterns associated with certain subtypes of lymphoma
- 5. 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
- 6. Examples
  - a. B cell small lymphocytic lymphoma- monoclonal light chain, CD19, CD20, CD5 positive, CD10 negative
  - b. B cell small cleaved lymphoma- monoclonal light chain, CD19, CD20, CD10 positive, CD5 negative
B. Molecular techniques
- 1. Detection of antigen receptor clonality
- 2. Detection of unique cytogenetic rearrangements
- 3. 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

XIII. Clinical features- non-Hodgkin's lymphoma

A. 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
B. 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

Ann Arbor Staging System

Stage	Distribution of Disease
I	Involvement of a single lymph node region (I) or involvement of a single extralymphatic organ or site (IE)
II	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)
III	Involvement of lymph node regions on both sides of the diaphragm (III), which may include the spleen (IIIs) and/or limited contiguous
IV	Multiple or disseminated foci of involvement of one or more extralymphatic organs or tissues with or without lymphatic involvement.

C. Therapy
- 1. Seminar cases will also discuss
- 2. Indolent lymphomas, limited stage (5-10% cases) treated with radiation therapy- can be curative
- 3. Indolent lymphomas, disseminated (90%) treated by
  - a. Low morbidity limited chemotherapy
    - 1) No expectation of cure
    - 2) Older patients
    - 3) Most will respond totally or partially, with months to years of disease free survival, but will relapse
    - 4) Many will respond to additional rounds of similar or alternative regimens
    - 5) Pts will eventually die of their disease, or another disease of elderly
    - 6) Death from disease due to
      - a.) Immune suppression- infections
      - b.) Progression to aggressive lymphoma
  - b. Bone marrow transplant (allo/auto/peripheral stem cell)
    - 1) Effort at cure-
    - 2) Younger patients
- 4. Aggressive lymphomas treated with multiagent (>/= 4 drugs) chemotherapy
  - a. Complete remission rates 60-80%
  - b.30-40% cured
  - c. Therapy determined by prognostic index- see below
- 5. Newer therapies and their roles still being established
  - a. Autologous bone marrow transplantation/high dose chemotherapy with peripheral stem cell harvest
  - b. Immunotherapy
D. Prognosis
- 1. Primarily based on inherent biology of tumor and stage
- 2. Are however additional factors that can be used for prognosis
  - a. International prognostic index- word recognition
    - 1). Five clinical and laboratory features proven by regression analysis to best stratify patients with large cell lymphoma into four risk groups with statistically different survival rates
    - 2). Used to decide on aggressiveness of therapy
    - 3). Used in evaluation of new therapies
    - 4). Although developed for large cell lymphoma, also has utility in stratifying indolent lymphomas
  - b. Cytogenetics/Oncogenes- know they exist
    - 1) Are cytogenetic/molecular abnormalities that predict more aggressive clinical course
    - 2) Others can predict acceleration/transformation from low to higher grade lymphoma
    - 3) Not routinely used beyond tertiary care centers; practicality/cost effectiveness still being established

XIV. Hodgkin's Lymphoma

A. Less common than NHL; approximately 10,000 cases per year
B. Incidence with respect to age bimodal, with one peak in late adolescence, young adulthood, second peak in sixth decade
- 1. This bimodal curve shifts to younger ages in undeveloped countries
C. Unlike nonHodgkin's lymphomas, diagnosed by the presence of a minor cellular component, the Reed Sternberg cell, found in the appropriate microscopic cellular background
D. Classification of Hodgkin's lymphoma has also been recently revised

Rye Classification	REAL/WHO Classification
Lymphocyte predominant-5%	Lymphocyte predominant, nodular
Nodular sclerosis-70%	Classical HL
Mixed cellularity-20%	Lymphocyte rich classical HL
Lymphocyte depleted-5%	Nodular sclerosis
	Mixed cellularity
	Lymphocyte depletion
	Unclassifiable classical HL

