Follicular lymphoma presenting like marginal zone lymphoma:A case report

lNTRODUCTlON

As the most common indolent lymphoma,follicular lymphoma(FL)is recognized as the neoplasm of B lymphocytes in germinal center,characterized by t(14;18)(q32;q21)[1].Clinically,FL is sensitive to treatments but manifests an incurable and recrudescent course.The neoplastic cells of FL are composed of small to medium-sized cleaved centrocytes and large non-cleaved centroblasts,whose proportion determines the grading system[2].The rearrangement of chromosomes 14 and 18 leads to the fusion of theandgenes,causing the overexpression of the anti-apoptotic protein BCL-2.Based on the morphology of neoplastic centrocytes and centroblasts in the follicles,as well as the typical immunophenotype of the malignant cells,the pathological diagnosis of FL is made,and the detection ofrearrangement makes the diagnosis overt.FL is occasionally associated with marginal zone or plasmacytic differentiation,sharing some morphologic and phenotypic features of marginal zone lymphoma(MZL)or plasmacytoma[3].

MZL is also a kind of indolent lymphoma,with different subtypes including nodal marginal zone lymphoma(NMZL),mucosa associated lymphoid tissue lymphoma and splenic marginal zone lymphoma(SMZL).The cells of MZL harbor a monocytoid shape and display a phenotype of postgerminal center B lymphocytes without the expression of CD10.The bone marrow(BM)is very likely to be involved in patients with SMZL and NMZL,and white blood cell count is often high in patients with SMZL.In this paper,we reported a case of FL with marginal zone differentiation,which showed distinct phenotypes in the lymph node(LN)and the BM and resembled the presentation of MZL.

CASE PRESENTATlON

Chief complaints

The hospitalized patient,a 54-year-old male,complained about fatigue and breathlessness.

History of present illness

The patient had fatigue for 1 mo and progressive breathlessness for 1 wk.

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History of past illness

The patient had no other remarkable medical histories,and there was no history of fever.

Personal and family history

Image examination demonstrated splenomegaly and multiple lymphadenopathy of the mediastinum and the enterocoelia.

Physical examination

Swelling of cervical,axillary and inguinal LNs was discovered through physical examination.

Laboratory examinations

The patient’s complete blood count showed: white blood cell count 142 × 10/L,lymphocyte count 133 × 10/L,hemoglobin 35 g/L,platelet count 298 × 10/L.Lactate dehydrogenase was elevated at a level of 412 U/L.

Imaging examinations

The patient had no previous or family history of similar illness.

Examinations of BM

Generally,different subtypes of B cell lymphoma represent different evolutional stages of normal lymphocytes.The primary site and the phenotype of lymphomas tend to resemble its normal counterparts.On the contrary,the morphology,the immunophenotype and the clinical presentation of the disease are deceiving when it is with marginal zone differentiation.Without genetic detection,this case can be easily misdiagnosed as concurrent existence of two types of lymphoma.Therefore,it is necessary to take a deep insight into the genetic message of the neoplasm when performing diagnosis.

Histological examinations

Then cervical LN biopsy was performed.Hematoxylin and eosin stain of the LN gave the information that the expanded follicles were infiltrated by large centroblasts and relatively smaller centrocytes.The number of large centroblasts in the follicles significantly increased,over 15/high power field.Numerous and serried monocytoid lymphocytes occupied the marginal zone surrounding and between the follicles,forming a dark background(Figure 2C and D).Immunohistochemical examination discovered that the overgrown follicular cells were positive for CD10(Figure 4A and B),BCL-6,CD20(Figure 4C and D)and Ki-67(40%)but negative for myeloid cell nuclear differentiation antigen,a marker closely associated with NMZL.The positive CD21 confirmed a follicular dendritic cell meshwork.The neoplastic cells in the marginal zone were negative for CD10(Figure 4A and B)but positive for CD20(Figure 4C and D).Fluorescencehybridization detection of the LN illustrated therearrangement in both follicles and marginal zone(Figure 3C and D).

FlNAL DlAGNOSlS

In the follicles,the phenotype of the cells was different from that in the marginal zone and the BM,but the two groups of cells with distinct phenotypes should be considered as one clone for the coexistence of the rearrangement of.The patient was diagnosed with follicular lymphoma with marginal zone differentiation involving the BM.

TREATMENT

The neoplastic cells in the germinal center and the marginal zone of this case were different in phenotype,but it was clear that they were related to genetics according to some previous studies[8,9].The molecular analysis of immunoglobulin heavy chain gene of the two components revealed that they shared identical or nearly identical complementarity determining region III sequences[4,10],and the rearrangement ofwas found to be a common event of them by PCR[11].In this case,the pathological manifestation of the LN was consistent with the features of FL with marginal zone differentiation,and the rearrangement ofconfirmed this diagnosis.The discordant phenotype in the follicle and the marginal area indicated the coexistence of two differentiation status in one neoplasm.

