Primary Penile Kaposi's Sarcoma in HIV-Seronegative Patient

Vol. 46 (5): 825-842, September - October, 2020 doi: 10.1590/S1677-5538.IBJU.2020.05.03 EXPERT OPINION

Primary penile Kaposi’s sarcoma in HIV-seronegative patient: a case report and literature review ______

Gianmartin Cito 1, Roberto Di Costanzo 1, Simone Morselli 1, Andrea Cocci 1, Raffaella Santi 2, Gabriella Nesi 2, Alessandro Natali 1, Andrea Minervini 1, Marco Carini 1, Fabrizio Travaglini 1 1 Department of Urology, Careggi Hospital, University of Florence, Florence, Italy; 2 Pathology Section, Department of Health Sciences, University of Florence, Florence, Italy

INTRODUCTION who are young or middle aged, not immunocom- promised (3, 4). The epidemiology suggests that Background this cancer had an origin independent of HIV, as Kaposi’s Sarcoma (KS) is a reticuloendothe- well as a directed search of DNA led to the disco- lial system tumor, that may involve the skin, muco- very of KSHV involvement in the pathogenesis of sa and viscera (1). It can be considered a malignant KS (5). Actually, it is known that a combination vasoformative neoplasia with endothelial prolifera- of KSHV infection and impaired host immunity tion and spindle cell formation on histologic exa- might be responsible for KS. However, although mination. In recent years, there have been several AIDSrelated KS and iatrogenic KS are associated changes in our understanding of KS, including its with welldefined immunodeficiency, the impaired evolving epidemiology, pathogenesis, new clini- immune function in classic KS (related to ‘immu- cal presentations and associations, descriptions of nosenescence’, as an ageing immune system) and new histologic variants, and the emergence of no- endemic KS (related to chronic infection and mal- vel biomarkers with promising targeted therapeutic nutrition) is not exactly characterized. In addition, agents (2). Despite these advances, KS remains the KSHV can cause: I) two lymphoproliferative di- most prevalent malignancy among patients with sorders, represented by the primary effusion lym- acquired immune deficiency syndrome (AIDS), phoma (PEL) (6) and the multicentric Castleman being related with drugs or transplant-associated disease (MCD) (7), II) an inflammatory syndrome immunosuppression. To our knowledge, this di- called KSHV inflammatory cytokine syndrome. sease has a tight link to Human Herpesvirus 8 Whit regard to the clinical presentation, (HHV-8) infection, also known as KSHV (Kaposi each recognized variant has different manifesta- Sarcoma-associated Herpes Virus). KS can occur tions and different visceral involvement. It has been in five different epidemiologic-clinical settings: estimated that KS confined to the penis is uncom- AIDS-related (also known as epidemic), iatrogenic mon and is more often observed in patients with (iatrogenic immunodeficiency, such as that seen in AIDS (8), representing the first manifestation of KS organ transplant recipients), endemic (commonly in approximately 2 to 3% of HIV-positive patients. in sub-Saharan Africa in individuals seronegative Otherwise, up to 20% of these patients may develop for human immunodeficiency virus, HIV), Clas- genital lesions in the course of the systemic disease sic (also known as sporadic KS) and MSM (man (9, 10). Even more rare primary KS of the penis may who have sex with man) without HIV infection, be in case of HIV seronegative patients.

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The aim of this study is to describe an se as episome and undergoes sporadic bouts of uncommon clinical presentation of genital KS in lytic reactivation (15). Virus can induce latency HIV-seronegative man and to perform a narrative in human B cells and endothelial cells, as others literature review of the cases described to date. Herpes virus. During the latent state expresses the latency locus, which includes ORF71 (who Epidemiology encoding viral inhibitory protein vFLIP), ORF72 KS, first described by Moritz Kaposi in (encoding vCyclin), ORF73 (encoding latency 1,872, is a rare neoplasm that origins from the associated nuclear protein (LANA)), ORFK12 (en- endovascular cells in a multifocal way-This enig- coding the kaposins, which are signalling pro- matic infrequent malignant disease has since re- teins) and several microRNAs (miRNAs) (16, 17). ceived much resonance after the AIDS epidemic The latent genes expressed can promote tumorige- in the early 1980s, with an incidence of classic nesis supporting the survival of the infected cell. KS ranged from 0.01 per 100.000 personyears for Indeed, vFLIP protein activates I κB kinase 1 (IKK1) the UK and 0.2 per 100.000 personyears for the to stimulate the nuclear factor κB (NFκ B) pathway USA. However, currently, the incidence of KS is to increase cell survival, viral miRNAs inhibit reported to be 200-fold higher in recipients of apoptosis. Finally, miRNAs also promote endothe- solidorgan transplants, known as iatrogenic KS lial cell reprogramming, and induces the migration form, rather than in the general population (11). and invasion of endothelial cells and vFLIP pro- The incidence of KSHV in south Africa is very motes vascular proliferation. The reactivation from high, reaching >90% in some population, while the latency is determined by different stimuli that in Europe prevalence is 20-30%, in Asia and USA are not well defined. During this phase, the virus is <10% (3). In the Early 1980s with the onset of induces, at first the expression of Immediate early AIDS emergency, one of the first sign was the rise (IE) genes than, Delayed early (DE) genes. Similar of KSHV infections. Indeed, a rise of KS inciden- to the protein products of latency genes, the pro- ce of 20.000 time in general population and 300 tein products of lytic genes can contribute to tu- times in AIDS patients was estimated compared morigenesis. The products of those genes (such as to other immunosuppressed patients (12) with a vIL6) can induce proinflammatory and angiogenic higher rate for MSM (13). Moreover, with the in- factors, including vascular endothelial growth troduction of combination antiretroviral therapy factor (VEGF) and plateletderived growth factor (cART) the incidence of AIDS related to KSHV (PDGF) (18, 19). In order to survive and to induce decreased considerably (14). cell survival and cell proliferation, KSHV modu- late many host cell signaling pathways, inclu- Physiopathology ding the phosphoinositide 3kinase (PI3K)-AKT- KSHV is a large double-stranded DNA -mTOR pathway, the mitogenactivated protein herpesvirus with a protein covering by an ico- kinase (MAPK) pathway and the NFκ B pathway. sahedral capsid, surrounded by tegument and KSHV encode also genes with the capacity to enclosed in a lipid envelope derived in part from inhibit host immune respond. K3 and K5 are lytic the cell membrane. Different glycoproteins in genes that encode modulator of immune recog- the viral envelope interact with celltypespecific nition 1 (MIR1) and MIR2 both of which inhibit cellular entry receptors such as integrins (inclu- major histocompatibility complex (MHC) class I ding α3β1, αVβ5 and αVβ3), the cystine-gluta- antigen presentation to prevent the immune sys- mate transporter xCT, heparan sulfate and the tem. KSHV homologues of interferon regulatory tyrosine protein kinase receptor EPHA2). KSHV factors (IRFs), viral IRFs (vIRFs), are lytic proteins can infect several different cell types, including that inhibit type I interferons. KSHV also enco- endothelial cells, B cells, epithelial cells, dendri- des three CCchemokine ligands (CCLs, formerly tic cells, monocytes and fibroblasts. Once inside known as vMIPs): vCCL1 (encoded by ORFK6), the cell and after uncoating the virus genome vCCL2 (encoded by ORFK4) and vCCL3 (encoded enter in the nucleus where enter in lantecy pha- by ORFK4.1), which can negatively regulate in-

