Alaibac, Mauro

Calabr\uf2, Maria Luisa

Calabrese, Fiorella

La Torre, Fabio Biagio

Marino, Dario

Ottaviano, Giancarlo

Vicario, Mattia

Medicine

English

Calabr&#242

Padua Research Archive

Recurrent Kaposi sarcoma associated with Koebner phenomenon in two HIV-seronegative patients

Dario Marino

Fiorella Calabrese

Giancarlo Ottaviano

Fabio Biagio La Torre

Mattia Vicario

Mauro Alaibac

Maria Luisa Calabrò

Crossref

MARINO, DARIO

Calabrò, Maria Luisa

Archivio istituzionale della ricerca - Università di Padova

Clinical Case Report Medicine®OPENRecurrent Kaposi sarcoma associated withKoebner phenomenon in two HIV-seronegativepatientsTwo case reports and a review of the literatureDario Marino, MD, PhDa, Fiorella Calabrese, MDb, Giancarlo Ottaviano, MDc, Fabio Biagio La Torre, MDc,Mattia Vicario, PhDd, Mauro Alaibac, MD, PhDe,∗, Maria Luisa Calabrò, BScDdAbstractRationale: Koebner phenomenon is occasionally reported in patients affected by classic Kaposi sarcoma (KS).Patient concerns: Here, we report 2 cases of KS associated with Koebner phenomenon and the correlation of humanherpesvirus 8 molecular analysis with the clinical outcome.Interventions: In the ﬁrst case, a patient with a history of sporadic cutaneous KS developed a recurrent lesion at the laryngeal tract,the site of a previous nodulectomy. In our second case, immunodeﬁciency induced by chemotherapy triggered the development ofKS and Koebner phenomenon was limited to the skin at the site of safenectomy.Lessons: Our observations suggest that careful planning of surgical treatment is required in immunocompetent andimmunocompromised patients with a medical history of KS. Moreover, mucosal sites (both respiratory and in the gastrointestinaltract) should be considered as potential sites for KS development.Abbreviations: AIDS = acquired immunodeﬁciency syndrome, CT = computerized tomography, GE = genome equivalents,HAART = highly active antiretroviral therapy, HBV = hepatitis B virus, HIV = human immunodeﬁciency virus, KS = Kaposi sarcoma,PBMC = peripheral blood mononuclear cells.Keywords: Kaposi sarcoma, Koebner phenomenon1. IntroductionKaposi sarcoma (KS) is a rare malignancy derived fromvasoformative mesenchyme, characterized by single or simulta-neous multiple inﬂammatory angiogenic lesions with predomi-nant involvement of the skin. It may be cutaneous or mucosal,nodal, or visceral and is often associated with immunosuppres-sion, such as following infection with human immunodeﬁciencyvirus (HIV) or immunosuppressive treatment after organtransplantation. Before the acquired immunodeﬁciency syn-Editor: N/A.Patient consent was not obtained as patient’s anonymity was maintained in bothwritten text and photographs.The authors have no conﬂicts of interest to disclose.a Department of Clinical and Experimental Oncology, Veneto Institute ofOncology, IOV IRCCS, bDepartment of Cardiac, Thoracic and Vascular Sciences,Section of Pathology, c Department of Neurosciences, Otolaryngology Section,University of Padua, d Immunology and Molecular Oncology, Veneto Institute ofOncology, IOV IRCCS, eDermatology Unit, Department of Medicine, University ofPadua, Padua, Italy.∗Correspondence: Mauro Alaibac, Dermatology Unit, Department of Medicine,University of Padua, Via Gallucci 4, 35128, Padua, Italy(e-mail: mauro.alaibac@unipd.it).Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.This is an open access article distributed under the Creative CommonsAttribution-NoDerivatives License 4.0, which allows for redistribution, commercialand non-commercial, as long as it is passed along unchanged and in whole, withcredit to the author.Medicine (2017) 96:52(e9467)Received: 13 November 2017 / Received in ﬁnal form: 4 December 2017 /Accepted: 6 December 2017http://dx.doi.org/10.1097/MD.00000000000094671drome (AIDS) epidemic, KS was a relatively rare neoplasmaffecting elderly men in certain Mediterranean countries (classic/Mediterranean form), adults and children in sub-Saharan Africa(endemic/African form), and transplant recipients undergoingimmunosuppressive therapy (post-transplant/iatrogenic form). Inthe early 1980s, KS was detected in people infected with HIV-1and, prior to the introduction of highly active antiretroviraltherapy, it became one of the most frequent malignancies in AIDSpatients (epidemic/AIDS-associated form).[1] Human herpesvirus8 (HHV8) is implicated in the etiopathogenesis of KS. The virus ispresent in virtually all cases of KS, although not all infectedindividuals develop KS.