EXTRANODAL MARGINAL ZONE B-CELL LYMPHOMA
Clinical Features
Most patients with extranodal marginal zone B-cell lymphoma are older adults, with a median age in the seventh decade in most series. Infrequently, young adults and, rarely, children and adolescents are affected. The most frequent site for the development of marginal zone lymphoma is the stomach; other sites in which this is the most common or one of the more common types of lymphoma include salivary glands, ocular adnexa, intestine, thyroid, lungs, skin, larynx, thymus, breast, liver, urinary bladder, urethra, trachea, and dura mater.1-11 Patients with gastric marginal zone lymphoma present with epigastric pain or dyspepsia, nausea, and vomiting; bleeding and weight loss may occur but are unusual.12 The symptoms may suggest gastritis or peptic ulcer disease rather than tumor.13 Patients with marginal zone lymphoma in other sites usually present with symptoms related to the presence of a mass, but without systemic symptoms.
Marginal zone lymphoma shows important site-specific clinical associations: gastric marginal zone lymphoma often arises in the setting of Helicobacter pylori gastritis. Marginal zone lymphoma arising in the salivary gland (most often the parotid) is strongly associated with Sjo?gren syndrome, as is a subset of pulmonary marginal zone lymphoma. A subset of ocular adnexal marginal zone lymphoma is associated with Chlamydia psittaci infection, but the proportion of patients affected shows marked variation among different studies, suggesting there may be some geographic variation in the incidence of this phenomenon. In one Italian study, 87% of cases were positive for C psittaci, 14 whereas an American study yielded no positive cases. 15 In one large study that included cases from the United States, several different countries in Europe, and Asia, 22% of cases overall were positive for C psittaci, ranging from 47% of cases from Germany to 11% from China.16
Thyroid lymphoma patients almost always have Hashimoto thyroiditis.2 The distinctive type of intestinal marginal zone lymphoma known as immunoproliferative small intestinal disease or α heavy chain disease is associated with Campylobacter jejuni. Some cutaneous marginal zone lymphomas have been associated with Borrelia burgdorferi infection. Thymic marginal zone lymphoma is associated with autoimmune disease. Hepatic lymphoma has been associated with a variety of inflammatory conditions, and lymphoma in the urinary bladder often has arisen in individuals with a history of chronic cystitis. Thus, although in many cases the cause remains unknown, it is clear that marginal zone lymphoma often arises in the setting of chronic inflammation or chronic antigenic stimulation, due to autoimmune disease or infection. Marginal zone lymphomas are typically localized at presentation and tend to remain localized for prolonged periods of time. They may spread to regional lymph nodes or give rise to isolated extranodal relapses, but most patients have long survival even with local therapy alone.
In 1993, Wotherspoon and colleagues17 described the remarkable observation of regression of marginal zone B-cell lymphoma upon eradication of H pylori using antibiotics. Since then, multiple other medical centers have reported the same phenomenon, with response rates ranging from 60% to 90%.12,18,19 The interval to histologic regression may be prolonged, with a range of 1 to 25 months and a median of 5 months.19,20 Features associated with failure of regression include a component of large B-cell lymphoma, invasion beyond the submucosa, spread beyond the stomach, and chromosomal abnormalities, such as t(11;18) and t(1;14).8,20,21 In cases that are histologically negative for lymphoma following H pylori eradication, clonal B cells can be detected by polymerase chain reaction up to several years later.19-21 Microdissection studies suggest that the clonal cells reside in basal lymphoid aggregates.19 When the lymphoma does not respond to or relapses following H pylori eradication, other modalities, including surgery, radiation, or chemotherapy, may be employed, 20,22-24 and cure can usually be obtained. The 5-year survival of gastric marginal zone B-cell lymphoma patients is approximately 90%.9,10,21,25
Only a few patients with ocular adnexal marginal zone lymphoma have been treated with antibiotics, but some have experienced regression of their lymphomas with this treatment.14 It is possible that successful treatment of the underlying causes of marginal zone lymphoma arising in other sites also will help to treat or prevent marginal zone lymphoma, analogous to the use of antibiotics for treatment of gastric marginal zone lymphoma.
