- Email: [email protected]
Other Lymphomas of Large B Cells
Other Lymphomas of Large B Cells Ithatn thisin the chapter we discuss a group of B-cell lymphomas current WHO classification are classified as “other lymphomas of large B-cells”. These include: l l l l l l l l
Primary mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma DLBCL associated with chronic inflammation Lymphomatoid granulomatosis ALK-positive LBCL Primary effusion lymphoma Plasmablastic lymphoma Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease.
Also, HHV8- and EBV-associated germinotropic lymphoproliferative disorder and B-cell lymphoma, unclassifiable with features intermediate between DLBCL and classical Hodgkin lymphoma are briefly discussed in this chapter.
Primary Mediastinal (Thymic) Large B-Cell Lymphoma Primary mediastinal (thymic) large B-cell lymphoma (MLBCL) is a distinct clinicopathologic subtype of DLBCL primarily involving the thymus. The major bulk of tumor at the time of diagnosis is confined to the anterior mediastinum. Primary MLBCL constitutes about 7% of DLBCLs and 2.4% of all non-Hodgkin lymphomas. Women are more affected than men, and the median age is around 40 years.
Atlas of Hematopathology. DOI: http://dx.doi.org/10.1016/B978-0-12-385183-3.00038-3 © 2013 Elsevier Inc. All rights reserved.
38
The affected patients usually show a bulky anterior mediastinal mass originating in the thymus. Superior vena cava syndrome is reported in over half of cases. Relapses are often extranodal involving liver, gastrointestinal tract, CNS, and other organs. Event-free 10-year survival is about 50%. Therapeutic regimens include CHOP or other alternative combination chemotherapy regimens followed by either involved field or modified mantle field radiation therapy.
MORPHOLOGY (FIGURES 38.1 AND 38.2) l
The involved tissue is diffusely infiltrated by large cells with variable amount of cytoplasm, which is often pale or clear. The nuclear features may resemble those of centroblasts or large centrocytes, often with the presence of large cells with multilobated nuclei. l Immunoblast-like cells may be dominant in a minority of cases. Reed–Sternberg-like cells may be present, as well as scattered eosinophils. Mitotic figures are frequent. Rare cases may depict spindle-shaped morphology. l Sclerosis is a common feature separating solid nests of tumor cells by thick hyalinized bands of connective tissue.
IMMUNOPHENOTYPE l l
Flow cytometric results are similar to those in other DLBCLs. By immunohistochemical studies, the neoplastic cells express B-cell antigens, such as CD19, CD20, CD22, and CD79a. In addition, they are positive for CD45, plus commonly positive for CD30, as well as CD23 and MUM1. CD15 may be detected in rare cases. The neoplastic cells variably express BCL2 and BCL6, but expression of CD10 is less common.
450
Other Lymphomas of Large B Cells
A
B
C
D
E
F
FIGURE 38.1 Primary mediastinal b-cell lymphoma. Aggregate of neoplastic large cells with areas of necrosis are separated by thick bands of hyalinized connective tissue (A, low power; B, intermediate power; C, high power). A field devoid of necrosis is shown (D). Higher power view shows large cells with variable amount of clear cytoplasm (E). Some cells mimic lacunar cells (arrows). The neoplastic cells express CD20 (F).
CYTOGENETIC AND MOLECULAR STUDIES
DIFFERENTIAL DIAGNOSIS
l
The differential diagnosis of MLBCL includes nodular sclerosis Hodgkin lymphoma, thymic neoplasms, and other mediastinal masses, such as seminoma and anaplastic large cell lymphoma. The neoplastic cells of MLBCL express B-cell-associated markers and CD45, and lack expression of CD15, cytokeratin, and T-cell-associated markers (Table 38.1).
While cytogenetic testing is not as informative here, the most frequent chromosomal abnormalities are gains of chromosomes 9p21 and 2p16. l The gains of 2p16 are due to the frequent amplification of the REL gene. l Immunoglobulin gene rearrangement studies are usually positive, (Figure 38), but BCL-2, BCL-6, and MYC genes lack rearrangements. l MAL, a gene that encodes a protein associated with lipid rafts in the T-cells and epithelial cells, is over-expressed in most cases.
Intravascular Large B-Cell Lymphoma
451
FIGURE 38.2 Primary mediastinal b-cell lymphoma. Aggregate of atypical neoplastic large cells embedded in a fibrous stroma (A and B) express CD20 (C), BCL-2 (D), CD30 (E) and Ki-67 (F).
A
B
C
D
E
F
Intravascular Large B-Cell Lymphoma
FIGURE 38.3 FISH analysis of neoplastic cells in a patient with primary mediastinal large B-cell lymphoma consistent with IGH@ gene rearrangement.
Intravascular large B-cell lymphoma (IVLBCL) is a rare and aggressive variant of extranodal large B-cell lymphoma characterized by the presence of aggregates of large to medium-size neoplastic B-cells within the lumens of small to medium-sized blood vessels. The lack of expression of adhesion molecules, such as CD29 (beta 1 integrin) and CD54 (ICAM-1), in some cases of IVLBCL suggests that the intravascular pattern is secondary to a defect in homing receptors in the tumor cells. IVLBCL is an aggressive systemic disorder. Clinical symptoms are mostly secondary to the occlusion of the small to medium-sized vessels in various organs. Clinical manifestations may include skin lesions, neurological symptoms, nephritic syndrome, and disseminated intravascular coagulation (DIC). Hepatosplenomegaly, anemia,
452
Other Lymphomas of Large B Cells
Table 38.1
Differential Diagnosis of Primary Mediastinal (Thymic) Large B-Cell Lymphoma (MLBCL) Pathology
Major Morphology
Immunophenotype
Other Remarks
MLBCL
Large cells with clear cytoplasm, sclerosis
Rearranged IGH@
NSHL, syncytial type
Dense sheets of large cells, numerous eosinophils, sclerosis, areas of necrosis Cohesive growth pattern, desmoplastic stroma, may depict squamous differentiation Round nuclei, glycogen+
CD45+, CD19+, CD20+, CD22+, CD10−, CD30+, CD23+ CD45−, CD30+, Fascin+, PAX5+ CD15±, CD20±; EBV+ in 35% of the cases Cytokeratin+, CD45−, CD20− CD45−, CD117+, placental alkaline phosphatase+ Pan-T±, CD30+, CD43+, ALK±, EMA±
Almost exclusively in males Rearranged TCR
Thymic carcinoma Seminoma ALCL
Large pleomorphic anaplastic cells, hallmark cells
NSHL, nodular sclerosis Hodgkin lymphoma; ALCL, anaplastic large cell lymphoma. FIGURE 38.4 Intravascular large b-cell lymphoma. Aggregates of large atypical lymphoid cells are in the lumen of blood vessels (A, low power; B, intermediate power; C, high power). The neoplastic cells express CD20 (D), BCL-2 (E) and Ki-67 (F).
A
B
C
D
E
F
and thrombocytopenia are reported in over 70% of patients. A correlation has been reported between CD5+, CD10− phenotype, and poor prognosis in patients with IVLBCL.
MORPHOLOGY l
The presence of aggregates of large to medium-size neoplastic B-cells within the lumens of small to medium-sized blood vessels (Figure 38.4).
Diffuse Large B-Cell Lymphoma Associated with Chronic Inflammation
453
Table 38.2
Immunophenotypic Features of Intravascular Large B-cell Lymphoma1 Phenotype
% Positive
CD5 CD10 CD19 CD20 CD23 Bcl-2 Bcl-6 MUM1/IRF4 Bcl-1 κ chain λ chain EBER (EBV)
38 13 85 96 4 91 26 95 0 71 18 0
FIGURE 38.5 A karyotype of diffuse large B-cell lymphoma: 46,XX,t(2;1;8)(p13;p34.3;q24),t(3;17)(q27;q23),der(5)t(5;10) (p15.3;q22),del(8)(q13q22), add(10)(q22),t(14;16)(q32;q22).
1
Adapted from Murase T, Yamaguchi M, Suzuki R, et al. Intravascular large B-cell lymphoma (IVLBCL): a clinicopathologic study of 96 cases with special reference to the immunophenotypic heterogeneity of CD5. Blood 2007; 109: 478–485.
l
The neoplastic cells show a vesicular nucleus and prominent nucleoli, resembling centroblasts or immunoblasts. l The intravascular tumor clusters may be associated with fibrin thrombi, and/or palisade along the vessel wall resembling angiosarcoma. l The presence of neoplastic cells in peripheral blood is uncommon.
IMMUNOPHENOTYPE The neoplastic cells are positive for B-cell-associated markers, such as Ig, CD19, CD20, CD22, and CD79a. They are commonly positive for BCL2, MUM1, and sometimes BCL6. Expression of CD5 is more common than CD10 (Table 38.2).
CYTOGENETIC AND MOLECULAR STUDIES l l
No recurrent cytogenetic abnormalities have been reported. BCL6 rearrangement has been reported sporadically but most show clonal IGH@ gene rearrangement (Figure 38.5).
