SAPIENS DISEASES - MARGINAL ZONE B-CELL LYMPHOMA (MZL / MZBL) (<
1% of all NHL): a group of related B-cell neoplasms that involve the lymphoid
tissues in the marginal zone, the patchy area outside the follicular mantle
nodal MZL (NMZL) (+/- monocytoid B cells)
(previously known as monocytoid B-cell lymphoma (MBCL)). By definition,
in the WHO classification the term nodal is used to design cases primarily
involving lymph nodes, and it excludes any case with prior or concurrent
localization in an extranodal site other than bone marrow, liver, or spleenref.
Although nodal MZL shares many histologic and immunologic features with
extranodal MZL of MALT typeref1,
clinical characteristics, natural history, and prognosis suggest that nodal
MZL should be considered a distinct disease entityref1,
Based on molecular findings, the relation between the 2 entities is still
. It has been debated whether MZL with primary nodal involvement has to
be considered a distinct disease or merely represents the dissemination
of EMZL of MALT-type. NMZL has a more frequent involvement of peripheral
lymph nodes and an advanced disease stage at the presentation compared
with EMZL of MALT-type. Moreover, NMZL has a shorter overall survival duration
than EMZL. Therefore, from a clinical point of view, NMZL seems to be more
similar to other low-grade NHLs such as follicular and lymphocytic lymphoma
marginal zone lymphoma (SMZL) / splenic marginal-zone B-cell lymphoma (SMZBCL)
(+/- villous lymphocytes) (indolentref)
: comprise both follicular and marginal-zone B cells, and often carry unmutated
variable (V)-region genes. These lymphomas might therefore be derived from
B cells prone to undergo marginal-zone B-cell differentiation. SMZL was
originally recognized either after histopathologic examination of surgically
removed spleens as SMZL itselfref
or by means of morphologic and immunophenotypical characterization of circulating
neoplastic lymphocytes as splenic
lymphoma with villous lymphocytes (SLVLs)ref.
Now it is quite clear that the 2 entities have the same pathologic basis
but different expressions of circulating cellsref1,
After the recognition of a peculiar intrasinusoidal bone marrow infiltration
in SMZL with or without villous lymphocytesref,
the diagnosis can even be made with the bone marrow biopsy aloneref1,
This feature is of great help because it allows a definitive diagnosis
to be made, avoiding an unnecessary splenectomy. In the case of splenomegaly
of unknown origin, the invasive procedure of choice for patients with hematologic
associations could be a bone marrow biopsyref.
For many years, the approaches to SMZL and SLVLs have been different. SMZL
has been prevalently diagnosed by pathologists and SLVL by clinicians.
Different observations coincide in pointing toward the relative molecular
heterogeneity of this neoplasia, as observed in the study of bcl-6 somatic
mutation frequency or 7q31-q32 deletionsref1,
Simultaneously, the allegedly marginal zone origin of this lymphoma has
increasingly been questioned. This hypothesis was based on the almost universal
presence of marginal zone differentiation when splenic sections were examined
in this tumor. However, it was brought into question because the examination
of other organs failed to discover marginal zone differentiation, thus
suggesting that the presence of marginal zone rims was dependent on the
localization of the lesion in the spleen. This suggestion has subsequently
been proven after showing that other lymphoma types, such as follicular
regularly show marginal zone differentiation when infiltrating the spleenref.
: the real incidence of SMZL has never been exactly calculated, even if
it has been estimated as < 1% of NHLref1,
However, in the series of Berger et alref,
SMZL accounts for 2.7% of all patients with lymphoma treated in their department.
This figure seems to be high and should be critically evaluated. SMZL constitutes
8% to 14% of lymphoma in surgically removed spleens involved by lymphoproliferative
The median age of patients is 68 years (range, 22-79 years) with a male-to-female
ratio of 1:1.8.
signs : almost all patients present moderate-to-massive splenomegaly
that can cause discomfort in the left hypochondrium. Hepatomegaly can be
sometimes observed, but lymphadenopathy is extremely rare. Nonspecific
symptoms relating to moderate anemia, which is reported in up to 64% of
cases, are frequently noted. B symptoms such as fever and night sweats
are rare. Similarly, alterations in levels of serum albumin, lactic dehydrogenase
(LDH), and b2-microglobulin may be
seen in variable percentages. Occasionally diagnosis can be made on splenectomy
specimens for traumatic or spontaneous ruptureref.