Pathologic Features
Microscopic examination reveals a diffuse or vaguely nodular infiltrate of marginal zone B cells, small or medium- sized cells with slightly irregular nuclei and distinct rims of clear cytoplasm. In about one third of cases, there is prominent plasmacytic differentiation in the form of aggregates of monotypic plasma cells. In sites with surface epithelium, such as the gastrointestinal tract or the conjunctiva, plasmacytic differentiation often takes the form of a bandlike infiltrate of plasma cells in the most super- ficial portion of the lymphoma. The plasma cells may have the appearance of normal, mature plasma cells or may have cytoplasm with crystalline inclusions or nuclei with Dutcher bodies. In some sites, especially stomach and salivary gland, clusters of neoplastic cells infiltrate and disrupt glands or ducts to form lymphoepithelial lesions. It often is possible to identify remnants of reactive lymphoid follicles within the lymphoma, sometimes with infiltration and replacement by neoplastic cells (follicular colonization). The cells colonizing the follicles are most commonly marginal zone-type cells, but plasma cells or large cells also may be found colonizing reactive follicles. Even when follicles cannot be seen on routinely stained sections, evidence of preexisting follicles can generally be found using antibodies to follicular dendritic cells, such as CD21. Small numbers of large cells are scattered among the marginal zone cells.7,13,21 There are some site-specific differences: marginal zone lymphoma in the thyroid is distinctive because of the frequent presence of an unusual type of lymphoepithelial lesion, the ''MALT-ball,'' which consists of clusters of neoplastic marginal zone cells within the lumens of thyroid follicles, and also because in this site, colonization of lymphoid follicles tends to be especially prominent,2 so that the lymphoma may have a nodular pattern and mimic follicular lymphoma. In the parotid, lymphoepithelial lesions tend to be especially large and prominent, with large aggregates of monocytoid B cells with abundant clear cytoplasm (Figure 1, A and B).
Immunophenotyping shows CD20^sup +^, CD5^sup -^, and CD10^sup -^, monotypic surface immunoglobulin (sIg)^sup +^ B cells with plasma cells expressing polytypic or monotypic cytoplasmic immunoglobulin (cIg; Figure 1, C and D). The immunoglobulin is most often IgM, but in some cases is IgA or IgG. The neoplastic cells are bcl-2 positive, although bcl- 2 may be lost in colonized follicles. CD43 is co-expressed in up to about one third of cases. An immunostain for cytokeratin can be helpful in highlighting lymphoepithelial lesions. The proliferation fraction as measured using antibody Ki-67 is low, although it is characteristically high in residual reactive follicle centers.11,13,20,26
Molecular genetic studies show clonally rearranged immunoglobulin heavy- and light-chain genes. Analysis of heavy-chain genes shows somatic hypermutation, consistent with neoplastic cells at a postgerminal center stage of development. Bcl-1 and bcl-2 are germline.13,21 Trisomy 3 is found in about one third of cases.27 Trisomy 18 is also common, being found in 23% of marginal zone lymphomas arising in a variety of sites in a recent large series.28 Approximately 10% of all marginal zone lymphomas29 and up to about 30% of gastric marginal zone B-cell lymphomas have a t(11;18)(q21;q21), a translocation involving the API2 gene on chromosome 11 and the MALT gene on chromosome 18, which results in a chimeric transcript that can be detected by reverse transcription-polymerase chain reaction. The fusion is believed to confer a survival advantage to the neoplastic cells. This translocation appears to be specific for extranodal marginal zone B-cell lymphoma. 30 In addition, it shows significant site-specific variation: it is frequent in marginal zone lymphomas of the gastrointestinal tract and the lung, but it is less common in the ocular adnexa and essentially absent in marginal zone lymphoma arising in the thyroid, salivary gland, and liver.7,31 Gastric marginal zone lymphomas that fail to regress with therapy to eradicate H pylori usually harbor the t(11;18) translocation, whereas t(11;18) is nearly consistently absent in cases that do regress with such therapy. This translocation also is associated with higher-stage disease. 7,8,32 Another cytogenetic abnormality associated with a small proportion of marginal zone lymphomas is t(1; 14)(p22;q32). This change results in deregulation of the BCL10 gene, with resultant loss of its normal proapoptotic activity and acquisition of oncogenic potential.7,8 Like the t(11;18) translocation, it is most closely associated with marginal zone lymphomas of the gastrointestinal tract and lung. In contrast, the MALT lymphoma-specific translocation t(14;18) involving IgH and MALT1 genes, while relatively common in marginal zone lymphomas from the skin,33 liver, and ocular adnexa, appears to be rare in gastrointestinal marginal zone lymphomas.7,28,34 These 3 mutually exclusive translocations appear to contribute to the development of lymphoma through activation of the nuclear factor- B (NF B) pathway, in which NF B is translocated to the nucleus and participates in the activation of genes important for cellular activation, proliferation, and survival.7 A translocation involving the genes for IgH and FoxP1, t(3;14)(p14.1;q32), has been described even more recently; this translocation appears to be most prevalent among marginal zone lymphomas of the thyroid,35 although only a few cases have been studied (Table).
Differential Diagnosis
Marginal Zone Lymphoma Versus Reactive Lymphoid Infiltrate. In favor of lymphoma, on routinely stained sections, is the presence of an expansile, destructive infiltrate with loss of normal architecture, cytologic atypia of the infiltrating cells (having the appearance of marginal zone B cells rather than normal small lymphocytes), and Dutcher bodies. Frequent, well-formed lymphoepithelial lesions favor lymphoma in certain sites, such as the stomach. Immunohistochemical studies often are of assistance when this question arises. Demonstration of monotypic Ig light chain expression confirms a diagnosis of lymphoma. A diffuse infiltrate of B cells and co-expression of CD43 by B cells both favor a diagnosis of lymphoma.
