A Rare Malignant Etiology of Zosteriform Lesions: Kaposi’s Christina Steinmetz-Rodriguez, DO,* Leslie Mills, DO,** Robin Shecter, DO, FAOCD***

*Third-year Resident, Palm Beach Consortium for Graduate Medical Education, JFK Medical Center North Campus, West Palm Beach, FL **Second-year Dermatology Resident, Palm Beach Consortium for Graduate Medical Education, JFK Medical Center North Campus, West Palm Beach, FL ***Program Director, Palm Beach Consortium for Graduate Medical Education, JFK Medical Center North Campus, West Palm Beach, FL

Disclosures: None Correspondence: Christina Steinmetz-Rodriguez, DO; [email protected]

Abstract Kaposi’s sarcoma, the most common occurring in acquired immunodeficiency syndrome (AIDS), is a vascular tumor with often varied clinical presentation and a prevalence of 5% to 25% in the United States.1,2 We present the case of a 28-year-old man presenting with nodular, red-to-purplish macules in a zosteriform distribution, ultimately diagnosed as Kaposi’s sarcoma. Only three other cases of zosteriform Kaposi’s sarcoma have been reported in the literature. We review the classification, histology, and treatment modalities of Kaposi’s as well as the of cutaneous diseases that present in a dermatomal pattern. Introduction with intravenous acyclovir for three days and to 5 cm in diameter, were visualized above the Kaposi’s sarcoma (KS) was first described in then oral valacyclovir for a week after discharge. medial malleolus and the medial . 1872 by the Hungarian dermatologist Moritz Medical history was remarkable for HIV with Shave of a representative lesion revealed Kaposi as a pigmented, idiopathic sarcoma a CD4 count of 264, hepatitis B, and a seizure a dermal tumor (Figure 3, low magnification). of the skin of elderly men. KS remains one disorder, as well as Hodgkin’s lymphoma two Increased magnification revealed atypical of the most common in AIDS 1,2 years prior, which was treated with doxorubicin pleomorphic spindle cells arranged in fascicles, patients. Before the 1980s, KS was only and paclitaxel. The patient’s medications with numerous extravasated erythrocytes and described in elderly men of Eastern European, included with efavirenz, emtricitabine, tenofovir, small capillaries between the collagen bundles Mediterranean, or Jewish descent. KS emerged levetiracetam, oxcarbazepine, and gabapentin. (Figure 4). Numerous mitotic figures were on a larger scale in the early 1980s in New York Family history was noncontributory. and San Francisco with the onset of the AIDS 2 Figure 2 epidemic. revealed a well-appearing man who was afebrile. There were numerous red- Four variants of KS have been described in the to-purple , 0.5 cm to 2 cm in diameter, literature: 1) the classic form, occurring in older confined to the right hemithorax at the T4 to men of Eastern European, Mediterranean, or T6 thoracic dermatomes; they did not cross the Jewish descent; 2) the endemic form, presenting in midline (Figures 1, 2). In addition, there was a young Bantu children in Africa; 3) the transplant- single macular lesion to the left upper anterior associated form, which appears months to years thorax. Regional adenopathy was appreciated after high doses of immunosuppressive agents; 3 in the right axilla. No lesions were found on and 4) the AIDS-related form. the hard palate. Faded purplish macules, 3 cm The etiology of this vascular neoplasm remained elusive until 1994, when Cheng et al. discovered a novel type of human herpesvirus in AIDS- associated KS lesions.4 The virus was found not only in nearly all KS lesions, but also in mice injected with the virus that later developed clinically and histologically KS-like skin Figure 3 lesions.3,5 This virus was later named human herpesvirus type 8 (HHV-8) and revolutionized our understanding of this neoplasm.

