6noopenopenBonin, Serena; Stinco, Giuseppe; Patriarca, Maria Martina; Trevisini, Sara; Di Meo, Nicola; Trevisan, GiustoBonin, Serena; Stinco, Giuseppe; Patriarca, Maria Martina; Trevisini, Sara; Di Meo, Nicola; Trevisan, Giust

Giuseppe Stinco

Giusto Trevisan

Maria Martina Patriarca

Nicola di Meo

Sara Trevisini

Serena Bonin

Indian Journal of Dermatology, Venereology and Leprology

Bonin, Serena

Patriarca, Maria Martina

Trevisini, Sara

Di Meo, Nicola

Trevisan, Giusto

STINCO, Giuseppe

Archivio istituzionale della ricerca - Università degli Studi di Udine

Home   LETTER TO THE EDITOR - OBSERVATION LETTER [Download PDF]  Year : 2016  |  Volume : 82  |  Issue : 1  |  Page : 81-84Could co-infection with Anaplasma play a role in Borrelia-associated primarycutaneous marginal zone B-cell lymphomas?Serena Bonin1, Giuseppe Stinco2, Maria Martina Patriarca2, Sara Trevisini1, Nicola di Meo1, Giusto Trevisan1,  1 Department of Medical Sciences, Unit of Dermatology, University of Trieste, Trieste, Italy2 Department of Experimental and Clinical Medicine, Institute of Dermatology, University of Udine, Udine, ItalyCorrespondence Address:Serena BoninDepartment of Medical Sciences, Unit of Dermatology, Cattinara Hospital, Strada di Fiume, 447, 34149 Trieste ItalyHow to cite this article:Bonin S, Stinco G, Patriarca MM, Trevisini S, di Meo N, Trevisan G. Could co-infection with Anaplasma play a role in Borrelia-associated primary cutaneous marginal zone B-cell lymphomas?.Indian J Dermatol Venereol Leprol 2016;82:81-84How to cite this URL:Bonin S, Stinco G, Patriarca MM, Trevisini S, di Meo N, Trevisan G. Could co-infection with Anaplasma play a role in Borrelia-associated primary cutaneous marginal zone B-cell lymphomas?. Indian J Dermatol Venereol Leprol [serial online] 2016[cited 2016 Nov 9 ];82:81-84 Available from: http://www.ijdvl.com/text.asp?2016/82/1/81/171011Full TextSir,Borrelia burgdorferi, the causative agent of Lyme disease, infects humans through Ixodes tick bites. In Europe,several Borrelia strains have been associated with primary cutaneous B-cell lymphoma, in particular, cutaneousmarginal zone B-cell lymphoma.[1] It has already been reported that clinical regression of B. burgdorferi-associated cutaneous marginal zone B-cell lymphomas did not occur after specific antimicrobial therapyalthough polymerase chain reaction (PCR) analysis for Borrelia became negative.[2] Persistence of thelymphoma could be related to host factors or another unknown antigenic stimulation unresponsive toantimicrobial treatment. Significant co-infections in Lyme disease could be due to microorganisms transmittedby the same vector. In our province, (Trieste, North-Eastern Italy) co-infection of Borrelia with Anaplasmaphagocytophilum and Rickettsia helvetica is rather frequent: 15 (3.5%) patients tested positive to Borrelia andA. phagocytophilum during 2013. To further investigate this association, we carried out a study investigatingthe presence of co-infections in patients with proven Borrelia-related cutaneous marginal zone B-celllymphoma.We report on four consecutive patients with the morphological features of primary cutaneous marginal zone B-cell lymphoma.The first three patients participating in this study had previously been reported.[3] Patients were investigatedfor the presence of B. burgdorferi, A. phagocytophilum and R. helvetica with conventional serology and forBorrelia also by PCR.[3]A 62-year-old man presented with cutaneous marginal zone B-cell lymphoma characterized by pink, non-tender, pruritic skin nodules on his right inner thigh [Figure 1]. Biopsy showed a nodular lymphoid proliferationof small lymphocytes within the dermis. Clonality of B lymphocytes was revealed by Ki67 staining. Bothserologic tests (ELISA IgG and Western blot) and PCR assays for B. burgdorferi were positive. Serologicanalysis for IgG antibodies to A. phagocytophilum was positive while the test was negative for R. helvetica.{Figure 1}A 46-year-old woman presented with five itchy erythematous, non-tender and painless papules on her right leg[Figure 1]. Routine laboratory investigations were normal. Biopsy of the lesion showed a dense nodularinfiltrate of lymphocytes separated from the epidermis by a Grenz zone [Figure 2].{Figure 2}B-cell clonality was assessed by lambda and kappa light chain immunohistochemistry in frozen sections [Figure2]. In view of these findings and the immunophenotype, a diagnosis of cutaneous marginal zone B-celllymphoma was made.Polymerase chain reaction assays for Borrelia DNA were positive both from biopsy and peripheral blood [Figure2]. Serological investigations for B. burgdorferi and R. helvetica were negative while A. phagocytophilumserology proved to be IgG positive.A healthy 35-year-old man developed an infiltrated erythematous patch on his right leg [Figure 1]. The patienthad a previous history of Lyme disease.