Diagnosing Extranodal Lymphomas in the New Millennium
Wednesday, March 10, 2004
Marsha C. Kinney and Steven H. Swerdlow
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T/NK Cell Lymphomas at Extranodal Sites
52 year old male initially presenting with anemia, thrombocytopenia
and normal leukocyte number/differential and splenomegaly. Splenectomy
revealed a "hematopoietic/lymphoid neoplasm, unclassified". Marrow
examination was negative except for a mild lymphocytosis. The patient was
followed and at one year developed hepatomegaly. An open liver biopsy was
Case 5 - Figure 1 - Hepatosplenic T-cell lymphoma, liver. Liver sinuses are expanded by a monomorphic population of lymphocytes. There is little involvement of portal triads (Upper right).
Case 5 - Figure 2 - Hepatosplenic T-cell lymphoma, liver. The lymphocytes are medium to large and have partially dispersed chromatin and indistinct, pale cytoplasm.
Case 5 - Figure 3 - Hepatosplenic T-cell lymphoma, liver, paraffin immunoperoxidase, antibody polyclonal-anti CDS. The lymphocytes are CD3+.
Case 5 - Figure 4 - Hepatosplenic T-cell lymphoma, spleen. The red pulp is expanded by a homogeneous population of medium-sized lymphocytes with preferential localization to the sinuses.
Subcutaneous Panniculitis-like T-cell Lymphoma (SCPTCL).
A 71 year old male with nodules on arms and abdomen.
Case 6 - Figure 1 - Subcutaneous panniculitis-like T-cell lymphoma, skin/soft tissue. Tumor cells infiltrate subcutaneous tissue in a lobular pattern. Areas of fat necrosis are present.
Case 6 - Figure 2 - Subcutaneous panniculitis-like T-cell lymphoma, skin/soft tissue. Tumor cells rim the fat cells and partially invade a small vessel. Most tumor cells are medium to large and have hyperchromatic, irregular nuclei. Focal areas of fat necrosis are present (Upper right).
Case 6 - Figure 3 - Subcutaneous panniculitis-like T-cell lymphoma, skin/soft tissue. Macrophages are prominent in areas of necrosis and some show erythrophagocytosis.
Primary Cutaneous Anaplastic Large Cell Lymphoma (ALCL)
A 90 year old male with pink, waxy nodular lesion, right shoulder.
Case 7 - Figure 1 - Primary cutaneous anaplastic large cell lymphoma, skin biopsy. Tumor cells diffusely efface the dermis with sparing of the epidermis.
Case 7 - Figure 2 - Primary cutaneous anaplastic large cell lymphoma, skin biopsy. The tumor cells are large, pleomorphic and have a high mitotic rate.
Case 7 - Figure 3 - Primary cutaneous anaplastic large cell lymphoma, skin biopsy, paraffin immunoperoxidase, antibody Ber-h-12. The tumor cells have strong CD30 expression in a membrane and Golgi pattern.
Case 7 - Figure 4 - Primary cutaneous anaplastic large cell lymphoma, skin biopsy, paraffin immunoperoxidase, antibody ALK1. The tumor cells are ALK1 negative (left panel) with a positive control (right panel).
Nasal/Nasal Type NK/T-cell Lymphoma
A 43 year old female with one year history of skin lesions. Biopsy of paranasal sinus.
Case 8 - Figure 1 - Nasal NK/T-cell lymphoma, paranasal sinus biopsy. Large areas of necrosis are present in the soft tissue.
Case 8 - Figure 2 - Nasal NK/T-cell lymphoma, paranasal sinus biopsy. Higher magnification reveals infiltration and destruction of a vessel by large, dysplastic tumor cells with hyperchromatic nuclei.
Case 8 - Figure 3 - Nasal NK/T-cell lymphoma, paranasal sinus biopsy, paraffin immunoperoxidase, antibody Beta-F1. The tumor cells lack expression of T cell receptor beta chain. A small reactive lymphocyte is positive.
