Paraneoplastic scleroderma in Kaposi's sarcoma: Report of two cases

Abstract Kaposi's sarcoma (KS) is a proliferative and multifocal disease with a double vascular and fibroblastic cell component, of mucocutaneous and visceral expression. It is a multifocal tumoral process, hyperplastic in nature without metastatic potential, induced by the human herpes virus 8 (HHV8). Paraneoplastic syndromes (PS) in KS are rare, with only a small number of cases reported and we have found no previous descriptions of a paraneoplastic scleroderma in KS in the literature. We report the cases of two patients with this atypical PS.


| INTRODUCTION
Kaposi's sarcoma (KS) is a proliferative and multifocal disease with a double vascular and fibroblastic cell component, of mucocutaneous and visceral expression. It is a multifocal tumoral process, hyperplastic in nature without metastatic potential, induced by the human herpes virus 8 (HHV8).
A paraneoplastic syndrome (PS) is a syndrome that is the consequence of neoplasia in the body, due to the production of chemical signalling molecules (such as hormones, chemokines, or cytokines) by tumour cells or by an immune response against the tumour. Unlike a mass effect, it is not due to the local presence of cancer cells. 1 PS in KS are rare, with only a small number of cases reported and we have found no previous descriptions of a paraneoplastic scleroderma in KS in the literature.
We report the cases of two patients with this atypical PS.

| Patient 1
An HIV-negative 45-year-old Moroccan patient, with a history of pulmonary tuberculosis treated in 2020 presented with angiomatous nodules of the lower limbs with a scleroderma-like condition that has been developing for 12 years. On clinical examination, we found ecchymotic purple nodules of hard consistency based on sclerotic plaques on the lower limbs, with sclerodactyly on the left side (Figure 1a,b). Raynaud phenomenon was absent and no capillaroscopy changes were noted.
The clinical differential diagnosis of the sclerodactyly included systemic sclerosis, acrodermatitis chronica atrophicans, POEMS syndrome and a diabetic cheiroarthropathy.
To rule out this diagnosis, a complete biologic work up was performed, including antinuclear antibodies (ANA) and borreliosis serology which were negative, and a protein electrophoresis which was normal. The electroneuromygram was normal.
Histological examination of the nodules showed spindle cells (Figure 2A.a) expressing the CD34 antigen with a positive HHV8 staining confirming KS, while the histology of the sclerotic lesions on the left hand showed scleroderma ( Figure 2B.a).
The extension assessment was carried out including a thoracic-abdominal-pelvic computed tomography scan and a fibrocolonoscopy which found no visceral involvement of KS nor systemic sclerosis.
The patient was treated with ABV chemotherapy (doxorubicin, bleomycin and vincristine) due to extensive skin involvement. The evolution was marked by the worsening of the lesions motivating a therapeutic switch to paclitaxel and the patient died after three sessions of taxanes after a septic shock secondary to chemotherapy-induced immune deficiency.

| Patient 2
An HIV-negative 50-year-old Moroccan patient previously healthy, presented with angiomatous nodular lesions localized on all four extremities, which had been developing for 2 years. Clinical examination also found lesions in favour of KS with a sclerodermiform appearance of the right hand characterized by irreducible flexion of the last three fingers (Figure 1c). In this case also, no Raynaud phenomenon nor capillaroscopy changes were noted.
Given the similar differential diagnosis as patient 1, the same biological and radiological assessment were performed eliminating the abovementioned diagnoses and no visceral involvement of KS or systemic sclerosis were found.
A skin biopsy of the nodules confirmed KS (Figure 2A.b) and the histopathological results of the sclerotic lesions showed scleroderma ( Figure 2B.b).
Bleomycin-based monochemotherapy was started for this patient, complicated by febrile pancytopenia, prompting the therapeutic switch to paclitaxel associated with growth factors.
The evolution was marked by the improvement of KS lesions and incomplete regression of sclerodactyly.

| DISCUSSION
KS is a multifocal disease. Its evolutionary spectrum ranges from an indolent locoregional form to a disseminated and fulminant form. PS in KS are rare, with only a small number of cases reported; autoimmune haemolytic anaemia is the most frequent 2 and three other PS have been reported and are represented in Table 1. [3][4][5] Dermatological paraneoplastic syndromes are a group of cutaneous or mucocutaneous syndromes characterized by their association with neoplasia and by a parallel evolution to the tumour 6 as in the case of our patients in whom the evolution of the KS and scleroderma was parallel.
The elimination of other diagnoses that could induce a scleroderma-like disorders helped us to retain the diagnosis of paraneoplastic scleroderma.
Unfortunately in the first case, the patient died due to complications of chemotherapy, without having had time to see the evolution of the sclerotic lesions or the KS. For the second case, the evolution after treatment was marked by an incomplete resolution of the sclerodactyly. The improvement would be due to the treatment of the KS, which reinforces the theory of paraneoplastic scleroderma.
The incomplete resolution of sclerodactyly is probably due to the importance of the fibrosis and its late stage.
The association between KS and a scleroderma is unclear, we suggest that since in KS both fibroblasts and endothelial cells are infected by HHV8, inducing the production of pro-angiogenic and inflammatory cytokines, 7 it could lead to cellular dysfunction and the overproduction of Transforming Growth Factor Beta and Vascular Endothelial Growth Factor that stimulate the fibroblasts to synthesis excess of collagen and fibrosis as it occurs in systemic scleroderma. 8 Summing up, our case suggests the possibility of the development of scleroderma through paraneoplastic mechanisms in subjects affected with KS. Future studies to shed light on this theory are needed.

CONFLICT OF INTEREST
The authors have no conflicts of interest to disclose.