[3] Skin biopsy showed a top-heavy atypical lymphocytic infiltrationinvolving the dermis and infiltrating the upper portion of subcutaneous fat. The characteristic Grenz zone ofnormal collagen was evident.Polymerase chain reaction assays for Borrelia DNA were positive both from biopsy and peripheral blood.Serology for Borrelia was negative, but it was positive for A. phagocytophilum and R. helvetica.A 36-year-old man developed a nodular erythematous lesion on his back [Figure 1] which was excised and adiagnosis of marginal cell lymphoma was made. Later, five small nodular lesions appeared around the surgicalscar. Results of routine laboratory examinations were normal. The biopsy showed a top-heavy atypicallymphocytic infiltration with a Grenz zone.Polymerase chain reaction assays for Borrelia DNA were positive both from peripheral blood and biopsy.Serology for Borrelia and A. phagocytophilum was positive, but negative for R. helvetica.All four patients underwent antibiotic treatment with doxycycline, 100 mg twice a day for 20 days. Lymphomaswere treated in all patients with electrochemotherapy as already reported.[3] A complete response wasobtained in all patients after 4 weeks. During the follow-up period, three patients relapsed as reported in[Table 1].{Table 1}The association between chronic infection with Borrelia and the development of cutaneous marginal zone B-celllymphoma is conceptually and clinically similar to the one seen in B-cell lymphomas of the stomach, aproportion of which are associated with infection by Helicobacter pylori. Similarly, the suspectedpathophysiology for the induction of lymphoma by Borrelia is chronic antigen-dependent immunostimulationtriggering sustained lymphoid proliferation with oligoclonal and ultimately monoclonal B-cell selection.[4] Ithas been hypothesized that H. pylori eradication leads to the disappearance of intratumoral H. pylori specific T-cells and to lymphoma regression.[2] In the same way, complete regression of lymphoma lesions has beenseen after antibiotic treatment for B. burgdorferi.[5]Patients with Borrelia- related cutaneous marginal zone B-cell lymphoma unresponsive to antibiotic treatmentmay be subjected to other chronic antigen stimulation.[1] We focused on A. phagocytophilum and R. helveticaco-infections which are the most frequent microorganisms co-infected with B. burgdorferi by Ixodes ricinus inour area. We were unable to find any previous reports of the association between primary cutaneous B-celllymphoma and other infections concurrent with Borrelia. Our data show that co-infections occur in somepatients with Borrelia-related lymphomas. The impact of concurrent infections in Lyme disease has not yetbeen fully clarified because multiple infections are difficult to analyse as it is usually impossible to establish theinfection that plays a predominant role in the pathological process due to frequent overlapping of clinicalsymptoms caused by borreliosis and co-infections. We speculate that in case of Borrelia- related primarycutaneous B-cell lymphoma, multiple infections may influence the immune system by decreasing co-surveillance and favoring a chronic B-cell stimulation towards an oligo/monoclonal B-cell proliferation. Thismay result in resistance to antibiotic therapy or in a persisting and self-maintaining disease driven by unknownantigenic stimulation even after the eradication of bacteria.Our study had limitations due to lack of facility to detect A. phagocytophilum in tissue biopsy to demonstratethe co-infection and that Borrelia infection was not confirmed by serology in two patients. Nevertheless, tostrengthen our data, three distinct PCR analyses have been carried out for Borrelia in both blood and biopsiesfor all patients. We were also limited by our small sample size and single geographic area. However, our studystresses on performing more comprehensive analyses in order to establish if A. phagocytophilum shouldalways be included in the serologic testing of patients with a history of tick bite, in patients with Lyme diseaseand B. burgdorferi-related cutaneous marginal zone B-cell lymphoma since co-infection could be more frequentthan so far suspected.AcknowledgmentsThis study was partially supported by the FRA2012 grant from the University of Trieste. The authors wouldthank Dr. Diego Signoretto and Dr. Eugenio Leonardo who provided us with histological images and details ofthe cases and Dr. Daniela Casotto who gave us information about co-infections of Borrelia and A.phagocytophilum in our population during 2013. The authors are also grateful to Dr. Valentina Melita for thelanguage revision of the manuscript. Financial support and sponsorshipThis study was partially supported by the FRA2012 grant from the University of Trieste.Conflicts of interestThere are no conflicts of interest.References1 Ponzoni M, Ferreri AJ, Mappa S, Pasini E, Govi S, Facchetti F, et al. Prevalence of Borrelia burgdorferiinfection in a series of 98 primary cutaneous lymphomas. Oncologist 2011;16:1582-8.2 Du MQ. MALT lymphoma: Recent advances in aetiology and molecular genetics. J Clin Exp Hematop2007;47:31-42.3 Gatti A, Stinco G, Trevisini S, di Meo N, Signoretto D, Leonardo E, et al. Electrochemotherapy as a noveltreatment for primary cutaneous marginal zone B-cell lymphomas. Dermatol Ther 2014;27:244-7.4 Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, et al. WHO-EORTC classification forcutaneous lymphomas. Blood 2005;105:3768-85.5 Sokol L, Naghashpour M, Glass LF. Primary cutaneous B-cell lymphomas: Recent advances in diagnosisand management. Cancer Control 2012;19:236-44. 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Could co-infection with Anaplasma play a role in Borrelia-associated primary cutaneous marginal zone B-cell lymphomas?

