Kaposi’s sarcoma in AIDS patients: a case series

Introduction

Kaposi’s sarcoma is a condition first described in the 19th century by the Viennese dermatologist Moritz Kaposi. The manifestation of the condition described at that time − now known as the classical or European type − is characterized by the presence of numerous small hemorrhagic plaques or nodules on the skin of the extremities. It predominantly affects elderly men in the Mediterranean region of Eastern Europe [1]. Other variants of Kaposi’s sarcoma, each with a distinct clinical presentation, include the endemic African form, the iatrogenic form associated with the use of immunosuppressive drugs, and the epidemic form seen in HIV-infected individuals [2].
The development of Kaposi’s sarcoma is linked to infection with a virus from the gamma herpesvirus family (Kaposi’s sarcoma-associated herpesvirus – KSHV, also known as HHV-8) [3]. HHV-8 was first identified in Kaposi’s sarcoma lesions in 1994 [4]. The mechanism underlying the pathogenicity of HHV-8 is not yet fully understood. HHV-8 is transmitted through various routes, including saliva, sexual contact, vertical transmission, and blood-borne exposure. The viral load in both the lesions and serum is associated with the progression of Kaposi’s sarcoma [5].
The incidence of Kaposi’s sarcoma in HIV-infected patients has significantly decreased following the introduction of highly active antiretroviral therapy (HAART). Unfortunately, the disease can also occur in patients with an undetectable viral load and a CD4 count above 300 cells/µl [3].
Tumor lesions in the AIDS-related form of Kaposi’s sarcoma lack a characteristic location; sarcoma can develop on the skin or in internal organs, including the kidneys, lungs, gastrointestinal mucosa, and lymph nodes. The likelihood of developing the disease is inversely related to the number of CD4+ cells, with a significant increase in risk occurring particularly when the CD4+ cell count falls below 200 cells/µl. Patients with a viral load greater than 100,000 copies/ml are also at an increased risk of developing Kaposi’s sarcoma.

Objective

We present 3 cases of Kaposi’s sarcoma in patients who, following suspicion of Kaposi’s sarcoma and extensive diagnostic work-up, were diagnosed with AIDS and subsequently started on treatment.

Case reports

Case 1

A 38-year-old patient was admitted to the Department of Infectious Diseases due to suspected HIV infection. During hospitalization, a consultation with a dermatologist was arranged to evaluate nodular-infiltrative skin lesions, reddish-brown in color, which the patient stated had initially appeared around 8 years prior. The lesions on the back followed skin tension lines (fig. 1), while those on the extremities were encircled by a distinct yellowish halo (fig. 2). On admission, the patient was cachectic and in fair general condition, without fever. Physical examination revealed enlarged peripheral lymph nodes, painless on palpation and forming clusters. During hospitalization, a series of laboratory tests were conducted, including tests for syphilis, chlamydia, HIV, HCV, and HBV. Physical examination revealed a dozen or so reddish-brown plaques, each approximately 1–2 cm in diameter. The patient reported no itching associated with the skin lesions. The man stated that an HIV screening test conducted 6 years prior had yielded a negative result; however, no medical documentation was provided to corroborate this claim. Physical examination showed enlarged peripheral inguinal and axillary lymph nodes.
Laboratory tests detected no other infectious diseases besides HIV infection. The HIV-1 RNA viral load was 1.91E+5 cp/ml, and the CD4 T cell count was 276 cells/µl (normal range > 540). Imaging studies revealed several abnormalities, including numerous scattered nonspecific nodular lesions of varying sizes (3–14 mm) in both lungs; enlarged lymph nodes in the pulmonary hila; enlarged, circumferentially enhancing lymph nodes in the thorax near the diaphragm; enlarged, circumferentially enhancing axillary lymph nodes; and very numerous circumferentially enhancing focal lesions in the liver. The appearance of the lesions in the liver and lungs was described as non-specific and could be indicative of changes associated with lymphoma, Kaposi’s sarcoma, metastasis, or inflammatory conditions (e.g. fungal infections). Gastroscopy revealed changes in the stomach and duodenum consistent with Kaposi’s sarcoma, and a biopsy of the lesions in the gastric body confirmed Kaposi’s sarcoma.
Laboratory tests showed mild anemia and elevated inflammatory markers. Histopathological examination of the skin revealed a proliferation of small vessels, with spindle cells and lymphoid infiltrates present (fig. 3). Immunohistochemical staining confirmed the endothelial origin of the spindle cells, based on the presence of CD34 and CD31 markers. Detection of HHV-8 through immunohistochemical staining confirmed nuclear transformation of the cells induced by HHV-8, a characteristic feature of Kaposi’s sarcoma (fig. 4).
The patient received antiretroviral therapy and oncological treatment (pegylated doxorubicin). He remains under the care of the Acquired Immunodeficiency Outpatient Clinic and the Dermatology Outpatient Clinic.