We describe a rare case of zosteriform KS in a 28-year-old man positive for human immunodeficiency virus (HIV) who presented with purplish papules in a dermatomal distribution on his chest that were unresponsive to herpes zoster antivirals. We also discuss the characteristics and findings of the subtypes of KS and review the differential diagnosis for papular dermatomal lesions. Case Presentation A 28-year-old, HIV-positive Caucasian man presented to the emergency room with intractable superficial thoracic pain in a zosteriform distribution associated with red-to- purple papules that had been present for three months. Four months prior to admission, the patient was hospitalized for appendicitis and underwent laparoscopic appendectomy. Post- operatively, he experienced thoracic dermatomal pain and developed eruptive, grouped vesicles on an erythematous base along the T4 to T6 thoracic dermatomes. The patient was treated Figure 1 Figure 4

STEINMETZ-RODRIGUEZ, MILLS, SHECTER Page 40 present as well. Immunohistochemical stains There are four subtypes of endemic KS: nodular, Finally, epidemic KS, which occurs in HIV- were positive for CD31 (Figure 5), CD34 florid, infiltrative and lymphadenopathic.2 The positive patients, has lesions that appear (Figure 6), factor VII-RAg, HHV-8 and nodular form presents similarly to classic KS and predominately on the face, neck and upper vimentin, while desmin was negative. Complete also demonstrates a good prognosis. The florid trunk, not the lower legs as in classical KS. blood count was within normal limits. form is more aggressive, forming fungating Furthermore, the lesions appear as reddish- Computed tomography of the chest and right and exophytic tumors.6 The infiltrative form to-pink macules and papules, as clinically shoulder showed right-sided lymphadenopathy involves invasion of the subcutaneous tissue demonstrated in our patient, not the purplish and lesions on the liver. and bone. Finally, the lymphadenopathic macules seen in classical KS.2 Lesions on the form, associated with a 100% fatality rate, is oral mucosa, such as the hard and soft palates The findings were most consistent with KS. The common in young Bantu children and presents and genitalia, are not uncommon.6 Reports patient was evaluated by with plans to with diffuse lymphadenopathy and visceral also note involvement of the lymph nodes and initiate outpatient treatment with doxorubicin; organ involvement. Treatment options include gastrointestinal tract as seen on endoscopy, however, the patient was lost to follow-up. combination chemotherapy; however, in one with lesions present from the esophagus to report looking at three-year follow-up of the rectum and on the lungs, liver and spleen, Discussion patients with the florid or infiltrative type, only as seen in our patient.2 Lesions evolve from By the spring of 1981, 21 cases of fulminant and 14% remained diseased-free, and 36% had died. faint and macular in the early patch stage to disseminated KS in young homosexual or bisexual papules and plaques in the plaque stage, finally men in California and New York were described, Iatrogenic KS presents in patients with severe 6 forming large, elevated nodules in the nodular baffling physicians across the coasts. The sudden immunosuppression resulting from organ stage.6 Systemic symptoms such as fever, chills, and rapidly increasing occurrence of KS in young transplant, autoimmune disease, or systemic weight loss, diarrhea and fatigue often appear men heralded the epidemic of a new, devastating immunosuppressive therapy for .2 with the nodular stage. Treatment includes disease now known as AIDS. KS is a multifocal Initially described in renal transplant patients, highly active antiretroviral therapy (HAART), hemorrhagic neoplastic process arising from cases have also been reported in patients with intralesional therapy with vinblastine, radiation vascular and lymphatic endothelium. KS has four vulgaris, , 9 7 therapy and topical alitretinoin. Systemic clinical variants (Table 1). Wegener’s granulomatosis, or systemic chemotherapy for extensive cutaneous lesions 6,8 erythematosus on immunosuppressive agents. or visceral involvement includes doxorubicin or Clinical Variants of Kaposi’s Sarcoma The average time for development of lesions is daunorubicin as first-line agents. Classic KS occurs most commonly in men 16 months after starting immunosuppressive over the age of 50 of European, Jewish or therapy, and the lesions most often remain Zosteriform Kaposi’s Sarcoma Mediterranean heritage. The lesions present localized to the skin.6 About 30% of patients will Zosteriform KS, as seen in our patient, is an as red-to-purple or blue papules, patches or die due to generalized KS, and tumor progression extremely rare clinical manifestation of KS, with nodules on the distal lower extremity. As is correlated to degree of immunosuppression. only three other cases reported in literature.7,10,11 the disease course progresses, lesions may Treatment options are difficult because the risk Herpes zoster is the most common eruption become ulcerated or fungated, and venous of death from organ rejection or autoimmune to follow a dermatomal distribution, giving stasis changes and lymphedema of the lower 6 illness from discontinuing immunosuppressive rise to the name zosteriform; however, other extremities are common. Prognosis is good, therapy must be weighed against the risk of cutaneous lesions have been reported to occur with an indolent course for 10 years to 15 years death from KS. in such a pattern, including papular lesions of or more, and individual lesions occasionally resolve spontaneously. Visceral or cutaneous Figure 6 involvement can occur in up to 10% of patients.2 Lymphoproliferative disorders such as non- Hodgkin’s lymphoma (previously diagnosed in our patient) can develop in up to one-third of patients with KS.6 Treatment options include radiotherapy, excision, electrocauterization and curettage, and systemic chemotherapy if advanced.6