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flammation. Finally, the KSHV K14 gene encodes are usually asymptomatic, but may bleed or for a viral OX2 (vOX2), an immunoglobulin su- cause obstruction, and their presence is usually perfamily member with homology to the cellular confirmed at endoscopy. However, CT scans, OX2 membrane glycoprotein (OX2, also known bronchoscopy and endoscopy are not warran- as CD200) that binds to the receptor CD200R and ted in patients unless they present symptoms suppressed neutrophil activation, decreased CCL2 indicative of visceral lesions (3). When there (also known as MCP1) and IL8 production and is clinical suspicion of KS, a biopsy sample is inhibited oxidative burst in neutrophils stimula- taken to confirm the diagnosis histologically. ted to undergo phagocytosis. Pathologic diagnosis can often be made using conventional hematoxylin and eosin (H&E) and Clinical presentation it shows some characteristic features such as, The behavior of the disease varies from a vascular proliferation in the dermis, an incre- singular lesion localized in the skin, to a fleeting ased number of vessels without an endothelial extensive respiratory and gastrointestinal visce- cell lining, the presence of extravasated blood, ral involvement. All variants of KS cutaneous spindle cells express endothelial markers and lesions usually present as multiple, pigmented, are considered to be the KS tumor cell (CD34, raised or flat, painless that do not blanch. Classic LYVE1 and VEGF receptor 3) (3). As concerned variant (also known as sporadic KS) is typically the therapy in patients with forms of KS when confined to lower limbs with few lesions. Vis- immunosuppression is potentially reversible, ceral and mucosal disease is rare and usually the firstline approach is to bolster the immune occurs in the gastrointestinal tract. Endemic system. IFNα and alitretinoin (a retinoid pan is a typical manifestation of African children agonist receptor), are approved for AIDSrelated often present with multiple lymph nodes with KS, as KSHV directed therapy (3). Otherwise, lymphoedema and a very aggressive natural regarding the management of genital KS, no history of the disease, including visceral dise- specific therapy has been described to date. ase. AIDS-related is characterized by multiple cutaneous lesions on the limbs, trunk and face. CASE DESCRIPTION Mucosal lesions, such as oral lesion, are common (identified in 20% of patients) and visceral A 71-year-old heterosexual, Caucasian involvement is seen in 15% of patients. Related man, referred to our department for the pre- with Iatrogenic immunodeficiency, such as in sence of penile neoformation appeared from organ transplantation. Often presents as cuta- at least 6 months. At the clinical examination, neous KS lesions but both mucosal and, rarely, a 0.6mm x 0.6mm x 0.3mm red painless ra- visceral disease can occur. Finally, in MSM pa- dish nodule hemangioma-like was found on tients the clinical manifestations included le- the gland near the frenulum (Figures 1A and sions that can occur at any skin sites, usually 1B). He did not complain penile bother nor few. Visceral and mucosal disease is rare (3). there were palpable inguinal lymph nodes. His Regarding visceral involvement, organ lesions past medical history reveled only hypertension are uncommon (in one study, only 15% of 469 and hyperuricemia under treatment. The uri- patients had visceral lesions upon diagnosis ne analysis and blood laboratory tests showed with AIDSrelated KS) (20). Gastrointestinal and normal results. The urine culture was negative pulmonary lesions are more present in AIDS for Neisseria Gonorrhoeae, Trichomonas Vagi- related KS. Pulmonary lesions present with nalis, Ureaplasma Urealitycum, Mycoplasma dyspnea, dry cough and sometimes hemopty- hominis, Mycoplasma Genitalium, Clamydia sis, with or without fever, are lifethreatening. Trachomatis. The enzyme-linked immunoassor- These lesions typically appear as a diffuse re- bant assay (ELISA) sierology was negative for ticule nodular infiltrate and/or pleural effusion Troponema pallidum and HIV 1-2 infections. A on chest radiography. Gastrointestinal lesions complete surgical excisional biopsy of the lesion

