Metachronous Marginal Zone Lymphoma Followed by a Peripheral T-Cell Lymphoma in the Same Patient. Report of Two Cases and Review of the Literature

Case Report

Austin Hematol. 2021; 6(1): 1031.

Metachronous Marginal Zone Lymphoma Followed by a Peripheral T-Cell Lymphoma in the Same Patient. Report of Two Cases and Review of the Literatures

Condom M1,4*, Climent F2, Varela M2, Gonzalez-Barca E1,3,4, Maluquer C1,4, Sureda A1,3,4 and Domingo-Domenech E1,4

1Department of Hematology, Catalan Institute of Oncology, Spain

2Department of Pathology, Bellvitge University Hospital, Spain

3Barcelona University, Spain

4Institut d’Investigació Biomèdica (IDIBELL), Spain

*Corresponding author: Maria Condom, Department of Hematology, Catalan Institute of Oncology, Hospital Duran i Reynals, Avinguda de la Gran via de l’Hospitalet, 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain

Received: January 12, 2021; Accepted: February 03, 2021;Published: February 10, 2021

Abstract

Marginal Zone Lymphomas (MZL) and Peripheral T Cell Lymphomas (PTCL) are uncommon neoplasms and patients affected by both lymphomas in a lifetime have been rarely reported. Here we present two patients with an initial diagnosis of a MZL who further developed a PTCL. We also present the review of the literature of six other cases of MZL. Half of the cases reported are synchronous and the other half metachronous. Most MZLs reported are MALT subtype. There is no predominant subtype amongst PTCLs. Chronic exposure to proinflammatory cytokines, genetic predisposition or exposure to carcinogenic agents could be possible causes underlying this rare phenomenon.

Keywords: Marginal zone lymphoma; Peripheral t-cell lymphoma; Synchronous; Metachronous

Case 1

A 45-year-old man with no previous medical records presented with asthenia in May 2014. Laboratory tests revealed iron-deficiency anemia. Serologies and autoimmunity tests including celiac disease study where negative. Thoracic-abdominal CT scan showed an enlargement of the first portion of the duodenum and enlarged mesenteric lymph nodes of 2cm. Helicobacter Pilory (HP) was negative. The duodenum biopsy showed a prominent lymphoid infiltrate involving the lamina propia. Immunohistochemistry markers were positive for B-cell and negative for CD3, CD5, CD10, BCL6 and cyclin D1. Ki67 index was <5%. IGH showed a clonal rearrangement. Bone marrow was not infiltrated. The diagnosis of Mucosa Associated Lymphoma Tissue (MALT) lymphoma stage II1E, with duodenal involvement was made. The patient received 3 cycles of R-CHOP achieving a complete response. In March 2016, he relapsed with multiple enlarged abdominal lymph nodes. Duodenum biopsy showed a MZL. TCR came out polyclonal. He received 4 cycles of Rituximab and Fludarabine, achieving a partial remission. On January 2018, he presented with abdominal pain. PET-CT scan showed an increased metabolic activity of the colon, and enlarged mesenteric lymph nodes (SUV max 17). Unfortunately, the patient presented rapid disease progression and died before a diagnostic biopsy could be performed. Necropsy showed a mesenteric mass also affecting the small bowel and right colon wall. Microscopically, it showed a diffuse infiltration of the serosa and the intestinal wall by medium-large cells that were positive for CD3, CD4, CD5, CD7, BF1 and cytotoxic markers (TIA and Granzyme B), and negative for CD8. CD30 was extensively positive especially in the larger cells. Ki67 index was 90%. B-cell markers, ALK and EBERs were negative. Molecular studies showed a clonal rearrangement of the TCR beta. IGH rearrangement was polyclonal. Differential diagnosis included ALK negative anaplastic large cell lymphoma and monomorphic epitheliotropic intestinal T-cell lymphoma, but morphologic and immunophenotypic analysis did not meet diagnostic criteria. Finally, a diagnosis of PTCL-NOS was made.

Case 2

A 62-year-old woman with no previous medical records presented with a right ocular mass and enlarged supraclavicular lymph nodes in October 2003. Blood tests were within normal ranges. Thoracicabdominal CT scan showed no relevant findings. Lachrymal gland biopsy showed infiltration by MZL. Bone marrow was infiltrated. She was diagnosed with stage IVA MALT lymphoma and received Chlorambucil 2mg/day for a year with clinical resolution of both ocular mass and lymph nodes.

She remained uneventful until 2017, when she presented with a cervical enlarged lymph node. PET CT-scan showed supra- and infradiaphragmatic lymph nodes (SUVmax 12.5). Cervical lymph node biopsy was diagnostic of a PTCL, with T-follicular helper phenotype. EBERs was negative and TCR was clonal. B-cell markers and IGH rearrangement showed a small residual B-cell clonal population. She was started on CHOP chemotherapy, but after six cycles she presented with progressive disease. She was then treated with Bendamustine but had no response. She received salvage therapy with GEMOX, with progressive disease including multiple bones lesions. Unexpectedly, a biopsy of one of these lesions showed an aggressive B-cell lymphoma. Clonality studies showed that this lymphoma was related to the previous MALT lymphoma. The patient deceased shortly after the diagnosis.

