Iatrogenic Kaposi`s sarcoma C46.-

Iatrogenic Kaposi's sarcoma (KS), also called drug-induced KS or immunosuppression-associated Kaposi's sarcoma, is a vascular neoplasia caused by human herpesvirus 8 (HHV-8) that manifests on the skin and mucous membranes of individuals with artificially impaired immune defenses.

Kaposi's sarcoma is classified as follows:

• Classic indolent Kaposi's sarcoma: This occurs in males in the 6th to 7th decade of life; often the initial lesion is a blue-red nodule of the skin associated with edema of the affected limb; subsequently there is a slow increase in the size as well as the number of lesions, ulceration may also occur. In a random Turkish collective of KS patients (n=137), the classic variant was the most common (64%).
• Endemic Kaposi's sarcoma: affects HIV-negative adults and children in Africa.
• AIDS-associated Kaposi 's sarcoma: most aggressive form of Kaposi's sarcoma in patients with AIDS; frequent skin lesions of the face, genitalia, and lower extremity; also frequent involvement of the oral mucosa, gastrointestinal tract, lymph nodes, or lungs.
• Iatrogenic Kaposi's sarcoma: affects patients after organ transplantation and on immunosuppressive therapy; very rare; develops after a few months to years after transplantation or immunosuppressive therapy. In a random Turkish collective of KS patients (n=137), the iatrogenic variant was the second most common variant at 27%. Approximately 30% of these patients were transplant recipients. 16 iatrogenic KS patients were systemically treated with a corticosteroid. 4 patients suffered from myasthenia gravis, 3 from rheumatoid arthritis (Baykal C et al. 2019).

Basically, from a clinical point of view, iatrogenic Kaposi's sarcoma can be distinguished between 2 collectives:

• Iatrogenic KS, after organ transplantation (0.5-5.3% of organ transplanted patients).
• Iatrogenic KS in various underlying diseases in which a long-term or permanent immunosuppressive therapy was necessary.

The iatrogenic variant is mainly associated with the use of immunosuppressive therapy.

Associated KS has been reported in the following underlying diseases:

• Rheumatoid arthritis (most reports of KS and drugs exist in this underlying disease).
• Psoriatic arthritis
• Sarcoidosis
• Eosinophilic granulomatosis with polyangiitis (Berti A et al. 2015)
• Myasthenia gravis (Frangiamore R et al 2021, Mantero V et al 2013; Baykal C et al 2019).
• Bullous pemphigoid (multicentric Kaposi's sarcoma of the skin developed after only a few months of immunosuppressive therapy with corticosteroids and mycophenolate mofetil (MMF) (Tremblay C et al. 2017).
• Pemphigus vulgaris (Avalos-Peralta P et al 2006).
• Severe atopic dermatitis
• Systemic lupus erythematosus
• Ulcerative colitis (in this underlying disease, it is not uncommon for Kaposi's sarcoma to have a cologenic lesional involvement of the intestine - see below. Kaposi's sarcoma and inflammatory bowel diseases).
• Crohn's disease (in this underlying disease, complicative KS occurs much less frequently than in ulcerative colitis).
• Granulomatosis with polyangiitis(Wegener's granulomatosis)
• bronchial asthma
• Thrombotic thrombocytopenic purpura
• Membrane proliferative glomerulonephritis

The following (immunosuppressive) drugs have been associated with Kaposi's sarcoma:

• Azathioprine/var. Diseases (Shahbazian H 2004).
• Corticosteroids/bullous pemphigoid/systemic lupus erythematosus/Crohn's disease/dermatomyositis/ bronchial asthma/membranoproliferative glomerulonephritis (Chen SA et al 2021/ Weiss VCet al 1982/ Hoshaw RA et al 1980/ Agbaht K et al 2007).
• Cyclophosphamide/Wegener's granulomatosis (Erban SB et al. 1988)
• Abatacept/rheumatoid arthritis (Olivo D et al. 2017)
• Infliximab/psoriatic arthritis(Ursini Fet al. 2010)
• Adalimumab/rheumatoid arthritis (Amadu Vet al. 2012)
• Golimumab/rheumatoid arthritis (Vural Set al. (2018)
• Leflunomide/Rheumatoid Arthritis. Skin and systemic organ involvement (Lee SY et al 2012).
• Mercaptopurine (Li J 2020)
• Methotrexate/bullous pemphigoid (Li J 2020/ Binois R et al. 2017)
• Mycophenolate mofetil/eosinophilic granulomatosis with polyangiitis (Berti A et al. 2015)
• Mycophenolatemofetil+prednisolone/pemphigus vulgaris (Avalos-Peralta P et al 2006)
• Rituximab/thrombotic thrombocytopenic purpura (Jerdan K et al 2017).
• Fingolimod/multiple sclerosis (Walker S et al. 2016)

While many affected patients are organ transplant patients, it must be considered that other forms of immunosuppression may also lead to the development of Kaposi's sarcoma. In transplant patients, iatrogenic KS can be observed due to the necessary application of systemic immunosuppressants.

Basically, HHV-8 is necessary for the development of Kaposi's sarcoma. Co-infection with human cytomegalovirus (HCMV) leads to pathogenicity enhancement of HHV-8 (Wells R et al. 2009). Furthermore, the type and duration of immunosuppressive therapy, age, and hormonal, geographic, ethnic, genetic, and environmental factors play a role in iatrogenic KS.

However, the histological picture of the four subtypes does not differ. While the early lesions of the skin are uncharacteristic, in the so-called patch stage an increased number of vascular clefts can be recognized. These are lined by flat to oval endothelial cells and show little or no atypia. Concomitantly, a lymphoplasmacytic cellular infiltrate may be present. Extravascular erythrocytes and hemosiderin are detectable.

In the plaque stage, all signs of the patch stage are somewhat more pronounced. In addition, hyaline globules may be found.

The nodular stage follows, in which the lesions are very sharply demarcated. They consist of spindle cells with only minor cytologic atypia and numerous slit-like cavities filled with erythrocytes. Again, hyaline deposits may be apparent both inside and outside the spindle cells.

Immunohistochemically, the cells of KS are positive for the endothelial markers CD31, CD34 and ERG as well as for the lymphatic marker D2-40. Likewise, they show nuclear expression of HHV8.

The first option is to discontinue or reduce the dose of the responsible immunosuppressive drugs. It is hoped that this will lead to healing or extensive regression of the lesions.

In addition,:

• radiotherapy for oral and cutaneous lesions
• Chemotherapy (local or systemic)
• Surgery (skin and intestine)
• Immunotherapy (local or systemic with interferon)
• Retinoic acid
• Imiquimod and
• cryosurgery as therapeutic options.

Clinical staging is essential for treatment. Localized disease can be treated with different local therapies, although there are no randomized trials comparing these different modalities. Aggressive, disseminated KS and cases with visceral involvement usually require systemic chemotherapy, usually with vinblastine, bleomycin , or paclitaxel.

KS after transplantation should be switched to m-TOR inhibitors if possible.

Ulcerative colitis: In cases of colonic involvement, proctocolectomy is the treatment of choice, as this therapeutic intervention can lead to cure of KS and ulcerative colitis (Li J et al. 2020; Svrcek M et al. 2009).

Iatrogenic KS, which develops in chronic rheumatic diseases due to prolonged use (consciously or unconsciously) of steroids, usually has a favorable course and often regresses with discontinuation and reduction of the dose of the drug. In patients receiving immunosuppressive treatment for nontransplant reasons, KS develops 2 to 4 times less frequently and much more slowly (Baykal C et al. 2019).

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