PRIMARY CUTANEOUS MARGINAL ZONE B-CELL LYMPHOMA – PITFALLS IN THE DIAGNOSIS LIMFOMUL CUTANAT...

ROMANIAN JOURNAL of CLINICAL and EXPERIMENTAL DERMATOLOGY114

Primary Cutaneous Marginal Zone B-Cell Lymphoma – Pitfalls in the Diagnosis

Cite this article: Aurel Doru Chiriţă, Irina Mărgăritescu. Primary Cutaneous Marginal Zone B-Cell Lymphoma – Pitfalls in the Diagnosis. RoJCED 2015; 2(2):114-119

Open Access Article

Keywords:

Cuvinte-cheie:

cutaneous T-cell lymphoma, primary cutaneous marginal zone B-cell lymphoma, lupus erythematosus

limfom cutanat cu celula T, limfom cutanat primar cu celula B de zonă marginală, lupus eritematos

Abstract

Rezumat

Primary cutaneous marginal zone B-cell lymphoma represents a low grade B-cell lymphoma that originates in the skin with no evidence of extracutaneous disease at the time of diagnosis. The diagnosis of this type of lymphoma can be very difficult especially when presenting with unusual features. Clinically, the lesions may simulate inflammatory processes or benign conditions. Histologically, the reactive T-cell infiltrate can be so abundant that the true neoplastic B-cell infiltrate is overlooked. Hence, integration of all clinical, histological, immunohistochemical and molecular data is critical in establishing the correct diagnosis and initiation of appropriate treatment. We present the case of a primary cutaneous marginal zone B-cell lymphoma with multifocal lesions, spontaneous resolution and formation of anetodermic scars that was misinterpreted as lupus erythematosus tumidus, Jessner-Kanof infiltrate, or benign lymphoid hyperplasia for 7 years. We emphasize the difficulties encountered in the diagnosis of this particular type of cutaneous lymphoma.

Aurel Doru Chiriţă MD1, Irina Mărgăritescu MD, PhD2

1) Department of Dermatology, “Carol Davila” Central Military Emergency University Hospital, Bucharest, Romania;

2) Laboratory of Anatomic Pathology, “Onco Team Diagnostic”, Monza Hospital, Bucharest, RomaniaCorresponding author:

Aurel Doru Chiriţă, MD, Dip. ICDP-UEMS, Department of Dermatology, “Carol Davila” Central University Emergency Military Hospital, Bucharest, Romania, 88 Mircea Vulcanescu street, Sector 1, 010825 Bucharest,

Romania, Phone +40-788-355-663, e-mail: [email protected]

Limfomul cutanat primar cu celula B de zonă marginală reprezintă un limfom cu celule B de grad jos care apare la nivelul pielii, fără să existe afectare extracutanată la momentul diagnosticului. Diagnosticul acestui tip de limfom poate fi foarte dificil, în special atunci când se prezintă cu anumite trăsături neobişnuite. Clinic, leziunile pot simula un proces inflamator sau o afecțiune benignă. Histologic, infiltratul reactiv cu celule T poate fi atât de abundent încât adevăratul infiltrat neoplazic cu celule B poate fi trecut cu vederea. De aceea, integrarea tuturor datelor clinice, histologice, imunohistochimice şi moleculare este esenţială pentru stabilirea unui diagnostic corect şi pentru iniţierea unui tratament adecvat. Prezentăm cazul unui limfom cutanat primar cu celula B de zona marginala cu leziuni multifocale, rezoluţie spontană şi formarea de cicatrici anetodermice şi care a fost greşit interpretat timp de 7 ani ca lupus eritematos tumidus, infiltrat Jessner-Kanof sau hiperplazie limfoidă benignă. Subliniem dificultăţile întâlnite în diagnosticul acestui tip de limfom cutanat.