Discussion

MZL and PTCL are rare neoplasms. The coexistence of both in the same patient cannot be explained by pure randomness, since the probability of these tumors is very low in our population. According to local registries [1], Marginal Zone Lymphomas and T/NKcell lymphomas have an incidence of 2.59 and 2.01/100.000/year, respectively. In our area, the chances of developing both neoplasms within a 15 year-period of time are approximately 0.000012%. To our knowledge, only six cases of MZL and PTCL occurring in the same patient have been reported before in the literature [2-7]. The characteristics of these patients are summarized in (Table 1) (synchronous) and (Table 2) (metachronous).

Table 1: Clinical, pathologic, phenotipical and molecular features in 3 cases of synchronous MALT and T cell Lymphoma.





  

    
Case/Sex/Age/Ref

    
Lymphoma    1

    
Lymphoma    2

  

  

    
Clinical    presentation

    
Anatomical

      site

    
Morphology

    
IHC

    
Molecular    tests

    
Diagnosis

    
Clinical    presentation

    
Chronology

      & anatomical sites

    
Morphology

    
IHC/FC

    
Molecula

      r tests

    
Diagnosis

  

  

    
4/F/6812

    
B    symptoms, toxic syndrome Md

      abdominal

      pain

    
Colon

    
Transmural    small-medum hymphoid cells with

      small-medium cytoplasm, slightly irregular

      nucei

    
LCA+,    CD20+, CD79a.

      Pax5+·

      Negative for T-cell markers

    
IGH    clonal TCRG not clonal

    
MALT

      lymphoma

    
Breathing    and

      swallng

      discomfort

    
2 years    later, esophagus

    
infitration    of the lamina propia by large lymphoid cells with irregular nuclei, prominent    nuclecli, mitosis

    
CD3+,CD4,CD56,    CD8-, CD30-

      "Negative for B-cell

      markers

    
TCRG

      clonal

      IGH

      clonal

    
PTCL,

      NOS

  

  

    
5/M/42/3

    
Toxic

      syndrome and

      abdominal pain

    
Stomach

      and bone

      marrow

    
n/d

    
CD20+,    CD5+, CD38+, K- LC

      CD10-.

      cyclin D1-

    
n/d

    
MALT

      lymphoma

    
n/d

    
6    months later, bone marrow

    
n/d

    
2    populations;

      1. T-cells: CD8+, CD3+, CD5+, CD7+,    CD45+,

      2. B-cells: CD19, CD79b, CD20, CD22,lgM, kappa LC

    
n/d

    
1. MALT

      lymphoma

      2.T-LGL

  

  

    
6/?/?/4

    
n/d

    
esophagus

    
n/d

    
n/d

    
n/d

    
MALT

      lymphoma

    
Bowel

      perforation

    
9 years    later,

      ileum

    
Dual    population

      of medium-sized and a few large lymphoid cells

    
CD3+,CD20-,    CD5-,CD56+,

      CD4+,CD8-.

      CD30+ (in the

      papulation of larger cells).TIA-1 and

      granzyme B.

    
n/d

    
EATL,

      type II

  

  

    
IHC: Immunohistochemistry;    FC: Flow Citometry; LC: Light Chain; ETL: Enteropathy-Type T Cell Lymphoma; EATL:    Enteropathy-Associated T-Cell Lymphoma; MALT L: MALT Lymphoma; MZL: Marginal    Zone Lymphoma; CHL: Classical Hodgkin Lymphoma; PTCL: Peripheral T Cell    Lymphoma; ND: Not Described, TCRG: T-Cell Receptor Gamma; HRS: Hodgkin Reen-Sternberg    Cells; Ref: Reference Number. 

  










Table 1: Clinical, pathologic, phenotipical and molecular features in 3 cases of synchronous MALT and T cell Lymphoma.

Table 2: Clinical, pathologic, phenotipical and molecular features in 3 cases of metachronous MALT and T cell Lymphoma.





  

    
Case/Sex/Age/Ref

    
Clinical    Presentation

    
Anatomical    sites

    
Marginal    Zone lymphoma

    
T-cell    lymphoma

  

  

    
 

    
Morphology

    
IHC

    
Molecular    tests

    
Diagnosis

    
Morphology

    
IHC

    
Molecular    tests

    
Diagnosis

  

  

    
1/F16415

    
Incidental    finding of gastric nodule inan endosoopy

    
Stomach

    
Small    cells infiltrating the lamina propia with round or mildly irregular nuclei

    
CD20+

    
IGH

      clonal

    
MALT    lymphoma

    
Smalllymphocytes    with mild atypia infitrating the surface and glandular epitelium

    
CD3+,CD8+,    TIA-1+

    
TCRGdonal

    
Ell.