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Figures 1 A and B - Red painless radish nodule hemangioma- was performed, with margin control (Figure-2). like on the gland near the frenulum. The histopathological examination showed a dermal tumor constituted by intersecting fascicles of spindle cells, arranged around slit-like vascular spaces admixed with numerous extravasated red blood cells and scattered inflammatory cells. The immunohistochemical staining evidences for HHV-8 both in the stromal cells and in the endothelial ones. In addition, the spindle cells were positively stained for CD31, CD34, and negatively for AE1, AE3, CITO-B, P63, ACTINA A4. These clinical and histopathological findings were compatible with a typical KS variant. Therefore, com- puted tomography (CT) of the abdomen and chest was scheduled, not showing any visceral involvement. The 3-months follow-up visit demonstrated the complete remission of the pathology without recurrences (Figure-3).

DISCUSSION

Literature review An English-language literature research

Figure 2 - Penile biopsy showed a dermal tumor constituted by intersecting fascicles of spindle cells, arranged around slit- like vascular spaces admixed with numerous extravasated red blood cells and scattered inflammatory cells (A). At higher magnification, spindle cells exhibited mild to moderate atypia (B). Neoplastic cells stained positively for CD34 (C) and HHV-8 (D).

A B

C D

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Figure 3 - Clinical examination revealed the complete mandatory. However, according to our case, remission of the pathology. only few patients referred to have risk sexual intercourse (21-23). As concerned to the immunological status, three patients with isolated penile KS reported an immunosuppression HIV related (23, 24). The lesions described are defi- nitely variable for manifestation, (nodule (23, 25-39), papular (22, 34, 40-44), ulcerated (27, 39, 45), granulomatous (21), verrucous (46) di- mension 0-5mm (24, 31-33, 35, 40, 42, 43, 47), >6mm (21, 26, 28, 30, 34, 36, 37, 40-42,46), site (gland (21-23, 25, 26, 28-45, 48), coronal sulcus (22, 26, 29, 37, 40, 44, 45), prepuce (24, 47, 49), penilshaft (27, 46, 48), scrotum (23), frenulum (30)), color (reddish (23, 25-27, 29, 32, 34, 36, 40, 44, 45, 49), purplish (23, 29, 30, 33, 39, 41, 42, 43,), bluish (30, 42), skin colored (24), dark brown (48), number (single (26-28, 30-33, 35, 36, 38, 39, 41-43, 45, 47, 49) was conducted, focusing on the cases of penile to multiple (21-25, 29, 34, 37, 40, 44, 46, 48,) KS in HIV positive and negative patients (Ta- and symptomatology (asymptomatic, painfull ble-1). Two different authors (GC. and R. DC.) (45)). The most frequently involved site is the independently searched Medline, Scopus and glans, sometimes in associations with swelling PubMed databases using a single query in order and lymphatic edema due to massive involve- to identify all the previous reports describing ment and the most common manifestation is the diagnosis, clinical presentation, histolo- a nodular reddish or purplish lesion, single or gical findings, therapy and recurrence rate of multiple, sometimes ulcerated too. Lesions may penile KS. The following terms were included: also involve the foreskin, the coronal sulcus, or ((penile) OR penis) AND Kaposi’s sarcoma) AND the meatus. In this last case urinary obstructive HIV. Finally, considering the period from 1985 symptoms may occur. The involvement of the to date, a total of 33 KS cases associated with shaft is rare, usually being related to lesions KSHV, with penis as the only manifestation located on the glans or coronal sulcus. Notably, site of the disease, were found in literature. KS the lesion observed in our patient was a sin- usually affects patients between the fifth and gle red radish pedunculated hemangioma-like eighth decade of life living on the Mediterrane- lesion of the gland next to the frenulum. To our an coastal areas where the HHV-8 infection is knowledge, this atypical clinical presentation is widespread. In the KS cases found in literature, similar to others described in literature. Indeed, patient’s average age was 55.7 years (range 26- other comparable lesions described in literature 78 years). As showed by epidemiological evi- varied from a red purple nodule, or radish 5mm dences that highlight the strong link between papule in diameter of gland to a 1mm nodule the disease pathogenesis and HHV-8 infection, next of the meatus. Nevertheless, it remains a most of the patients with penile KS resulted po- rather infrequent manifestation because of its sitive for serology HHV-8 research. Equally, the appearance, that could simulate a benign pe- histopathological examination found typical dunculated lesion of vessels. According to other features of KS (Table-2). Since it was descri- cases in literature, our case refers to an immu- bed a high HHV-8 sero-prevalence in indivi- nocompetent HIV-seronegative patient. The- duals with high risk sexual activity, including refore, similar cases although rare, could not homosexual, a focus on sexual behaviors are be infrequent. However, the management of

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Table 1 - Data of patients with Kaposi’s Sarcoma.

