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B-Cell Non-Hodgkin’s Lymphomaswith a Small Cell to Intermediate CellPhenotype

Contents

Chronic B-Cell Lymphocytic Leukemia(Small B-Cell Lymphocytic Lymphoma;B-CLL/SLL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Liver Pathology in Chronic B-Cell Lymphocytic

Leukemia/Small B-CellLymphocytic Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Histopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Hepatic Failure in CLL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Chronic Lymphocytic Leukemia-Associated

Cholangiopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Chronic Lymphocytic Leukemia and Portal

Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6General Histopathology of Chronic B-Cell

Lymphocytic Leukemia/Small B-CellLymphocytic Lymphoma) . . . . . . . . . . . . . . . . . . . . . . . . . 6

B-Cell Prolymphocytic Leukemia . . . . . . . . . . . . . . . . . . 6Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7Morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7Liver Involvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7Cytogenetic and Molecular Genetic Features . . . . . . . . 7

Follicular Lymphoma of the HepatobiliaryTract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Morphology and Grading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Primary Follicular Lymphoma of the Hepatobiliary

Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Secondary FL Involvement of the Liver . . . . . . . . . . . . . . 10Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10Cytogenetic and Molecular Features . . . . . . . . . . . . . . . . . . 10

Mantle Cell Lymphoma of the Liver . . . . . . . . . . . . . . . 11Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Liver Involvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Cytogenetic and Molecular Features . . . . . . . . . . . . . . . . . . 11

Extranodal Marginal Zone B-Cell Lymphomaof Mucosa-Associated Lymphoid Tissue(MALT Lymphoma) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Liver Involvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Primary Hepatic Low-Grade MALT Lymphoma . . . . . 13Macroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Histopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Immunohistochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14Nonparenchymal Involvement of the Hepatobiliary

Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14Pathogenic Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

# Springer International Publishing Switzerland 2016A. Zimmermann, Tumors and Tumor-Like Lesions of the Hepatobiliary Tract,DOI 10.1007/978-3-319-26587-2_89-1

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AbstractB-cell non-Hodgkin’s lymphomas (B-cellNHLs) showing a proliferation of small- tomedium-sized neoplastic cells have a strongtendency to infiltrate the liver. In particular,small lymphoma cells are capable to circulateand recirculate in the body and to leave themicrocirculation in several organs. The mostcommon B-cell NHL is chronic lymphocyticleukemia of the B-cell type. In this slowlyprogressing neoplasia, the liver is almostalways involved. Accumulation of neoplasticcells causes hepatomegaly, a typical and fre-quent finding, with liver weights slowlyincreasing over time to sometimes reachingseveral kilograms. The exterior aspect of theliver may become grayish white, and the cutsurface shows numerous small whitish nod-ules. The histologic substrate is markedlyenlarged portal tracts which are densely infil-trated by small neoplastic lymphocytes. Inlong-standing disease, larger nodular lesionscan develop, mimicking metastatic disease. Asimilar type of liver involvement is seen in therare B-cell prolymphocytic leukemia. Focaland nodular hepatic infiltration is also observedin follicular NHL, mantle cell lymphoma, andextranodal marginal zone B-cell NHL ofmucosa-associated lymphoid tissue/MALT.

Chronic B-Cell Lymphocytic Leukemia(Small B-Cell Lymphocytic Lymphoma;B-CLL/SLL)

ICD-O code 9823/3

Introduction

Based on the 2008 WHO classification, chroniclymphocytic leukemia/small lymphocytic lym-phoma (CLL/SLL) is defined as a neoplasm com-posed of monomorphic small, round to slightlyirregular B lymphocytes in the peripheral blood,bone marrow, spleen, lymph nodes, and otherorgans and tissues. CLL/SLL is often admixed

with prolymphocytes and paraimmunoblasts andcan form proliferation centers in tissue infiltrates.The general cytologic and histologic features ofCLL are briefly discussed at the end of thischapter.

Chronic B-cell lymphocytic leukemia(B-CLL) and the underlying lymphoma, smallB-cell lymphocytic lymphoma (SLL), belong tothe group of so-called mature B-cell lymphopro-liferative disorders (MBCLDs). SLL and its leu-kemic manifestation, B-CLL, are classified as onedisorder, but in fact this apparent entity consists ofseveral different B-cell diseases that arerepresented under this name. This phenotypic het-erogeneity is reflected by a variability of chromo-somal/genetic abnormalities, alterations in theexpression of apoptosis-related proteins andother effectors, and mutations of growth factors(Caligaris-Cappio and Hamblin 1999; Wierda andKipps 1999; Bannerji and Byrd 2000; Guipaudet al. 2003; Messmer et al. 2004).

Epidemiology

In Western countries, CLL is the most commonleukemia of adults, with an incidence rate ofapproximately two to six cases per 100,000 per-sons per year, to reach 12.8 cases per 100,000persons per year in the age group 65 years andmore. CLL has a gender distribution ofM/F = 1.5–2.0:1 (androtropy). The disease ismuch less common in Eastern countries, likelyto be based on genetic factors, as the low inci-dence persists in migrants from such countries.

Clinical Features

CLL leads to a progressive expansion of small Blymphocytes in blood, bone marrow, and periph-eral tissues. As the neoplastic cells, similar to theirnormal counterparts, circulate and recirculate inthe organism, almost any tissue can be involvedwith time. Clinically relevant manifestations aremainly caused by bone marrow replacement andstructural and functional disorders of inner organssuch as the spleen. In the first and usually long

2 B-Cell Non-Hodgkin’s Lymphomas with a Small Cell to Intermediate Cell Phenotype

period of disease development, most patients areasymptomatic. Rare patients present withaleukemic tissue involvement.

