The Pathologic Basis for the Classification of Non-Hodgkin and Hodgkin Lymphomas

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) usually presents in adults with generalized lymphadenopathy, frequent bone marrow and peripheral blood involvement, and often hepatosplenomegaly. Presentation as leukemia, that is, CLL, is more common than as lymphoma, SLL. Even in patients with a lymphomatous presentation, careful examination of the blood may reveal a circulating monoclonal B-cell component. Nevertheless, there are some patients who will present with generalized adenopathy, and whereas progression to CLL is frequent, it does not necessarily occur in all cases.

The increased sensitivity of immunophenotypic/molecular methodologies has resulted in the detection of clonal lymphoid proliferations with a CLL phenotype in the general population, even in the absence of clinical lymphocytosis, a condition now designated monoclonal B-cell lymphocytosis (MBL) (see box on Early Events in Lymphoid Neoplasia ). The International Workshop on CLL proposed new diagnostic criteria that were then included in the WHO classification of 2008. Recent studies have distinguished between high count and low count MBL, with a count of monoclonal B cells greater than 5.0 × 10 ³ /L being more clinically significant. Similar to peripheral blood, small clonal populations with a CLL phenotype can be detected in lymph nodes as an incidental finding and appear to represent a tissue counterpart of MBL. Histologically, the lymph node involved by CLL/SLL shows diffuse architectural effacement ( Fig. 78.1 ), although occasional residual naked germinal centers can be observed. The predominant cell type is a small lymphocyte with clumped chromatin, but a spectrum of nuclear morphology is usually seen. Pseudofollicular growth centers or proliferation centers are present in the majority of cases and contain a spectrum of cells ranging from small lymphocytes to prolymphocytes and paraimmunoblasts. The prolymphocytes and paraimmunoblasts have more dispersed chromatin and more prominent nucleoli usually centrally placed. The presence of proliferation centers is also a helpful criterion in the differential diagnosis with mantle cell lymphoma (MCL), which may show otherwise some overlapping features with CLL. If needed, immunophenotypic studies can be helpful in this differential diagnosis.

aMost common entities are bold and italicized. Provisional entities are in non-bold italics. Some rare entities or variants are omitted (see reference 3 for complete list).ALK, Anaplastic lymphoma kinase; CNS, central nervous system; EBV, Epstein-Barr virus; NK, natural killer; NOS, not otherwise specified.

CLL/SLL is characterized by CD5 ⁺ , CD23 ⁺ , LEF1 ⁺ B cells expressing dim CD20, and usually dim surface immunoglobulin (sIg). Cyclin D1 is negative, in contrast to MCL. CLL has been shown to have a greater degree of heterogeneity biologically, and different subgroups have been identified based on immunoglobulin (Ig) heavy-chain mutational status, cytogenetics, ZAP-70 expression, and CD38 expression. The latter two have been used as partial surrogate markers for the mutational status. ZAP-70 expression correlates with an unmutated status and poorer prognosis ( Fig. 78.1 ). In fact, ZAP-70 expression has been suggested to be more clinically relevant than mutation status when the two markers are discordant. The use of CD38 as surrogate marker for mutational status is less useful, but its high expression is also associated with a poor prognosis. Recently, recurrent somatic mutations have been identified in a subset of CLL patients using whole-genome and exome sequencing techniques, and some of them have been associated with clinical outcome and may be useful in the future for risk stratification including CLL-International Prognostic Index (IPI). In addition, deletions at 17p, or mutations in TP53 correlate with a more aggressive clinical course.

Histologic transformation over time may occur in CLL, a phenomenon known as Richter syndrome. Short of progression to diffuse large B-cell lymphoma (DLBCL), lymph nodes may show an increased number of prolymphocytes and paraimmunoblasts, sometimes referred to as “accelerated phase” or “prolymphocytoid” transformation ( Fig. 78.1E ). The two overt lymphomatous forms of Richter transformation include classic Hodgkin lymphoma (CHL) and more commonly, DLBCL. While a significant proportion of CHL cases are Epstein-Barr virus (EBV) associated, most DLBCLs are unrelated to EBV. Treatment with immunosuppressive agents such as fludarabine appears to increase the risk of transformation.

