1

Pathology of Non-Hodgkins Lymphoma

THOMAS M. GROGAN, MD MARINA A. JARAMILLO, MD

Emphasizing the integration of all available morphologic and laboratory data to establish the multiparameter definition of discrete lymphoma entities, the International Lymphoma Study Group (ILSG) codified and published a revised European-American lymphoid neoplasms (REAL) classification.1 By combining morphologic, immunologic, cytogenetic, and molecular biologic features, this classification proposed 34 biologically well-defined lymphoma entities.2,3 This classification placed the emphasis on the underlying biologic aberrations of the specific lymphoma subtypes. Recently, this REAL Classification has been modestly revised to take an even more global stature as the World Health Organization (WHO) Classification (Table 11).4 Since the closely related REAL Classification, in both full and abbreviated forms, is previously published, 46 this review will provide a different focal point. It will elaborate selected non-Hodgkins entities from the newly combined WHO/REAL listing (see Table 11; Figures 11 to 114).6 It will emphasize the immunophenotypic (see Figures 11 and 110) and microanatomic and clinical features. It will also detail some of the salient chromosomal changes (Table 12) and some of the newly emerging etiologic associations (Table 13). B-CELL LYMPHOMAS Relationship to B-Cell Development The B-cell lymphomas, although manifesting pathologic aberrations [eg monoclonality, idiosyncratic loss of pan B-cell antigens, and cytogenetic abnormalities

such as t(11;14) and t(8;14)], nonetheless maintain many physiologic properties of B cells. In retaining normal phenotypic properties, the neoplastic B cells typically recapitulate a specific stage of B-cell differentiation (Figure 11). As shown, an immature B-lymphoblastic lymphoma accordingly expresses terminal deoxynucleotidyl transferase (TdT) and CD10 (CALLA, common acute lymphocytic leukemia antigen). At the other extreme, a mature plasma cell expresses CD38 and cytoplasmic immunoglobulin (Ig) in the absence of pan-B antigens and surface Ig. By following this B-cell scheme, the phenotype of many of the WHO/REAL B-cell entities are readily predicted. As illustrated, the mid-phase B cell in particular shows an elaborate array of surface markers heralding specific functional properties. For example, CD23, as found in small lymphocytic lymphoma (SLL)/chronic lymphocytic leukemia (CLL) cells, is associated with B-cell homing and accordingly correlates with SLL/CLL involvement of the peripheral blood. This contrasts with mantle cell lymphoma (MCL), which shows comparable coexpression of CD5 (as SLL/CLL), without CD23 expression, and with characteristic overexpression of cyclin D1. In many cases, the specific phenotype aids in the delineation of lymphoma diagnosis. For example, monocytoid B-cell lymphoma (MCBL) and hairy cell leukemia (HCL) can appear morphologically similar in the marrow. However, although both co-express pan-B antigens and CD11c monocytic antigens, it is HCL that co-expresses CD25 and CD103, not MCBL. The following section will elaborate several of the WHO/REAL B-cell lymphomas, illustrating
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MALIGNANT LYMPHOMAS

their microanatomic and immunotopographic features and placing these entities in the above-mentioned scheme of B-cell differentiation.
Table 11. WHO/REAL CLASSIFICATION OF LYMPHOID NEOPLASMS

Selected B-Cell Neoplasms

Precursor B-Cell Lymphoblastic Leukemia/Lymphoma

B-Cell Neoplasms Precursor B-cell neoplasm Precursor B-lymphoblastic leukemia/lymphoma (precursor B-acute lymphoblastic leukemia) Mature (peripheral) B-neoplasms B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Splenic marginal zone B-cell lymphoma ( villous lymphocytes)* Hairy cell leukemia Plasma cell myeloma/plasmacytoma Extranodal marginal zone B-cell lymphoma of MALT type Nodal marginal zone B-cell lymphoma ( monocytoid B cells)* Follicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma Mediastinal large B-cell lymphoma Primary effusion lymphoma Burkitts lymphoma/Burkitt cell leukemia T and NK-Cell Neoplasms Precursor T-cell neoplasm Precursor T-lymphoblastic leukemia/lymphoma (precursor T-acute lymphoblastic leukemia) Mature (peripheral) T neoplasms T-cell chronic lymphocytic leukemia/small lymphocytic lymphoma T-cell prolymphocytic leukemia T-cell granular lymphocytic leukemiall Aggressive NK leukemiall Adult T-cell lymphoma/leukemia (HTLV-1+) Extranodal NK/T-cell lymphoma, nasal type# Enteropathy-like T-cell lymphoma** Hepatosplenic T-cell lymphoma* Subcutaneous panniculitis-like T-cell lymphoma* Mycosis fungoides/Szary syndrome Anaplastic large cell lymphoma, T/null cell, primary cutaneous type Peripheral T-cell lymphoma, not otherwise characterized Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma, T/null cell, primary systemic type Hodgkins Lymphoma (Hodgkins Disease) Nodular lymphocyte predominance Hodgkins lymphoma Classic Hodgkins lymphoma Nodular sclerosis Hodgkins lymphoma (grades 1 and 2) Lymphocyte-rich classic Hodgkins lymphoma Mixed cellularity Hodgkins lymphoma Lymphocyte depletion Hodgkins lymphoma
*Provisional entities in the REAL classification. Not described in REAL classification. Formerly known as lymphoplasmacytoid lymphoma or immunocytoma. Includes the so-called Burkitt-like lymphomas. ll Entities formally grouped under the heading large granular lymphocyte leukemia of T- and NK-cell types. # Formerly known as angiocentric lymphoma. **Formerly known as intestinal T-cell lymphoma.

Morphology and Immunophenotyping (Figure 12). This lymphoreticular malignancy is composed of medium-sized cells with high nuclear-tocytoplasmic ratio and immature nuclear appearance with finely dispersed, blastic chromatin. The pattern of growth is diffuse. Numerous mitotic figures are usually present.7 The phenotypic profile reflects the immature nature of the neoplastic cells. There is positivity for early B-cell markers (CD19, CD79a) and variable expression of CD20, a marker that characterizes more mature B cells. No surface immunoglobulin (Ig) expression is detected, but up to one-third of the cases show cytoplasmic chain (pre-B-cell phenotype). The hallmark of this entity is the presence of nuclear Tdt expression in association with strong cytoplasmic CD10.812 Cytogenetics. There is rearrangement of both light and heavy chain Ig genes. The two most common translocations include t(1;19) and t(9;22). Clinical Features. This is a highly aggressive disease, which is rapidly fatal without treatment.7,13 Currently, thanks to newer chemotherapeutic regimens, this entity is potentially curable and complete remission can be attained in up to 50 percent of patients.
Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia

Morphology and Immunophenotyping (Figure 13). Small lymphocytic lymphoma is a neoplasm composed of cells that have the appearance of the unstimulated, small, resting B cells normally present in primary follicles or mantle zones. The pattern of growth is diffuse, with complete replacement of the lymph node architecture by sheets of small lymphocytes. On low-power view, pale nodular areas, referred to as pseudofollicles (proliferative centers or epicenters of atypicality), are usually seen interrupting the characteristic monotony of this neoplasm.14 The neoplastic cells express pan-B-cell markers including CD19, CD23, and CD79a and usually pos-

Pathology of Non-Hodgkins Lymphoma

Figure 11.