Associated clinical conditions : autoimmune
phenomena, such as primary
appearance of lupus anticoagulantref,
Gale R 340, 1116 represent the most frequent associated conditions,
even though in some cases they could be induced by treatmentref.
A combination of warm autoimmune hemolytic anemia and pure red cell aplasia
has been reported in a single patientref.
A type II (IgM-IgG) cryoglobulin, detected in the serum, caused leukocytoclastic
vasculitis in one patientref.
is sometimes seen, but it is severe only in 15% of cases. Mild neutropenia
due to a combination of splenic sequestration and bone marrow infiltration
is commonly observed, but only 5% of patients present neutropenia below
1 × 109/Lref.
Absolute lymphocytosis is reported in 75% of patients. Lymphocytosis can
ensue in the course of the disease after diagnosis. A frequent rise in
lymphocyte count is observed after splenectomy. The presence of a small
M band, IgM or IgG, usually < 30 g/L, can be documented in up to 50%
spleen : recognition of this kind of lymphoma started with the pathologic
studies on surgically removed spleens. Several reports have outlined the
The spleen is enlarged, weighing from 270 to 5500 g with a median of 1750
g. The cut surface generally shows multiple, small-to-moderate gray-tan
nodules throughout the parenchyma (Figure 2A). A diffuse variant with no
nodule formation has been recently describedref.
Histologically, the splenic architecture can be retained in initial phases.
Hyperplastic white pulp shows expansion of marginal zones (Figure 2B),
with frequent merging and coalescence. Residual reactive follicles with
germinal centers can be occasionally noted. Germinal centers can be frequently
involuted. Neoplastic cells extend from the marginal zone to the red pulp
with variable involvement. In advanced phases, diffuse obliteration of
splenic architecture is made by sheets of neoplastic cells that obscure
white and red compartments; in these cases no residual follicular structures
can be identified. Involvement of splenic sinuses is typical (Figure 2C-D).
The sinuses are filled up with neoplastic cells morphologically identical
to the cells seen in the marginal zones. Cytologically, the neoplastic
cells are medium sized with roundish or slightly irregular nucleus, clumped
chromatin, frequent small nucleolus, and a moderate amount of cytoplasm
with distinct borders sometimes of villous appearance (Figure 2E).
bone marrow is invariably involved. Isolated and initial reports of cases
with no bone marrow involvement can be attributed to subtle lymphoid infiltration,
not easily recognized without immunohistochemical studiesref.
Different types of infiltration have been described, namely, intrasinusoidal,
interstitial, nodular, and even paratrabecularref1,
However, intrasinusoidal infiltration can be considered highly characteristic
of SMZL (Figure 2F-G); so far there is no report of intrasinusoidal infiltration
in other kinds of low-grade B-cell lymphoma, with the exception of subtle
infiltration in a proportion of cases of extranodal marginal lymphomaref.
Sometimes, perisinusoidal infiltration can be seen (Figure 2H). Different
patterns of infiltration could be an expression of different phases of
the disease; in early phases, the intrasinusoidal pattern prevails, whereas
in advanced ones it tends to diminish and nodular formations tend to increaseref.
peripheral blood involvement is reported at different percentages. The
previous provisional nomenclature of SMZL with or without villous lymphocytes
exemplifies at best this variability. The amount of circulating cells can
be so small that it cannot be detected. In obvious peripheral blood involvement,
numerous mature B lymphocytes with pale cytoplasm, irregular cytoplasmic
borders, and villous projections can easily be recognized (Figure 2I).
Larger cells with prominent nucleoli can be seen in the aggressive variantref.
lymph nodes : involvement of hilar splenic lymph nodes is commonly observed
(Figure 2J). Peripheral lymph nodes can be involved as well, but to a lesser
extent. Complete or partial effacement of lymph node architecture is made
by a nodular lymphoid infiltrate. Neoplastic nodules can contain a central
reactive follicular center. Sinuses are generally spared or can show variable
degrees of dilation. The characteristic sinusoidal involvement seen in
other organs has not been described in lymph nodes. Different expression
of adhesion molecules in the various lymphoid compartments might explain,
at least in part, this phenomenon. Extensive lymph node involvement can
rarely produce diffuse replacement. Scattered blasts with nucleoli can
sometimes be present, especially at the periphery of the nodules. A primary
nodal counterpart of SMZL, occurring in the absence of splenomegaly, has
been hypothesized and shows a similar histologic picture to that observed
in hilar splenic lymph nodes of SMZLref.
liver : few data are available on liver involvement in SMZLref1,
The liver is involved in almost 90% of cases prevalently showing nodular
infiltration of portal tracts. Lobular invasion is reported to a lesser
However, no special reference is made on immunohistochemical studies. Liver
biopsies in our patients show an invariable sinusoidal infiltration together
with lymphoid nodules in portal tracts (Figure 2K-L).
other organs : rarely are nonhematolymphoid organs massively involved,
at least at presentation. Involvement of nonhematopoietic sites is reported
in 6.6% of cases in a recent seriesref.