Marginal Zone Lymphoma Versus Other Low-Grade Lymphomas. In most extranodal sites, marginal zone lymphoma is much more common than follicular lymphoma or mantle cell lymphoma. However, either of these may present in an extranodal site and mimic marginal zone lymphoma. Marginal zone lymphoma is composed of CD5^sup -^, CD10^sup -^ B cells with relatively abundant clear cytoplasm and may show plasmacytic differentiation and an admixture of a few large cells. Mantle cell lymphoma is composed of a monotonous population of small to medium- sized CD5^sup +^, cyclin D1^sup +^ B cells with scant cytoplasm and without a large cell or plasmacytic component. Follicular lymphoma generally has a more distinct follicular architecture and is composed of CD10^sup +^, bcl-6^sup +^ B cells with nuclei that are usually more irregular and cytoplasm that is usually more scant than those of marginal zone B cells.
Transformation to Large B-Cell Lymphoma Versus Marginal Zone Lymphoma With Increased Large Cells. Sheets or confluent clusters of large, transformed cells found outside of follicles in a background of marginal zone lymphoma represent large-cell transformation. Most authorities require clusters of at least 20 large cells for large-cell transformation9,36 and report that diffusely scattered large cells representing 5% to 10%9 or even 20%25 of the total population are not associated with a worse prognosis so long as clusters of large cells are not seen. Before diagnosing focal large-cell transformation it is important to exclude the possibility that the large cells are residual reactive germinal center cells or neoplastic large cells con- fined to colonized follicles. Immunohistochemical stains to demonstrate a follicular dendritic network can be helpful in resolving uncertainties.
Poorly Preserved High-Grade Lymphoma Versus Marginal Zone B-Cell Lymphoma. In a small biopsy with artifactual distortion harboring large B-cell lymphoma or Burkitt lymphoma, there may be cellular shrinkage, leading to a false impression of low-grade lymphoma. The presence of apoptotic debris or mitotic figures suggests a higher-grade tumor. Staining with the proliferation marker Ki-67 can be quite helpful in distinguishing low- and high-grade lymphomas. Clinical information such as the endoscopic appearance or the apparent rate of growth of the tumor can also provide a clue to the diagnosis.21
Plasmacytoma Versus Marginal Zone B-Cell Lymphoma. Extramedullary plasmacytomas are uncommon in typical MALT sites. Some cases reported as such are most likely marginal zone lymphomas with prominent plasmacytic differentiation. In favor of lymphoma are the presence of a component of B lymphocytes, lymphoepithelial lesions, reactive lymphoid follicles, and IgM^sup +^ neoplastic cells (although a minority of marginal zone lymphomas express other heavy chains).
DIFFUSE LARGE B-CELL LYMPHOMA
Diffuse large B-cell lymphoma is the most common extranodal lymphoma; it is by far the most common lymphoma encountered in the central nervous system, including the eyes,37-40 the paranasal sinuses,41 Waldeyer ring,42-44 bone,45-48 heart,49,50 adrenals,51,52 and testis.6,53,54 It is the most common type of lymphoma encountered in the gastrointestinal tract9-11,21,55,56 and the female genital tract,6,57 and it also occurs in the salivary glands,58,59 thyroid,2 the mediastinum, the orbit, the oral cavity, and other sites.60 Diffuse large B-cell lymphoma is the most common type of lymphoma in human immunodeficiency virus (HIV)- positive patients,61 a subset of patients among whom extranodal lymphoma is relatively common. This is mainly a disease of older adults, with a median age in the seventh decade, but younger adults and children are occasionally affected. There is a slight male preponderance overall, but this varies among anatomic sites. Diffuse large B-cell lymphoma typically produces large, destructive lesions that may invade adjacent structures.21,41 Microscopic examination reveals a diffuse proliferation of large cells with round, oval, irregular, or lobated nuclei, distinct nucleoli, and scant cytoplasm. In a few cases, neoplastic cells may be bizarre or anaplastic, and in occasional cases, they may show plasmacytoid differentiation. In some cases, there is a concomitant component of low-grade lymphoma or a history of low-grade lymphoma (marginal zone lymphoma, follicular lymphoma, etc) consistent with large-cell transformation.62 In most cases, patients present with localized (Ann Arbor stage I or II) disease.9,10,25,41
Diffuse large B-cell lymphoma almost always expresses pan-B-cell markers, such as CD20. Most express surface immunoglobulin, although they are occasionally immunoglobulin negative. Most are bcl-6^sup +^, many are bcl-2^sup +^, and a minority are CD10^sup +^. Rarely, they are CD5^sup +^ 63; the differential diagnosis in such cases includes the blastoid variant of mantle cell lymphoma, but diffuse large B-cell lymphoma is negative for cyclin D1. Immunoglobulin genes are clonally rearranged.