PRIMARY CUTANEOUS MARGINAL ZONE B-CELL LYMPHOMA – PITFALLS IN THE DIAGNOSISLIMFOMUL CUTANAT PRIMAR CU CELULA B DE ZONĂ MARGINALĂ – CAPCANE ALE DIAGNOSTICULUI

Oncology and Dermato-oncology

May 2015 115

Aurel Doru Chiriţă, Irina Mărgăritescu

IntroductionPrimary cutaneous marginal zone B-cell lymphoma

(PCMZL) represents a low grade B-cell lymphoma that originates in the skin with no evidence of extra-cutaneous disease at the time of diagnosis (1). Patients are usually males in their 4th and 5th decades of life (2-5), who present with asymptomatic solitary lesions (6) localized especially on the upper trunk or upper extremities. Multicentric or generalized eruptions are encountered less often and they are associated with frequent recurrences after various treatment mo-dalities. Spontaneous resolution with development of anetoderma is an unusual feature that has very rarely been described (7). This peculiar phenomenon may be a potential pitfall in the diagnosis of PCMZL especially when it presents with papules and small nodules only, without obvious tumoral lesions. These types of lesions can be easily misinterpreted as in-flammatory or benign processes, both clinically and histopathologically. Hence, the correct diagnosis can be delayed for a long period of time, sometimes for decades (4).

We present a case of PCMZL with multifocal lesions, spontaneous resolution and formation of anetoder-mic scars that was misinterpreted as lupus erythe-matosus tumidus, Jessner-Kanof infiltrate, or benign lymphoid hyperplasia for 7 years. We emphasize the difficulties encountered in the diagnosis of this par-ticular cutaneous lymphoma.

Patient, Methods and ResultsA 25 years-old man presented with a 7 year history

of erythematous papules and nodules located on the upper trunk and upper arms. Over these 7 years the lesions were interpreted as either lupus erythema-tosus tumidus, Jessner-Kanof infiltrate, borrelial lym-phocytoma cutis or benign lymphoid hyperplasia, based on clinical features and/or histological aspects revealed by three consecutive biopsies. Close-up clin-ical examination revealed lesions in various stages of evolution, namely: perifollicular papules (Figure 1A), infiltrated plaques, small indurated nodules (Figure 1B), nodules with anetodermic surface (Figure 1C), and anetodermic scars (Figure 1D). The patient was in good health. Complete physical examination did not reveal lymphadenopathy, hepato-splenomegaly, or any other pathological findings. Blood tests includ-ing serological tests for lupus erythematosus and B. burgdorferi, a full CT scan, and a bone marrow biopsy were within normal limits.

All three biopsies were available for evaluation. First biopsy performed at the onset of the disease showed a moderate superficial perivascular and in-terstitial infiltrate (Figure 2A) composed mainly of small lymphocytes with a variable number of plas-mocytoid cells and mature plasma cells (Figure 2B). Second biopsy (not shown) performed several years later revealed similar histological findings. The last biopsy performed 7 years after the onset of the dis-

Figure 1. A 25 years-old man presented with a 7 year history of erythematous papules and nodules located on the upper back and upper arms. Close-up clinical examination revealed lesions in various stages of evolution, namely: (A) perifollicular papules, (B) infiltrated plaques, indurated nodules, (C) nodules with anetodermic surface, and (D) anetodermic scars

A

C

B

D



ease showed a dense nodular and diffuse infiltrate sparing the epidermis and the papillary dermis and occupying the whole reticular dermis with involve-ment of the superficial part of the subcutaneous fat (Figure 3A). The infiltrate showed a remarkable verti-cal orientation with perifollicular involvement (Figure 3B) and distruction of the adnexa (Figure 3C). Various reactive germinal centers were apparent. A popula-tion of small-medium cells with indented nuclei, non-prominent nucleoli, and abundant pale cytoplasm (centrocytes-like cells) accompanied by plasma cells, lympho-plasmacytoid cells, a few immunoblasts, and many reactive small lymphocytes occupied the peri-follicular and interfollicular spaces (Figure 3D). The histological findings of the 3rd biopsy were highly sug-gestive of cutaneous marginal zone B-cell lymphoma.

