HHV8-Positive Castleman Disease and in Situ Mantle Cell Neoplasia Within Dermatopathic Lymphadenitis, in Longstanding Psoriasis

Home , Castleman disease, Perugia, Terni

diagnostics

Interesting Images HHV8-Positive Castleman Disease and In Situ Mantle Cell Neoplasia within Dermatopathic Lymphadenitis, in Longstanding Psoriasis

Magda Zanelli 1,* , Luca Stingeni 2 , Maurizio Zizzo 3,4, Giovanni Martino 5, Francesca Sanguedolce 6, Andrea Marra 7, Barbara Crescenzi 8, Stefano A. Pileri 9 and Stefano Ascani 5

1 Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42112 Reggio Emilia, Italy 2 Dermatology Section, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy; [email protected] 3 Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; [email protected] 4 Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41121 Modena, Italy 5 Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy; [email protected] (G.M.); [email protected] (S.A.) 6 Pathology Unit, Policlinico Riuniti, University of Foggia, 71122 Foggia, Italy; [email protected] 7 Centre of Hemato-Oncology Research (CREO), Institute of Hematology, University and Hospital of Perugia, 06129 Perugia, Italy; [email protected] 8 Laboratory of Molecular Medicine, CREO, Azienda Ospedaliera di Perugia, University of Perugia, 06129 Perugia, Italy; [email protected] Citation: Zanelli, M.; Stingeni, L.; 9 Haematopathology Division, European Institute of Oncology—IEO IRCCS, 20141 Milan, Italy; Zizzo, M.; Martino, G.; Sanguedolce, [email protected] F.; Marra, A.; Crescenzi, B.; Pileri, * Correspondence: [email protected]; Tel.: +39-0522-296372; Fax: +39-0522-296945 S.A.; Ascani, S. HHV8-Positive Castleman Disease and In Situ Mantle Abstract: A 73-year-old man presented with multiple lymphadenopathy. He had a 20-year history Cell Neoplasia within Dermatopathic of palmoplantar psoriasis evolved to a diffuse erythrodermic picture in the last two years. Topic Lymphadenitis, in Longstanding and systemic medications including prednisolone, acitretin, anti-IL17 (ixekizumab), TNF inhibitor Psoriasis. Diagnostics 2021, 11, 1150. (adalimumab), anti-IL23 (guselkumab), methotrexate, cyclosporine, and phosphodiesterase 4 in- https://doi.org/10.3390/ diagnostics11071150 hibitor (apremilast) were ineffective. Repeated skin biopsies excluded mycosis fungoides, confirming psoriasis; molecular analysis of T-cell receptor genes ruled out clonality. The axillary lymph node Academic Editor: Chyi-Chia histology documented a dermatopathic lymphadenitis, often associated with chronic cutaneous Richard Lee inflammatory diseases. At an accurate morphological evaluation, features of HHV8-positive multicentric Castleman disease were observed. Moreover, in a few follicles, in situ mantle cell neoplasia Received: 31 May 2021 was identified. The translocation t(11;14)(q13;q32), characteristic of mantle cell lymphoma, and the Accepted: 23 June 2021 monoclonal IGH gene rearrangement were present. HHV8 DNA was identified on plasma sample. Published: 24 June 2021 Multicentric Castleman disease in psoriatic patients is a rare event and it might be favored by the immunomodulatory treatment in longstanding psoriasis. Multicentric Castleman disease patients are Publisher’s Note: MDPI stays neutral predisposed to developing simultaneous or subsequent lymphoma. In situ mantle cell neoplasia often with regard to jurisdictional claims in behaves indolently, although it may progress to overt mantle cell lymphoma. Rituximab achieved published maps and institutional affil- a good control of psoriasis. Unfortunately, the patient developed Staphylococcus aureus sepsis for iations. which he is currently on antibiotic therapy.

Keywords: psoriasis; castleman disease; HHV8; mantle cell; lymphoma; dermatopathic lympadenitis

Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article A 73-year-old man presented with multiple superﬁcial and profound lymphadenopa- distributed under the terms and thy. The patient had a 20-year history of palmoplantar psoriasis. In the last two years he conditions of the Creative Commons developed a diffuse erythrodermic picture (Figure1). Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Diagnostics 2021, 11, 1150. https://doi.org/10.3390/diagnostics11071150 https://www.mdpi.com/journal/diagnostics Diagnostics 2021, 11, 1150 2 of 5 DiagnosticsDiagnostics 20212021,, 1111,, xx FORFOR PEERPEER REVIEWREVIEW 22 ofof 55

Figure 1. Clinical image showing a diffuse erythrodermic picture of psoriasis. FigureFigure 1.1.Clinical Clinical imageimage showingshowing aa diffusediffuse erythrodermicerythrodermic picture picture of of psoriasis. psoriasis.