Case 2

A 55-year-old male patient was referred to the Department of Dermatology with suspected sarcoidosis due to infiltrated blue-red plaques on the tip of the nose, upper limbs, in the oral cavity, and in the genital area. Some of the lesions were encircled by a yellowish halo (fig. 5). Dermoscopic evaluation of the skin lesions revealed blue-red, structureless areas, along with white nodules on a pink-red background (fig. 6). Initially, the patient denied any involvement in sexual activities that could be considered high-risk. Laboratory tests showed the following abnormalities: HIV Ag/Ab positivity, TPHA positivity, and RPR negativity.
After reviewing the test results and informing the patient about the infection, further updated information was obtained from his history: MSM, with high-risk passive and active anal sexual contacts starting at the age of 20.
Since the patient had not received treatment for syphilis previously, treatment with benzathine penicillin was initiated. HBV, HCV, Neisseria gonorrhoeae, and Chlamydia trachomatis infections were excluded. The CD4 T lymphocyte count was 395 cells/µl. The patient was referred to an infectious disease specialist for further evaluation. Following additional diagnostic tests, HIV treatment was initiated as per the recommendations (bictegravir, emtricitabine, and tenofovir).
The patient was referred for oncology treatment. At an outpatient follow-up 1 year after initiating treatment with pegylated doxorubicin, a significant improvement in skin lesions was observed.
The patient remains under the care of the Acquired Immunodeficiency Outpatient Clinic, the Oncology Outpatient Clinic, and the Dermatology Outpatient Clinic.

Case 3

A 35-year-old patient was evaluated by a dermatologist due to infiltrated blue-red plaques on the tip of the nose and lower limbs, as well as nodular lesions on the hard and soft palate (fig. 7). Based on information obtained from the patient, the skin lesions had been present for many years, and it was only the development of lesions on the palate, hindering food intake, that led the patient to seek medical attention. The lesions were painless.
The MSM patient reported a history of high-risk sexual activities. Laboratory tests showed HIV Ag/Ab positivity, TPHA negativity, and RPR negativity. Further testing confirmed the presence of HIV-1. No Chlamydia trachomatis or Neisseria gonorrhoeae was detected in swabs from the nasopharynx, urethra, and anus. The viral load was 1.91E+5 cp/ml, while the CD4 T cell count was 276 cells/µl.
The diagnosis of Kaposi’s sarcoma was confirmed through histopathological analysis of tissue samples taken from the skin and palate lesions. The microscopic image reveals a skin fragment with proliferation of small vessels and spindle cells, accompanied by lymphoid infiltrates containing plasma cells and hemosiderin granules. Immunohistochemical tests showed the following results: ERG (+), HHV-8(+), CD34(+), CD31(+), Ki67 (approx. 30%), confirming infiltration of the dermis by spindle-shaped cells with endothelial markers, with HHV-8 transformation and a proliferative activity of approximately 30%.
In the Department of Infectious Diseases, the patient underwent an expanded diagnostic work-up, and antiretroviral treatment was initiated. Because Kaposi’s sarcoma was found to involve the gastrointestinal tract, the patient was referred for oncological treatment.