Liver Pathology in Chronic B-CellLymphocytic Leukemia/Small B-CellLymphocytic Lymphoma

MacroscopyHepatomegaly is a typical and frequent finding,with liver weights caused by marked cellular infil-tration range from little more than normal in earlydisease to several kilograms in advanced disease.In most patients, marked hepatomegaly is associ-ated with splenomegaly, but splenic weight inB-CLL is usually less elevated than in myelopro-liferative disorders. Due to sometimes massiveinfiltration, the liver capsule may be tense andthe liver margins effaced. The exterior aspect ofthe unfixed liver may be grayish red or evengrayish white. In a minority of cases, the livercapsule is mottled owing to multiple small hem-orrhages. Moreover, the capsule may be turbiddue to a serosal fibrinous reaction. The consis-tency of the tissue varies from firm to highlyfriable or flabby, depending on the density oflymphoma infiltration and the degree of tissuedecay. The fresh cut surface typically showsnumerous and mostly small whitish nodulesreflecting the spacing of the densely infiltratedportal tracts. This location of the spots or dots tothe lobular periphery has been recognized for along time as being characteristic for CLL (Naegeli1923). In the most typical situation, the lesions aremiliar, i.e., one to about 3 or 4 mm in diameter,and may thus be confounded with granulomas.However, granulomas are never so regularlyspaced all over the organ as are the lesions inCLL. In case of massive infiltration, these areasmay show confluence or “lymphomatous bridg-ing,” resulting in a distinct network of grayish-white color. In other patients, and specifically inlonger-standing disease and/or in case of blastictransformation, larger lesions can ensue, some-times forming nodules of one or more cm diame-ter or even forming massive tumors occupyingone or more segments of the liver. These patterns

may mimic metastatic disease. Larger lesions areknown to obstruct intrahepatic bile ducts, causingcholestasis with greenish discoloration of theentire organ or part of the organ, depending onthe level of obstruction. Bile may leak from dam-aged bile ducts and then stain the lymphoma nod-ules yellow or greenish yellow. Liver organchanges in CLL not directly related to lymphomacell infiltration include hemorrhages, abscesses,hepatic infarctions, and other rarer lesions.

The locoregional lymph nodes of the hepatichilar/perihilar region are frequently enlarged. Inmost cases, this lymphadenomegaly is caused bylymph node infiltration, but other causes can con-tribute to node enlargement, including a cellularreaction to tissue breakdown in the liver, accumu-lation of iron-laden macrophages and of foamycells subsequent to hepatic hemorrhage, granu-loma formation, and immune reactions associatedwith accompanying liver inflammations (e.g.,viral hepatitis).

Histopathology

B-CLL shares the patterns of liver infiltrationswith other small cell non-Hodgkin’s lymphomas(Barcos et al. 1987; Baumhoer et al. 2008). In theliver, B-CLL/SLL chiefly involves the portal tractspaces and, less so, the lumina of the sinusoids(Prinz 1951). The dense and often well-delineatedportal tract infiltrates are typically monomorphicand already visualized at low magnification in theform of blue foci. In advanced disease, the entireportal tract space is occupied by the neoplasticcells, which cause expansion and rounding-up ofthe tracts, with or without spillover of cells intohepatic parenchyma (Figs. 1, 2, 3, and 4). In mostcases, interface lesions are not prominent, andtherefore, the boundary between portal tracts andparenchyma is rather sharp, in contrast to chronicactive viral hepatitis. Due to dense infiltration,preexisting portal tract structures (blood vesselsand bile ducts) are almost effaced, as the smallround cells encircle these structures. More than95% of infiltrate cells are small B cells, and only aminor contribution of macrophages, plasma cells,and granulocytes is seen. The infiltrate is

Chronic B-Cell Lymphocytic Leukemia (Small B-Cell Lymphocytic Lymphoma; B-CLL/SLL) 3

dominated by small lymphocytes which are, how-ever, somewhat larger than normal lymphocytesand are also larger than the leukemic lymphocytescirculating in blood. As in involved lymph nodes,so-called paraimmunoblasts or lymphoblasts arealways seen, characterized as cells with a largersize, readily visible cytoplasm, oval nuclei withfine chromatin, and a single, centrally placedbasophilic nucleolus. The neoplastic infiltratesalso always contains few prolymphocytes, which

are larger than small lymphocytes and have anucleus with an open chromatin. The nucleus ofprolymphocytes may be oval or irregular, resem-bling centrocyte nuclei. Paraimmunoblasts andprolymphocytes are the cell components showingmitotic figures. In situations where greater num-bers of paraimmunoblasts are present, these cellsare mostly clustered as proliferating aggregates,causing a pseudofollicular phenotype (so-calledproliferation centers).

Fig. 3 Sinusoidal accumulation of cells in B-CLL. Tumorcells form rows and “Indian files” and are in close contactwith the endothelial surface (hematoxylin and eosin stain)

Fig. 4 Portal tract infiltrate in B-CLL. The neoplastic cellsare strongly CD79a positive (CD79a immunostain)

Fig. 1 Involvement of the liver in chronic B-cell lympho-cytic leukemia. Small lymphoid cells are present withinsinusoids (reflecting leukemia) and form a dense infiltratein portal tracts. In contrast to infiltrates in chronic hepatitis,the portal tract infiltrate is highly monotonous (hematoxy-lin and eosin stain)

Fig. 2 Liver involvement in B-CLL. The monotonousdense portal tract infiltrate has led to destruction of thehepatic limiting plate (“leukemic/lymphomatous interfacelesions or piecemeal necrosis”). The endothelium of thesmall portal vein branch is damaged by the lymphoma cells(hematoxylin and eosin stain)


Immunohistochemically, a small componentof T cells may be noted. Portal tract infiltratesmay show a nodular configuration, but truelymph follicles or germinal centers are notfound. An interesting phenomenon in someinvolved livers is parenchymal atrophy of lobu-lar zone 1 and sometimes also 2, zone 3 beingspared. The fact that the pericentral zone 3 is notor much less involved speaks against ischemiacaused by blockage of sinusoidal entry sites, buteffects of cytokines/chemokines may be consid-ered. An increased number of small lymphocytesis seen in the sinusoids, but this feature is lessprominent than portal tract infiltrates. The den-sity of intrasinusoidal small B cells reflects leu-kemia, i.e., the number of neoplastic cellscirculating in blood. A subset of patients willdevelop, usually in later phases of disease,tumorous nodules in the liver substance, mostlycomposed of prolymphocytes (intrahepatic smallB-cell lymphoma; tumor-forming CLL). Intumor-forming CLL, the preexisting reticulinfiber network is effaced, and the cells have atendency to infiltrate and destroy small- tomedium-sized veins and to invade the adventitiaof arteries, with splitting of the adventitia. Theliver can also show tumorous hepatomegaly inpatients with Richter syndrome (Tadmoret al. 2011).