TopicTopicTopic and andand systemic systemicsystemic medications medicationsmedications includingincludingincluding prednisolone,prprednisolone,ednisolone, acitretin,acitretin, anti-IL17anti-IL17 (ixeki- (ixek-(ixeki- izumab),zumab),zumab), TNFTNFTNF inhibitor inhibitorinhibitor (adalimumab), (adali(adalimumab),mumab), anti-IL23 anti-IL23anti-IL23 (guselkumab), (guselkumab),(guselkumab), methotrexate, methotrexate,methotrexate, cyclosporine, cyclospor-cyclospor- andine,ine, phosphodiesterase andand phosphodiesterasephosphodiesterase 4 inhibitor 44 inhibitorinhibitor (apremilast) (apremilast)(apremilast) obtained obtainedobtained little beneﬁt. littlelittle benefit.benefit. Repeated RepeatedRepeated skin biop- skinskin siesbiopsiesbiopsies ruled ruledruled out mycosis outout mycosismycosis fungoides, fungfungoides,oides, as the asas histopathology thethe histopathologyhistopathology was consistent wawass consistentconsistent with psoriasiswithwith psoriasispsoriasis and molecularandand molecularmolecular analysis analysisanalysis excluded excludedexcluded T-cell T-cellT-cell receptor receptorreceptor (TCR) (TCR)(TCR) gene clonality.genegene clonality.clonality. TheTheThe excised excisedexcised axillary axillaryaxillary lymph lymphlymph node nodenode showed showedshowed distinctive didistinctivestinctive reactive reactivereactive features featuresfeatures of dermatopathic ofof dermato-dermato- lymphadenitispathicpathic lymphadenitislymphadenitis with paracortical withwith paracorticalparacortical hyperplasia andhyperplasiahyperplasia melanin-pigmented andand melanin-pigmentedmelanin-pigmented macrophages (Figure macro-macro-2), typicallyphagesphages (Figure(Figure seen in 2),2), chronic typicallytypically cutaneous seenseen inin inﬂammatory chchronicronic cutaneouscutaneous diseases. inflammatoryinflammatory diseases.diseases.

Figure 2. High power view of dermatopathic lymphadenitis with melanin-laden macrophages (HE, FigureFigure 2.2.High High powerpower viewview ofof dermatopathicdermatopathic lymphadenitislymphadenitis withwith melanin-ladenmelanin-laden macrophagesmacrophages (HE,(HE, 400× magnification). 400400×× magniﬁcation).magnification).

Additionally,Additionally,Additionally, atrophic, atrophic,atrophic, hyalinized hyalinizedhyalinized germinal germinalgerminal centers centerscenters with withwith prominent prominentprominent penetrating penetratingpenetrating venules ven-ven- (Figureulesules (Figure(Figure3) and 3)3) interfollicular andand interfollicularinterfollicular polytypic polytypicpolytypic plasma plasmaplasma cells were cellscells noted. werewere noted.noted. Scattered ScatteredScattered Human HumanHuman Her- pesvirusHerpesvirusHerpesvirus 8 (HHV8)-positive 88 (HHV8)-positive(HHV8)-positive cells cells (Figurecells (Figure(Figure4) within 4)4) withinwithin the mantle thethe mantlemantle and interfollicular andand interfollicularinterfollicular regions re-re- weregionsgions identiﬁed. werewere identified.identified. A subtle AA subtlesubtle rim of rimrim cyclin ofof cyclincyclin D1-positive D1-positiveD1-positive mantle mantlemantle cells was cellscells disclosed waswas discloseddisclosed within withinwithin few reactive-appearingfewfew reactive-appearingreactive-appearing follicles folliclesfollicles (Figure (Figure(Figure5). 5).5).

Diagnostics 2021, 11, 1150 3 of 5 Diagnostics 2021, 11, x FOR PEER REVIEW 3 of 5 Diagnostics 2021, 11, x FOR PEER REVIEW 3 of 5

Figure 3. Hyalinized germinal centers with penetrating venules characteristic of Castleman disease Figure 3. Hyalinized germinal centers with penetrating venules characteristic of Castleman disease Figure(HE, 400× 3. Hyalinized magnification). germinal centers with penetrating venules characteristic of Castleman disease (HE,(HE, 400 400×× magniﬁcation).magnification).

Figure 4. Scattered cells positive for HHV8 immunostaining (magnification 200×). FigureFigure 4. 4.Scattered Scattered cells cells positive positive for for HHV8 HHV8 immunostaining immunostaining (magniﬁcation (magnification 200 200×).×).

