Dermatologic Manifestations of Kaposi Sarcoma

In 1872, Moritz Kaposi (1837-1902) of Kaposvar, Hungary, a dermatology faculty member at the University of Vienna, first described idiopathisches multiples Pigmentsarkom der Haut, which has become known as Kaposi sarcoma (KS). Kaposi sarcoma had brownish red–to–bluish red cutaneous nodules that tended to enlarge into dome-shaped tumors. Kaposi observed similar neoplasms of the mucosa, especially of the larynx, trachea, stomach, liver, and colon. Kaposi's original 1872 description of 5 patients is more similar to the Kaposi sarcoma seen in AIDS (KS-AIDS) than the Kaposi sarcoma expected in elderly men of Italian, Jewish, or Mediterranean linkage, in whom the disease behavior is benign. Kaposi's original 5 patients died within 2-3 years. Kaposi later updated his data, noting that all of his 16 patients were men with a prognosis that remained unfavorable.

In 1882, Tommaso De Amici, Professor and Head, Dermatology, University of Naples, Italy published in monograph form a detailed analysis of 12 patients with Kaposi sarcoma.[11, 12]

For most of the first 3 quarters of the 20th century, Kaposi sarcoma was viewed as an indolent slowly growing cancer, and patients were expected to die with, rather than of, Kaposi sarcoma. The aggressive course originally noted by Kaposi has become part of the devastation of AIDS, especially among men who have sex with men.[13, 14]

HIV transactivating (tat) gene, cytokine, and HHV-8 stories in Kaposi sarcoma (KS) are fascinating. Each begins with a classic study. In 1988, the human immunodeficiency virus type 1 (HIV-1) tat gene was introduced into transgenic mice, inducing nodules that resembled Kaposi sarcoma in 33 of 37 males but in none of 15 females. Therefore, it appeared that HIV could play a direct role in causing Kaposi sarcoma. The medication quinine may be a potentially overlooked triggering factor in millions of Africans with Kaposi sarcoma.[15]

The second saga was a result of efforts to grow Kaposi sarcoma cells in culture, requiring a long-term growth factor. Conditioned medium from T cells infected with human T-cell leukemia virus type II (rather than HIV-1 or human T-cell leukemia virus type I) best supported the growth and long-term culture of Kaposi sarcoma cells derived from KS-AIDS lesions. In 1992, this growth factor proved to be a cytokine previously termed oncostatin M, since it had been identified earlier for its inhibitory effects on a variety of cancer cells. Another cytokine scatter factor was found in large quantities in this medium, inducing endothelial cells to demonstrate a Kaposi sarcoma tumor cell-like phenotype. The importance of oncostatin M, scatter factor, and the tat protein has been shown in the pathogenesis of Kaposi sarcoma.

Other cytokines, including interleukin 1 (IL-1), tumor necrosis factor, interleukin 6 (IL-6), and basic fibroblastic growth factor (bFGF), may work synergistically with the HIV tat gene product. Scatter factor may be involved both in initiation and in maintenance of Kaposi sarcoma. Scatter factor stimulates endothelial cells to migrate nearby and become factor XIIIa–positive c-Met- expressing spindle-shaped Kaposi sarcoma cells. The cells further expand neovascularization by producing cytokines and promoting autocrine-mediated and paracrine-mediated growth of Kaposi sarcoma cells. The scatter factor receptor, c-Met proto-oncogene, is expressed by Kaposi sarcoma cells; the oncogene int-2 of the fibroblast growth factor family also may be evident.

Herpes-type viruses have been linked with Kaposi sarcoma for more than 3 decades. A landmark study showed short DNA sequences of a unique human herpesvirus in Kaposi sarcoma tissues via a new molecular biological technique termed representational difference analysis. They resembled herpesvirus saimiri but proved to be a new type of human herpesvirus now termed HHV-8. This virus appears to interact with the HIV tat protein, excess levels of basic fibroblast growth factor, scatter factor, and IL-6. For example, HHV-8–encoded IL-6 has been found to induce endogenous human IL-6 secretion. An HHV-8 oncogene, Kaposin (ORF K12), has been characterized; however, additional factors remain to be found. For example, a 53% prevalence of HHV-8 subtype E in Brazilian Indians does not appear to be linked with the development of Kaposi sarcoma in this population.[16]

Classic Kaposi sarcoma is seen in Italy with hot spots being in the Po River Valley, Sardinia, and southern Italy. It has been suggested that volcanic soil or birthplace/residency in areas abundant with bloodsucking insects may be a risk factor.[17] A survey evaluated the correlation between HHV-8 infection and classic Kaposi sarcoma incidence in northern Sardinia.[18] It revealed that seroprevalence was 35%, within a range of 15.3-46.3% in the five areas. Age was as an important risk factor. Subjects aged older than 50 years had a higher seroprevalence to HHV-8 as compared with younger individuals. A strong direct correlation between HHV-8 prevalence and classic Kaposi sarcoma incidence was also observed.

