Extranodal lymphomas

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Haematopoietic and Lymphoid Tissues (2008),2 are characterized by exclusively extranodal origin. Others may arise at either nodal or extranodal sites with varying frequencies, and some almost always arise within lymph nodes but may involve extranodal sites secondarily. Both the lymphoma subtype and the organ involved may influence the clinical behaviour and management of the lymphoma.

Extranodal lymphomas Chris M Bacon

Abstract The assessment of extranodal lymphomas poses considerable challenges to general surgical histopathologists and specialist haematopathologists alike. The breadth of lymphoma subtypes that may occur at extranodal sites, the variation in morphology, immunophenotype, genetics and clinical features within and between these entities, the difficulties in distinguishing these lymphomas from reactive lymphoid infiltrates or other neoplasms, and the different clinical significance of lymphomas with primary versus secondary involvement of extranodal sites, all contribute to these challenges. In this review, I will discuss several lymphomas defined by extranodal origin (in particular extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue/MALT lymphoma, and enteropathy-associated T cell lymphoma) and aspects of selected others likely to be encountered at extranodal sites, with an emphasis on practical histopathological assessment. Lymphomas of the spleen, skin, bone marrow and thymus are not covered, as these are comprehensively reviewed in companion articles.

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) e MALT lymphoma MALT lymphomas are small B cell lymphomas that arise in mucosal (e.g. GI tract, lung), glandular (e.g. salivary and thyroid glands, breast) or, more rarely, other extranodal tissues (e.g. kidney, dura), often on a background of chronic inflammation of infective or autoimmune aetiology that induces the formation of lymphoid tissue (acquired MALT) where previously there was none.3e5 Most firmly associated with MALT lymphoma are Helicobacter pylori-associated gastritis (stomach),6 Sjogren syndrome (salivary gland) and Hashimoto thyroiditis (thyroid gland). Indeed, eradication of H. pylori by antibiotic therapy is standard first-line therapy for most patients with gastric MALT lymphoma, resulting in remission in approximately 75% of cases, and pathologists reporting gastric MALT lymphomas should routinely seek H. pylori, using immunohistochemistry if necessary.6,7 Other associations of less certain clinical impact include Chlamydia psittaci and ocular adnexal MALT lymphoma,8 Campylobacter jejuni and the MALT lymphoma variant immunoproliferative small intestinal disease/alpha heavy chain disease, and Borrelia burgdorferi and cutaneous MALT lymphoma. Careful staging shows that MALT lymphoma, particularly at extragastric sites, is a disseminated (stage III/IV) disease at diagnosis in approximately 30% of patients. In many cases this is due to involvement of multiple mucosal sites; involvement of distal lymph nodes or bone marrow is uncommon (<10% and 2e15% respectively).3,9 MALT lymphoma has a characteristically indolent course and is typically treated with antibiotics, radiotherapy or relatively nonaggressive chemotherapy.7

Keywords diffuse large B cell lymphoma; enteropathy-associated T cell lymphoma; extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue; extranodal NK/T cell lymphoma nasal type; follicular lymphoma; histopathology; immunohistochemistry; lymphoma; molecular pathology

Introduction Proposed definitions of extranodal lymphoma vary, according to purpose, from lymphomas restricted to a single extranodal site and its regional lymph nodes to lymphomas which may be more widespread but in which an extranodal organ is the presenting and predominant site of disease, to which therapy may be primarily aimed. Depending on geography and definition, including whether sites rich in primary lymphoid tissue such as Waldeyer’s ring and spleen are considered extranodal, extranodal lymphomas represent approximately 25e50% of all nonHodgkin lymphomas (only 2e5% of classical Hodgkin lymphomas present at extranodal sites).1 Most common are lymphomas of the gastrointestinal (GI) tract, followed by those arising in the skin, Waldeyer’s ring, central nervous system, salivary glands, orbit, lung, bone, sinonasal tract, thyroid gland, testes, breast and other sites.1 Some lymphoma subtypes, as classified in the WHO Classification of Tumours of

Morphology and immunophenotype General features: MALT lymphomas recapitulate the architecture and cytology of physiological MALT.2,10,11 The neoplastic cells resemble, and appear to arise from, the marginal zone B cell compartment. They are typically seen surrounding reactive follicles (which have CD10þ, Bcl6þ, Bcl2 germinal centres and IgDþ mantle zones), spreading outwards beyond the normal boundaries of the marginal zone to form diffuse or vaguely nodular infiltrates which efface the underlying tissue architecture (Figure 1). The lymphoma cells may resemble small mature lymphocytes with round nuclei and little cytoplasm, centrocytelike cells with slightly larger, rather irregular nuclei, or monocytoid cells with abundant pale cytoplasm (Figure 2). Regardless of cytology, the neoplastic B cells almost always express a ‘‘marginal zone’’ immunophenotype: CD20þ, CD79aþ, IgD, IgM([IgA/IgG)þ, CD5, CD10, Bcl6, cyclin D1, with a low Ki67-proliferation fraction. A population of large transformed, nucleolated, neoplastic B cells is usually scattered amongst the small cells, and there are often numerous CD3þ

Chris M Bacon MB ChB PhD FRCPath is a Royal College of Pathologists/ Health Foundation/Pathological Society of Great Britain & Ireland Senior Clinician Scientist Fellow and Senior Lecturer in Haematopathology at the Northern Institute for Cancer Research, Paul O’Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH; and an Honorary Consultant Haematopathologist at Newcastle upon Tyne Hospitals NHS Foundation Trust, UK.

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Basic immunoarchitecture of MALT lymphoma. In this example of a gastric MALT lymphoma, the mucosa is heavily infiltrated by neoplastic CD79apositive B cells surrounding reactive lymphoid follicles a, b. Staining for CD10 c and IgD d highlights a CD10-positive reactive germinal centre surrounded by a residual IgD-positive mantle zone, beyond which are IgD-negative lymphoma cells in an expanded marginal zone distribution. The neoplastic B cells typically form lymphoepithelial lesions e. A marginal zone distribution is also often seen when MALT lymphoma spreads to lymph nodes f. Figure 1

small reactive T cells. In approximately a third of cases, the neoplastic clone shows plasma cell differentiation, which may be so marked as to suggest an extramedullary plasmacytoma. Neoplastic plasma cells are best distinguished from reactive plasma cells by the demonstration of immunoglobulin light chain restriction by immunohistochemistry or in situ hybridization. In many cases, immunohistochemistry can also demonstrate immunoglobulin light chain restriction of the small B cells. The expression, in approximately a third of cases, of CD43 by sheets of small B cells is also helpful in suggesting lymphoma. Caution is warranted however, as CD43 may be expressed by intraepithelial B cells in MALT and in myoepithelial sialadenitis, and in B cells undergoing plasma cell differentiation.