  

  

    
3/F/65/6

    
Cutaneous    nodules (foream and leg), enlarged cervical and retroperitioneal lymph nodes

    
Skin:    MZL + PTCL

      Cervical    lymph node: cHL + PTCL

    
SKIN    -Sheets of lymphoid cells with small indeded nuclei mixed with plasma cells    infitrating deep dermis and subcutaneous tissue *T-cells: n/d

    
·C020+

    
IGH

      clonal (skin)

    
Primary    cutaneous marginal zone B cell lymphoma

    
LN:

      ·HRS cells *T-cells: n/d

    
LN    & SKIN: T

      cells: CD3+, CD4+, TCRB negative

    
TCRGdonal

      (Skin and LN)

    
PTCL,NOS

  

  

    
2/F/57/7

    
Multiple

      lung/pleural lesions

    
Lung    and pleura

    
Nodular    infitrate os small-intermediate lymphocytes within the lung parenchima

    
CD20+,    C079a+, BCL2+,CD5-,

      cyclin D1, CD23-, BCL6-, CD10-

    
IGH

      clonal

    
MALT

      lymphoma

    
Large    cells with plemorphic nuclei and abundant eosinophilic cytoplasm in pleural    area

    
CD30+,CD8+,    CD2+, CD3w, CD7+/-, CD5-,

      CD15-,ALK1-

    
TCRG    clonal

    
ALCL,    ALK negative

  

  

    
IHC:    Immunohistochemistry; FC: Flow Citometry; LC: Light Chain; ETL:    Enteropathy-Type T Cell Lymphoma; EATL: Enteropathy-Associated T-Cell    Lymphoma; MALT L: MALT Lymphoma; MZL: Marginal Zone Lymphoma; CHL: Classical    Hodgkin Lymphoma; PTCL: Peripheral T Cell Lymphoma; ND: Not Described, TCRG:    T-Cell Receptor Gamma; HRS: Hodgkin Reen-Sternberg Cells; Ref: Reference    Number. 

  










Table 2: Clinical, pathologic, phenotipical and molecular features in 3 cases of metachronous MALT and T cell Lymphoma.

Four possible explanations for the development of B and T-cell neoplasms in the same patient were posed by Medeiros and Stetler- Stevenson in 1992 [8]: First, that there might be a common stem cell precursor with the capacity to differentiate into a B- or T-cell tumor. Secondly, there could be an underlying genetic predisposition given by the activation of oncogenes or alterations in tumor suppressor genes. Third, previous exposure to a common carcinogen could independently transform B and T precursors. And fourth, the neoplastic B-cells secrete various cytokines that might chronically stimulate T-cells, leading to the development of small clones of T cells that might eventually transform into an aggressive lymphoma.

Other known factors associated with lymphomagenesis of MALT lymphomas are autoimmune disorders and chronic infections, but these have not been related to PTCLs [9]. Acquired immunodeficiencies caused by infectious agents or by previous cytotoxic treatments could play a role in the emergence of a second lymphoma. Also, Epstein Barr Virus (EBV) in immunosuppressed patients has the ability to induce a malignant transformation of normal B-cells [10], and these cells may stimulate a T-cell proliferation that might become clonal through a process of clonal selection. However, none of our patients was positive for EBV.

In our first case, chronic exposure to proinflammatory cytokines secreted by MALT lymphoma could have locally stimulated T-cell proliferation that at a point became clonal and eventually transformed into a PTCL. This theory is reinforced by the fact that the MALT lymphoma relapsed or responded partially to different treatments, being this proinflammatory state sustained and also by the fact that PTCL appeared in the same site as the MALT lymphoma.

Regarding the second case, a genetic predisposition or an exposure to a common carcinogenic agent could explain the fact that she developed two different lymphomas. In summary, coexistence of MALT lymphomas and PTCL is extremely rare and the exact mechanisms underlying this phenomenon are yet to be elucidated. It is important to re-biopsy all the relapses of MALT lymphomas, in order to properly diagnose and treat the lymphoma. Further genetic or epigenetic studies could help us explain this co-existence in the future.

Acknowledgement

MC, FC, EDD-literature search, study design, figure design, writing of the report. AS-critical review. MC, CM, EGB-patient registration and treatment, data collection. FC, MV-Pathology review. We thank CERCA programme/Generalitat de Catalunya for institutional support.

References

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Citation:Condom M, Climent F, Varela M, Gonzalez-Barca E, Maluquer C, Sureda A, et al. Metachronous Marginal Zone Lymphoma Followed by a Peripheral T-Cell Lymphoma in the Same Patient. Report of Two Cases and Review of the Literature. Austin Hematol. 2021; 6(1): 1031.