Strategiile terapeutice și abordarea îngrijilor paliative în sarcomul Kaposi non-HIV avansat – studiu de caz şi revizuire a literaturii

Introduction

Although in most cases it develops slowly, Kaposi’s sarcoma (KS) is a rare angioproliferative tumor, mostly cutaneous, which under some circumstances can show aggressive behavior, leading to local invasion and visceral involvement⁽¹⁾. Four types of this pathology have been epidemiologically distinguished: classic Kaposi’s sarcoma, AIDS-associated Kaposi’s sarcoma, endemic Kaposi’s sarcoma, and iatrogenic post-transplant Kaposi’s sarcoma. Human herpesvirus type 8 (HHV-8) infection – sometimes referred to as Kaposi’s sarcoma-associated herpesvirus (KSHV) – is linked to etiology^(1-5).

With a notable frequency in Sub-Saharan Africa, where the endemic variant predominates, the incidence of KS has been calculated globally at 0.39 per 100,000 individuals. With incidence rates in Europe between 0.3 and 3 per 100,000 individuals, classic KS mostly affects elderly men of Mediterranean or Eastern European background. Related with immunosuppression (e.g., post-transplant or as a result of oncological treatments), iatrogenic KS has an incidence almost 100 times higher among transplant patients than in the general population^(6,7).

There is a quite different prognosis for non-HIV-associated KS. Whereas the endemic form in Africa has a moderate survival, estimated between 60% and 70%⁽⁴⁾, classic Kaposi’s sarcoma has a five-year survival rate between 81% and 90%. With a survival rate of about 54%, iatrogenic Kaposi’s sarcoma has the most reserved prognosis. Nodular lesions, visceral involvement and a high plasma viral load of HHV-8 – all linked with higher mortality – are negative prognostic elements⁽⁸⁾.

Therapeutic choices depend on the subtype and stage of the disease, as well as the immunological state of the patient. While aiming for total elimination of the formations, KS therapy emphasizes on stopping tumor growth⁽⁹⁾. Although surgery was once used in treating classic Kaposi’s sarcoma, given the high sensitivity of lesions to ionizing radiation, radiotherapy and chemotherapy are the therapeutic alternatives of choice nowadays⁽¹⁰⁾.

Emphasizing the need of a multimodal patient-centered approach, this article seeks to underline the part of palliative care and investigate several therapeutic approaches in the management of non-HIV-associated Kaposi’s sarcoma. In the framework of enhancing the patient’s quality of life, we hope to contribute to the development of ideal therapeutic management strategies for this rare oncological pathology by presenting this advanced case and comparing the outcomes with data found in recently reviewed literature, so addressing both symptom management and prevention of complications.

Case history

We report the case of a 76-year-old male patient diag­nosed with classic Kaposi’s sarcoma, who had a com­pli­ca­ted medical history, including several chronic co­mor­bi­di­ties: NYHA class I heart failure, atrial fibrillation, chronic obliterative arteriopathy, deep venous insufficiency, and type 2 diabetes mellitus. Given that this pathology is mostly linked to human immunodeficiency virus (HIV), the diagnosis in 2010 was non-HIV Kaposi’s sarcoma – a rare occurrence. Histopathological analysis confirmed an atrophic epidermis, underlying collagen sclerosis areas, lymphohistiocytic inflammatory infiltrate, and partially hyalinized capillary vascular proliferation, thus establishing the diagnosis.

Under external radiotherapy with 6-mEV electrons (30 Grey, 2 Gy/fraction, 15 fractions), Kaposi’s sarcoma changed and showed cutaneous lesions on the lower limbs in 2012. A fast development of KS was seen in the next months, and new lesions on the upper and lower limbs started to show. Consequently, a second course of external radiotherapy was instituted, with the same dosages, obtaining a favorable response: the treated lesions completely remitted, but in non-irradiated areas (thighs and upper limbs), erythematous-angiomatous and vesicular lesions with constant dimensions persisted.

Six months following the last course of external irradiation, in 2013, the patient showed up with a new recurrence of KS accompanied by noticeable lesions on the upper and lower limbs. While these treatments resulted in total remission of the treated lesions, repeated recurrences were gradually found during the course of the disease.

The patient thus showed several recurrences between 2015 and 2018, manifested by the appearance of notable purplish plaques, infiltrated, with red-purplish hemispherical nodules, up to 1-2 cm, located on the forearms, legs and posterior thighs. Although the disease was progressing, these lesions were not treated with radiation during that period.

With an extensive polymorphic eruption including macules, infiltrated plaques, and purplish tumors isolated and confluent, distributed on the upper and lower limbs, the patient presented to the dermatology department in February 2024, presenting lymphoedema of the left lower limb. Under local anesthesia with 2% Xyline, surgical intervention consisted in excisional debridement of the tumoral formations on the anteromedial side of the right thigh, then suture and dressing.