These findings were consistent with HHV8-positive multicentric Castleman disease (MCD) of mixed type associated with in situ mantle cell neoplasia (isMCN). The translocation t(11;14)(q13;q32) characteristic of mantle cell lymphoma (MCL) and the monoclonal IGH gene rearrangement were identified by fluorescence in situ hybridization (FISH) analysis and molecular study, respectively. HHV8 DNA (71 copies/mL) was identified by polymerase chain reaction (PCR) on the plasma sample.

Diagnostics 2021, 11, 1150 4 of 5 Diagnostics 2021, 11, x FOR PEER REVIEW 4 of 5

Figure 5. Cyclin D1-positive cells within the mantle zone of a reactive-appearing follicle (im- Figure 5. Cyclin D1-positive cells within the mantle zone of a reactive-appearing follicle (immunos- munostain, 200× magnification). tain, 200× magniﬁcation).

TheThese patient findings received were infusionsconsistent of with the monoclonalHHV8-positive antibody multicentric rituximab Castleman (375 mg/m disease2, once(MCD) every of mixed two weeks type xassociated four doses). with Rituximab in situ mantle is also cell reported neoplasia to be(isMCN). helpful The in treating translo- MCDcation [1 t(11;14)(q13;q32)]. The treatment wascharacteristic completed of about mantle a month cell lymphoma before our (MCL) case description,and the monoclonal achiev- ingIGH good gene control rearrangement of his psoriasis. were identified Unfortunately, by fluorescence the patient in developed situ hybridization Staphylococcus (FISH) aureusanalysis sepsis, and molecular for which hestudy, is currently respectively. on antibiotic HHV8 DNA treatment. (71 copies/mL) was identified by polymeraseAccording chain to the reaction current (PCR) 2017 Worldon the Health plasma Organization sample. (WHO) classification, HHV8- positiveThe MCD patient belongs received to HHV8-associated infusions of the lymphoproliferative monoclonal antibody disorders rituximab [1– 5(375]. mg/m2, onceMCD every commonly two weeks occurs x four in doses). immunosuppressed Rituximab is patients,also reported being to often be helpful reported in intreating asso- ciationMCD [1]. with The HIV treatment infection, was but completed it may also about develop a month in HIV-negative before our case individuals, description, especially achiev- originatinging good control from HHV8-endemic of his psoriasis. regions Unfortun [1].ately, MCD the is usuallypatient negativedeveloped for Staphylococcus Epstein Barr virus,aureus whereas sepsis, for it is which strongly he is associated currently withon antibiotic Human treatment. Herpes virus 8 (HHV8) infection, detectedAccording in almost to all the HIV-positive current 2017 cases World and inHealth 50% of Organization HIV-negative (WHO) ones [1 ].classification, HHV8-positiveIt presents oftenMCD withbelongs constitutional to HHV8-associated symptoms lymphoproliferative (e.g., fever, asthenia, disorders weight [1–5]. loss), generalizedMCD commonly lymphadenopathy, occurs in splenomegalyimmunosuppressed and hepatomegaly patients, being [1 ].often Laboratory reported testsin as- revealsociation cytopenia, with HIV hypoalbuminemia, infection, but it may hypergammaglobulinemia, also develop in HIV-negative elevated individuals, serum levels espe- of inflammatorycially originating markers from (C-reactive HHV8-endemic protein regions and IL-6) [1]. [ 1MCD]. It usually is usually follows negative an unfavorable for Epstein outcomeBarr virus, [1]. whereas it is strongly associated with Human Herpes virus 8 (HHV8) infection, detectedIn patients in almost with all psoriasis, HIV-positive HHV8-positive cases and in MCD 50% isof very HIV-negative rarely reported ones [1]. [6]. Its emer- genceIt has presents been supposed often with to be constitutional linked to the immunomodulatorysymptoms (e.g., fever, treatment, asthenia, particularly weight loss), in severegeneralized and longstanding lymphadenopathy, psoriasis splenomegaly [6]. It is worth an mentioningd hepatomegaly the relevance [1]. Laboratory of discussing tests re- withveal the cytopenia, patient about hypoalbuminemia, possible risks andhypergammaglobulinemia, benefits of the immunomodulatory elevated serum treatment, levels as of itinflammatory was adequately markers done in(C-reactive the present protein case. and IL-6) [1]. It usually follows an unfavorable outcomeMCD [1]. patients have an increased risk of developing simultaneous or subsequent lymphomasIn patients of different with psoriasis, subtypes, HHV8-positive which generally MCD follow is very an aggressive rarely reported course [6]. [1 ,Its7–9 emer-]. genceMCL has isbeen a non-Hodgkin supposed to be B-cell linked lymphoma, to the immunomodulatory traditionally considered treatment, an aggressiveparticularly disease,in severe although and longstanding more indolent psoriasis forms, [6]. including It is worth isMCN, mentioning are currently the relevance well known of discuss- [1]. ing isMCNwith the represents patient about a rare possible event, usually risks an identifiedd benefits incidentally. of the immunomodulatory It generally follows treat- an indolentment, as course, it was althoughadequately it maydone rarely in the progresspresent case. to overt MCL after many years [1]. isMCNMCD patients has been have exceptionally an increased reported risk of indeveloping association simultaneous with Castleman or subsequent disease [10 lym-]. phomas of different subtypes, which generally follow an aggressive course [1,7–9].

