Pathology of lymph nodes
Dr. Norman Levy

November 25, 1996

I. Goals

• A. Review the histology and cytology of the normal lymph node
• B. Review normal lymphopoiesis
• C. Present the major pathologic processes occurring within the lymph nodes
  • 1. Reactive hyperplasias
  • 2. Malignant lymphoma (non-Hodgkin's Lymphoma - NHL)
  • 3. Hodgkin's disease
• D. Relate lymphoid malignancies to their benign counterparts

II. Objectives

• A. The student should know the anatomic regions of the normal lymph node, and the cytologic populations that occupy them
• B. The student should know the relationship between lymph node structure and the immunologic functions of the lymphoid immune system that occur within them
  • 1. The sites of B and T cell homing
  • 2. The sites of B and T cell expansion in response to antigenic stimulation
• C. The student should know the basic features of normal lymphopoiesis
  • 1. The locations and immunologic changes of antigen independent maturation, B and T cell
  • 2. The locations, morphologic changes, associated with antigen stimulated B and T cell maturation and differentiation
• D. The student should be able to relate the cytologic features of lymphoid cells to their physiologic state: resting, activated, cycling.
• E. The student should know the major patterns of lymph node reaction
• F. The student should know the current classification and major histologic subtypes of the non- Hodgkin's lymphomas and Hodgkin's disease.
• G. The student should be able to relate the major subtypes of non Hodgkin's lymphomas to their benign counterparts, and understand the biologic and therapeutic significance of these relationships.
• H. The student should know what types of ancillary diagnostic studies are used in the diagnosis and prognosis of these diseases: immunologic, cytogenetic, molecular.
  • 1. Flow cytmetry
  • 2. Immunohistochemistry
  • 3. Gene rearrangement studies
  • 4. (The student is expected to know that these techniques exist, and how they are generally used, but is not expected to memorize the antigens/antibodies/molecular probes used in their performance)
• I. The student should know the common and unique clinical presentations of lymphoid malignancies.
• J. The student should know the major staging system for lymphoid malignancies.
• K. The student should know the basic treatment strategies for lymphoid malignancies.

  III. Format

  • A. 8-10:00 Lecture/Computer demonstration

  IV. Reading:

  • A. Robbins Pathologic Basis of Disease, 5th edition Chapter 14: 629-648

V. Computer assisted learning

• A. This lecture and the microscopic images will be available for review through a World Wide Web browser such as Netscape Navigator or Microsoft Explorer, available through the Dartmouth College Public server. There are several ways the lecture can be accessed.
  • 1. Through the Medical library Macintosh workstations used for review of other computer assisted programs.
    • a. Open Netscape
    • b. Go to Bookmarks
    • c. Select "Levy lecture/Pathology of Lymph Nodes"
  • 2. Through any Macintosh (or PC) with a color monitor, 8 megs of RAM, a WWW browser, and access to the Internet via the Dartmouth college network or any other WWW access
  • 3. The program can be viewed on the network at: HTTP://www.dartmouth.edu/~nlevy/levylecture.html
  • 4. (Or you can take the more homorous route and get there by my personal homepage at URL://HTTP://www.dartmouth.edu/~nlevy
    • a. Go to Pathology resources
    • b. Double click on Pathology of lymph nodes lecture
  • 5. It can also be viewed through Netscape on your own computer by
    • a. Downloading the lecture from the Dartmouth College ftplocal server using Fetch (or your WWW browser, but Fetch does some automatic cleanup)
      • 1). Host: ftplocal.dartmouth.edu
      • 2). User: Anonymous
      • 3). Password: Leave blank
      • 4). Directory: /levy
      • 5). Tell Fetch to: Get file. It will download compressed file to wherever you tell it. Approximate size 4 Mb. compressed.
    • b. Double click file after download to initiate self extraction of compressed files
    • c. Start Netscape, use FILE menu to access "Open file.." and then select LEVYLECTURE.HTML from your computer.
• B. The lecture is based on WWW hypertext markup language. All underlined words are linked to other text, graphics, or photomicrographs. All small images surrounded by a border are also linked, either to larger versions of the same image, or to related information
• C. Enjoy, or curse- feedback appreciated via E-mail.