DIFFERENTIAL DIAGNOSIS Differential diagnosis includes acute leukemias, carcinomatosis and angiosarcoma. The neoplastic cells in ALL often express TdT and CD34, whereas cells in IVLBCL are negative for TdT and CD34. AML cells may show some cytoplasmic granularity and express myeloid-associated markers, such as MOP, CD13, CD33, and CD117. In carcinomatosis, the neoplastic cells are CD45− and cytokeratin+. The tumor cells in angiosarcoma express CD34 and are CD20-negative.
Diffuse Large B-Cell Lymphoma Associated with Chronic Inflammation This rare subtype of DLBCL is associated with EBV and longstanding chronic inflammation. It usually involves bone marrow, pleural space or other body cavities. DLBCL associated with chronic pleuritis (pyothoraxassociated lymphoma) is often observed in tuberculous pleuritis. It is a male-predominance disorder with a male to female ratio of about 12:1. The average age is around 70 years. It is found more in Japan than in Western countries. Other EBV-associated longstanding chronic inflammations, such as chronic osteomyelitis, chronic cutaneous ulcer, or metallic implantation, may occasionally lead to EBV-associated DLBCL.
MORPHOLOGY The involved tissue shows diffuse and destructive infiltration of atypical large cells which are morphologically similar to conventional DLBCL cells.
IMMUNOPHENOTYPE Immunohistochemical studies show neoplastic cells positive for CD20 and CD79a in most cases, while some cases display loss of CD20 and/or CD79a, with plasmacytic differentiation expressing MUM1 and CD138. CD30 can be positive. Occasionally, T-cell antigens can be variably
454
Other Lymphomas of Large B Cells
positive. EBV-positivity can be demonstrated by in situ hybridization studies.
MOLECULAR AND CYTOGENETIC STUDIES Most cases will demonstrate clonal immunoglobulin gene rearrangements, often with a background polyclonal gene rearrangement signal produced from the inflammatory infiltrate.
suspended in pleural fluid, which express CD30, CD138, and IRF4/MUM-1, and are often negative for CD20. On the other hand, pyrothorax-associated lymphoma forms solid masses expresses CD20 and is negative for CD138. Non-hematopoietic neoplasms are negative for CD45 and express their associated specific markers.
DIFFERENTIAL DIAGNOSIS
Lymphomatoid Granulomatosis
The differential diagnosis includes primary effusion lymphoma, anaplastic types of plasma cell neoplasms, and certain types of non-hematopoietic tumors (mesothelioma, carcinoma, sarcoma). Primary effusion lymphoma occurs in HIV-infected patients, with large pleomorphic, plasmablastic tumor cells,
Lymphomatoid granulomatosis is a rare, extranodal, angiocentric lymphoproliferative disorder consisting of large, EBV-positive B-cells in a background of polymorphous reactive cells, predominantly consisting of T-lymphocytes. It is an EBV-associated lymphoproliferative
A
B
C
D
E
F
FIGURE 38.6 Lymphomatoid granulomatosis. Lung biopsy section demonstrates a dense polymorphic, angiocentric lymphoid infiltrate (A, low power; B, intermediate power; C, high power). Numerous large cells are CD20-positive (D) and some express CD30 (E) and/or EBV-EBER (F ).
Lymphomatoid Granulomatosis
disorder developed under an immunodeficiency setting, such as HIV infection, X-linked lymphoproliferative syndrome, methotrexate therapy, allogeneic organ transplantation, or Wiscott–Aldrich syndrome. Lymphomatoid granulomatosis is usually observed in adult males. The most common sites of involvement in order of frequency are lung, skin, kidney, liver, and brain. Other sites, such as upper respiratory and gastrointestinal tracts, spleen, and lymph nodes are occasionally affected. Clinical symptoms are related to the involved organ, with respiratory symptoms being the most common presentation. The clinical course, particularly for grades II and III (see below), is often aggressive. However, some patients may show a fluctuating clinical course with occasional spontaneous remission.
455
identical in different sites. Establishment of clonality in the grade I lesions may not be conclusive. l Most cases show EBV infection demonstrated by EBER or other EBV-specific markers using either in situ hybridization or PCR. l The EBV infection in some cases is clonal.
MORPHOLOGY (FIGURES 38.6 AND 38.7) Lymphomatoid granulomatosis is an angiocentric and angiodestructive polymorphous lymphoproliferative process characterized by the presence of a small number of EBV-positive large B-cells in a background of inflammatory cells. The large EBV-positive cells resemble immunoblasts, but bizarre large cells with multilobated nuclei or Reed– Sternberg-like cells may be present. The inflammatory component consists of mixed small lymphocytes, plasma cells, immunoblasts, and histiocytes, with scattered eosinophils and rare neutrophils. This lymphoproliferative disorder characteristically infiltrates into the vascular structures and may cause vascular damage, fibrinoid necrosis, and ischemic changes in the surrounding tissues. There are three histological grades: Grade I consisting of a polymorphous lymphoid infiltrate with absent or rare large, immunoblastic, EBV-positive lymphocytes (<5/hpf). l Grade II consisting of a polymorphous lymphoid infiltrate with moderate numbers of large, immunoblastic, EBV-positive lymphocytes (5–20/hpf). Necrosis is often present. l Grade III is considered a variant of DLBCL and consists of numerous large, immunoblastic, and EBV-positive lymphocytes (>50/hpf). In some areas, these cells may appear in clusters or small sheets. Necrosis is often extensive. Large bizarre cells with multilobed nucleus and Reed–Sternberg-like cells are often present.
A
l
B
IMMUNOPHENOTYPE l l
The EBV-positive large cells are positive for CD20 and CD5. Expression of CD79a and CD30 is variable, but CD15 is negative. Background reactive lymphocytes are commonly CD4positive T-cells.
CYTOGENETIC AND MOLECULAR STUDIES l
No recurrent chromosomal abnormalities have been reported. l There is evidence of clonal IGH@ gene rearrangement in most grade II and III cases. The clonal population may not be
C FIGURE 38.7 Lymphomatoid granulomatosis. Lung tissue demonstrating interstitial lymphoid infiltrate and fibrosis (A, low power; B, intermediate power). The infiltrate is polymorphic consisting of small and large lymphoid cells (C, high power).
456
Other Lymphomas of Large B Cells
Table 38.3
Differential Diagnosis of Lymphomatoid Granulomatosis (LG) Pathology
Major Features
Immunophenotype
Other Remarks
LG
Angiocentric, scattered or clusters of large cells in a polymorphic background of inflammatory cells, predominantly T-cells History of immune-suppression, abundant B-cells Associated with a history of chronic inflammation, usually pleural-based Angiocentric, predominantly atypical T-cells HRS cells in a polymorphic background of inflammatory cells Patchy necrosis surrounded by palisading granulomas; inflammatory infiltrate contains neutrophils
Large cells CD20+, PAX5+, CD79a+
Large cells EBER+
Predominant cells expressing pan-B-cell markers Large cells CD20+, PAX5+, CD79a+ CD3+, CD56+
EBV±
HRS cells CD15+, CD30+, CD45−
EBV±
Post-transplant LPD DLBCL with chronic inflammation Extranodal T/NK-cell lymphoma Classical HL Wegener granulomatosis
Large cells EBV+ EBV+, Rearranged TCR
Non-specific
HL, Hodgkin lymphoma; HRS, Hodgkin/Reed–Sternberg; LPD, lymphoproliferative disorders.
DIFFERENTIAL DIAGNOSIS The differential diagnosis of lymphomatoid granulomatosis includes a garden variety of reactive and neoplastic lymphproliferative disorders including post-tranplant lymphoproliferative disorders, DLBCL with chronic inflammation, extranodal T/NK-cell lymphoma, classical Hodgkin lymphoma, and Wegener granulomatosis. Table 38.3 shows the major clinicopathologic differences between these entities.
ALK-Positive Large B-Cell Lymphoma ALK-positive LBCL is a rare, aggressive subtype of DLBCL. It tends to appear in children (30%) and young adults. The median age is about 35 years with a male to female ratio of 3:1. Patients are usually at the advanced stages (III or IV) at the time of diagnosis, and the prognosis is poor.
l
In addition, they are positive for CD138 and EMA, with only occasional weak staining for CD45. l Cytoplasmic Ig and light chain restriction is common. l The neoplastic cells are negative for B- or T-cell lineage-associated antigens, and CD30 is usually negative.
MOLECULAR AND CYTOGENETIC STUDIES l
FISH and PCR studies show the most commonly observed cytogenetic abnormality of ALK-positive DLBCL, t(2;17) (p23;q23) involving Clathrin (CLTC) on 17q23 and ALK on 2p23. l ALK-positive DLBCL with t(2;5)(p23;q35) involving ALK on 2p23 and nucleophosmin on 5q35, as seen in the majority of T/null anaplastic large cell lymphomas, have also been rarely reported. l These cases are negative for EBV.
DIFFERENTIAL DIAGNOSIS Differential diagnosis of ALK+ large B-cell lymphoma includes DLBCL with sinusoidal pattern, anaplastic large cell lymphoma (see Chapter 51), and plasmablastic lymphoma (see below).