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In glandular tissue, an important diagnostic feature is the presence of convincing lymphoepithelial lesions (LELs): infiltration and distortion of epithelial structures by aggregates of (three or more) lymphocytes, often resulting in degenerative eosinophilic change to, or destruction of, the epithelial cells10,11 (Figure 1). Immunostaining for cytokeratin can be helpful in revealing unrecognized LELs or scattered epithelial remnants of destroyed glands. Care must be taken not to over-interpret the normal lymphoepithelium overlying lymphoid follicles in MALT, the infiltration of epithelium by T cells or the small lymphoepithelial lesions occasionally seen in florid chronic inflammation at mucosal or glandular sites. LELs may also be formed by lymphomas other than MALT lymphomas.

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Cytological spectrum of MALT lymphoma. The neoplastic B cells in MALT lymphoma may have the morphology of small lymphocytes a, ‘‘centrocytelike’’ cells b, ‘‘monocytoid’’ cells c, or plasma cells d. Variable numbers of large transformed cells are often present a. Figure 2

Reactive lymphoid follicles may not always be identified due to the sampling bias inherent in the small biopsies taken at many extranodal sites. They may also be overrun by lymphoma, resulting in a vaguely nodular appearance in which the follicles are betrayed by scattered Bcl6þ, CD10þ/ germinal centre fragments, residual IgDþ mantle zone cells and expanded underlying follicular dendritic cell meshworks revealed by staining for CD21. Less often, germinal centres are selectively infiltrated by lymphoma cells, which typically become slightly enlarged, but which may undergo transformation to large blasts or, rarely, to plasma cells.11,12 Occasionally, prominent follicular colonization may lead to morphological similarities to follicular lymphoma (FL).13 The distinction of a colonized follicle from a reactive follicle or from FL is aided by immunohistochemical

demonstration that the cells within the follicle centre are neoplastic (e.g. light chain restricted and/or Bcl2þ) but not of germinal centre phenotype (e.g. CD10, Bcl6) (Figure 3). However, the situation is complicated somewhat by the observations that both MALT lymphoma cells colonizing follicles and extranodal FL may be negative for Bcl2,14 that follicular lymphomas may be CD10, and that MALT lymphoma cells undergoing large cell transformation upon follicular colonization may sometimes express Bcl6. Occasionally, MALT lymphomas undergo high grade transformation to diffuse large B cell lymphoma (DLBCL). This is associated with more aggressive clinical behaviour and is usually an indication for anthracycline-based chemotherapy. Transformation to DLBCL is indicated by ‘‘solid or sheet-like

Follicular colonization in a MALT lymphoma. The germinal centre is replaced by neoplastic B cells, including large transformed cells a. The demonstration of underlying follicular dendritic cell meshworks is helpful in distinguishing these follicles from small foci of diffuse large B cell lymphoma b. The colonizing lymphoma cells are CD10-negative c and may be positive or negative for Bcl2 (in this case positive) d. Figure 3

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(Figure 4).19 Therapeutic responses are associated with regression of the diffuse infiltrate and the LELs, together with fibrosis or ‘‘emptying’’ of the lamina propria with gland loss and replacement by loose connective tissue and scattered plasma cells. In some cases, small basal lymphoid aggregates containing T cells and small B cells remain. Although molecular studies suggest that these aggregates often contain B cells that are part of the neoplastic clone,20 and they are thus considered ‘‘probable minimal residual disease’’ in the GELA scheme, they are not active disease and can be considered a state of histological remission suitable for continued endoscopic follow-up.21 Indeed, long-term follow-up of patients with infiltrates consistent with ‘‘responding residual disease’’ remaining 12 months from therapy shows that the majority either attain remission or follow a prolonged stable course without disease progression, such that in the absence of symptoms continued follow-up alone may be appropriate in this group as well.22 In patients showing ‘‘no change’’, second-line therapy is considered.

proliferations of transformed cells’’, but minimal criteria for such proliferations are lacking.2 Some authors have considered the presence of clusters of more than 20 large cells, usually in a background of dispersed large cells representing more than 10% of all cells, to represent large cell transformation in gastric MALT lymphoma and have demonstrated an adverse prognostic significance of such clusters.15,16 The significance of the number of individually-disposed large blasts present in MALT lymphomas is currently uncertain and at present there are no established guidelines for histological ‘‘grading’’ of MALT lymphoma in this way. Transformation to DLBCL should be reported as such and the confusing term ‘‘high grade MALT lymphoma’’ is discouraged.2 Site-specific features Gastric MALT lymphoma: the most frequent problem in the diagnosis of gastric MALT lymphoma is its differentiation from chronic gastritis in small biopsies in which architectural information may be limited. Helpful morphological features favouring MALT lymphoma are a dense lymphoid infiltrate extending to the luminal surface, prominent LELs, more than occasional Dutcher bodies in plasma cells, and moderate cytological atypia or monotony of lymphoid cells.17 Wotherspoon et al have proposed a useful scoring system to relate morphological findings to the likelihood of a lymphoid infiltrate being a gastric MALT lymphoma (Table 1).18 The immunohistochemical confirmation of an aberrant immunoarchitecture, with a densely packed infiltrate of IgD- B cells extending beyond the follicular marginal zone, between glands or to an extent not typical of reactive B cells, is strongly supportive of MALT lymphoma and demonstration of light chain restriction is diagnostic. Such features are also helpful in the distinction of MALT lymphoma from reactive lymphoid hyperplasia at other mucosal sites. A further area of difficulty is the assessment of endoscopic biopsies taken to assess the response of gastric MALT lymphomas to H. pylori-eradication therapy. To facilitate meaningful and consistent reporting of such biopsies, a helpful and reproducible grading system has been devised by the Groupe d’etude des Lymphomes de l’Adulte (GELA) (Table 2)

Salivary gland MALT lymphoma: salivary gland MALT lymphoma often arises, and must be distinguished, from myoepithelial sialadenitis. In early stages of MESA, reactive periductal lymphoid infiltrates structurally resembling MALT are readily distinguished from MALT lymphoma by their limited extent. When advanced, atrophic acinar tissue is overrun by B cells, plasma cells and admixed reactive T cells, often with reactive lymphoid follicles, and characteristically with numerous epimyoepithelial islands. The latter are solid islands of proliferated ductal epithelium infiltrated by small B lymphocytes. The earliest morphological sign of the development of a MALT lymphoma is the presence of collars of pale monocytoid B cells around the epimyoepithelial islands. More established MALT lymphomas are expansile, often destructive, lymphoproliferations with the typical features of MALT lymphomas including cavitating LELs.23 Pulmonary MALT lymphoma: MALT lymphomas of the lung characteristically show a lymphangitic pattern of infiltration, spreading around blood vessels and along bronchovascular bundles, interlobular septa and visceral pleura, coalescing to

Wotherspoon scoring system for diagnosis of gastric MALT lymphoma Score 0 1 2 3

Description Normal. Chronic active gastritis. Chronic active gastritis with florid lymphoid follicle formation. Suspicious lymphoid infiltrate, probably reactive.