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. ITS 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 infonnation in a later clinical seminar.

• A. As with other organs, Iymph 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 on nontender, +/-
  • 2. Compression, obstruction or infiltration of adjacent structures +/-
  • 3. "Systemic" symptoms of fever, and weight loss
• C. Infectious organisms can stimulate the same acute, chronic or granulomatous reactions in the draining Iymph nodes as they characteristically stimulate at other sites
• D. Several types of immune stimuli can cause "reactive" enlargement of the entire Iymph node, or selective expansion of cortical, paracortical or medullary regions
• E. Metastatic tumors spread to the Iymph nodes primarily via Iymphatic 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 (NHL), and Hodgkin's disease (HD)
• H. Malignant lymphomas are more common, and can be simply divided into indolent, or slow growing types, and aggressive types
• I. Malignant Iymphomas represent clonal malignancies in which the majority of cells are frozen at a single stage of normal Iymphocyte differentiation
• J. Lymphomas frozen at a stage associated with high replication rates yield aggressive Iymphomas; Iymphomas frozen at stages associated with recirculation or final function yield indolent Iymphomas
• K. The diagnosis of malignant Iymphomas is based on the dominant cytologic cell type, supplemented by immunologic and molecular techniques
• L. The prognosis and treatment of lymphomas is based on the dominant cell type (and it's inherent biologic behavior), the extent of spread (Stage) and the underlying health of the patient
• M. The above are complicated by the fact that indolent Iymphomas can further mutate to aggressive types
• N. Hodgkin's disease 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 four histologic subtypes, but prognosis is based primarily on extent and location of disease
• P. Hodgkin's disease is a more curable disease than malignant (non-Hodgkin's) Iymphomas
• 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 Immune 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-

• 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 and antigenic material 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 primary follicles, composed of small B lymphocytes which may be virgin B lymphocytes or recirculating memory B cells. There is also a fine meshwork of 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 peripheral blood and home to specific sites within the lymph node (and the other 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

• 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 cells reactive 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 or plasma cell precursors
    • 1). Small cleaved cells have clumped chromatin like small lymphocytes, but irregular folded and cleaved nuclear profiles. Large cell variant may have nucleolus
    • 2). Nonproliferating population
• 3. Immunoblasts- Proliferating large cells found outside the germinal centers. May be of B or T cell type. Again have characteristics or replicating lymphocytes- vesicular chromatin, nucleoli
• 4. Accessory cells
  • a. Antigen processing cells-process and present antigen to B and T lymphocytes- invisible in normal lymph node
    • 1). T cell paracortex- interdigitating reticulum cells
    • 2). B cell germinal centers- dendritic reticulum 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. 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 the medullary sinus histiocytes-
    • a. Adjacent cancer
    • b. Infections
• B. Malignant lymphomas (Non-Hodgkins' lymphomas-NHLs)
  • 1. Malignancies of the lymphoid system in which the primary manifestations of disease occur outside the bone marrow, at the sites of normal lymphoid homing
    • a. Lymph nodes
    • b. Spleen
    • c. MALT
    • d. Anywhere
    • e. (Lymphomas outside lymph nodes and spleen are referred to as extranodal lymphomas)
  • 2. Approximately 40, 000 cases per year, 20,000 deaths
  • 3. Composed of cells frozen at a single stage of normal lymphoid maturation/differentiation
  • 4. Recapitulate the biologic behavior and immunophenotype of normal cell they mimic
  • 5. Since there are several cytologically recognizable stages of normal lymphoid maturation, there are several cytologic types of lymphomas
  • 6. Clonal malignancies, all derived from a single cell that has undergone a malignant transformation, mutation
  • 7. Best conceptualized as two major clinical types
    • a. Indolent lymphomas
    • b. Aggressive lymphomas
  • 8. Indolent lymphomas
    • a. Lymphomas frozen at stages which are not normally replicating, but may be circulating
    • b. Often widespread throughout the body at diagnosis
    • c. Prolonged natural history, median survivals greater than 3 years
    • d. Will usually respond very well to chemo- or radiation therapy, yielding complete or partial clinical remission- gross, radiologic (and pathologic) evidence of disease disappearance
    • e. Will usually relapse, and currently incurable unless
      • 1. Localized disease (see below) or
      • 2. Bone marrow transplant
    • f. Classification of indolent lymphomas- see below
  • 9. Aggressive lymphomas
    • a. Lymphomas frozen at stages normally characterized by replication and accelerated growth
    • b. More often localized at presentation than indolent lymphomas; more often extranodal
    • c. Short natural history; median survival 2 years or less
    • d. Require more aggressive forms of chemotherapy to achieve clinical remission
    • e. Despite aggressive natural history, approximately 30-40% curable with aggressive therapy
  • 10. Individual cell types within these common clusters do have characteristic clinical presentations and behavior
  • 11. Classification of lymphomas
    • a. Rarely unanimous acceptance of any one classification scheme.
    • b. Often changing terminology, reflecting classifier bias and new information
    • c. Often lags behind advances in immunology, research pathology
    • d. Current classification called Working Formulation for Clinical Usage, initially published in 1982
    • e. Based on
      • 1). The dominant cytologic cell type observed under the microscope
      • 2). Presence or absence of "follicularity" - mimicing of normal lymphoid follicle formation
      • 3). The observed clinical history of 1200 patients classified according to the terminology below
      