Discussion

In the course of Kaposi’s sarcoma, a variety of skin lesions are observed, including macules with an ecchymotic appearance, infiltrates, nodules, and ulcerations. Possible bleeding within the lesions and subsequent hemosiderin deposition result in a yellowish or greenish halo surrounding the lesions [6]. Kaposi’s sarcoma lesions are cohesive and detectable on palpation, even during the erythematous phase. Initially, they are oval in shape, and on the trunk their arrangement follows the skin’s tension lines (fig. 1). Dermoscopic features of Kaposi’s sarcoma include white lines, white papules, the collar sign, polychromy, and various vessel patterns such as serpentine, dotted, and curved [7–9]. Skin lesions and changes within the mucous membranes usually occur without any subjective symptoms. The differential diagnosis should include lymphoma, angiosarcoma, gummatous syphilis, sarcoidosis, bacillary angiomatosis, blastomycosis, and cryptococcosis [10].
In HIV-infected patients, lesions typically appear early on the face, genital mucous membranes, eyes, and oral cavity. Internal organ involvement may include the gastrointestinal tract and respiratory system. Respiratory involvement may manifest as a persistent cough unresponsive to treatment, shortness of breath, and progressive respiratory failure.
Kaposi’s sarcoma is a tumor originating from the endothelial cells of blood and lymphatic vessels. It is characterized by the proliferation of spindle-shaped cells, leading to the formation of vascular gaps lined with abnormal endothelium. Initially, Kaposi’s sarcoma growth presents as extensive reactive proliferation in response to angiogenic factors [5]. The image is not ‘typically’ indicative of malignancy; therefore, it is crucial to raise clinical suspicion of Kaposi’s sarcoma and inform the pathomorphologist evaluating the biopsy specimen in the referral. Over time, the proliferation becomes monoclonal. The diagnosis of Kaposi’s sarcoma is based on the clinical presentation and histopathological examination, supplemented by immunohistochemical evaluation, including the detection of KSHV LANA (latency-associated nuclear antigen) and CD34. In patients with negative immunohistochemical results for HHV-8, when the histopathological findings suggest Kaposi’s sarcoma, PCR testing is recommended to detect the presence of HHV-8. According to the literature, negative HHV-8 test results in some cases of Kaposi’s sarcoma may be attributed to low tumor differentiation [11].
The exact mechanism by which endothelial cell transformation occurs as a result of HHV-8 infection and the development of Kaposi’s sarcoma is not known [12]. The latent nuclear antigen-1 (LNA-1) genes, the gene encoding cyclin D homolog (v-cyclin), the v-FLIP protein homolog, and the activation of the PI-3, MAP, and mTOR kinase signaling pathways are likely involved in the process.
Kaposi’s sarcoma is an aggressive vascular tumor that can involve internal organs. For diagnostic purposes, it is recommended that patients undergo comprehensive imaging examinations, including computed tomography of the lungs, abdomen, and pelvis. In patients with symptoms suggesting gastrointestinal involvement, endoscopic examinations are essential. If lung imaging results are suggestive of an underlying disease process, bronchoscopy is advised for further evaluation [13].
In patients with Kaposi’s sarcoma limited to the skin, complete resolution of lesions is achievable with Highly Active Antiretroviral Therapy (HAART). This treatment regimen consists of a combination of three or more antiretroviral drugs. Another term for HAART is combination antiretroviral therapy (cART). The core principle of HAART is the concurrent use of multiple drugs that inhibit HIV replication through various mechanisms, so that potential resistance to one drug does not necessarily lead to a lack of a therapeutic effect. HAART works by inhibiting HIV replication and directly hindering angiogenesis.
In patients with severe skin lesions due to Kaposi’s sarcoma, local treatment may be recommended in addition to cART. The literature reports also suggest the use of 0.1% alitretinoin (gel, unavailable in Poland) [14], as well as imiquimod and timolol [15]. Gu et al. described a local treatment regimen for Kaposi’s sarcoma consisting of cryotherapy followed by the application of imiquimod cream three times per week for 2 months in a group of 9 patients. The patients were monitored every 3 months, with the median time to remission being 30.5 weeks, which corresponded to two treatment cycles [16].
Glucocorticosteroids, whether used systemically or topically, are contraindicated in patients with Kaposi’s sarcoma due to the risk of disease progression.
In cases of severe skin lesions, causing significant defects, patients may be referred for systemic chemotherapy or radiotherapy.
When the gastrointestinal or lung mucosa, lymph nodes, or parenchymal organs are involved, chemotherapy is required in addition to cART. Anthracyclines are considered the primary therapeutic option. Doxorubicin is an anthracycline antibiotic with cell-toxic properties. One of the proposed mechanisms of action of doxorubicin involves the formation of stable complexes with DNA molecules and enzymes responsible for maintaining DNA’s normal structure. The process disrupts nucleic acid integrity, inhibits replication and transcription, and ultimately leads to cell death. This action primarily targets rapidly dividing cells, including cancer cells. Pegylated doxorubicin is available in liposomal form, with the doxorubicin solution enclosed inside the liposomes. Compared to the standard form of doxorubicin, liposomal doxorubicin stays in circulation longer and has reduced cardiotoxicity. If liposomal doxorubicin proves ineffective or in the case of disease relapse, paclitaxel preparations are used. An alternative treatment option is pomalidomide. Other therapeutic modalities when prior treatment has failed include bevacizumab, gemcitabine, imatinib, etoposide, interferon, nab-paclitaxel, thalidomide and vinorelbine [17, 18].
Oncological treatment of Kaposi’s sarcoma does not eradicate HHV-8, which leaves a risk of disease relapse. After completing first-line treatment, if the patient achieves remission or the disease stabilizes, they are monitored under oncological supervision for at least 2 years.
According to the literature, the proportion of patients achieving complete remission of Kaposi’s sarcoma with cART alone ranges from 20% to 80%. Therapeutic efficacy is greater in patients with disease limited to the skin [19].

Conclusions

Kaposi’s sarcoma is a tumor of vascular origin that can affect the skin and mucous membranes, and in more aggressive forms, especially in immunosuppressed patients, also internal organs. In the treatment of HIV-infected patients with Kaposi’s sarcoma, ARV therapy plays a crucial role. Since early diagnosis is vital for prognosis, attention should be given to the typical clinical features of this tumor.

Funding

No. 503/1-064-01/503-11-001.

Ethical approval

Not applicable.

Conflict of interest

The authors declare no conflict of interest.

References