MORPHOLOGY l
The neoplasntic cells are large and may show centroblastic or immunoblastic morphologic features. l Sinusoidal infiltration is a common feature, and sometimes a cohesive growth pattern may be seen, mimicking metastatic carcinoma.
IMMUNOPHENOTYPE l
The neoplastic cells express ALK with a unique cytoplasmic granular pattern.
Primary Effusion Lymphoma Primary effusion lymphoma (PEL) is a rare variant of large cell lymphoma characterized by malignant serous effusions without detectable tumor masses. Rare cases may show solid organ involvements, such as skin and heart. It has been primarily observed in AIDS patients and is associated with human herpes virus 8 (HHV8). However, rare
Primary Effusion Lymphoma
457
cases of HHV-8-negative PEL have been reported. The majority of cases are also co-infected with EBV. Pleural, pericardial, and peritoneal cavities are the most frequent sites of involvement. Most patients are men. Clinical symptoms are secondary to the effusions. Most patients do not respond to conventional chemotherapy and have a short survival time, usually <6 months.
MORPHOLOGY l
Cytocentrifuge slide preparations of the lymphomatous effusions show large neoplastic cells with immunoblastic, plasmablastic, and/or anaplastic features (Figures 38.8 and 38.9). These cells have a variable amount of basophilic cytoplasm. A paranuclear hof may be present. l Nuclei are round or irregular and show prominent nucleoli. Binucleated or multilobated nuclei may be present, and some tumor cells may resemble Reed–Sternberg cells.
A
IMMUNOPHENOTYPE Flow cytometric features (Figure 38.10) include: l
Negative to dim expression of CD45. Expression of CD38 and/or CD138. l Absence of B-cell-associated antigens, including CD19, CD20, and CD79a. l Absence of surface or intracellular light chain restriction. l
By IHC studies, the neoplastic cells are also positive for EMA and CD30. They are positive for HHV8, plus EBVEBER. In the solid form of PEL, variable expression of B-cell antigens may be seen occasionally.
B
CYTOGENETIC AND MOLECULAR STUDIES l Complex
karyotypes are observed. Recurrent chromosome aberrations include: partial trisomies 12, trisomies 7, and aberrations of 1q21–25. l Although the tumor cells often lack the expression of membrane or cytoplasmic Ig, the Ig genes are rearranged and mutated, so molecular studies are more appropriate here than in many of the other B-cell lymphomas. However, mutations affecting PCR primer hybridization targets can cause falsenegative results. l Some cases may also show TCR gene rearrangement. In these situations, additional clonality testing using J-κ gene PCR may be helpful. l HHV8 viral genomes are detected in virtually all patients, and most cases show EBV infection demonstrated by EBER using either in situ hybridization or PCR.
DIFFERENTIAL DIAGNOSIS The differential diagnosis includes secondary involvement of body cavities with anaplastic plasma cell myeloma, subtypes of DLBCL, anaplastic large cell lymphoma, and metastatic non-hematopoietic tumors (Table 38.4).
C FIGURE 38.8 Primary effusion lymphoma. Pericardial effusion demonstrating large plasmablastic cells with dark blue cytoplasm and irregular nuclei mixed with red cells and inflammatory cells (A, low power; B, high power). The plasmablastic cells express CD138 (C).
458
Other Lymphomas of Large B Cells FIGURE 38.9 Primary effusion lymphoma. Peritoneal fluid demonstrating large plasmablastic cells with dark blue cytoplasm and round or irregular nuclei (A). These cells are EBV-EBER+ (B), HHV8+ (C) and EMA+ (D).
A
B
C
D FIGURE 38.10 Flow cytometric findings of primary effusion lymphoma. Open gate density displays (in blue) demonstrate a predominantly large cell population that is partially and very dimly positive for CD45. These large cells are positive for CD30 and CD38, but negative for CD3, CD15, CD19, CD22, as well as surface (not shown) and intracellular light chains.
Table 38.4
Differential Diagnosis of Primary Effusion Lymphoma (PEL) Pathology
Major Features
Immunophenotype
Other Remarks
PEL
Anaplastic/plasmablastic morphology, rare solid organ involvement Primary bone marrow involvement
Pan-B−, CD30+, CD138+, EBV+, HHV-8+ Pan-B−, CD30−, CD138+, cIgG+ or cIgA+, CD117+, CD56± Pan-B±, CD30±, CD138−, cIgMλ, EBV+, HHV-8+ IRF4/MUM1+, CD10−, CD20−, CD79a−, BCL-2− and BCL-6− CD45−, expression of specific non-hematopoietic marker, such as cytokeratin, S100 or others
Rearranged IGH@
Anaplastic plasma cell myeloma LBCL arising in HHV8+ multicentric Castleman disease HHV8/EBV+ germinotropic lymphoproliferative disorder Metastatic non-hematopoietic
Lymph node and splenic involvement Lymph node, preserved architechure, plasmablasts in germinal centers Primary solid tissue involvement
Rearranged IGH@, t(11;14), aneuploidy Rearranged IGH@ Favorable prognosis No IGH@ rearrangement
Plasmablastic Lymphoma
459
IMMUNOPHENOTYPE (FIGURE 38.13)
Plasmablastic Lymphoma
l
Plasmablastic lymphoma is a rare type of DLBCL with morphologic features of plasmablasts, commonly reported in HIV-infected patients. This entity does not include primary effusion lymphoma, ALK+ large B-cell lymphoma, and HHV8+ germinotropic lymphoproliferative disorder. This tumor typically involves the oral cavity of AIDS patients, though extra-oral cases have also been reported. The extra-oral sites include nasal cavity, lung, gastrointestinal tract (including the anus), skin, bone, and soft tissue. In addition to HIV-infected patients, plasmablastic lymphoma has been reported in organ transplant recipients, patients with autoimmine diseases, and individuals without immunodeficiency. The disease occurs predominantly in men and has a poor prognosis
MORPHOLOGY (FIGURES 38.11 AND 38.12) l
There is a diffuse infiltrate of large cells resembling immunoblasts or atypical immature plasma cells with variable amounts of basophilic cytoplasm, often with paranuclear hof. The nucleus is often eccentric, round, or irregular, with open nuclear chromatin and one or several prominent nucleoli. l Starry sky pattern with tingible body macrophages, numerous mitotic figures, and the presence of variable numbers of mature lymphocytes and plasma cells are frequent features
The neoplastic cells express CD38, CD138, MUM1, and are variably positive for CD79a. In addition, they are commonly positive for EMA and CD30. l Cytoplasmic Ig and light chain restriction is often observed. l They are negative to occasionally weak positive for CD45, CD20, and PAX5. Ki67 proliferation rate is greater than 90%. l EBV-EBER is positive in most cases, while HHV8 is consistently negative.
CYTOGENETIC AND MOLECULAR STUDIES l
No recurrent cytogenetic abnormalities have been reported. However, plasmablastic transformation is highly associated with MYC translocation along with IGH@ partners. In addition, this finding can be observed in both de novo plasmablastic lymphoma and in the plasmablastic transformation of a lower grade plasma cell neoplasm, including plasma cell myeloma. l The Ig genes are clonally rearranged. l HHV8 viral genomes are detected in virtually all patients. l Most cases show molecular markers of EBV infection.
DIFFERENTIAL DIAGNOSIS The differential diagnosis includes anaplastic plasmacytoma, LBCL arising in HHV8-associated multicentric Castleman disease (see below), primary effusion lymphoma (see above), and Burkitt lymphoma.
FIGURE 38.11 Plasmablastic lymphoma in a patient with AIDS. Aggregates of plasmablasts are present (A, low power; B, high power). These cells express CD138 (C) and Ig lambda light chain (D).
A
B
C
D
460
Other Lymphomas of Large B Cells FIGURE 38.12 Plasmablastic lymphoma in a patient with AIDS. Fibroadipose tissue of breast is infiltrated by large clusters of plasmablasts and scattered tingible body macrophages (A, low power; B, intermediate power; C, high power). The plasmablasts are positive for EBV-EBER (D).
AA
B
C
D
Large B-Cell Lymphoma Arising in HHV8-Associated Multicentric Castleman Disease
l
They are variably positive for CD20, and sometimes CD38, but negative for CD79a, CD138, and EBV-EBER.
MOLECULAR AND CYTOGENETIC STUDIES
This rare category of LBCL arises in a background of multicentric Castleman disease and is associated with HHV8 and HIV. Patients demonstrate enlarged lymph nodes, splenomegaly, marked immunodeficiency, and often Kaposi sarcoma. It is a highly aggressive lymphoma with poor prognosis.
The karyotypes are commonly normal. Some rare non-specific aberrations such as t(1;6)(p11.2;p11.2), del(7)(q21q22), and del(8)(q12q22) have been reported. l Most cases should demonstrate clonal immunoglobulin gene rearrangements. l HHV8 genomic sequences are detectable by in situ hybridization or PCR.
MORPHOLOGY
DIFFERENTIAL DIAGNOSIS
Two morphologic subtypes have been described. HHV8+ multicentric Castleman disease:
Differential diagnosis includes all categories of LBCL which have a plasmablastic morphology, are associated with immunodeficiency, and are positive for HHV8 and/or HIV (see Table 38.4).
l
Lymph node and splenic sections show hyalinization of the germinal centers with expansion of the mantle zone. l Scattered or clusters of large plasmablastic cells are present within the mantle zone. These cells have abundant dark blue cytoplasm, eccentric nucleus, and one to two prominent nucleoli.
