Lymphoplasmacytic lymphoma and marginal zone lymphoma involving bone marrow: A diagnostic dilemma. Useful clinicopathological features to accurate the diagnosis

Abstract Lymphoplasmacytic lymphoma (LPL) and marginal zone lymphoma (MZL) frequently infiltrate the bone marrow with similar histologic and immunohistochemical characteristics posing diagnostic problems. Bone marrow biopsy specimens from 25 LPL and 16 MZL have been studied, correlating with clinical, laboratory parameters and the MYD88_p.L265P mutation. Paratrabecular and interstitial infiltration pattern, serum IgM paraprotein levels, and MYD88_p.L265P mutation were significantly more frequent in LPL. Nodular or intrasinusoidal pattern with lymphocytosis and splenomegaly were associated with MZL diagnosis. Different clinical and histological parameters should be collected when LPL or MZL is suspected in bone marrow biopsy specimens.

The aim of the present article is to study the clinical and bone marrow histological features from series of LPL and MZL cases, highlighting the distinctive features that could help in the differential diagnosis.

Patient selection
A retrospective review of bone marrow biopsy specimens with the diagnosis of LPL and MZL from 2017 to 2021 from the Pathology Department files of Ramón y Cajal Universitary Hospital was performed. In total, 25 patients with LPL and 16 patients with MZL were included (eight SMZL and eight NMZL).

Histological and immunohistochemical study
Bone marrow trephine biopsies were reviewed by two pathologists The cut-off value for defining lymphoma with plasmacytic differentiation was CD138 expression in the neoplastic cells higher than 10% [7].
We considered an arbitrary cut-off value for defining overexpression of mast cells as 10% or higher of the global bone marrow cellularity.

Clinical data
Clinical and laboratory parameters such as age, gender, the presence of lymphocytosis (≥5 × 10 [9]/L), lymphadenopathy, splenomegaly, and elevated serum IgM paraprotein were collected from electronic clinical records.

Statistical analysis
Continuous variables were expressed as mean ± standard deviation and qualitative variables were expressed as number and percentage.
Continuous variables were compared using Student's t test or the Mann-Whitney U test according to their distribution, and categorical variables were compared using the chi-squared test or the Fisher's exact test as appropriate.

Molecular analysis
MYD88_p. L265P mutation status was determined using real-time allele-specific polymerase chain reaction and Sanger DNA sequencing from diagnostic bone marrow aspirates and/or peripheral blood.

RESULTS
Clinical, histological and laboratory parameters are described in Table 1. A summary of the clinical and pathological features of lymphoplasmacytic lymphoma and marginal zone lymphoma with statistical significance is defined in Table 2.

B-cell lymphoproliferative disorders with plasmacytic differentiation
involving bone marrow represent a diagnostic challenge. Traditionally, it has been proposed that the presence of serum IgM paraprotein is useful for LPL diagnosis and could help in the differential diagnosis of MZL [11,12]. However, IgM paraprotein can be seen in MZL in other B cell neoplasms.
In our study, the presence of elevated serum IgM monoclonal component was significantly more frequent in LPL than MZL. On the other hand, MZL presented significantly more blood lymphocytosis and splenomegaly. Lymphadenopathy was seen in both cases.
The histological patterns of bone marrow infiltration in each entity have been described by some authors as a very useful feature, with no concordant results. Bassarova et el. [8] have proposed the paratrabecular infiltration as the most characteristic architectural feature of LPL, although other authors have described intrasinusoidal and paratrabecular infiltration as characteristic of MZL [9,10]. In accordance with other publications [13,14], in our study, paratrabecular and interstitial patterns of infiltration were significantly higher in LPL, whereas intrasinusoidal or nodular infiltration was distinctive features of MZL.
It has been suggested that LPL and MZL also differ in the percentage of plasmacytic cells in the neoplastic infiltrate suggesting that a percentage of plasma cells higher than 10% could support LPL diagnosis [7]. In our cases, plasma cells were more abundant in LPL, without statistically significant difference. Moreover, according to Morice et al. [15], the percentage of cells with light chain restriction was signifi-  [15]. In our series, no significant differences were found in the expression of CD5 or CD25.
Regarding the higher percentage of mast cells that have been described in LPL [17], our results conclude that this feature is relatively nonspecific and does not help in the differential diagnosis.   García-Cosío Pique wrote the paper.

CONFLICT OF INTEREST
There is no conflict of interest of any of the authors with the results of this study.

DATA AVAILABILITY STATEMENT
The data that supports the findings of this study are available in the references of this article.

FUNDING INFORMATION
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

ETHICS STATEMENT
This study was approved by the Ramón y Cajal Universitary Hospital ethic committee and was conducted in accordance with the