Kaposi sarcoma–associated herpesvirus (KSHV), or human herpesvirus 8 (HHV-8), is the most frequent cause of malignancy in patients with AIDS.[19] KSHV and related herpesviruses have pirated cellular cDNAs from the host genome. Many of the viral regulatory homologs encode proteins that directly inhibit host adaptive and innate immunity. Other viral proteins may target retinoblastoma protein and p53 control of tumor suppressor pathways, which play key effector roles in intracellular immune responses. The immune evasion strategies used by KSHV in targeting tumor suppressor pathways activated during immune system signaling, may lead to inadvertent cell proliferation and tumorigenesis in susceptible hosts.

HHV-8 variants have been found heterogeneously distributed in diverse geographic regions, but their pathogenicity in Kaposi sarcoma development is unknown.[20] The frequency of KSHV genotypes has been evaluated in numerous settings.[21, 22] The frequency of these genotypes isolated from Kaposi sarcoma lesions among 50 patients from one center in Brazil was evaluated. The most frequently detected viral genotypes were A (50%) and C (48%); the B genotype was isolated only in one case.[23] A genotype was predominant in those HIV-positive, whereas the C genotype was mostly in those in the HIV-negative group. An association between E genotype and Kaposi sarcoma development was observed in Peru.

The origin of the spindle cell, the hallmark cell of Kaposi sarcoma, is unknown. Most research favors a lymphatic endothelial cell or an endothelial-cell precursor evolving into a lymphatic phenotype, both preferentially targeted by KSHV.[24]

HHV-8 has been linked convincingly with all 4 types of KS, an association that is necessary, but not sufficient, to develop KS; therefore, other factors also are important. At this point, immunosuppression appears to be the most significant cofactor.

The use of prednisolone as an adjunct to treatment in HIV-1–associated pleural tuberculosis in Uganda was associated with a significantly higher incidence of KS (4.2 cases per 100 person-years, compared with 0 cases per 100 person-years [P = .02]),[25] which is a dramatic example of the induction of KS by immunosuppressive therapy with corticosteroids.

Frequency

United States

The incidence of Kaposi sarcoma (KS) has been estimated at 0.02-0.06%. Traditional Kaposi sarcoma of middle-aged and older American men of Mediterranean and Eastern European (Ashkenazi) Jewish lineage represents approximately 0.2% of cancer cases in the United States. Iatrogenic Kaposi sarcoma has a 400% increased incidence compared to the American population at large. The incidence of Kaposi sarcoma among American renal transplant recipients is approximately 0.4%. In the AIDS grouping, Kaposi sarcoma originally accounted for as many as 35% of patients, an incidence that has been declining with early detection of AIDS, although Kaposi sarcoma prevalence may remain high. Nevertheless, it may develop in HIV patients with well-controlled HIV disease and may be a significant factor in morbidity and mortality.[26]  In the United States, a few emigrants arrive from Kaposi sarcoma–endemic regions (primarily Africa). The largest immigrant population in this category may be Haitians; however, recent evidence suggests that Haitian AIDS originated directly in New York rather than Africa.

International

Four groups are predisposed to Kaposi sarcoma including (1) older men of Mediterranean and Jewish lineage; (2) Africans from areas including Uganda, the Congo Republic, Congo (Brazzaville), and Zambia; (3) persons who are iatrogenically immunosuppressed; and (4) men who are have sex with men. Kaposi sarcoma traditionally is an uncommon disease in middle-aged and elderly European men of Mediterranean or Jewish lineage.

A similar focus of Kaposi sarcoma exists in the same age and sex groups in Africa. If a crudely calculated incidence of 28 cases of Kaposi sarcoma per 100,000 in the Arabian population is correct, Kaposi sarcoma may be more common among Arabians than among Mediterranean people. A previously unrecognized genetic predisposition for Kaposi sarcoma among Arabians has been suggested. The incidence of Kaposi sarcoma among renal transplant recipients may be as high as 3.5% or higher in regions endemic for Kaposi sarcoma, which is significantly higher than the 0.4% incidence renal transplant recipients in the United States and Western Europe.