Lymphoplasmacytic Lymphoma

The definition of lymphoplasmacytic lymphoma (LPL) and its relationship to other B-cell lymphomas associated with plasmacytoid differentiation and monoclonal gammopathy has been clarified in recent years. LPL is frequently associated with Waldenström macroglobulinemia (WM). The 2008 WHO classification adopted the approach advocated at the second international workshop on WM, which defined WM as the presence of an immunoglobulin M (IgM) monoclonal gammopathy of any concentration associated with bone marrow involvement by LPL. Hence, LPL and WM are not synonymous, with WM defining a subset of LPL.

More recently, recurrent mutations in MYD88 (L265P) have been identified in greater than 90% of WM patients and are highly associated with LPL but infrequently seen in other B-cell lymphomas with plasmacytoid features, such as marginal zone lymphomas. In addition, nonsense and frameshift mutations involving CXC-chemokine receptor 4, similar to those occurring in warts hypogammaglobulinemia infections myelokathexis (WHIM) patients, were reported and are associated with heavy disease burden.

LPL is a disease of adult life that usually presents with bone marrow involvement and sometimes with nodal and splenic involvement (splenomegaly), vague constitutional symptoms, and anemia (see Chapter 92 ). The tumor consists of a diffuse proliferation of small lymphocytes, plasmacytoid lymphocytes, and plasma cells, with or without Dutcher bodies ( Fig. 78.2 ). The growth pattern is often interfollicular, with sparing of the sinuses. The cells have surface and cytoplasmic Ig, usually of IgM type, usually lack IgD, and express B-cell-associated antigens (CD19, CD20, CD22, CD79a). They are usually negative for CD5 and CD10. CD25 or CD11c may be weakly expressed in some cases. The lack of CD5 and the presence of strong cytoplasmic Ig are useful in the distinction from CLL. The postulated normal counterpart is thought to be a postfollicular B-cell-based in part on the presence of somatic mutations in the Ig heavy and light-chain variable region genes.

Mantle Cell Lymphoma

MCL is a distinct entity that has been more precisely defined in recent years through the integration of immunophenotypic, molecular genetic, and clinicopathologic studies. The molecular hallmark of MCL is the t(11;14)(q13;q32) involving Cyclin D1 ( CCND1 ) and the IGH gene. Cyclin D1 overexpression is believed to be essential in the pathogenesis of MCL. However, rare variants negative for Cyclin D1 with similar immunomorphology and gene expression signature have been identified, and most often have translocations involving CCND2 . Sox11 is overexpressed in most Cyclin D1 positive and negative cases. The postulated normal counterpart is the CD5 ⁺ , sIgM ⁺ and sIgD ⁺ , “naïve” B cell that can be found in the peripheral blood and mantle zones of reactive germinal centers. Mutational analysis of the rearranged Ig variable region genes shows few or no somatic mutations; however, similarly to CLL, a subset of MCL has mutated IG genes.

Recently, because of the widespread use of immunohistochemistry (IHC), early involvement of lymph node by cells carrying t(11;14) translocation with subsequent overexpression of Cyclin D1 has been documented in several cases, referred to initially in the WHO 2008 as “in situ MCL” but now termed “in situ MC Neoplasia” (in situ MCN) in the WHO 2017 update, reflecting that this is an early lesion. Most often, these represent an incidental finding, but some cases will eventually progress to overt MCL. In some cases, in situ MCN is detected in a lymph node involved by another lymphoma type, such as follicular lymphoma (FL). The risk of progression of in situ MCN is difficult to ascertain, as the number of reported cases is few. In a recent multicentric retrospective study, it was noted that the expression of Sox11 was more frequently associated with progression to MCL since the majority of in situ cases lacked Sox11 expression. Also, similar to in situ follicular neoplasia (ISFN), a distinction should be made between partial involvement by MCL with a mantle zone pattern and in situ MCN. The latter refers to a reactive lymph node with Cyclin D1 positive cells limited to an otherwise normal-appearing follicle mantle.