Hepatic Failure in CLL

Marked hepatic infiltration leads to a variety offunctional derangements of the organ. In rareinstances, hepatic involvement in CLL resultsin severe hepatocyte injury and acute liver failure(Shehab et al. 1997; Costa et al. 1998; Hasuikeet al. 2004; Esfahani et al. 2011). In one patient,this complication occurred in the setting ofchronic hepatitis B, but autopsy revealed nodularand massive invasion of the liver by neoplasticlymphocytes associated with hepatocyte necrosis(Hasuike et al. 2004). Hepatocyte injury is prob-ably not only caused by direct physical effects ofinfiltrating cells and ischemia due to sinusoidalobstruction but also by cytokines and

chemokines delivered from immune and tumorcells.

Chronic Lymphocytic Leukemia-Associated Cholangiopathy

CLL-associated cholangiopathy is a recentlydescribed disorder (Mann et al. 2011). The indexpatient was a 41-year-old female with untreatedCLL and with elevated liver enzymes in serum,including elevated alkaline phosphatase andgamma-glutamyl transferase. Autoimmune anti-bodies were negative. A liver biopsy showedthat small bile ducts were pushed toward theperiphery of infiltrated portal tracts. Some ofthese bile ducts displayed intraepithelial lympho-cyte infiltration, resulting in significant narrowingof the duct lumen (cholangiopathy). The infiltrat-ing lymphocytes had the same immunophenotypeas leukemia cells.

Chronic Lymphocytic Leukemiaand Portal Hypertension

Non-cirrhotic portal hypertension complicatingCLL has been reported several times (Papadakiset al. 1986; Lindor et al. 1987; Rozmanet al. 1989; Nakamura et al. 1989; Moulyet al. 1996; Pauwels et al. 2000). In part of thecases, hepatic infiltration was found to be thelikely cause of intrahepatic block of blood flow(Rozman et al. 1989; Pauwels et al. 2000), inparticular lymphocytic infiltration of the portaltracts that might impair blood flow from smallportal venous branches into the sinusoidal vascu-lar bed (Nakamura et al. 1989; Mouly et al. 1996),thus representing a pre-sinusoidal intrahepaticblock. Another pathogenic mechanism is nodularregenerative hyperplasia induced by leukemicinfiltration (Rozman et al. 1989). Portal hyperten-sion in CLL can develop in the absence of liverinfiltration and has been suggested to be caused byan increased spleno-portal flow (Wilputteet al. 2003). This view is supported by the obser-vation of reversal of portal hypertension upon

Chronic B-Cell Lymphocytic Leukemia (Small B-Cell Lymphocytic Lymphoma; B-CLL/SLL) 5

resection of an involved spleen (Lindoret al. 1987).

Differential Diagnosis

Without immunohistochemistry, the morphologicpresentation of B-CLL may be similar to fourother lymphoproliferative diseases, i.e.,lymphoplasmacytic lymphoma, lymphomas witha high proportion of centrocytes, prolymphocyticleukemia, and lymphocyte-rich forms ofHodgkin’s lymphoma.

General Histopathology of ChronicB-Cell Lymphocytic Leukemia/SmallB-Cell Lymphocytic Lymphoma)

The cellular and tissue features of B-CLL/SLLhave recently been reviewed (Pileri et al. 2004).On a cellular level, the disorder is characterized bya distinct set of neoplastic lymphoid elements thatcan be classified into small lymphocytes (about6 μm diameter), prolymphocytes, and paraimmu-noblasts. It is of importance to note that the smalllymphocyte component consists of cells that areslightly larger than small nonneoplastic lympho-cytes. The basophilic cytoplasm is scant; thenuclei are usually spheroid, with a chromatinstructure that is slightly more coarse than that ofnormal small lymphocytes. Cleaved nuclei resem-bling the nuclei of centrocytes may occur.Prolymphocytes exhibit an amphophilic or acido-philic cytoplasm and are clearly larger than smalllymphocytes, and their nuclei display a small buteasily evident nucleolus. Paraimmunoblasts havea diameter more than three times larger than smalllymphocytes, a gray cytoplasm in the Giemsastain, and a frequently ovoid nucleus with a prom-inent nucleolus.

Immunohistochemically, the cells of interestin B-CLL are reactive for CD19, CD45, CD79a,CD5, and CD23 but less consistently for CD20.CD20 is weakly or not expressed in the small cellcomponent and is markedly expressed inprolymphocytes and paraimmunoblasts. TheB-CLL cells are typically reactive for CD5 and

CD23, usually more so in prolymphocytes andparaimmunoblasts. Furthermore, the neoplasticB cells usually express Bcl-2, being involved inthe apoptosis protection in this long-lived cellpopulation (see above). The cells are also posi-tive for CD27, a typical memory B-cell marker:Small cells express the B-cell-specific activatorprotein (BSAP) encoded by the PAX-5 gene,while prolymphocytes and paraimmunoblastsgathering in proliferation centers/pseudo-follicles express interferon-regulating factor4 (IRF4) encoded by the MUM-1 gene (undernormal conditions typically expressed in cells ofthe late germinal center cell pathway; cells leav-ing the germinal centers upon somatichypermutation to become memory B cells orplasma cells; Pileri et al. 2004). B-CLL cells donot express CD27.

B-Cell Prolymphocytic Leukemia

ICD-O code 9833/3

Introduction

Prolymphocytic leukemia of B-cell subtype(B-PLL) is a very rare, highly aggressive diseasewith characteristic morphologic, immunocyto-chemical, cytogenetic, and molecular genetic fea-tures. About 1 % of all lymphocytic leukemias areB-PLL (reviews: Melo et al. 1987; Bolding andJacobs 1988; Krishnan et al. 2006; Dungarwallaet al. 2008). The WHO classification of tumorsdefines B-PLL as a neoplasm of Bprolymphocytes affecting the peripheral blood,bone marrow, and spleen. For diagnosis,prolymphocytes must exceed 55 % of lymphoidcells in the peripheral blood. According to WHO,cases of transformed chronic lymphocytic leuke-mia (CLL), with increased prolymphocytes, andlymphoid proliferations with relatively similarmorphology but carrying the t(11;14)(q13;q32)translocation are excluded. CLL and B-PLL canoccur as two concurrent lesions derived from twoseparate clones (Cao et al. 2011). Recently,B-PLL was considered as a specific subgroup of


leukemic mantle cell lymphoma (van der Veldenet al. 2014).

