Kaposi sarcoma associated with lymphoproliferative malignancies is rather rare; therefore, there are limited data in managing patients with this disease. Typically, classic KS follows a benign course and predominantly occurs in elderly people, particularly males of Mediterranean, Eastern European, and Middle Eastern descent. In North America and Northern Europe, classic KS is rare. The highest incidence rates in Europe were reported in two Mediterranean Italian islands—Sardinia and Sicily—whereas the lowest rates were reported in England and Wales. In Greece, classic KS has an estimated annual incidence of 0.47 new cases per 100 000 individuals (incidence in males, 0.62; incidence in females, 0.32). In Peloponnesus, the estimated rate is 0.8 per 100 000 individuals, with a dense clustering in parts of southern Peloponnesus. In Greece, classic KS exhibits some unique characteristics, including older age of onset, lower male to female ratio, endemic clustering, and disseminated skin disease at diagnosis. In addition, it is often accompanied by lymphedema along with visceral or lymph node involvement. It is also frequently associated with secondary malignancies. It occurs more frequently during the fifth and sixth decades of life. Worldwide, occasional cases of classic KS have been reported in children, whereas only 4% to 8% of the classic KS cases were observed in individuals younger than 50 years. Furthermore, a higher incidence of KS among males than females has been reported and, in general, lower sex ratios for classic KS occur in populations with low incidence rates. A temporal increase in the incidence rate of classic KS has been observed, probably due to general improvements in health care for elderly people, improved information/registration processes, iatrogenic immunodeficiencies (eg, by corticosteroids), and medical procedures that result in mild immunologic impairment.
Classic KS first manifests as bluish-red, well-demarcated, painless maculae on distal portions of the lower limbs, often resembling granulation tissue. In most instances, the lesions progress slowly and may merge into large plaques. However, solitary lesions occasionally progress to form nodular and fungi-formed, brownish-red tumors. Old lesions may erode, bleed, and even ulcerate. Unilateral involvement generally is observed at the onset of KS; however, subsequently, the disease tends to be bilateral and "multifocal" with centripetal spreading. They can also become brownish and may display verrucous and hyperkeratotic surfaces. Eczematous changes can be seen, especially along with stasis dermatitis. Unlike early "angiomatous" lesions, which are soft and spongy, the older tumors are hard and solid. A striking edema can also accompany the main lesion. It can occasionally antedate the cutaneous lesions and can be particularly pronounced on the lower extremities. As with the cutaneous lesions, the edema initially is unilateral, later involving both lower extremities. The initial pitting edema can evolve into nonpitting, fibrotic swelling of the involved limb.
Pathophysiology, Classification, and Treatment
Kaposi sarcoma lesions are classified clinically into 6 major overlapping types: patch, plaque, nodular, lymphadenopathic, infiltrative, and florid. Other variants, such as telangiectatic KS, are rarely observed. Three additional clinical forms of KS lesions have been described: KS presenting as generalized lymphedema, ecchymotic KS, and keloidal KS. Ecchymotic KS is characterized by persistent ecchymotic patches, which may be periorbital and contain massive amounts of extravasated erythrocytes. Keloidal KS is frequently found in patients with classic KS and is characterized by fibrous patches localized in the lower extremities. The form and appearance of the skin lesions can vary within the same patient as different stages of development of KS can be present simultaneously. Sites other than the skin can also be involved, such as the gastrointestinal tract, lungs, lymph nodes, and upper airway. Involvement of internal organs in classic KS occurs only in approximately 10% of the cases. Enlargement of the lymph nodes, both superficial and deep, may precede the cutaneous manifestations. KS has been reported in virtually all anatomic sites, such as the nervous system, major salivary glands, adrenal glands, heart, and breast. The occurrence of KS in any of these atypical sites makes the diagnosis very difficult, especially when patients are asymptomatic. Kaposi sarcoma also can develop in traumatized tissue lesions (possibly Koebner phenomenon) or pemphigus.
