Annals of Oncology Advance Access published online on August 21, 2008
Annals of Oncology, doi:10.1093/annonc/mdn563
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Bone marrow histology in marginal zone B-cell lymphomas: correlation with clinical parameters and flow cytometry in 120 patients
1 Institute of Surgical Pathology
2 Division of Hematology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
* Correspondence to: Dr E. Boveri, Institute of Surgical Pathology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Via Forlanini 14, 27100 Pavia, Italy. Tel: +39-0382-501483; Fax: +39-0382-525866; E-mail: embover{at}tin.it
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Abstract |
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Background: Among marginal zone lymphomas (MZLs), bone marrow (BM) involvement features are well established in the splenic marginal zone lymphoma (SMZL); few data are available for extranodal marginal zone lymphoma (EMZL) and nodal marginal zone lymphoma (NMZL).
Patients and methods: Incidence and patterns of histologic BM involvement are studied in 120 MZL patients (48 SMZL, 59 EMZL, 13 NMZL) at onset and during follow-up; relationships between clinical features, BM histology and flow cytometry (FC) are analyzed.
Results: At diagnosis, BM involvement occurs in 90% SMZL, 22% EMZL and 54% NMZL (P < 0.0001); at reevaluation, incidence raises to 96% in SMZL and 34% in EMZL. Concordance between histology and FC is found in 87% of cases; most discordant cases have positive histology but negative FC. SMZL and EMZL show a nodular BM infiltration; the interstitial pattern is frequent in NMZL (P < 0.0001); sinusoidal localization is typical of SMZL, frequent in NMZL and occasional in EMZL (P = 0.0001). Stage, leukemic disease, B symptoms, more than one extranodal involved site, splenomegaly, elevated β2-microglobulin, serum monoclonal component, International Prognostic Index (IPI) and age-adjusted IPI are directly related to BM infiltration.
Conclusions: The different prevalence of BM involvement in MZL subtypes reflects their heterogeneous dissemination modalities; histology seems more sensible than FC to detect BM infiltration; development of BM involvement during follow-up is typical of EMZL.
bone marrow histology, flow cytometry, hepatitis C virus (HCV), marginal zone lymphoma
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingReferences |
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The World Health Organization (WHO) classification recognizes [1] three distinct subtypes of B-cell marginal zone lymphoma (MZLs), the splenic MZL (SMZL), the extranodal MZL (EMZL) of mucosa-associated lymphoid tissue (MALT) and the nodal MZL (NMZL). These clinicopathological entities share similarities in terms of morphology and immunophenotype [2], but they differ for clinical presentation [3]. SMZL is characterized by splenomegaly, cytopenias and leukemic disease [4], while EMZL usually presents at early stage [5, 6]; NMZL is a rare disorder, commonly presenting with lymphadenopathy, without spleen enlargement and/or involvement of MALT sites [7].
The prevalence of bone marrow (BM) involvement at diagnosis differs in the three MZL subtypes: it is present in almost all cases of SMZL [8], while reported percentages in EMZL range from 5% to 44% [9–11]; few data are available for NMZL due to the rarity of this disease [7].
In SMZL, a sinusoidal pattern of involvement has been proposed as typical on BM biopsy [12], but it can be occasionally detected in other lymphoma subtypes [13]. Moreover, in SMZL, histological and immunohistochemical findings on BM biopsy, coupled with clinical data and flow cytometry (FC) analysis, can lead to an accurate diagnosis without need of splenectomy.
Our study evaluated the prevalence and the histologic patterns of BM involvement in 120 patients (pts) affected by MZL of splenic, extranodal and nodal subtypes, compared histology and FC and related BM status with clinical parameters.