[2] Nowadays, KS diagnosis in biopticlesion specimens usually requires not only histological andimmunohistochemical characterization but also HHV8 detectionusing molecular biology techniques. Thus, surgical biopsy ishighly recommended to provide sufﬁciently large samples toallow for adequate morphological and molecular investigations.Moreover, detection and measurement of HHV8-speciﬁc anti-bodies and DNA sequences through serological and molecularassays performed in blood samples and other biological ﬂuidsmay further delineate the virological status (latent versus activeinfection) of patients.[2]KS tumors often progress soon after a systemic inﬂammatorycondition, and KS lesions may arise precisely at sites of previouslocal injury, such as surgical or traumatic wounds, a characteris-tic known as the Koebner phenomenon. Indeed, the tissue repairprocess can recruit circulating HHV8-infected endothelialprecursors and promote spindle cell proliferation. Different skindiseases present this complication, notably psoriasis, lichenplanus, cutaneous sarcoidosis, vitiligo, lupus erythematosus, andviral warts, although its etiopathogenesis is not fully under-[3]Figure 1. Computed tomography image (A), microlaryngoscopy showing thickening and hyperdensity (arrows) of the laryngeal vestibule and the right vocal cord(B), and hematoxylin and eosin (HE) staining of the laryngeal polyp showing thin-walled dilated vessels and ﬁbrinous exudates in edematous mucosa (C). HE=hematoxylin and eosin.Marino et al. Medicine (2017) 96:52 Medicinestood. In this article, we report 2 cases of Koebner phenomenonassociated with KS and review the literature concerning thiscomplication in KS patients.Figure 2. Computed tomography image (A), microlaryngoscopy showinggranulomatous tissue involving large areas of trachea (B). Polypoidgranulomatous tissue (HE) (C). Abundant vascular spaces associated withinﬂammatory cells and numerous spindle cells (HE) (D). Positive CD31immunohistochemistry (E). Atypical endothelial proliferation (F). Many nucleimmunoreactive for HHV8 (G). HE=hematoxylin and eosin.2. Case 1In 2005, a 61-year-old HIV-negative man who is a hepatitis Bvirus (HBV) occult carrier developed bilateral lesions on the legs.KS was histologically/immunohistochemically proven and clini-cal and instrumental examinations conﬁrmed a stage IAcutaneous involvement. The disease remained localized in thelower limbs for almost 5 years and no therapy was administered.In 2010, the patient developed hoarseness, dry cough, anddyspnea due to a right true vocal fold swelling associated with areduced right vocal fold motility and with a signiﬁcant reductionof the respiratory glottis space (Fig. 1B). After a contrast-enhanced computerized tomography (CT) scan of the neckshowed a thickening hyperdensity of the laryngeal vestibule andthe right vocal fold (Fig. 1A), the lesion was biopsied undermicrolaryngoscopy control. The ﬁnal histological diagnosis wasconsistent with laryngeal polyp (Fig. 1C). Given the reducedglottis lumen, a temporary tracheostomy was also performed.During the following year, the patient underwent 2 CO2 laser-assisted excisions of the laryngeal lesions and treatment withhigh-dose corticosteroids. Fifteen months later the patientprogressively developed a granulomatous tissue involving largeareas of the tracheal tract (Fig. 2A and B); high-dose corticoste-roids were administrated and a debulking of the mass under rigidtracheoscopy control was performed. Histological investigationof the granulomatous tissue revealed the presence of KS andHHV8 was detected by immunohistochemistry (Fig. 2C–G). Thelife-threatening site of the disease required antiblastic treatmentusing chemotherapy according to ABV schedule (Adriamycin, 10mg/m2, Bleomycin, 15 UI; and Vincristine, 1mg; every 2 weeksfor 12 cycles). Antiviral prophylaxis with lamivudine andvalacyclovir was also administered due the status of occultHBV carrier and the elevated risk of opportunistic herpesvirusinfection. Complete remission was achieved. HHV8 molecularanalysis was performed before treatment and a high viral loadwas detected, with a cell-associated burden of 308 genomeequivalents (GE) per 100,000 cells and a cell-free plasmatic loadof 1370GE/mL (Fig. 3). HHV8 load decreased initially duringchemotherapy and antiviral prophylaxis, but subsequentlyincreased progressively suggesting a reactivation of the lytic2iFigure 3. Trend of HHV8 load in the peripheral blood compartment (case 1).HHV8 load in peripheral blood mononuclear