B-cell differentiation scheme.

sess weak CD20 and monotypic surface Ig expression. CD5, CD43, and CD23 positivity is a constant finding in this neoplasm, whereas CD10 is always absent.15 In tissue sections, SLL is indistinguishable from the solid phase of CLL; both the morphologic appearance and the immunophenotypic profile are virtually identical.16 In fact, these two entities are believed to be manifestations of the same disease process.

Cytogenetics. As expected, there is rearrangement of both light and heavy chain Ig genes. An abnormal karyotype is observed in the majority of SLLs and/or CLLs. Some patients have a t(14;19), resulting in an altered expression of BCL3, an NFKB-inhibitor.17 Patients with 13q14 show heavy somatic mutations in their Ig V genes and typically lack CD38. This suggests a post-germinal center

Figure 12. B-cell lymphoblastic lymphoma. A, The lymphoma is characterized by small round blastic lymphocytes with a high proliferative rate (hematoxylin and eosin; 1,000 original magnification). B, Marrow involvement with nuclear expression of terminal deoxynucleotidyl transferace (Tdt) (hematoxylin and eosin, and diamino benzidine; 400 original magnification).

MALIGNANT LYMPHOMAS

B
Figure 13. Small lymphocytic lymphoma (SLL), B-cell type. A, This lymphoma is characterized by small, dark, round, resting lymphocytes with focal light areas representing epicenters of atypicality (hematoxylin and eosin; 250400 original magnification). B, Tissue sections phenotype reveals light chain restriction ( Ig+, Ig) with coexpression of CD5 and CD23 as characteristic of SLL (see Figure 11) (250 original magnification).

Pathology of Non-Hodgkins Lymphoma

antigen-driven process. In contrast, patients with trisomy 12, the most common chromosomal abnormality in this entity, have unmutated immunoglobulin VH genes and CD38 expression, suggesting derivation from nave pre-germinal center B cells.18 Clinical Features. Most patients are older adults and present with nodal, bone marrow, and peripheral blood involvement.1921 The production of autoantibodies by the neoplastic clone explains the relatively common occurrence of autoimmune cytopenias.22 Although indolent in nature, this entity is not curable with the therapy currently available.23 Prolymphocytic transformation conveys a worse prognosis and represents a more accelerated phase of the disease.24 Other cases are complicated by diffuse large lymphoma (Richters transformation), which may represent a true transformation or a second malignancy. Both Ig V somatic mutation status and CD38 status are predictors of clinical outcome, with mutated, CD38-negative cases having benign disease and unmutated CD38-positive cases having atypical morphology and progressive disease.25
B-Cell Prolymphocytic Leukemia

occur as a primary disease but commonly represents the transformation phase of CLL;28 in these cases, prolymphocytes should account for greater than 55 percent of the leukemic population.
Lymphoplasmacytoid Lymphoma (Immunocytoma)

Morphology and Immunophenotyping. This disease is characterized by marked absolute peripheral lymphocytosis (~ 100 103/mm3). The neoplastic prolymphocytes have round nuclei with a prominent, centrally located nucleolus and moderately abundant, pale blue cytoplasm. Spleen involvement starts in the white pulp and secondarily extends to the red pulp.26 The neoplastic cells typically display strong surface Ig and are positive for these pan-B-cell markers: CD19, CD20, CD22, and CD79a. The strong surface Ig and absence of CD5 help differentiate B-cell prolymphocytic leukemia from SLL/CLL.2730 Cytogenetics. Cytogenetic studies show rearrangement of immunoglobulin heavy chains. Translocation is uncommon, with rare cases of t(11;14) described in prolymphocytic leukemia.31 Clinical Features. This disease typically affects elderly male patients and is characterized by marked lymphocytosis, peripheral cytopenias, striking splenomegaly, and minimal or no lymph node involvement. Prolymphocytic leukemia can

Morphology and Immunophenotyping. Lymphoplasmacytoid lymphoma typically exhibits a diffuse pattern of growth and is composed of a polymorphous neoplastic population that includes small lymphocytes, plasmacytoid lymphocytes, and plasma cells. Dutcher bodies, accumulations of immunoglobulins within the nucleus, are a constant finding in these cases. Immunophenotyping reveals positivity for panB-cell markers (CD20, CD79a) and variable expression of some plasma cell-related antigens (CD43 and CD38). There is usually strong surface and cytoplasm Ig expression. The Ig isotype is commonly of IgM type, although IgG and IgA types are described. Absent are CD5 and CD10.16,32,33 Cytogenetics. As expected, there is rearrangement of both light and heavy chain Ig genes. Translocation of the PAX5 gene via t(9;14) is the most common cytogenetic aberrancy described in immunocytoma.3438 Analysis of the variable region in immunoglobulin heavy and light chains shows somatic hypermutation with restricted, preferential expression of the VH51p1/VL KV 325 genes in hepatitis C virusassociated immunocytomas. These findings are consistent with an antigen-driven process and support a role for chronic antigen stimulation via hepatitis C.39 Clinical Features. This disease occurs in older patients and has an indolent course; however, it is not curable with the currently available therapy, with complete remission found in only 15 percent of patients on multiple chemotherapies.40,41 It characteristically involves lymph nodes, spleen, bone marrow, and ultimately peripheral blood and has the potential to transform to large cell lymphoma. As in other immunosecretory disorders, the finding of a monoclonal immunoglobulin, usually IgM, is characteristic.42 As previously mentioned, an association with hepatitis C virus infection and immunocytoma has been described.4346

MALIGNANT LYMPHOMAS

Splenic Marginal Zone B-Cell Lymphoma ( Villous Lymphocytes)

Morphology and Immunophenotyping (Figure 14). This entity is characterized by marked expansion of the marginal zones of the white pulp, which results in a nodular pattern of growth. The neoplastic cells are relatively small and have an open chromatin pattern. The cytoplasm is pale blue and abundant. When identified in the circulation, these cells sometimes exhibit villous cytoplasmic projections (villous lymphocytes).47,48 Immunophenotyping reveals positivity for panB-cell markers (CD19, CD20, CD22, CD79a) and negativity for CD5, CD10, CD25, and CD43. There is strong surface Ig expression.49 Cytogenetics. Rearrangement of the genes encoding for light and heavy chains is a constant finding.50 Trisomy 3 is seen less frequently than in other marginal lymphomas.51 So far, no unique chromosomal anomaly has been described. Clinical Features. This is a rare disease of adults that typically presents with prominent splenomegaly and mild-to-moderate lymphocytosis.52 Bone marrow involvement is frequent. In contrast, lymph node involvement is characteristically uncommon. In up to 40 percent of patients, a monoclonal gammopathy can be detected. This disease is indolent and usually exhibits a slowly progressive course; however, it is not usually curable with the currently available modalities of therapy.
Hairy Cell Leukemia

appearance, given their relatively abundant cytoplasm and well-spaced nuclei. Immunophenotyping reveals positivity for pan-Bcell markers (CD19, CD20, CD22, CD79a) and strong expression of monoclonal surface Ig. The lymphoid cells characteristically express CD11c, CD25, and CD103. Co-expression of CD11c, CD20, CD22, and CD25 is the hallmark of the disease and may be demonstrated by flow cytometry. In addition, cytochemical stains reveal the presence of tartrate-resistant acid phosphatase (TRAP). Nuclear cyclin D1 is overexpressed in most hairy cell leukemia cells; however, the levels of expression are much lower than in mantle cell lymphoma, and this expression is not associated with BCL1 rearrangement.54 Cytogenetics. Cytogenetic studies reveal both light and heavy chain Ig gene rearrangements. Clinical Features. Hairy cell leukemia affects adults, with the median age at presentation being 50 years. Males are affected preferentially. The disease characteristically presents with splenomegaly and pancytopenia (bicytopenia and monocytopenia also occur).55 Bone marrow, spleen (red pulp), and peripheral blood are the usual sites of involvement; no or minimal lymph node involvement is seen at presentation. The course is indolent,56 with a median survival of 5 years.
Extranodal Marginal Zone B-Cell Lymphoma (B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue Type)