      
      Table 1: International Working Formulation for Clinical Usage
      • Low grade:
        • ML, small lymphocytic
        • ML, follicular small cleaved cell
        • ML, follicular, mixed small cleaved 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, diffuse, large cell, immunoblastic
        • ML, lymphoblastic
        • ML, small non-cleaved cell (Burkitt's vs non-Burkitt's)
      • Miscellaneous (mycosis fungoides, true histiocytic, etc.)
      
      
    • f. Divided into three "grades" of lymphoma-low, intermediate and high.
      • 1). Low grade (+) = indolent
      • 2). Intermediate and high = aggressive
    • g. 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). Loss of cellular heterogeneity
        • b). Monotonous domination by a single cell type
    • h. Low grade lymphoma cell types
      • 1). Small lymphocytic- 5% NHL
        • a). Benign equivalent is the small lymphocyte of primary follicle, mantle zone, interfollicular area
        • b). Round nucleus, clumped chromatin, scant cytoplasm
        • c). Diffuse histology
        • d). Low mitotic rate
        • e). May produce pseudofollicles (oh oh)
        • f). Disease of older adults>50
        • g). Closely related to chronic lymphocytic leukemia- extent of peripheral blood versus nodal disease determines how classified
        • h). Usually of B cell lineage
        • i). Occasionally associated with paraprotein secretion-plasmacytoid variant
        • j). May autoimmune and immune deficiency complications
      • 2). Small cleaved follicular-30% NHL
        • a). Benign equivalent is small cleaved cell of germinal center
        • b). Cytologic features: clumped chromatin and infrequent nucleolus like small lymphocyte, but irregular nuclear profile, with nuclear folds
        • c). Retain follicular structure, but monotonous accumulation of single cell type
        • d). Again disease of older adults
      • 3). Follicular mixed, small cleaved and large cell
        • a). Mixture of two cell types
        • b). Loss of normal architecture
      • 4). New entity- not in Working Formulation- know indolent, that's all
        • a). Low grade lymphoma of M.A.L.T.
    • i. Intermediate grade lymphomas
      • 1). Large cell lymphoma- 30% NHL
        • a). Benign equivalent- large replicating cells of germinal center- B cell , paracortex- T cell/B cell
        • b). Oval or cleaved nucleus with vesicular chromatin and 1-3 nucleoli
        • c). Nucleus larger than that of reactive macrophage
        • d). Increased mitotic rate
        • e). Often necrosis
        • f). Can be follicular of diffuse
        • g). Can be seen in children as well as adults
        • h). Several cytologic subtypes initially felt to have differing clinical behavior. Yielded division into intermediate versus high grade types- now not felt valid or significant.
      • 2). Small cleaved diffuse/mantle cell lymphoma
    • j. High grade lymphomas
      • 1). Small noncleaved (Burkitt's or nonBurkitts)
        • a). Benign equivalent is replicating small noncleaved cell of germinal center
        • b). Initially recognized in Africa by Thomas Burkitt- noted association with Epstein Barr virus infection and localization in jaw
        • c). In US, usually presents in ileocecal region of children- 1/3 of all childhood lymphomas
        • d). Round to oval nucleus, smaller than that of reactive macrophages
        • e). Vesicular chromatin and 2-5 nucleoli
        • f). Very high mitotic rate, lot of ineffective proliferation
        • g). Attracts macrophages to phagocytize> "starry sky" pattern at low power
      • 2). Lymphoblastic
        • a). Unlike others above, benign equivalent is immature replicating lymphoid precursor, normally found in thymus or bone marrow, not in lymph nodes
