Gerlini, G.

Massi, Daniela

Mori, M.

Pimpinelli, Nicola

English

Florence Research

 208 © 2003 European Academy of Dermatology and Venereology CA SE REPOR T JEADV  (2003)  17 , 208–212 Blackwell Science, LtdSpecific immune therapy-related cutaneous B-cell pseudolymphoma with following dissemination G   Gerlini,    M   Mori,    D   Massi,à   N   Pimpinelli * Departments of  † Dermatological Sciences and  ‡ Human Pathology and Oncology, University of Florence Medical School, Florence, Italy.  * Corresponding author, Department of Dermatological Sciences, University of Florence, Via degli Alfani, 37, Firenze, Italy, tel. +39 055 2344422; fax +39 055 2758757; E-mail: pimpi@unifi.it or nicopimpi@interfree.it ABSTRACT We report two cases of cutaneous B-cell pseudolymphoma (PCBCL) induced by intradermal antigeninjections for specific immune therapy (SIT). In both cases, the lesions had first developed on the area ofinjection; years later, new lesions appeared far from the original site. The histological, immunohistochemical,and molecular findings of the lesions showed features consistent with the diagnosis of PCBCL in both cases.In particular, the staining for sIg light chains showed a polyclonal pattern, and the molecular analysis byreverse transcriptase-polymerase chain reaction (RT-PCR) and Southern blot showed a germ-line configu-ration of the Ig heavy chain genes. While the development of PCBCL related to a specific stimulus is wellknown and widely reported, the development of histologically and immunohistologically identical lesionsfar from the injection site is definitely worthy of note. This behaviour might be due to the presence ofretained antigens in the injection site. This chronic antigenic stimulation could induce the progressiveselection – and subsequent dissemination – of antigen-specific B cell clones. Key words: pseudolymphoma, B-cell, skin, specific immune therapy  Received: 23 January 2002, accepted 12 June 2002 Introduction Cutaneous B-cell pseudolymphoma (PCBCL), otherwiseknown as cutaneous lymphoid hyperplasia (CLH), is a reactiveB-cell hyperplasia that clinically and histologically mimicscutaneous B-cell lymphoma (CBCL). 1–4  Both primary cutaneousB-cell lymphoma (CBCL) and PCBCL share indolent clinicalcourse and good response to non-aggressive treatment,therefore, these features are not crucial in the differentialdiagnosis. According to a widely accepted opinion, the only keydiagnostic criteria to date are the demonstration of clonality (byimmunohistochemistry and/or molecular analysis) and/or thecorrelation with known environmental stimuli: insect orarthropod bites, tattoos, infection by  Borrelia burgdorferi . 5–10 In these latter conditions, skin lesions usually arise on the areaaffected by the specific trigger.In this paper, we report two cases of PCBCL induced by sub-cutaneous antigen injections (specific immune therapy, SIT) inwhich, years later, the dissemination of lesions far from theinjection site did occur. Case reports Case 1 A 30-year-old woman presented with erythemato-cyanoticplaques and nodules located on the lateral surface of both arms(fig. 1a), left buttock and left thigh (fig. 1b). The lesions of thearms had been present for 10 years, and developed soon afterSIT by the coalescence of small papules and nodules. Thepatient had a family and personal history of atopy (rhinitis,atopic dermatitis). Total IgE and specific IgE for Parietaria andGraminaciae were increased, and prick tests for these latterallergens were positive. In addition, the patient was sensitized tonickel sulphate. The lesions on the left thigh and buttock haddeveloped approximately 2 years before our observation.A previous biopsy, taken from the right arm in another hospital,showed a dermal nodular lymphohystiocytic infiltrate withtypical lymphoid follicles. A complete staging was carried out,including bone marrow biopsy, without any pathologicfindings. New samples from both left arm and left thigh Cutaneous B-cell pseudolymphoma 209 © 2003 European Academy of Dermatology and Venereology  JEADV  (2003)  17 , 208–212 lesions were taken and processed for routine histology, immu-nohistochemistry (fixed/embedded and frozen tissue), andmolecular analysis. The histology showed the same pattern inboth examined lesions: nodular and diffuse lymphohystiocyticinfiltrate in the superficial and mid dermis, with presence ofnumerous typical reactive lymphoid follicles (figs 2,3). Immu-nohistochemical