REFERENCE PATIENT SEXUAL IMMUNODEPRESSION HIV+ HHV CLINICAL FEATURES AGE RISK

Case of classic Kaposi 65 NO NO NO HHV-8 asymptomatic reddish sarcoma of the penis nodules on the glans penis successfully treated with radiotherapy. Kuriyama, et al. (21)

Kaposi’s sarcoma: An 75 NO NO NO HHV-8 painful ulcerated red lesion unusual penile lesion in a on the glans that stretched HIV negative patient. from the urethral meatus to De Rose, et al. (22) the coronal skin

Topical imiquimod 5% as 43 YES NO NO HHV-8 two fleshy granulomatous a treatment for localized lesions on the glans and genital Kaposi’s sarcoma corona of the penis, 5–6 mm in an HIV-negative man: a in diameter case report. Fairley, et al. (23)

Penile Kaposi’s sarcoma 50 NO NO NO HHV-8 0,5 cm in size on the inner in a HIV negative HHV-8 layer of the prepuce positive man. Kampantais, et al. (24)

Isolated penile Kaposi’s 40 NO YES YES HHV-8 two skin-coloured KS sarcoma in a HIV-positive lesions on the prepuce of the patient stable on treatment penis, 5mm for three years. in diameter on the inner layer Lebari, et al. (25) of the prepuce

Kaposi Sarcoma of the 52 NO NO NO IgG translucent, domeshaped, Penis in an HIV-Negative NEGATIVE reddish nodule on the glans Patient. PER HHV-8 penis near the coronal Cecchi, et al. (26) sulcus. 8 mm in diameter

Primary Kaposi Sarcoma 47 YES NO NO HHV-8 papular indurate glandular of Penis in HIV Negative and subcoronal multiple Patient. lesions Karami, et al. (27)

Kaposi’s Sarcoma of 28 YES YES YES HHV-8 growing red-purple nodule the Penis as an Initial on his glans penis Urological Manifestation of AIDS A Report of Two Cases. Angulo, et al. (28)

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Kaposi’s Sarcoma of 26 YES YES YES HHV-8 multiple cutaneous lesions the Penis as an Initial in the penis, scrotum, right Urological Manifestation calf and leg of AIDS A Report of Two Cases. Angulo, et al. (28)

Penile Kaposi’s sarcomas 55 NO NO NO not use two reddish papules,5 in a circumcised and HIV- HHV-8 test mm in diameter on coronal seronegative patient. on patient sulcus near the frenulum Gonen, et al. (29) and 2 mm in diameter on the glans

Primary Classic Kaposi’s 68 NO NO NO HHV-8 ulcerated dark reddish Sarcoma of the Penis in an nodule on the penile shaft HIV-Negative Patient. Kim, et al. (30)

Isolated Kaposi Sarcoma 34 NO NO NO HHV-8 The nodule was (1x1 cm) in two HIV negative in size, on the glans penis patients. lateral to urethral meatus Seleit, et al. (31)

Exclusive penile Kaposi’s 71 NO NO NO HHV-8 oedematous penis with sarcoma: report of an HIV- purplish macular lesions negative man successfully over the glans penis and a treated with radiotherapy. few reddish small nodules on Zargari, (32) the coronal sulcus

Kaposi sarcoma of the 48 NO NO NO HHV-8 The lesion was a purple penis in an HIV-negative color papule over the glans patient Sarcoma de Kaposi near the urethral meatus, de pênis em paciente HIV measuring approximately negativo. 1cm Guevara, et al. (33)

Kaposi sarcoma limited to 67 N/A N/A N/A N/A Single purplish slightly glans penis. raised nodule (Ø 10 mm) on Conger K, et al. (34) the glans near the frenulum

Kaposi sarcoma limited to 55 N/A N/A N/A N/A Single painless bluish wart- glans penis. like lesion on the frenulum Conger, et al. (34)

Kaposi’s sarcoma of penis. 70 N/A N/A N/A N/A Single nodule (Ø 5 mm) on Maiche, et al. (35) the glans; local swelling

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Disseminated Kaposi’s 44 N/A N/A NO N/A Single red-brown nodule (Ø sarcoma that is not 5 mm) on the glans associated with acquired immunodeficiency syndrome in a bisexual man. Marquart, et al. (36)

Kaposi’s sarcoma of the 74 N/A N/A N/A N/A Single painless, firm, smooth conjunctiva. and purple nodule (Ø 5 mm) Jaimowich, et al. (37) on the glans near the meatus

Spontaneous healing of 77 N/A N/A N/A N/A Six red smooth papulo- Kaposi’s angiosarcoma of nodules (Ø 3–7 mm) on the the penis. glans and inner aspect of the Casado, et al. (38) foreskin

Kaposi’s sarcoma of the 47 N/A N/A NO N/A Single brown pedunculate penis. lesion on the inner aspect Zambolin, et al. (39) of the prepuce near the frenulum

Radiation therapy for 54 N/A N/A NO N/A Multiple blue-purple to classic Kaposi’s sarcoma brown macules and papules presenting only on the (Ø 2–6 mm) on the glans glans penis. Lands, et al. (40)

Radiation therapy for 50 N/A N/A NO N/A Maroon linear growth (8 classic Kaposi’s sarcoma mm) on the glans presenting only on the glans penis. Lands, et al. (40)

Kaposi sarcoma limited to 70 N/A N/A NO N/A Single purplish, slightly the glans penis. raised nodule (Ø 5 mm) on Myslovaty, et al. (41) the glans