Morphology and Immunophenotyping. The neoplastic infiltrate consists of small lymphoid cells with a round to oval or kidney-shaped nucleus, condensed chromatin pattern, and relatively abundant pale cytoplasm. On peripheral blood smears, villous cytoplasmic projections can be seen, giving the neoplastic cells their characteristic hairy appearance.53 These hairy cells can be hard to find, given the small number usually present in circulation. The pattern of bone marrow involvement is diffuse with associated bone marrow reticulosis, resulting in a dry tap on marrow aspiration. On tissue sections, the neoplastic cells have a characteristic fried egg

Morphology and Immunophenotyping (Figure 15). The pattern of growth is perifollicular and interfollicular, with marked expansion of the marginal zones and extension into the adjacent mucosa. The hallmark finding is the presence of lymphoepithelial lesions, characterized by invasion of the epithelial lining by small clusters of neoplastic B cells (clustered invasion of the mucosa). Not uncommonly, there is also extension into the adjacent germinal centers in a process known as follicular colonization. The neoplastic population consists of small, marginal zone cells (centrocyte-like) and monocytoid B cells, with the latter being the predominant component in many cases. Often there is an associated plasmacytosis.57,58

Pathology of Non-Hodgkins Lymphoma

Figure 14. Splenic lymphoma with villous lymphocytes (SLVLs) in bone marrow. The neoplastic lymphoid cells efface the marrow. The SLVL cells are small ovoid cells with cytoplasm showing villous protrusions and scattered, tartrate-resistant acid phosphatase (TRAP) activity ( 40100 original magnification).

Figure 15. Mucosa-associated lymphoma (MALT lymphoma) of stomach. The stomach shows localized invasion of the mucosa to produce lymphoepithelial lesions. The lesional cells are CD20 positive. These CD20+ cells (blue) produce lacunae within the cytokeratin (CD20, brown) gastric mucosa. In the same mucosa are found abundant Helicobacter pylori (HP) organisms ( 100400 original magnification).

MALIGNANT LYMPHOMAS

Phenotyping reveals expression of pan-B-cell markers such as CD19, CD20, CD22, and CD79a. There is variable expression of CD43, and the monocytic marker CD68 is occasionally present in a characteristically speckled perinuclear pattern. Also characteristic is the altered nuclear expression of BCL10. Typically absent are CD5 and CD10. Usually, there is a strong pattern of surface Ig expression. Doublelabeling with cytokeratin and CD20 greatly facilitates the search for lymphoepithelial lesions, highlighting the clusters of neoplastic B cells within the cytokeratin-positive epithelium (see Figure 15). Cytogenetics. The most frequent cytogenetic abnormality in mucosa-associated lymphoid tissue (MALT)-type lymphomas is the t(11;18) translocation. Also common is the t(1;14) translocation, resulting in altered BCL10 apoptotic regulatory molecule expression in MALT lymphoma nuclei.59 Rearrangement of both heavy and light Ig chain genes is also a constant finding. Clinical Features. This is the most common category of primary extranodal marginal zone lymphoma. Although any epithelial organ can be involved, there is a strong predilection for the gastric mucosa, particularly in patients with preexistent Helicobacter pylori infection and secondary chronic gastritis.60 Other organs include salivary glands, thyroid, lung, breast, and skin. 61 In some of these cases, there is a history of an autoimmune condition involving the affected organ, such as Sjgrens syndrome and Hashimotos thyroiditis. Interestingly, primary cutaneous MALT-type lymphomas have been associated with Borrelia burgdorferi, the spirochete responsible for Lyme disease.62,63 MALT-type lymphoma is an indolent lymphoma that tends to remain localized to the primary site and can be cured with local therapy. Helicobacter pyloriassociated MALTomas are curable 70 percent of the time with multiple antibiotic therapy.64 The 30 percent of H. pylori-associated MALT lymphomas that do not regress with antibiotic therapy are often (in 75% of cases) associated with a t(11;18) translocation, indicating that genetic change has had an immortalizing effect.65,66 Transformation to a high-grade neoplasm does occur in some patients. This transformation is usually accompanied by an increase in the cytologic grade, an increase in the proliferative rate,

and evidence of oncogene activation as demonstrated by P53 nuclear expression.

Nodal Marginal Zone B-Cell Lymphoma (Monocytoid B-Cell Lymphoma)

Morphology and Immunophenotyping (Figure 16). The pattern of growth is characterized by expansion of the marginal zones with extension into the interfollicular, sinusoidal, and parasinusoidal areas. Occasionally, follicular colonization is present and can give a deceitfully follicular appearance to the lesion. The neoplastic population is somewhat heterogeneous and includes small lymphocytes, marginal zone B cells, monocytoid B cells, and plasma cells. Monocytoid B cells are usually the predominant cell type; these cells are characterized by nuclear irregularity and relatively abundant pale blue cytoplasm.6769 Immunophenotyping reveals a monoclonal B-cell population that expresses pan-B-cell markers including CD19, CD20, CD22, and CD79a. In addition, there is variable expression of CD43 and CD11c (speckled). No reactivity for CD5 or CD10 is seen.70 Cytogenetics. Rearrangement of heavy and light chain immunoglobulin genes is a constant finding in these patients. Clinical Features. This is a disease of adults and often affects women with a history of Sjgrens syndrome. Nodal marginal zone B-cell lymphoma usually occurs in isolation as a primary process but occasionally represents the nodal spread of a previously diagnosed or occult extranodal marginalzone lymphoma of MALT type.63,71 The nodal involvement at presentation can be localized or disseminated. Bone marrow involvement with peripheralization of the neoplastic population is the exception. The disease has an indolent course; however, it is slowly progressive and usually incurable when disseminated.72
Follicular Lymphoma

Morphology and Immunophenotyping (Figure 17). Follicular lymphomas are composed of cells that resemble those normally present in germinal centers, including centrocytes (small cleaved cells) and