Clinical Features

Clinically, patients with B-PLL experience rapidincrease of B prolymphocytes in the peripheralblood and commonly show marked or even mas-sive splenomegaly, with spleen weights some-times exceeding 2000 g, while lymph nodeenlargement is not a prominent feature or evenlacking (Bearman et al. 1978). In contrast toT-PLL, patients with B-PLL can have aprolonged progression-free survival under ade-quate therapy (review: Absi et al. 2005), andthere is a subset of B-PLL patients who have amore indolent course (Shvidel et al. 1999). In astudy of 41 patients with B-PLL, the median ageat diagnosis was 67 years, with a male-femalesex ratio of 2.4. A high level of surface IgMand/or IgD expression was found in all cases,FMC7+ in 76 %, and CD5+ in 67 %. The medianoverall survival time was 5 years and the event-free survival time was 37 months. No differencein outcome was found between primary BCPLLand secondary B-PLL derived from CLL(Hercher et al. 2001). Lymphocytic leukemiaand B-PLL with MYC translocations are rareentities which seem to be associated with adverseprognostic features and unfavorable outcome(Put et al. 2012).

Morphology

The majority (more than 55 % per definition andoften more than 90 %) of circulating cells areprolymphocytes. These are medium-sized cells,about twice the size of normal unstimulated lym-phocytes, with a small amount of basophilic cyto-plasm, round nuclei with condensed chromatin,and a prominent central nucleolus. Ultrastructur-ally, B-PLL is characterized by the predominanceof a relatively large lymphoid cell with a promi-nent nucleolus, well-condensed peripheralnuclear chromatin, and a variable amount of het-erochromatin in intranuclear clumps (Costello

et al. 1980). The immunophenotype is character-ized by strong expression of surface IgM andusually also IgD, the cells being positive forB-cell markers (CD19, CD20, CD22, CD79aand b, and FMC7). Twenty to thirty percent ofcases show positivity for CD5 and 10–20 % forCD23.

Liver Involvement

Similar to the spleen, B-PLL can cause infiltrationof the liver with prolymphocytes in a CLL-likedistribution pattern (Lampert et al. 1980). Thesecells are present in the lumina of hepatic sinu-soids, depending on the leukemic cell count inthe peripheral blood. More impressive are oftendense leukemic cell infiltrates occupying theexpanded portal tracts, in a pattern often closelyresembling that seen in B-CLL . The neoplasticcells first fill the portal tract space, encroachingupon small bile ducts and blood vessels. In thecourse of the disease, the cells leave the filledportal tract compartment and start to invade theperiportal lobular zone 1, causing an ill-defined“blue” and highly cellular infiltrate effacing theportal tract structure. In case of massive hepaticinfiltration, acute hepatic failure may ensue (Steidlet al. 1994).

Cytogenetic and Molecular GeneticFeatures

Complex karyotypes are common in B-PLL.Among these, del(17p) is detectable in 50 % ofcases and is associated with p53 mutations. Incells of B-PLL, Ig genes are clonally rearrangedwith an unmutated heavy chain gene in about halfof the cases. CLL and B-PLL have different anddistinctive gene expression signatures (review:Del Giudice et al. 2009). B-PLL shows the highestrate of p53 mutations in B-cell malignancies andmay be a major factor responsible for the aggres-sive course with frequent resistance to therapy(Lens et al. 1997). In a subset of B-PLL, BRAFV600E mutation has been detected (Langabeeret al. 2012). B-PLL and CLL with MYC gene

B-Cell Prolymphocytic Leukemia 7

translocations form a subgroup with an aggressivedisease course (Put et al. 2012).

Follicular Lymphomaof the Hepatobiliary Tract

ICD-O codes: Follicular lymphoma, 9690/3(grade 1, 9695.3; grade 2, 9691/3; grade 3A,9698/3; grade 3B, 9698/3)

Introduction

According to the definition of the WHO classifi-cation, follicular lymphoma (FL) is a neoplasmcomposed of follicle center (germinal center) Bcells, typically both centrocytes and centroblasts/large transformed cells. This lymphoma typicallyproduces a follicular pattern (at least partially). Incase of complete formation of large follicularstructures resembling giant follicles with germinalcenters, the lesion is what has previously beentermed Brill-Symmers disease (synonyms: giantfollicular lymphoblastoma; giant follicular lym-phoma, germinoblastoma; Brill et al. 1925;Symmers 1927). If diffuse areas of any size com-prised predominantly or entirely of blastic lym-phoid cells are present in any case of follicularlymphoma, a diagnosis of diffuse large B-celllymphoma is also made (reviews: Klapper 2011;Roulland et al. 2011; Stevenson and Stevenson2012).

Follicular lymphoma is a rather common lesionin the non-Hodgkin’s lymphoma group, withabout 20 % of all lymphomas. This high figureis, however, only valid for the USA and WesternEurope; in Eastern Europe and Asia, FH is lesscommon. FL is mainly a neoplasm of adults, mostpatients being diagnosed with FL in the sixthdecade, with a slight female preponderance. Inthe pediatric age group, which is rarely involved,males clearly predominate. FL is mainly a diseaseof lymph nodes, but also the extranodal lymphatictissues, including the spleen, are regularlyinvolved. Infiltration of solid organs usuallyoccurs in patients with extensive nodal disease,but (apparently) primary involvement of deep

organs also occurs. Similar to other lymphomas,FL can transform to an aggressive lymphoma(Wong and Dickinson 2012).

Clinical Features

Patients commonly show widespread nodalinvolvement at diagnosis, often with splenomeg-aly, but the majority of patients are asymptomaticat diagnosis (Freedman 2012). Bone marrowinvolvement is found in 40–70 % of patients.Patients with FL are classified in regard to riskby use of the international prognostic index(FLIUPI) in the National LymphoCare Study(NLCS). FL in the pediatric age group differs inseveral respects from adult-type FL (Louissaintet al. 2012).

Morphology and Grading

The hallmark of FL is the presence of lesionmimicking lymphoid follicles that efface thepreexisting lymphoid tissue or form a tumorouslesion in non-lymphoid tissues and organs. Thefollicles usually lack a well-defined mantle zoneand typically lack macrophages with tingible bod-ies. In case of large follicular structures (Brill-Symmers pattern), a distinction between hyper-plastic normal follicles and neoplastic lesionsmay be difficult, but immunostaining for folliculardendritic cells (Cd21/Cd23) will deliver the cor-rect answer. Cytologically, FL is composed of twocell types of the B-cell lineage, i.e., small- tomedium-sized cells with angulated or cleavednuclei and scant cytoplasm (the centrocytes) andlarge cells, with round to oval nuclei and a thin rimof cytoplasm (the centroblasts). Centroblasts arealways present, but usually form the minority. Inpart of the cases, FL cells may contain prominentDutcher body formation (Wang et al. 2012a).Dutcher bodies (Dutcher and Fahey 1959) areintranuclear and intracytoplasmic, PAS-positive,Ig chain-related glycoprotein inclusions that werefirst recognized in patients with Waldenström’sdisease. The nuclear inclusions are in fact invag-inations of cytoplasmic inclusions.