EXTRANODAL VARIANTS OF DIFFUSE LARGE B-CELL LYMPHOMA
Mediastinal (Thymic) Large B-Cell Lymphoma
This lymphoma tends to affect adults and, in contrast to many other types of lymphomas, females are more commonly affected than males. Most patients are in the third to fifth decade at time of presentation. Patients present with a large mediastinal mass, which appears to arise from the thymus. Regional nodes may or may not be affected. Distant spread is rare at the time of diagnosis. Patients are often symptomatic due to a large infiltrative mass. They may have superior vena cava syndrome or airway obstruction. This is an aggressive lymphoma, and it is potentially curable, although more intensive therapy than cytoxan, Adriamycin, vincristine, and prednisone (CHOP) may be required for optimal outcome64,65; but this topic is controversial. When it does disseminate, it tends to spread to extranodal sites, including kidneys, ovaries, central nervous system, gastrointestinal tract, and liver.
Histologic examination shows a diffuse infiltrate of centroblasts, immunoblasts, multilobated cells, and/or Reed- Sternberg-like cells, often associated with delicate packeting sclerosis or with coarse sclerosis (Figure 2, A and B). Sometimes the cells have a distinctive clear cytoplasm. Immunophenotyping shows that they often lack immunoglobulin. They express pan-B markers and lack CD15 and usually CD30. The immunoglobulin heavy and light chains are clonally rearranged. The bcl-2, bcl-6, and c-myc genes are usually germline, but there are distinctive genetic features in that these tumors are often hyperdiploid, and they often have additional chromosomal material from 9p and REL gene amplification. The normal counterpart is believed to be the thymic B cell.66-70 The NF B pathway is believed to be important in the pathogenesis of mediastinal large B-cell lymphoma.71 Microarray studies show a genetic profile sharing many features with classical Hodgkin lymphoma.72
Intravascular Large B-Cell Lymphoma
This lymphoma was previously known as malignant angioendotheliomatosis prior to its recognition as a type of lymphoma and has also been referred to as angiotropic lymphoma. It affects middle-aged to older adults. Patients present with protean symptoms related to vascular obstruction in a wide variety of extranodal sites. The central nervous system, kidneys, adrenals, lungs, genitourinary tract, skin, and other anatomic sites can be involved. Involvement of lymph nodes and spleen is uncommon. The mortality rate is high, but prognosis appears to be better when therapy appropriate for lymphoma is given in a timely manner. The high mortality is partly related to the unusual symptomatology, so that in many cases diagnosis is delayed or is only established on postmortem examination. The histologic hallmark of this disorder is the finding of blood vessels that are filled and distended by large transformed lymphoid cells, generally with the appearance of centroblasts or immunoblasts. This infiltrate is often associated with thrombosis. Extravascular lymphoma can be found in some cases. Immunophenotyping shows that these cells express pan-B-cell antigens, and a number of cases have been described with CD5 expression. Rare cases of intravascular lymphoma are of T lineage. The pathogenesis of this unusual lymphoma is uncertain, but it has been postulated that the neoplastic cells harbor a homing receptor defect.73-77
Primary Effusion Lymphoma
This rare lymphoma is also known as body cavity- based lymphoma. It affects young and middle-aged adults, with males much more often affected than females. Nearly all patients are HIV positive; they present late in the course of disease and are generally profoundly immunodeficient by the time they develop lymphoma. This type of lymphoma is also rarely found in elderly people of Mediterranean origin. Patients present with a pleural effusion, a pericardial effusion, ascites, or a combination of these findings. By definition, there is no discrete contiguous lymphomatous mass associated with the effusion. Patients with this lymphoma have a very poor prognosis, although among HIV-positive patients receiving highly active antiretroviral therapy, outcome appears to be improved. 78 Death is often due to a combination of lymphoma, opportunistic infection, and/or Kaposi sarcoma. The neoplastic cells are uniform or pleomorphic and very large. Some are binucleated or multinucleated, and some of them may resemble Reed-Sternberg cells. Immunophenotyping shows expression of CD45 and CD30. Although they are of B-cell origin, they lack pan-B-cell antigens in most cases. The immunoglobulin heavy- and light-chain genes are rearranged, and the human herpes virus 8 (HHV-8), also known as Kaposi sarcoma-associated herpes virus, is present in the neoplastic cells. Epstein-Barr virus (EBV) is also usually present within the neoplastic cells, although EBV-negative cases are described.79 Rare HHV-8^sup +^ lymphomas with similar cytology and immunophenotype have presented as solid masses in extranodal sites, such as the gastrointestinal tract, as well as in lymph nodes.80-82
The differential diagnosis in cases of primary effusion lymphoma includes a secondary lymphomatous effusion, which can be excluded on clinical grounds, and the rare pyothorax-associated lymphoma, which has been found mainly in Japan in association with long-standing tuberculosis, and which forms a discrete pleural mass composed of large cells expressing B antigens.83-85 Other lymphomas that may be included in the differential diagnosis of primary effusion lymphoma are negative for HHV-8.
