Part 7—Nodal marginal zone lymphoma
In parts one to six in this series we discussed the basic principles of lymphoid pathology. Subsequently we described some of the nodal lymphomas that have a cutaneous counterpart. Despite often identical morphologies, it was demonstrated that the cutaneous counterparts have a favorable prognoses and often express distinct phenotypic and/or genotypic features. In this part, we will discuss principally nodal Marginal zone lymphoma with few notes about its paediatric, splenic, extranodal and cutaneous counterparts.
Nodal marginal zone lymphoma
Marginal zone lymphoma (MZL) is a term used to describe a malignant neoplasm showing mature post germinal center B-lymphocytic phenotype. It represents less than 2% all malignant lymphomas.  Most cases occur in adults with a median age of 60 years and in equal sex distribution, however, a pediatric onset, which predominantly affects males can occur. Patients are usually asymptomatic presenting with localized or generalized lymphadenopathy with the peripheral blood and bone marrow occasionally involved. By definition, absence of extranodal involvement is an essential criterion to make a diagnosis of nodal MZL, as when both nodal and extranodal MZL coexist, and is usually due to nodal involvement by the extranodal variety.
Morphologically, defining a “marginal zone” in a normal lymph node is often difficult, as this area is distinct only in the spleen, however, the ill-circumscribed areas that lie between germinal follicles and the paracortical zone is the best place to look for marginal zone differentiation and for early MZL (fig. 1). Marginal zone differentiation is usually characterized by a mixture of cells, the principal of which is small-to-medium sized, pale, cleaved, centrocyte-like (monocytoid) B-cells (fig. 2). Mixed with these cells, which are often called marginal one cells, are variable numbers of plasmacytoid lymphocytes, plasma cells and blast cells (figs. 3 and 4). Only rarely the cell population is predominantly monomorphic of the marginal zone type.
A low power view showing the relation between the characteristic pale appearance of marginal zone lymphoma which surrounds a benign follicle.
The characteristic marginal zone cells. Notice the abundant pale cytoplasm giving B-cells a “monocytoid appearance.” In addition,a slightly cleaved nuclear membrane gives it a “centrocyte like” appearance.
A mixture of plasma cell differentiation including occasional Dutcher’s bodies could be seen. A large immunoblast with central nucleolus is also present.
A low power view showing the polymorphic nature of the infiltrate in marginal zone lymphoma with variation in shape and size of cells.
Tumor cells often surround benign reactive germinal follicles and spread progressively into the interfollicular area. Follicular colonization may occur giving difficulty in the differential diagnosis from follicular lymphoma using morphology alone. Eventually the infiltrate becomes diffuse effacing the nodal architecture with or without few residual reactive follicles. The latter can be highlighted by staining for follicular dendritic meshwork markers (CD21 and CD23). Tumor cells stain for B-cell markers (CD20, CD19, CD79a) and commonly co-express Bcl-2 and CD43. Stains for CD5, CD23, Bcl-6, CD10 and Cyclin-D1 are negative.
The cytogenetic abnormalities in nodal MZL are different from those associated with extranodal MZL mentioned below.
The prognosis is best predicted by the International Prognostic Index with an overall 5-year survival of 60-80%. An increase in the proportion of blast cells does not seem to imply worse prognosis, and a diagnosis of a transformation to a diffuse large B-cell lymphoma could be made only when there are sheets of large cells.
This variant usually presents in males (ratio 20:1) as a localized disease mainly in the head and neck region. The morphological features are similar to the adult type except that the reactive follicles show features of ‘progressive transformation’ (disrupted borders of reactive follicles which are infiltrated by tumor cells). The prognosis is excellent with very low rate of relapse and long survival after treatment. 
It is important to differentiate this condition from atypical marginal zone hyperplasia with monotypic Ig expression, as this condition can show co-expression of CD43 in B-cells. As this problem can be also encountered in extranodal MZL, demonstration of clonal rearrangement of IgH gene is the gold standard for confirming malignancy rather than Immunohistochemistry.