Grading of FL (Table 1), based on the propor-tion of centroblasts, has been advocated as a prog-nosticator, but the significance of FL grading isstill debated. In principle, FL grading is based oncounting or estimating the proportion or absolutenumber of centroblasts in ten neoplastic folliclesat 40� magnification (high-power field, HPF),whereby at least ten HPFs within different folli-cles are evaluated.

Grade 3B is currently identified as a distinctentity by molecular analysis. Transformation todiffuse follicular lymphoma, characterized by aneoplastic proliferation of cells resemblingcentrocytes in the absence of a follicular pattern,occurs in about 30–40 % of patients, at a rate ofaround 3 % each year. Diffuse (or high-grade)transformations confer a more aggressive course(review: Takata et al. 2014). The cells must dis-play immunohistochemical features of germinalcenter cells, and the diagnosis should only bemade with an adequate tissue sample, as diagnosisis prone to considerable sampling error.

Immunohistochemically, the tumor cellsexpress B-cell markers (CD19, CD20, CD22,CD79a). They are also reactive for BCL2,BCL6, and CD10, but negative for CD5, CD43,and IRF4/MUM1. The follicular areas may showsparse networks or meshworks of CD21-positivefollicular dendritic cells. The tumor cells are usu-ally positive for surface Igs. At least part of neo-plastic cells express centerin (SERPINA9/GCEt1), a germinal center serpin variant (Frazer

et al. 2000; Pan et al. 2003; Montes-Morenoet al. 2008). In part of FL, centerin is stronglyexpressed (Paterson et al. 2008).

Primary Follicular Lymphomaof the Hepatobiliary Tract

Primary follicular lymphoma of the liver has onlybeen reported few times (Torres 1969; Michettiet al. 1978; Ryan et al. 1988; Ohsawa et al. 1992;Lei 1998; Yeshurun et al. 2001; Bronowickiet al 2003; Gomyo et al. 2007; Raimondoet al. 2012). It is estimated that only about1–4 % of primary hepatic lymphomas are FL(Ohsawa et al. 1992). Primary FL of the livermay present as a solitary nodule or multiple nod-ules, sometimes mimicking a primary epithelialhepatic tumor. In a compilation of nine cases fromthe literature, five cases were solitary and fourwere multiple tumors (Gomyo et al. 2007). Incase of multiple lesions, FL can cause markedhepatomegaly. In an autopsy case, the liverweighed 2240 g, and both the external and cutsurfaces were studded by in part confluent nodulesof tumor, some having a shallow central dimplingand measuring from 1.0 to 2.0 cm in diameter.Microscopically, the nodules consisted of lym-phocytic NHL forming numerous and sometimesvery large follicular aggregates that had effacedthe liver structure, with some remaining small bileducts reflecting previous portal tracts (Torres

Table 1 Grading of follicular lymphoma (WHO classification 2008)

Grading

Grade 1–2: Low grade

Grade 1: 0–5 centroblasts per HPF

Grade 2: 6–15 centroblasts per HPF

Grade 3: High grade, >15 centroblasts per HPF

Grade 3A: Centrocytes present

Grade 3B: Solid sheets of centroblasts

Reporting of pattern Proportion follicular

Follicular >75 %

Follicular and diffuse 25–75 %

Focally follicular <25 %

Diffuse 0 %

Diffuse areas containing >15 centroblasts per HPF are diagnosed as diffuse large B-cell lymphoma with follicularlymphoma

Follicular Lymphoma of the Hepatobiliary Tract 9

1969). In case of marked hepatic infiltration, acuteliver failure may be the initial manifestation oflow-grade hepatic FL (Yeshurun et al. 2001).The follicular pattern may vary from one part ofthe hepatic tumors to the other, the more diffusegrowth pattern of the lymphoma irregularlyblending into the partly atrophic liver substance.The portal tract infiltrate can encroach upon dam-aged interlobular bile ducts, thus inducing a “lym-phomatous bile duct lesion.”

Primary FL has also been identified in extrahe-patic bile ducts, in one patient mimicking a hilarcholangiocarcinoma (Sugawara et al. 2008;Christophides et al. 2009). .

Secondary FL Involvement of the Liver

The liver can be involved in widespread FL(Fig. 5). Several cases have been described asliver involvement in Brill-Symmers disease ornot otherwise specified lymphomas with forma-tion of follicle-like structures (Terplan 1929;Symmers 1942; Cohen and Bergstrom 1946;Wells 1954; Wissmer et al. 1955; Fresen 1956;Baessler 1959). In the early report of Terpan(1929), the disorder is described as a “granu-loma-like systemic disease,” the giant folliclesinterpreted as granulomatous lesions. Symmers’patient (1942) showed, at autopsy, a markedlyenlarged liver with tumor-like infiltrates measur-ing up to 1 cm in diameter. The patient of Cohen

and Bergstrom (1946) showed white focal lesionsof 1–2 mm size in the liver at autopsy. Among31 patients with stage II–IV disease, 2 had liverinvolvement (Takagi et al. 1989).


An important histopathologic differential diagno-sis of FL of the truly follicular type is nodularlymphoid hyperplasia of the liver (Jimenezet al. 2007). The much rarer diffuse variety maybe confounded with other diffusely growinghepatic lymphomas.