Pathology of Non-Hodgkins Lymphoma

centroblasts. Typically, there is replacement of the lymph node architecture by expanded, back-to-back follicles. In transformed, high-grade lesions, the pattern of growth tends to be diffuse, although focal areas of follicularity are usually found. The phenotype of follicular lymphoma is characteristic and reflects the germinal center origin of this entity. The neoplastic cells show positivity for panB-cell antigens such as CD20 and CD79a, whereas antigens commonly seen in other indolent lymphomas, specifically CD5 and CD43, are lacking. The presence of CD10, which is characteristically overexpressed, is evidence of the germinal center derivation of this neoplasm. Finally, there is aberrant co-expression of BCL2 within the neoplastic follicles, in contrast with the physiologic pattern of BCL2 absence seen in reactive germinal centers.73 The combined CD10+ BCL2+ follicle phenotype is characteristic and useful in the differential diagnosis from reactive lymphoid tissues.74,75

Cytogenetics. The great majority of cases have the t(14; 18) translocation with rearrangement of the BCL2 gene, resulting in overexpression of the BCL2 protein, which is not present in normal or reactive germinal centers. In addition, there is re-arrangement of IgH and IgL genes. Clinical Features. This is the most common lymphoma in the Western world and accounts for approximately 40 percent of the non-Hodgkins lymphomas in the United States. It presents as generalized lymphadenopathy and usually affects older adults with a median age at presentation of 55 years. Follicular lymphoma is an indolent malignancy that is initially responsive to chemotherapy. Although remissions are the rule, true cures are uncommon.
Mantle Cell Lymphoma

Morphology and Immunophenotyping (Figure 18). Mantle cell lymphomas grow in a pattern that ranges from vaguely nodular (mantle-zone configu-

Figure 16. Monocytoid B-cell lymphoma (MBCL) involving spleen. A, The neoplastic cells are found as a pale cloud at the edge of the white pulp within the marginal zone ( 40 original magnification). B, The neoplastic cells have abundant pale cytoplasm and ovoid, partially lobate nuclei, giving a monocytoid appearance (Wright stain; 1,000 original magnification). C, The neoplastic cells express CD20 ( 400 original magnification). D, The neoplastic cells characteristically co-express CD68 in a speckled cytoplasmic pattern ( 400 original magnification).

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MALIGNANT LYMPHOMAS

ration) to diffuse. The neoplastic cells are slightly larger than mature lymphocytes and are uniform in size and shape, giving this lymphoma a very monotonous appearance. The nuclei have a dispersed, fine chromatin pattern. The nuclear envelope is moderately irregular and the cytoplasm is scant. Scattered throughout the sheets of neoplastic cells are large

non-neoplastic epithelioid histiocytes.76 Follicular colonization of germinal centers may occur, causing confusion with follicular lymphoma.77,78 Phenotyping demonstrates a phenotypic profile similar to small lymphocytic lymphoma, with expression pan-B-cell markers (CD20, CD79a) and co-expression of CD5 and CD43. In contrast to SLL,

B
Figure 17. Follicular lymphoma (FL). A, This lymphoma has characteristic back-to-back nodule formation effacing the node (hematoxylin and eosin; 40 original magnification). B, There is characteristic overexpression of BCL2 within the neoplastic nodules (see lower right), in contrast with absent BCL2 within normal tonsil germinal centers (lower left). ( 40100 original magnification).

Pathology of Non-Hodgkins Lymphoma

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Figure 18. Mantle cell lymphoma. This lymphoma has an initial nodular pattern reflecting a mantle cell site of microanatomic involvement. Also shown are characteristic admixed epithelioid histiocytes. The quintessential phenotypic feature is the expression of nuclear cyclin D1 ( 100400 original magnification).

mantle cell lymphoma does not express CD23 and has the unique property of expressing nuclear cyclin D1, which, combined with CD5 and pan-B coexpression, is the phenotypic signature of this entity. Cytogenetics. The characteristic chromosomal anomaly seen in mantle cell lymphoma is the translocation t(11;14). This translocation results in overexpression of PRAD1 gene, which encodes for cyclin D1, a cycle protein that promotes cell proliferation.79 Since mantle cell lymphoma has a poorer prognosis than other small B-cell lymphomas and may proceed to transplantation, a definitive diagnosis is essential. Accordingly, two-color fluorescence in situ hybridization (FISH) may be used to directly detect the t(11;14)(q13;q32) translocation.80 Rearrangement of Ig heavy and light chains is also present. Clinical Features. This disease characteristically affects older adults over the age of 60 years and is usually diagnosed at an advanced stage. At

presentation, there is usually involvement of both nodal and extranodal sites including the spleen. A typical site of extranodal involvement is the gastrointestinal tract, in the form of multiple mucosal nodules, the so-called lymphomatoid polyposis. Although historically considered an indolent variety of lymphoma, this disease is incurable with the current therapies and has a relatively aggressive course, with a median survival of 3 years.63
Diffuse Large B-Cell Lymphoma (DLBCL)

Morphology and Immunophenotyping. As indicated by its name, this entity is characterized by a diffuse pattern of growth with complete effacement of the nodal architecture. The neoplastic population is composed of large cells with prominent nucleoli and relatively scanty cytoplasm. Under this category are included those B-cell lymphomas with anaplastic features (diffuse large B-cell lymphoma with

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anaplastic features)81 and the so-called T-cell-rich B-cell lymphomas. By immunophenotyping, there is variable expression of monotypic surface Ig. As expected, the neoplastic cells show positivity for pan-B-cell markers (CD19, CD20, CD22, CD79a). There is variable expression of CD5, CD10, and CD43.82 The proliferative rate is significantly increased, usually over 40%. Cytogenetics. There is rearrangement of both light and heavy chain genes. In addition, rearrangements of BCL2 or BCL6 genes are relatively common, and each is seen in up to 30 percent of cases.83,84 Gene expression profiling using DNA microarrays reveals two molecularly distinct forms of DLBCL: the germinal center type and the activated type, with the former patients having better overall survival than those with the activated DLBCL.85 Clinical Features. Diffuse large cell lymphoma accounts for 30 to 40 percent of all non-Hodgkins lymphomas in the United States. This is a fairly heterogeneous entity that affects all age groups, including children. It can occur as a primary disease process or as the transformation phase of a preexisting, more indolent lymphoma (follicular lymphoma, marginal-zone lymphoma, etc.). It usually presents as a rapidly growing, sometimes single nodal mass. In up to 40 percent of cases it involves an extranodal site at presentation, such as the gastrointestinal tract, skin, bone, genitourinary tract, and central nervous system. Although aggressive in nature, it is potentially curable with the currently available therapies.86
Burkitts Lymphoma

Immunophenotyping reveals strong positivity for pan-B-cell markers (CD20, CD79a) and CD10, in the absence of BCL2 expression, and a nearly 90 percent proliferation rate as measured by Ki67 positivity.87 Cytogenetics. There is rearrangement of both light and heavy immunoglobulin chain genes. The characteristic translocation of this entity is t(8;14), which leads to rearrangement of the c-myc gene. Burkitts lymphomas express immunoglobulin VH genes with a moderate number of antigen-selected somatic mutations, indicating that the cell of origin is from the germinal center and not a nave, nonmutated pre-germinal center B cell.88 Epstein-Barr virus is virtually always present in endemic cases (> 95%), but is infrequent in sporadic ones (15 to 20%). Clinical Features. This is an aggressive, but potentially curable, disease. It is endemic to Africa, where most of the patients are in the pediatric population and present with rapidly enlarging masses involving facial bones, especially the jaw. Sporadic cases seen in developed countries are more common in adults and characteristically present in extranodal locations, including the ileum, cecum, kidneys, gonads, and breast. T-CELL AND NATURAL KILLER (NK) CELL NEOPLASMS Relationship to T-Cell Development The T-cell neoplasms reflect known physiologic counterparts with immature and mature (peripheral) T-cell types, natural killer, and hybrid natural killer-like Tcell lymphomas (Figure 110). The most common Tcell neoplasm is comprised of the broad category of peripheral T-cell lymphoma (PTL), which has spawned the specific entities within WHO/REAL Classification. The broad category of PTL will be discussed first as most of the immunophenotypic features of PTL apply to other T-cell neoplasms. Peripheral T-Cell lymphoma Peripheral T-cell lymphoma is an immunologically defined category of non-Hodgkins lymphomas,89 which was not present in older morphologic classifications like the Working Formulation (WF) but is