Cutaneous involvement has been reported in 2 patients showing dermal tumoral
infiltration located around cutaneous appendages and blood vessels with
some degree of epidermotropismref.
Pleura localization is seen in 5% of cases in a large seriesref.
In a single patient of ours we found a massive perirectal localization
of soft tissue. Sporadic soft-tissue involvement in SLVLs has been previously
described by Orero et alref
in the thoracic region and by Yamazaki et alref
in perirenal area. Meningeal involvement has also been reported and can
induce altered mental status and seizuresref1,
Pathologic features of SMZL. (A) Splenic cut surface in typical SMZL. Note
the widespread micronodular appearance. (B) Histologic picture of spleen
in SMZL. Widening of the marginal zone is evident; in initial phase, the
differentiation with a reactive marginal expansion can be impossible (hematoxylin
and eosin, × 125). (C) Splenic sinuses are characterized by the presence
of mature lymphocytes (hematoxylin and eosin, × 500). (D) CD20 positivity
in SMZL. Note sinusal involvement (avidin-biotin-peroxidase complex [ABC]
method, × 250). (E) Imprint cytology of SMZL. Medium-sized lymphoid
cells with clumped nucleus and villous cytoplasmic borders (arrow; Giemsa,
× 1000). (F) Bone marrow biopsy in a typical case of SMZL shows peculiar
intrasinusoidal infiltration (arrows; × 400). (G) Intrasinusoidal
infiltration in bone marrow biopsy (Cd45RB; ABC method, × 500). (H)
Rarely, lymphoid cells infiltrate bone marrow in a perisinusoidal pattern
(CD20; ABC method, × 300). (I) Ultrastructure of circulating villous
lymphocytes.(uranyl acetate-lead citrate, × 2000). (J) CD79a positivity
in a hilar splenic lymph node involved by SMZL (ABC method, × 500).
(K) Liver involvement in SMZL. Lymphoid infiltration is present in portal
tract and in sinusoids (hematoxylin and eosin, × 250). (L) Sinusoidal
involvement in liver biopsy is highlighted by immunocytochemistry (CD45
RA; ABC method, × 250).
immunophenotype : positivity for CD20, CD45RA, CD45RB, CD79a, PAX5/BSAP,
IgM, and bcl2 and negativity for CD43, CD23, CD10, bcl6, and cyclin D1
are constantly observed. Occasional positivity for CD5 has been reported
in a minority of patientsref1,
but it should be critically analyzed. T-cell antigens are always negative.
DBA44 gives variable staining; weak positivity for acid phosphatase
isoenzyme 5 (TRAP) is reported in a proportion of casesref.
SMZL shares with nodal and extranodal marginal lymphomas the absence
of telomerase activity, which is conversely highly expressed in other
kinds of low-grade B-cell neoplasmsref.
High, low, or no expression of p27 has also been reportedref1,
ultrastructural studies have been rarely performed. Hammer et alref
studied 11 of 14 cases of their series by electron microscopy. Neoplastic
marginal zone cells have a moderately developed curvilinear rough endoplasmic
reticulum, approaching that seen in plasmacytoid cells. The cytoplasmic
ribosomes are either clustered or scattered. Nuclei generally show more
evident and peripherally located nucleoli than in normal marginal zone
cells. Cell-to-cell contact is characterized by surface interdigitations,
diagnosis : among low-grade lymphoid neoplasias, various disorders
can enter into differential diagnosis of SMZL. In most cases, a definitive
diagnostic judgment can be reached after histologic examination along with
immunohistochemical study in conjunction with clinical data. Only rarely
are molecular biology and cytogenetics or ultrastructure helpful in distinguishing
the various entities.