The immunohistochemical analysis was accom-plished on 5-μm-thick sections, on poly-L-Lysine coated slides. The immunohistochemical technique used was an indirect bistadial one, based on polym-erized Dextran conjugated with secondary antibody and horseradish peroxidase (DAKO, EnVision), using overnight primary antibodies incubation and DAB saline solution with 0.03% hydrogen peroxide as sub-strate. Both positive and negative controls were used. The following antibodies were used: CD3 (monoclo-nal mouse anti-human CD3, clone F7.2.38, dilution 1:50; Dako), CD20 (monoclonal mouse anti-human CD20cy, Clone L26, dilution 1:200, Dako), CD30 (monoclonal mouse anti-human CD30, clone Ber-H2, dilution 1:20, Dako), CD10 (monoclonal mouse anti-human CD10, clone 56C6, dilution 1:40; Dako), CD43 (monoclonal mouse anti-human CD43, clone DF-T1, dilution 1:100; Dako), CD79 (monoclonal mouse anti-human CD79α, dilution 1:25; Dako), bcl2 (mono-clonal mouse anti-human bcl2 oncoprotein, clone 124, dilution 1:50; Dako), bcl6 (monoclonal mouse anti-human bcl6 protein, clone PG-B6P, dilution 1:10;

Dako), κ (polyclonal rabbit anti-human kappa light chains, dilution 1:80000, Dako), λ (polyclonal rabbit anti-human lambda light chains, dilution 1:80000, Dako). Histopathological and immunohistochemi-cal evaluation was performed with Leica DM2500 microscope and images were acquired using Leica DFC490 camera.

Immunohistochemically, numerous cells disposed in nodular aggregates outside reactive follicular cen-ters stained with CD20 (Figure 4A), CD79 (Figure 4B), bcl2 (Figure 4C) and CD43, and were negative for bcl6 and CD10. A prominent reactive T-cell infiltrate (Figure 4D) that obscuredthe neoplastic B-cell popu-lation was apparent. Plasma cells were monotypic, with the restriction of the Ig light chain kappa (κ:λ ra-tio > 5:1) (Figures 4E, F).

Molecular genetic studies using polymerase chain reaction-based methods demonstrated a monoclo-nal population for the FR2-JH region of the immuno-globuline heavy chains, indicating the presence of a monoclonal B-cell population. Four reactions without amplifications at the level of the V and J regions of γ T cell receptor chains (TCR) were conducted.

Clinical, histological, and immunohistochemical findings coupled with paraclinical and molecular ge-netic studies established the final diagnosis of prima-ry cutaneous marginal zone B-cell lymphoma.

The patient underwent various treatments such as systemic corticosteroids, topical corticosteroids, intra-lesional steroid injections, cryotherapy, and surgical excisions with limited effects. Two years after diagno-sis of lymphoma was established and nine years from the onset of the disease the patient is in good health with disease limited to the skin.

DiscussionPCMZL represents a low grade B-cell lymphoma

that originates in the skin with no evidence of extra-

Figure 2. First biopsy performed at the onset of the disease showed (A) a moderate superficial perivascular and interstitial infiltrate composed mainly of (B) small lymphocytes with a variable number of plasmocytoid cells and mature plasma cells (HE stain, 50x, and 400x)


May 2015 117


cutaneous disease at the time of diagnosis (1). Most patients are in the 4th and 5th decades of life but the age at presentation ranges from 12 to 80 years (2-4).The disease mainly affects males (61% males vs 49% females) (5).The usual presentation of PCMZL is with asymptomatic solitary lesions (6). Patients may also present with clusters of erythematous papules, plaques or nodules involving one or more anatomical sites. Generalized eruption was classically considered to be rare. However, a recent study (8) conducted on 137 patients with PCMZL showed that generalized skin lesions affected an important number (20%) of patients. Upper trunk and upper arms are particularly affected but any other body site may be involved (1, 9, 10). Spontaneous resolution with development of anetoderma, as in our case, has rarely been observed (7). This peculiar phenomenon may be a potential pit-fall in the diagnosis of PCMZL as one usually do not expect a neoplastic lymphoid infiltrate (except for lymphomatoidpapulosis cases and some cases of primary cutaneous anaplastic large T-cell lymphoma) to completely disappear without therapeutic inter-