HHV8+ plasmablastic lymphoma: l
Small sheets of plasmablasts with partial or complete effacement of nodal or splenic architecture. l In addition to the splenic involvement, neoplastic infiltrate may be present in the liver, lung, and/or GI tract. l Occasionally tumor cells may appear in the peripheral blood (leukemic phase).
IMMUNOPHENOTYPE l
The plasmablasts demonstrate nuclear expression of LANA-1 antigen, and strong expression of cytoplasmic IgM with lambda light chain restriction.
l
HHV8- and EBVAssociated Germinotropic Lymphoproliferative Disorder This is a rare, localized, nodal disorder which has been reported in HIV seronegative patients. The overall nodal architecture is preserved and there is no feature of Castleman disease. The germinal centers are expanded and partially or totally replaced by clusters of plasmablasts. The plasmablasts are positive for IRF4/MUM1 but negative for CD10, CD20, CD79a, BCL-2, and BCL-6.
HHV8- and EBV-Associated Germinotropic Lymphoproliferative Disorder
461
FIGURE 38.13 Plasmablastic lymphoma; same case as Figure 38.11. The plasmablasts express CD138 (A), lambda light chain (B), MUM1 (C) and Ki-67 (D).
A
B
C
D
A
B
C
D
E
F
FIGURE 38.14 Germinotropic lymphoproliferative process. The germinal centers are expanded and replaced by plasmablasts consisting of large pleomorphic cells with round or convoluted nuclei and one or several nucleoli (A, low power; B, intermediate power; C, high power). The plasmablasts are surrounded by a mantle zone expressing CD5 (D) and CD20 (E). The plasmablasts are positive for IRF4/MUM1 (F) but negative for CD10, CD20, CD79a, BCL-2, and BCL-6 (not shown).
462
Other Lymphomas of Large B Cells
A
B
C FIGURE 38.15 The “Inside-out follicle” pattern. The plasmablasts are at the periphery and surround centrally located small lymphocytes (A, intermediate power; B, high power). The plasmablasts express MUM1 (C).
They show a polyclonal or oligoclonal pattern of Ig gene rearrangements on PCR. The disorder responds well to radiation or chemotherapy. Figures 38.14 and 38.15 present a germinotropic lymphoproliferative process in a patient with a history of nodular sclerosis Hodgkin lymphoma. However, the lesion was negative for both EBV and HHV8.
B-Cell Lymphoma, Unclassifiable, with Features Intermediate between DLBCL and Classical Hodgkin Lymphoma This title refers to the B lineage lymphomas that show overlapping clinicopathologic features between DLBCL
and classical Hodgkin lymphoma. These tumors often appear as an anterior mediastinal mass. Superior vena caval syndrome and/or respiratory distress are among clinical symptoms. The tumor consists of sheets of large pleomorphic cells diffusely infiltrating a fibrous stroma (Figure 38.16). Some of the pleomorphic cells resemble lacunar or Hodgkin cells. Necrotic areas are frequently present, and there may be scattered eosinophils, lymphocytes, and histiocytes. The neoplastic cells express CD20, CD79a, CD15, and CD30 and are often positive for PAX5, OCT-2, and BOB.1. ALK and CD10 are generally negative.
B-Cell Lymphoma, Unclassifiable, with Features Intermediate between DLBCL and Classical Hodgkin Lymphoma
A
B
C
D
E
F
463
FIGURE 38.16 b-cell lymphoma with features intermediate between DLBCL and classical Hodgkin lymphoma. Lymph node section demonstrating clusters of atypical large cells, some resembling HRS cells (A). The large cells express CD45 (B), Pax5 (C), CD30 (D), BOB.1 (E), and Oct2 (F).
464
Other Lymphomas of Large B Cells
Additional Resources Ascoli V, Lo Coco F, Torelli G, et al: Human herpesvirus 8-associated primary effusion lymphoma in HIV-patients: a clinicopidemiologic variant resembling classic Kaposi’s sarcoma, Haematologica 87:339– 343, 2002. Beltran B, Castillo J, Salas R, et al: ALK-positive diffuse large B-cell lymphoma: report of four cases and review of the literature, J Hematol Oncol 27:2–11, 2009. Brimo F, Michel RP, Khetani K, et al: Primary effusion lymphoma: a series of 4 cases and review of the literature with emphasis on cytomorphologic and immunocytochemical differential diagnosis, Cancer 111:224–233, 2007. Castillo J, Pantanowitz L, Dezube BJ: HIV-associated plasmablastic lymphoma: lessons learned from 112 published cases, Am J Hematol 83:804–809, 2008. Castillo JJ, Reagan JL: Plasmablastic lymphoma: a systematic review, ScientificWorldJournal 11:687–696, 2011. Chan JK: Anaplastic large cell lymphoma: redefining its morphologic spectrum and importance of recognition of the ALK-positive subset, Adv Anat Pathol 5:281–313, 1998. Chen YB, Rahemtullah A, Hochberg E: Primary effusion lymphoma, Oncologist 12:569–576, 2007.
Hutchinson CB, Wang E: Primary mediastinal (thymic) large B-cell lymphoma: a short review with brief discussion of mediastinal gray zone lymphoma, Arch Pathol Lab Med 135:394–398, 2011. Jaffe ES, Wilson WH: Lymphomatoid granulomatosis: pathogenesis, pathology and clinical implications, Cancer Surv 30:233–248, 1997. Katzenstein AL, Doxtader E, Narendra S: Lymphomatoid granulomatosis: insights gained over 4 decades, Am J Surg Pathol 34:e35–48, 2010. Loong F, Chan AC, Ho BC, et al: Diffuse large B-cell lymphoma associated with chronic inflammation as an incidental finding and new clinical scenarios, Mod Pathol 23:493–501, 2010. Lundell RB, Weenig RH, Gibson LE: Lymphomatoid granulomatosis, Cancer Treat Res 142:265–272, 2008. Nakashima MO, Roy DB, Nagamine M, et al: Intravascular large B-cell lymphoma: a mimicker of many maladies and a difficult and often delayed diagnosis, J Clin Oncol 29:e138–140, 2011. Oschlies I, Burkhardt B, Salaverria I, et al: Clinical, pathological and genetic features of primary mediastinal large B-cell lymphomas and mediastinal gray zone lymphomas in children, Haematologica 96:262, 2011.
Copie-Bergman C, Niedobitek G, Mangham DC, et al: Epstein-Barr virus in B-cell lymphomas associated with chronic suppurative inflammation, J Pathol 183:287–292, 1997.
Pervez S, Khawaja RD: Mediastinal lymphomas: primary mediastinal (thymic) large B-cell lymphoma versus classical Hodgkin lymphoma, histopathologic dilemma solved? Pathol Res Pract 206:365–367, 2010.
D’Antonio A, Addesso M, Memoli D, et al: Lymph node-based disease and HHV-8/KSHV infection in HIV seronegative patients: report of three new cases of a heterogeneous group of diseases, Int J Hematol 93:795–801, 2011.
Ponzoni M, Ferreri AJ, Campo E, et al: Definition, diagnosis, and management of intravascular large B-cell lymphoma: proposals and perspectives from an international consensus meeting, J Clin Oncol 25:3168–3173, 2007.
Du MQ, Diss TC, Liu H, et al: KSHV- and EBV-associated germinotropic lymphoproliferative disorder, Blood 100:3415–3418, 2002.
Rafaniello Raviele P, Pruneri G, Maiorano E: Plasmablastic lymphoma: a review, Oral Dis 15:38–45, 2009.
Erös N, Károlyi Z, Kovács A, et al: Intravascular B-cell lymphoma, J Am Acad Dermatol 47(Suppl 5):S260–S262, 2002.
Steidl C, Gascoyne RD: The molecular pathogenesis of primary mediastinal large B cell lymphoma, Blood 118:2659–2669, 2011.
Ferreri AJ, Campo E, Seymour JF, et al: International Extranodal Lymphoma Study Group (IELSG). Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the ‘cutaneous variant’, Br J Haematol 127:173–183, 2004.
Sukpanichnant S, Sivayathorn A, Visudhiphan S, et al: Multicentric Castleman’s disease, non-Hodgkin’s lymphoma, and Kaposi’s sarcoma: a rare simultaneous occurrence, Asian Pac J Allergy Immunol 20:127–133, 2002.
Gitelson E, Al-Saleem T, Smith MR: Review: lymphomatoid granulomatosis: challenges in diagnosis and treatment, Clin Adv Hematol Oncol 7:68–70, 2009. Hsi ED, Lorsbach RB, Fend F, et al: Plasmablastic lymphoma and related disorders, Am J Clin Pathol 136:183–194, 2011.
Van Roosbroeck K, Cools J, Dierickx D, et al: ALK-positive large B-cell lymphomas with cryptic SEC31A-ALK and NPM1-ALK fusions, Haematologica 95:509–513, 2010. Zinzani PL, Piccaluga PP: Primary mediastinal DLBCL: evolving biologic understanding and therapeutic strategies, Curr Oncol Rep 13:407–415, 2011.