        • b). Most often found in thymus of adolescent males as anterior mediastinal mass
        • c). Cytologic features: small to intermediate sized cells with fine chromatin and 0-1 nucleolus. Nuclear chromatin not as open as small, noncleaved cell nor as clumped as small cleaved.
        • d). High mitotic rate and starry sky pattern
        • e). Often has bone marrow involvement at diagnosis
  • 12. R.E.A.L. (Revised European American Classification of Lymphomas) Harris, N.L., et al, Blood, 1994, 84:1361-1382
    • a. Newly proposed; future unclear
    • b. Reflects newer insights into lymphocyte biology and pathology, and the use of immunologic tools in diagnosis
    • c. Listed as exposure to what might be the future- will NOT be tested
  • 13. 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). The B cell antigen receptor is the 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 CD130.
      • 4). Expression, normal and aberrant, can be used to:
        • a). Determine lineage, B versus T
        • b). Detect clonality- light chain disproportion
        • 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, CD5 negative, CD10 positive
    • b. Molecular techniques
      • 1). Detection of antigen receptor clonality
      • 2). Detection of unique cytogenetic rearrangements
        • a). Are characteristic translocations associated with different histologic types of lymphomas, and different prognostic groups
        • b). Examples:
          • (1). 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
          • (2). T(8;14) and Burkitt's lymphoma- involves Ig heavy chain gene and myc oncogene, chr.8, which normally controls entry into cell cycle
  • 14. Clinical presentation
    • a. Enlarging mass(es), typically painless, at sites of nodal/lymphoid tissue
    • b. Obstruction, ulceration of hollow organs- MALT- pain
    • c. Interference with normal organ function- solid organ infiltration- kidneys, liver, bone marrow
  • 15. Clinical staging of lymphomas
    • a. Defines extent of disease; determines therapy and prognosis
    • b. Based on physical, radiologic examination, bone marrow biopsy and aspiration
    • c. Ann Arbor Staging system
  
  • d. B symptoms- fever, weight loss> 10% body weight
  • 16. Therapy
    • a. Seminar cases will also discuss
    • b. Limited stage, low grade lymphomas (5-10% cases) treated with radiation therapy- can be curative
    • c. Disseminated low grade lymphomas (90%) treated by
      • 1). No therapy
      • 2). Low morbidity limited chemotherapy
        • a). No expectation of cure
        • b). Older patients
        • c). Most will respond totally or partially, with months to years of disease free survival, but will relapse
        • d). Many will respond to additional rounds of similar or alternative regimens
        • e). Pts will eventually die of their disease, or another disease of elderly
        • f). Death from disease due to
          • (1). Immune suppression- infections
          • (2). Progression to aggressive lymphoma
      • 3). Bone marrow transplant- effort at cure- younger patients
    • d. Aggressive lymphomas treated with multiagent (>/= 5 drugs) chemotherapy
      • 1). Complete remission rates 60-80%
      • 2). 30-40% cured
    • e. Newer therapies and their roles still being established
      • 1). Autologous bone marrow transplantation
      • 2). Immunotherapy
  • 17. Prognosis
    • a. Aggressive lymphomas
      • 1). International prognostic index- word recognition
        • a). 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
        • b). Used to decide on aggressiveness of therapy
        • c). Used in evaluation of new therapies
    • b. Cytogenetics- know it exists
    • c. Oncogenes- know they exist
  
