© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

J Cutan Pathol 2013: 40: 1035–1041 doi: 10.1111/cup.12230 John Wiley & Sons. Printed in Singapore

Journal of Cutaneous Pathology

Primary cutaneous marginal zone lymphoma with sequential development of nodal marginal zone lymphoma in a patient with selective immunoglobulin A deficiency Multiple lymphoma subtypes occurring within one patient is rare in the context of B-cell lymphoma, and only few such cases have been reported in association with primary cutaneous marginal zone lymphoma (PCMZL). We herein describe the case of a 43-year-old patient who was diagnosed with PCMZL and subsequently developed a clonally unrelated nodal marginal zone lymphoma (MZL). At the time of diagnosis of PCMZL, multiple skin lesions were present. The atypical lymphoid infiltrate showed monotypic expression of immunoglobulin light chain lambda and heavy chain (IgM) on immunohistochemistry and an identical B-cell clone. No sign of systemic lymphoma was present in staging examinations. Complete remission was achieved utilizing rituximab. After a 3-year clinical course of repetitive cutaneous relapses and remissions, the patient additionally developed nodal lymphoma involvement by MZL which, however, harbored an immunophenotype and a genetic clone distinct from the cutaneous lymphoma counterpart. Therefore, the rare occurrence of two different types of MZL with sequential evolution was diagnosed. In this uncommon case, we hypothesize that selective immunoglobulin A deficiency may play a promoting role for the metachronous development of the two MZL that occurred in our patient. Keywords: cancer research, cutaneous lymphomas, dermatopathology, immunocytochemistry Wobser M, Kerstan A, Kneitz H, Goebeler M, Kunzmann V, Rosenwald A, Geissinger E. Primary cutaneous marginal zone lymphoma with sequential development of nodal marginal zone lymphoma in a patient with selective immunoglobulin A deficiency. J Cutan Pathol 2013; 40: 1035–1041. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Marginal zone lymphoma (MZL) represents an indolent neoplasm of mature B-cells and comprises both non-cutaneous [nodal, splenic and mucosa-associated lymphoid tissue (MALT)] as

Marion Wobser1 , Andreas Kerstan1 , Hermann Kneitz1 , Matthias Goebeler1 , Volker Kunzmann2 , Andreas Rosenwald3 and Eva Geissinger3 1

Department of Dermatology, University Clinic Wuerzburg, Wuerzburg, Germany, 2 Department of Internal Medicine, University Clinic Wuerzburg, Wuerzburg, Germany, and 3 Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany

Marion Wobser, MD Department of Dermatology, University Clinic Wuerzburg, Josef-Schneider-Str. 2, 97080 Wuerzburg, Germany Tel: +49 931 201 26733 Fax: +49 931 201 26700 e-mail: [email protected] Accepted for publication September 3, 2013

well as primary cutaneous MZL (PCMZL) according to the current European Organization of Research and Treatment of Cancer (EORTC)-WHO classification.1 – 3 Within this rather

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Wobser et al. heterogeneous group of lymphomas, PCMZL [MZL of skin-associated lymphoid tissue (SALT)] has to be regarded as a separate entity because it exhibits an extraordinary biological behavior with a consistent, indolent clinical course. PCMZL is composed of a mixed infiltrate comprising centrocyte-like, plasmacytoid and monocytoid B-cells intermingled with sheets and clusters of monoclonal plasma cells and reactive T-cells. The exact nature of the actual tumor cell is still unknown. Given the frequent association with persistent antigen stimulation and immunological activation, it has been postulated that PCMZL represents the evolutionary and neoplastic stage of an initially benign, reactive cellular response via the step-wise acquisition of genetic mutations within an inflammatory cell of hitherto unknown origin. Despite similar morphological appearance and some shared pathogenetic features4,5 , PCMZL differs in its molecular profile from extracutaneous MZL and usually lacks the common cytogenetic aberrations present in MALT-type lymphoma such as t(14;18)(q32;q21) involving the immunoglobulin heavy chain (IGH) gene or the MALT1 gene.6 – 8 While non-cutaneous MZL may impair the patient’s life expectancy and often warrants more aggressive treatment, even frequent cutaneous relapses of PCMZL do not limit the overall excellent prognosis with 5-year survival rates close to 100%. Hence, treatment strategies for PCMZL are generally palliative with the choice of non-aggressive modalities (local excision, radiotherapy, intralesional or systemic rituximab). Non-cutaneous dissemination of PCMZL or lymphoma-associated death is extremely rare.9 Transformation to high-grade lymphoma is not a common feature of PCMZL.7 Moreover, the simultaneous or metachronous occurrence of another kind of hematological neoplasia (Hodgkin lymphoma, B or T-cell non-Hodgkin lymphoma) seems to be a rather rare event in patients with PCMZL and the reported cases most likely represent a coincidental phenomenon.10 However, in non-cutaneous MZL (nodal, splenic) simultaneous or metachronous evolvement of a second lymphoma subtype – partly by transformation to a high-grade lymphoma – may occur in up to 5% of cases.11 – 16 These different lymphomas within the same patient may be clonally related17 or unrelated.18,19 The combination of a PCMZL with a non-cutaneous MZL has not been reported so far. We herein present a patient with PCMZL who developed a sequential, clonally unrelated nodal MZL. We discuss the potential role of the selective immunoglobulin A (IgA) deficiency for the metachronous development of these two lymphoma subtypes.