Diffuse Large B-Cell Lymphoma, Plasmablastic Type (Plasmablastic Lymphoma)
In the World Health Organization classification, plasmablastic lymphoma is classified as a variant of diffuse large B-cell lymphoma.75 This lymphoma typically affects HIV-positive patients, although we have observed occasional cases in elderly patients with no specific underlying immunodeficiency. It was originally described in the oral cavity but has since been recognized in other sites, such as the gastrointestinal tract and bone and soft tissue.86 There may be a monomorphic population of mediumsized to large cells, or there may be a range of cellular morphology, with some cells showing definitive plasmacytic differentiation1 (Figure 3, A and B). Making a diagnosis relying on immunophenotype can be difficult, because the neoplastic cells may be negative for CD45 and CD20. The neoplastic cells do express plasma cell-associated markers (MUM-1 or CD138 may be positive; Figure 3, C and D) and have a high proliferation fraction. The majority of cases harbor EBV (Figure 3, E). In contrast to primary effusion lymphoma, HHV-8 is absent. A poor prognosis is associated with this disorder.86-89
MANTLE CELL LYMPHOMA
Clinical Features
Mantle cell lymphoma is a disease of older adults, with a male preponderance. Most patients present with disseminated disease, with lymphadenopathy, often with splenomegaly, and frequent involvement of the bone marrow. With progression of disease, some patients develop peripheral blood involvement (''mantle cell leukemia''). A minority of patients present with extranodal disease, most often involving the gastrointestinal tract,13,90,91 and occasionally involving Waldeyer ring,44,92 but rarely presenting with involvement of other extranodal sites, such as the skin93 or the ocular adnexa.4 Nearly all patients with extranodal presentation of mantle cell lymphoma will be found to have lymphadenopathy or more widespread disease on staging.
Pathologic Features
Mantle cell lymphoma presenting in extranodal sites has cytologic and immunophenotypic features similar to those of mantle cell lymphoma in lymph nodes. Neoplastic cells are usually small to medium-sized with slightly irregular, dark nuclei and scant cytoplasm. In the blastoid variant of mantle cell lymphoma, the mitotic rate is high, and neoplastic cells are larger and sometimes pleomorphic and can resemble lymphoblasts or large atypical lymphoid cells. When this lymphoma involves the gastrointestinal tract, the most common manifestation is multiple lymphomatous polyposis. Multiple lymphomatous polyposis has the appearance of innumerable, nonulcerated polypoid nodules, 0.5 to 2 cm in greatest dimension, involving the mucosa, sometimes also superficially involving the submucosa. Less commonly, mantle cell lymphoma takes the form of a discrete mass or an ulcerated lesion.21 Microscopic examination shows a bandlike infiltrate or multiple ill-defined nodules of neoplastic mantle cells. In multiple lymphomatous polyposis, neoplastic cells tend to displace and obliterate intestinal glands without formation of true lymphoepithelial lesions.13,94 The neoplastic cells are typically CD20^sup +^, CD5^sup +^, CD10^sup -^, CD23^sup -^, cyclin D1^sup +^, bright surface immunoglobulin^sup +^ (IgM^sup +^, with ρ more often than θ)75 (Figure 4, A through D).
Differential Diagnosis
Occasionally, lymphomas other than mantle cell lymphoma, including follicular lymphoma21,91,95,96 and, occasionally, marginal zone lymphoma,96,97 have the appearance of lymphomatous polyposis; conversely, not all mantle cell lymphomas take the form of lymphomatous polyposis. Diagnosis and subclassification in such cases can be established using study of routine sections augmented by immunohistochemistry. The distinction is important, because mantle cell lymphoma has a significantly worse outcome than other lymphomas in the differential diagnosis.
FOLLICULAR LYMPHOMA
Follicular lymphoma is among the most common lymphomas in Western countries; it most often presents with lymphadenopathy. In a minority of cases, follicular lymphoma presents primarily with extranodal disease. Extranodal sites that may be involved include the gastrointestinal tract,98 the skin,99 the ocular adnexa,4 the breast, and others.