vention.Another diagnostic difficulty may arise when presentation is with papules and small nodules only, without obvious tumoral lesions.These lesions can be easily mistaken for inflammatory or benign processes like lupus erythematosus tumidus, Jessner-Kanof in-filtrate, or benign lymphoid hyperplasia. Hence, the correct diagnosis can be delayed. Our case illustrates very well these diagnostic challenges. The lesions started as erythematous perifollicular papules with progressive enlargement and confluence into slightly elevated and infiltrated plaques and small indurated nodules and never progressed to large tumors. In time, some lesions developed an atrophic surface and few others spontaneously disappeared leaving anetodermic scars.

Histologically, PCMZL can also pose diagnostic problems. Biopsies from early lesions only show a sparse to moderate superficial perivascular and inter-stitial lymphoid infiltrate composed of predominantly small lymphocytes, a few plasmacytoid cells and ma-ture plasma cells (Figure 2). Also, established lesions can sometimes show a top-heavy infiltrate (Figure 3),

Figure 3. The last biopsy performed 7 years after the onset of the disease showed (A) a dense nodular and diffuse infiltrate sparing the papillary dermis and occupying the whole reticular dermis with involvement of the superficial part of the subcutaneous fat. (B) The infiltrate showed a remarkable vertical orientation with perifollicular involvement and (C) destruction of the adnexa. (D) A population of small-medium cells with indented nuclei, non-prominent nucleoli, and abundant pale cytoplasm (centrocytes-like cells) accompanied by plasma cells, lympho-plasmacytoid cells, a few immunoblasts, and many reactive small lymphocytes occupied the perifollicular and interfollicular spaces (HE stain, 12,5x, 100x, 200x, and 400x)

A

C

B

D



more in keeping with a pseudolymphomatous pro-cess. Moreover, many reactive germinal centers are usually observed. However, there are certain impor-tant clues that point to the real nature of the neoplas-tic infiltrate. At scanning power, the infiltrate shows a biphasic or triphasic appearance, with areas of pale cells located outside dark lymphoid nodules or reac-tive germinal centers (6, 11). The density of the infiltrate is also of concern. The nodular to diffuse infiltrate in-volves the whole reticular dermis and sometimes the superficial part of the subcutaneous fat and spares the epidermis and papillary dermis. The infiltrate shows a characteristic vertical orientation along adnexa (12, 13) that can be both a clue and a pitfall in the diagnosis. Adnexal involvement is a usual feature in lupus ery-

thematosus that can also rarely present with reactive germinal centers. However, in PCMZL the neoplastic infiltrate usually destroys the hair follicles, arrector pili muscles, and eccrine glands with accompanying necrosis. At higher power, the peri- and interfollicu-lar pale areas are shown to be composed of small- to medium-sized cells with irregular nuclei, inconspicu-ous nucleoli, and abundant pale cytoplasm (centro-cyte-like cells), i.e. marginal zone B cells, lymphoplas-macytoid cells, plasma cells, a few centroblast- or immunoblast-like cells, and many reactive T cells. An important aid to the diagnosis is the identification of plasma cells at the periphery of the infiltrates and in the superficial dermis beneath the epidermis (11). One of the major histologic pitfalls is the presence of many

Figure 4. Immunohistochemically, numerous cells disposed in nodular aggregates outside reactive follicular centers stained with (A) CD20, (B) CD79, and (C) bcl2. A prominent reactive T-cell infiltrate, stained with (D) CD3, obscured the neoplastic B-cell infiltrate. Plasma cells were monotypic, (E) κ: (F) λ ratio > 5:1 (cd20 stain, 25x; cd79 stain, 25x; bcl2 stain, 25x; cd3 stain, 25x; κ stain, 200x; λ stain, 200x)

A

C

E

B

D

F


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reactive small lymphocytes that can be so abundant as to obscure the neoplastic infiltrate (T-cell rich B-cell lymphoma) (9, 11).