Case 8 - Figure 4 - Nasal NK/T-cell lymphoma, paranasal sinus biopsy, paraffin immunoperoxidase, antibody T1A-1. Tumor cells express the cytolytic granule protein TIA-1.
Introduction to extranodal lymphomas
Extranodal lymphomas are of great interest as they are common and will be
seen by both general surgical pathologists and hematopathologists. Furthermore, many of the more recent
changes in lymphoma classification deal with extranodal lymphomas and the recognition of important
entities with clinical and biologic implications. Neither this short course, nor this handout, aim to
cover this entire topic which is covered in detail in the published proceedings of the University of
Pittsburgh School of Medicine/Society for Hematopathology workshop on extranodal hematopoietic/lymphoid
disorders and in the excellent textbook on extranodal lymphomas by Isaacson and Norton.
Both references are aging but rather gracefully. The monograph describing the WHO classification of
tumors of the hematopoietic and lymphoid tissues is another extremely important resource.
This short course aims to approach the topic of extranodal lymphomas from an up-to-date but practical perspective.
Extranodal lymphomas: definition
| Traditional: Lymphomas that are restricted to a single extranodal site ± its contiguous lymph node group.|
| Isaacson & Norton (1994): Extranodal lymphomas are those that present "with the main bulk of disease at an extranodal site, usually necessitating the direction of treatment primarily to that site." |
Frequency of extranodal lymphomas
| ~25-40% of all lymphomas are of extranodal type.|
| The incidence of extranodal lymphomas is increasing, like with other lymphomas, not just related to the AIDS epidemic or revised criteria for their recognition. |
| Immunodeficiency-associated lymphomas/ lymphoproliferative disorders do commonly involve extranodal sites and changes in the criteria for many of the extranodal lymphomas do mean that many of yesterday's pseudolymphomas are today's low grade lymphomas. |
Sites of involvement
| Reported frequency of involvement at different sites varies but GI tract is the most common site (especially stomach) followed by skin and Waldeyer's ring.|
| Whereas most extranodal lymphomas used to be categorized together with the nodal non-Hodgkin's lymphomas, now many extranodal lymphomas are categorized as distinct entities. The major exception to this is the relatively common extranodal lymphomas of large B-cell type that are not officially separately designated at the current time.|
| Classic nodal lymphomas can involve extranodal sites, eg, follicular lymphomas, mantle cell lymphomas, etc!|
Lymphoma Classification in the New Millennium
In order to deal with extranodal lymphomas in 2004, one must be able to use the most
recent lymphoma classifications. Understanding some of the older classifications is also important in
being familiar with the wide range of terminology used today, being able to communicate with a broad
spectrum of clinicians and comprehending some of the very critical concepts that are now taken for
granted but that were considered controversial in the past. The older classifications are listed,
reviewed and discussed in many different texts. 
Major lymphoma classifications of the last three decades
| Functional classifications: Lukes/Collins & Kiel|
| NCI Working Formulation|
| REAL classification|
| WHO classification|
The strictly morphologic Rappaport classification of the 1950s/1960s was
followed in the 1970s by the two functional classifications that recognized that malignant lymphomas are
neoplasms of the immune system and therefore should be related to the normal cells and compartments of
the immune system. Although differently organized in their initial forms, the Lukes/Collins and Kiel
classifications were felt to be essentially concordant by their authors.
updated in the 1980s. The Lukes/Collins classification divided lymphomas based on their "cell of origin"
meaning the normal lymphoid counterpart that most closely resembled the neoplastic cells. 
Lymphomas therefore were divided first into those of B- or T-cell origin and then further subdivided
based on what type of B- or T-cell they most closely resembled using the knowledge that existed more than
25 years ago. The only extranodal lymphoma specifically recognized was mycosis fungoides/Sezary
Originally intended as a formulation for translating terminology from one
classification into another, the NCI Working Formulation published in 1982 became a very widely
used classification based on morphology and survival data from patients from the 1970s. 
