This is the first report of pNMZL in a middle aged person. This 44 year old man had a typical presentation, morphologic picture revealing PTGC-like changes and marked expansion of the follicular marginal zone, and his exceptionally benign clinical course is also consistent with pNMZL. In contrast, classical NMZL typically affects older individuals with median age at diagnosis around 60 years, has slight female predominance, usually manifests with advanced lymphadenopathy at the time of diagnosis, has propensity for bone marrow involvement and relatively short median overall survival of approximately 5–6 years, compared to other MZL, such as splenic MZL or MALT type which typically have much longer survival.
Pediatric NMZL is now described as a separate variant of NMZL in the most recent WHO classification of tumors of hematologic and lymphoid tissues [1
]. It has distinctive morphology and clinical presentation and stands out as an indolent disease with better overall prognosis compared to classic NMZL.
The most comprehensive report on pediatric NMZL included thirty two children and young adults[7
]. The median age was 16, ranging from 2 to 27 years. There was striking male to female predominance of 5.4:1. The disease was limited in 88% of the patients, preferentially affecting the head and neck area. Lymph node morphology showed significant destruction of normal lymph node architecture with obliteration of the sinuses and predominantly interfollicular distribution of the atypical cells with substantially expanded marginal zones. In 21 of 32 cases the follicular structures resembled PTGC with markedly enlarged follicles with mantle cells infiltrating the remaining germinal centers leading to fragmentation. In contrast to reactive PTGC features, the peripheral rim of the follicle was irregular due to disruption by the expanded marginal zone. The authors reported immunohistochemical findings consistent with classic NMZL and no unique markers were identified: the atypical cells were positive for CD19 and CD20, CD43 was coexpressed in 70% of cases, while CD5, CD10, CD23, and CD3 were negative. Light chain restriction by immunohistochemistry was seen in 48% of cases, while monoclonal IgH gene rearrangement was identified in 84% of the studied cases. CD10 and BCL6 were negative in tumor cells but highlighted residual non-malignant germinal centers. BCL2 was weakly or moderately positive in 42% and p53 was negative.
Morphologic change resembling PTGC is a dominant morphologic feature of this entity, and was described in 66% of the reported cases [7
]. PTGC is seen in approximately 10% of cases with asymptomatic reactive lymphadenopathy showing marked follicular hyperplasia and represent reactive polyclonal process. It is yet to be determined whether reactive PTGC may have preceded the development of clonal proliferation and progression to pNMZL. PTGC has been associated with nodular lymphocyte predominant Hodgkin’s lymphoma and less frequently with classic Hodgkin’s lymphoma but not with NMZL. The majority of patients with reactive lymphadenopathy and PTGC recover without any consequences [[8
Karube et al. presented 6 cases from Japan of what was referred to as “floral” variant of NMZL [11
]. There were 4 male and 2 female patients with the age ranging from 18 to 66 years and 5/6 patients presented with asymptomatic localized cervical or axillary lymphadenopathy. Histological picture resembled that of a PTGC with irregular and often disturbed peripheral rim of the follicles with an expanded marginal zone and enlarged ‘floral’ lymph follicles with distinct germinal centers and thick mantle zones. The CD10 positive germinal centers were partially infiltrated by CD10−/CD20+ tumor cells. CD21 staining revealed disruption of the meshwork of follicular dendritic cells by infiltrating tumor cells. EBV was undetectable in all cases. The variant was differentiated from reactive follicular hyperplasia with PTGC and from ‘floral’ variant of follicular lymphoma. The authors suggested probable overlap between clinical and morphologic presentations of some cases of ‘floral’ NMZL and pNMZL, noting however more advanced age at presentation, with 4 of 6 cases between 34 and 66 years [7
]. This “floral” variant of NMZL and pNMZL are similar in having atypical marginal zone lymphocytic proliferation with a tendency to colonize the germinal centers. However, in the “floral” variant residual germinal centers have irregular borders and are more prominent.