Primary classic Kaposi’s 69 N/A N/A NO N/A Single smooth reddish-violet sarcoma of glans penis – nodule on the glans (Ø 15 appearance on magnetic mm) resonance imaging. Guy, et al. (42)

Purplish penile papule 75 N/A N/A NO N/A Single, non-tender, purplish as a presenting sign papule (Ø 5 mm) on the of Kaposi’s sarcoma. glans Grunwald, et al. (43)

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Kaposi’s sarcoma limited 78 N/A N/A NO N/A Multiple dome-shaped to the penis treated with violaceous and crusted cobalt-60 radiotherapy. nodules (Ø 5–10 mm) on the Ruszczack, et al. (44) glans, coronal sulcus and foreskin; massive oedema of distal shaft

Primary Kaposi’s sarcoma 52 N/A N/A NO N/A Single painless nodule on of the glans penis. the glans Koyuncuoglu, et al. (45)

Adult genitourinary 55 N/A N/A N/A N/A Single purplish ulcerated sarcomas: a report of nodule on the glans seventeen cases and review of the literature. Berkmen, et al. (46)

Adult genitourinary 60 N/A N/A N/A N/A Single purplish ulcerated sarcomas: a report of nodule on the glans seventeen cases and review of the literature. Berkmen, et al. (46)

A case of classical 54 N/A N/A NO N/A Multiple, dark-brownish Kaposi’s sarcoma of the plaques on the glans and penis showing a good shaft response to high energy pulsed carbon dioxide laser therapy. Chun, et al. (47)

Penile Kaposi’s sarcoma 45 N/A N/A NO N/A Lymphoedema followed preceded by chronic penile by onset of two verrucous lymphoedema. lesions on the glans and on Schwartz, et al. (48) the ventral shaft (Ø 30 mm) 2.5 years later

Penile Kaposi’s 43 N/A N/A NO N/A Two reddish and smooth sarcoma in a human papules (Ø 4 mm) on the immunodeficiency virus- glans and coronal sulcus seronegative patient. Kavak, et al. (49)

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Table 2 - Treatment, histopathological findings and recurrence of patients with KS.

REFERENCE HISTOLOGY TREATMENT RECURRANCE RECURRENCE RECURRENCE FEATURE THERAPY

Case of classic Kaposi sarcoma slit-like spaces 4-MV X-ray NO N/A N/A of the penis filled with red blood radiotherapy, a successfully cells and extensive total of 60 Gy. treated with proliferation of radiotherapy. spindle-shaped cells Kuriyama, et al. (21)

Kaposi’s sarcoma: An unusual penile groups of spindle subtotal NO N/A N/A lesion in a HIV cells, extravascular circumcision negative patient. erythrocytes, and and a glans De Rose, et al. macrophages filled biopsy (22) with hemosiderin

Topical imiquimod 5% as a treatment spindle-cell cryotherapy; NO N/A N/A for localized proliferation. High At week 8 genital Kaposi’s cellularity and imiquimod sarcoma in an mitoses. Vascular 5% cream HIV-negative man: spaces and capillaries for a total of a case report. with some red blood six weeks of Fairley, et al. (23) cells entrapped treatment. between spindle cells

Penile Kaposi’s sarcoma in a HIV classical Kaposi’s excision NO N/A N/A negative HHV-8 sarcoma positive man. Kampantais, et al. (24)

Isolated penile Kaposi’s sarcoma penile prepuce KS. excision of the YES new skin- cryotherapy in a HIV-positive lesion coloured and 5% patient stable lesion at the imiquimod on treatment for frenulum of + surgical three years. the glans excision Lebari, et al. (25) penis, 6X6X3 biopsy mm

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Kaposi Sarcoma of the Penis in spindle-shaped excision of the NO N/A N/A an HIV-Negative cells intermingled lesion Patient. with vascular slits Cecchi, et al. (26) with intra- and extravascular red blood cells

Primary Kaposi Sarcoma of Penis N/A NO NO N/A N/A in HIV Negative Patient. Karami, et al. (27)

Kaposi’s Sarcoma of the Penis as an KS NO NO N/A N/A Initial Urological Manifestation of AIDS A Report of Two Cases. Angulo, et al. (28)

Penile Kaposi’s sarcomas in a vascular lesions excision of the NO N/A N/A circumcised and with spindle cell lesion HIV-seronegative proliferation and patient. increased mitotic Gonen, et al. (29) activity. Vascular clefts with blood elements. Atypical spindle cells are organized as interlacing bundles with extravascular erythrocytes scattered around

Primary Classic Kaposi’s Sarcoma spindle cells scattered circumcision NO N/A N/A of the Penis in between collagen an HIV-Negative bundles and small Patient. vascular proliferation Kim, et al. (30) (CD31-cd34 +)

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Isolated Kaposi Sarcoma in two Confirmatory excision NO N/A N/A HIV negative immunohisto. patients. chemical staining for Seleit, et al. (31) CD 34 antibody was done and reve. aled positive staining for endothelial cells and malignant spindle shaped cells

Exclusive penile Kaposi’s sarcoma: proliferation of radiotherapy NO N/A N/A report of an HIV- spindle cells forming with 3000 rad negative man slit-like structures in fractionated in successfully the dermis, compatible 10 consecutive treated with with typical Kaposi’s days. radiotherapy. sarcoma Zargari, (32)