Endemic KS, also known as African KS, was reported in the 1950s in the Bantu tribesman of South Africa and later was responsible for Figure 5 up to 9% of all seen in Ugandan males.6 Table 1. Summary of Kaposi’s Sarcoma types and characteristics2,6 Type Patient Population Clinical Presentation Treatment Prognosis Radiotherapy excision, Older men; European, Jewish electrocauterization and Classic Purplish macules or papules on lower extremity Good; slow course or Mediterranean heritage curettage; if advanced, systemic chemotherapy Nodular Like classic KS Florid Exophytic tumors 100% fatality rate for African young adults and Invasion of subcutaneous Endemic Infiltrative Combination chemotherapy lymphadenopathic form; children tissue and bone progressive Diffuse lymphadenopathy Lymphadenopathic and visceral organ involvement Radiotherapy, Dependent on Patients on immunosuppressive Iatrogenic Predominately cutaneous lesions discontinuation of immunosuppression; 30% therapy immunosuppressants fatality rate Pinker lesions appear on face, neck, upper trunk, HAART; if severe, systemic Progressive; influenced by Epidemic HIV+ patients mucous membranes chemotherapy HIV progression

Page 41 A RARE MALIGNANT ETIOLOGY OF ZOSTERIFORM LESIONS: KAPOSI’S SARCOMA lichen striatus, linear epidermal , nevus like or angulated vessels are present throughout 3 References comedonicus, verruca plana, , the . A mild inflammatory infiltrate of 1. Kaposi, M. Idiopathisches multiples lymphangioma circumscriptum, Hailey-Hailey lymphocytes, plasma cells and extravasation of Pigmentsarkom der Haut. Arch Dermatol Syphil. disease, Darier disease, and syringoma (Table erythrocytes is often noted as well. When the 1872;4:265-73. 2).12 Uncommonly, the skin can present as a native vessels and adnexal structures protrude site of metastasis, with an incidence of 2.5% into the lumens of the neoplastic vascular 12 15 2. Geraminejad P, Memar O, Aronson I, Rady PL, to 5%, also in a dermatomal distribution. channels, promontory sign has taken shape. Hengge U, Tyring SK. Kaposi’s sarcoma and other Lipoma, , blue rubber bleb It should be noted that the promontory sign is manifestations of human herpesvirus 8. J Am Acad nevus, vascular hamartoma, and granuloma not pathognomonic for KS and has also been Dermatol. 2002 Nov;47(5):641-55. annulare must be ruled out as well. Lesions reported in malignant lesions of angiosarcoma reported as occurring at prior sites of herpes and benign lymphatic malformations of 3. Babál P, Péc J. Kaposi’s sarcoma - still an zoster include those of , targetoid hemosiderotic , among 16 enigma. J Eur Acad Dermatol Venereol. 2003 sarcoidosis, angiosarcoma, lymphoma and, in others. As lesions become clinically thicker Jul;17(4):377-80. one case, KS.7 Zosteriform lesions of KS at in the patch stage, a diffuse dermal infiltrate, sites of prior herpes zoster is hypothesized with lesions sometimes extending into the 4. Chang Y, Cesarman E, Pessin MS, Lee 10 15 to occur via the Koebner phenomenon. subcutaneous tissues, can be seen. The tumor F, Culpepper J, Knowles DM, Moore PS. Numerous accounts in the literature note the cells become more spindled; however, mitotic Identification of herpesvirus-like DNA sequences onset of KS lesions at sites of trauma such as figures and cytological atypia is rare. Also visible in AIDS-associated Kaposi’s sarcoma. Science. horse bites, gnat bites, human bites, surgery are promontory sign and dissecting vascular 1994 Dec;266(5192):1865-9. and puncture wounds.10,12 Thus, in our channels filled with erythrocytes surrounded by patient, herpes infection might have resulted fascicles of spindle cells.3 A clear paranuclear 5. Foreman KE, Friborg J, Chandran B, Katano from decreased resistance in the dermatomes vacuole in the cytoplasm of the spindle cells H, Sata T, Mercader M, Nabel GJ, Nickoloff .BJ affected by the zoster, resulting in attraction can sometimes be present in cross section and is Injection of human herpesvirus-8 in human skin of metastases to an area of traumatized skin.13 known as autolumination.15 As tumors approach engrafted on SCID mice induces Kaposi’s sarcoma- Other possible etiologies include spread via the nodular stage, solid, uniform spindle like lesions. J Dermatol Sci. 2001 Jul;26(3):182-93. lymphatic and hematogenous routes or via cells arranged in fascicles with erythrocytes the fenestrated vasculature of the dorsal root between slit-like channels become apparent. 