The seeming simplicity of the classification which had three clinical grades (low, intermediate and high)
and ten types of lymphoma was embraced by many even though its short comings were well recognized from
the start. Aside from the fact that the Working Formulation rejects the basic premise that tumors should
be classified based on their cell type (eg, chondrosarcoma versus osteogenic sarcoma), the grades and
even specific categories have become insufficient, in at least selected circumstances, for optimal
therapeutic and/or prognostic purposes. Some distinct clinicopathologic entities are included in more
than one category and some categories include more than one distinct clinicopathologic entity.
Furthermore the working formulation is inconsistent with the trend towards more targeted therapies, for
example using anti-CD20 antibodies.
Growing dissatisfaction with the NCI Working Formulation, together with major advances in the fields
of immunology and neoplastic hematology, led to the "revised" European-American lymphoma (REAL)
classification that was published by the International Lymphoma Study Group in 1994. 
In 2001, a larger group of hematopathologists, together with a Clinical Advisory
Committee, published a new World Health Organization classification in an extensively illustrated
monograph entitled "Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues".
 Although based on the premise that the overriding necessity in a lymphoma classification
is to recognize clinicopathologic entities rather than just be biologically correct, the WHO
classification initially divides lymphomas into whether they are of B- or T/NK-cell origin, then into
whether they are composed of precursor (lymphoblastic) or mature lymphoid cells, and finally into more
Working Formulation type clinical grading is not recognized in the WHO (or REAL) classification. This
means that the precise type of lymphoma becomes more important. Rejection of lymphoma grades was agreed
to by the clinicians of the WHO Clinical Advisory Committee.
The WHO classification is on the following page. Note that more than ten of the categories of
lymphoma in the WHO classification represent extranodal lymphomas.
Some examples of diagnostic decisions considered important in 2004 that cannot be dealt with using the
NCI Working Formulation and which are discussed in this short course include:
|Recognition of marginal zone B-cell lymphomas of MALT type and of splenic type.|
|Recognition of mantle cell lymphomas.|
|Recognition of some specific types of mature T-cell lymphomas with well documented clinical features, eg subcutaneous panniculitis-like T-cell lymphoma.|
|Recognition of anaplastic large cell lymphomas (cutaneous & systemic).|
WHO classification of lymphomas - Summary 
| B-CELL NEOPLASMS|
|Precursor B-cell neoplasm|
| Precursor B-lymphoblastic leukemia/lymphoma (precursor B-cell ALL)|
|Mature B-cell neoplasms|
| Chronic lymphocytic leukemia/small lymphocytic lymphoma|
| B-cell prolymphocytic leukemia|
| Lymphoplasmacytic lymphoma|
| Splenic marginal zone B-cell lymphoma|
| Hairy cell leukemia|
| Plasma cell myeloma|
| Solitary plasmacytoma of bone|
| Extraosseous plasmacytoma|
| Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT-lymphoma)|
| Nodal marginal zone B-cell lymphoma|
| Follicular lymphoma|
| Mantle cell lymphoma|
| Diffuse large B-cell lymphoma|
| Mediastinal (thymic) large B-cell lymphoma|
| Intravascular large B-cell lymphoma|
| Primary effusion lymphoma|
| Burkitt lymphoma/leukemia|
| B-cell proliferations of uncertain malignant potential|
| Lymphomatoid granulomatosis|
| Post-transplant lymphoproliferative disorder, polymorphic|
| T AND NK-CELL NEOPLASMS|
| Precursor T-cell neoplasms|
| Precursor T-lymphoblastic leukemia/lymphoma (precursor T-cell ALL)|
| Blastic NK cell lymphoma|
|Mature T-cell and NK-cell neoplasms|
| T-cell prolymphocytic leukemia|
| T-cell large granular lymphocytic leukemia|