Background: Borrelia burgdorferi has been associated with primary cutaneous B-cell lymphoma, in particular with cutaneous marginal zone B cell lymphoma. Ixodes ticks, which are vectors of Borrelia burgdorferi, can also transmit many other microorganisms such as Anaplasma phagocytophilum and Rickettsia helvetica. Nowadays data on the frequency of these co-infections are still conflicting, but in our geographical area (north-eastern of Italy) they appear rather frequently.
Aim: To investigate the presence of co-infections with Anaplasma phagocytophilum and Rickettsia helvetica, in patients with proven Borrelia burgdorferi-related cutaneous marginal zone B cell lymphoma. 
Methods: Four consecutive patients with a histopathological diagnosis of cutaneous marginal zone B cell lymphoma were investigated for the presence of Borrelia burgdorferi with conventional serology and with PCR, and for the presence of  Anaplasma phagocytophilum and Rickettsia helvetica with conventional serology.
Results: Serologic test for Borrelia burgdorferi was positive in 2 cases, while PCR assays for Borrelia burgdorferi performed on DNA from the biopsy and peripheral blood was positive in all four patients. Serologic analysis for Rickettsia helvetica was positive in one patient, while serologic analysis for Anaplasma phagocytophilum was positive in all patients.
Conclusions: Our case series have revealed a co-infection between Borrelia burgdorferi and Anaplasma phagocytophilum in all patients with cutaneous marginal zone B cell lymphoma.  Therefore more comprehensive analyses on the co-existence of Anaplasma phagocytophilum infection should be performed in patients with Borrelia burgdorferi-related cutaneous marginal zone B cell lymphoma

BONIN, Serena

STINCO, GIUSEPPE

TREVISINI, SARA

DI MEO, NICOLA

TREVISAN, GIUSTO

Patriarca, Mm

Archivio istituzionale della ricerca - Università di Trieste

Could co-infection with anaplasma play a role in borrelia-associated Primary Cutaneous Marginal Zone B-Cell Lymphomas?

Could co-infection with Anaplasma play a role in Borrelia-associated primary cutaneous marginal zone B-cell lymphomas?

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