: although circulating cells and clinical setting are similar, in the bone
marrow, hairy cells produce patchy infiltration with progressive replacement
of normal hematopoietic series and low cellular density. Neoplastic infiltration
is characteristically intermingled with extravasated red cells. The reticulin
fiber content is almost invariably increased and accounts for the high
frequency of "dry taps". In the spleen, HCL diffusely involves the red
pulp, whereas the white pulp is atrophied. Cytochemically, hairy cells
are diffusely and strongly positive for tartrate-resistant acid phosphatase
(TRAP). The immunophenotype profile of HCL is similar to that of SMZL.
However, HCL differs for CD25 and CD103 positivity. Ultrastructural analysis
shows characteristic ribosome-lamella complex in hairy cell cytoplasm.
B-cell chronic lymphocytic leukemia
: morphologically, B-CLL is composed of small mature lymphoid cells, with
high nuclear-to-cytoplasm ratio, scant cytoplasm, and round nuclei with
highly condensed chromatin and inconspicuous nucleolus. Admixed with these
cells may be prolymphocytes and paraimmunoblasts, characterized by larger
size and prominent nucleoli. In the bone marrow the pattern of infiltration
can be interstitial, nodular, or diffuse, but never intrasinusoidal. Immunohistochemically,
B-CLL differs from SMZL for a lower expression of CD20 and positivity for
mantle cell lymphoma (MCL)
is clinically different from SMZL due to the high frequency of peripheral
lymphadenopathy, but some example of massive splenomegaly with bone marrow
involvement without prominent lymphadenopathy can be observed. Neoplastic
cells are small to medium sized with irregular nuclei, morphologically
resembling centrocytes/cleaved follicular center cells, but with less irregular
nuclear contours. The bone marrow infiltration can be interstitial, diffuse,
or nodular; an intrasinusoidal component has never been observed. MCL is
characteristically CD5+, CD43+, and cyclin D1+.
cytogenetics and molecular biology : In contrast to the well-established
chromosomal changes associated with other B-cell NHLs, few genetic alterations
have been reported in association with SMZL and no consistent or unique
abnormalities have been so far documented. IgVH mutations have
been described and are consistent with their postfollicular marginal zone
whereas the occurrence of ongoing mutations could be acquired in the splenic
Recently, the study of matched splenic and blood neoplastic cells in 4
patients with SMZL showed identical VH sequences between cells
from different tissues; 3 patients showed an unmutated germ line configuration,
whereas the fourth one, who had developed a clonally related diffuse
large B-cell lymphoma (DLBCL)
of the chest wall, showed a significant somatic mutation of the subclone
with intraclonal heterogeneity. This finding stresses the concept that
an environmental factor can initiate in vivo somatic mutation, thus
influencing tumor behavior and, possibly, disease progressionref.
Rearrangement of bcl-6 was identified in some marginal zone lymphomas (MZLs)ref,
whereas another study did not confirm this findingref.
A molecular heterogeneity of SMZL has been therefore suggested, thus supporting
the hypothesis that besides the proportion of cases derived from marginal
zone cells, showing bcl-6 hypermutation, another significant proportion
of cases could originate from an unmutated naive precursor possibly located
in the mantle zoneref.
The t(11;14), typical of MCL, was reported in some cases of SMZL leading
to 2 possible explanations: (1) misdiagnosis because review of lymph node
histology was not performed, and (2) a different bcl-1 breakpoint in SLVLsref.
Abnormalities of chromosome 14, at band q32.33 harboring the immunoglobulin
heavy chain (IgH) gene, are found throughout among NHLs with different
morphologic and clinical manifestationsref.
The chromosomal abnormalities involving chromosome 14 more frequently encountered
in patients with SLVLs were translocation t(6;14)ref1,
and microdeletion of 13q14ref.
The t(9;14)(p13;q32) translocation involves the IgH 14q32 in a head-to-head
configuration to the PAX5 gene on chromosome 9p13. PAX5 normally codes
for the transcription factor BSAP and is expressed from the earliest B-cell
lymphopoiesis stages up to the mature B-cell stage with subsequent down-regulation
during terminal plasma cell differentiation. The finding of t(9;14)(p13;q32)
translocation in B-cell NHLs with plasmacytoid differentiation suggests
that deregulation of PAX5 interferes with the cell cycle regulation of
mature B cells and, by preventing them to enter the quiescent state, may
contribute to the lymphomagenesis. This finding was reported in cases of
SMZLs, whose origin is postulated to derive from transformed memory B cells
of the marginal zone with potential of differentiation into plasma cells.