Another newly identified variant is an indolent form of MCL characterized by a leukemic phase without nodal disease, but often with long-standing splenomegaly. These patients have an indolent clinical course and do not appear to require aggressive chemotherapy. These cases carry t(11;14) with few additional chromosomal abnormalities and lack the expression of Sox11 in contrast to conventional MCL.

MCL occurs in adults (median age 62), with a high male-to-female ratio. Most patients present with advanced stage at diagnosis. Common sites of involvement include lymph nodes, spleen, bone marrow, and lymphoid tissue of Waldeyer ring. Gastrointestinal (GI) tract involvement is frequent and is associated with the picture of lymphomatous polyposis.

The hallmark of MCL is a very monotonous cellular composition. In the typical case, the cells are slightly larger than a normal lymphocyte with finely clumped chromatin, scant cytoplasm, and inconspicuous nucleoli ( Fig. 78.3 ). The nuclear contour is usually irregular or cleaved. Some cytologic variants, blastoid and pleomorphic, tend to be associated with a more aggressive course and adverse biologic features, such as tetraploidy or p53 mutation/deletion. The proliferation rate was previously identified as prognostically important based on the scoring of Ki67 ⁺ cells (<10%, 10% to 30%, and >30%). More recently, gene expression profiling (GEP), using genes involved in cell cycle progression and DNA synthesis, has identified a proliferation signature that delineates cohorts with varied prognoses. These correlate to some extent with cytologic subtypes. For example, the blastoid variant has a high proliferation rate, utilizing both KI-67 and GEP signature. More recent data indicate that high P53 expression (>20%) has adverse prognostic significance independent of KI-67 or the MCL-IPI.

Follicular Lymphoma

FL is the most common subtype of non-Hodgkin lymphoma within the United States and accounts for approximately 45% of all newly diagnosed cases. It has a peak incidence in the fifth and sixth decades and is rare under the age of 20. Men and women are equally affected. FL is less common in Black and Asian populations. Most patients have stage 3 or 4 disease at diagnosis, with generalized lymphadenopathy. Staging evaluation will usually detect bone marrow involvement. Approximately 10% of patients will have circulating malignant cells. However, careful immunophenotypic or molecular analyses may disclose peripheral blood involvement in a higher proportion of patients. A more accurate prognostic index than the IPI, the FL IPI, has been proposed for FL and has been widely adopted.

The natural history of the disease is associated with histologic progression in both pattern and cell type ( Fig. 78.4 ). A heterogeneous cytologic composition is one of the hallmarks of FL. Usually, all of the follicle center cells are represented, but in varying proportions. It should be stressed that the variation in cytologic grade is a continuum, and therefore, precise morphologic criteria for subclassification are difficult to establish.

According to the WHO classification, all low-grade FL are combined into a single category, Grade 1–2, all containing overall a predominance of centrocytes with fewer than 15 centroblasts/high power field (hpf). FL grade 3 (with >15 centroblasts/hpf) is further subdivided into 3 A and 3B based on the presence or absence of centrocytes in the background.

The vast majority of FL (approximately 85%) are associated with a t(14;18) involving rearrangement of the BCL2 gene. This translocation appears to result in constitutive expression of BCL2 protein, which is capable of inhibiting apoptosis in lymphoid cells. The cells of FL accumulate and are at risk to acquire secondary mutations, which may be associated with histologic progression. It has been postulated that the BCL2/IGH translocation occurs during Ig gene rearrangement in the bone marrow at the pre-B cell stage of development. This fact might contribute to the difficulty in eradicating the neoplastic clone with chemotherapy.

Biologically, the pathogenesis of most cases of FL grade 3B differs from that of FL grades 1–2/3 A, in lacking the BCL2/IGH , but also differs from DLBCL, in having a low incidence of BCL6 aberrations. These data provide a biologic explanation for the greater curability of grade 3B FL with aggressive therapy, although some studies have not found support for this hypothesis. Differences in diagnostic criteria might account for this apparent discrepancy, and the correlation between grade 3A versus 3B and molecular alterations is imprecise. Other phenotypic variants appear to have prognostic significance, such as FL negative for CD10 but positive for MUM1/IRF4. These cases are usually of higher grade and interestingly also lack the BCL2 translocation. Evolution toward a molecularly defined classification of FL is a possibility for the future.