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Report of a case A 43-year-old woman presented with asymptomatic subcutaneous nodules involving the left upper extremity of several weeks’ duration. Injury, local or systemic infections or injections at this site were denied. The patient suffered from an undifferentiated collagenosis without need for therapy and an autoimmune primary biliary cirrhosis being treated with ursodesoxycholic acid. No further medication was taken and the patient presented in good clinical health free of B-symptoms. Physical examination showed a non-tender, erythematous subcutaneous tumor of 1.3 × 0.4 × 1.0 cm diameter at the left upper arm. A similar nodule was detected at the left lower arm. Whole body clinical examination revealed no further cutaneous or subcutaneous tumors nor enlarged lymph nodes at that time. Histopathologic examination of the tumor at the left upper arm exhibited dense dermal infiltrates of small lymphocytes with round, hyperchromatic nuclei which showed periadnexal distribution and extension into the subcutis. The epidermis was spared by a Grenz zone (Fig. 1A). Immunohistochemical studies demonstrated a predominance of CD20-positive B-cells with few intermingled CD3-positive T-cells. Germinal centres were not present. The neoplastic lymphoid cells co-expressed bcl-2 but stained negative for CD10, bcl-6 and cyclin D1. Plasmacytic differentiation was mainly observed in sheets and clusters towards the margins of the neoplastic lymphoid infiltrates (Fig. 1B–D) with secretory differentiation showing immunoglobulin IgM heavy and lambda light chain restriction with only few reactive plasma cells positive for immunoglobulin kappa light chain (Fig. 2). To note, immunohistochemical staining for IgA or IgG was negative in the neoplastic infiltrate and, moreover, while few IgG-positive reactive plasma cells could be detected, IgA and IgG4-positive reactive plasma cells could not be identified. Molecular studies using polymerase chain reaction (PCR) analysis of the FR3A region of the IGH gene revealed a monoclonal amplificate of 106 base pair length. A complete blood cell count and flow cytometry was unremarkable. Likewise, lactate dehydrogenase, beta-2-microglobulin and chemistry panel were within normal ranges. However, electrophoretic analysis of serum immunoglobulins concealed a selective IgA deficiency. Further staging examinations including computed tomography scans of chest, abdomen and pelvis, ultrasound of cervical, inguinal and axillary lymph nodes, flow cytometry of peripheral blood and bone marrow biopsy were without evidence of systemic lymphoma manifestation. Given the negative systemic work-up, a diagnosis of PCMZL with multiple skin lesions was rendered

Marginal zone lymphoma with IgA deficiency A

B

C

D

Fig. 1. (A and B) Histopathologic appearance of the initial primary cutaneous marginal zone lymphoma (PCMZL) manifestation exhibits a dense dermal infiltrate of small lymphocytes. Hematoxylin/eosin staining. (C and D) Plasmacytic differentiation was observed in clusters, especially at the margins of the infiltrate. Hematoxylin eosin staining (C), giemsa staining (D).