The patient benefited from multimodal therapy between March and July 2024: external radiotherapy at the Clinac linear accelerator, electron regimen, with curative intent, on the posterior side of the left thigh with a TD-30 Grey, 2 Gy/fraction, 15 fractions administered; systemic chemotherapy with doxorubicin-6 sequences, 40 mg/m², administered every three weeks, for the control of disseminated cutaneous disease and prevention of distant metastases. An improvement in pain symptomatology was noted at the end of therapy; this was shown by tissue epithelialization and the disappearance of ulcerations on the legs, indicating macroscopic appearance of cutaneous lesions. Still, the thighs’ lesions did not totally heal, and ongoing perilesional inflammatory edema persisted.

This case presents a series of particularities, including the absence of HIV infection, which makes this form of non-HIV Kaposi’s sarcoma quite rare, the unpredictable and distributed evolution of lesions, with multiple recurrences and variable response to treatment, and the presence of severe comorbidities, which can constitute risk factors for an unfavorable evolution of the disease, complicating the therapeutic management.

Discussion

The therapy of this case of non-HIV Kaposi’s sarcoma with high cutaneous dissemination and recurrent nature and several comorbidities required a multimodal therapy. The patient’s age and the existing comorbidities made it necessary to develop a therapeutic strategy that would aim at local control of the disease without causing significant systemic toxicity.

Elderly patients with comorbidities have Kaposi’s sarcoma, which is a complex therapeutic challenge in non-HIV patients and requires a specific and multimodal approach. Since the classical Kaposi’s sarcoma (CKS) affects the elderly with a median age at diagnosis of about 70 years old, the patient’s age is an important factor in the management of this type of the disease. Selecting a therapeutic plan should take the level of toxicity into consideration, as well as the efficacy of the treatment, especially in the elderly, who are likely to have other  comorbidities, such as cardiovascular diseases, diabetes mellitus and renal insufficiency, to stay away from severe adverse effects^(11-13). 

A study conducted in 2023 on patients with CKS treated with paclitaxel established that the mean age of the patients at the time of diagnosis was 67 years old, with a range of 39-86 years old. This is significant because the patient’s age is a critical determinant of the tolerance to chemotherapy and can vary greatly among patients based on their physiological reserve and tolerance to systemic toxicities which are to some extent dependent on themselves. Since Kaposi’s sarcoma is a recurrent disease and has a tendency to metastasize to different parts of the body, the management of the disease has to be done on an individual patient basis⁽¹⁴⁾. However, the progressive nature of the disease demands that many systems are put in place to control the disease which can decrease the therapeutic tolerance, increase the incidence of cumulative toxicity, and have adverse effects on the quality of life of the patients⁽¹³⁾. 

The use of radiotherapy is primary in the management of the disease. For the given patient, radiotherapy was the most appropriate local therapy, because it is used to alleviate skin lesions and prevent the spread of the disease. The patient also benefited from several sessions of external irradiation with electrons, without increasing the side effects and maximizing the therapeutic response. In the initial stages of the disease, external radiotherapy was used to manage localized lower limb lesions, and the patient achieved a complete remission. However, the disease continued to progress to other parts that were not irradiated and the management of new lesions depended on the degree of lesion development which required consecutive courses of external irradiation. The patient was palliatively treated with new radiotherapy on the posterior side of the left thigh in 2024. Although the treatment led to the healing of the skin ulcers and inflammation of the cutaneous lesions, it did not kill all the lesions on the thighs, and the edema was still present in the perilesional areas. 

The effects of radiotherapy on Kaposi’s sarcoma were noted once the first cases were reported at the end of the century, and this dermatologic condition has been confirmed to be radiosensitive^(15,16). Radiotherapy has remained a standard treatment for localized KS for many years, and it leads to high rates of clinical response when used both for curative and palliative purposes to alleviate symptoms and prevent disease progression⁽¹⁷⁾. Radiotherapy is a well-tolerated option that also improves the quality of life of patients and also shrinks the lesions⁽¹⁸⁾. 

Palliative or curative, the lesions’ location and the patient’s general condition, as well as the therapeutic goals will be used to determine the dose and treatment plan which will be designed for  the patient⁽¹⁹⁾. The side effects of the therapeutic plans used in radiotherapy for KS have been reported to be similar to those of various dose levels⁽²⁰⁾.

The cross-sectional research done in various journals show that tumors are sensitive to moderate doses of radiation, and the most common doses used are between 20 and 30 Gy. The overall tumor response rate noted in the literature ranges between 47% and 99%, thus showing that this treatment is effective. Furthermore, it is shown that all types of KS are radiosensitive: classical (sporadic), African (endemic), AIDS-related (epidemic), and iatrogenic (induced by immunosuppressive therapy)⁽¹⁷⁾.