E. Classification:
F. Are characteristic patterns of involvement, and characteristic variants of Reed Sternberg cell associated with different subtypes
- 1. Lymphocyte predominant
  - a. Usually presents with limited disease in the neck of young adults
  - b. Associated with L and H (lymphocytic and histiocytic) cell (popcorn cell) variant RS RS cell
- 2. Nodular sclerosis
  - a. Usually presents in the anterior mediastinum and neck of young adult females
  - b. Associated with lacunar variant Reed Sternberg cell
- 3 Lymphocyte depleted
  - a Often presents in retroperitoneum
  - b Accompanied by sclerosis and pleomorphic RS cell variants
G. As in NHL, there are ancillary immunologic studies that can assist the dx of Hodgkins' lymphoma, and distinguish from immunoblast reaction or unusual variants of NHL
- 1. Expression of CD15 and CD30 antigens in golgi and on cell membrane by immunohistochemistry.
H. Hodgkin's lymphoma spreads contiguously via lymphatics
I. Staging as in NHL- may or may not include laparotomy/splenectomy
J. Therapy
- 1. Hodgkins lymphoma is a curable malignancy
- 2. Overall cure rate approximately 80%
- 3. 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- see C5 above.
- 4. Limited stage, low bulk disease treated with radiation therapy
- 5. Higher stage, symptomatic (IIB-IV) treated with multi-agent chemotherapy+/- radiation therapy
K. Complications of therapy
- 1. Radiation/chemotherapy effects to lungs, heart, bone marrow
- 2. Sterility
- 3. Splenectomy associated sepsis
- 4. Therapy associated second malignancies
L. Pathobiology
- 1. The etiology of Hodgkins lymphoma is still unknown, and until very recently, the lineage of the R-S cell was also obscure
- 2. The mixed cellular infiltrate, unusual large cells, clustered familial cases, and early evidence of immune dysfunction suggest an infectious etiology
  - a Approximately 30% of cases/Reed Sternberg cells contain Epstein Barr virus within the RS cells
- 3. Recent molecular studies, utilizing single cell dissection and PCR based sequencing of the antigen receptor genes indicate that the Reed-Sternberg cell in the majority of cases is in fact an altered B cell.
- 4. Therefore Hodgkin's lymphoma is a type of B cell lymphoma, but one with a very different biology than the other types of B cell lymphoma, and hence still deserves a separate category in the classification system.
- 5. The molecular abnormalities within the different types of R-S variants effect the expression of lineage associated antigens
  - a. L and H cells of lymphocyte predominant Hodgkin's disease express B cell antigens, and are clonal proliferations of this cell type
  - b. Reed Sternberg cells of other types may express T cell, B cell and macrophage associated antigens, but at the molecular level, show B cell gene rearrangements, often with out of frame mutations.

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Lymph nodes- not lymphoma

http://www.pathologyoutlines.com/lymphnodes.html

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Lymphedema People Cancer related pages:

Cervical cancer, breast, ovarian cancer

Secondary Lymphedema in the cancer patient

Kidney and Renal Cancer

Hodgkins Disease or Hodgkins Lymphoma

Gynecological cancer

Leg Lymphedema Gynecological Cancer

Kaposi's Sarcoma

Skin Cancer

Testicular Cancer

Primary Lymphedema and Cancer

Cutaneous T-cell Lymphoma

Cutaneous B-cell Lymphoma

Lymphedema Affect Quality of Life

Angiosarcoma and Long Term Lymphedema

Lymphedema After Cancer - How Serious Is It?