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patients
We studied 120 patients with MZL, consecutively diagnosed between 1992 and 2005 at the Department of Pathology (48 SMZL, 59 EMZL and 13 NMZL) and treated at the Division of Hematology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Italy. Diagnosis was assessed according to the WHO criteria [1] on histologic specimens (spleens, lymph nodes, extranodal and BM biopsies); in 15 pts, diagnosis of SMZL was based on BM histology combined with clinical, cytological and immunophenotypical data. Gastric EMZL was not included due to the rarity of BM involvement in this EMZL subtype [14]: in the same period, we diagnosed 16 pts with gastric EMZL, and in the six cases in which BM was analyzed, it was negative for lymphoma localization both by histology and FC, either at diagnosis or during follow-up. Primary EMZL sites were as follows: 15 skin and subcutis, 12 Waldeyer's ring, 11 ocular adnexa, 10 salivary glands, four lung, three breast, two liver and two female genitals.
Clinical features at diagnosis are summarized in Table 1.
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This retrospective study was approved by the local institutional ethics committee; data management and analysis were carried out in accordance to the institutional ethical rules and the Helsinki Declaration of 1964, as revised in 2000.
BM histology
We reviewed 174 formalin-fixed BM biopsies (120 at diagnosis, 54 from 49 pts during the course of disease); 75 specimens were plastic embedded and 99 paraffin embedded. Hematoxylin–eosin and Giemsa stains were used for morphology; immunohistochemistry was carried out by means of the streptavidin–biotin peroxidase technique, using antibodies directed against the following antigens: CD20, CD79a, bcl6, CD76/DBA44, p53, IgM, IgD (Dako, Glostrup, Denmark), CD3, CD10, CD5, CD23, CD25 (Novocastra, Newcastle Upon Type, UK), CD34 (Ylem, Roma, Italy) and bcl1/cyclinD1 (Bio-Optica, Milano, Italy). Enzymatic or microwave oven pretreatments were applied, when needed; positive and negative controls were stained appropriately for each reaction.
FC analysis
The analysis of B cells in BM was carried out in 115 cases with the following mAbs: CD20, CD19, CD45, CD5, CD10, kappa, lambda, CD9, CD11c, CD15, CD22, cCD22, CD23, CD25, CD13, CD33, CD34, CD38, CD43, CD58, CD76/DBA.44, cCD79a, CD79b, CD103, FMC7, IgM and IgD. In all these cases, FC was also applied to peripheral blood to detect circulating clonal B-cell populations.
statistical analysis
Numeric variables were summarized by their median and range. Categorical variables were described by counts and relative frequencies. Association between BM involvement and the categorical variables was tested via Fisher’s exact test (for 2 x 2 tables) or using the 
2 approximation for larger tables. The variables analyzed for correlation with BM involvement were as follows: Ann Arbor stage, number of extranodal and nodal sites, leukemic and bulky disease, Eastern Cooperative Oncology Group score, B symptoms, splenomegaly, hemoglobin <12 g/dl, platelet count <100 000/µl, white blood cell count <3500/µl, lymphocyte count >9000/µl, serum monoclonal component (MC), abnormal lactate dehydrogenase level, elevated β2-microglobulin, IPI, age-adjusted IPI, albumin <3.5 g/dl, HBsAg and HCV serology. All computations were carried out using Statistica 7.1 by StatSoft, Inc. (2005) and Microsoft Excel 97.
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BM histology at diagnosis
prevalence of BM involvement.
Prevalence of histological BM involvement by lymphoma at diagnosis was 90% for SMZL, 22% for EMZL and 54% for NMZL (P < 0.0001) and the median extent of BM histological substitution was 35% (range 10%–90%) for the whole series (Table 2).
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In 100 of 115 pts (87%), FC results were in agreement with histological findings and directly related to the percentage of BM disease detectable by histology (P < 0.0001). In 12 cases (five SMZL, five EMZL, two NMZL), FC was negative despite a positive histology (median extent of BM involvement: 20%, range 10–50%); in three cases only (two SMZL, one NMZL), BM biopsy did not reveal lymphoma infiltration that was detected by FC alone.
Our series of MZL was characterized by a high rate of HCV infection, especially among SMZL (30%) and EMZL (42%): prevalence of BM involvement did not differ between HCV-positive and HCV-negative subsets, as BM was involved in 80% of HCV-positive and in 92% of HCV-negative SMZL pts, in 30% of HCV-positive and 20% of HCV-negative EMZL subjects.