Apart from this conventional variant of PCMZL there are cases characterized by a predominance of lympho-plasmacytoid lymphocytes, small lymphocytes and plasma cells (lymphoplasmacytic variant of PCMZL), and cases characterized by a predominance of plasma cells (plasmacytic variant of PCMZL) (14). Also, there are rare reported cases with predominance of blasts.

Given the clinical and histologic diagnostic difficul-ties, immunohistochemistry and molecular studies are crucial to arriving at the correct diagnosis. Immu-nohistochemically, the tumour cells forming nodules outside lymphoid follicles express CD20, CD79a and Bcl-2 and are negative for Bcl-6, CD5 and CD10 (1). The neoplastic infiltrate usually shows either κ or λ light chain restriction. Reactive follicles are positive for Bcl-6 and CD10 and negative for Bcl-2.A monoclonal rearrangement of the immunoglobulin heavy chain (JH) gene can be detected in most cases (15).

Translocation t(14;18)(q32;q21)/IgH-malt1, t(3;14)(p14;q32) involving IgH and FoxP1 genes has been reported in a minority of cases (16).

The association of PCMZL with B. burgdorferi has been observed in some European cases, especially in the lyphoplasmacytic variant of it (17, 18).

In general, patients with PCMZL have an excel-lent prognosis with an estimated 5 year survival of almost 100%(2).Dissemination to extracutaneous sites is exceedingly rare. However, cases with mul-tiple lesions have a tendency to recur in the skin af-tertreatment, regardless of the method used (8). This

was also the case with our patient. For solitary le-sions or localized disease, the recommended treat-ment is surgical excision, radiotherapy or combina-tion of these methods. No significant differences were observed between surgery and radiotherapy, but surgery alone was associated with more fre-quent recurrences at the initial site (8). Antibiother-apy is the treatment of choice for cases associated with B. burgdorferi infection and for cases with lym-phoplasmacytic predominance. Other treatment modalities such as IFNα, rituximab, chlorambucil, and corticosteroids may be of benefit in cases with multifocal skin lesions.

ConclusionsThe diagnosis of PCMZL can be very difficult es-

pecially when presenting with unusual features like spontaneous resolution and formation of anetodermic scars. In the absence of large tumors, presentation with papular and small nodular lesions can be misleading as these lesions may simulate inflammatory processes or benign conditions. Histologically, the reactive T-cell infiltrate can be so abundant that the true neoplastic B-cell infiltrate can be overlooked. Hence, integration of all clinical, histological, immunohistochemical and molecular data is critical in establishing the correct di-agnosis and initiation of appropriate treatment.

1. Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, Ralfkiaer E, Chimenti S, Diaz-Perez JL, Duncan LM, Grange F, Harris NL, Kempf W, Kerl H, Kurrer M, Knobler R, Pimpinelli N, Sander C, Santucci M, Sterry W, Vermeer MH, Wechsler J, Whittaker S, Meijer CJ. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; (105): 3768–85.2. Fink-Puches R, Chott A, Ardigó M, Simonitsch I, Ferrara G, Kerl H, Cerroni L. The spectrum of cutaneous lymphomas in patients less than 20 years of age. PediatrDermatol. 2004; 21:525–533.3. Park MY, Jung HJ, Park JE, Kim YC. Pediatric primary cutaneous marginal zone B-cell lymphoma treated with intralesional rituximab. Eur J Dermatol. 2010;20:533–534.4. Hoefnagel JJ, Vermeer MH, Jansen PM, Heule F, van Voorst Vader PC, Sanders CJ, Gerritsen MJ, Geerts ML, Meijer CJ, Noordijk EM, Willemze R. Primary cutaneous marginal zone B-cell lymphoma: clinical and therapeutic features in 50 cases. Arch Dermatol. 2005;141(9):1139-45.5. Brenner I, Roth S, Puppe B, Wobser M, Rosenwald A, Geissinger E.Primary cutaneous marginal zone lymphomas with plasmacytic differentiation show frequent IgG4 expression. Mod Pathol. 2013;26(12):1568-76.6. Cerroni L, Signoretti S, Höfler G, Annessi G, Pütz B, Lackinger E, Metze D, Giannetti A, Kerl H. Primary cutaneous marginal zone B-cell lymphoma: a recently described entity of low-grade malignant cutaneous B-cell lymphoma. Am J SurgPathol 1997; (21): 1307–15.7. Child FJ, Woollons A, Price ML, Calonje E, Russell-Jones R. Multiple cutaneous immunocytoma with secondary anetoderma: a report of two cases. Br J Dermatol 2000; (143): 165–70.8. Servitje O, Muniesa C, Benavente Y, Monsálvez V, Garcia-Muret MP, Gallardo F, Domingo-Domenech E, Lucas A, Climent F, Rodriguez-Peralto JL, Ortiz-Romero PL, Sandoval J, Pujol RM, Estrach MT. Primary cutaneous marginal zone B-cell lymphoma: response to treatment and disease-free survival in a series of 137 patients. J Am AcadDermatol. 2013;69(3):357-65.9. Sander CA1, Kaudewitz P, Kutzner H, Simon M, Schirren CG, Sioutos N, Cossman J, Plewig G, Kind P, Jaffe ES. T-cell-rich B-cell lymphoma presenting in skin. A clinicopathologic analysis of six cases. J CutanPathol. 1996; 23(2):101-8.