4

Suspicious lymphoid infiltrate, probably lymphoma.

5

MALT lymphoma.

Histological features Scattered plasma cells in LP. No lymphoid follicles. Small clusters of lymphocytes in LP. No lymphoid follicles. No LEL. Prominent lymphoid follicles with surrounding mantle zone and plasma cells. No LEL. Lymphoid follicles surrounded by small lymphocytes that infiltrate diffusely in LP and occasionally into epithelium. Lymphoid follicles surrounded by marginal zone cells that infiltrate diffusely in LP and into epithelium in small groups. Presence of dense diffuse infiltrate of marginal zone cells in LP with prominent LEL.

Biopsies with a score of 3 or more should be analyzed by immunohistochemistry and, when required, molecular analysis as discussed in the text.28 LP, lamina propria; LEL, lymphoepithelial lesions.

Table 1

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GELA histological grading system for post-treatment evaluation of gastric MALT lymphoma Score CR pMRD rRD NC

Lymphoid infiltrate Absent or scattered plasma cells and small lymphoid cells in the LP. Aggregates of lymphoid cells or lymphoid nodules in the LP/MM and/or SM. Dense, diffuse or nodular extending around glands in the LP. Dense, diffuse or nodular.

LEL   /þ þ

Stromal changes Normal or empty LP and/or fibrosis. Empty LP and/or fibrosis. Focal empty LP and/or fibrosis. No changes.

CR, complete histological remission; pMRD, probable minimal residual disease; rRD, responding residual disease; NC, no change; LEL, lymphoepithelial lesions; LP, lamina propria; MM, muscularis mucosa; SM, submucosa.

Table 2

(e.g. Wotherspoon score 3 or 4, Table 1) is diagnostic of lymphoma.27 Care must be taken not to over-interpret as clonal the temporally-variable pseudoclonal bands/peaks which may result from the selective amplification of rearranged IG genes from an oligoclonal B cell population present within a few reactive germinal centres or from a sparse lamina propria infiltrate. The role of B cell clonality analysis at other sites of MALT lymphoma is less well studied, but in general, as long as one understands the possible causes of false positive results, the demonstration of clonality in an extranodal lymphoid infiltrate suggestive of MALT lymphoma is strongly supportive of neoplasia. In contrast, current evidence does not support the need for B cell clonality analysis in the follow-up of gastric MALT lymphomas.

form confluent masses which efface the pulmonary parenchyma.24,25 This architecture, together with extension of B cells beyond the confines of reactive lymphoid follicles in the nodular areas, helps to distinguish MALT lymphoma from follicular bronchiolitis and rare cases of nodular lymphoid hyperplasia, which are more localized and have a reactive immunoarchitecture, and from lymphoid interstitial pneumonia in which the diffuse septal infiltrate is predominantly of T cells. LELs are formed with bronchial and bronchiolar epithelium but these are not specific for lymphoma in the lung. Occasionally, prominent deposition of amyloid or immunoglobulin leads to similarity to nodular amyloidosis. Diagnostic molecular pathology of MALT lymphoma Clonality analysis: in cases in which the morphological and immunohistological findings are suggestive but not diagnostic of MALT lymphoma, the careful application of molecular biological techniques for the detection of B cell clonality is often helpful. The current gold-standard PCR-based protocols, which produce highly sensitive and specific results in formalin-fixed paraffin-embedded tissues, are those of the BIOMED-2 Concerted Action program.26 In gastric biopsies, the demonstration of unequivocal monoclonality in a lymphoid infiltrate suspicious for MALT lymphoma

Detection of recurrent genetic abnormalities: the detection by interphase fluorescence in situ hybridization (FISH) of recurrent chromosomal abnormalities in MALT lymphomas may also be diagnostically and prognostically helpful.28 The major translocations in MALT lymphomas are t(11;18)(q21;q21)/ API2-MALT1, t(14;18)(q32;q21)/IGH-MALT1, t(1;14)(p22;q32)/ IGH-BCL10 and t(3;14)(p14;q32)/IGH-FOXP1, the molecular biology of which has been described elsewhere.29,30 The most prevalent of these, t(11;18)(q21;q21) is found most frequently in

Appearances of gastric MALT lymphoma following Helicobacter pylori-eradication therapy. Both biopsies show an ‘‘empty’’, oedematous lamina propria associated with a therapeutic response. a, b Responding residual disease; c, d Probable minimal residual disease. Figure 4

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gastric and intestinal (approximately 25% of cases) and pulmonary (40%) cases, less often in ocular adnexal MALT lymphomas (5e15%), and rarely in MALT lymphomas of the skin, salivary gland, and thyroid gland.31 While its detection can be helpful in the initial diagnosis of MALT lymphoma at prevalent sites, its major importance lies in the prognostication of gastric MALT lymphoma. The presence of t(11;18)(q21;q21) in gastric MALT lymphomas is associated with H. pylori negative disease, with spread beyond the stomach, with a lack of responsiveness to H. pylori-eradication therapy and possibly with a worse response to oral alkylating agents.32e35 Furthermore, t(11;18)(q21;q21) is rarely found in gastric DLBCL, with or without a MALT lymphoma component, suggesting that MALT lymphomas containing the translocation are less likely to transform to DLBCL than t(11;18)(q21;q21) negative cases.30

The t(14;18)(q32;q21)/IGH-MALT1 is found infrequently in MALT lymphomas arising at non-gastric sites, being identified in 5e20% of cases arising in the ocular adnexa, lung, and salivary gland.31 Only a small minority of MALT lymphomas (e.g. 4e8% of gastric and pulmonary MALT lymphomas) contain a t(1;14)(p22;q32).31 The t(3;14)(p14;q32), or variant translocations of FOXP1 to non-IGH partner genes, are similarly uncommon having been identified in only occasional MALT lymphomas of the stomach, thyroid gland and orbit.31,36 There is preliminary evidence that the t(1;14)(p22;q32) may be of similar prognostic significance to t(11;18)(q21;q21) in gastric MALT lymphomas,37 but the low prevalence of these translocations limits the clinical utility of their detection. More frequent, especially in t(11;18)(q21;q21)-negative cases is aneuploidy, particularly trisomy 3 and trisomy 18. However, while the