Of the 11 EMZL pts with more than one nodal site, eight show BM involvement and three multiple extranodal sites. We compared BM histological features between this subset with disseminated disease and the remaining EMZL and we did not find any difference.
histological characteristics of BM involvement.
The predominant histological pattern of BM involvement was statistically different in the three subtypes (P < 0.001). In 88% of SMZL and in all EMZL, BM was involved in the form of nodules, both in the intertrabecular (more frequently) and paratrabecular zone (Figure 1A and B), while it more often showed an interstitial pattern in NMZL (57%; Figure 1C). Only two SMZL pts had a massive BM substitution. Sinusoidal localization of neoplastic lymphoid cells was observed in 75% of SMZL (Figure 1D), in 57% of NMZL and in only one EMZL case. It more often coexisted with other patterns of involvement, usually in the form of nodular aggregates; only three cases (two SMZL, one NMZL) had a pure sinusoidal infiltrate. Notably, 6 of 11 SMZL cases, in which sinusoidal localization was unapparent, had plastic-embedded BM biopsies, on which we did not succeed in performing immunohistochemistry.
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In all the MZL subtypes, the neoplastic population on BM biopsies showed cytologic features similar to those seen in spleens, extranodal sites and lymph nodes: neoplastic B cells were small to medium, with centrocyte-like, marginal zone cell-like, lymphoplasmacytic features and, more rarely, they resembled monocytoid B cells.
In all the cases, the immunophenotypic profile of BM neoplastic population (CD20+, CD79a+, CD3–, CD5–, CD10–, bcl1/cyclinD1–-, bcl6–) was consistent with a marginal zone-derived neoplasm and in agreement with the results obtained on non-BM histological specimens and by FC (Table 3). Minor differences in phenotypes between immunohistochemistry and FC regarded the detection of CD23, DBA44 or CD25 in the clonal B-cell population by FC in part of the cases; however, we never observed by FC the classic phenotype of hairy cell leukemia (CD11c+, CD103+, CD25+, DBA.44+). In 32 cases, IgM and IgD were evaluated by immunohistochemistry and FC: coexpression of these heavy chains was seen in 14 of 20 SMZL, two of seven EMZL and one of five NMZL.
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In the 15 SMZL pts diagnosed without splenectomy, BM biopsies displayed morphological (nodular plus sinusoidal) and immunophenotypical features completely overlapping with those observed in splenectomized subjects.
In most cases with nodular BM involvement (27 of 40 assessable cases: 18 of 27 SMZL, 8 of 11 EMZL, one of two NMZL), CD23 immunostaining revealed the presence of a follicular dendritic cell meshwork inside the lymphoid aggregates (Figure 1B, inset). In only four SMZL, small groups of non-neoplastic CD10+, bcl-6+ germinal center cells (centroblasts and centrocytes) were clearly distinguishable in the nodular areas.
As HCV is frequently associated with MZL and plays a role in the formation of BM lymphoid nodules (i.e. mixed type II cryoglobunemia) [15], we examined the relationship between the infection, the nodular pattern and the presence of a CD23+ dendritic cellular meshwork: no significant correlation was found in the whole series, but a borderline P value (0.06) was observed in EMZL: the dendritic cell meshwork was evident in six of eight HCV-positive cases and in two of eight HCV-negative specimens.
BM histologic features of progression to high-grade B-cell lymphoma were absent in all cases at diagnosis.
correlation with clinical features
In the whole series, BM infiltration was statistically related to Ann Arbor stage, leukemic disease, B symptoms, more than one extranodal site of involvement, splenomegaly, elevated β2-microglobulin, serum MC, IPI and age-adjusted IPI (Table 4).
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In EMZL, the presence of a serum MC was borderline significantly associated with BM involvement (P = 0.09): BM was positive in five of 10 pts with MC (two HCV positive without cryoglobulinemia) and only in four of 22 pts without MC.
No statistical correlation was found between any histologic patterns and clinical parameters: in particular, leukemic disease did not relate to sinusoidal localization (P = 0.6).