Primary mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma DLBCL associated with chronic inflammation Lymphomatoid granulomatosis ALK-positive LBCL Primary effusion lymphoma Plasmablastic lymphoma Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease.
Also, HHV8- and EBV-associated germinotropic lymphoproliferative disorder and B-cell lymphoma, unclassifiable with features intermediate between DLBCL and classical Hodgkin lymphoma are briefly discussed in this chapter.
Primary Mediastinal (Thymic) Large B-Cell Lymphoma Primary mediastinal (thymic) large B-cell lymphoma (MLBCL) is a distinct clinicopathologic subtype of DLBCL primarily involving the thymus. The major bulk of tumor at the time of diagnosis is confined to the anterior mediastinum. Primary MLBCL constitutes about 7% of DLBCLs and 2.4% of all non-Hodgkin lymphomas. Women are more affected than men, and the median age is around 40 years.
Atlas of Hematopathology. DOI: http://dx.doi.org/10.1016/B978-0-12-385183-3.00038-3 © 2013 Elsevier Inc. All rights reserved.
38
The affected patients usually show a bulky anterior mediastinal mass originating in the thymus. Superior vena cava syndrome is reported in over half of cases. Relapses are often extranodal involving liver, gastrointestinal tract, CNS, and other organs. Event-free 10-year survival is about 50%. Therapeutic regimens include CHOP or other alternative combination chemotherapy regimens followed by either involved field or modified mantle field radiation therapy.
MORPHOLOGY (FIGURES 38.1 AND 38.2) l
The involved tissue is diffusely infiltrated by large cells with variable amount of cytoplasm, which is often pale or clear. The nuclear features may resemble those of centroblasts or large centrocytes, often with the presence of large cells with multilobated nuclei. l Immunoblast-like cells may be dominant in a minority of cases. Reed–Sternberg-like cells may be present, as well as scattered eosinophils. Mitotic figures are frequent. Rare cases may depict spindle-shaped morphology. l Sclerosis is a common feature separating solid nests of tumor cells by thick hyalinized bands of connective tissue.
IMMUNOPHENOTYPE l l
Flow cytometric results are similar to those in other DLBCLs. By immunohistochemical studies, the neoplastic cells express B-cell antigens, such as CD19, CD20, CD22, and CD79a. In addition, they are positive for CD45, plus commonly positive for CD30, as well as CD23 and MUM1. CD15 may be detected in rare cases. The neoplastic cells variably express BCL2 and BCL6, but expression of CD10 is less common.
450
Other Lymphomas of Large B Cells
A
B
C
D
E
F
FIGURE 38.1 Primary mediastinal b-cell lymphoma. Aggregate of neoplastic large cells with areas of necrosis are separated by thick bands of hyalinized connective tissue (A, low power; B, intermediate power; C, high power). A field devoid of necrosis is shown (D). Higher power view shows large cells with variable amount of clear cytoplasm (E). Some cells mimic lacunar cells (arrows). The neoplastic cells express CD20 (F).
CYTOGENETIC AND MOLECULAR STUDIES
DIFFERENTIAL DIAGNOSIS
l
The differential diagnosis of MLBCL includes nodular sclerosis Hodgkin lymphoma, thymic neoplasms, and other mediastinal masses, such as seminoma and anaplastic large cell lymphoma. The neoplastic cells of MLBCL express B-cell-associated markers and CD45, and lack expression of CD15, cytokeratin, and T-cell-associated markers (Table 38.1).
While cytogenetic testing is not as informative here, the most frequent chromosomal abnormalities are gains of chromosomes 9p21 and 2p16. l The gains of 2p16 are due to the frequent amplification of the REL gene. l Immunoglobulin gene rearrangement studies are usually positive, (Figure 38), but BCL-2, BCL-6, and MYC genes lack rearrangements. l MAL, a gene that encodes a protein associated with lipid rafts in the T-cells and epithelial cells, is over-expressed in most cases.
Intravascular Large B-Cell Lymphoma
451
FIGURE 38.2 Primary mediastinal b-cell lymphoma. Aggregate of atypical neoplastic large cells embedded in a fibrous stroma (A and B) express CD20 (C), BCL-2 (D), CD30 (E) and Ki-67 (F).
A
B
C
D
E
F
Intravascular Large B-Cell Lymphoma
FIGURE 38.3 FISH analysis of neoplastic cells in a patient with primary mediastinal large B-cell lymphoma consistent with IGH@ gene rearrangement.
Intravascular large B-cell lymphoma (IVLBCL) is a rare and aggressive variant of extranodal large B-cell lymphoma characterized by the presence of aggregates of large to medium-size neoplastic B-cells within the lumens of small to medium-sized blood vessels. The lack of expression of adhesion molecules, such as CD29 (beta 1 integrin) and CD54 (ICAM-1), in some cases of IVLBCL suggests that the intravascular pattern is secondary to a defect in homing receptors in the tumor cells. IVLBCL is an aggressive systemic disorder. Clinical symptoms are mostly secondary to the occlusion of the small to medium-sized vessels in various organs. Clinical manifestations may include skin lesions, neurological symptoms, nephritic syndrome, and disseminated intravascular coagulation (DIC). Hepatosplenomegaly, anemia,
452
Other Lymphomas of Large B Cells
Table 38.1
Differential Diagnosis of Primary Mediastinal (Thymic) Large B-Cell Lymphoma (MLBCL) Pathology
Major Morphology
Immunophenotype
Other Remarks
MLBCL
Large cells with clear cytoplasm, sclerosis
Rearranged IGH@
NSHL, syncytial type
Dense sheets of large cells, numerous eosinophils, sclerosis, areas of necrosis Cohesive growth pattern, desmoplastic stroma, may depict squamous differentiation Round nuclei, glycogen+
CD45+, CD19+, CD20+, CD22+, CD10−, CD30+, CD23+ CD45−, CD30+, Fascin+, PAX5+ CD15±, CD20±; EBV+ in 35% of the cases Cytokeratin+, CD45−, CD20− CD45−, CD117+, placental alkaline phosphatase+ Pan-T±, CD30+, CD43+, ALK±, EMA±
Almost exclusively in males Rearranged TCR
Thymic carcinoma Seminoma ALCL
Large pleomorphic anaplastic cells, hallmark cells
NSHL, nodular sclerosis Hodgkin lymphoma; ALCL, anaplastic large cell lymphoma. FIGURE 38.4 Intravascular large b-cell lymphoma. Aggregates of large atypical lymphoid cells are in the lumen of blood vessels (A, low power; B, intermediate power; C, high power). The neoplastic cells express CD20 (D), BCL-2 (E) and Ki-67 (F).
A
B
C
D
E
F
and thrombocytopenia are reported in over 70% of patients. A correlation has been reported between CD5+, CD10− phenotype, and poor prognosis in patients with IVLBCL.
MORPHOLOGY l
The presence of aggregates of large to medium-size neoplastic B-cells within the lumens of small to medium-sized blood vessels (Figure 38.4).
Diffuse Large B-Cell Lymphoma Associated with Chronic Inflammation
453
Table 38.2
Immunophenotypic Features of Intravascular Large B-cell Lymphoma1 Phenotype
% Positive
CD5 CD10 CD19 CD20 CD23 Bcl-2 Bcl-6 MUM1/IRF4 Bcl-1 κ chain λ chain EBER (EBV)
38 13 85 96 4 91 26 95 0 71 18 0
FIGURE 38.5 A karyotype of diffuse large B-cell lymphoma: 46,XX,t(2;1;8)(p13;p34.3;q24),t(3;17)(q27;q23),der(5)t(5;10) (p15.3;q22),del(8)(q13q22), add(10)(q22),t(14;16)(q32;q22).
1
Adapted from Murase T, Yamaguchi M, Suzuki R, et al. Intravascular large B-cell lymphoma (IVLBCL): a clinicopathologic study of 96 cases with special reference to the immunophenotypic heterogeneity of CD5. Blood 2007; 109: 478–485.
l
The neoplastic cells show a vesicular nucleus and prominent nucleoli, resembling centroblasts or immunoblasts. l The intravascular tumor clusters may be associated with fibrin thrombi, and/or palisade along the vessel wall resembling angiosarcoma. l The presence of neoplastic cells in peripheral blood is uncommon.
IMMUNOPHENOTYPE The neoplastic cells are positive for B-cell-associated markers, such as Ig, CD19, CD20, CD22, and CD79a. They are commonly positive for BCL2, MUM1, and sometimes BCL6. Expression of CD5 is more common than CD10 (Table 38.2).
CYTOGENETIC AND MOLECULAR STUDIES l l
No recurrent cytogenetic abnormalities have been reported. BCL6 rearrangement has been reported sporadically but most show clonal IGH@ gene rearrangement (Figure 38.5).