Primary extranodal follicular lymphoma. Follicular lymphoma of the duodenum a, showing expression of CD10 b and Bcl2 c. Other primary extranodal follicular lymphomas, such as this example in the thyroid gland d, may express CD10 e but be negative for Bcl2 f. Figure 5

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Other small B cell lymphomas/leukaemias While it is unusual for chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) alone to generate an extranodal mass, CLL/SLL is not infrequently found incidentally in biopsies of extranodal tissues, often in association with additional pathology. In some cases this represents the first diagnosis of CLL/SLL, which can remain sub-clinical for a prolonged period. A dense, monotonous infiltrate of small mature lymphocytes should raise a suspicion of CLL/SLL and prompt immunohistochemical assessment. Finally, it is noteworthy both that MALT lymphoma may be associated with paraproteinaemia, usually of IgM type, and that lymphoplasmacytic lymphoma may mimic MALT lymphoma when it secondarily involves extranodal sites, such that in some cases clinicopathological correlation is needed to distinguish these diagnoses.48

presence of these numerical abnormalities supports a diagnosis of lymphoma, they are not specific for MALT lymphoma.

Extranodal presentation of other small B cell lymphomas Follicular lymphoma While extranodal involvement by FL most often occurs as dissemination of nodal disease, primary extranodal FL accounts for approximately 10e15% of cases and is well documented at sites including the GI tract, especially the duodenum, salivary and thyroid glands, orbit, breast and testes.1 FL represents approximately 5e10% of lymphomas of Waldeyer’s ring and is thus rather under-represented at this site compared to lymph nodes.38 In general, the morphological features of extranodal FL are similar to those of nodal FL. Notably, a prominent diffuse component is more often seen in extranodal than nodal cases,39,40 sometimes leading to diagnostic difficulty and a reliance on immunophenotyping when a small biopsy lacks follicles. Many extranodal FLs share the immunomorphological and genetic features of typical adult nodal FL: a preponderance of WHO grade 1/2 disease, a CD10þ, Bcl6þ, Bcl2þ immunophenotype, and the t(14;18)(q32;q21)/IGH-BCL2. In particular, primary duodenal FL, which typically presents with localized disease and has an excellent prognosis, is characterized by these features.41 However, other cases, particularly at sites such as the testis, thyroid and salivary gland, may show (often concurrently) variant features such as negativity for t(14;18)(q32;q21), Bcl2 and CD10, and a tendency to be WHO grade 340,42e44 (Figure 5). The degree to which these features are over-represented in extranodal FL (as opposed to stage 1 disease regardless of site), and their clinical significance, is debated but they can undoubtedly lead to diagnostic difficulties. When t(14;18)(q32;q21) and Bcl2 are negative, distinction of FL from a reactive infiltrate depends largely on morphological assessment, demonstration of a reduced germinal centre Ki67-proliferation fraction and demonstration of extrafollicular spread of germinal centre cells. CD10-negativity can be problematic when assessing the extrafollicular small B cell population in a small biopsy, and in distinguishing a neoplastic follicle in FL from one colonized by MALT lymphoma (see above). This difficulty is compounded by the fact that extranodal FL can show florid marginal zone differentiation mimicking a MALT lymphoma.45

Extranodal (non-thymic) diffuse large B cell lymphomas and Burkitt lymphoma ‘‘Diffuse large B cell lymphomas’’ are a clinically and biologically heterogeneous group of aggressive lymphomas. The current WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (2008) identifies several distinct types of ‘‘diffuse large B cell lymphoma’’ as distinct clinicopathological entities.2 Many of these, discussed briefly below, are partly defined by their typically extranodal presentation. However, up to 40% of the large remaining group, diffuse large B cell lymphoma, not otherwise specified (DLBCL-NOS), also arise at extranodal sites, most often in the GI tract but also in Waldeyer’s ring, liver, soft tissue, bone, breast, gonads, endocrine and exocrine tissues and other organs.1 At most of these sites, DLBCL-NOS is the most frequent lymphoma subtype. Extranodal DLBCL-NOS is relatively increased in frequency in immunosuppressed individuals. Although sharing features typical of DLBCLNOS at any site e destructive tumours composed of diffuse sheets of large atypical B cells with prominent nucleoli and a high proliferative rate e DLBCL-NOS arising at some extranodal sites has characteristic features. For example, DLBCL-NOS arising in bone often has multilobated nuclei, and DLBCL-NOS of the testis and stomach are usually of non-germinal centre immunophenotype while those of the small intestine and Waldeyer’s ring are more often of germinal centre phenotype.49e52 There is also emerging evidence of differences and similarities in somatic genetic abnormalities between DLBCL-NOS arising at different sites. For example, DLBCL-NOS of the testis and CNS-DLBCL (both tumours of immune privileged sites) share characteristic deletions of chromosome 6p21.3 leading to loss of HLA genes, not seen in nodal DLBCL.53 Clinically, DLBCL-NOS of Waldeyer’s ring and the GI tract have a better prognosis than DLBCL-NOS overall, while testicular DLBCL-NOS has a worse outcome with a tendency for spread or relapse to other extranodal sites, particularly the CNS, and a propensity for late relapse.52,54 Undoubtedly, there is more to be learned of the pathogenesis of diffuse large B cell lymphomas at distinct extranodal sites.

Mantle cell lymphoma Most patients who develop extranodal mantle cell lymphoma (MCL) do so in the GI tract or Waldeyer’s ring, in the context of disseminated nodal disease. In fact, approximately 90% of MCL patients have endoscopic evidence of GI involvement at diagnosis.46 Primary extranodal disease does occur however, again most often in the GI tract. In many cases this takes the form of multiple lymphomatous polyposis, although some GI MCL present with solitary lesons and lymphomatous polyposis can also be a manifestation of FL and MALT lymphoma.47 Extranodal MCL has identical, histological, immunophenotypic and genetic features to that present in lymph nodes. Distinction of MCL from other small B cell lymphomas is critical as it typically has a more aggressive clinical behaviour. Routine inclusion of cyclin D1 in the immunophenotypic assessment of extranodal small B cell proliferations should prevent misdiagnosis.