| Aggressive NK-cell leukemia|
| Adult T-cell leukemia/lymphoma|
| Extranodal NK/T-cell lymphoma, nasal-type|
| Enteropathy-type T-cell lymphoma|
| Hepatosplenic T-cell lymphoma|
| Subcutaneous panniculitis-like T-cell lymphoma|
| Mycosis fungoides|
| Sezary syndrome|
| Primary cutaneous anaplastic large cell lymphoma|
| Peripheral T-cell lymphoma, unspecified|
| Angioimmunoblastic T-cell lymphoma|
| Anaplastic large cell lymphoma|
| T-cell proliferation of uncertain malignant potential|
| Lymphomatoid papulosis|
| HODGKIN LYMPHOMA|
|Nodular lymphocyte predominant Hodgkin lymphoma|
| Classical Hodgkin lymphoma|
| Nodular sclerosis classical Hodgkin lymphoma|
| Lymphocyte-rich classical Hodgkin lymphoma|
| Mixed cellularity classical Hodgkin lymphoma|
| Lymphocyte depleted classical Hodgkin lymphoma|
T/NK Cell Lymphomas at Extranodal Sites
T/NK-Cell Lymphomas at Extranodal Sites
T- cell lymphomas are difficult to diagnose for several reasons:
| They are relatively rare in the Western world, representing only 10-15% of lymphomas overall.|
| Even after excluding mycosis fungoides, almost one-third of T-cell lymphomas occur as primary tumors in extranodal sites where the diagnosis may be unsuspected initially and delayed due limited workup on the front end.|
| There are no specific cytologic or morphologic correlates of T-cell origin such as follicular nodulation or plasmacytic differentiation in B cell neoplasms; prior to recent classification systems, T-cell neoplasms were included in the heterogeneous categories diffuse mixed small and large cell or large cell immunoblastic.|
| Most T-cell lymphomas do not have a specific immunophenotype.|
| There are no immunologic markers of T-cell clonality; pan T-cell antigen loss is useful in identifying an abnormal T-cell population.|
| The ontogeny from naive to effector T-cell is largely obscure. T-cells and their neoplasms are biologically complex consisting of populations with ab and gd receptors and helper and suppressor/cytotoxic phenotypes; also NK -cells resemble T-cells in antigen expression, function, and patterns of disease.|
The WHO classification has made several important contributions in classifying T-cell lymphomas:
| Emphasized that extranodal lymphomas are extrinsically different from their nodal counterparts|
| Integrated clinical features (particularly site of disease) with more traditional pathologic criteria in defining lymphomas|
| Introduced NK cell neoplasms into the classification scheme|
We have selected four cases to illustrate some of the common clinical and pathologic features of extranodal T-cell lymphomas and discuss difficulties in their diagnosis
Common features of extranodal T-cell lymphomas include:
| A broad cytologic spectrum with variability from pleomorphic mixed small, medium or large cells to large cell predominant|
| Clinical features, particularly anatomic site, are important in disease definition.|
| Immunophenotype in most cases is not specific.|
| Tumors spread to or relapse at extranodal sites; nodal involvement is infrequent.|
| Most have a cytotoxic T-cell or NK-cell phenotype with frequent apoptosis and/or necrosis.|
| Increased incidence of a hemophagocytic syndrome.|
| EBV positivity correlates with anatomic site and geographic features.|
To provide a foundation for understanding T and NK-cell neoplasms, our discussion will begin with a brief review of their biology.
T-Cell and NK-Cell Biology
Figure 1 is a simple illustration of T-cell and NK-cell differentiation:
From Kinney, MC, 1999 
Most T-cells express the ab T-cell receptor (TCR) protein and have a helper (CD4+) or
suppressor/cytotoxic (CD8+) phenotype. A small population of T-cells express the gd TCR and usually have
a double negative (CD4-CD8-) phenotype, although some may express CD8, or more rarely, CD4. Normal gd
T-cells are preferentially located at extranodal sites such as the splenic red pulp, gastrointestinal
tract, and skin.