Kaposi sarcoma of the penis in proliferation and N/A N/A N/A an HIV-negative fascicles of spindle patient Sarcoma cells associated with de Kaposi de angiogenesis pênis em paciente HIV negativo. Guevara, et al. (33)

Kaposi sarcoma limited to glans N/A Local excision YES Onset of a N/A penis. new lesion on Conger, et al. (34) the toe after 1 year

Kaposi sarcoma limited to glans N/A Local excision NO No recurrence N/A penis. after 5 years Conger, et al. (34)

Kaposi’s sarcoma of penis. N/A Local excision YES Local N/A Maiche, et al. (35) recurrence after 1.5 years; no further recurrences after 3 years

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Disseminated Kaposi’s N/A Local excision + YES Onset of three N/A sarcoma that is IFN-α new lesions not associated on the toe, the with acquired thigh and the immunodeficiency knee after 2 syndrome in a years bisexual man. Marquart, et al. (36)

Kaposi’s sarcoma of the conjunctiva. N/A Not performed YES Spontaneous N/A Jaimowich, et al. regression of (37) the primary lesion and onset of a new lesion on the back after 7 months; new lesions on both legs and in the conjunctiva after 1 year

Spontaneous healing of N/A Not performed YES Spontaneous N/A Kaposi’s regression of angiosarcoma of the primary the penis. lesions after Casado, et al. (38) 1 year; no recurrences after 1.5 years

Kaposi’s sarcoma of the penis. N/A Circumcision NO No N/A Zambolin, et al. recurrences (39) after 10 months

Radiation therapy for classic N/A Radiation NO No N/A Kaposi’s sarcoma therapy recurrences presenting only after 1.5 on the glans months penis. Lands, et al. (40)

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Radiation therapy for classic N/A Radiation NO N/A N/A Kaposi’s sarcoma therapy presenting only on the glans penis. Lands, et al. (40)

Kaposi sarcoma limited to the N/A Local excision NO No N/A glans penis. recurrences Myslovaty, et al. after 6 months (41)

Primary classic Kaposi’s sarcoma N/A Local excision YES Onset of new N/A of glans penis lesions on – appearance the lower on magnetic extremities resonance after 2 years imaging. Guy, et al. (42)

Purplish penile papule as a N/A Local excision NO No recurrence N/A presenting sign of after 2 years Kaposi’s sarcoma. Grunwald, et al. (43)

Kaposi’s sarcoma limited to the N/A Radiation NO N/A N/A penis treated therapy with cobalt-60 radiotherapy. Ruszczack, et al. (44)

Primary Kaposi’s sarcoma of the N/A Local excision NO N/A N/A glans penis. Koyuncuoglu, et al. (45)

Adult genitourinary sarcomas: a report N/A Local excision YES Onset of three N/A of seventeen cases new lesions on and review of the the shaft after literature. 1 year Berkmen, et al. (46)

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Adult genitourinary N/A Local excision + YES Persistence of N/A sarcomas: chemotherapy slight oedema a report of after 1 year seventeen cases and review of the literature. Berkmen, et al. (46)

A case of classical Kaposi’s sarcoma N/A CO2 laser YES Onset of a new N/A of the penis therapy lesion on the showing a good dorsum of the response to high left hand after energy pulsed 5 months carbon dioxide laser therapy. Chun, et al. (47)

Penile Kaposi’s sarcoma preceded N/A Local excision N/A N/A N/A by chronic penile + radiation lymphoedema. therapy Schwartz, et al. (48)

Penile Kaposi’s sarcoma in N/A Local excision N/A N/A N/A a human immunodeficiency virus-seronegative patient. Kavak, et al. (49)

patients with KS should include: exams to ex- of about 1-2 years. Other approaches described clude ongoing infectious diseases, assessment in literature could include radiotherapy (25, 29, of patient’s immunological status, histological 37, 42), subtotal circumcision associated with analysis following surgical biopsy and visceral biopsy (45), cryotherapy associated with 5% involvement evaluation through CT or ultra- Imiquimod cream (21), excisional biopsy asso- sounds, despite it is not necessary in asymp- ciated with IFNα (32), biopsy with chemothe- tomatic patients, according to others studies rapy (39), CO2 (48), biopsy with radiotherapy (3). In our case, we managed it with complete (46). Furthermore, in five cases no therapy was surgical excision of the lesion, as described by performed (22, 23, 33, 34), two of them for the other authors (24, 26, 28, 30, 31, 35, 36, 38- spontaneous regression of the disease (33, 34). 40, 43, 44, 47, 49), with a disease recurrence The clinical course of primary penile KS is va- in five cases (24, 30, 31, 36, 39) from a period riable and no standardized follow-up exists to