and systemic treatment with rituximab 375 mg/m2 body surface area was initiated. Complete clinical remission was achieved after 4 months of intravenous rituximab in 1–4 weekly intervals without evidence of residual disease in extensive radiological and laboratory staging examinations. However, 1 month later, a solitary subcutaneous relapse of cutaneous marginal zone lymphoma involving the back was detected and exhibited the identical lymphoma immunophenotype and molecular clone as in the previous skin biopsy. Hence, another course of systemic treatment with intravenous rituximab combined with local radiotherapy (total dose 36 gray) was successfully applied. During the following 30 months repetitive subcutaneous relapses – which all showed the identical lymphoma clone on the molecular level – were treated by radiotherapy or local excision. Repetitive staging examinations including computed tomography of chest and abdomen, blood analysis and bone marrow biopsy showed no further lymphoma involvement. However, 42 months after first diagnosis of PCMZL the patient presented again with several new subcutaneous nodules at her right arm and trunk and an enlarged lymph node in the right axilla as well suspicious mediastinal lymph nodes. Two biopsies of two different subcutaneous nodules at the right arm were taken. Pathologic examination of one nodule revealed subcutaneous lymphoma relapse of soft tissue which

exhibited the same immunophenotype and an identical molecular clone as in all the previous skin biopsies. However, microscopic examination of the other nodule showed a lymph node with involvement by lymphoma. The regular architecture of the enlarged lymph node was altered by a dense infiltrate of small lymphocytes (Fig. 3A) which were predominantly located in the marginal zone around residual lymph follicles (Fig. 3B,C). Few intermingled larger lymphocytes with blastic morphology were present. Immunohistochemically, the neoplastic lymphocytes were positive for CD20 and the blastic and plasmacytic cells expressed IgM and the immunoglobulin kappa chain (Fig. 3D,E) whereas admixed reactive plasma cells showed an orderly polytopic light chain expression pattern. Staining for IgG was only positive in very few bystander cells and not in the neoplastic infiltrate itself. IgA and IgG4positive plasma cells could not be detected. Only residual germinal centers and colonized follicular network structures were highlighted by bcl-6, CD10 and CD23, respectively. Molecular analysis revealed a monoclonal rearrangement of the FR3A region of the IGH gene showing a monoclonal amplificate of 98 base pairs. The monoclonal amplificate of the IGH gene, which was consistently present in all previously analyzed skin specimens, could not be detected in the lymph node and vice versa. As plasmacytoid dendritic cells (PDC) have recently been assigned a putative role in the

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Wobser et al. A

B

C

Fig. 2. Within the lymphoid infiltrate, the plasmacytic cells show secretory differentiation for IgM (A) and lambda light chain (C) whereas kappa light chain was only positive in some reactive plasma cells (B).

pathogenesis of PCMZL, we analyzed the presence of CD123-positive PDC within both cutaneous as well as nodal MZL tissue. In both specimens, CD123positive and CD68-negative PDC were present to variable extents mainly arranged in small clusters (data not shown). Further staging examination [computed tomography (CT) of chest and abdomen, ultrasound of lymph nodes and soft tissue, magnetic resonance tomography of soft tissue, bone marrow biopsy, gastroscopy and laboratory analysis] revealed no further lymphoma beside the known mediastinal lymphoma manifestations. B-symptoms, clinically relevant laboratory abnormalities or recurrent infections were absent. Taken together, the diagnosis of clonally unrelated, sequential marginal zone lymphomas of both the cutaneous and the nodal compartment was made. The patient is currently scheduled in regular follow-up according to a watch-and-wait strategy. Discussion Deviations of immune responses or chronic antigen stimulation have been suggested to play an important role in the development of MZL of both cutaneous and extracutaneous tissue as evidenced

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by frequent association with chronic inflammatory, infectious and/or autoimmune conditions. Chronic sialadenitis, Sj¨ogren syndrome, rheumatoid arthritis as well as Helicobacter pylori infection, Chlamydia infection or Borrelia burgdorferi infection all represent predisposing conditions for the development of different types of MZL.20 – 25 As known from post-transplant B-cell lymphoproliferative disorders ongoing stimulation can result in the occurence of clonal B-cells.26,27 On the other hand, the elimination of the underlying chronic immune stimulus may lead to lymphoma regression. In gastric MALT lymphoma eradication of H. pylori by antibiotic treatment achieves complete remission in up to 90% of patients.28 Antibiotic treatment of B. burgdorferiassociated PCMZL shows clinical efficacy in at least a subset of patients.22 In this context, the role of the tumor-associated inflammatory infiltrate and of CD123-positive, CD68-negative PDC for the pathogenesis of PCMZL has been recently delineated.29,30 PDC represent a specialized subset of dendritic cells which play a role for the initiation and perpetuation of immunological responses by different properties including antigen presentation, production of type I interferon, activation of T-cells and induction of