Kaposi sarcoma is one of the most enigmatic malignancies. It remains unclear whether it is a true malignancy, a reactive proliferation, or both. Early KS seems to be a reactive process of polyclonal nature, which in some cases remains so, or in other cases, progresses to become a true sarcoma. Its cellular origin is difficult to determine because the lesions include several cell types. Patch-stage KS, the earliest pattern, typically arises in the reticular dermis. A proliferation of small and irregular endothelium-lined spaces surrounding normal dermal vessels and adnexal structures accompanied by a variable, inflammatory lymphocytic infiltrate (with or without plasma cells) is characteristic.[4,12] Plaque-stage KS represents the expansion of a spindle-cell vascular process throughout the entire dermis, extending in some cases to the subcutaneous fat. Spindle cells form irregular, cleft-like, angulated vascular channels that contain varying numbers of erythrocytes.[4,12] Hemosiderin deposits and eosinophilic hyaline globules are typically present, along with a perivascular inflammatory infiltrate. In addition, histiocytes (with phenotype factor XIIIA or S-100), dermal dendritic cells, and T cells and B cells, including plasma cells, are also present.[4,12] Nodular-stage KS lesions are composed of sheets and fascicles of spindle cells with mild to moderate cytologic atypia, single-cell necrosis, and trapped erythrocytes within an extensive network of slit-like vascular spaces. Vessels lack a prominent investment of pericytes and have a fragmented basal lamina with frequent discontinuities in the endothelial lining.[4,12] Erythrophagocytosis and necrosis of individual endothelial cells may also occur. Most of the spindle cells in KS lesions express endothelial markers, including CD31 and CD34. Considerably fewer numbers of cells express factor VIII-related antigen. However, KS spindle cells also express markers of smooth muscle cells, macrophages (CD68), and dendritic cells, suggesting that spindle cells are either derived from pluripotent mesenchymal precursors or represent a heterogeneous population of cells. Importantly, KS spindle cells do not stain with PAL-E, a marker expressed on vascular endothelium, but not on lymphatic endothelium.[4,12]
In 1994, Chang et al identified a new human herpesvirus, HHV-8 . Further studies proved that HHV-8 was present in more than 90% of the KS lesions, including those unrelated to HIV. Subsequently, HHV-8 has been documented in 95% of patients with 1 of the 4 types of KS. Found in saliva and semen, HHV-8 appears to be spread through sexual activity, kissing, and contact with saliva—similar to routes of transmission of other herpes viruses. Studies have shown that the prevalence of HHV-8 antibodies increases with age, shows wide fluctuations geographically, and is dependent on the detection assay (ie, antibodies to latency-associated nuclear antigens or lytic cycle antigens).
Because classic KS is an indolent disease and rarely accounts for patient demise, it may denote an underlying other malignancy.[4,5] Thus, it may serve as a clinical indicator for altered immunologic surveillance mechanisms, resulting in primary classic KS and subsequent neoplasm or vice versa. Associations between KS and non-Hodgkin lymphoma, Hodgkin lymphoma, leukemia, thymoma, multiple myeloma, and malignant melanoma were observed more than 100 years ago, prior to the AIDS epidemic. It appears to be a 20-fold increased risk of the development of hematopoietic neoplasms (mostly non-Hodgkin lymphoma and leukemia) once classic KS is diagnosed. Thus, KS could be the product of a myriad of complex interactions between HHV-8 infection, immunosuppression, and selected substances such as angiotensin-converting enzyme inhibitors, nitrite inhalants, platelet-derived growth factor beta, tumor necrosis factor, interleukins, basic fibroblast growth factor, oncostatin-M, vascular endothelial growth factor, granulocyte-macrophage colony-stimulating factor, transforming growth factor beta, and gamma interferon.[2,3] Inflammatory cytokines and growth factors have been shown to have potent effects on the recruitment of herpesvirus-infected cells into tissue sites and induction of virus replication, leading to local dissemination of the infection.
A proposed staging system for KS is based on objective criteria that more closely follow the clinical variability of the disease, making the therapeutic choices easier. This staging system comprises 4 stages based on skin lesions: localization, presence or absence of complications, and visceral involvement (Table). In stages I and II (slow evolution), therapeutic strategies include different approaches depending on the features of KS, specifically clinical monitoring, or local therapy such as excision, laser, cryotherapy, radiation therapy, alitretinoin, and intralesional injection of vinblastine, although the disease tends to recur.[11,15] Short-term cure rates of 70% with cryotherapy in cutaneous KS have been reported. For the patients with stage III or IV and patients with stage II who present with rapid evolution or complications, systemic chemotherapy is generally warranted. Liposomal doxorubicin has proved to be an effective and safe choice in managing classic KS in the elderly population.
Cryotherapy for the treatment of patients with cutaneous KS has been evaluated in a case series by Kutlubay et al. In this study with excellent results, 13 cases with 125 lesions were treated in an average of 3.2 sessions. Complete response was observed in 19 of the 30 patients (63%) after cryotherapy treatment with no recurrence. The patients did not present significant adverse events, and the treatment was well tolerated.
Wounds. 2022;34(1):E1-E6. © 2022 HMP Communications, LLC