  
• C. Hodgkins' Disease
  • 1. Less common than NHL; approximately 10,000 cases per year
  • 2. Incidence with respect to age bimodal, with one peak in late adolescence, young adulthood, second peak in sixth decade
    • a. This bimodal curve shifts to younger ages in undeveloped countries
  • 3. Unlike nonHodgkin's lymphomas, diagnosed by the presence of a minor cellular component, the Reed Sternberg cell, found in the appropriate microscopic cellular background
  • 4. Classification of Hodgkin's disease-Rye Classification
    • a. Lymphocyte predominant 5%
    • b. Nodular sclerosis-70%
    • c. Mixed cellularity-20%
    • d. Lymphocyte depleted-5%
  
  • 6. Are characteristic patterns of involvement, and characteristic variants of Reed Sternberg cell associated with different subtypes
    • a. Lymphocyte predominant
      • 1). Usually presents with limited disease in the neck of young adults
      • 2.) May be nodular or diffuse histology
      • 3.) Lymphocyte is predominant cell- classic R-S cells infrequent
      • 4). Associated with L and H (lymphoctytic and histiocytic) cell (popcorn cell) variant RS cell
    • b. Nodular sclerosis
      • 1.) Most common type of HD in industrialized countries
      • 2). Usually presents in the anterior mediastinum and neck of young adult females
      • 3.) Lymph node or thymus divided into variably sized nodules by collagenous bands ("sclerosis") extending from a thickened capsule
      • 4.) Nodules composed of mix of lymphocytes, eosinophils, histiocytes, classic R-S cells and
      • 5). Lacunar variant Reed Sternberg cell
    • c. Mixed cellularity
      • 1.) Contains a mixture of lymphocytes, eosinophils, histiocytes, and larger numbers of R-S cells
      • 2.) Increased numbers of mononuclear variant R-S cells
    • d. Lymphocyte depleted (LD)
      • 1). Uncommon type HD; now know many cases previously diagnosed as LD HD were in fact nonHodgkin's lymphomas
      • 2.) Can present in retroperitoneum, without peripheral nodal disease
      • 3). Tissues contain precollagenous sclerosis, and pleomorphic RS cell variants
  • 7. As in NHL, there are ancillary immunologic studies that can assist the dx of Hodgkins' disease, and distinguish from immunoblast reaction or unusual variants of NHL
    • a. Expression of CD15 and CD30 antigens in golgi and on cell membrane- detected by immunohistochemistry
  • 8. Hodgkin's disease spreads contiguously via lymphatics
  • 9. Staging as in NHL- may or may not include laparotomy/splenectomy
  • 10. Therapy
    • a. Hodgkins disease is a curable malignancy
    • b. Overall cure rate approximately 80%
    • c. 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.
    • d. Limited stage, low bulk disease treated with radiation therapy
    • e. Higher stage (III-IV) treated with multi-agent chemotherapy+/- radiation therapy
  • 11. Potential complications of therapy
    • a. Radiation effects to lungs, heart,bone marrow
    • b. Sterility
    • c. Splenectomy associated sepsis
    • d. Therapy associated second malignancies
  • 12. Pathobiology
    • a. The origin of the Reed Sternberg cell and the etiology of Hodgkins disease is still unknown
    • b. The mixed cellular infiltrate, unusual large cells, clustered familial cases, and early evidence of immune disfunction suggest an infectious etiology
      • 1). Approximately 30% of cases, Reed-Sternberg cells contain Epstein Barr virus within the RS cells
    • c. Recent molecular studies suggest Hodgkin's disease may not be one disease
      • 1). L and H cells of lymphocyte predominant Hodgkin's disease are B cells, which may or may not be clonal
      • 2). Reed Sternberg cells of other types may express T cell, B cell and macrophage associated antigens

XI. Additional figures useful in correlating normal lymphopoiesis with different types of lymphoma

• A. Lymphocyte development
• B. Tissue distribution
• C. Cell lineage in lymphoproliferative disorders
• D. Stages of lymphopoiesis/immune response and related lymphoproliferative disorders
• E. Lukes-Collins concept of relationship- incorrect