839 IBJU | EXPERT OPINION

date. In general, local recurrences are rare if the 3. Cesarman E, Damania B, Krown SE, Martin J, Bower primary tumor is completely removed. In one of M, Whitby D. Kaposi sarcoma. Nat Rev Dis Primers. them (33) the authors refer recurrence of a new 2019;5:9. penis lesion after seven months, then after one 4. Friedman-Kien AE, Saltzman BR, Cao YZ, Nestor MS, year two lesions on both legs and one on con- Mirabile M, Li JJ, et al. Kaposi’s sarcoma in HIV-negative homosexual men. Lancet. 1990;335:168-9. junctiva. Other cases of recurrences occurred 5. Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, for therapy with biopsy with IFNα (32) and with Knowles DM, et al. Identification of herpesvirus-like CO2 (48). Respect the management of recurrence, DNA sequences in AIDS-associated Kaposi’s sarcoma. it was described only a recurrence after excisional Science. 1994;266:1865-9. biopsy (24) in which case it was treated with a 6. Cesarman E, Chang Y, Moore PS, Said JW, Knowles new biopsy with radiotherapy, with no recurren- DM. Kaposi’s sarcoma-associated herpesvirus-like ce. In our patient, at 6-months from surgery there DNA sequences in AIDS-related body-cavity-based are no signs of disease progression, although it is lymphomas. N Engl J Med. 1995;332:1186-91. a too short follow-up period. 7. Soulier J, Grollet L, Oksenhendler E, Cacoub P, Cazals- Hatem D, Babinet P, et al. Kaposi’s sarcoma-associated CONCLUSION herpesvirus-like DNA sequences in multicentric Castleman’s disease. Blood. 1995;86:1276-80. 8. Marmor M, Friedman-Kien AE, Laubenstein L, Byrum RD, New-onset apparently benign lesions of William DC, D’onofrio S, et al. Risk factors for Kaposi’s penis in immunocompetent patients, even in sarcoma in homosexual men. Lancet. 1982;1:1083-7. absence of risk factors for sexually transmitted 9. Bayne D, Wise GJ. Kaposi sarcoma of penis and genitalia: diseases, should be always investigated, becau- a disease of our times. Urology. 1988;31:22-5. se it could represent the first manifestation of 10. Lowe FC, Lattimer DG, Metroka CE. Kaposi’s sarcoma primary KS in which penis could be the only of the penis in patients with acquired immunodeficiency isolated clinical presentation. The surgical ma- syndrome. J Urol. 1989;142:1475-7. nagement could represent a good therapeutic 11. Grulich AE, Vajdic CM. The epidemiology of cancers in option, leading to disease clinical resolution human immunodeficiency virus infection and after organ with no further recurrence, thus providing his- transplantation. Semin Oncol. 2015;42:247-57. tological diagnosis. 12. Beral V, Peterman TA, Berkelman RL, Jaffe HW. Kaposi’s sarcoma among persons with AIDS: a sexually transmitted infection? Lancet. 1990;335:123-8. 13. International Agency for Reseach on Cancer. in IARC CONFLICT OF INTEREST Monographs on the Evaluation of Carcinogenic Risks to Humans Vol. 100B (International Agency for Reseach on None declared. Cancer, 2012). 14. Roshan R, Labo N, Trivett M, Miley W, Marshall V, Coren L, et al. T-cell responses to KSHV infection: a systematic approach. Oncotarget. 2017;8:109402-16. REFERENCES 15. Bechtel JT, Liang Y, Hvidding J, Ganem D. Host range of Kaposi’s sarcoma-associated herpesvirus in cultured cells. J Virol. 2003;77:6474-81. 1. Antman K, Chang Y. Kaposi’s sarcoma. N Engl J Med. 16. Sarid R, Flore O, Bohenzky RA, Chang Y, Moore PS. 2000;342:1027-38. Transcription mapping of the Kaposi’s sarcoma- 2. Pantanowitz L, Dezube BJ. Advances in the pathobiology associated herpesvirus (human herpesvirus 8) genome and treatment of Kaposi sarcoma. Curr Opin Oncol. in a body cavity-based lymphoma cell line (BC-1). J Virol. 2004;16:443-9. 1998;72:1005-12.