6. Buonaguro FM, Tornesello ML, Buonaguro L, ganglion, perineural lymphatic invasion as seen Rare mitotic figures can be seen along with Satriano RA, Ruocco E, Castello G, Ruocco V. in prostate , and HHV-8 viral particles autolumination. Immunohistochemistry in all Kaposi’s sarcoma: aetiopathogenesis, histology and existing in the nerve ganglion cells.12 stages demonstrates positivity for CD31, CD34, clinical features. J Eur Acad Dermatol Venereol. factor VIII-RAg and vimentin, as demonstrated 2003 Mar;17(2):138-54. Histology in our patient.3 Desmin is often negative, Regardless of KS subtype, all lesions appear differentiating KS from a , 7. Eisman S, O’Toole EA, Collis C, Rustin MH. 6 histologically identical on pathology. The while the lymphatic marker D2-40 is positive.17 Zosteriform Kaposi’s sarcoma. Clin Exp Dermatol. histologic hallmark of KS is an admixture of Unfortunately, many of these markers are 2001 Jul;26(5):402-4. 14 spindle cells and slit-like vascular spaces. As present in other vascular tumors. Identification lesions clinically progress through the patch, of HHV-8 using the viral protein latent nuclear 8. Saxena A, Netchiporouk E, Al-Rajaibi R, Billick plaque and nodular stages, so does the histology antigen-1 (LNA-1) is often one of the best stains R, Roshdy O. Iatrogenic Kaposi’s sarcoma after (Table 3). In the patch stage, thin-walled, slit- for differentiating KS from its mimics. LNA-1 immunosuppressive treatment for granulomatosis acts as a transcriptional regulator that is highly with polyangiitis (Wegener’s). JAAD Case Rep. Table 2. Differential diagnosis of papular expressed in all latently infected tumor cells and 2015 Mar;1(2):71-3. 7,19 dermatomal skin lesions demonstrates a nuclear stippled pattern when 18 9. Mouden K, Khmou M, Loughmari S, Semmar Differential Diagnosis of Zosteriform Papular Lesions viewed under the microscope. This staining would also be positive in other HHV-8 positive A, El Kacemi H, El Khannoussi B, Kebdani T, Lichen striatus tumors such as multicentric Castleman disease Elmajjaoui S, Benjaafar N. Primary Kaposi’s sarcoma of the nasal cavity: a case report and review Epidermal nevi and primary effusion lymphoma. of the literature. Clin Sarcoma Res. 2016 Mar;6(4). Basal cell nevus syndrome Conclusion Nevus comedonicus Zosteriform KS is a very rare presentation of 10. Niedt GW, Prioleau PG. Kaposi’s sarcoma occurring in a dermatome previously involved Verruca plana KS, with only three other reported cases in the literature. It is important to keep in mind by herpes zoster. J Am Acad Dermatol. 1988 Lichen planus that dermatomal lesions do not always indicate Feb;18(2):448-51. Hailey-Hailey disease herpes zoster, and having a broader differential 11. Kim CH, Kim DH, Jeon JS, Kang SG, Kim Darier’s disease diagnosis for papular dermatomal lesions is very important for both the dermatopathologist and DW, Cho MK. A Case of Zosteriform Kaposi’s Syringoma dermatologist as they work together to reach Sarcoma after Prednisolon Treatment. Korean J Dermatol. 2009 Apr;47(5):583-7. Becker’s nevus the correct diagnosis. The importance of a biopsy cannot be understated, and in this case, nevus 12. Williams LR, Levine LJ, Kauh YC. Cutaneous the patient’s correct management hindered on malignancies mimicking herpes zoster. Int J Granuloma annulare the astute clinician thinking outside the usual Dermatol. 1991 Jun;30(6):432-4. Localized parameters of dermatology. Sarcoidosis Table 3: Histologic Characteristics of KS15 Histological Immunohistochemical Type Important Signs Cutaneous leishmaniasis Characteristics Markers Angiokeratomas Subtle thin-walled or Patch Promontory sign Lichen aureus jagged vascular spaces CD31+, CD34+, Factor Localized lymphangioma circumscriptum VII RAg +, vimentin Diffuse dermal vascular Autolumination, +, D2-40+, HHV-8 Plaque infiltrate with dissecting Promontory sign LNA-1+ Porokeratosis vascular channels Malignancies: angiosarcoma, visceral and Spindled cells arranged Desmin - Nodular Autolumination hematologic in fascicles