Morphology and Immunophenotyping (Figure 19). A monotonous and uniform population of mediumsized cells characterizes Burkitts lymphoma. The nuclei are round and have a finely dispersed, almost blastic chromatin pattern, and the cytoplasm is basophilic and relatively abundant. The pattern of growth is diffuse, with a characteristic starry-sky appearance due to the presence of scattered macrophages loaded with phagocytic debris. The neoplastic cells have squared off cell borders, resulting in a jigsaw-like appearance. Countless mitoses as well as apoptotic cells are seen, as a result of the rapid cell turnover that characterizes this entity.

Pathology of Non-Hodgkins Lymphoma

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emphasized in immunologically based classifications like the Kiel classification, or the more recent revised European-American lymphoid neoplasms (REAL)/WHO Classifications.1 The emergence of PTL as a lymphoma category despite diverse morphology and outcome reflects several facts: First, its immunologic specificity: mature, post-thymic, acti-

vated T-cell status with novel aberrant pan-T expression. Second, PTL, as a broad category, has spawned specific entities of etiologic definition (eg, HTLV-related PTL), clinical distinctiveness (eg, gluten enteropathyassociated PTL), organ specificity (eg, hepatosplenic / PTL), phenotypic specificity (eg, NK-like CD56+ PTL), morphologic dis-

B
Figure 19. Burkitts lymphoma (BL). A, This touch prep reveals a starry sky pattern and neoplastic lymphoid cells with a high nuclear-to-cytoplasmic ratio and basophilic cytoplasm with vacuoles (1,000 original magnification). B, This Burkitts lymphoma has a starry sky and a distinctive phenotype: (1) very high proliferation (100% Ki-67 reactivity), (2) CD20 positivity, (3) positivity for the Epstein-Barr virus (400 original magnification).

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Figure 110.

T-cell differentiation scheme.

tinctiveness (eg, anaplastic lymphoma), and cytogenetic definition (eg, anaplastic LCL with the t(2;5) translocation).1 In short, there has emerged under the rubric of PTL a number of distinct clinical, pathologic entities not accounted for in the WF but now tabulated in the WHO/REAL schemes.1 This section focuses on the broad categorization of PTL. Immunophenotypic Features of Peripheral T-Cell Lymphomas By definition, peripheral T-cell lymphomas are neoplasms of mature T cells that derive from peripheral lymphoid sites outside the thymus, in contrast with the central thymic origin for immature T-cell lymphoblastic lymphomas.90,91 As a neoplastic clone derived from post-thymic T cells, these cells then expectedly express pan-T cells (eg, CD2, -5, -7), lack immature antigens (eg, CD1a, -10, -34), and lack B-cell antigens, as shown in Figure 110. Physiologically, several distinct functional and genotypic subsets of mature T cells exist, and their neoplastic counterparts largely reflect the subsetrestricted phenotype of the cell of origin (see Figure 110). Two major genotypic and phenotypic subpopulations of T cells have been described, based on T-cell antigen receptor (TCR) gene rearrangements and expressions. These include the first TCR related to and gene rearrangements (TCR1) and

the classic TCR expression related to and genes (TCR2).92 The TCR1 designation reflects the belief that progenitor thymocytes first undergo and gene rearrangement, and if no functional / receptor is produced, a further attempt is then made with and genes. The majority (> 95%) of both thymocytes and circulating T cells express TCR / or TCR2, whereas a minority (< 5%) express TCR1. TCR1 cells are frequently found in epithelium, including the skin and intestinal tract.93 The majority of TCR2 cells function as either helper or cytotoxic/suppressor T cells (CD4+8 or CD48+), whereas most TCR1+ cells are double negatives (CD48) belonging to neither functional subgroup.92 The TCR is critical for T-cell reactivity with non-self (foreign antigens). This reactivity with non-self antigens entails reactivity of the TCR two-chain heterodimer ( and TCR chains) with the major histocompatibility complex (MHC). Aside from non-self, T cells may also interact with self (eg, B cells), mediated through a variety of molecules, including cell adhesion molecules (CAM), integrins (eg, LFA-1), and their ligands (ICAMs).94 Functionally different subpopulations of T lymphocytes can be recognized by expression of either the CD4 or CD8 molecules that occur respectively on helper/inducer T cells and cytotoxic/suppressor T cells.94 CD8-positive T cells via TCR2 recognize foreign antigens in association with MHC class I

Pathology of Non-Hodgkins Lymphoma

15

molecules and then function to eliminate foreign antigens and cells by direct cell contact (cell-mediated immunity). CD4-positive T cells, also via TCR2, recognize foreign antigens associated with self-MHC class II and thereby stimulate a B-cell humoral response.94 Neoplasms derived from these functional subsets may sometimes dramatically

retain these normal functional capacities, as in the PTL with striking associated plasmacytosis due to functional helper T-cell activity.95 In the lymphoid tissues around the body (excepting the tonsil), T cells generally outnumber B cells by 3:1 or 4:1 in an admixed polyclonal configuration.91,94 Within specific lymphoid organs, T cells are

B
Figure 111. T-cell lymphoblastic lymphoma. A, The lymphoblastic cells are small with fine, blastic (salt-and-pepper) chromatin and irregular nuclear envelopes ( 1,000 original magnification). B, The lymphoblastic cells are positive for nuclear Tdt (left) and surface CD1a (right) ( 400 original magnification).