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Plasmablastic lymphoma Plasmablastic lymphoma (PBL), as originally described by Delecluse et al,55 is a tumour of large lymphoid cells with immunoblastic morphology (vesicular nuclei, large central

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nucleoli and moderately abundant basophilic cytoplasm) but with the immunophenotype of plasma cells (negative or weakly positive for CD20, Pax5 and CD45, variably positive for CD79a, positive for CD138, CD38, and MUM1, generally with demonstrable cytoplasmic immunoglobulin). These PBLs occur most often in HIV-positive individuals, sometimes in the context of other forms of immunosuppression, and rarely in the immunocompetent. They typically occur in the oral or sinonasal cavities, also at other extranodal sites such as the lower GI tract, but rarely in lymph nodes. Most cases (approximately 75%) are EBVpositive, expressing EBER but not LMP1. More recently it has been considered that the spectrum of PBL includes cases composed of large cells showing plasmablastic morphology (round nuclei containing moderately clumped chromatin and variably prominent nucleoli, often eccentrically situated in basophilic cytoplasm) admixed with variable numbers of smaller cells with plasmacytic morphology, including binucleate forms.56 Many cases with such plasmacytic differentiation are EBVþ and present classically with oral disease in the immunosuppressed, but higher proportions of extra-oral or nodal cases, of cases in immunocompetent individuals, and of EBV-negative cases are seen in this group. A minority of PBL express CD30, Bcl6, CD10 or CD4. PBL typically has a high Ki67-proliferation fraction and an aggressive clinical behaviour. MYC translocations are present in approximately 40% of cases. Other types of large B cell lymphoma which may show plasmablastic immunomorphology at extranodal sites and must be distinguished from PBL include ALK-positive large B cell lymphoma, DLBCL associated with chronic inflammation, and extra-cavitary primary effusion lymphoma, as well as both DLBCL-NOS and Burkitt lymphoma with plasma cell (secretory) differentiation, which are distinguished by their complete B cell immunophenotypes.2 However, at times the most difficult differential diagnosis is between a PBL with plasmacytic differentiation and an extramedullary plasmablastic/anaplastic plasmacytoma or plasma cell tumour associated with plasma cell myeloma. Indeed, these may be morphologically and immunophenotypically indistinguishable, particularly as PBL may express proteins such as CD56 typically associated with plasma cell neoplasms, and plasmablastic/anaplastic plasmacytoma may have a high Ki67-proliferation fraction and may occasionally be EBV-positive.56e58 In general, EBV-positivity, a low proportion of mature plasma cells, a very high Ki67-proliferation fraction and immunosuppression favour PBL, but clinical studies and follow-up to exclude a myeloma are prudent.

and fever. Finally, some patients, typically female, present with exclusively cutaneous disease without haematological manifestations and have a significantly better outcome. The neoplastic cells express B cell antigens CD20 and CD79a, have variable expression of CD5, CD10 and Bcl6, and have a high Ki67-proliferation fraction. Some cases with the typical features of intravascular large B cell lymphoma (IVLBCL) occur before, concomitant with, or after a solid lymphoma of varying morphology. The relationship between these components is unclear, but IVLBCL must be distinguished from vascular involvement by small B cell lymphomas or T cell lymphomas. Primary diffuse large B cell lymphoma of the CNS CNS-DLBCL are aggressive lymphomas that present as single or multiple lesions in the brain parenchyma or as intra-ocular lymphoma.2 There may be spread between the brain and the eye, but dissemination to extraneural sites is very rare. Morphologically, CNS-DLBCL are diffuse infiltrates of centroblasts or immunoblasts, with a tendency to cluster around cerebral blood vessels, often accompanied by small reactive T cells and reactive accessory cells. There is often marked tumour necrosis, especially following the administration of corticosteroids. Approximately 90% of cases show a non-germinal centre immunophenotype (CD10, Bcl6þ/, MUM1þ).61 BCL6 rearrangements and del(6)(q22) are seen in approximately 20% and 45% of cases respectively, and may be associated with an adverse prognosis.62 The Ki67-proliferation fraction is typically high. CNS-DLBCL presenting in immunosuppressed individuals is often EBV-positive. CNS-DLBCL must be differentiated clinically from secondary CNS involvement by systemic DLBCL, for which the involvement of multiple extranodal sites or specific extranodal sites such as the testis and sinonasal cavity is a risk factor. Occasional T cell lymphomas and other B cell lymphomas such as dural MALT lymphomas must also be distinguished. Primary effusion lymphoma Primary effusion lymphomas (PEL) are rare human herpesvirus 8 (HHV8)-associated lymphomas that usually present as serous effusions in the pleural, peritoneal and pericardial cavities.2,63,64 The majority of patients are profoundly immunosuppressed HIVpositive individuals, but PEL also sometimes develop in the setting of iatrogenic immunosuppression or in elderly people from areas of high HHV8 seroprevalence. Some patients with body cavitybased PEL develop solid, frequently extranodal, tumours during the course of their disease (Figure 6) and rarely a solid mass is the only manifestation (extra-cavitary PEL).65 The neoplastic cells are large immunoblastic, plasmablastic or anaplastic cells. Although they may express CD45, they typically lack pan-B cell antigens, CD10, Bcl6 and immunoglobulin, while often expressing plasma cell and activation antigens such as CD138, MUM1, CD38 and CD30. HHV8 is best detected by immunohistochemistry for the nuclear LANA-1 protein. In most PEL the neoplastic cells are co-infected by EBV, detectable by EBER in situ hybridization, but LMP1 is not expressed. The prognosis of PEL is very poor. Other lymphomatous effusions, secondary to solid lymphomas or leukaemias such as DLBCL, Burkitt lymphoma and precursor lymphoblastic lymphoma/leukaemia, are distinguishable from PEL on clinical grounds, morphologically and by use of immunohistochemistry, particularly for LANA-1.