10. Rijlaarsdam JU, van der Putte SC, Berti E, Kerl H, Rieger E, Toonstra J, Geerts ML, Meijer CJ, Willemze R. Cutaneous immunocytomas: a clinicopathologic study of 26 cases. Histopathology. 1993; 23(2):117-25.11. Cerroni L, Gatter K, Helmut K. Granulomatous mycosis fungoides/granulomatous slack skin. In: Cerroni L, Gatter K, Helmut K (eds). Skin Lymphoma: The Illustrated Guide. Section 1, Cutaneous NK/T-cell lymphomas. 3rd edition, Wiley-Blackwell, Oxford, Hoboken, 2009, 141-155.12. Gerami P, Wickless SC, Rosen S, Kuzel TM, Ciurea A, Havey J, Guitart J. Applying the new TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome in primary cutaneous marginal zone lymphoma. J Am AcadDermatol. 2008;59(2):245-54.]13. Gerami P, Wickless SC, Querfeld C, Rosen ST, Kuzel TM, Guitart J. Cutaneous involvement with marginal zone lymphoma. J Am AcadDermatol. 2010;63(1):142-514. Kiyohara T, Kumakiri M, Kobayashi H, Nakamura H, Ohkawara A. Cutaneous marginal zone B-cell lymphoma: a case accompanied by massive plasmacytoid cells. J Am AcadDermatol. 2003;48(5 Suppl):S82-515. Child FJ, Woolford AJ, Calonje E, Russell-Jones R, Whittaker SJ. Molecular analysis of the immunoglobulin heavy chain gene in the diagnosis of primary cutaneous B-cell lymphoma. J Invest Dermatol 2001; (117): 984–9.16. Palmedo G1, Hantschke M, Rütten A, Mentzel T, Kempf W, Tomasini D, Kutzner H. Primary cutaneous marginal zone B-cell lymphoma may exhibit both the t(14;18)(q32;q21) IGH/BCL2 and the t(14;18)(q32;q21) IGH/MALT1 translocation: an indicator for clonal transformation towards higher-grade B-cell lymphoma? Am J Dermatopathol. 2007;29(3):231-6.17. Goodlad JR, Davidson MM, Hollowood K, Batstone P, Ho-Yen DO. Borreliaburgdorferi-associated cutaneous marginal zone lymphoma: a clinicopathological study of two cases illustrating the temporal progression of B. burgdorferi-associated B-cell proliferation in the skin. Histopathology. 2000;37(6):501-8.18. Ponzoni M1, Ferreri AJ, Mappa S, Pasini E, Govi S, Facchetti F, Fanoni D, Tucci A, Vino A, Doglioni C, Berti E, Dolcetti R. Prevalence of Borreliaburgdorferi infection in a series of 98 primary cutaneous lymphomas. Oncologist. 2011; 16(11):1582-8.

BibliographyBibliography

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