Secondary Lymphedema in the Cancer Patient

Complications of Breast Cancer Radiotherapy

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Join us as we work for lymphedema patients everywhere:

Advocates for Lymphedema

Dedicated to be an advocacy group for lymphedema patients. Working towards education, legal reform, changing insurance practices, promoting research, reaching for a cure.

http://health.groups.yahoo.com/group/AdvocatesforLymphedema/

Subscribe:

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Pat O'Connor

Lymphedema People / Advocates for Lymphedema

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For information about Lymphedema

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For Information about Lymphedema Complications

http://www.lymphedemapeople.com/wiki/doku.php?id=complications_of_lymphedema

For Lymphedema Personal Stories

http://www.lymphedemapeople.com/phpBB2/viewforum.php?f=3

For information about How to Treat a Lymphedema Wound

http://www.lymphedemapeople.com/wiki/doku.php?id=how_to_treat_a_lymphedema_wound

For information about Lymphedema Treatment

http://www.lymphedemapeople.com/wiki/doku.php?id=treatment

For information about Exercises for Lymphedema

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For information on Infections Associated with Lymphedema

http://www.lymphedemapeople.com/wiki/doku.php?id=infections_associated_with_lymphedema

For information on Lymphedema in Children

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_in_children

Lymphedema Glossary

http://www.lymphedemapeople.com/wiki/doku.php?id=glossary:listing

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Lymphedema People - Support Groups

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Children with Lymphedema

The time has come for families, parents, caregivers to have a support group of their own. Support group for parents, families and caregivers of chilren with lymphedema. Sharing information on coping, diagnosis, treatment and prognosis. Sponsored by Lymphedema People.

http://health.groups.yahoo.com/group/childrenwithlymphedema/

Subscribe: childrenwithlymphedema-subscribe@yahoogroups.com

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Lipedema Lipodema Lipoedema

No matter how you spell it, this is another very little understood and totally frustrating conditions out there. This will be a support group for those suffering with lipedema/lipodema. A place for information, sharing experiences, exploring treatment options and coping.

Come join, be a part of the family!

http://health.groups.yahoo.com/group/lipedema_lipodema_lipoedema/?yguid=209645515

Subscribe: lipedema_lipodema_lipoedema-subscribe@yahoogroups.com

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MEN WITH LYMPHEDEMA

If you are a man with lymphedema; a man with a loved one with lymphedema who you are trying to help and understand come join us and discover what it is to be the master instead of the sufferer of lymphedema.

http://health.groups.yahoo.com/group/menwithlymphedema/

Subscribe: menwithlymphedema-subscribe@yahoogroups.com

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All About Lymphangiectasia

Support group for parents, patients, children who suffer from all forms of lymphangiectasia. This condition is caused by dilation of the lymphatics. It can affect the intestinal tract, lungs and other critical body areas.

http://health.groups.yahoo.com/group/allaboutlymphangiectasia/

Subscribe: allaboutlymphangiectasia-subscribe@yahoogroups.com

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Lymphatic Disorders Support Group @ Yahoo Groups

While we have a number of support groups for lymphedema... there is nothing out there for other lymphatic disorders. Because we have one of the most comprehensive information sites on all lymphatic disorders, I thought perhaps, it is time that one be offered.

DISCRIPTION

Information and support for rare and unusual disorders affecting the lymph system. Includes lymphangiomas, lymphatic malformations, telangiectasia, hennekam's syndrome, distichiasis, Figueroa
syndrome, ptosis syndrome, plus many more. Extensive database of information available through sister site Lymphedema People.

http://health.groups.yahoo.com/group/lymphaticdisorders/

Subscribe: lymphaticdisorders-subscribe@yahoogroups.com

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Lymphedema People New Wiki Pages

Have you seen our new “Wiki” pages yet? Listed below are just a sample of the more than 140 pages now listed in our Wiki section. We are also working on hundred more. Come and take a stroll!

Lymphedema Glossary

http://www.lymphedemapeople.com/wiki/doku.php?id=glossary:listing

Lymphedema

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema

Arm Lymphedema

http://www.lymphedemapeople.com/wiki/doku.php?id=arm_lymphedema

Leg Lymphedema

http://www.lymphedemapeople.com/wiki/doku.php?id=leg_lymphedema

Acute Lymphedema

http://www.lymphedemapeople.com/wiki/doku.php?id=acute_lymphedema

The Lymphedema Diet

http://www.lymphedemapeople.com/wiki/doku.php?id=the_lymphedema_diet