BM findings at reevaluation
BM histological involvement was detected in 29 pts (18 of 27 SMZL, nine of 19 EMZL, two of three NMZL) and absent in the remaining 20 cases (Table 5). Histology was in keeping with FC in 32 of 42 tested cases.
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Considering the BM status at diagnosis, 15 SMZL, two EMZL and two NMZL with positive BM at onset showed again BM involvement. BM persisted to be negative in one SMZL and in eight EMZL, while 10 cases with negative BM at diagnosis (three SMZL, seven EMZL) developed BM localizations, raising the overall prevalence of BM involvement to 96% for SMZL and 34% for EMZL.
For 27 SMZL pts (23 with positive, four with negative BM at diagnosis), a BM biopsy was repeated during the course of disease after a median interval of 11 months (range 4–31 months). Before the second biopsy, seven pts underwent splenectomy [plus combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) in four, interferon in one, chlorambucil in two]. Eight cases showed BM negativity for lymphoma, both by histology and FC, but two of four pts with more than one BM reevaluation had documented BM relapses.
BM biopsies at diagnosis and at reevaluation did not show significant differences in the extent and pattern of involvement, but in the second BM biopsies the sinusoidal localization was observed in SMZL only.
In three cases, the BM neoplastic population differed in its cytological features at reevaluation from those observed at diagnosis. One NMZL patient, with a high serum monoclonal IgGk component and an interstitial BM involvement at diagnosis (small centrocyte-like and monocytoid cells), had two subsequent BM biopsies, after chemotherapy (CHOP), showing a predominant plasmacytic ‘myeloma-like’ infiltrate. In two EMZL pts, both with negative BM at diagnosis, the BM biopsies, respectively, after 12 and 6 years from the onset, documented a histological shift to high-grade large B-cell lymphoma with acquisition of bcl-6 and p53 expressions (Figure 2A and B).
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We detail the morphological and immunophenotypical features of BM biopsies from a large series of pts, comprising the whole MZL spectrum. Our study comprises both plastic- and paraffin-embedded specimens: cytological details are better preserved with the first method, but immunohistochemical analysis, which is achieving more and more importance in BM pathology diagnosis, is more easily and less expensively carried out on EDTA-decalcified, paraffin-embedded materials, which offer a good compromise between morphology and antigen preserving [16].
BM involvement has different prevalence in the three subtypes: our results overlap with the data already reported by other groups for SMZL and NMZL [8, 17]; in contrast, the percentage of EMZL pts with BM involvement in our series (22% at diagnosis, 34% considering the whole course of disease) is similar to the value reported by the GELA series [10], but higher than the results of the IELSG study [18]. These findings are in contrast with the traditional concept of EMZL as a localized disease, and they confirm the need for extensive staging in all EMZL pts [19] because features of widespread disease (BM and nodal involvement, multiple MALT sites) are associated with shorter overall and event-free survivals [5].
Studies comparing the effectiveness of FC and histology in detecting BM lymphoma involvement provide discordant results [20, 21], mostly depending on the lymphoma subtypes considered. In our study, the results of BM histology are in agreement with FC in 87% of cases and a direct relationship is found in the extent of BM infiltration detected by the two methods. In most discordant cases, histology detects lymphoma despite negative FC, although the median percentage of BM histologic substitution is slightly lower in this group (20%) than in the whole series (35%).
Our MZL series is characterized by a high prevalence of HCV infection; in the clinical subsets of HCV-positive pts, lymphoid nodules can be often observed on BM biopsy [15, 22]; thus, we investigated whether the presence of the infection could induce a histological overestimate of BM lymphoma involvement. In our series, statistical analysis does not show significant differences in the rate of BM involvement between HCV-positive and HCV-negative subjects.