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found physiologically in the paracortex of lymph nodes, in the periarterial lymphoid sheath (PALS) of splenic white pulp, in the marrow paratrabeculum, and in the peripheral blood as the dominant lymphoid element (85% T cells).94,96 Interestingly, although T cells are predominant physiologically, T-cell lymphomas are a relative rarity compared to the far more common B-cell lymphomas. In the United States, Bcell lymphomas predominate over PTLs by a factor of 8 or 9 to 1.93 In the pathologic circumstance of Tcell neoplasia, the usual proportions of T-cell subsets are commonly altered, and the microanatomic context is also aberrant. In particular, there may be expansion of the nodal paracortex or expanded splenic PALS region or increased marrow paratrabecular infiltration (Figure 112). The subset antigens may also be expressed in a mutually exclusive fashion (CD4+8 or CD48+), signifying a monoclonal helper/inducer or cytotoxic/suppressor T-cell malignancy.91 Most PTLs (75%) are of helper sub-

type.89,9799 Since occasional non-neoplastic T-cell inflammatory proliferations may show very aberrant helper/suppressor T-cell ratios (eg, 20:1 and vice versa), the CD4/8 antigens are not reliable clonal markers as an isolated finding.100 In this circumstance, the judgment of T-cell monoclonality is greatly aided by immunoblot or PCR assessment of TCR genes to establish clonal rearrangements. However, even molecular assays of clonality may prove problematic unless both / and / assays are performed. Complicating the diagnosis, phenotypically proven mature T-cell lymphomas without TCR rearrangements have been described.101 A more useful phenotypic finding of diagnostic import in PTL is the aberrant idiosyncratic loss of pan-T antigens (CD2, -3, -5, -7, -45RO) (see Figure 16).89,99,102 In the majority of PTLs (80%) there is loss of one or more pan-T antigens. This phenotypic loss, which is inconsistent with the expected physiologic phenotype (see Figure 110), is highly associ-

Figure 112. Small lymphocytic lymphoma, T-cell type. The upper left panel shows effacement of the node in a paracortical location. Note small residual germinal center. The lesional lymphoid cells are small, round, and regular, with moderate chromatin density. The lesional lymphoid cells are CD20 negative and CD3 positive ( 250 original magnification).

Pathology of Non-Hodgkins Lymphoma

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Figure 113. Angioimmunoblastic lymphadenopathy-like (AILD) peripheral T-cell lymphoma (PTL). This lymph node shows the emergence of large CD3-positive T-cell clusters in the context of AILD. The clustering of large T cells is considered characteristic of the transition to true neoplasia (404,000 original magnification).

ated with clonal rearrangement of the TCR genes in PTL and is decidedly not usual in benign inflammatory T-cell proliferations.89,99,102 These abnormal PTL phenotypes have no corresponding counterpart in normal T-cell ontogeny. This suggests that, unlike Bcell neoplasms, PTLs are not as likely to slavishly recapitulate normal lymphoid development. This novel or idiosyncratic phenotype of PTL helps to define it as a distinct aberrant immunologic entity, and the failure of PTL to fully mimic normalcy can serve a diagnostic purpose.89,99,103 The use of pan-T antigen loss to establish neoplasia has some caveats notably that occasionally a pan-T antigen (eg, CD7 in cutaneous infiltrates) may be absent in inflammatory conditions.93 Therefore, the loss of more than one pan-T-cell marker, and in particular one beyond CD7, is more reliable. Besides loss of pan-T antigens, another lineagerelated phenomenon of PTL serves as a diagnostic aid: unusual cross-lineage co-expression. In particular, CD20 pan-B antigen may be expressed rarely in

some PTLs.104 In this instance, the CD20+ CD3+ PTL has a normal counterpart in the form of a rare (< 1%) population of normal circulating T cells. However, in the neoplastic process, the emergence of this rare clone to predominance is decidedly pathologic, and the unexpected cross-lineage pattern of markers is the key phenotypic clue.104 Besides the common helper T-cell PTL and less frequent cytotoxic T-cell PTL, other variants of PTL exist. These include rare cases of aberrant double expression of CD4 and CD8.90,93 This CD4+ 8+ PTL mimics the thymic cortex phenotype, except that Tdt is absent and it is, in fact, a mature aberrant PTL phenotype. There are also PTLs with absence of both CD4 and -8 known as double-negative PTL.6,63,105 These include PTL with / rearrangements without CD4 and CD8, as shown in Figure 110 and S100+ PTL with some NK-like antigen co-expressions.1 Finally, there are double-negative PTLs without S100 and with NK antigens (eg, CD56), which represent NK-like PTL variants.1

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B
Figure 114. Anaplastic large cell lymphoma, T-cell type. A, The lymphoma cells are large, anaplastic, pleomorphic cells with frequent wreath-like and horseshoe-like multinucleate forms (hematoxylin and eosin; 40, 100, 1,000, 1,000 original magnification) (touch preparation, Wrights stain). B, The pattern of growth is cohesive and involves primarily the sinusoids. The neoplastic cells are CD30 positive and sometimes ALK-1 positive as well ( 40100 original magnification).

Pathology of Non-Hodgkins Lymphoma

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Table 12. CHROMOSOMAL TRANSLOCATION AS A MECHANISM OF ONCOGENE ACTIVATION IN B-CELL MALIGNANCIES Oncogene Translocation t(1;19) t(11;14) t(14;18) t(14;19) t(8;14) t(2;8) t(8;22) t(3;14) t(11;18) t(1;14) t(9;14) Protein Disease LBL-B* Mantle cell lymphoma Follicular lymphoma CLL/SLL Burkitts lymphoma

BCL1 BCL2 BCL3 CMYC

Cyclin D1 Anti-apoptosis NF-KB inhibitor Mitogenic factor

BCL6 API2 BCL10 PAX5

Zinc finger transcription factor Antiapoptosis Antiapoptosis B-cell differentiation factor

Large B-cell lymphoma MALT lymphoma MALT lymphoma Immunocytoma (lymphoplasmacytic lymphoma)

*Lymphoblastic lymphoma B-cell type. Chronic lymphocytic leukemia/small lymphocytic lymphoma.

Lastly, many PTLs are mature T-cell neoplasms derived from activated T cells and therefore have abundant expression of activation antigens (eg, HLA-DR), IL-2 receptors (CD25), T-cell activation antigen (TAC), and CD30 Ki-1 antigen, a nerve growth factor receptor.1 Selected T-Cell Neoplasms This section focuses on selected T-cell neoplasms more specifically named beyond the broad categorization of PTL (Figures 111 to 118).
Precursor T-Cell Lymphoblastic Leukemia/Lymphoma

Morphology and Immunophenotyping (Figure 111). Morphologically, precursor T-cell lymphoblastic leukemia/lymphoma is indistinguishable from its B-cell counterpart. The neoplastic population consists of medium-sized cells, with round or slightly convoluted nuclei, fine and evenly dispersed chromatin, and scant blue cytoplasm. The proliferative rate is very high. Phenotyping demonstrates a T-cell phenotype with cytoplasmic CD3 (in the absence of surface CD3) and fairly constant expression of other pan-T-cell antigens CD2, CD5, and CD7. The neoplastic cells may or may not express CD4 and/or CD8. There may be aberrant patterns of expression such as double negative or double positive for CD4 and CD8. The phenotypic hallmark is the presence of nuclear Tdt, which occurs in virtually every single case.9,106

Cytogenetics. Rearrangement of the TCR genes is variable. IgH gene rearrangement is sometimes seen. The most common chromosomal abnormality consists of rearrangements of 14q11. Clinical Features. This disease affects children, adolescents, and young adults and is rarely seen in older adults. It accounts for more than 40 percent of childhood lymphomas and 15 percent of acute lymphoblastic leukemias and shows a male predominance (M:F = 10:1). It usually presents as a rapidly growing mediastinal mass or supradiaphragmatic lymph node. Other sites of involvement include the thymus, bone marrow, blood, gonads, and central nervous system. Up to one-third of patients have peripheral blood and/or bone marrow involvement at presentation. The disease usually presents at an advanced stage and is characterized by a highly aggressive behavior. Although it is potentially curable with chemotherapy, it has a worse prognosis than its B-cell counterpart (shorter disease-free survival).