The phenomenon of localization of FL cells to isolated germinal centers within a lymph node has been termed ISFN. The likelihood of evolution to clinically significant FL is low for these patients if there is no other evidence of disease at the time of diagnosis. Indeed, this translocation can be found in the peripheral blood and lymphoid organs of healthy individuals and suggests that the BCL2 / IGH translocation is necessary but not sufficient for the development of FL. ISFN should be distinguished from partial involvement by FL. In the true “in situ” lesion, clusters of B cells strongly positive for CD10 and BCL2 are localized to germinal centers in an otherwise reactive lymph node. It often represents an incidental finding in a lymph node biopsied for other reasons.

The 2017 WHO classification recognizes other lymphomas of follicle center derivation that may resemble nodal FL but exhibit significant differences either clinically or biologically. These include diffuse follicular FL, pediatric forms of FL, primary intestinal FL (“duodenal-type”), and cutaneous lymphomas of follicle center cell derivation. Intestinal FL, most often presenting in the duodenum, is associated with the BCL2/IGH translocation but usually presents as isolated mucosal polyps with a low risk of dissemination. FL in the pediatric age group is histologically diverse. Most nodal cases are cytologically high grade, composed of blastoid cells, but are usually localized, and may be cured in a number of instances with surgical excision and carry underlying TNFRSF14 and MAP2K1 mutations. This so-called pediatric type of FL may also be seen in adults more rarely and shows a strong male predominance. Another form of FL seen in children and young adults is associated with translocations involving IRF4 and shows overexpression of MUM1 by IHC. These cases frequently present in a Waldeyer ring.

There are rare variants of FL with a mainly diffuse growth pattern. These often present as bulky localized inguinal masses and lack the BCL2 translocation but often have deletions at 1p36. Primary cutaneous follicle center lymphoma, which also frequently lacks the BCL2 translocation and BCL2 expression, is now considered by the WHO classification as a separate entity. They usually present in the head or upper trunk and can be managed conservatively with local approaches. However, when BCL2 expression is detected, the possibility that this may represent a secondary site of involvement should be considered.

Extranodal Marginal-Zone Lymphoma of Mucosa-Associated Lymphoid Tissue Type

Most lymphomas of marginal-zone derivation present in extranodal sites and have the histopathologic and clinical features identified by Isaacson and Wright as part of the spectrum of mucosa-associated lymphoid tissue (MALT) lymphomas. MALT lymphomas are characterized by a heterogeneous cellular composition that includes marginal-zone or centrocyte-like cells, monocytoid B cells, small lymphocytes, and plasma cells ( Fig. 78.5A ). In most cases, large transformed cells are infrequent. Reactive germinal centers are nearly always present. When follicular colonization occurs, the process may simulate FL. Clonality is confirmed by molecular and or immunohistochemical studies.

MALT lymphomas have been described in nearly every anatomic site but are most frequent in the stomach, lung, thyroid, salivary gland, and lacrimal gland. Other less common sites of involvement include the orbit, breast, conjunctiva, bladder and kidney, and thymus gland. Widespread nodal involvement is infrequent, as is marrow involvement. The clinical course is usually quite indolent, and many patients are asymptomatic. MALT lymphomas tend to relapse in other MALT-associated sites.

MALT lymphomas of the salivary gland and thyroid are usually associated with a history of autoimmune diseases. Helicobacter gastritis is frequent in most patients with gastric MALT lymphomas. Other infectious agents have been described in MALT lymphomas involving skin ( Borrelia burgdorferi ), ocular adnexae ( Chlamydia psittaci ), and small intestine ( Campylobacter jejuni ); however, in this latter group, a causal relationship has not yet been demonstrated. Chronic antigen stimulation is critical to both the development of a MALT lymphoma and the maintenance of the neoplastic state. Indeed, in some cases, antibiotic therapy and the eradication of Helicobacter pylori have led to the spontaneous remission of gastric MALT lymphoma in cases lacking genetic aberrations.