Altogether, these findings suggest that histology seems to have a higher sensibility than FC in detecting BM infiltration in MZL. When comparing the immunophenotypic profile detected by the two methods (Table 3), the same results are seen for the main antigens required for the diagnosis of MZL (CD20, CD5, CD10), while molecules like CD23, DBA.44 and CD25 seem to be detected easier in SMZL by FC than by immunohistochemistry, probably because of phenomena of ‘antigen masking’ during fixation and/or decalcification of the BM biopsy. The detection of these antigens has been already reported in SMZL [23] and does not role out this diagnosis; moreover, we never observed by FC the classical phenotype of hairy cell leukemia (coexpression of CD103, CD25, CD11c, DBA.44), thus excluding this disease.
BM biopsy in lymphoma usually has a staging significance, without a direct role in the identification of specific histotypes. However, it may provide useful informations to classify lymphoproliferative diseases, when combining patterns, cytologic and immunophenotypical features of the infiltrate [24, 25].
In our series, SMZL and EMZL share the nodular pattern of BM infiltration, with nodules either in the intertrabecular (more frequently) and paratrabecular area [11, 26]; in contrast, a predominant interstitial BM pattern is observed in NMZL (57%).
Sinusoidal infiltration of neoplastic B cells was proposed as a histologic hallmark of SMZL on BM biopsies [12]. We observe this peculiar aspect usually in SMZL (74%), frequently in NMZL (57%), but rarely in EMZL (8%) and more often in association with other patterns. An exclusive sinusoidal BM localization is exceedingly rare and observed in three cases only (two SMZL, one NMZL). On such basis, the nodular plus sinusoidal pattern of BM infiltration, combined with the typical clinical presentation and phenotype [3], can be considered specific for SMZL, thus avoiding splenectomy for diagnostic purposes [8], at least in pts at high surgical risk. The detection of a high rate of sinusoidal infiltration in more than one half of NMZL is also a notable finding because the nosologic definition of SMZL with adenopathy and its biological and clinical relationship with ‘true’ NMZL are still matter of debate [4, 27].
In our cases, the neoplastic BM nodules frequently contain a CD23+ dendritic cell meshwork; in four SMZL only we also detect scattered true CD10/bcl-6-positive germinal center cells. These immunoarchitectural features suggest a germinal center-based growth of MZL in the BM, associated with phenomena of neoplastic colonization of the follicular structures: this morphological aspect is in fact typical of MZL also in lymph node, spleen and mucosal sites of involvement [28].
When considering the BM status at reevaluation, the entity of BM substitution and histological patterns do not significantly differ from those observed at diagnosis: notably the sinusoidal infiltration is noticed in SMZL only, suggesting that this peculiar BM involvement is retained during the whole clinical course of SMZL.
In eight SMZL after therapy, BM resulted negative for lymphoma either by histology or FC: it would be of some concern to evaluate whether molecular biology techniques may reveal a higher sensibility than histology and FC to detect minimal residual BM disease, as in follicular lymphoma [29]. We recently demonstrated BM involvement by PCR technique in a SMZL case with inconspicuous histologic and immunophenotypic findings [30].
In all the three subtypes of MZL, the cytological features of BM lymphoid infiltrate do not change during the disease course, other than a single NMZL case, showing, at reevaluation, a plasmacytic myeloma-like infiltrate similar to the SMZL case reported by Audouin after therapy [26].
MZL can progress to high-grade lymphomas, but in our study such features are constantly absent at diagnosis and observed in two EMZL pts only, who, after a long clinical course, displayed morphological and immunophenotypical features consistent with a shift to large B-cell lymphoma.
In conclusion, SMZL, EMZL and NMZL have different prevalence of BM involvement, which probably reflects different pathways of spread. The typical nodular plus sinusoidal pattern of BM infiltration, although not mandatory, strongly points out for SMZL, when coupled with the characteristic clinical and immunophenotypic features. The detection of BM involvement in one-third of EMZL confirms the need for BM evaluation as an integral part of staging work-up also in these pts, who are often considered with localized disease. Being NMZL the rarest of MZL, further studies on larger series of this subtype are needed to drive definitive conclusions on its features of BM involvement.
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Fondazione IRCCS Policlinico San Matteo, Pavia and Ministry of University and Research, Roma, Italy.
Received for publication April 10, 2008. Revision received July 13, 2008. Accepted for publication July 16, 2008.
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