NK cells arise from a pluripotential cell and are related to T-cells, but at some point they branch
off to form a separate lineage.  NK cells are distinguished immunologically by the absence
of TCR gene rearrangements and TCR protein expression and lack of surface CD3 (Leu-4). NK cells
and T cells can express
CD2, CD7, and in paraffin sections cytoplasmic CD3 (the episilon chain), CD45RO and CD43. Most
NK-cells are CD4-CD8- followed by CD4-CD8+. NK-cells usually express one or more "NK-associated"
antigens (CD11b, CD16, CD56, CD57), but some populations of NK-cells do not express these antigens and
are identified by functional studies. A subset of cytotoxic T-cells also expresses NK associated
antigens (see Table 1).
NK-cells and a subset of T-cells function as cytotoxic cells. Cytotoxic cells can be divided into
three groups based on immunologic, molecular, and functional characteristics (see Table 1).
Table 1. Classification of Cytotoxic Cells According to Immunophenotype, Molecular, and Functional Parameters
| Parameter ||T ||NK-Like T ||NK|
|NK antigen ||- ||+ ||+*|
|Cytoplasmic CD3(epsilon chain) ||+ ||+ ||+/-|
|Surface CD3 ||+ ||+ ||-|
|CD4, CD8 ||CD8+>>>CD4+ C||D8+>CD4-CD8->>CD4+ ||CD4-CD8+/-|
|TCRab, g/d† ||+ ||+ ||-|
|Cytotoxic granules ||+ ||+ ||+|
|Killing mechanism ||MHC restricted ||Non-MHC restricted ||Non-MHC restricted|
TCR = T-cell receptor
MHC = major histocompatibility complex
* Some populations lack NK cell antigens
†TCR gene rearrangement and protein expression
From Kinney MC, 1999 
Most cytotoxic T-cells recognize antigen on target cells in the context of major histocompatibility
complex (MHC) antigens leading to specific killing. Most are CD8+ and recognize class I MHC molecules; a
minor population is CD4+ and recognizes class II MHC molecules. The majority of cytotoxic T-cells
express the ab TCR and a small number are gd T-cells. A subset of cytotoxic T-cells are "NK-like",
express NK antigens, and kill target cells in a non-MHC restricted manner.
broader reactivity than T- cells in that they do not require previous exposure to antigen, and the target
cell does not have to express MHC molecules. Recent evidence indicates NK-cells do recognize MHC class
I, and if present on the target cell, lysis by NK-cells is inhibited. If MHC class I molecules are
decreased, absent, or altered (as frequently occurs in tumors or virus infected cells), NK-cell lysis is
activated.  The two main groups of NK-cell receptors that recognize HLA class I molecules are
C-type lectin receptors (NKG2 and CD94) and immunoglobulin superfamily receptors that include killer
immunoglobulin-like receptors (KIRs) and others. [17a] These receptors are not specific for
NK-cells and can be expressed on a subset of T-cells.
Cytotoxic cells have two main effector mechanisms of killing their target either through activation
of the Fas-Fas-L (CD95L) apoptotic pathway or by release of cytotoxic granules (perforin [membranolytic
protein], granzymes [apoptotic protein], or TIA-1 [RNA binding protein]) that lead to osmotic cell lysis
or apoptotic DNA fragmentation of the target cell.
NK-cells or cytotoxic T-cells may be the first line of defense at mucosal sites and the skin and
they are more common in these sites. It is not surprising that many extranodal lymphomas arising in
these areas are tumors of cytotoxic lymphocytes.