In some sites, such as the gastrointestinal tract, the immunophenotypic and cytogenetic features are similar to those of nodal follicular lymphoma, in that bcl-2 protein is usually expressed, and there is usually a translocation involving the genes for bcl-2 and IgH. Follicular lymphoma rarely arises in the gastrointestinal tract; any portion of the gastrointestinal tract may be involved,100 but the duodenum is the most common site, particularly the area of the ampulla of Vater.101-104 Patients are adults, with women more often affected than men. Some present with abdominal pain, but patients are occasionally asymptomatic, and the lymphoma is an incidental finding.98,100,105 Endoscopy reveals mucosal nodularity or small polypoid masses.100,103,105 Some patients have larger, deeply invasive lesions associated with biliary obstruction, mimicking pancreatic or duodenal carcinoma.104 The histologic, immunohistologic, and genetic features are similar to those of nodal follicular lymphoma (Figure 5, A through F), except that frequent expression of both IgA and α4β7, the mucosal homing receptor, has been described.101 In most cases, the follicular lymphoma is low grade (grade 1 or 2 of 3). Some patients have regional lymph node involvement, 100,101,103,104 but more extensive disease is usually absent. 103,104 Treatment has not been uniform, but overall duodenal follicular lymphoma has a favorable prognosis. 100,103,104 The reason for the preferential duodenal localization is uncertain, but the clinical and pathologic findings suggest that follicular lymphoma of the duodenum is a distinct entity that may originate from local antigen- responsive B cells.101
In other sites, the follicular lymphomas may be negative for bcl-2 protein and may lack the bcl-2 translocation.Most follicular lymphomas arising in the skin (referred to as primary cutaneous follicle center lymphoma)99 are of this type. A second example in this category is testicular follicular lymphoma. Primary testicular lymphoma is almost always diffuse large B-cell lymphoma and mainly affects older adults. A small number of testicular lymphomas are follicular lymphomas; these mainly affect children106-108; adults also rarely develop testicular follicular lymphoma. 109 Most have been stage I follicular lymphoma, grade 3 of 3. As for cutaneous follicle center lymphomas, they are also typically bcl-2 protein negative, with no bcl-2 gene rearrangement when this has been evaluated.106-109 For both primary cutaneous follicle center lymphoma and testicular follicular lymphoma, spread beyond the primary site is very unusual, and patients with these lymphomas have an excellent prognosis. Thus, the natural history and the pathogenesis of certain extranodal follicular lymphomas are distinct from those of follicular lymphoma arising in lymph nodes.
EXTRANODAL NATURAL KILLER/T-CELL LYMPHOMA, NASAL-TYPE
Clinical Features
Extranodal natural killer (NK)/T-cell lymphoma (previously known as polymorphic reticulosis or lethal midline granuloma) is a rare disorder in the United States and Europe; it is more common in the Orient and in parts of South America. Most cases are NK-cell lineage, but in a few cases, neoplastic cells are T cells. The pathogenesis of this type of lymphoma has been linked to EBV (see below). It usually affects adults, but children are occasionally affected; there is a male preponderance. This lymphoma produces ulcerative, destructive lesions in extranodal sites: most often midline facial structures (nose and palate),41 but also skin,110 testis,111 gastrointestinal tract, and soft tissue. 75 The clinical course is usually aggressive, and in most series, NK/T-cell lymphoma has been associated with a high mortality. Stage at presentation is important prognostically. In a series of patients studied at the Massachusetts General Hospital, patients with localized disease had a good response to radiation.41 Hemophagocytic syndromes may develop and are responsible for some of the fatalities in patients with extranodal NK/T-cell lymphoma.
Pathologic Features
This disorder is characterized by an angioinvasive and angiodestructive infiltrate usually composed of a mixture of normal-appearing small lymphocytes and variable numbers of small and large atypical lymphoid cells, along with plasma cells and, less often, eosinophils and histiocytes. The appearance of the neoplastic population varies from case to case. In some, there is a predominance of obviously malignant large lymphoid cells, whereas in others, small to intermediate-sized cells with subtle atypia predominate. The neoplastic cells may have distinct rims of clear cytoplasm. Angioinvasion and angiodestruction are common, although angiodestruction, necrosis, and vascular thrombosis may be absent in cases in which there is a predominance of small neoplastic cells.112 The vascular damage is usually associated with prominent ischemic necrosis of both tumor cells and normal tissue and fibrinoid change of the vascular wall. Karyorrhectic debris may be abundant. Cytoplasmic azurophilic granules are often present when touch preps are examined.
Most cases have an NK-cell immunophenotype: CD2^sup +^, CD45RO^sup +^, CD43^sup +^, CD56^sup +^, T-cell receptor αβ (TCRαβ^sup -^), TCRκδ^sup -^. Surface CD3 is usually absent, but cytoplasmic CD3 (cCD3) may be detected on paraffin sections. Although the entire CD3 complex is not expressed by NK cells, the CD3 η chain, which is recognized by paraffin section antibodies to CD3, may be found in NK cells. TCR and immunoglobulin (Ig) genes are usually germline (NK lineage); T-lineage cases have clonally rearranged TCR genes and express surface CD3. EBV genomes are present in most cells in most cases and are clonal.41,75,113-116
Differential Diagnosis
Reactive/Infectious Process with Extensive Necrosis. One difficulty in making a diagnosis of NK/T-cell lymphoma is obtaining adequate viable tissue. In cases in which lymphoma is a consideration, the surgeon must perform biopsies until diagnostic tissue is obtained.