Marginal zone lymphoma with IgA deficiency A

C

B

D

E

Fig. 3. (A–C) Nodal involvement by marginal zone lymphoma. Hematoxylin eosin staining. Interspersed blastic lymphocytes within the lymph node show secretory differentiation for IgM (D) and kappa light chain (E). Note that this secretory differentiation is distinct from the secretory type of the cutaneous marginal zone lymphoma.

plasmacellular differentiation.31 – 33 PDC are relevant for antiviral immune responses as evidenced by their presence in inflammatory molluscum contagiosum virus-induced skin lesions.34 While in antigen-driven PCMZL, PDC and T-cells are readily detected, they are only sparsely found in the neoplastic infiltrate of other cutaneous B-cell lymphomas like primary cutaneous follicle center lymphoma and absent in diffuse large B-cell lymphoma. In non-cutaneous MZL including other MALT-type lymphoma, the role of PDC has not been elucidated so far. Recent studies have delineated that infection with B. burgdorferi may be less important for the pathogenesis of PCMZL than initially suspected and might only be relevant for a small subset of PCMZL in certain geographic regions.22,25,35 – 38 Likewise, the role of chronic antigen exposure for nodal MZL remains elusive. In our patient, B. burgdorferi serology was negative. However, autoimmune diseases may predispose to lymphoma development in case of immunosuppressive therapy39 – 41 and, likewise, one single prior report has described the simultaneous occurence of PCMZL and chronic lymphocytic leukemia in a patient with rheumatoid arthritis.23 However, in our patient primary biliary cirrhosis and rheumatoid arthritis did not demand immunosuppressive therapy due to a mild clinical course. The autoimmune diseases in our patient may result from an impaired immune regulation due to a selective IgA deficiency.

The selective IgA deficiency in our patient probably represents the most relevant predisposing factor for lymphoma evolvement. Patients with selective IgA deficiency – the most common primary immunodeficiency disease – are prone to infections or autoimmune disorders and bear a higher propensity to develop neoplasias.42,43 Lack of secretory IgA has been hypothesized to compromise the defense against infection with H. pylori which is pathogenetically related to gastric cancer and MALT lymphoma.44 In a large study among Danish and Swedish subjects suffering from common invariable immunodeficiency (CVID) or selective IgA deficiency, the incidence of cancer was increased [standardized incidence ratio (SIR) 1.8] including that of stomach cancer (SIR 10.3) and malignant lymphoma (SIR 12.1).45 To note, during histopathologic work-up of our patient’s lymphomas the complete absence of IgA within the lymphoma infiltrate of skin and lymph node alerted us to further look for selective IgA deficiency in the patient. Hampered immunoregulation with stimulation of tumor-promoting PDC may result in oncogenic transformation at sites of chronic inflammation with the advent of marginal zone lymphoma of both the skin and lymph nodes, as seen in our patient. As the two lymphomas showed a different heavy chain rearrangement proven by PCR and distinct light chain restriction, a common clonal origin

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Wobser et al. seems extremely unlikely. Up to now, seven case reports have illustrated biclonal or clonally unrelated PCMZL either in synchronous or in metachronous evolution.46 – 50 The simultaneous occurence of clonally unrelated PCMZL and nodal MZL has not been published yet.

To summarize, the occurence of two MZL without any shared, common genetic features might result from a compromised capacity to adequately cope with exogenous antigens, autoantigens or chronic immune stimulation in the light of selective IgA deficiency.

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Primary cutaneous marginal zone lymphoma with sequential development of nodal marginal zone lymphoma in a patient with selective immunoglobulin A deficiency.

Multiple lymphoma subtypes occurring within one patient is rare in the context of B-cell lymphoma, and only few such cases have been reported in assoc...
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