Cutaneous Squamous Cell Carcinoma Mimicking Kaposi Sarcoma in an HIV-Positive Patient: Diagnostic Challenges and Therapeutic Response to Liposomal Doxorubicin

Cutaneous malignancies are among the most common cancers worldwide, with cutaneous squamous cell carcinoma (cSCC) being the second most frequent non-melanoma skin cancer. In people living with HIV (PLHIV), cSCC may present atypically and overlap clinically with opportunistic tumors such as Kaposi sarcoma (KS), complicating diagnosis and management. Immunosuppression increases the risk of aggressive and multifocal cSCC, often delaying diagnosis. Liposomal doxorubicin, an anthracycline-based chemotherapy standardly used for KS, has shown limited off-label activity against other cutaneous malignancies. This report describes an unusual case of HIV-associated cSCC that initially mimicked Kaposi sarcoma and responded unexpectedly to liposomal doxorubicin. We report a 64-year-old woman with well-controlled HIV infection on antiretroviral therapy who presented with a progressively enlarging, exophytic scalp lesion. The initial punch biopsy was inconclusive. Imaging showed no bony involvement, although advanced modalities (MRI or PET/CT) could have better assessed soft tissue and distant spread. Given clinical suspicion of KS and inoperability of the lesion, empirical treatment with liposomal doxorubicin (20 mg/m²) was initiated. After four cycles, the lesion demonstrated marked clinical and radiologic regression. Subsequent surgical excision revealed keratinizing squamous cell carcinoma with tumor-free margins. The patient tolerated chemotherapy well, and a six-month follow-up showed no recurrence. This case underscores the diagnostic overlap between KS and cSCC in HIV-positive patients, emphasizing the limitations of single biopsies and the need for repeated histopathology and multidisciplinary evaluation. The unexpected regression of cSCC with liposomal doxorubicin suggests potential off-label antitumor activity through DNA intercalation, topoisomerase II inhibition, and reactive oxygen species generation. While not a standard therapy for cSCC, doxorubicin may act as a bridge to definitive surgery in select high-risk or immunocompromised patients. Clinicians should maintain high suspicion for atypical cSCC in PLHIV. Repeated histopathologic assessment and multidisciplinary management are essential. This case highlights the potential dual benefit of liposomal doxorubicin in inducing regression of non-Kaposi cutaneous malignancies, supporting further investigation into its role as a bridge to curative surgery.