Abstract:
Nodal Marginal Zone Lymphomas (NMZL), along with Splenic Marginal Zone Lymphoma (SMZL), Extranodal Marginal Zone Lymphoma (EMZL) and primary cutaneous Marginal Zone Lymphoma (PCMZL), belong to the group of marginal zone lymphomas, which are mature small B-cell lymphomas. MZL account for approximately 6% of all lymphoid neoplasms. NMZL, as the rarest entity in this group, thus corresponds to only 1.5-1.8% of all lymphoid neoplasms. The diagnosis of this lymphoma presents a constant challenge in clinical practice. There are usually several differential diagnoses, including BCL2 negative follicular lymphoma, chronic lymphocytic leukemia and lymphoplasmacytic lymphoma. NMZL frequently is a diagnosis of exclusion. Accurate histopathologic, immunophenotypic, and genetic analysis is essential. To date, no specific treatment exists for this type of lymphoma, which is why the therapeutic principles of other, more common indolent B-cell lymphomas are being adopted. Histologically, the growth pattern and morphology of the malignant cells is heterogeneous. In addition, the immunophenotype is rather unspecific, which makes a reliable diagnosis difficult. Mutation analysis may be an important pillar of diagnosis. In the past, some studies on the genetic background have been performed, but their validity is often limited by the low number of cases. The main objective of this thesis was to gain a more detailed insight into the genetic background of this entity by analyzing a large number of NMZL cases. For this purpose, all cases with differential diagnosis of NMZL from 2010 to 2023 were histologically evaluated and DNA integrity was assessed using PCR, and subsequently subjected to NGS. Five cases had to be excluded from mutation analysis due to poor quality, with a final cohort of 44 cases. After obtaining the mutation analysis, these cases were again subjected to histopathological evaluation and then divided into 3 groups: NMZL, t(14;18) negative FL, and CLL with atypical immunohistochemical profiles. The former comprised 29 cases, which were subdivided into 3 histological subgroups: 22 cases corresponded to the classic presentation of NMZL, 4 were CD5 positive, and 3 could be assigned to the splenic subtype. Overall, KLF2 was the most frequently mutated gene. Physiologically, this factor is crucial for the development of B cells and is usually associated with a loss-of-function mutation in lymphomas. Since this mutation occurs frequently in MZL and rather rarely in other small B-cell lymphomas, its occurrence could facilitate the diagnosis of NMZL. Furthermore, it can be assumed that aberrations in chromatin remodeling and epigenetic regulation play a particularly important role in the development of NMZL, since genes involved in these processes were mutated most frequently, including KMT2D and TBL1XR1. Moreover, we observed that NF-KB and NOTCH signaling pathways, which are essential for normal B-cell development and maturation, were often affected by mutations. These results seem to be in close agreement with comparable studies. Overall, the mutational pattern is very similar to that of SMZL, which is why other aspects are more relevant to distinguish NMZL from SMZL. However, for the differential diagnoses with FL and CLL, mutation analysis is of value as demonstrated in this study. In summary, we identified STAT6 mutations in BCL2-negative FLs and ATM mutations in CLL, each of which were not observed in the group of NMZL. Nevertheless, the number of cases was too small to draw a substantiated conclusion. Because of the size of the panel we were unable to identify mutations in all cases.
Our study demonstrates that not a single mutation is exclusive to any disease; however, the mutational profile was very helpful to increase the accuracy in the diagnosis.
In the future, this could help to achieve the overall goal of providing NMZL patients with a targeted therapy tailored to their specific mutation profile.
Nodal Marginal Zone Lymphoma