Cryotherapy Treatment of Cutaneous Kaposi Sarcoma in a Patient With B-Cell Chronic Lymphocytic Leukemia: A Case Report and Short Review of the Literature

Kaposi sarcoma (KS), a low-grade mesenchymal tumor involving the blood and the lymphatic vessels, primarily effaces the skin and is mediated by human herpesvirus 8 (HHV-8) in more than 90% of patients.^1-4

It was first described as multiple idiopathic pigmented hemangiosarcoma in elderly males by Moritz Kaposi at the University of Vienna in 1872.² Since then, clinicians have described 4 distinct types of KS. The endemic African form of KS was first described in 1914 and occurs predominantly among black adult men aged 25 to 40 years. In addition, a lymphadenopathic subvariant of the African form affects children at a mean age of 3 years.³ In the 1970s, the third form of KS was described, mainly in patients who are immunosuppressed. Indeed, immunosuppressant treatment in organ transplant recipients and patients on long-term corticosteroids or other immunosuppressive therapy is associated with increased risk for KS development. Additionally, the development of KS is more likely in patients who are immunosuppressed because of malignancy.¹ Finally, a fourth form, epidemic, has been recognized after the emergence of the HIV infection (AIDS-related KS), being predominantly multicentric, visceral, and disseminated, with a more aggressive behavior in comparison with classic KS.⁵

Chronic lymphocytic leukemia (CLL) associated with KS is a relatively rare clinical condition compared with the classic and AIDS-related variants; thus, only a few cases have been reported.^6-10 Reported is the case of an 87-year-old female with B-cell CLL in whom cutaneous KS developed and was managed with cryotherapy. Signed informed consent was obtained from the patient for publication of this case report and accompanying figures.

An 87-year-old female in whom B-cell CLL was diagnosed 4 years prior without any further special treatment was admitted to the authors’ institution. The patient reported a rapidly progressive, painless skin lesion on the dorsum of the left foot that first appeared 1 month prior. Personal medical history also included hypertension, type 2 diabetes, dyslipidemia, and beta thalassemia minor. One year before the current admission, cutaneous KS localized on the patient’s right foot was diagnosed and managed with local excision. The patient’s medications at the time of admission were enalapril and atorvastatin.

On admission, the patient’s weight was 58 kg and height was 1.65 m. Physical examination was unremarkable and the patient was afebrile. Blood pressure was 110/70 mm Hg, pulse rate was 80 beats per minute and regular, and respiratory rate was 17 breaths per minute. The skin lesion on the left foot was a dark brown, well-shaped nodule, 1.5 cm in diameter with a cicatricial nucleus and no accompanying edema (Figure 1). No other lesions were found. There was no lymphadenopathy.

Laboratory tests showed the following: erythrocytes 5.630/mm³, hemoglobin 11.2 g/dL, hematocrit 35.9%, leukocytes 21.340/mm³ (neutrophils 18.1%, lymphocytes 77.8%; monocytes 2.3%, eosinophils 0.9%; basophils 0.9%), platelets 197 000/mm³. Additional laboratory tests and a chest radiograph revealed no pathologic findings. Skin biopsy of the lesion was positive for KS. The lesion was negative for fungi and bacteria. Computed tomography of the chest, abdomen, and pelvis was performed, and neither tumor nor lymphadenopathy was revealed. Serologic tests for HHV-8 were not performed.

After the biopsy results were received, liquid nitrogen was sprayed on the tumor in a double freeze-thaw cycle once a week with freezing periods ranging from 10 to 30 seconds. After 4 weeks, most adhesions of the tumor had been lysed. The nodule had transformed into a red-brown fungiform tumor adherent to the dorsum of the foot (Figure 2), making it easily removable. The tumor was completely removed from the foot, and local pain was relieved by acetaminophen. The patient received daily standard wound care by a health care professional, and the wound was completely healed within 2 weeks. On reexamination 20 weeks later, the patient was asymptomatic; the lesion had no evidence of secondary infection, and the cosmetic result was considered acceptable (Figure 3). The patient experienced no complications or adverse events related to the cryotherapy treatment.

Epidemiology

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.³ In North America and Northern Europe, classic KS is rare.³ 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.¹¹ 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).¹² In Peloponnesus, the estimated rate is 0.8 per 100 000 individuals, with a dense clustering in parts of southern Peloponnesus.¹² 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.¹² It occurs more frequently during the fifth and sixth decades of life.³ 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.³ 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.³ 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.³

Clinical presentation

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.³ 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.³ 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.³ 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.¹³ 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.¹⁴ Enlargement of the lymph nodes, both superficial and deep, may precede the cutaneous manifestations.³ KS has been reported in virtually all anatomic sites, such as the nervous system, major salivary glands, adrenal glands, heart, and breast.¹⁵ 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.¹⁵

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.¹² 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 al¹ 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.¹ Subsequently, HHV-8 has been documented in 95% of patients with 1 of the 4 types of KS.² 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).²

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.³ 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.¹¹

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 involvement¹¹(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.¹⁶ 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.¹⁵

Cryotherapy for the treatment of patients with cutaneous KS has been evaluated in a case series by Kutlubay et al.¹⁷  In this study with excellent results, 13 cases with 125 lesions were treated in an average of 3.2 sessions.¹⁷ 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.¹⁷

This case report provides limited supporting evidence due to the nature of cryotherapy being applied in only one case. In addition, this case represents the potential effect of cryotherapy in one of the types of KS and as such, may not accurately refer to the entire KS population. Further studies should be conducted to support the effectiveness of this method.

Cryotherapy has been used in a variety of cutaneous malignancies. The microscopic effects of liquid nitrogen application on tissues mainly due to the reduction of local temperature and consequent freezing have been studied widely in vitro and in vivo. Considering that the method is relatively simple and with few adverse effects, the authors of the current study believe that cryotherapy may represent a simple and safe treatment method for cutaneous KS. However, more studies should be conducted to further evaluate the effectiveness of cryotherapy as a promising treatment for cutaneous KS.

Authors: John Doupis, MD, PhD¹; Georgios Festas, MD¹; Konstantinos Tsekouras, MD¹; Antonios Seretis, MD¹; and Christos Fountzilas, MD, FACP²

Affiliations: ¹Department of Internal Medicine and Diabetes, Salamis Naval and Veterans Hospital, Salamis, Greece; ²Roswell Park Comprehensive Cancer Center, Scott Bieler Clinical Science Center, Buffalo, NY

Disclosure: The authors disclose no financial or other conflicts of interest.

Correspondence: John Doupis, MD, PhD, Department of Internal Medicine and Diabetes, Salamis Naval and Veterans Hospital, Salamis Naval Station, 18900, Salamis, Greece; john.doupis@harvard-alumni.org