Immunophenotype MALT lymphomas are positive for B-cell-associated antigens CD19, CD20, and CD22, but are negative for CD5 and CD10. The absence of cyclin D1 is useful in ruling out MCL, especially in intestinal disease. Rare cases of MALT lymphoma have been reported to be CD5 ⁺ , and in some but not all instances, this has been associated with more aggressive disease. The clinical significance of increased transformed cells is still uncertain, and no formal grading system exists for MALT lymphoma. The putative cell of origin of MALT lymphoma is a postgerminal center B-cell.

MALT lymphomas also have several recurring cytogenetic abnormalities, including t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), t(3;14)(q27;q32), and t(3;14)(p14.1;q32), which are observed with variable frequency, often depending upon the anatomic site. Although several genes are involved in these translocations, at least three of them, t(11;18), t(1;14), and t(14;18), share a common pathway, leading to the activation of NF-κB and its downstream targets. By genome-wide DNA profiling integrated with GEP, differences were detected among the three different main types of marginal zone lymphomas, lending support to the current WHO classification that separates these three entities.

Nodal Marginal-Zone B-Cell Lymphoma

Nodal marginal zone lymphoma (NMZL) is a primary nodal disease that resembles other marginal zone lymphomas, extranodal or splenic types. These patients often present with bone marrow involvement and tend to have a more aggressive clinical course than those with extranodal MALT. The neoplastic proliferation is polymorphous and composed of monocytoid B cells, plasmacytoid cells, with interspersed large blast-like cells. There is an expansion of the marginal-zone area, often with preservation of the nodal architecture (see Fig. 78.5C ). The mantle zone may be intact, attenuated, or effaced. The immunophenotype is similar to other MZL, that is, CD20 ⁺ , CD10 ⁻ , CD5 ⁻ , with variable expression of IgD (weak to negative). Because there are no precise immunophenotypic or genotypic markers of NMZL, the diagnosis is sometimes one of exclusion. The differential diagnosis with LPL may be problematic; however, the MYD88 (L265P) somatic mutation is detected infrequently in MZL lymphomas and its presence should raise the possibility of LPL. More stringent criteria are needed to separate these two entities. A variant of nodal MZL occurs in children; these cases show a striking male predominance; present with localized disease, exhibiting a morphologic pattern; and can be managed with local therapies.

Splenic Marginal-Zone Lymphoma

Splenic marginal-zone lymphoma (SMZL) presents in adults and is slightly more frequent in females than males. The clinical presentation is splenomegaly, usually without peripheral lymphadenopathy. The majority of patients have marrow involvement, but there is usually only a modest lymphocytosis, with elevations in the lymphocyte count usually less than that seen in CLL. Some evidence of plasmacytoid differentiation may be seen, and patients may have a small M component. The abundant pale cytoplasm evident in tissue sections may also be seen in blood smears. The course is indolent, and splenectomy may be followed by a prolonged remission.

Histologically, the spleen shows expansion of the white pulp, but usually some infiltration of the red pulp is also present (see Fig. 78.5D ). A characteristic biphasic pattern in the neoplastic white pulp has been described, with the neoplastic cells surrounding regressed follicles. The immunophenotype of these cells resembles that of other marginal-zone B-cell lymphomas; however, IgD expression is more frequently observed. Progression to DLBCL can be seen.

Although the molecular pathogenesis of SMZL has not been fully delineated, a frequent cytogenetic alteration involving deletions of the region 7q(22-32) has been reported. Mutations in NOTCH2 are the most common event, but other genes in the NOTCH pathway may be targeted. Many of the affected genes appear to play a role in marginal zone B-cell development. The differential diagnosis of SMZL includes other unspecified B-cell lymphomas of the spleen, including splenic lymphoma with villous lymphocytes (SLVL), and hairy cell variant. The latter have been grouped together under splenic B-cell lymphoma/leukemia unclassifiable, and the interrelationship among these disorders is not fully resolved.