DIFFERENTIAL DIAGNOSIS Differential diagnosis includes acute leukemias, carcinomatosis and angiosarcoma. The neoplastic cells in ALL often express TdT and CD34, whereas cells in IVLBCL are negative for TdT and CD34. AML cells may show some cytoplasmic granularity and express myeloid-associated markers, such as MOP, CD13, CD33, and CD117. In carcinomatosis, the neoplastic cells are CD45− and cytokeratin+. The tumor cells in angiosarcoma express CD34 and are CD20-negative.
Diffuse Large B-Cell Lymphoma Associated with Chronic Inflammation This rare subtype of DLBCL is associated with EBV and longstanding chronic inflammation. It usually involves bone marrow, pleural space or other body cavities. DLBCL associated with chronic pleuritis (pyothoraxassociated lymphoma) is often observed in tuberculous pleuritis. It is a male-predominance disorder with a male to female ratio of about 12:1. The average age is around 70 years. It is found more in Japan than in Western countries. Other EBV-associated longstanding chronic inflammations, such as chronic osteomyelitis, chronic cutaneous ulcer, or metallic implantation, may occasionally lead to EBV-associated DLBCL.
MORPHOLOGY The involved tissue shows diffuse and destructive infiltration of atypical large cells which are morphologically similar to conventional DLBCL cells.
IMMUNOPHENOTYPE Immunohistochemical studies show neoplastic cells positive for CD20 and CD79a in most cases, while some cases display loss of CD20 and/or CD79a, with plasmacytic differentiation expressing MUM1 and CD138. CD30 can be positive. Occasionally, T-cell antigens can be variably
454
Other Lymphomas of Large B Cells
positive. EBV-positivity can be demonstrated by in situ hybridization studies.
MOLECULAR AND CYTOGENETIC STUDIES Most cases will demonstrate clonal immunoglobulin gene rearrangements, often with a background polyclonal gene rearrangement signal produced from the inflammatory infiltrate.
suspended in pleural fluid, which express CD30, CD138, and IRF4/MUM-1, and are often negative for CD20. On the other hand, pyrothorax-associated lymphoma forms solid masses expresses CD20 and is negative for CD138. Non-hematopoietic neoplasms are negative for CD45 and express their associated specific markers.
DIFFERENTIAL DIAGNOSIS
Lymphomatoid Granulomatosis
The differential diagnosis includes primary effusion lymphoma, anaplastic types of plasma cell neoplasms, and certain types of non-hematopoietic tumors (mesothelioma, carcinoma, sarcoma). Primary effusion lymphoma occurs in HIV-infected patients, with large pleomorphic, plasmablastic tumor cells,
Lymphomatoid granulomatosis is a rare, extranodal, angiocentric lymphoproliferative disorder consisting of large, EBV-positive B-cells in a background of polymorphous reactive cells, predominantly consisting of T-lymphocytes. It is an EBV-associated lymphoproliferative
A
B
C
D
E
F
FIGURE 38.6 Lymphomatoid granulomatosis. Lung biopsy section demonstrates a dense polymorphic, angiocentric lymphoid infiltrate (A, low power; B, intermediate power; C, high power). Numerous large cells are CD20-positive (D) and some express CD30 (E) and/or EBV-EBER (F ).
Lymphomatoid Granulomatosis
disorder developed under an immunodeficiency setting, such as HIV infection, X-linked lymphoproliferative syndrome, methotrexate therapy, allogeneic organ transplantation, or Wiscott–Aldrich syndrome. Lymphomatoid granulomatosis is usually observed in adult males. The most common sites of involvement in order of frequency are lung, skin, kidney, liver, and brain. Other sites, such as upper respiratory and gastrointestinal tracts, spleen, and lymph nodes are occasionally affected. Clinical symptoms are related to the involved organ, with respiratory symptoms being the most common presentation. The clinical course, particularly for grades II and III (see below), is often aggressive. However, some patients may show a fluctuating clinical course with occasional spontaneous remission.
455
identical in different sites. Establishment of clonality in the grade I lesions may not be conclusive. l Most cases show EBV infection demonstrated by EBER or other EBV-specific markers using either in situ hybridization or PCR. l The EBV infection in some cases is clonal.
MORPHOLOGY (FIGURES 38.6 AND 38.7) Lymphomatoid granulomatosis is an angiocentric and angiodestructive polymorphous lymphoproliferative process characterized by the presence of a small number of EBV-positive large B-cells in a background of inflammatory cells. The large EBV-positive cells resemble immunoblasts, but bizarre large cells with multilobated nuclei or Reed– Sternberg-like cells may be present. The inflammatory component consists of mixed small lymphocytes, plasma cells, immunoblasts, and histiocytes, with scattered eosinophils and rare neutrophils. This lymphoproliferative disorder characteristically infiltrates into the vascular structures and may cause vascular damage, fibrinoid necrosis, and ischemic changes in the surrounding tissues. There are three histological grades: Grade I consisting of a polymorphous lymphoid infiltrate with absent or rare large, immunoblastic, EBV-positive lymphocytes (<5/hpf). l Grade II consisting of a polymorphous lymphoid infiltrate with moderate numbers of large, immunoblastic, EBV-positive lymphocytes (5–20/hpf). Necrosis is often present. l Grade III is considered a variant of DLBCL and consists of numerous large, immunoblastic, and EBV-positive lymphocytes (>50/hpf). In some areas, these cells may appear in clusters or small sheets. Necrosis is often extensive. Large bizarre cells with multilobed nucleus and Reed–Sternberg-like cells are often present.
A
l
B
IMMUNOPHENOTYPE l l
The EBV-positive large cells are positive for CD20 and CD5. Expression of CD79a and CD30 is variable, but CD15 is negative. Background reactive lymphocytes are commonly CD4positive T-cells.
CYTOGENETIC AND MOLECULAR STUDIES l
No recurrent chromosomal abnormalities have been reported. l There is evidence of clonal IGH@ gene rearrangement in most grade II and III cases. The clonal population may not be
C FIGURE 38.7 Lymphomatoid granulomatosis. Lung tissue demonstrating interstitial lymphoid infiltrate and fibrosis (A, low power; B, intermediate power). The infiltrate is polymorphic consisting of small and large lymphoid cells (C, high power).
456
Other Lymphomas of Large B Cells
Table 38.3
Differential Diagnosis of Lymphomatoid Granulomatosis (LG) Pathology
Major Features
Immunophenotype
Other Remarks
LG
Angiocentric, scattered or clusters of large cells in a polymorphic background of inflammatory cells, predominantly T-cells History of immune-suppression, abundant B-cells Associated with a history of chronic inflammation, usually pleural-based Angiocentric, predominantly atypical T-cells HRS cells in a polymorphic background of inflammatory cells Patchy necrosis surrounded by palisading granulomas; inflammatory infiltrate contains neutrophils
Large cells CD20+, PAX5+, CD79a+
Large cells EBER+
Predominant cells expressing pan-B-cell markers Large cells CD20+, PAX5+, CD79a+ CD3+, CD56+
EBV±
HRS cells CD15+, CD30+, CD45−
EBV±
Post-transplant LPD DLBCL with chronic inflammation Extranodal T/NK-cell lymphoma Classical HL Wegener granulomatosis
Large cells EBV+ EBV+, Rearranged TCR
Non-specific
HL, Hodgkin lymphoma; HRS, Hodgkin/Reed–Sternberg; LPD, lymphoproliferative disorders.
DIFFERENTIAL DIAGNOSIS The differential diagnosis of lymphomatoid granulomatosis includes a garden variety of reactive and neoplastic lymphproliferative disorders including post-tranplant lymphoproliferative disorders, DLBCL with chronic inflammation, extranodal T/NK-cell lymphoma, classical Hodgkin lymphoma, and Wegener granulomatosis. Table 38.3 shows the major clinicopathologic differences between these entities.
ALK-Positive Large B-Cell Lymphoma ALK-positive LBCL is a rare, aggressive subtype of DLBCL. It tends to appear in children (30%) and young adults. The median age is about 35 years with a male to female ratio of 3:1. Patients are usually at the advanced stages (III or IV) at the time of diagnosis, and the prognosis is poor.
l
In addition, they are positive for CD138 and EMA, with only occasional weak staining for CD45. l Cytoplasmic Ig and light chain restriction is common. l The neoplastic cells are negative for B- or T-cell lineage-associated antigens, and CD30 is usually negative.
MOLECULAR AND CYTOGENETIC STUDIES l
FISH and PCR studies show the most commonly observed cytogenetic abnormality of ALK-positive DLBCL, t(2;17) (p23;q23) involving Clathrin (CLTC) on 17q23 and ALK on 2p23. l ALK-positive DLBCL with t(2;5)(p23;q35) involving ALK on 2p23 and nucleophosmin on 5q35, as seen in the majority of T/null anaplastic large cell lymphomas, have also been rarely reported. l These cases are negative for EBV.
DIFFERENTIAL DIAGNOSIS Differential diagnosis of ALK+ large B-cell lymphoma includes DLBCL with sinusoidal pattern, anaplastic large cell lymphoma (see Chapter 51), and plasmablastic lymphoma (see below).
MORPHOLOGY l
The neoplasntic cells are large and may show centroblastic or immunoblastic morphologic features. l Sinusoidal infiltration is a common feature, and sometimes a cohesive growth pattern may be seen, mimicking metastatic carcinoma.