Cytogenetic and Molecular Features

Approximately 80 % of FL exhibit the transloca-tion t(14;18)(q32;q21) and BCL2 generearrangements, mainly in low-grade lesions.This translocation is therefore a genetic hallmarkof FL (review: Kishimoto and Nishikori 2014).BCL2 rearrangements are much less common ingrade 3B FL. Five to fifteen percent of FL showabnormalities in 3q27-28 and/or BCL6rearrangements, predominantly in low-gradelesions (grade 3B). Various other chromosomaland molecular abnormalities have been identifiedin FL (Oricchio et al. 2011; Kridel et al. 2012).Most patients with FL variably express BAFF(B-cell activation factor) and BAFF-RE, highexpression of BAFF-R being an independent riskfactor for overall survival (Li et al. 2012). Epige-netic inactivation of p16, p15,MGMT, and DAPKgenes can take place in FL, concurrent hyper-methylation of MGMT and DAPK genes beingmarkers of chemoresistance and disease recur-rence (Krajnovic et al. 2013). FL is characterizedby a unique microRNA signature, wherebymiR-20a/b and miR-194 targeting CDKN1A andSOCS2 potentially contribute to tumor cell prolif-eration and survival (Wang et al. 2012b). Apartfrom the neoplastic lymphoid B cells, the lympho-ma’s microenvironment is an important factor fortumor progression (Wahlin et al. 2012), and stro-mal cells associated with FL lymphoma cells playa significant pathogenic role (Mourcin

Fig. 5 Follicular non-Hodgkin’s lymphoma of the liver.Abnormal follicular structures are found to the left and atthe bottom of the figure (hematoxylin and eosin stain)


et al. 2012). Furthermore, follicular helper T cellsplay a role for the survival of follicular neoplasticB cells (Amé-Thomas et al. 2012).

Mantle Cell Lymphoma of the Liver

ICD-O 9673/3

Introduction

According to the 2008 WHO classification, man-tle cell lymphoma (MCL) is defined as a B-cellneoplasm composed of monomorphic small- tomedium-sized lymphoid cells with irregularnuclear contours and a CCND1 translocation.MCL is a rare lymphoma which account forabout 3–10 % of all non-Hodgkin’s lymphomas.The average age at diagnosis is 60 years, with avariable male predominance. The most commonsite of involvement is the lymph nodes, but thespleen and bone marrow also often participate,and the peripheral blood may be involved. Atypical manifestation in the gastrointestinal tractis multiple lymphomatous polyposis. Clinically,many patients present with advanced stage atdiagnosis, with lymphadenopathy, hepatosple-nomegaly, and bone marrow and peripheralblood involvement (Weisenburger et al. 1982;Swerdlow et al. 1983; Decaudin et al. 1997; Laiand Medeiros 2000; Sander 2011; Kiel and Smith2012; Shah et al. 2012; Vose 2013; Dreyling andEuropean Mantle Cell Lymphoma Network 2014;Gordon et al. 2014).

Morphology

MCL is characterized by a monomorphic prolif-eration of small- to medium-sized lymphoidround cells with irregularly shaped nuclei, resem-bling centrocytes. Centroblast-like cells areabsent. In nodes, these cells reveal a growth pat-tern with diffuse, vaguely nodular, mantle zone orrarely follicular areas. MCL often showshyalinized small vessels. Large infiltrates mayhave interspersed pale histiocytes/macrophages,

sometimes with a “starry sky” effect. MCL hasfew variants of prognostic significance, includingblastoid and pleomorphic variants. Immunocyto-chemically, the cells express surface IgM/IgD,more often with a lambda than kappa light chainrestriction. Cells are reactive for CD5, CD43,FMC-7, cyclinD1, and BCL2, but negative forCD10 and BCL6.

Liver Involvement

Primary Hepatic Mantle Cell LymphomaIn rare instances, MCL was observed to developas a primary liver lymphoma (Itoh et al. 1995; Leiet al. 1995; Zhang et al. 2010).

Secondary Involvement of the LiverInvolvement of the liver has been documentedseveral times (Swerdlow et al. 1983; Franchiet al. 1995; Sousa et al. 1997). In a study of102 patients, the liver was infiltrated in 22.64 %of cases (Ji et al. 2007). Also the blastic variantcan involve the liver substance (Rodleret al. 2004). As in other small to intermediatecell lymphomas, the portal tract space is the pref-erential compartment for tumor cell proliferationand homing, with variable extension into theperiportal lobular zone 1 (“lymphomatous piece-meal necrosis”; lymphomatous interface lesions).MCL can undergo peritoneal seeding (Bahatet al. 2010) and may thus involve the livercapsule.


As cyclinD1 is normally not expressed in B lym-phocytes, cyclinD1 immunostaining is the keydiagnostic marker for MCL and a chief discrimi-nator in differential diagnoses of liverlymphomas.

Cytogenetic and Molecular Features

There is clonal rearrangement of Ig genes. Almostall cases show the translocation t(11;14)(q13;q32)

Mantle Cell Lymphoma of the Liver 11

juxtaposing IGH and cyclinD1/CCND1, consid-ered as the primary genetic event in MCLlymphomagenesis (Jares et al. 2012; Royoet al. 2011; Dreyling and European Mantle CellLymphoma Network 2014). The translocationcauses a reregulated overexpression of cyclinD1.In a simplified pathogenetic scheme, thecyclinD1/cyclin-dependent kinase 4/6 complexpromotes phosphorylation of the retinoblastomaprotein, Rb, leading to the release of the E2Ftranscription factors inducing progression throughthe cell cycle into S phase. The 4/6 complex isinhibited by p16INK4a. There are several molec-ular/cytogenetic variants of MCL, includingcyclinD1-negative MCL, cases with trisomy12, MYC translocation, and BCL6/3q27 translo-cation. In cyclinD1/CCND1-negative MCL,CCDN2 rearrangements were the most frequentgenetic events (Salaverria et al. 2013). Recently,several recurrent mutations were identified inMCL, including ATM, CCND1, MLL2, TP53,RB1, WHSC1, POT1, and SMARCA4 genes(Zhang et al. 2014). In addition, MCL shows ahigh number of nonrandom secondary chromo-somal aberrations. Among molecular subsets ofMCL, those defined by the IGHV mutational sta-tus and SOX11 expression have distinct biologicand clinical features (Navarro et al. 2012). InMCL biology and progression, the compositionand features of the microenvironment play a sig-nificant role, e.g., the production of IL-6, which isan MCL survival factor (Zhang et al. 2012).