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17. Cai X, Lu S, Zhang Z, Gonzalez CM, Damania B, Cullen BR. 31. Seleit I, Attia A, Maraee A, Samaka R, Bakry O, Eid E. Isolated Kaposi’s sarcoma-associated herpesvirus expresses an Kaposi Sarcoma in two HIV negative patients. J Dermatol array of viral microRNAs in latently infected cells. Proc Natl Case Rep. 2011;5:24-6. Acad Sci U S A. 2005;102:5570-5. 32. Zargari O. Exclusive penile Kaposi’s sarcoma: report of an 18. Arvanitakis L, Geras-Raaka E, Varma A, Gershengorn HIV-negative man successfully treated with radiotherapy. J MC, Cesarman E. Human herpesvirus KSHV encodes a Eur Acad Dermatol Venereol. 2006;20:318-20. constitutively active G-protein-coupled receptor linked to cell 33. Guevara JFA, Fernández SL, Claros OR, Villalta PG, proliferation. Nature. 1997;385:347-50. Lostal JLC, Abarzuza MAR. Kaposi sarcoma of th e 19. Cavallin LE, Ma Q, Naipauer J, Gupta S, Kurian M, Locatelli penis in anHIV-negative patient. Einstein (Sao Paulo). P, et al. KSHV-induced ligand mediated activation of PDGF 2019;17:eRC4504. receptor-alpha drives Kaposi’s sarcomagenesis. PLoS 34. Conger K, Sporer A. Kaposi sarcoma limited to glans penis. Pathog. 2018;14:e1007175. Urology. 1985;26:173-5. 20. Bower M, Dalla Pria A, Coyle C, Andrews E, Tittle V, Dhoot S, 35. Maiche AG, Holsti P, Gröhn P, Wasenius VM. Kaposi’s et al. Prospective stage-stratified approach to AIDS-related sarcoma of penis. Br J Urol. 1986;58:557. Kaposi’s sarcoma. J Clin Oncol. 2014;32:409-14. 36. Marquart KH, Oehlschlaegel G, Engst R. Disseminated 21. Kuriyama Y, Shimizu A, Yamada K, Yasuda M, Amano Kaposi’s sarcoma that is not associated with acquired H, Tamura A, et al. Case of classic Kaposi sarcoma of the immunodeficiency syndrome in a bisexual man. Arch Pathol penis successfully treated with radiotherapy. J Dermatol. Lab Med. 1986;110:346-7. 2018;45:e175-e176. 37. Jaimovich L, Calb I, Kaminsky A. Kaposi’s sarcoma of the 22. De Rose AF, Justich M, Mantica G, Testino N, Terrone C. conjunctiva. J Am Acad Dermatol. 1986;14:589-92. Kaposi’s sarcoma: An unusual penile lesion in a HIV negative 38. Casado M, Jimenez F, Borbujo J, Almagro M. Spontaneous healing patient. Arch Ital Urol Androl. 2017;89:164-5. of Kaposi’s angiosarcoma of the penis. J Urol. 1988;139:1313-5. 23. Fairley JL, Denham I, Yoganathan S, Read TR. Topical 39. Zambolin T, Simeone C, Baronchelli C, Cunico SC. Kaposi’s imiquimod 5% as a treatment for localized genital Kaposi’s sarcoma of the penis. Br J Urol. 1989;63:645-6. sarcoma in an HIV-negative man: a case report. Int J STD 40. Lands RH, Ange D, Hartman DL. Radiation therapy for classic AIDS. 2012;23:907-8. Kaposi’s sarcoma presenting only on the glans penis. J Urol. 24. Kampantais S, Gourvas V, Ioannidis S. Penile Kaposi’s sarcoma 1992;147:468-70. in a HIV negative HHV-8 positive man. Hippokratia. 2013;17:96. 41. Myslovaty B, Kyzer S, Koren R, Chaimoff C. Kaposi sarcoma 25. Lebari D, Gohil J, Patnaik L, Wasef W. Isolated penile Kaposi’s limited to the glans penis. Plast Reconstr Surg. 1993;92:764. sarcoma in a HIV-positive patient stable on treatment for 42. Guy M, Singer D, Barzilai N, Eisenkraft S. Primary classic three years. Int J STD AIDS. 2014;25:607-10. Kaposi’s sarcoma of glans penis--appearance on magnetic 26. Cecchi R, Troiano M, Ghilardi M, Bartoli L. Kaposi sarcoma resonance imaging. Br J Urol. 1994;74:521-2. of the penis in an HIV-negative patient. J Cutan Med Surg. 43. Grunwald MH, Amichai B, Halevy S. Purplish penile papule 2011;15:118-20. as a presenting sign of Kaposi’s sarcoma. Br J Urol. 27. Karami H, Bagher-Tabrizi A, Yaghoobi M. Primary Kaposi 1994;74:517. Sarcoma of Penis in HIV Negative Patient. Iran J Cancer 44. Ruszczak Z, Stadler R, Schwartz RA. Kaposi’s sarcoma Prev. 2012 Fall;5:225-7. limited to penis treated with cobalt-60 radiotherapy. J Med. 28. Angulo JC, Lopez JI, Unda-Urzaiz M, Larrinaga JR, Zubiaur 1996;27:211-20. CL, Flores NC. Kaposi’s sarcoma of the penis as an initial 45. Koyuncuoğlu M, Yalçin N, Ozkan S, Kirkali Z. Primary Kaposi’s urological manifestation of AIDS. A report of two cases. Urol sarcoma of the glans penis. Br J Urol. 1996;77:614-5. Int. 1991;46:235-7. 46. Berkmen F, Celebioğlu AS. Adult genitourinary sarcomas: a 29. Gönen M, Cenker A, Kiyici H, Kalkan M. Penile Kaposi’s report of seventeen cases and review of the literature. J Exp sarcomas in a circumcised and HIV-seronegative patient. Int Clin Cancer Res. 1997;16:45-8. J Urol. 2006;13:318-20. 47. Chun YS, Chang SN, Park WH. A case of classical Kaposi’s 30. Kim KH, Choi JI, Ryu KH, Kang IH, Leng YH, Lee JW, et al. sarcoma of the penis showing a good response to high- Primary Classic Kaposi’s Sarcoma of the Penis in an HIV- energy pulsed carbon dioxide laser therapy. J Dermatol. Negative Patient. Korean J Urol. 2010;51:803-6. 1999;26:240-3.

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48. Schwartz RA, Cohen JB, Watson RA, Gascón P, Ahkami 49. Kavak A, Akman RY, Alper M, Büyükbabani N. Penile RN, Ruszczak Z, et al. Penile Kaposi’s sarcoma preceded Kaposi’s sarcoma in a human immunodeficiency virus- by chronic penile lymphoedema. Br J Dermatol. seronegative patient. Br J Dermatol. 2001;144:207-8. 2000;142:153-6.

ARTICLE INFO Gianmartin Cito, MD

Department of Urology Gianmartin Cito Careggi Hospital, University of Florence http://orcid.org/0000-0001-7526-4025 Largo Brambilla, 3, 50134 Florence, Italy Telephone: + 39 055 794-9203 Int Braz J Urol. 2020; 46: 825-42 E-mail: [email protected]

______Submitted for publication: July 02, 2019 ______Accepted after revision: October 06, 2019 ______Published as Ahead of Print: November 30, 2019

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