When the neoplastic cells are relatively small, the infiltrate may also be difficult to distinguish from an inflammatory process. When the cells in the infiltrate have nuclear atypia, rims of clear cytoplasm, mitotic activity, and demonstrable EBV, lymphoma is favored. Also, because CD56^sup +^ lymphocytes are typically found in very small numbers in reactive lymphoid infiltrates, the presence of many CD56^sup +^ cells supports a diagnosis of lymphoma.
Diffuse Large B-Cell Lymphoma. Two main types of lymphoma are found in the sinonasal tract: diffuse large B-cell lymphoma and extranodal NK/T-cell lymphoma. Lymphomas that arise in paranasal sinuses are almost always diffuse large B-cell type, whereas most lymphomas arising in the nasal cavity are extranodal NK/T-cell lymphomas. 41,117-119 Diffuse large B-cell lymphoma and extranodal NK/T-cell lymphoma may be difficult to distinguish on routine sections. Angioinvasion and angiocentric localization, prominent necrosis, epitheliotropism, and pseudoepitheliomatous hyperplasia favor extranodal NK/ T-cell lymphoma. B-cell lymphomas more commonly arise in paranasal sinuses, whereas nasal localization and midfacial destructive disease favor NK/T-cell lymphoma. Most B-cell lymphomas are composed of a diffuse proliferation of large cells, so any other cellular composition with a diffuse pattern, especially a mixture of small and large cells or of medium-sized cells, should raise the question of NK/T-cell lymphoma. B-cell and NK/T-cell lymphomas can be distinguished easily with immunophenotyping. B-cell lymphoma is virtually always CD20^sup +^. NK/ T-cell lymphoma is usually CD2^sup +^, cCD3^sup +^, CD56^sup +^, often with lack of other T-cell antigens, including CD5 and both CD4 and CD8. Virtually all cases are EBV^sup +^, so that absence of EBV provides strong evidence against NK/ T-cell lymphoma.
Squamous Cell Carcinoma. Nasal lymphoma can be associated with marked hyperplasia of the overlying epithelium. The atypia of the lymphoid infiltrate and lack of significant atypia of the epithelial cells supports a diagnosis of T-cell lymphoma.
ENTEROPATHY-TYPE INTESTINAL T-CELL LYMPHOMA
Clinical Features
Enteropathy-type T-cell lymphoma occurs in adults over a wide age range (20-80 years, with a mean or median age in the fifties or sixties), with a slight male preponderance. 7,120-122 The development of this lymphoma is closely linked to celiac disease, so that, like celiac disease, it is more prevalent among individuals of European descent, in particular among those from the United Kingdom, especially Ireland and Wales.120 Patients with enteropathytype T-cell lymphoma often have a history of celiac disease, which may be of long or short duration.120 Strict adherence to a gluten-free diet reportedly substantially diminishes the risk for development of lymphoma.123 A subset of patients with enteropathy-type T-cell lymphoma have no prior history of celiac disease; in some of these cases, there is histologic evidence of enteropathy, suggesting that the patients had subclinical celiac disease. Even when no enteropathy is found, the presence of antibodies to gliadin or endomysium or the HLA phenotype typical of celiac disease (HLA DQA1, DQB1) may be found.7,124
Patients with enteropathy-type T-cell lymphoma present with abdominal pain, weight loss, diarrhea, vomiting, symptoms related to perforation or obstruction, fever, night sweats, or a combination of these findings. Among patients with a history of celiac disease, symptoms often appear to be worsening of the celiac disease, with loss of response to a gluten-free diet.7,55,120 Only a small minority have a palpable mass on physical examination, and peripheral lymphadenopathy is very uncommon.120 Rarely, patients present with evidence of distant spread of disease125 and only later are found to have enteropathy-type lymphoma.7 The lymphoma affects the jejunum more frequently than the ileum, and in some instances involves both jejunum and ileum. The stomach and the colon are uncommonly involved. Mesenteric lymph nodes are often involved by lymphoma. Staging reveals spread in a minority of cases to such sites as the bone marrow, skin, lung, or liver. In most cases, lymphoma is confined to the abdomen at the time of presentation.