Extranodal Marginal Zone B-CellLymphoma of Mucosa-AssociatedLymphoid Tissue (MALT Lymphoma)

ICD-O: 9699/3

Introduction

Extranodal marginal zone B-cell lymphoma ofmucosa-associated lymphoid tissue (MALT;MALT lymphoma) is a low-grade extranodalNHL developing in several extranodal sites,

including the gastrointestinal tract, thyroidgland, salivary glands, ocular adnexa, lung,breast, and liver. This type of lymphoma accountsfor about 8 % of NHLs and 50 % of primarygastric lymphomas. Most cases develop in adults,with a median age at diagnosis of 61 years, with aslight female preponderance. MALT lymphomasbelong to the group of marginal zone B-cell lym-phomas (MZBL). Several features suggest that thethree different clinicopathologic types of MZBL(nodal, extranodal, and splenic MZBL) are in factthree different diseases. Clinically, most patientspresent with stage I or stage II disease. Only aminority of patients show bone marrow involve-ment. Multiple extranodal sites may be affected inup to 25 % of patients with gastric MALT lym-phoma and up to 45 % in those with extragastricdisease (Isaacson and Du 2004; Zinzani 2012).

Morphology

In lymph nodes, the tumor cells of MALT lym-phoma grow in a marginal zone distribution andspread out to form diffuse confluent areas. Thecells are small to medium sized, with slightlyirregular nuclei and inconspicuous nucleoli, partof the cells closely resembling centrocytes. Thecytoplasm is rather abundant and pale, resulting ina monocytoid morphology. In gastric MALT lym-phoma, up to a third of cases reveal plasmacytoiddifferentiation. A minority of cells exhibit acentroblast-like morphology. Where the tumorcells are in contact with epithelial surfaces orglandular structures, lymphoepithelial lesionsdevelop. Small groups of lymphoma cells are inclose association with epithelial cells, associatedwith epithelial disarray and signs of epithelialdamage, such as eosinophilic degeneration.Immunocytochemically, the cells express IgMand less often IgA and IgG and are reactive forCD20, CD79a, CD21, CD35, and, rarely, CD5,negative for CD10 and CD23, and variably posi-tive for CD43. A novel selectively expressedmarker for MALT lymphoma is immunoglobulinsuperfamily receptor translocation-associated1/IRTA1 (Falini et al. 2012).


Liver Involvement

Primary Hepatic Low-Grade MALTLymphoma

Primary low-grade marginal zone B-cell lym-phoma of MALT of the liver is very rare, lessthan 50 cases having been reported (Isaacsonet al. 1995; Ueda et al. 1996; Maes et al. 1997;Prabhu et al. 1998; Ascoli et al. 1998; Kirket al. 1999; Ye et al. 2000; Chen et al. 2000;Charton-Bain et al. 2000; Murakami et al. 2002;Yago et al. 2002; Golli et al. 2003; Mehrainet al. 2003; Takeshima et al. 2004; Gockelet al. 2005; Nart et al. 2005; Hamada et al. 2006;Shin et al 2006; Doi et al. 2008; Koubaa Mahjoubet al. 2008; Nakayama et al. 2010; Kiesewetteret al. 2012; Kikuma et al. 2012; Yu et al. 2013;Zhong et al. 2014). In most cases reported so far,the hepatic NHL was identified incidentally, usu-ally by imaging investigations for liver dysfunc-tion or other diseases, including metastases(Chatelain et al. 2006). Nodules of MALT lym-phoma can in fact closely mimic liver metastases.Among the 14 patients reviewed in a recent study(Murakami et al. 2002), nine patients were female,and this NHL involved elderly patients (medianage: 64 years). Seven of the patients had preced-ing but variable liver disease. The lymphoma canbe associated with HCV infection (Yagoet al. 2002; Bronowicki et al. 2003; Orregoet al. 2005; Viswanatha and Dogan 2007; Arcainiet al. 2012), gastric Helicobacter pylori infection(Iida et al. 2007), or primary biliary cirrhosis(Prabhu et al. 1998; Ye et al. 2000; Nakayamaet al. 2010). Primary hepatic MALT lymphomac12/14 lesions were solitary. The dimensions ofthe hepatic masses ranged from less than 2 to7.5 cm. Three of the patients reported so far suf-fered from primary biliary cirrhosis (Prabhuet al. 1998; Ye et al. 2000; Golli et al. 2003).This association had been suggested to eventuallybe related to an effect of chronic antigenic stimu-lation favoring the development of MALT-typeNHL (Prabhu et al. 1998; Ye et al. 2000). Excep-tionally, MALT lymphoma in the liver presents ashigh-grade lymphoma. In one patient, this

lymphoma was diagnosed several years aftercomplete remission of a gastric low-gradeMALT lymphoma and was thought to have prob-ably transformed from this gastric lymphoma(Chung et al. 2006).

Macroscopy

In the few cases that have been described, MALTNHL of the liver presented as ill-defined solid andfirm masses of grayish-red color, sometimes inclose relationship with vessels of bile ducts andwith signs of necrosis and hemorrhage(Yu et al. 2013).

Histopathology

In more detail, the nodular hepatic growths inMALT lymphoma of the liver consist of small- tomedium-sized cells that are slightly larger thannormal small lymphocytes and that showcentrocyte-like nuclei . In the Giemsa prepara-tion, the moderate cytoplasm stains light or evenclear. In addition to this main cell population,other cell types may occur, including elementswith monocytoid features (with kidney-shapednuclei) and cells resembling lymphoplas-macytoid cells. Similar to MALT NHL in thegastrointestinal tract, where about a third of thecases show cells with a plasma cell differentia-tion, plasma cells are also seen in hepatic lesions.The diffuse or nodular/follicular growth of NHLof the MALT type is intermingled with usuallyrather few large basophilic blasts of theimmunoblast phenotype. Of particular interestfor hepatic MALT lymphoma is the observationthat the typical lymphoepithelial lesions are alsofound, but involving the epithelial lining of bileducts. These biliary lymphoepithelial lesionshave been reported in the literature (Maeset al. 1997; Charton-Bain et al. 2000; Yeet al. 2000; Iida et al. 2007; Baumhoeret al. 2008). This type of lesion is characterizedby a disarray of involved small- to medium-sizedbile ducts, with crowding of nuclei, loss of

Liver Involvement 13

cholangiocytes, and intraepithelial infiltratesconsisting of both tumor cells and normal-looking small lymphocytes. The lesions some-what resemble the bile duct lesions seen in pri-mary biliary cirrhosis and autoimmunecholangiopathy, and the epithelial damage isbest visualized by use of biliary cytokeratinimmunohistochemistry.