The NCCN Guidelines state that the management of Kaposi’s sarcoma is determined by the patient’s characteristics and the stage of the disease. Symptomatic or cosmetic lesions can be observed without treatment in the initial stage. Local radiotherapy is recommended for symptomatic or cosmetically annoying lesions; the doses are between 20 and 30 Gy, and are given in fractions, depending on the area to be treated⁽²¹⁾. Fifteen Gy is effective in improving symptoms of oral lesions that can interfere with swallowing and eating, including ulceration. Eight Gy can be used as a single dose in a situation where there is a need for urgent intervention or in a case of a single and limited lesion; however, these produce lower rates of complete response. The choice of fractionation ranges from a single dose to the formulation of more extended schemes with smaller doses given weekly^(22,23).

Advanced forms of Kaposi’s sarcoma, with either systemic symptoms, visceral involvement, or extensive cutaneous dissemination, call for a systemic therapeutic approach. Depending on patient tolerance, first-line chemotherapy consists in courses of paclitaxel (80-100 mg/m²) or liposomal doxorubicin (20 mg/m² every 2-3 weeks). Being used for pain management, bleeding and edema reduction, as well as for cosmetic enhancement of cutaneous lesions, palliative radiotherapy is indispensable in controlling local symptoms in patients with Kaposi’s sarcoma^(27,28).

Examining 172 lesions in 71 treated patients, the paper “A dose-response analysis for classical Kaposi’s sarcoma management by radiotherapy”⁽²⁷⁾ investigated the dose-response relationship in radiotherapy for classic Kaposi’s sarcoma. Fractions of 1.8-8 Gy were used in total doses ranging from 8 to 64 Gy. The findings showed that rates of complete response were much higher in an equivalent dose in 2-Gy fractions (EQD2) of minimum 20 Gy than in lower doses^{(22,26,27,29,30)}.

The advised therapeutic approach for managing the spread of disease is systematic chemotherapy. The particular subtype of the disease, its degree, clinical evolution and patient symptoms define Kaposi’s sarcoma (KS) management. Systemic therapy’s primary goals are not the cure but rather the control of disease progress, symptom reduction, and patient quality of life maintenance⁽³¹⁾.

Systemic chemotherapy using pegylated liposomal doxorubicin was started, considering the high cutaneous dissemination and the risk of distant metastatic lesions. Aiming to control cutaneous disease and stop the emergence of distant metastases, this was given in six cycles (40 mg/m² every three weeks). The patient’s clinical condition improved significantly at the end of treatment; pain was reduced and the lesions on the legs showed regression.

Remarkably effective in both HIV-associated forms and advanced non-HIV cases, pegylated liposomal doxorubicin (PLD) has transformed the treatment of Kaposi’s sarcoma (KS). Particularly in the classic form, advanced non-HIV Kaposi’s sarcoma has responded completely at rates ranging between 71% and 100%. By helping doxorubicin to be preferably absorbed at the tumor level, the liposomal component increases its efficiency. This leads to a 10-20 times higher agent concentration in KS lesions than in unaffected skin, so contributing to better antitumor activity⁽³²⁾.

Few recent studies especially target the use of doxorubicin in advanced non-HIV Kaposi’s sarcoma. Since this kind of KS is still a more common and pressing issue worldwide, most of the available studies center on AIDS-associated Kaposi’s sarcoma. While PLD is generally agreed upon as first-line treatment for advanced Kaposi’s sarcoma – including in non-HIV cases –, most data come from older studies or research targeted on HIV-positive patient cohorts^(1,8,33).

Another research on doxorubicin in the framework of treatment alternatives for Kaposi’s sarcoma (KS) was released in 2023 in the Journal of Medical Virology. Using regimens developed even for AIDS-associated KS, the authors note that all forms of KS are essentially treated with cytotoxic chemotherapy, prior to the introduction of combined antiretroviral therapy (cART)⁽²⁾. The publication underlines that, since the introduction of pegylated liposomal doxorubicin, the therapeutic options have not notably advanced⁽³⁴⁾.

Depending on the features and location of the lesions, this could call for lesion excision, electrosurgery, or cryotherapy. Regarding advanced non-HIV Kaposi’s sarcoma, surgical intervention is quite important in controlling symptomatic and localized cutaneous lesions^(35,36).

Although used for local excision of significant ulcerative lesions, the surgical interventions have had a limited role during the course of the disease. Under local anesthesia with 2% Xyline, the patient underwent excisional debridement of tumor formations found on the anteromedial aspect of the right thigh in February 2024, then suturing and dressing. This operation was carried out with a palliative aim, in order to minimize pain and stop local complications.