Immunophenotyping T- and NK-cells and their neoplasms:
In recent years many antibodies useful in identifying T-cells, their subsets and NK-cells have been
developed that are reactive in fixed tissue (Table 2). Although these antibodies are useful in
determining the cell of origin of a neoplastic process, the immunophenotype of most T-or NK-cell
neoplasms is not specific except where pathogenetic markers (ie, ALK protein in systemic anaplastic large
cell lymphoma) have been developed. Diagnosis of T or NK cell neoplasms requires a combination of
clinical, morphologic and immunophenotypic data. Some markers, such as CD56, may have prognostic
Table 2. Paraffin Reactive Antibodies Useful in Characterizing T and
| CD Number ||Antibody/Source ||Principal Reactivity|
|CD3 ||CD3(polyclonal)/DAKO ||T-cells, activated NK cells|
|CD45RO ||UCHL-1/DAKO ||Memory T-cells|
|CD43 ||Leu-22(L60),MT1/Becton-Dickinson, DAKO, BioGenex ||T-cells, myeloid cells, B-cell subset|
|-- ||bF-1 /EndoGen ||ab T-cells|
|-- ||TCR-gd/EndoGen ||gd T-cells|
|CD4 ||CD4/Novocastra ||Helper T-cells, monocytes|
|CD8 ||CD8/DAKO ||Suppressor/cytotoxic T cells; NK cell subset|
|-- ||TIA-1/Coulter ||Cytotoxic T cells, NK cells|
|-- ||Granzyme B/Monosan ||Activated cytotoxic T cells, NK cells|
|CD56 ||123C3/Zymed ||NK cells and some cytotoxic T cells|
|CD57 ||Leu-7/Becton-Dickinson ||Cytotoxic T-cells and some NK cells|
|-- ||ALK-1/DAKO ||ALCL; small subset B cell lymphomas; neural tissue; inflammatory myofibroblastic tumors|
|-- ||EMA/multiple vendors ||Epithelial cells, ALCL, LPHD, plasma cells|
Initially a screening panel is performed that includes B and T-cell markers. Usually two T- cell
markers are included (we use CD3 and CD45RO, UCHL-1) as some T-cell antigens are not expressed in T-cell
neoplasms. Various combinations of the antibodies listed in Table 2 are used to further define
NK-cells and NK-like T-cells may be difficult to distinguish; a comparison of their immunophenotypes
is listed in Table 3.
Table 3. Immunophenotypic Comparison of NK-like T-cells and NK-cells
| NK-like T-cell ||NK-cell|
|cytoplasmic CD3+ ||cytoplasmic CD3+/-|
|surface CD3+* ||surface CD3-|
|TCRab+ or less frequently gd+ ||TCRab- and gd-|
* may be absent in some T cell neoplasms
A summary of the characteristic immunophenotypic features of extranodal T/NK-cell tumors is listed in
Table 4. Characteristic Immunophenotype of Extranodal T/NK-Cell
| Lymphoma Type ||T-cell Subset ||CD56 ||Cytotoxic Proteins ||CD30 ||EBV ||Cell Type|
|Hepatosplenic ||CD4-CD8->CD8+ ||+ ||+ * ||-/+ ||- ||gd>>ab|
|SCPTCL ||CD8+>CD4-CD8->CD4+ ||-/+ ||+ ||+/- ||- ||ab>gd|
|ALCL, primary cutaneous ||CD4+>CD4-CD8->CD8+ ||-/+ *** ||+/- ||+ ||- ** ||ab>gd|
|Nasal/nasal type NK/T cell ||CD8+>CD4-CD8- ||+ ||+ ||+/- ||+ ||NK>gd>ab|
|Aggressive NK leukemia ||CD8+,CD4-CD8- ||+ ||+ ||NT ||+/- ||NK|
|Intestinal ||CD4-CD8->CD8+>CD4+ ||-/+ ||+ ||+/- ||-/+ ||ab>gd>>NK|
|Blastic NK cell lymphoma ||CD4 ||+ ||+ ||NT ||- ||NK|
Modified from Kinney, 1999 ; + = 50%-100%; +/- = 25%-49%; -/+ = 5%-24%; - = <5%
* - most cases have a non-activated phenotype (TIA-1+, granzyme B-, perforin-)
** - based on nodal cases
NT - not tested
*** - wide range (12%-75%) of cases tested
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