IMMUNOPHENOTYPE l
The neoplastic cells express ALK with a unique cytoplasmic granular pattern.
Primary Effusion Lymphoma Primary effusion lymphoma (PEL) is a rare variant of large cell lymphoma characterized by malignant serous effusions without detectable tumor masses. Rare cases may show solid organ involvements, such as skin and heart. It has been primarily observed in AIDS patients and is associated with human herpes virus 8 (HHV8). However, rare
Primary Effusion Lymphoma
457
cases of HHV-8-negative PEL have been reported. The majority of cases are also co-infected with EBV. Pleural, pericardial, and peritoneal cavities are the most frequent sites of involvement. Most patients are men. Clinical symptoms are secondary to the effusions. Most patients do not respond to conventional chemotherapy and have a short survival time, usually <6 months.
MORPHOLOGY l
Cytocentrifuge slide preparations of the lymphomatous effusions show large neoplastic cells with immunoblastic, plasmablastic, and/or anaplastic features (Figures 38.8 and 38.9). These cells have a variable amount of basophilic cytoplasm. A paranuclear hof may be present. l Nuclei are round or irregular and show prominent nucleoli. Binucleated or multilobated nuclei may be present, and some tumor cells may resemble Reed–Sternberg cells.
A
IMMUNOPHENOTYPE Flow cytometric features (Figure 38.10) include: l
Negative to dim expression of CD45. Expression of CD38 and/or CD138. l Absence of B-cell-associated antigens, including CD19, CD20, and CD79a. l Absence of surface or intracellular light chain restriction. l
By IHC studies, the neoplastic cells are also positive for EMA and CD30. They are positive for HHV8, plus EBVEBER. In the solid form of PEL, variable expression of B-cell antigens may be seen occasionally.
B
CYTOGENETIC AND MOLECULAR STUDIES l Complex
karyotypes are observed. Recurrent chromosome aberrations include: partial trisomies 12, trisomies 7, and aberrations of 1q21–25. l Although the tumor cells often lack the expression of membrane or cytoplasmic Ig, the Ig genes are rearranged and mutated, so molecular studies are more appropriate here than in many of the other B-cell lymphomas. However, mutations affecting PCR primer hybridization targets can cause falsenegative results. l Some cases may also show TCR gene rearrangement. In these situations, additional clonality testing using J-κ gene PCR may be helpful. l HHV8 viral genomes are detected in virtually all patients, and most cases show EBV infection demonstrated by EBER using either in situ hybridization or PCR.
DIFFERENTIAL DIAGNOSIS The differential diagnosis includes secondary involvement of body cavities with anaplastic plasma cell myeloma, subtypes of DLBCL, anaplastic large cell lymphoma, and metastatic non-hematopoietic tumors (Table 38.4).
C FIGURE 38.8 Primary effusion lymphoma. Pericardial effusion demonstrating large plasmablastic cells with dark blue cytoplasm and irregular nuclei mixed with red cells and inflammatory cells (A, low power; B, high power). The plasmablastic cells express CD138 (C).
458
Other Lymphomas of Large B Cells FIGURE 38.9 Primary effusion lymphoma. Peritoneal fluid demonstrating large plasmablastic cells with dark blue cytoplasm and round or irregular nuclei (A). These cells are EBV-EBER+ (B), HHV8+ (C) and EMA+ (D).
A
B
C
D FIGURE 38.10 Flow cytometric findings of primary effusion lymphoma. Open gate density displays (in blue) demonstrate a predominantly large cell population that is partially and very dimly positive for CD45. These large cells are positive for CD30 and CD38, but negative for CD3, CD15, CD19, CD22, as well as surface (not shown) and intracellular light chains.
Table 38.4
Differential Diagnosis of Primary Effusion Lymphoma (PEL) Pathology
Major Features
Immunophenotype
Other Remarks
PEL
Anaplastic/plasmablastic morphology, rare solid organ involvement Primary bone marrow involvement
Pan-B−, CD30+, CD138+, EBV+, HHV-8+ Pan-B−, CD30−, CD138+, cIgG+ or cIgA+, CD117+, CD56± Pan-B±, CD30±, CD138−, cIgMλ, EBV+, HHV-8+ IRF4/MUM1+, CD10−, CD20−, CD79a−, BCL-2− and BCL-6− CD45−, expression of specific non-hematopoietic marker, such as cytokeratin, S100 or others
Rearranged IGH@
Anaplastic plasma cell myeloma LBCL arising in HHV8+ multicentric Castleman disease HHV8/EBV+ germinotropic lymphoproliferative disorder Metastatic non-hematopoietic
Lymph node and splenic involvement Lymph node, preserved architechure, plasmablasts in germinal centers Primary solid tissue involvement
Rearranged IGH@, t(11;14), aneuploidy Rearranged IGH@ Favorable prognosis No IGH@ rearrangement
Plasmablastic Lymphoma
459
IMMUNOPHENOTYPE (FIGURE 38.13)
Plasmablastic Lymphoma
l
Plasmablastic lymphoma is a rare type of DLBCL with morphologic features of plasmablasts, commonly reported in HIV-infected patients. This entity does not include primary effusion lymphoma, ALK+ large B-cell lymphoma, and HHV8+ germinotropic lymphoproliferative disorder. This tumor typically involves the oral cavity of AIDS patients, though extra-oral cases have also been reported. The extra-oral sites include nasal cavity, lung, gastrointestinal tract (including the anus), skin, bone, and soft tissue. In addition to HIV-infected patients, plasmablastic lymphoma has been reported in organ transplant recipients, patients with autoimmine diseases, and individuals without immunodeficiency. The disease occurs predominantly in men and has a poor prognosis
MORPHOLOGY (FIGURES 38.11 AND 38.12) l
There is a diffuse infiltrate of large cells resembling immunoblasts or atypical immature plasma cells with variable amounts of basophilic cytoplasm, often with paranuclear hof. The nucleus is often eccentric, round, or irregular, with open nuclear chromatin and one or several prominent nucleoli. l Starry sky pattern with tingible body macrophages, numerous mitotic figures, and the presence of variable numbers of mature lymphocytes and plasma cells are frequent features
The neoplastic cells express CD38, CD138, MUM1, and are variably positive for CD79a. In addition, they are commonly positive for EMA and CD30. l Cytoplasmic Ig and light chain restriction is often observed. l They are negative to occasionally weak positive for CD45, CD20, and PAX5. Ki67 proliferation rate is greater than 90%. l EBV-EBER is positive in most cases, while HHV8 is consistently negative.
CYTOGENETIC AND MOLECULAR STUDIES l
No recurrent cytogenetic abnormalities have been reported. However, plasmablastic transformation is highly associated with MYC translocation along with IGH@ partners. In addition, this finding can be observed in both de novo plasmablastic lymphoma and in the plasmablastic transformation of a lower grade plasma cell neoplasm, including plasma cell myeloma. l The Ig genes are clonally rearranged. l HHV8 viral genomes are detected in virtually all patients. l Most cases show molecular markers of EBV infection.
DIFFERENTIAL DIAGNOSIS The differential diagnosis includes anaplastic plasmacytoma, LBCL arising in HHV8-associated multicentric Castleman disease (see below), primary effusion lymphoma (see above), and Burkitt lymphoma.
FIGURE 38.11 Plasmablastic lymphoma in a patient with AIDS. Aggregates of plasmablasts are present (A, low power; B, high power). These cells express CD138 (C) and Ig lambda light chain (D).
A
B
C
D
460
Other Lymphomas of Large B Cells FIGURE 38.12 Plasmablastic lymphoma in a patient with AIDS. Fibroadipose tissue of breast is infiltrated by large clusters of plasmablasts and scattered tingible body macrophages (A, low power; B, intermediate power; C, high power). The plasmablasts are positive for EBV-EBER (D).
AA
B
C
D
Large B-Cell Lymphoma Arising in HHV8-Associated Multicentric Castleman Disease
l
They are variably positive for CD20, and sometimes CD38, but negative for CD79a, CD138, and EBV-EBER.
MOLECULAR AND CYTOGENETIC STUDIES
This rare category of LBCL arises in a background of multicentric Castleman disease and is associated with HHV8 and HIV. Patients demonstrate enlarged lymph nodes, splenomegaly, marked immunodeficiency, and often Kaposi sarcoma. It is a highly aggressive lymphoma with poor prognosis.
The karyotypes are commonly normal. Some rare non-specific aberrations such as t(1;6)(p11.2;p11.2), del(7)(q21q22), and del(8)(q12q22) have been reported. l Most cases should demonstrate clonal immunoglobulin gene rearrangements. l HHV8 genomic sequences are detectable by in situ hybridization or PCR.
MORPHOLOGY
DIFFERENTIAL DIAGNOSIS
Two morphologic subtypes have been described. HHV8+ multicentric Castleman disease:
Differential diagnosis includes all categories of LBCL which have a plasmablastic morphology, are associated with immunodeficiency, and are positive for HHV8 and/or HIV (see Table 38.4).
l
Lymph node and splenic sections show hyalinization of the germinal centers with expansion of the mantle zone. l Scattered or clusters of large plasmablastic cells are present within the mantle zone. These cells have abundant dark blue cytoplasm, eccentric nucleus, and one to two prominent nucleoli.