The t(9;14)(p13;q32) translocation corresponds to a gain-of-function mutation
of the human PAX5 gene with coding of a wild-type of BSAP proteinref.
Structural abnormalities of 7q (7q32 deletions and 7q22 translocation),
commonly reported in myeloid malignancies, were found to occur in 3.6%
of patients with chronic lymphoproliferative disorders, mainly in patients
with SLVLs and HCL variant (26%)ref.
Moreover, alterations of chromosome 7q, mainly allelic loss, are frequently
observed in splenic lymphomasref1,
with subsequent dysregulation of cyclin-dependent kinase 6 (CDK6) gene,
possibly playing a role in the pathogenesis of SMZL and SLVLsref.
The occurrence of 2 cytogenetic subtypes, characterized, respectively,
from gain of 3q and loss of 7q, was suggestedref.
Recently, by means of analysis of the IgVH somatic mutations in SMZL, a
significant group (49%) of unmutated cases with frequent 7q and adverse
clinical course was reportedref,
suggesting that 7q deletion may play an alternative role in the inactivation
of p53 pathway for tumor progressionref.
The relationship between SMZL and MZLs arising at other sites, particularly
those of mucosa-associated lymphoid tissue (MALT) type, has also been discussed.
The t(11;18) (q21;q21), which represents the most frequent structural chromosomal
alteration in extranodal low-grade MALT lymphomas, leads to a fusion between
the apoptosis inhibitor-2 (API2) gene, on the chromosome 11 and the MALT
lymphoma-associated translocation (MLT) gene on chromosome 18, thus prompting
speculation about the critical role of abrogation of apoptosis in the development
of these lymphomasref1,
Despite the common pathogenesis postulatedref,83
no case of SMZL shows API2-MLT fusion, thus favoring the hypothesis of
separate lymphoma entitiesref1,
Similarly, the search in cases of SMZL for microsatellite instability,
described in association with p53 mutation in patients with MZL of MALT
type, gave negative resultsref.
This concept was further strengthened by the finding of different genetic
alterations in MZLs arising at different sites, suggesting that fundamental
differences exist between the subtypes of MZLsref.
Trisomy 3 represents the most frequent cytogenetic abnormalities reported
in MZLs, occurring in a high proportion of extranodal, nodal, and splenic
In contrast with this finding, another study reported a high frequency
of trisomy 3 in extranodal and nodal MZLs but not in splenic ones. This
fact strengthens the idea that these different subtypes are genetically
In some studies, the finding of cytogenetic alterations was put into relationship
with clinical course and prognosis. Translocations t(2;8)(p12;q24) and
t(14;18)(q32;q21) were reported in a case of an aggressive variant of SMZLref.
Complex chromosome defects including 6q, 11q, +12, and 17p were found to
be usually associated with switching into high-grade histologyref
and, among several genomic imbalances encountered, gains, involving more
frequently 3q, 5q, 12q, 20q, 9q, and 4q were more frequent than losses;
the latter, mainly involving 7q and 17p, were associated with shorter survivalref.
The 17p losses, which occur frequently in human cancersref
including several histotypes of NHLsref,
usually involve the region encompassing the p53 tumor suppressor gene locus,
17p13.1. The occurrence of p53 abnormalities in cases of SLVL has been
very infrequently reported and seems to be associated with a more aggressive
disease and poor prognosisref1,
Other studies, dealing with SMZL or SLVLs and cytogenetics, reported the
expression of TCL1 oncogene, activated by recurrent reciprocal translocations
at chromosome 14q32ref
or the presence of a point mutation in the mtDNA tRNA methionine generef.
In a recent paper, Bahler et alref
postulated the existence of 2 different groups of SMZL, the first carrying
unmutated VH genes and showing IgD expression consistent with
a naïve B-cell origin and the other with mutated VH genes
and IgD, consistent with a memory B-cell origin.
SMZL in animal models : some mouse lymphomas have strong histologic similarities
with human SMZLref.
SMZLs have been found to occur spontaneously at a high frequency in particular
strains of miceref1,
In transgenic mice, in which a transcription factor derived from human
lymphoblastic leukemia was placed in the DNA of their lymphocytes, a lymphoid
expansion of splenic marginal zones was evident before the development
of diffuse B-cell lymphomaref.
Clonal integration of murine leukemia virus is able to develop B-cell lymphoma
in the splenic marginal zoneref.