staining on paraffin sections showed that reac-tive follicles were mostly CD20+, although they occasionallyharboured scattered CD3+ T-lymphocytes (fig. 4). The inter-follicular areas were rich in T-lymphocytes (fig. 4), with isolatedor small groups of B cells and CD68+ histiocytes. The reactivegerminal centres were bcl-2 negative, contrasting with the pos-itive cells in the mantles and interfollicular areas (fig. 5). Theimmunohistochemical analysis (APAAP technique) on frozensections showed a mixed B- and T-cell infiltrate, with a distinctcompartmentalization: nodular aggregates with typical featuresof secondary lymphoid follicles (CD22+ B cells with a CD5-/CD10+ phenotype associated with CD35+ follicular dendriticcells in the germinal centre; in the mantle, CD22+ B cells withCD5+/CD10- [mantle cell] or CD5-/CD10- [marginal cell]phenotype) were irregularly surrounded by ‘interfollicular’areas in which CD3+, CD4+ T-cells and CD22+, CD5-, CD10-B cells were strictly intermingled. The staining for sIg lightchains showed a polyclonal pattern (kappa/lambda ratio 4 : 1)in both areas. This finding was essential to establish the diagno-sis of PCBCL. The molecular analysis by reverse transcriptase–polymerase chain reaction (RT-PCR) and Southern blot showeda germ-line configuration of the immunoglobulin heavy chaingenes. Case 2 A 47-year-old female presented in our Department withpigmented plaques on the lateral surface of both arms, thighs,buttocks and lower back. The lesions of the arms haddeveloped, initially as grouped papules and small nodules, soonafter SIT performed 18 years before. One year later, due to thepersistence of such lesions, the patient was treated in anotherfig. 1 (a) Patient 1. Erithematous and pigmented plaque on the lateralsurface of left arm, site of previous (10 years) specific immune therapy.(b) Patient 1. Erythematous plaque of the left thigh. This and other skinlesions (left buttock) had developed approximately 8 years after that shownin fig. 1.fig. 2 Patient 1, left thigh. Nodular and diffuse lymphohystiocytic infiltratein the upper-mid reticular dermis, with presence of typical reactive lymphoidfollicles (H&E, original magnification ·  40). 210 Gerlini  et al . © 2003 European Academy of Dermatology and Venereology  JEADV  (2003)  17 , 208–212 centre by local radiotherapy with no improvement. To follow,she was treated by intralesional corticosteroids, with eventu-ation in thinner, pigmented plaques. The lesions on the thighs,buttocks and back had appeared about 2 years later as itching,pigmented and infiltrated plaques. The patient reported a20-year-history of rhinitis and conjunctivitis induced byGraminaciae. Total IgE were highly increased (963 UI/mL),as well as specific IgE for Graminaciae. Prick tests were alsopositive.A biopsy taken in another centre from lesions of the left armshowed a nodular and diffuse lymphohystiocitic infiltratecomposed by T and B cells, these latter organized in typicallymphoid follicles with germinal centres in the mid and deepdermis. New biopsy specimens taken from both right arm andback were processed for histology, immunohistochemistryand molecular analysis. The histology showed the samepattern in both examined lesions: nodular lymphohystiocyticinfiltrate in the superficial and mid dermis, with no evidence ofhistologically typical lymphoid follicles. The immunohistochemicalanalysis on frozen sections showed a single typical, secondarylymphoid follicle, irregularly surrounded by an infiltrate whosefeatures were not different from those observed in the interfol-licular areas in case 1. The staining for sIg light chains showed apolyclonal pattern (kappa/lambda ratio 3 : 1) in both follicularand perifollicular areas. The molecular analysis by RT-PCRand Southern blot showed a germ-line configuration of theimmunoglobulin heavy chain genes. Discussion The interest of our cases essentially concerns the occurrence ofnew lesions far from the injection site of SIT some years after thedevelopment of primary lesions at the injection site. Indeed,cases of PCBCL resulting from antigen injections (pneumo-allergens) for SIT and limited to the injection site have beenpreviously reported. 