Intravascular large B cell lymphoma These are rare, aggressive and often widely disseminated lymphomas in which there is selective growth of large B cells in small blood vessels, capillaries and sinusoids of extranodal tissues. They may float within vessel lumina or aggregate and expand the vessel; minimal extravascular spread may be seen. Three apparently distinct clinicopathological variants are recognized.2,59,60 The classical form (Western form, but not limited to the West) is characterized by frequent involvement of the CNS and skin, as well as liver, spleen, bone marrow, lungs, kidneys and endocrine organs, with symptoms relating to the sites of disease. The haemophagocytosis-related (Asian) form is associated with morphological and clinical features of haemophagocytic syndrome including hepatosplenomegaly, pancytopenia

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Primary effusion lymphoma. The bowel wall is effaced by an ulcerated solid lymphoma a composed of large pleomorphic cells with prominent nucleoli b. Similar cells are present in ascitic fluid c. Immunostaining shows expression of plasma cell antigens such as CD138 d but not pan-B cell antigens such as CD20 and Pax5 (not shown). The cells are positive for HHV8 e and EBV (positive staining is blue-black) f. Figure 6

Lymphomatoid granulomatosis Lymphomatoid granulomatosis (LyG) is a rare extranodal, EBVassociated, lymphoproliferative disorder with a spectrum of histological grade and associated clinical aggressiveness.2,66,67 The lungs are involved in >90% of patients, but other sites such as the skin, brain, kidneys and liver may be involved. LyG presents as nodules formed by an angiocentric and angiodestructive polymorphous infiltrate rich in reactive T cells of variable size, macrophages and plasma cells. Amongst these are varying numbers of large EBV-positive B cells which may be immunoblastic or more pleomorphic, resembling Hodgkin cells. The atypical cells express CD20 and CD79a and may express CD30 and LMP1, but are CD15-negative. There is typically transmural

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vascular infiltration leading to infarct-like tissue necrosis. LyG is subclassified based upon the number of large EBV-positive B cells present into three grades, from grade 1 in which there are only rare large atypical EBV-positive cells, highlighted by immunohistochemistry and in situ hybridization for EBER, to grade 3 in which there are numerous large, often pleomorphic, atypical EBV-positive cells which often form sheets. Grade 3 LyG is considered an aggressive lymphoma and is managed as such. Grade 1 and 2 cases may progress to frank lymphoma or follow a more indolent course. The differential diagnosis of LyG can be very difficult, especially in small biopsies in which atypical cells may be scarce. The general absence of epithelioid granulomas, multinucleate giant cells and necrotizing vasculitis, and the EBV-positivity, aid

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distinction from Wegener granulomatosis. Amongst lymphomas, extranodal natural killer (NK)/T cell lymphoma, nasal type (discussed below) and classical Hodgkin lymphoma in particular may mimic LyG histologically. The presence of classical ReedeSternberg cells with loss of B cell antigens suggests the latter. Polymorphic post-transplant lymphoproliferative disorders may have an LyG-like appearance.

nucleoli amongst which are tingible body macrophages but few reactive lymphocytes; CD20þ, CD10þ, Bcl6þ, Bcl2, Ki67 >98% immunophenotype; and IG-MYC, but no other, chromosomal translocations. However, as discussed elsewhere2 (see also the review in this issue by Gatter and Pezzella), some aggressive extranodal lymphomas in which Burkitt lymphoma is in the differential diagnosis share sufficient overlapping biological features with DLBCL, NOS to be best considered B cell lymphoma, unclassifiable, with features intermediate between large B cell lymphoma and Burkitt lymphoma.

Diffuse large B cell lymphoma associated with chronic inflammation DLBCL associated with chronic inflammation (DLBCL-CI) is an EBV-associated large B cell lymphoma with aggressive behaviour, which develops at sites of prolonged (usually more than 10e20 years) chronic inflammation.2 The prototypic example is pyothorax-associated lymphoma (PAL), which occasionally develops as a solid mass in the pleura or peripheral lung of patients in whom an artificial pneumothorax has been induced to treat tuberculosis.68 Similar tumours rarely develop in the bones, joints or skin in the context of chronic osteomyelitis, metallic orthopaedic implants, or chronic skin ulcers. Most remain localized. The neoplastic large B cells usually have a nongerminal centre immunoprofile or may show plasmablastic features as discussed above.

Extranodal T cell lymphomas Enteropathy-associated T cell lymphoma Typical (type 1) enteropathy-associated T cell lymphoma (EATL) is an uncommon aggressive tumour derived from intestinal intraepithelial T lymphocytes (IELs), usually occurring in adult patients with coeliac disease (CD).2,70 Accordingly, EATL is most frequent in Northern European countries were CD is relatively prevalent. EATL patients may have a history of CD or refractory CD (RCD; see below) of variable duration, or be diagnosed with CD concurrently with the diagnosis of EATL. In rare patients without a prior diagnosis of CD, perhaps those with latent CD, diagnostic mucosal features of enteropathy are not present but the anti-gliadin/endomysial/tissue transglutaminase antibodies and HLA-DQ2/8 genotype typical of CD are nevertheless identified. EATL may present with worsening of CD despite a gluten-free diet (GFD), abdominal pain, weight loss, or intestinal obstruction or perforation.71 The lymphoma typically involves the jejunum or ileum, but may involve other parts of the GI tract, and produces single or multifocal ulcers, plaques, nodules, strictures and less often masses. The disease is localized to the intestine and mesenteric lymph nodes in approximately 70% of patients. It may disseminate to other extranodal sites such as liver, spleen, lung or skin, but rarely involves the bone marrow. In occasional patients, presentation is with extra-gastrointestinal lymphoma and only subsequently is intestinal lymphoma or RCD detected. The median survival from EATL is less than 12 months, partly because many patients are not fit for combination chemotherapy and this, when given, is frequently complicated by significant comorbidity. Those treated have a 5 year overall survival of approximately 30%.71

EBV-positive diffuse large B cell lymphoma of the elderly EBV-positive DLBCL of the elderly is a group of clonal B cell lymphoproliferations, similar in many respects to EBV-associated lymphoproliferative disorders seen in immunosuppressed patients, but occurring in patients over 50 years old in whom the immunological deterioration associated with ageing is the only factor predisposing to EBV-driven pathology.2,69 70% of patients have disease affecting extranodal sites, predominantly the skin, lung, stomach and tonsil. The tissue architecture is effaced (in contrast to infectious mononucleosis) by either polymorphic or monomorphic large B cell infiltrates, with frequent immunoblastic or Hodgkin/ReedeSternberg-like cells, accompanied by a variable reactive lymphohistocytic component and frequent necrosis. The EBV-positive B cells are usually positive for CD20, CD79a, MUM1 and LMP1, often for CD30 and cytoplasmic immunoglobulin, but not for CD15, CD10 or Bcl6. Distinction of the polymorphic cases from classical Hodgkin lymphoma can be difficult, but uniform expression of pan-B cell markers and immunoglobulin light chain restriction favours the former, while CD15 expression favours the latter.