Homozygous p53-deficient mice develop SMZL, assessed with morphologic,
immunohistochemical, flow cytometry, and immunoglobulin heavy-chain rearrangement
However, the mechanism of lymphoma development in animal models remains
SMZL has been included in the Bethesda proposals for classification of
lymphoid neoplasms in miceref.
SMZL and infectious agents : a high prevalence of a chronic liver disease,
usually chronic hepatitis or cirrhosis, was described in Japan by Murakami
in 1988 in a review of primary splenic lymphoma. HCV
has been observed in 36% of cases of primary splenic lymphomaref.
Satoh et alref
hypothesized a role of HCV infection in the development of primary splenic
lymphoma after the description of a HCV+ patient whose spleen
was grossly and histologically indistinguishable from SMZL. Other descriptions
of SMZL in patients with HCV infection make this association more than
In nodal marginal lymphoma, HCV+ specimens harbor different
VH somatic mutation compared to that of HCV ones, suggesting a role for
a HCV antigen epitope in the B-cell selectionref.
The pathogenetic mechanism underlying the development of SMZL during HCV
infection remains unexplained. HCV might provide the initial antigenic
stimulus for B-cell clonal expansion, as part of the multistep progression
toward lymphomagenesis. Abruzzo et alref
recently described data on a patient with SMZL, treated with fludarabine,
who subsequently developed an EBV+ B-cell lymphoproliferative
disorder. Raised EBV antibody levels without a concomitant increase in
the detection of viral genomes in the peripheral blood has been demonstrated
in tropical SLVLref.
A relationship between SLVL and malaria has been hypothesizedref.
In West Africa, SLVL and hyperreactive malarial splenomegaly are demographically,
clinically, and immunologically indistinguishableref.
PCR analysis of immunoglobulin genes can be useful in distinguishing the
Although the etiopathologic link is not yet fully understood, it is possible
that an altered immune response to repeated malaria infections can stimulate
or select a proliferating pool of naive B cells, altering their
growth and apoptosisref.
adhesion molecules : the presence of its circulating counterpart, previously
classified as SLVL, indicates that homing and circulation of neoplastic
cells must be under the influence of adhesion molecule action. The migration
and localization of lymphocytes from the blood into the splenic white pulp
is influenced by adhesive interactions, as evidenced by the expression
of adhesion molecules on sinus lining cells in the marginal zone of the
It is now clear that the recruitment and retention of both T and B lymphocytes
are based on selective interactions involving several adhesion molecules
like human mucosal addressin cell adhesion molecule 1 (MAdCAM-1)ref,
whose expression is well documented in endothelial cells at mucosal sites
such as mesenteric lymph nodes, lamina propria of small and large intestine
and lactating mammary gland, and its exclusive integrin receptor a4b7ref.
Moreover, splenic white pulp B cells in marginal zones have been shown
to be diffusely positive for L (leukocyte)-selectinref.
Similarly, the first step in the homing of hematopoietic progenitor cells
from the peripheral blood to the bone marrow is regulated by selective
mechanisms controlling their adhesion to the bone marrow endotheliumref1,
This step is then followed by their migration through the endothelial cell
barrier and adhesion to stromal cells and extracellular matrixref.129
In this process of adhesion, molecules such as E -selectin, VCAM-1, ICAM-1,
and the cell surface receptor for hyaluronic acid CD44 have been shown
to play a roleref.
SLVL shows a low expression of L-selectin that represents a discordant
feature if compared to the fact that all white pulp B cells, including
marginal zone ones, are L-selectin positiveref.
Moreover, in HCL, a pathologic condition closely related to SLVL, adhesion
molecules have an important role in the interactions between hairy cells
and endothelium/accessory cells in the red pulp of the spleenref.
The expression of a series of adhesion receptors (L-selectin, several integrins,
ICAM-1, and CD44) investigated by means of flow cytometry in cases of both
B-cell leukemic disorders and related lymphomas showed a reverse pattern
of expression, namely, high expression of L-selectin and low expression
of integrin molecules (LFA-1, VLA-4, ICAM-1) in CLL and low L-selectin
positivity and high integrin expression in non-CLL disorders, including
Therapy : to date there
is no definitive standard treatment for SMZL. About 66% of patients are
asymptomatic at diagnosis and as many as one third will never require therapy.