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OUTCOME AND FOLLOW-UP

In BM and peripheral blood,the MZL cells have been reported to be polymorphic and predominantly monocytoid while infrequently centrocytoid or plasmacytic[12,13].But for FL,the BM is mainly involved by centrocytoid cells,with typical“cleaved or notched”nuclei[14-16].The MZL cells display markers of post-germinal center B cell and are negative for CD10,which is different from the FL cells in BM.In addition,it is a normal event of FL infiltrating the BM,but it is rare for the peripheral blood to be involved,not to mention in a hyperleukocytic pattern[14,16].This is in contrast to MZL,especially SMZL,which usually takes on hyperlymphocytosis.In this case,the BM and the peripheral blood were mainly infiltrated by the CD10 negative monocytoid cells,with a few cleaved or notched-nuclei cells.Also,the white blood cell count massively increased,resembling the features of MZL.Nevertheless,the rearrangement ofwas detected in both the LN and the BM,while it has been scarcely detected in MZL[17,18].Additionally,FL is abundant in mutations of genes that encode histone modifiers,such as,and[19].The concurrent mutations ofand,in addition to therearrangement,strongly indicated that the neoplasm was germinal center originated instead of MZL.These genetic alterations suggested that the cells in the LN and BM were from the identical clone of FL essentially.

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DlSCUSSlON

The morphologic manifestations of FL with marginal zone differentiation have been described as neoplastic follicles that were surrounded by proliferative monocytoid B lymphocytes[4,5].This was extensively observed in this case.The follicles were infiltrated by centroblasts and centrocytes,and the interfollicular area was occupied by vast monocytoid lymphocytes.But in this case,the phenotype of the two parts was discordant,reflecting two successive stages in B lymphocyte differentiation.The positive stain of CD20 indicated that both components were B cell-derived,while the marginal zone component was negative for CD10,which was positive in the follicles.In addition,it was reported that myeloid cell nuclear differentiation antigen was widely expressed in NMZL but scarcely in FL[6,7].The absence of its expression could distinguish FL with concurrent NMZL.

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The patient received six cycles of immune-chemotherapy of R-CHOP(rituximab,cyclophosphamide,liposomal doxorubicin,vindesine and prednisone).After that,his symptoms were markedly relieved,and the hemoglobin level and white blood cell and platelet count became normal.The whole-body computed tomography scan revealed significant shrinkage of the LNs and the spleen.

The patient received the maintenance therapy of rituximab every 2 mo.However,he died of relapse after 2 years.

The authors have no conflicts of interest to declare.

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The patient responded to the R-CHOP regimen well,which also applies to MZL patients.However,he suffered from an early relapse,due to the dismal prognosis of the disease harboring the mutation of53.

CONCLUSlON

BM aspirate revealed prominent hyperplasia of lymphocytes,between small and medium size,accounting for 85% of the nucleated cells.Most of the lymphocytes were small with a round nucleus,while a small fraction of them had cleaved or notched nuclei(Figure 1A and B).Flow cytometry analysis proved a clonal population of mature B lymphocytes,positive for CD19,CD20,CD79b and FMC7 instead of CD3,CD5 or CD10(Figure 1C).BM biopsy confirmed the paratrabecular infiltration of the neoplastic lymphocytes and a phenotype consistent with flow cytometry analysis(Figure 2A and B).The fusion of theandgenes were detected by fluorescencehybridization of the BM(Figure 3A and B).The next generation sequencing of the BM revealed mutations of genes,(p.R1446H)and(p.Q1613X).

FOOTNOTES

Peng HY wrote the manuscript;Xiu YJ provided the pathological pictures and contributed to the diagnosis;Chen WH reviewed the cases and edited the manuscript;Gu QL was in charge of the follow-up;Du X designed the study;all authors issued final approval for the version to be submitted;All authors approved the manuscript for publication.

Written informed consent was obtained from the patient for publication of this report and any accompanying images.

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There were reports that FL cells occasionally lost the expression of CD10 when BM was involved,but the underlying reasons were not clarified[20].FL cells with marginal zone differentiation tended to mimic the biological behavior and the clinical presentation of MZL,and the CD10 of the marginal zone component was usually missing[8].Therefore,it is presumable that,in this case,the marginal zone component of the lymphoma migrated to the blood and the marrow,displaying the features of MZL(the monocytoid shape,the absence of CD10,being hyperleukocytic and splenomegaly,)but carrying the intrinsic genetic abnormalities of FL.

The authors have read the CARE Checklist(2016),and the manuscript was prepared and revised according to the CARE Checklist(2016).

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Hao-Yu Peng 0000-0001-9743-0282;Ying-Jie Xiu 0000-0001-8154-7347;Wei-Hong Chen 0000-0002-2972-1069;Qing-Li Gu 0000-0001-6118-5852;Xin Du 0000-0002-4077-5578.

Gong ZM

Filipodia

Gong ZM