Morphology, immunophenotype and genetics of type 1 EATL: microscopic examination of intestinal EATL reveals a diffuse, invasive infiltrate of neoplastic lymphoid cells, associated with ulceration, necrosis, fibrosis and a variable, often prominent, inflammatory component, including numerous macrophages and eosinophils that may be sufficient to obscure the lymphoma cells (Figure 7). The latter are most frequently uniform large cells with round or irregular nuclei and prominent nucleoli. In many cases they are pleomorphic, but they may be immunoblastic or frankly anaplastic.70 The neoplastic cells characteristically express cytoplasmic (but not surface) CD3, CD7 and cytotoxic granule proteins, but lack CD5 and CD4. Most are CD8-negative and express cytoplasmic (but not surface) TCRb. In most cases, CD30 is expressed by a varying proportion of cells and, when morphologically anaplastic, uniform expression of CD30 can lead to confusion with anaplastic large cell lymphoma. In most cases, the aEb7 integrin, recognized by antibodies to CD103/aE

Burkitt lymphoma The propensity of Burkitt lymphoma to present at extranodal sites must also be remembered. Although the classical facial presentation of endemic Burkitt lymphoma is extremely rare in sporadic cases, the latter often present with abdominal masses, particularly of the ileo-caecal region. The breasts, ovaries, kidneys and retroperitoneum may also be involved. Immunodeficiency-associated cases are more likely to involve lymph nodes. Distinction of Burkitt lymphoma from DLBCL variants is of critical importance due to its more aggressive behaviour, but potential for cure using high-intensity chemotherapy. Most cases can be accurately diagnosed based upon typical morphological, immunophenotypic and genetic features: monotonous infiltrates of medium-sized cells with basophilic cytoplasm and several

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Enteropathy-associated T cell lymphoma. The small intestinal wall contains a partially necrotic fissuring lymphoma, arising in an enteropathic mucosa a, and composed of large atypical lymphoid cells b. Immunostaining shows typical expression of CD3 c but not CD5 d. This case shows strong expression of CD30 e. There is characteristic expression of cytotoxic granule proteins (e.g. perforin, f ). Figure 7

integrin, is present. CD103 is expressed by normal IELs and, among T cell lymphomas, it is highly selective for EATL. In making the diagnosis of EATL it is important to examine the mucosa distal to the lymphoma, particularly in the jejunum. In many cases it shows typical features of active CD, but in some cases the only abnormality may be a subtle increase in IELs. Although cytologically normal, the distant IELs often have an aberrant immunophenotype identical to that of the lymphoma, CD8 negativity being most often demonstrated.72 In addition, molecular studies have shown these aberrant IELs to share the same clonal TCR gene rearrangements as the tumour, strengthening the assertion that EATL arises from IELs.72,73 Examination

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of involved mesenteric lymph nodes shows diffuse, paracortical or sinusoidal infiltration by lymphoma. However, enlarged nodes are not always involved by lymphoma: they may show nonspecific reactive features or lymph node cavitation, a peculiar reaction associated with malnutrition and CD, in which lymph nodes undergo central cystic change with peripheral displacement of lymphoid tissue.74 EATL shows a high frequency of chromosomal copy number abnormalities, but no recurrent translocations have been identified. Recurrent abnormalities in type 1 EATL include gain of 9q31.3dqter (approximately 70% cases) and almost mutually exclusive loss of 16q21.1 (30%), as well as gains of 1q32.2eq41

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Refractory coeliac disease e type II. The small intestinal mucosa shows features of active coeliac disease including a prominent intra-epithelial lymphocytosis a. The intra-epithelial lymphocytes are morphologically normal, but most have an aberrant CD3-positive b, CD8-negative c immunophenotype. Figure 8

(75%) and 5q34eq35.2 (80%).75 At present, detection of these abnormalities does not have clinical utility, but given their frequency, they represent promising targets for diagnosis and for understanding disease pathogenesis. EBV is rarely present in Western cases.

neoplastic and that RCD-II represents a cryptic intestinal T cell lymphoma.81 Some patients with RCD (usually RCD-II) develop ulcerative jejunitis, in which multiple mucosal ulcers and strictures develop. Although these lesions have non-specific inflammatory-looking histology, they have also been shown to contain T cells clonally identical to those in distant enteropathic mucosa and in subsequent EATL tumours, suggesting that ulcerative jejunitis also is a neoplastic phenomenon in many cases.73 The above discussion highlights the importance of histopathological assessment of the IEL population in CD patients with persistent symptoms or histological features of enteropathy despite adherence to a GFD. In this situation, immunohistochemical staining for CD3 and CD8, and PCR-based analysis of T cell clonality, are mandatory. The presence of >40e50% CD3þ, CD8 IELs and the demonstration of T cell clonality, particularly when concurrent, are suggestive of RCD-II. Care must be taken in interpretation of the results of a single biopsy as either an aberrant immunophenotype or clonality may occasionally be seen transiently in uncomplicated CD, particularly in the context of non-compliance with a GFD. However, the persistence in serial biopsies of concurrent aberrant immunophenotype and monoclonality is essentially diagnostic of established or emerging RCD-II. In a longitudinal series of RCD patients, Liu et al96 found that the recurrent demonstration of 80% CD3þ, CD8 IELs with concurrent monoclonality was a strong predictor of progression to EATL. Serial examination of all RCD patients in this way is required as patients initially lacking an abnormal IEL population may develop one with time, and the proportion of these cells within the epithelium of RCD-II patients often continues to rise with time.

Refractory coeliac disease: approximately 5% of CD patients present with, or develop secondarily, refractory coeliac disease (RCD): persistent clinical and histological features of CD despite prolonged adherence to a GFD.76e78 In some RCD patients (RCDI), most IELs have a normal immunophenotype (surface and cytoplasmic CD3þ, CD8þ) in keeping with that of the major CD3þ, CD8þ, TCRa/b IEL subset present in normal mucosa. These patients suffer considerable morbidity but uncommonly develop EATL. In contrast, RCD-II is defined by the presence of an abnormal IEL population with an aberrant immunophenotype (surface CD3, cytoplasmic CD3þ, CD8, often TCRa/b and g/d, and occasionally CD30þ) and/or with evidence of monoclonal TCR gene rearrangement76,79 (Figure 8). The aberrant immunophenotype and monoclonality are typically concurrent and persistent over repeated biopsies. Importantly, this group of patients has a more severe presentation and a worse prognosis than those with RCD-I, developing EATL in up to 50% of cases.77,78 Indeed, several studies have shown that, although cytologically normal, the aberrant IELs in RCD-II are clonally identical to the frankly malignant lymphoma cells in subsequent EATLs.80 Similarly, gains of 1q22eq44, equivalent to the chromosome 1q gains found in most type 1 EATLs, are found in cell lines derived from IELs in almost all RCD-II cases.78 There is thus considerable evidence that the abnormal IELs in RCD-II are