Immunohistochemistry

Immunohistochemically, the tumor cells expresssurface immunoglobulins (usually IgM), CD20,and CD79a, but not CD43 or CD45RO (Iidaet al. 2007; Doi et al. 2008), the latter in cellsubsets displaying varying degrees of plasmacyticdifferentiation, where also CD38 is positive.There is typically no immunoreactivity for CD23and cyclin D1, but, in contrast to gastrointestinalNHL of the MALT type, extra-GIT lesions mayexpress CD5. The nodular/follicular componentscontain CD23- and CD35-positive follicular den-dritic cells, however with variable colonizationdensities.

Nonparenchymal Involvementof the Hepatobiliary Tract

Extranodal marginal zone B-cell lymphoma of theMALTalso occurs in the gallbladder and along theextrahepatic bile ducts to the papilla of Vater(Pelstring et al. 1991; Mosnier et al. 1992;McCluggage et al. 1996; Ventrucci et al. 1998;Bickel et al. 1999; Tsuchiya et al. 2001; Kanget al. 2001; Chim et al. 2002; Isomotoet al. 2003). This issue is further discussed in thepart on biliary tumors.


MALT lymphoma of the liver has to be distin-guished from other small B-cell lymphomas,either primary or secondary. Furthermore, hepaticpseudolymphomasmay sometimes closely resem-ble MLAT lymphoma in conventional tissue

sections (Willenbrock et al. 2006; Hayashiet al. 2011).

Pathogenic Pathways

The development of MALT lymphoma dependson antigen-driven T-cell-mediated stimulation,whereby, in gastric lymphomas, immune stimula-tion by Helicobacter pylori plays a significantrole. MALT lymphoma bears specific transloca-tions (reviews: M€uller-Hermelink 2003; Bertoniand Zucca 2006). In the primary and most fre-quent t(11;18)(q21;q21) translocation, an inhibi-tor of apoptosis, API2 (apoptosis inhibitor-2),assigned to chromosome 11, and MALT1 areinvolved in this type of translocation, formingfusion transcripts of different lengths due to sev-eral breakpoints in the MALT1 gene and a ratherconstant breakpoint in the API2 gene. The secondtranslocation, t(14;18)(q32;q21), fuses the immu-noglobulin heavy chain gene (IGH) with MALT1.The latter translocation was detected most fre-quently in MALT lymphomas of the conjunctiva,liver, skin, parotid gland, and other salivaryglands. It has furthermore observed that the t(14;18)(q32;q21) transcription can also involvefusion of IGH with bcl-2 in a subset of MALTlymphomas in patients with HCV infection (Libraet al. 2004). There are other translocations inMALT lymphoma, including the recently reportedtranslocation t(X;14)(p11;q32), which deregu-lates expression of an orphan G-protein-coupledreceptor, GPR34 (Ansell et al. 2012), and t(11;14)(q23;q32), involving IGh and DDX6 (Staryet al. 2013). .

MALT1/paracaspase is a caspase-like proteinmaking part of an evolutionarily conserved super-family of caspase-like proteins, the paracaspasesand metacaspases (Uren et al. 2000; Yu andLenardo 2003; Hachmann et al. 2012; Kirchhoferand Vucic 2012;Wiesmann et al. 2012), that holdsa central role in lymphocyte activation. This hasbeen demonstrated by the use of paracaspase-defi-cient mice that are defective in antigen receptor-induced NF-kappaB activation and cytokine pro-duction (Ruefli-Brasse et al. 2003). MALT1 con-tains an N-terminal death domain, two


immunoglobulin (Ig)-like domains, and aC-terminal caspase-like domain. MALT1 bindsto bcl10 through its Ig-like domains and cooper-ates with bcl10 to activate NF-kappaB. ChimericAPI2/MALT1 proteins are thought to function asoncogenes that bilaterally confer a proliferativeadvantage to the clone by activating theNF-kappaB signaling pathway and also inhibitingp53 protein-mediated apoptosis (Stoffelet al. 2004; Stoffel and Levine 2004). In fact, thechimeric protein binds to several protein partnersthat regulate apoptotic pathways, including Smac,HtrA2, and TRAF2 (Hosokawa et al. 2004). TheNF-kappaB pathway is affected by a series ofadaptor proteins, including MALT1/paracaspase(Hailfinger et al. 2011; Rosebeck et al. 2011),CARMA3 (a member of the membrane-associated guanylate kinase {MAGUK} familyof scaffold proteins; Sun 2010; Jianget al. 2011), BCAP, the E3 ubiquitin ligase mindbomb-2 (Stempin et al. 2011), and BCL10 (B-celllymphoma 10) (Thome 2004), forming a proteincomplex (the CARMA3-BCL10-MALT1signalosome; Delekta et al. 2010; McAllister-Lucas et al. 2010), depending in its assembly onneuroepithelial transforming gene 1/Net1(Vessichelli et al. 2012), in which BCL10 isthought to facilitate the oligomerization ofMALT1 monomers (Simeoni et al. 2004). Bythis, the paracaspase MALT1 can potently acti-vate NF-kappaB, suggesting that MALT1 mightstimulate the kinase complex (IKK, inhibitor ofNF-kappaB kinase) responsible for activatingcytoplasmic NF-kappaB for translocation intothe nucleus. The tripartite protein complex isalso responsible for the ubiquitination of NEMOcritical for NF-kappaB activation (Lynch andGadina 2004). Specifically, BCL10 activatesNF-kappaB through ubiquitination of NEMO(Zhou et al. 2004). On the other hand, theCARD domain of BCL10 can also activateNF-kappaB by its own, and both MALT1 andbcl10 seem to do so by a mediating action ofTRAF6 ubiquitin ligase and TAK1.

The MALT1/paracaspase oligomers bind toTRAF6, induce TRAF6 oligomerization, and acti-vate the ligase activity of TRAF6 topolyubiquitinate NEMO (Sun et al. 2004). The

MALT1/paracaspase is also involved in T-cellreceptor-induced NF-kappaB activation. MALT1is required into the lipid rafts of the immunolog-ical synapse following activation of the T-cellreceptor (TCR) and the CD28 coreceptor(CD3/CD28 costimulation). This recruitment ofMALT1 is dependent on CARMA1, andMALT1 associates with CARMA1 in a bcl10-dependent manner (the tripartite/trimolecularcomplex; Che et al. 2004). It has recently beenshown that expression of MALT1 in hematopoi-etic stem cells in mice recapitulates the pathogen-esis of human lymphoma (Vicente-Duenaset al. 2012).

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