Table 13. LYMPHOMAS WITH INFECTIOUS ETIOLOGY Lymphoma Burkitts lymphoma Hodgkins disease HIV-associated lymphoma Pleural-based lymphoma Japanese T-cell lymphoma/ leukemia Immunocytoma MALT lymphoma Agent Epstein-Barr virus Epstein-Barr virus HIV-1 HHV8, TB-associated HTLV-1 Hepatitis C virus Helicobacter pylori (stomach) Borrelia burgdorfi (skin, Lyme disease) Intestinal pathogen(s)

Mediterranean lymphoma

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MALIGNANT LYMPHOMAS

Anaplastic Large Cell T-Cell Lymphoma

Morphology and Immunophenotyping (Figure 114). The distribution of the neoplastic infiltrate is characteristically perifollicular and sinusoidal; the pattern of growth is deceitfully cohesive, sometimes simulating carcinoma. The malignant population consists of large anaplastic lymphoid cells. The chromatin pattern is somewhat blastic, and the nuclei are extremely pleomorphic, often with multinucleate wreath-like or horseshoe-like forms. Nucleoli are prominent and eosinophilic. ReedSternberg-like cells are usually present. Immunophenotyping reveals an aberrant T-cell phenotype with variable expression of pan-T-cell antigens (CD2, CD3, CD5, CD7, CD45RO) and constant expression of CD30 in the usual absence of CD15. The unique fusion protein ALK1 is sometimes present.107111 Cytogenetics. Up to 50 percent of cases exhibit the t(2;5) translocation,112,113 which results in the fusion of the NPM gene with the ALK gene.114,115 This abnormality is much more common in patients under 30 years of age, particularly pediatric patients with nodal disease. In addition, up to 60 percent of patients have clonal rearrangement of the TCR genes.116 Clinical Features. Anaplastic large cell lymphoma can present as a systemic disease, with nodal or extranodal involvement, or as a cutaneous form, in which the disease is confined to the skin.117119 The systemic form is more aggressive, but it is potentially curable. The cutaneous counterpart has a more indolent course but appears to be incurable, although spontaneous regressions have been described.
Mycosis Fungoides

Cytogenetics. Cytogenetic studies reveal translocation of the TCR genes.122,123 Clinical Features. This is the most common of the cutaneous T-cell lymphomas. Multiple skin plaques or nodules characterize this entity clinically.124 Because of the scaly nature of the lesions, sometimes mycosis fungoides is misdiagnosed as psoriasis. Lymph node and/or peripheral blood involvement occurs late in the course of the disease (Szary syndrome).125 Mycosis fungoides occurs almost exclusively in adults and follows an indolent course; however, transformation to a high-grade lesion, including anaplastic large cell lymphoma, has been described.126
Adult T-Cell Lymphoma/Leukemia

Morphology and Immunophenotyping (Figure 115). This entity is characterized by skin infiltration by small resting lymphoid cells with prominent epidermotropism. The diagnostic lesion is the socalled Pautriers abscess, characterized by clustered invasion of the epidermis by aggregates of neoplastic T cells. The lymphoid cells have a highly complex, cerebriform nuclear envelope.120 Immunophenotyping demonstrates a T-cell population that in most cases is of T-cell helper lineage (CD4+, CD8).121 Partial loss of pan T-cell antigens is sometimes seen.

Morphology and Immunophenotyping. Pronounced nuclear pleomorphism with hyperlobated nuclei (flower or clover-leaf nuclei) is found in the peripheral blood.105 The nodes are involved with a heterogeneous mix of small and large lymphoid cells with some multinucleate cells similar to ReedSternberg cells. Typical HTLV-1-associated neoplastic cells have a natural helper T-cell phenotype with co-expression of CD2, -3, -4, and -5 with absent CD7. The IL-2 receptor (CD25) is commonly highly expressed. The occasional admixed large Reed-Sternberg cells may be CD30 or CD15 positive, adding to diagnostic difficulty.105,127130 Cytogenetics. TCR2 genes are typically clonally rearranged. Demonstration of monoclonal or oligoclonal integration of HIV-III (HTLV-1) provirus by Southern blotting provides definitive proof of etiology. More recently, PCR methodologies have demonstrated proviral sequences in DNA extracted from tissues fixed in formalin and embedded in paraffin.131133 Clinical Features. Adult T-cell lymphoma/ leukemia (ATLL) is caused by the human retrovirus known as human T-cell leukemia virus 1 (HTLV-1).134,135 Common sites of involvement include lymph nodes, skin, liver, spleen, central nervous system, bone marrow, and peripheral blood, with widespread stage IV presentation being most frequent.

Pathology of Non-Hodgkins Lymphoma

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This entity occurs in adults in the endemic areas of Kyushu, Japan, the Caribbean, and the southern United States. The latter patients are largely but not exclusively African-American.128,129 The acute form presents with a high peripheral blood cell white count, hepatosplenomegaly, hypercalcemia, and lytic bone lesions with an aggressive course (survival < 1 year).105 Rarely, it may occur as chronic or smoldering subtypes frequently with a predominance of cutaneous involvement.

Hypercalcemia and lytic bone lesions are commonly found. Bony osteoclastic activity appears to be an untoward effect of the tax gene product of HTLVI, which induces a parathyroid-like hormone resulting in osteoclastic activity and hypercalcemia.136
Subcutaneous Panniculitis-Like PTL

Morphology and Phenotyping (Figure 116). Panniculitic peripheral T-cell lymphomas are lymphomas

B
Figure 115. Mycosis fungoides. A, There is a top-heavy cutaneous infiltration by small lymphocytes (hematoxylin and eosin; 100 original magnification). B, The epidermotropic lymphocytes form clusters within lacunae without adjacent spongiosis, known as Pautriers microabscesses (hematoxylin and eosin; 100 original magnification).

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that involve primarily the subcutaneous tissues, morphologically mimicking panniculitis.137140 Lymphoid cells infiltrate between and rim fat cells, creating a lace-like pattern suggesting panniculitis (see Figure 116). Critically, the majority of the lymphoid cells are morphologically atypical (see Figure 116). Most of the infiltrates would be classified as diffuse mixed small cleaved and large cell, diffuse large cell, or immunoblastic, under the Working Formulation, or as mixed medium and large cell or large cell by the REAL Classification scheme.137140 Karyorrhexis and frequent mitotic figures are characteristic (see Figure 19). Larger lesions show necrosis of connective tissue and fat. Scattered single benign histiocytes, granulomas, and foreign body giant cells may be seen within these areas of necrosis. In cases associated with the hemophagocytic syndrome, erythrophagocytosis by histiocytes is present.137140 The lymph nodes from patients with panniculitic PTL are not involved by lymphoma but may show sinus histiocytosis and erythrophagocytosis.