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14. Iwamasa T, Chinen K, Hirayasu T, Nakazato I, Tsuhako K, Kamada Y, Miyamoto K. Epidemic and non-epidemic Kaposi’s sarcoma: diagnosis, staging and treatment. Crit Rev Oncol Hematol. 1996 Nov;24(3):153-63.

15. Grayson W, Pantanowitz L. Histological variants of cutaneous Kaposi sarcoma. Diagn Pathol. 2008 Jul;3(31).

16. Lazova R, McNiff ,JM Glusac EJ, Godic A. Promontory sign--present in patch and plaque stage of angiosarcoma! Am J Dermatopathol. 2009 Apr;31(2):132-6.

17. Dubina M, Goldenberg G. Positive staining of tumor-stage Kaposi sarcoma with lymphatic marker D2-40. J Am Acad Dermatol. 2009 Aug;61(2):276-80.

18. Ablashi DV, Chatlynne LG, Whitman JE Jr, Cesarman E. Spectrum of Kaposi’s sarcoma-associated herpesvirus, or human herpesvirus 8, diseases. Clin Microbiol Rev. 2002 Jul;15(3):439-64.

19. Manteaux A, Cohen PR, Rapini RP. Zosteriform and epidermotropic metastasis: report of two cases. J Dermatol Surg Oncol. 1992 Feb;18(2):97-100.

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