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Extranodal NK/T cell lymphoma, nasal type. This typical example shows necrosis a and angioinvasive, angiodestructive growth b. There are sheets of medium-sized to large atypical lymphoid cells c which express CD3 d and CD56 e. They are positive for EBV f. Figure 9

Finally, it is important to appreciate that the immunophenotypically aberrant clonal IELs in RCD-II are often disseminated throughout the GI tract, producing a picture resembling lymphocytic colitis and lymphocytic gastritis. They are also often detectable in peripheral blood and bone marrow as well as in skin, lung and liver.78,82 In addition to intestinal EATL, CD is also associated with an increased risk of non-intestinal T cell lymphomas.83 In some cases, these are morphologically and immunophenotypically consistent with EATL, including CD30þ large cell lymphomas, and both expression of CD103 and clonal identity with intestinal IELs in RCD-II suggest that at least some of these may be derived from disseminated neoplastic IELs.81,84 In the skin of RCD-II patients, atypical papular or ulcerated lesions can develop, from which frank lymphomas may arise.78

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Other intestinal T cell lymphomas: in addition to type 1 EATL, a type 2 variant has been described.2,75,85 The neoplastic cells are monomorphic medium-sized cells with dark, round nuclei and little cytoplasm, and a CD3þ, CD8þ, CD56þ, TCRa/ bþ immunophenotype that differs from type 1 EATL. While type 1 and type 2 EATLs share 9q gains and 16q deletions, the latter usually lacks gains of 1q and 5q and instead has more frequent gain of the MYC locus on 8q24. Clonally related IELs of identical phenotype can be seen in non-lymphomatous mucosa, and the lymphoma may arise from a small subset of normal CD56þ IELs, but histological features of enteropathy are usually mild or lacking and coeliac disease appears not to be an associated factor in most cases. A poorly understood spectrum of other primary intestinal cytotoxic NK/T cell lymphomas has been reported,

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often from Asian countries. A proportion of these fulfil the WHO criteria for extranodal NK/T cell lymphoma, nasal type (see below) and others may be part of the spectrum of mucocutaneous g/d T cell lymphomas.86 Finally, occasional cases of small intestinal lymphoma comprising non-epitheliotropic small CD4þ T cells and demonstrating a relatively indolent clinical course are seen.87 These would be best classified as peripheral T cell lymphoma, not otherwise specified, with a comment in the report about their likely behaviour.

overlaps with that of HSTCL and distinction is aided by consideration of blood/bone marrow morphology, EBV status and clinical features. T cell prolymphocytic leukaemia (T-PLL) and adult T cell leukaemia/lymphoma (ATL) may present in the liver with portal and/or sinusoidal infiltration.92,93 The latter may present with several different clinical syndromes; patients with acute ATL present with diffuse leukaemic infiltration of many extranodal sites such as lung, liver, GI tract and CNS, and patients with the lymphomatous form may also have extranodal disease. T cell lymphomas which occur predominantly in lymph nodes (discussed in more detail in this issue by Dogan) may also present at extranodal sites. Anaplastic large cell lymphomas (ALCL), particularly anaplastic large cell lymphoma, ALK-positive, involve extranodal sites such as bone, soft tissues and lung in a significant proportion of cases. Notably, several reports have described ALCL, ALK-negative occurring as either a seroma or a localized mass adjacent to a cosmetic breast implant inserted several years earlier.94 Importantly, these cases have generally followed an indolent clinical course. Angioimmunoblastic T cell lymphoma (AITL) typically presents with advanced stage disease and often involves extranodal tissues such as skin, lung and liver. Extranodal infiltrates range from non-specific mixed infiltrates in which immunohistochemical demonstration of CD10þ and/or PD1þ atypical T cells or molecular clonality analysis may be required for diagnosis, to more florid infiltrates with many of the typical histological features seen in involved lymph nodes.95 Many extranodal mature T cell lymphomas cannot be further subclassified and these may be appropriately designated peripheral T cell lymphoma, not otherwise specified. A

Extranodal NK/T cell lymphoma, nasal type Extranodal NK/T cell lymphoma, nasal type is an EBV-associated malignancy of NK cells or, less frequently, of NK-like T cells, most common amongst Asians and native Americans.2,88,89 Two thirds of cases present in the upper aerodigestive tract while ‘‘extranasal’’ cases most often involve the GI tract, skin, lung, testis or soft tissues. The lymphomas are locally very destructive but extranasal cases in particular are frequently disseminated at presentation. Histologically there is a diffuse or angiocentric/ angiodestructive infiltrate often accompanied by extensive coagulative necrosis, prominent apoptosis, and/or numerous admixed inflammatory cells (Figure 9). The neoplastic cells may be of any size with a variable degree of pleomorphism and anaplasia. Nuclei are often irregular with dark granular chromatin. Typical cases have a CD3þ, CD5, CD4, CD8, cytotoxic granule proteinþ, CD56þ, CD30þ/ immunophenotype. EBV is always present and is best detected by in situ hybridization for EBER as immunostaining for LMP1 is only variably positive. Expression of TCR proteins is rare, but approximately 25% of cases demonstrate clonal TCR gene rearrangement, suggesting that derivation from T cells may be more common than initially appreciated.88,89 The diagnosis can be made in the absence of CD56 if all other features are typical. The clinical outcome is very poor, although the up-front use of radiotherapy has improved the outcome of low stage disease in recent years. Extranasal cases are associated with more adverse clinical findings and have a worse overall survival independent of stage at presentation.88

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Extranodal presentation of other T cell lymphomas/ leukaemias Although relatively uncommon, the presentation of other T cell lymphomas at non-cutaneous extranodal sites is also important to recognize. As its name suggests, the rare, poor prognosis, hepatosplenic T cell lymphoma (HSTCL; discussed in more detail elsewhere in this issue) usually presents with hepatomegaly as well as splenomegly and bone marrow infiltration.90 Monotonous medium-sized T cells infiltrate hepatic sinuses with relative sparing of portal tracts. These cells have a typical CD3þ, CD5/ þ, CD4, CD8/þ, CD56þ/, CD57 þ/ immunophenotype. They express the cytotoxic granule protein TIA1, and sometimes also granzyme B and perforin. While most cases are of TCR g/d origin, an unquantified minority with otherwise similar features are of TCRa/b type.91 Isochromosome 7q is present in most cases. Similar, predominantly sinusoidal, infiltration can be seen in hepatic infiltration by other lymphoid neoplasms including T cell large granulocytic leukaemia, aggressive NK cell leukaemia, splenic marginal zone lymphoma and hairy cell leukaemia. The immunophenotype of the first two of these

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