Diagnostics 2021, 11, 1150 5 of 5

Author Contributions: Conceptualization, M.Z. (Magda Zanelli) and S.A.; methodology, M.Z. (Magda Zanelli), L.S., and S.A.; investigation, B.C. and L.S.; data curation, A.M., F.S., G.M., and M.Z. (Maurizio Zizzo); writing—original draft preparation, M.Z. (Magda Zanelli); writing—review and editing, M.Z. (Magda Zanelli); supervision, S.A. and S.A.P. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Ethical review and approval were waived for this study, due to the description of a single case. Informed Consent Statement: Informed consent was obtained from the patient involved in the study. Data Availability Statement: The data presented in this study are available from the corresponding author upon request. Conﬂicts of Interest: The authors declare no conﬂict of interest.

References 1. Said, J.; Isaacson, P.G.; Campo, E.; Harris, N.L. WHO Classiﬁcation of Tumours of Haematopoietic and Lymphoid Tissues, 4th ed.; WHO Classiﬁcation of Tumours Editorial Board, Ed.; IARC: Lyon, France, 2017; pp. 325–327. 2. Zanelli, M.; Sanguedolce, F.; Zizzo, M.; Palicelli, A.; Bassi, M.C.; Santandrea, G.; Martino, G.; Soriano, A.; Caprera, C.; Corsi, M.; et al. Primary effusion lymphoma occurring in the setting of transplanted patients: A systematic review of a rare, life-threatening post-transplantation occurrence. BMC Cancer 2021, 21, 468. [CrossRef][PubMed] 3. Zanelli, M.; Zizzo, M.; Bisagni, A.; Froio, E.; De Marco, L.; Valli, R.; Filosa, A.; Luminari, S.; Martino, G.; Massaro, F.; et al. Germinotropic lymphoproliferative disorder: A systematic review. Ann. Hematol. 2020, 99, 2243–2253. [CrossRef][PubMed] 4. Zanelli, M.; Fraternali Orcioni, G.; Zizzo, M.; De Marco, L.; Martino, G.; Cerrone, G.; Cabras, A.D.; Ascani, S. HHV-8-and EBV-positive germinotropic lymphoproliferative disorder. Ann. Hematol. 2019, 98, 2439–2441. [CrossRef][PubMed] 5. Zanelli, M.; Bertuzzi, C.; Zizzo, M.; Martino, G.; Sabattini, E.; Ascani, S. Extracavitary primary effusion lymphoma in a post-transplantation patient. Br. J. Hematol. 2019, 187, 555. [CrossRef][PubMed] 6. Mohagheghi, M.A.; Omranipur, R.; Ensani, F.; Ghannadan, A.; Shahriaran, S.; Samiee, F.; Sedighi, Z. A case of advanced unicentric retroperitoneal Castleman’s disease associated with psoriasis. Acta Med. Iran. 2017, 55, 277–279. [PubMed] 7. Larroche, C.; Cacoub, P.; Soulier, J.; Oksenhendler, E.; Clauvel, J.P.; Piette, J.C.; Raphael, M. Castleman’s disease and lymphoma: Report of eight cases in HIV-negative patients and literature review. Am. J. Hematol. 2002, 69, 119–126. [CrossRef][PubMed] 8. Parente, P.; Zanelli, M.; Zizzo, M.; Covelli, C.; Carosi, I.; Ascani, S.; Graziano, P. Primary effusion lymphoma metachronous to multicentric Castleman disease in an immunocompetent patient. Pathol. Res. Pract. 2020, 216, 153024. [CrossRef][PubMed] 9. Yoshida, T.; Sakai, A.; Imagawa, J.; Noda, M.; Takada, S.; Yoshino, T.; Kimura, A. Mantle cell lymphoma superimposed on multicentric Castleman’s disease. J. Clin. Exp. Hematopathol. 2011, 51, 147–150. [CrossRef] 10. Dobrea, C.; Mihai, M.; Danaila, E.; Gaman, A.; Coriu, D.; Ursuleac, I. “In situ” mantle cell lymphoma associated with hyaline- vascular Castleman disease. Rom. J. Morphol. Embryol. 2011, 52, 1147–1151.