This type of lymphoma accounts for around 2% of all malignant lymphomas but, in contradistinction to chronic lymphocytic leukemia, it is the main cause of involvement of the peripheral blood by a mature B-cell lymphoma/leukemia that lacks CD5 positivity. Tumor cells infiltrate the splenic germinal follicles of the white pulp. These consist of a mixture of small dark cells merging progressively with outer larger and paler lymphoid cells. Scattered blasts, lymphoplasmacytoid and plasma cells are also commonly seen as in the nodal type. The peripheral blood, bone marrow, and splenic hilar nodes are commonly involved, however, other lymph node groups are very rarely involved. Circulating neoplastic cells often show a villous morphology, hence the name splenic lymphoma with villous lymphocytes (SLVL). Tumor cells are positive for B-cell markers CD20 and CD19 without CD5 expression. Absence of expression of CD10 and BCL-6 excludes a follicular lymphoma. Negativity for CD23 excludes chronic lymphocytic leukaemia, and for Cyclin-D1excludes Mantle cell lymphoma. A negative reaction to Annexin A1 excludes the important morphological mimic of hairy cell leukemia. The cytogenetic abnormalities seen in non-splenic extranodal MZL are not seen in this variety.
The clinical course is usually indolent and patients respond poorly to conventional chemotherapy of chronic leukemias, however, splenectomy usually offers long term survival and improvement in peripheral blood indices. 
Extranodal MZL of mucosal tissue (MALT lymphoma)
This type of lymphoma is more common than the nodal variety. It represents around 8% of malignant lymphomas. It can present in the gastrointestinal tract, lungs, ocular adnexa, skin, salivary and thyroid glands. The tumour usually follows a long period of chronic inflammation caused by either a chronic infection or chronic autoimmune disease.
Gastritis induced by Helicobacter pylori, ocular adnexal infection by Chlamydia psittaci, and cutaneous infection by Borrelia burgdoferi, followed by MALT lymphomas respectively represent examples of the first mechanism. On the other hand, Hashimoto’s thyroiditis and epimyoepithelial sialadenitis of Sjogren’s disease represent examples of the latter mechanism.
Similar mixtures of cell types occur as in the nodal variety with the additional feature of infiltration of mucosal epithelial cells by the neoplastic lymphoid cells (lymphoepithelial lesions) (fig. 5). Treatment of the infectious agent by antibiotics has been associated with regression of the neoplastic lymphoid proliferation.
Gastric MZL (MALT lymphoma) showing intraepithelial atypical lymphocytes (lymphoepithelial lesion) and plasma cell differentiation in the lamina propria. Notice the resemblance to lymphocytic gastritis. In some cases only clonal gene rearrangement can distinguish between severe gastritis and a MALT lymphoma.
Distinct cytogenetic abnormalities have been detected in different sites of extranodal MZL, the most important of which is t(11;18) (q21;q21) in the gastric type. The latter can produce abnormal proteins such as AP12-MALT-1 and BCL-10.
The prognosis is excellent with an indolent course and long disease free survival following local treatment even in cases of multiple extranodal involvements. 
A note on primary cutaneous MZL
This special variant of extranodal MZL has been an area of continuous debate between Dermatopathologists and Haematopathologists. The EORTC classification has included it under immunocytomas and the WHO classification has included it under extranodal MZL. It usually present by a single or multiple red to brown nodules in the trunk and extremities of young adults.  Histomorphology is similar to MZL elsewhere (fig. 6).
Cutaneous MZL. Notice the nodular pattern which mimics follicular lymphoma. In MZL the center of the follicles is still benign.
A relation to Borrelia burgdorferi has been demonstrated in some case series, but in others this was not the case, suggesting a possible region specific association. The idea that cutaneous MZL is distinct from other extranodal MZL is becoming less likely as similarity in indolent behaviour. Favorable response to localized treatment and the presence of similar molecular abnormalities in BCL-10 and MALT-1 can be seen in both.
As mentioned above, the prognosis is excellent regardless of the modality of the treatment used. These can vary from surgical excision, systemic steroids, radiotherapy, and watchful observation. Chemotherapy is reserved for cases with systemic involvement. 
In this part the main features of marginal zone differentiation has been discussed. Many morphological similarities exist among the various types of MZL, however, the clinical presentations seem distinctive for each of the major categories. Recognizing the natural history of each type is essential to planning appropriate treatment and advising the patients on the expected long-term outcome.
Essam Raweily, M.D., is a pathologist at the Department of Pathology, Epsom & St Helier NHS Trust, England, UK. This article is an invited contribution and was reviewed solely by the Editor-in-Chief. Contact corresponding author via e-mail: firstname.lastname@example.org .
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