cells (PBMC) and in plasmaspecimens is expressed in genome equivalents (GE). Four months after the endof chemotherapy, the patient presented with aggressive KS relapse (arrow),characterized by high plasmatic HHV8 load, extended cutaneous involvementand a new KS lesion at the site of tracheostomy. HHV8=human herpesvirus 8,KS=Kaposi sarcoma, PBMC=peripheral blood mononuclear cells.Marino et al. Medicine (2017) 96:52 www.md-journal.comcycle. Indeed, high plasmatic HHV8 viremia (1411GE/mL) wasmeasured 3months after the end of treatment (Fig. 3). Onemonthlater, a new lesionwas documented at the site of the tracheostomyand recurrent KS was conﬁrmed histologically. In this setting,plasmatic HHV8 load was high (2422GE/mL) indicatingpersistent viral replication. The patient was admitted to ourhospital due to progressive dyspnea. Chest x-ray and echocardi-ography revealed a pleuro-pericardial effusion. Pericardiocent-esis was performed with blood-serum ﬂuid drainage and acytological examination revealed the presence of malignantmesenchymal cells. Cell-free and cell-associated virus was alsodetected in the pericardial fraction (3511GE/mL and 9GE/100,000 cells) suggesting that viral replication also occurred inthe pericardial cavity (Fig. 3). Cytoﬂuorimetric analysis wasnegative for clonal B lymphocytes excluding the development of aprimary effusion lymphoma. At this stage, KS was extensivelydisseminated as the patient presented with papular red lesions onthe legs, limbs, and trunk. Intrapericardial bleomycin chemo-therapy (15IU) was administered without adverse events.Second-line chemotherapy with paclitaxel (100mg/m2 every 2weeks) was started. The patient received 16 bi-weekly paclitaxeldoses achieving complete disappearance of cutaneous lesions andinvolvement of pericardial ﬂuid. Viral load measurement after 8cycles of chemotherapy showed an undetectable HHV8 load inthe peripheral compartment (Fig. 3). The chemotherapy wasstopped due to peripheral G3 neuropathy. Two years after theend of chemotherapy the patient presented in good clinicalcondition and in complete remission with no evidence ofcutaneous lesions or pericardial effusion. A recent total bodyCT scan was negative for KS involvement and the tracheotomywas removed (data not shown).3. Case 2A 65-year-old man with a pT3pN1M0 colorectal carcinoma wastreated with radical colectomy followed by adjuvant chemother-apy according to FOLFOX4 regimen for 12 cycles. Six months3after the end of chemotherapy he developed a cutaneous papularred nodule on the left leg and scrotum, with bilateral inguinallymphadenopathy. He underwent surgical excision and thehistological diagnosis was consistent with nodular KS; immuno-histochemical analyses showed strong and speciﬁc reactivity forCD34, HHV8, S100, and factor VIII. The patient was HIV-negative and HHV8 molecular analysis revealed high circulatingviremia (plasmatic 3154GE/mL and 93 GE/100,000 cells inperipheral blood mononuclear cells [PBMC]). The patient was incomplete remission until May 2010 when he developed newnodular lesions at the site of the scar of a safenectomy performed2 months before. Histological diagnosis after surgical excisionconﬁrmed the diagnosis of KS. At this time, HHV8 viral loaddecreased to 22 genomic copies/100,000 PBMCand undetectableplasma levels, in the absence of therapy. At present, the patient isin complete remission.4. DiscussionSince 1987, only 12 cases of KS occurring as Koebnerphenomenon were reported in the literature: 5 cases occurredin transplant recipients,[4–8] 4 in HIV-positive patients,[9–12] andonly 3 in classic KS.[13–15] The typical site of Koebnerphenomenon is the skin, but Sachsenberg-Studer et al[6] describeda KS of the skin and of a lung graft localized to sites of a previoustrauma, suggesting that not only immunodeﬁciency but alsotrauma and physical stimuli may lead to the development of KS asKoebner phenomenon.The Koebner phenomenon, one of the most well-knownentities in dermatology, has been documented in several skindiseases, including psoriasis, vitiligo, lichen planus, and viralwarts.