11,12  In the cases reported herein, secondarylesions did not show any histological, immunohistological andmolecular difference as compared to the primary ones.fig. 3 Reactive lymphoid follicles were composed of a central, pale staininggerminal centre surrounded by a corona of small lymphocytes comprisingthe mantle zone (H&E, original magnification ·  100).fig. 4 Immunohistochemical stain for CD3 shows that reactive lymphoid fol-licles occasionally harbour scattered CD3+ T-lymphocytes. These latter areclearly prevalent in interfollicular areas (APAAP, original magnification ·  100). Cutaneous B-cell pseudolymphoma 211 © 2003 European Academy of Dermatology and Venereology  JEADV  (2003)  17 , 208–212 We might argue that SIT antigen(s) produce(s) a progressiveselection of antigen-specific B cell clones, which subsequentlyspread from regional nodes to peripheral blood. These cells,which reasonably retain their skin-homing properties, can berecruited in the skin sites of contact with these airborne allergens.The above hypothesis, i.e. continuous antigenic stimulusproducing selection and subsequent ‘dissemination’ of antigen-specific B cell clones, could explain the occurrence of dissemi-nated B-cell pseudolymphoma. 13,14  Conversely, the casesreported here do not support the hypothesis, suggested anddebated in the literature, of the progression of true PCBCL toCBCL. 6,15–17  In this regard, the development of CBCL related to Borrelia burgdorferi  infection 9,10  is also particularly worthy ofattention, due to close similarity between the concepts of Helicobacter pylori  infection  fi  acquired MALT (Mucosa-Associated Lymphoid Tissue)/MALT gastritis  fi  MALTlymphoma on one hand, and of  Borrelia burgdorferi  infection fi  acquired SALT (Skin-Associated Lymphoid Tissue)/PCBCL fi  CBCL. 18–20  The hypothesis of a different sequential develop-ment of immune events related to SIT as compared to bacterialinfections like those from  Borrelia burgdorferi  and  Helicobacterpylori , with a lower likelihood to eventuate into (immune)dysplasia and neoplasia, can be reasonably suggested.Speculations apart, it is a fact that we did not observe any his-tologic, immunohistologic and/or molecular signs of aberrancyin the lesions which had developed years after the primary onesfar from the injection site, e.g. dendritic cells ‘skipping’ thegerminal centre of reactive follicles, ‘invasion’ of reactive folliclesby neoplastic cells of the interfollicular areas, or clonalrearrangement of Ig heavy chains. 5,6,15–17,19,20References 1 Burg G, Braun Falco O.  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Cutaneous lymphoma: a clinically relevant classification.  Int J Dermatol  1993;  32 : 695–700.8 Willemze R, Kerl H, Sterry W  et al.  EORTC classification for cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment.  Blood  1997;  90 : 354–371.9 Garbe C, Stein H, Dienemann D, Orfanos CE. Borrelia burgdorferi-associated cutaneous B-cell lymphoma: clinical and immunohistological characterization of four cases.  J Am Acad Dermatol  1994;  24 : 584–589.10 Cerroni L, Zuchling N, Putz B, Kerl H. Infection by Borrelia burgdorferi and cutaneous B-cell lymphoma.  J Cutan Pathol  1997;  24 : 457–461.11 Bernstein H, Shupack J, Ackerman B. Cutaneous pseudolymphoma resulting from antigen injections.  Arch Dermatol  1974;  110 : 756–757.12 Lanzafame S, Micali G. Cutaneous lymphoid hyperplasia (pseudolymphoma) secondary to vaccination.  Pathologica  1993;  85 : 555–561.fig. 5 Immunohistochemical stain for Bcl-2 well distinguishes germinal cen-tre cells from mantle zone B lymphocytes and adjacent T lymphocytes in theinterfollicular areas, which strongly express this antigen (APAAP, originalmagnification ·  200). 212 Gerlini  et al . © 2003 European Academy of Dermatology and Venereology  JEADV  (2003)  17 , 208–21213 Torne R, Roura M, Umbert P. Generalized cutaneous B-cell pseudolymphoma. Report of a case studied by immunohistochemistry.  Am J Dermatopathol  1989;  11 : 544–548.14 Zackheim HS, LeBoit PE, Stein KM. Disseminated recurrent papular B-cell pseudolymphoma.  Int J Dermatol  1997;  36 : 614–618.15 Nakayama H, Mihara M, Shimao S. Malignant transformation of lymphoadenosis benigna cutis: a possibly transformed case and B-cell lymphoma.  Int J Dermatol  1987;  14 : 266–269.16 Wood GS, Ngan B, Tung R  et al.  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SPECIFIC IMMUNE THERAPY-RELATED CUTANEOUS b-CELL PSEUDOLYMPHOMA WITH FOLLOWING DISSEMINATION

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SPECIFIC IMMUNE THERAPY-RELATED CUTANEOUS b-CELL PSEUDOLYMPHOMA WITH FOLLOWING DISSEMINATION

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