Diffuse Large B-Cell Lymphoma, Not Otherwise Specified

DLBCL is one of the more common subtypes of non-Hodgkin lymphoma, representing up to 40% of cases. It has an aggressive natural history but responds well to chemotherapy. The complete remission rate with modern regimens is 75% to 80%, with long-term disease-free survival approaching 50% or more in most series. This lymphoma may present in lymph nodes or in extranodal sites. Frequent extranodal sites of involvement include bone, skin, thyroid, GI tract, and lung.

DLBCL represents one of the most heterogeneous categories in the WHO, and attempts to identify prognostic groups based on morphology and phenotype have shown limited usefulness and reproducibility (see box on Varied Basis for the Recognition of Diverse Entities ). To address these issues, DLBCLs were among the first cases to be analyzed by complementary DNA (cDNA) array technology, and more recently also by genome-wide analysis. By GEP, three groups were identified based on the differential expression of a large set of genes, namely germinal center-like group (GCB), activated B-cell–like group (ABC), and primary mediastinal (thymic) large B-cell lymphoma (PMBL). PMBL is now recognized as a separate entity, and adaptations in GEP now allow profiling of formalin-fixed paraffin-embedded (FFPE) biopsies. The ABC subtype frequently exhibits mutations in the BCR-signaling and NF-κB pathways providing new insight in the pathogenesis of DLBCL and new potential therapeutic targets. Recurrent mutations in the GCB type of DLBCL appear to target histone-modifying genes. Somatic mutations in EZH2 also have been identified in FL, another tumor of germinal center derivation.

DLBCLs are composed of large, transformed lymphoid cells with nuclei at least twice the size of a small lymphocyte ( Fig. 78.6 ). The nuclei generally have vesicular chromatin, prominent nucleoli, and basophilic cytoplasm, resembling the centroblasts of the normal germinal center. The immunoblastic variant is characterized by cells with prominent central nucleoli and abundant deeply staining cytoplasm. Although there is no absolute correlation between morphology and GEP, the majority of centroblastic DLBCL falls into the GCB group, and the majority of immunoblastic fall into the ABC group.

Algorithms based on immunophenotype have been proposed as surrogates for cDNA microarray using CD10/BCL6 positivity for GCB and MUM1/IRF-4 for ABC with the addition of BCL2 in combination with IPI and may improve the stratification of DLBCL. Because of emerging differences in the treatment of GCB versus ABC (or non-GCB) DLBCL, it is recommended to include the subtype by integrating GEP and/or IHC results in the report with clarification of the method used and the type of algorithm. As noted, newer GEP methods may be applicable to FFPE material.

Diffuse Large B-Cell Lymphomas, Other Variants, and Subtypes

The spectrum of aggressive B-cell lymphomas has broadened in recent years, incorporating new entities based on unique clinical features such as age or anatomic site, viral pathogenesis (EBV, human herpesvirus [HHV]-8), or distinctive pathologic features. T-cell/histiocyte - rich large B-cell lymphoma (THRLBCL) has distinctive morphologic and clinical features. It is associated with aggressive clinical behavior and often presents with advanced stage and bone marrow involvement. The relevance of the microenvironment and recruitment mechanism of the inflammatory cells, which are the main histologic component, has been the focus of recent studies.

The WHO classification recognizes that some lymphomas arising in certain anatomic sites may have distinctive features both clinically and biologically. Among these are primary DLBCL of the central nervous system (CNS) and DLBCL of the testis . DLBCLs in these sanctuary sites differ at the genomic level from the usual nodal DLBCL. Both primary CNS DLBCL and intraocular large B-cell lymphomas commonly have mutations in MYD88.

Primary cutaneous DLBCL, leg type, has a GEP resembling the ABC type of DLBCL, presents most often in older adult females, and generally has an aggressive clinical course. As with nodal DLBCL, BCL2 expression is an adverse prognostic factor.