[3] In susceptible individuals, koebnerization can beinduced by a variety of triggers, all of which cause predominantlyepidermal cell injury or inﬂammation. Numerous factors areknown to trigger Koebner phenomenon, including trauma,animal or insect bites, burns, needle scariﬁcation, pressure, skingrafts, surgical incision, allergic and drug reactions, vaccinations,tattoos, and various dermatoses. In addition, both epidermal cellinjury and inﬂammation of the papillary dermis are necessary forthe induction of Koebner phenomenon.The development of KS associated with Koebner phenomenonrepresents an example of inﬂammatory oncotaxis. Basicﬁbroblast growth factor released from traumatized keratinocytesmay also play a role in the pathogenesis of KS. Duringinﬂammatory reactions, other angiogenic cytokines, such asinterleukin-1 and -6, tumor necrosis factor-a, vascular endothe-lial growth factor, platelet-derived growth factor, and granulo-cyte colony-stimulating factor, may also play a part inkoebnerization along with an increased expression of cell-adhesion molecules.In the ﬁrst case, a patient with a history of sporadic cutaneousKS developed a recurrent lesion at the laryngeal tract, the site of aprevious nodulectomy. To the best of our knowledge, this is theﬁrst case described in the literature of Koebner phenomenon withmucosal involvement. Laryngeal biopsies and high-dose cortico-steroids could have caused a rapid and exuberant KS recurrencerequiring tracheostomy followed by chemotherapy due tovisceral involvement.In our second case, there was a temporal correlation betweenthe cytotoxic treatment for colorectal cancer and development ofKS as well as between scar formation and disease relapse afterfour years of indolent natural history. In this patient,immunodeﬁciency induced by chemotherapy triggered the[4] Micali G, Gasparri O, Nasca MR, et al. Kaposi sarcoma occurring deMarino et al. Medicine (2017) 96:52 Medicinedevelopment of KS, and the Koebner phenomenon was limited tothe skin at the site of the safenectomy. The patient did not requireany speciﬁc oncologic treatment as the lesion was limited to theskin without visceral involvement.In conclusion, our observations suggest that careful planningof surgical treatment is required in immunocompetent andimmunocompromised patients with a medical history of KS.Moreover, mucosal sites (both respiratory and in the gastroin-testinal tract) should be considered as potential sites for KSdevelopment.AcknowledgmentsWethankChristinaDrace forhelp inpreparing themanuscript. Thisstudy was supported by 5X1000-IOV2010 (fellowship to MV).References[1] Jakob L, Metzler G, Chen K, et al. Non-AIDS associated Kaposi’ssarcoma: clinical features and treatment outcome. PLoS One 2011;12:e18397.[2] Sarid R, Calabrò ML. Kaposi’s sarcoma-associated herpesvirus: Epidemi-ology, Biological Characteristics and Pathogenesis. In: Kaslow RA,Stanberry LR, LeDuc JW, eds. Viral Infections of Humans: Epidemiologyand Control 5th ed. New York, NY: Springer, 2014;897–931.[3] Sagi L,TrauH.TheKoebnerphenomenon.ClinDermatol2011;29:231–6.4novo in the surgical scar in a heart transplant recipient. J Am AcadDermatol 1992;27:273–4.[5] SeçkinD,OzcanG,Demirag A, et al. TheKoebner phenomenon inKaposisarcoma in a renal transplant recipient. Br J Dermatol 1998;139:346–8.[6] Sachsenberg-Studer EM, Dobrinski N, Sheldon J, et al. Human herpes-virus 8 seropositive patient with skin and graft Kaposi’s sarcoma afterlung transplantation. J Am Acad Dermatol 1999;40:308–11.[7] Maral T. The Koebner phenomenon in immunosuppression-relatedKaposi sarcoma. Ann Plast Surg 2000;44:646–8.[8] Stoebner PE, Fabre C, Kabbaj NEL, et al. Koebnerizing Kaposi sarcomamimics a laparotomic hypertrophic scar in a liver transplant recipient.Liver Transpl 2009;15:994–6.[9] Niedt GW, Prioleau PG. Kaposi sarcoma occurring in a dermatomepreviously involved by herpes zoster. JAmAcadDermatol 1988;18:448–51.[10] Plettenberg A, Engelmann L, Meigel W. Pathogenesis of HIV-associatedKaposi sarcoma—the Koebner phenomenon as a possible pathogeneticmechanism. Z Hautkr 1990;65:684–6.[11] Janier M, Morel P, Civatte J. The Koebner phenomenon in AIDS-relatedKaposi sarcoma. J Am Acad Dermatol 1990;22:125–6.[12] French PD, Harris JRW, Mercey DE. The Koebner phenomenon andAIDS-related Kaposi sarcoma. Br J Dermatol 1994;131:746–7.[13] Webster-Cyriaque J. Development of Kaposi’s sarcoma in a surgicalwound. N Engl J Med 2002;346:1207–10.[14] Brambilla L, Boneschi V, Fossati S, et al. Recurrence of Kaposi’s sarcomaat the site of a graft for radiodermatitis ulcer. G Ital Dermatol Venereol1987;122:655–7.[15] Potouridou I, Katsambas A, Pantazi V, et al. Koebner phenomenon inclassic Kaposi’s sarcoma. Acta Derm Venereol 1997;77:481.

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Recurrent Kaposi sarcoma associated with Koebner phenomenon in two HIV-seronegative patients

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