For Kaposi’s sarcoma lesions with isolated and accessible features, local excision is the main therapeutic modality used, since it helps to totally remove tumor tissue. Particularly advised for patients with lesions subject to frequent trauma or causing great discomfort, this operation offers both esthetic and functional advantages. In clinical settings marked by significant disease, however, local excision may prove unworkable, and complementary therapeutic approaches may be necessary^(11-13,36).

Published in February 2024 as part of the therapeutic protocols offered by the National Cancer Institute of the United States of America (www.cancer.gov), Treatment of Kaposi’s Sarcoma (PDQ)⁽²⁸⁾ describes treatment strategies for many stages and types of Kaposi’s sarcoma^(14,16,28). Although it notes surgical excision as a possibility, its main emphasis is on other localized treatments for advanced disease, including systemic therapies⁽²⁸⁾.

Based on the idea of destroying tumor cells by controlled freezing, cryotherapy is a therapeutic method applied in the treatment of cutaneous lesions linked to Kaposi’s sarcoma. For minor and superficial lesions especially, this approach is especially successful, since it causes localized tissue necrosis and accelerates healing process^(37,38). Important criteria in pretherapeutic evaluation are size, location, and count of cutaneous lesions. While extensive or deep lesions may require other therapeutic approaches, small and superficial lesions are regarded to be sensitive to cryotherapy⁽³⁹⁾. Still, frequent interventions could be required to obtain the best results.

Cryotherapy is linked to local discomfort or pain, as well as the possibility of hypopigmentation or scarring⁽⁴⁰⁾. Particularly in limited cases of cutaneous Kaposi’s sarcoma, this approach is safe and effective, according to the authors of study from February 2025 that provided a valuable therapeutic alternative particularly for small and superficial lesions. Notably, the study concentrated on cutaneous forms of the disease and omitted to specify the type of Kaposi’s sarcoma – HIV-associated or non-HIV⁽³⁹⁾.

At the end of multimodal therapy in 2024, a partial remission of the disease was noted in the patient under observation in this case study; lesions on the legs disappeared and pain symptomatology improved. Still linked to perilesional inflammatory edema, the lesions on the thighs showed incomplete regression. The patient is under close clinical observation right now; she is scheduled for reassessment in three months to ascertain the post-irradiation response and modify the treatment plan, depending on disease development.

The aim of the therapy is to reduce the size of cutaneous lesions, relieve pain and local discomfort resulting from inflammatory edema, and manage the symptoms causing pain and local discomfort. Though the absence of lesions on the legs and the pain relief are encouraging indicators, the persistence of lesions on the thighs suggests that the disease has not been totally eradicated. In advanced Kaposi’s sarcoma, this partial response is not unusual; hence, constant monitoring and treatment modification are crucial to provide the best possibilities of survival and improvement of quality of life⁽³⁷⁾. Characterized by regression of some lesions while others persisted, the partial response seen in treatment reflects a commonly encountered clinical situation. This partial reactivity underlines the need of tailored treatment plans and ongoing observation of disease development^(37,41,42).

Even though there was an initial clinical improvement, the continuation of perilesional inflammatory edema on the thighs indicates a higher risk of recurrence, thus being a negative prognostic factor. Therapeutic challenges faced by the management of advanced and recurrent KS often hinder treatment choices and frequent recurrences^(37,41-43). In advanced stages, the disease can spread distantly (pulmonary, hepatic metastases), greatly changing the patient’s quality of life through systemic symptoms, inclu­ding dyspnea, abdominal pain or jaundice, and in some cases fever, night sweats and inexplicable weight loss^(43-45).

Conclusions

The treatment of advanced non-HIV Kaposi’s sarcoma is a complex clinical challenge requiring a multimodal and personalized approach due to frequent recurrences, variable treatment response, and multiple comorbidities. Radiotherapy plays a key role in local disease control, effectively managing cutaneous lesions and reducing symptoms, but the need for repeated treatments highlights the aggressive and recurrent nature of the disease.

Systemic chemotherapy with pegylated liposomal doxorubicin provides significant benefits in controlling disseminated disease and improving quality of life, despite persistent local lesions. It remains the first-line systemic therapy for advanced non-HIV Kaposi’s sarcoma, though therapeutic options remain limited. Recent studies suggest that immunotherapy could enhance patient outcomes.

Palliative care remains crucial for maintaining the patient’s quality of life, particularly given the psychological and physical burden of recurrent disease. While radiotherapy and systemic chemotherapy are essential treatments, frequent relapses and disease progression underscore the need for innovative strategies and continuous monitoring for timely intervention.

Autor corespondent: Anda-Elena Crișan E-mail: anda_crisan2005@yahoo.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.