Both the selection and the timing of therapy are basically established
on an empirical ground because of the indolent natural history of SMZL,
the lack of prospective therapeutic trials, and the absence of response
criteria and prognostic scores. There are 4 main types of initial treatment
strategies: (1) no treatment, (2) splenic irradiation, (3) chemotherapy,
and (4) splenectomy. In patients who do not undergo splenectomy the diagnosis
is made with morphologic and immunophenotypical analysis of peripheral
blood and bone marrow.
no treatment : treatment abstention should be considered in patients with
favorable prognostic factors. Patients with mild lymphocytosis and no cytopenia
are in the eligible condition for the "wait and see" policyref1,
In untreated patients the 5-year overall survival rate is 88%ref.
10 of 14 untreated patients of the series of Mulligan et alref
remained alive between 1 and 6 years from diagnosis. Patients with stable
disease have been monitored for up to 15 years, without requiring any treatmentref
splenic irradiation has been used in a limited series of patients. 3 of
7 patients in the Mulligan series benefited from splenic irradiationref.
Among the 7 patients treated by Troussard et alref
with 6 to 8 Gy with 1 or 2 fractions over 2 weeks, 3 had a relapse; none
of the patients receiving only irradiation died. Even low-dose radiotherapy
(4 Gy) may be effective, producing a dramatic reduction in circulating
villous lymphocytes, regression of splenomegaly, and improvement of cytopeniasref.
Radiotherapy seems to be a reasonable and effective treatment option in
SLVL when splenectomy is contraindicated and/or when pancytopenia is present
and likely to give rise to excessive toxicity when chemotherapy is administered.
chemotherapy : many drugs with different schemes have been administered.
There is no univocal convergence when and how to use chemotherapy. Chemotherapy
is generally used as first-line treatment in patients with more advanced
disease. The role of alkylating agents such as chlorambucil or cyclophosphamide
is marginal. Few patients benefit when these are used as first-line therapyref.
However, in cases of disease progression, especially after splenectomy,
alkylating agents may achieve good response, but seldom complete remission.
Mean duration of response in patients treated with alkylating agents alone
or in combination with other drugs is 6 months, whereas the 5-year overall
survival rate is 64%ref.
The use of purine analogues is more promising, but so far it has been tested
in relatively few patients. Complete or partial hematologic remission has
been achieved with 2-deoxycoformycinref.
Good responses with 2-chlorodeoxyadenosine have been also reportedref,
whereas in other cases only partial responses with high frequency of relapses
Some complete remissions have been achieved with fludarabine
as first- or second-line therapyref1,
: rhere is a general consensus, as indicated by the 2 largest retrospective
studies, in considering splenectomy the best first-line therapyref1,
A huge symptomatic splenomegaly or a severe cytopenia or both are the main
indications to perform splenectomy. Long and sustained improvement of cytopenia
and relief of abdominal discomfort have been achieved with splenectomy
alone. Moreover, in retrospective studies, splenectomized patients have
a significantly better overall survival than those treated with chemotherapyref.
However, these data should be interpreted cautiously because this could
be, at least partially, an expression of a selection bias, because patients
with more aggressive disease are more likely to be treated with chemotherapy.
Furthermore, it is intuitive that splenectomy alone cannot reduce extrasplenic
lymphomatous infiltrations. A group has reported a change in the bone marrow
infiltration with increase in tumor burden after splenectomyref.
In particular, we demonstrated a modification from intrasinusoidal to nodular
of the infiltrates in the bone marrow after splenectomy in most patients
with SMZL. Conversely, in those patients who did not undergo splenectomy,
bone marrow intrasinusoidal infiltration remained stable. Therefore, splenectomy
seems to induce important changes in bone marrow infiltration, probably
through the lack of microenvironmental homing factors on circulating B
radiolabeled anti-CD20 monoclonal antibodies are currently in development
for the treatment of low-grade B-cell NHLsref.
These include the iodine-labeled (tositumomab) and yttrium-labeled anti-CD20
(ibritumomab). Such approaches possess potential as future therapeutic
agents but await investigations and clinical trials
a hematologic response after antiviral treatment of HCV
infection with IFN-a2b
(3 million IU 3 times per week) alone or in combination with ribavirin
(1000 to 1200 mg/day) has been reported in 7 out of 8 patients with SLVL
and HCV, vs. 0 out of 6 patients with SLVL and HCV. It is unlikely that
this difference is due to the selection of a group of patients who are
more sensitive to therapy, since more of the HCV-positive patients had
previously received chemotherapy. Thus, a direct antiproliferative effect
of interferon on SLVL probably did not account for the response observed
in these patients. The relation between the course of SLVL and the HCV
RNA load was also illustrated by the observation that a complete hematologic
response occurred in patients who had a partial response or a relapse after
the addition of ribavirin treatment and the loss of detectable HCV RNA.