HHV8+ plasmablastic lymphoma: l
Small sheets of plasmablasts with partial or complete effacement of nodal or splenic architecture. l In addition to the splenic involvement, neoplastic infiltrate may be present in the liver, lung, and/or GI tract. l Occasionally tumor cells may appear in the peripheral blood (leukemic phase).
IMMUNOPHENOTYPE l
The plasmablasts demonstrate nuclear expression of LANA-1 antigen, and strong expression of cytoplasmic IgM with lambda light chain restriction.
l
HHV8- and EBVAssociated Germinotropic Lymphoproliferative Disorder This is a rare, localized, nodal disorder which has been reported in HIV seronegative patients. The overall nodal architecture is preserved and there is no feature of Castleman disease. The germinal centers are expanded and partially or totally replaced by clusters of plasmablasts. The plasmablasts are positive for IRF4/MUM1 but negative for CD10, CD20, CD79a, BCL-2, and BCL-6.
HHV8- and EBV-Associated Germinotropic Lymphoproliferative Disorder
461
FIGURE 38.13 Plasmablastic lymphoma; same case as Figure 38.11. The plasmablasts express CD138 (A), lambda light chain (B), MUM1 (C) and Ki-67 (D).
A
B
C
D
A
B
C
D
E
F
FIGURE 38.14 Germinotropic lymphoproliferative process. The germinal centers are expanded and replaced by plasmablasts consisting of large pleomorphic cells with round or convoluted nuclei and one or several nucleoli (A, low power; B, intermediate power; C, high power). The plasmablasts are surrounded by a mantle zone expressing CD5 (D) and CD20 (E). The plasmablasts are positive for IRF4/MUM1 (F) but negative for CD10, CD20, CD79a, BCL-2, and BCL-6 (not shown).
462
Other Lymphomas of Large B Cells
A
B
C FIGURE 38.15 The “Inside-out follicle” pattern. The plasmablasts are at the periphery and surround centrally located small lymphocytes (A, intermediate power; B, high power). The plasmablasts express MUM1 (C).
They show a polyclonal or oligoclonal pattern of Ig gene rearrangements on PCR. The disorder responds well to radiation or chemotherapy. Figures 38.14 and 38.15 present a germinotropic lymphoproliferative process in a patient with a history of nodular sclerosis Hodgkin lymphoma. However, the lesion was negative for both EBV and HHV8.
B-Cell Lymphoma, Unclassifiable, with Features Intermediate between DLBCL and Classical Hodgkin Lymphoma This title refers to the B lineage lymphomas that show overlapping clinicopathologic features between DLBCL
and classical Hodgkin lymphoma. These tumors often appear as an anterior mediastinal mass. Superior vena caval syndrome and/or respiratory distress are among clinical symptoms. The tumor consists of sheets of large pleomorphic cells diffusely infiltrating a fibrous stroma (Figure 38.16). Some of the pleomorphic cells resemble lacunar or Hodgkin cells. Necrotic areas are frequently present, and there may be scattered eosinophils, lymphocytes, and histiocytes. The neoplastic cells express CD20, CD79a, CD15, and CD30 and are often positive for PAX5, OCT-2, and BOB.1. ALK and CD10 are generally negative.
B-Cell Lymphoma, Unclassifiable, with Features Intermediate between DLBCL and Classical Hodgkin Lymphoma
A
B
C
D
E
F
463
FIGURE 38.16 b-cell lymphoma with features intermediate between DLBCL and classical Hodgkin lymphoma. Lymph node section demonstrating clusters of atypical large cells, some resembling HRS cells (A). The large cells express CD45 (B), Pax5 (C), CD30 (D), BOB.1 (E), and Oct2 (F).
464
Other Lymphomas of Large B Cells
Additional Resources Ascoli V, Lo Coco F, Torelli G, et al: Human herpesvirus 8-associated primary effusion lymphoma in HIV-patients: a clinicopidemiologic variant resembling classic Kaposi’s sarcoma, Haematologica 87:339– 343, 2002. Beltran B, Castillo J, Salas R, et al: ALK-positive diffuse large B-cell lymphoma: report of four cases and review of the literature, J Hematol Oncol 27:2–11, 2009. Brimo F, Michel RP, Khetani K, et al: Primary effusion lymphoma: a series of 4 cases and review of the literature with emphasis on cytomorphologic and immunocytochemical differential diagnosis, Cancer 111:224–233, 2007. Castillo J, Pantanowitz L, Dezube BJ: HIV-associated plasmablastic lymphoma: lessons learned from 112 published cases, Am J Hematol 83:804–809, 2008. Castillo JJ, Reagan JL: Plasmablastic lymphoma: a systematic review, ScientificWorldJournal 11:687–696, 2011. Chan JK: Anaplastic large cell lymphoma: redefining its morphologic spectrum and importance of recognition of the ALK-positive subset, Adv Anat Pathol 5:281–313, 1998. Chen YB, Rahemtullah A, Hochberg E: Primary effusion lymphoma, Oncologist 12:569–576, 2007.
Hutchinson CB, Wang E: Primary mediastinal (thymic) large B-cell lymphoma: a short review with brief discussion of mediastinal gray zone lymphoma, Arch Pathol Lab Med 135:394–398, 2011. Jaffe ES, Wilson WH: Lymphomatoid granulomatosis: pathogenesis, pathology and clinical implications, Cancer Surv 30:233–248, 1997. Katzenstein AL, Doxtader E, Narendra S: Lymphomatoid granulomatosis: insights gained over 4 decades, Am J Surg Pathol 34:e35–48, 2010. Loong F, Chan AC, Ho BC, et al: Diffuse large B-cell lymphoma associated with chronic inflammation as an incidental finding and new clinical scenarios, Mod Pathol 23:493–501, 2010. Lundell RB, Weenig RH, Gibson LE: Lymphomatoid granulomatosis, Cancer Treat Res 142:265–272, 2008. Nakashima MO, Roy DB, Nagamine M, et al: Intravascular large B-cell lymphoma: a mimicker of many maladies and a difficult and often delayed diagnosis, J Clin Oncol 29:e138–140, 2011. Oschlies I, Burkhardt B, Salaverria I, et al: Clinical, pathological and genetic features of primary mediastinal large B-cell lymphomas and mediastinal gray zone lymphomas in children, Haematologica 96:262, 2011.
Copie-Bergman C, Niedobitek G, Mangham DC, et al: Epstein-Barr virus in B-cell lymphomas associated with chronic suppurative inflammation, J Pathol 183:287–292, 1997.
Pervez S, Khawaja RD: Mediastinal lymphomas: primary mediastinal (thymic) large B-cell lymphoma versus classical Hodgkin lymphoma, histopathologic dilemma solved? Pathol Res Pract 206:365–367, 2010.
D’Antonio A, Addesso M, Memoli D, et al: Lymph node-based disease and HHV-8/KSHV infection in HIV seronegative patients: report of three new cases of a heterogeneous group of diseases, Int J Hematol 93:795–801, 2011.
Ponzoni M, Ferreri AJ, Campo E, et al: Definition, diagnosis, and management of intravascular large B-cell lymphoma: proposals and perspectives from an international consensus meeting, J Clin Oncol 25:3168–3173, 2007.
Du MQ, Diss TC, Liu H, et al: KSHV- and EBV-associated germinotropic lymphoproliferative disorder, Blood 100:3415–3418, 2002.
Rafaniello Raviele P, Pruneri G, Maiorano E: Plasmablastic lymphoma: a review, Oral Dis 15:38–45, 2009.
Erös N, Károlyi Z, Kovács A, et al: Intravascular B-cell lymphoma, J Am Acad Dermatol 47(Suppl 5):S260–S262, 2002.
Steidl C, Gascoyne RD: The molecular pathogenesis of primary mediastinal large B cell lymphoma, Blood 118:2659–2669, 2011.
Ferreri AJ, Campo E, Seymour JF, et al: International Extranodal Lymphoma Study Group (IELSG). Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the ‘cutaneous variant’, Br J Haematol 127:173–183, 2004.
Sukpanichnant S, Sivayathorn A, Visudhiphan S, et al: Multicentric Castleman’s disease, non-Hodgkin’s lymphoma, and Kaposi’s sarcoma: a rare simultaneous occurrence, Asian Pac J Allergy Immunol 20:127–133, 2002.
Gitelson E, Al-Saleem T, Smith MR: Review: lymphomatoid granulomatosis: challenges in diagnosis and treatment, Clin Adv Hematol Oncol 7:68–70, 2009. Hsi ED, Lorsbach RB, Fend F, et al: Plasmablastic lymphoma and related disorders, Am J Clin Pathol 136:183–194, 2011.
Van Roosbroeck K, Cools J, Dierickx D, et al: ALK-positive large B-cell lymphomas with cryptic SEC31A-ALK and NPM1-ALK fusions, Haematologica 95:509–513, 2010. Zinzani PL, Piccaluga PP: Primary mediastinal DLBCL: evolving biologic understanding and therapeutic strategies, Curr Oncol Rep 13:407–415, 2011.