With immunohistochemistry, the majority of the panniculitic PTL are of cytotoxic T-cell type with expression of CD8 without CD4. Also, cytotoxic granular cell proteins are expressed (TIA-1 and perforin).141 Pan-T-cell antigens are often aberrant (eg, CD3+, 5; see Figure 116). The abundant karyorrhectic cells are thought to reflect release of cytotoxic granular cell proteins.141 Cytogenetics. Rearrangement of the T-cell receptor / chain gene is characteristic of the majority of cases, with TCR / rearrangement in others.137,138,141 Clinical Features. Patients are adults (reported age range of 19 to 54 years) who present with subcutaneous nodules, 1 to 13 cm in size, classically of the extremities. Most patients develop an associated hemophagocytic syndrome. The syndrome has been attributed to cytokine production by the malignant T cells.140 The hemophagocytic syndrome is generally florid and is often fatal. The differential diagnosis of panniculitic-like T-cell lymphoma includes virus-associated hemo-

Figure 116. Subcutaneous panniculitis-like T-cell lymphoma. There is a characteristic microanatomic pattern of lymphoma cells rimming individual adipocytes with expression of T-cell antigens (eg, CD3+43+) ( 400 original magnification).

Pathology of Non-Hodgkins Lymphoma

23

phagocytic syndrome. Patients with the latter disease may have a skin exanthema from a viral illness but do not show the subcutaneous infiltrate or the degree of pleomorphism seen in panniculitis-like PTL.
Enteropathy-Associated T-Cell Lymphoma (Intestinal T-Cell Lymphoma)

Morphology and Immunophenotyping (Figure 117). This T-cell lymphoma derives from the intraepithelial mucosal T cells of the small bowel. The tumor infiltrates the lamina propria and overlying epithelium and may invade through the muscularis propria, leading to thickening of the bowel wall (see Figure 117). Malignant cells invade the epithelium singly and in groups, giving rise to tumor cell collections resembling Pautriers microabscesses in mycosis fungoides and also resembling the lymphoepithelial lesions of clustered mucosal invasion found in mucosa-associated B-cell lymphomas (MALTomas) (see Figure 117).142 The tumor cells are usually large or immunoblastic, although in a minority of cases, a

predominant small cell component is found. There may be a background of celiac disease changes (villous atrophy) and increased numbers of normalappearing intraepithelial T cells.143,144 The neoplastic cells are T cells, with a characteristic CD3+, CD7+, CD4, CD8/+ phenotype. CD5 and HLA-DR are generally absent.144 The CD3+, CD7+, CD4, CD8 double-negative phenotype is also found in a proportion of intraepithelial T cells in normal small intestine. Interestingly, it is this same T-cell subset that is expanded in celiac disease.145 The tumor cells also frequently express HML-1, an antigen expressed by, though not specific for, intestinal intraepithelial T cells.145,146 By paraffin immunohistochemistry, the neoplastic cells stain with CD3 and CD45RO. CD30 is also frequently expressed and may be a useful marker to detect malignant cells in areas where the neoplastic infiltrate is obscured by acute inflammation from mucosal ulceration.147 The tumor cells also express P53 and generally show a very high proliferative index when stained with MIB1, a marker of proliferating cells.147

Figure 117. Intestinal T-cell lymphoma. There is a full-thickness infiltrate of the jejunum with superficial mucosal infiltration by CD3+ lymphoma cells ( 40, 100, 400, 400 original magnification).

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B
Figure 118. NK-like T-cell lymphoma/leukemia. A, These small blastoid lymphoid cells are superficially invading the dermis (upper left), paracortex of a lymph node (upper right), and the bone marrow (lower panels) ( 40, 40, 40, 250 original magnification). B, The same blastoid infiltrate shows expression of CD56 (NK-like) and aberrant T-cell features (CD3+5) ( 400 original magnification).

Pathology of Non-Hodgkins Lymphoma

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Cytogenetics. Genotyping shows rearrangement of the T-cell receptor / chain gene. Interestingly, this rearrangement is also frequently detected in areas of the small bowel unaffected by tumor but involved by celiac disease.147,148 / Chain rearrangement has been described in small-bowel biopsies from a patient with adult-onset celiac disease without evidence of malignant lymphoma, suggesting that the celiac disease lesions may be precursors of T-cell lymphoma lesions.148,149 Clinical Features. Enteropathy-associated T-cell lymphoma usually involves the small bowel, in particular the jejunum, where over 70 percent of the neoplasms are found, and is frequently multifocal.144,146 Generalized disease can involve not only lymph nodes but also other sites including spleen, liver, and lung.144,150 Enteropathy-associated T-cell lymphoma is a disease of older patients, with a median age of about 60 years. Although controversial, it is generally believed that the disease is strongly associated with celiac disease.151 Many patients present with celiac diseasetype symptoms with months to years of abdominal pain and weight loss. However, a significant number presents as an acute abdominal emergency with perforation or obstruction,144 without antecedent celiac disease symptoms. The disease is generally aggressive with frequent recurrences. The majority of patients die within 6 months of diagnosis. Survival is better in patients with localized (stage I), rather than advanced, disease.144,152
Hepatosplenic / T-Cell Lymphoma

The neoplastic cells phenotype as CD3+, TCR/+, and TCR/.156 Characteristically, they lack both CD4 and CD8 expression and are double negative by typing, although CD4, -8+ cases have been described (see Figure 110).157 Expression of the other pan-T-cell antigens, CD2 and CD5, may be weak or absent.154,155 Most of the cases described express the neural cell adhesion molecule, NCAM, CD56 and CD16 without CD25 and -57.153155 In paraffin section immunohistochemistry, the neoplastic infiltrate phenotypes as a T-cell infiltrate (CD3+, CD43+, CD45RO+). Cytogenetics. All cases show rearrangement of the TCR / receptor, and, additionally, some may show TCR / rearrangement.153155 Clinical Features. The disease may be aggressive, requiring multiagent chemotherapy. Patients typically present with fever, myalgia, arthralgia, and weight loss.158 This may lead to a clinical evaluation for fever of unknown origin. Splenomegaly and hepatomegaly are characteristic. The peripheral blood often shows a normal white blood cell count and anemia. However, there may be either thrombocytopenia or thrombocytosis. Although the white cell count is normal, examination of the peripheral smear reveals the presence of atypical lymphocytes. CONCLUSION As detailed above, the REAL/WHO classifications provided us with well-defined morphologic, immunologic and genotypic lymphoma entities. Most of these entities have clear-cut clinical definitions.57,58,63 The Nebraska study, in particular, shows that most REAL/WHO categories are readily and reproducibly diagnosed and have clinical relevance. We may now look forward to a universal, global definition of lymphomas, with a shift in emphasis away from taxonomy and on to identification of appropriate molecular targets of therapymoving toward curing all forms of lymphoma.

Morphology and Immunophenotyping. This is a neoplasm of / double-negative T cells that is characteristically associated with hepatosplenomegaly but with minimal lymph node involvement.153155 In the spleen, there is sinusoidal infiltration of the red pulp by uniform, medium-sized lymphoid cells, which have oval or folded, somewhat condensed, chromatin and moderate amounts of pale cytoplasm.153 Splenic involvement may lead to massive splenic enlargement. A similar lymphoid infiltrate is seen in the hepatic sinusoids. Lymph node involvement is likewise characterized by a sinusoidal and interfollicular neoplastic infiltrate leading to partial or complete nodal effacement.

ACKNOWLEDGMENTS The authors wish to thank Ms. Yvette Frutiger, Ms. Roshni Mehta, and Ms. Catherine Rangel for their

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technical assistance. This work was supported in part by the National Cancer Grant CA-32102-13.
17.

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