Among small intestinal lymphomas, enteropathy-type T-cell lymphoma has the worst prognosis.55 Treatment is complicated by the severe malnutrition that characterizes many of these patients, and fewer than half of the patients are able to complete their planned chemotherapeutic regimens. 120,122 Chemotherapy may be complicated by perforation, gastrointestinal bleeding, or sepsis.120 In one study of 31 patients, 84% of patients died of their lymphoma or of complications of therapy.120 In another study, the median survival was 3 months, and 70% of patients had died within 6 months.122 The perforation associated with intestinal involvement is the most common cause of death, but in some cases dissemination of disease to lymph nodes and a wide variety of extranodal sites, including liver, spleen, brain, heart, bone marrow, lungs, kidney, thyroid, and other sites, contributes to mortality.120,126
Pathologic Features
Within the intestine, lesions may be single or multiple. They take the form of plaques, nodules, or strictures with circumferential ulceration and sometimes perforation. Large masses are uncommon.7,55,120 Microscopic examination reveals a dense, diffuse infiltrate of atypical lymphoid cells associated with ulceration and a variable admixture of inflammatory cells, often with many histiocytes. Occasionally, eosinophils are numerous; in such cases, there may be peripheral eosinophilia.7,124 The neoplastic cells may be small, medium-sized, or large, and they may even have an anaplastic appearance. Large neoplastic cells are often pleomorphic, but occasionally may resemble immunoblasts. 7 Changes of celiac disease are often seen in the mucosa away from the lymphoma, including increased numbers of intraepithelial lymphocytes, villous atrophy, crypt hyperplasia, and a lymphoplasmacytic infiltrate in the lamina propria120,126,127 (Figure 6, A through C).
Immunophenotyping shows that neoplastic cells usually express leukocyte common antigen (CD45), CD3, and CD7, but often lack CD5. CD8 is expressed in some cases, but in most cases CD4 and CD8 are both absent.121 CD30 is expressed by some lymphomas with anaplastic morphology. The neoplastic cells have a cytotoxic phenotype: they express T-cell intracellular antigen 1 (TIA-1) and sometimes granzyme B and perforin.121,126,128 The cytotoxic nature of the neoplastic cells and of the intraepithelial cells from which they arise could be responsible for the tissue damage, including villous atrophy, ulceration, and necrosis seen with celiac disease and lymphoma. In most cases, CD103, the human mucosal lymphocyte antigen (HML- 1), is expressed. CD103 is expressed by intestinal intraepithelial lymphocytes and by a subset of lamina propria lymphocytes. Among lymphomas, its expression is nearly unique for enteropathy-type T-cell lymphoma,129 except that CD103 is also expressed by hairy cell leukemia. The cell of origin appears to be the intraepithelial T cell.130
Molecular genetic studies have shown clonal rearrangement of TCR β and chain genes.122,128,131 Enteropathy-type T-cell lymphomas show a high frequency of genetic imbalances, with the most frequent abnormality being amplification of chromosome 9q34, a region containing the NOTCH1 and ABL1 genes, both important in regulation of hematopoiesis and possibly important in the pathogenesis of a subset of enteropathy-type T-cell lymphoma.132,133 Loss of heterozygosity at chromosome 9p21, a region containing tumor suppressor genes p14/p15/p16, is also relatively frequent; cases with loss of genetic material in this area show loss of p16 protein expression, suggesting this genetic change is functionally significant.134 In situ hybridization using probes for EBV-encoded RNA is negative in most Western cases. EBV has been detected in Mexican cases classified as enteropathy-type T-cell lymphoma,135 and EBV may also be found in cases arising in immunocompromised patients.
In most patients with celiac disease not responding to a gluten-free diet (refractory sprue) and in cases of ulcerative jejunitis associated with celiac disease, intraepithelial lymphocytes are usually clonal T cells that are predominantly surface CD3 (sCD3)^sup -^, cytoplasmic CD3 (cCD3)^sup +^, CD4^sup -^, CD8^sup -^.125,128,131 This immunophenotype (cCD3^sup +^, CD4^sup -^, CD8^sup -^) is the same found in most enteropathy-type T-cell lymphomas. In addition, in cases in which lymphoma follows refractory sprue or ulcerative jejunitis, the same clone is found in the lymphoma.131,136 These observations have led some investigators to speculate that refractory sprue and ulcerative jejunitis are neoplastic disorders; designations such as cryptic enteropathy-associated T-cell lymphoma,125 epitheliotropic lymphoma, and intraepithelial lymphoma134 have been suggested to describe these histologically benign but immunophenotypically atypical clonal T-cell proliferations. When overt lymphoma and the surrounding mucosa are analyzed, the same clonal T-cell rearrangement is found in both sites.128
Mesenteric lymph nodes are almost always enlarged, although they are not always involved by lymphoma. In partially involved lymph nodes, the lymphoma may be found in sinuses or in the paracortex.13 Enlarged nodes free of tumor may show nonspecific reactive changes, edema, or mesenteric lymph node cavitation. In the latter condition, lymph nodes may be markedly enlarged (up to 8 cm) and show cystic change, so that the lymph node consists of thickened capsule and a thin rim of lymphoid tissue surrounding clear or turbid fluid that most likely represents lymph.137 Mesenteric lymph node cavitation is not specific for enteropathy-type T-cell lymphoma; it may be seen in celiac disease without lymphoma and in refractory sprue. The condition may be related to severe malnutrition. Upon correction of the malnutrition, the lymph nodal changes may regress.125
Since celiac disease has a genetic basis, establishing a diagnosis of enteropathy-type T-cell lymphoma is of importance not only for the patient, but also for family members.
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