In all 5 patients in whom molecular studies were performed, the rearrangement
of the monoclonal immunoglobulin gene observed at diagnosis was still detectable
in the blood even after a complete hematologic response had been achieved.
These findings differ from those of Zuckerman et al.ref,
who recently reported the disappearance of B-cell clones from the blood
of HCV-infected patients after antiviral therapy. This discrepancy might
be explained by the fact that the population of patients studied by Zuckerman
et al. did not have clinically evident lymphoma and were thus probably
still dependent on HCV stimulation for B-cell survival. The mechanisms
by which HCV infection leads to the development of B-cell lymphoma remain
to be determined. Our results bring to mind the finding that Helicobacter
pylori infection has a pathogenic role in the development of gastric
lymphoma involving MALT, another subtype of MZL that originates in marginal
B cells of the mucosa. Most cases of MALT gastric NHL regress after the
eradication of H. pylori infection, as was also the case in our
patients with splenic lymphoma with villous lymphocytes who had a complete
hematologic response after antiviral therapy and the loss of detectable
In the case of H. pylori infection, NHL is supposed to be due to
the chronic stimulation of immunologic tissues by bacterial antigens, resulting
in clonal expansion of B cells and secondary progression to NHL. Stimulation
of marginal-zone B cells in the spleen by persistent HCV antigens, particularly
the E2 viral antigen, might also be involved in the pathogenesis of SLVLref1,
since, on antigenic stimulation, the normal marginal-zone B cells exhibit
somatic hypermutation and expand clonallyref1,
These CD5–IgM+ clones may persist and enter the circulation.
Alternatively, HCV may have a direct oncogenic effect on B cells. Indeed,
HCV is capable of infecting B cells, and LDLRsref
are candidate receptors for the virus. Moreover, some HCV proteins, such
as HCV protein core and NS5A, apparently have a direct effect on cellular
proliferation and viabilityref1,
However, no HCV proteins were detected in villous lymphocytes or any particular
mixed cryoglobulinemia (EMC)
was present in all 18 cases and was symptomatic in 13 (72%). All patients
were treated with interferon alone or in association with ribavirin. Hematologic
and virologic responses were correlated. 14 (78%) patients achieved a sustained
complete hematologic response after clearance of HCV RNA. 2 patients had
a virologic partial response and achieved a complete hematologic response.
2 virologic nonresponders achieved partial hematologic response. Regardless
of the response, monoclonal immunoglobulin gene rearrangement persisted
Prognosis : SMZL is
universally considered a low-grade lymphoma with an indolent clinical course.
Many cases show a protracted uncomplicated evolution, a good response to
splenectomy or chemotherapy, or even an unmodified clinical picture in
the absence of any kind of treatment. The 5-year overall survival rate
ranges from 65% to 78%ref1,
Even in the absence of treatment or complete response, the time to progression
exceeds 5 yearsref.
After therapy, complete remission and good clinical hematologic response
with no evidence of active disease were cumulatively observed in 80% of
cases in the series of Chacòn et alref,
whereas partial response is observed in 13.3% of cases. Failure to obtain
complete remission, involvement of nonhematopoietic sites at diagnosis,
high performance status scores, and p53 expression are the 4 factors associated
with poorer survivalref.
Thieblemont et alref
reported a median survival of 10.5 years, which becomes significantly shorter
in the presence of M component, elevated b2-microglobulin
level, leukocyte count > 20 000/µL, and lymphocytes more than 9000/µL.
Despite its low aggressive course, histologic progression with increased
number of blasts has been described in sporadic reportsref1,
In the series of Camacho et alref,
blastic transformation occurred in 13% of cases, which was lower than in
follicular lymphoma (25%-60%) and mantle cell lymphoma (11%-39%) and similar
to that observed in small lymphocytic lymphoma (1%-10%). Blastic transformation
correlated with higher mean proliferative index and could be associated
with p53 deletion but seems independent of p16INK4a inactivationref.
Response to treatment and survival after transformation are poor. In contrast
with the favorable survival for the group as a whole, patients who died
from lymphoma had a median survival time of less than 2 yearsref1,