pNMZL may be confused with follicular lymphoma with marginal zone differentiation (FLMZD), especially in cases of pNMZL showing marked colonization of germinal centers. FLMZD is a rare type of follicular lymphoma characterized by a prominent marginal zone surrounding and infiltrating neoplastic germinal centers. Characteristically, neoplastic cells express germinal center markers BCL6 and CD10 which are usually lacking in NMZL. CD10 was dimly expressed by flow cytometry in the monoclonal B cells in both of our cases. However, in both cases the atypical lymphoma-like proliferation was composed of CD10 negative marginal zone cells disrupting the reactive germinal centers. Unlike pNMZL, lymph nodes of FLMZD had follicular center and monocytoid/marginal zone components clonally related to each other, both components were positive for t(14;18) translocation and were light chain restricted [13
]. In addition to t(14;18) translocation, abnormalities involving chromosome 3 were reported in FLMZD, in particular, trisomy 3 which is a frequent abnormality in classic MZL [15
]. It is yet to be defined if pNMZL has any specific chromosomal abnormalities distinguishing this form from other low grade lymphomas. Clinical behavior of FLMZD differs from the indolent course of pNMZL as the 30 reported cases of FLMZD had significantly shorter failure free survival (P= 0.001) and overall survival (P=0.04) compared to 252 patients with pure follicular lymphoma [17
Whereas the etiology of MZL is likely diverse there is an association with chronic antigen stimulation and inflammation. However, the antigenic driving force of NMZL and/or pNMZL remains unknown. Classic NMZL as well as splenic MZL have been linked to hepatitis C virus (HCV) in approximately 20–25% according to some reports [4
]. Given the preponderance of young patients in pediatric NMZL, an association with HCV infection is unlikely, yet needs to be further addressed. pNMZL was not associated with acquired or congenital immunodeficiency in the reported cases [7
] or in the patients presented here and there was no known association with Epstein-Barr virus in any of the studied lymph nodes. It is not clear whether the antecedent Raynaud’s phenomenon in case 1 was a paraneoplastic process or was a marker for immune dysfunction predisposing to lymphoma. Given the resolution after therapy, a paraneoplastic phenomenon seems more likely.
Chronic antigenic stimulation with a microbial pathogen of Helicobacter pylori
is linked to Mucosa associated lymphoid tissue lymphomas (MALT) of the stomach, MALT lymphomas of the thyroid are believed to be related in some cases to chronic exposure to autoantigens of Hashimoto thyroiditis and MALT lymphomas of the salivary glands are frequently associated with Sjogren syndrome. In pNMZL one would suspect as potential antigenic candidates bacterial or viral antigens with tropism to upper aerodigestive tract given its manifestation as predominantly local disease in the head and neck area. Traverse-Glehen et al. reported biased usage of Vh gene with overrepresentation of Vh1 in 13 out of 35 and Vh4 in 7 out of 14 cases in splenic MZL and NMZL, respectively suggesting distinctive antigen driven mutations in 2 different entities of MZLs [19
] Analysis of Vh gene usage might be useful in pNMZL.
Thus, there is a spectrum of indolent B cell lymphomas that involve disturbed architecture of germinal centers and surrounding marginal zones. Some of these may be antigen driven. It can be difficult to determine when they have progressed from antigen-dependent oligo- or mono- clonal proliferations to independent monoclonal growth, especially given the polyclonal reactive background and residual cells.
The true incidence of this newly recognized rare variant of NMZL is unclear. The first 2 cases were described in 1997 in 2 boys who were otherwise healthy and without evidence of congenital or acquired immune deficiency [12
]. Increased awareness of this clinico-pathologic entity, due to inclusion in the WHO classification and reports such as ours in non-pediatric patients, may lead to enhanced recognition, especially in adults, which will help further characterize this rare disease. Distinct histologic features and characteristic benign clinical course help distinguish this variant from other NMZL in the adult population. Clinically, recognition is important to avoid unnecessary overtreatment of this indolent form. The name pediatric NMZL may need revision if further reports confirm our observation of this variant in older individuals. With enhanced awareness of this entity, future reports of pNMZL across all age groups should improve our knowledge of this poorly understood low grade B cell lymphoma, including incidence, clinical manifestations, cytogenetic abnormalities, molecular studies and overall prognosis to define its place within MZLs.