EBV-positive DLBCL was a provisional entity in the 2008 WHO classification and was accepted as a definitive entity in WHO 2017. It was first recognized in the older adult. More recent studies have shown a wider age distribution. Decreased immune surveillance in the older adult or a tolerogenic immune microenvironment may facilitate tumor development. The morphologic spectrum is broad, but most cases have a prominent inflammatory background. The prognosis in the older adult is poor, but younger patients have a good outcome. EBV-positive DLBCL should be distinguished from EBV ⁺ mucocutaneous ulcer, which affects mainly cutaneous sites, and often has a self-limited clinical course. These lesions arise in a setting of decreased immune surveillance, most often in the elderly, and frequently with iatrogenic immune suppression.

Lymphomatoid granulomatosis is an EBV ⁺ B-cell lymphoproliferative disorder (LPD) associated with an inflammatory background rich in T cells. The lung is nearly always involved, with skin, kidney, liver, and brain being frequently affected as well. DLBCL associated with chronic inflammation was first described in association with chronic pyothorax but now has been associated with EBV-driven large B-cell proliferations in diverse clinical settings and is usually associated with a confined anatomic space and a background of chronic inflammation. These cases appear to have a good prognosis if successfully resected.

There are several LPDs associated with HHV-8/Kaposi sarcoma-associated herpesvirus (KSHV). These include primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD) . The cells of PEL are usually coinfected with EBV, and the disease is most often diagnosed in the setting of human immunodeficiency virus (HIV) infection and immunosuppression. While pleural or peritoneal effusions are most common, extracavitary PEL can present as a tumor mass, usually in extranodal sites. PEL has a phenotype resembling that of terminally differentiated B-cells, i.e., plasmablastic ( Fig. 78.7 ).

Two other lymphomas with a plasmablastic phenotype include plasmablastic lymphoma (PBL) and anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma . PBL is usually positive for EBV, most often extranodal, and associated with immunosuppression from either HIV infection or advanced age. Recent studies have identified a high incidence of MYC translocation in PBL. ALK-positive large B-cell lymphomas show overexpression of ALK, usually as a consequence of translocation involving a partner gene other than NPM1 . They mainly affect older individuals but can occur at any age. Interestingly, IgA is often expressed.

Intravascular Large B-Cell Lymphoma

Intravascular large B-cell lymphoma is a rare form of DLBCL characterized by the presence of lymphoma cells only in the lumens of small vessels, particularly capillaries ( Fig. 78.8A ). The neoplastic cells express B-cell related antigens including CD19 and CD20. The tumor cells are large, with vesicular nuclei and prominent nucleoli, resembling centroblasts or immunoblasts. Lymph node involvement is rare, and the tumor presents in extranodal sites, most readily diagnosed in the skin or bone marrow biopsy. Neurologic symptoms associated with the plugging of small vessels in the CNS are common. The disease is often not diagnosed until autopsy because of the lack of definitive radiologic or clinical evidence of disease and diverse symptomatology.

Primary Mediastinal (Thymic) Large B-Cell Lymphoma

PMBL has emerged in recent years as a distinct clinicopathologic entity, typically arising in young women, with a peak incidence in the fourth decade. Patients present with a mediastinal mass, with frequent superior vena cava syndrome. Regional lymph nodes may be involved but spread to distant nodal sites is uncommon. Frequent extranodal sites of involvement, particularly at relapse, include the liver, kidneys, adrenal glands, ovaries, GI tract, and CNS.

Histologically, PMBL is characterized by fine compartmentalizing sclerosis and large lymphoid cells with abundant pale cytoplasm (see Fig. 78.8C ). An origin from medullary thymic B cells is proposed. The cells express CD20 and CD79a but do not express surface Ig. Recently, expression of the MAL gene has been detected in PMBL and not in other DLBCLs. PMBL usually lack rearrangement for BCL2 , BCL6 ; however, REL amplification is a common feature. A common cytogenetic abnormality seen in approximately 50% of cases includes gains in 9p, which may be associated with amplification of JAK2 and PDL1/PDL2 as well as translocations involving MHC class II transactivator ( CIITA ). Recently, GEP studies have found that PMBL bears a distinct molecular signature that differs from that of other DLBCLs and shares features of CHL; however, the same signature is not restricted to mediastinal sites since it can also be detected in other DLBCLs not otherwise specified (NOS) at nonmediastinal sites.