Endemic African Kaposi sarcoma has accounted for 10% of cancers and has been seen in a male-to-female ratio of 15:1. The Kampala Cancer Registry, one of the continent's first and foremost, has shown a significant alteration in the incidence of Kaposi sarcoma in the era of AIDS. In Uganda, Kaposi sarcoma has caused almost one half (48.9%) of cancer cases in men and 17.9% in women. The incidence in men (30.1 cases per 100,000) represents a more than 10-fold increase in men since the 1950s and is approximately 3 times the incidence found in women (11 cases per 100,000). The incidence in boys and girls was approximately the same in childhood (birth to 14 y), with small peaks in girls younger than 5 years and boys aged 5-9 years. Subsequently, a progressive rise in incidence peaked in women aged 25-29 years and in men aged 35-39 years. Lymphadenopathic Kaposi sarcoma affected 12% of total cases; 42% of childhood cases were of this type.

Of 73 Ugandan children with epidemic Kaposi sarcoma from the Uganda Cancer Institute in Kampala (from 2004-2007), 37 were boys and 36 were girls, with a median age of 10.1 years (range 2-18 y).[27]

In neighboring Zambia, the disorder was particularly aggressive among children, more than 80% of whom were HIV seropositive. Kaposi sarcoma was found to represent as much as 25% of childhood cancers. The average male-to-female ratio was 1.76:1, with male predominance higher in children older than 5 years (2.5:1 ratio) than in children younger than 5 years (1.4:1 ratio). The prevalence of HIV-related Kaposi sarcoma seems to be increasing in Nigeria, probably owing to more females having HIV disease.[28]

In Italy, KS-AIDS has produced notable epidemiologic changes. A doubling of Kaposi sarcoma incidence rates was noted in Italian men younger than 50 years from 1976-1984 to 1985-1990; however, no change, or possibly a decline, was observed in older men. The incidence of Kaposi sarcoma was estimated in the region around Venice, Italy, with rates higher in the coast and alpine valleys; in the latter, there was an excess of cases for both sexes combined (SIR = 191.1; CI = 113.2-302.0).[17] The standardized incidence rate for Kaposi sarcoma in Italy declined markedly in the highly active antiretroviral treatment (HAART) period.[29]

Classic Kaposi sarcoma in Greece seems to have an older age of onset; lower male-to-female ratio; endemic clustering; and disseminated skin disease at diagnosis, often accompanied by lymphedema and not unusual visceral or lymph node involvement.[30, 31, 32] A clustering was noted, with a high proportion of the patients being born in Peloponnesos (42.42%) and residing in Athens (51.51%) or in Peloponnesos (24.24%).

The incidence rates of classic Kaposi sarcoma in Italy after the spread of AIDS was evaluated.[18] The rates were 1 case per 100,000 population in men and 0.4 case per 100,000 population in women, varying from 0.3 cases per 100,000 population for men in Umbria and 4.7 cases per 100,000 population for men in Sassari in men and from 0.1 case per 100,000 population for women in Parma and 1.7 cases per 100,000 population for women in Sassari.

The rate of classic Kaposi sarcoma in southern Sardinia (Italy) from 1998-2002 was found to be 2.49 cases per 100 000 population per year (standardized), which was the highest rate recorded in the island.[33]

A Finnish nationwide registry–based analysis of cancer clustering detected a strong familial occurrence of Kaposi sarcoma. This study found Kaposi sarcoma had a very high cluster score, with Kaposi sarcoma patients forming clusters of close relatives.[34] One family was documented with 5 affected individuals in 2 generations. Several other families had 2 first-degree relatives with Kaposi sarcoma.

The increasing availability of antiretroviral therapy in Latin America has produced a marked decrease in Kaposi sarcoma since 2000, with its incidence there stabilizing and the risk being highest before and shortly after antiretroviral therapy initiation.[35]

Race

Kaposi sarcoma is an uncommon disease of middle-aged and elderly American and European men of Mediterranean or Jewish lineage. This propensity also is seen in individuals with iatrogenically induced Kaposi sarcoma but not among persons in the KS-AIDS group. Kaposi sarcoma is rare in American Blacks, despite its large foci among Blacks in certain regions of Africa.

Sex

Classic Kaposi sarcoma has an overwhelming male predominance, with a male-to-female ratio of approximately 10-15:1.

For endemic Kaposi sarcoma in Central Africa, the male-to-female ratio is near unity in childhood Kaposi sarcoma cases but often rises in puberty to 15:1.

In Corsica and Sardinia (where classic Kaposi sarcoma is endemic), with the arrival of AIDS, the ratio of male-to-female cases has dropped from 10:1 to 3:1. Children of women who are HIV-1 seropositive without Kaposi sarcoma have an aggressive form of childhood HIV-associated Kaposi sarcoma. A male-to-female ratio of 1.5:1 was observed.

A male-to-female ratio of 1.5:1 also was evident among renal transplant recipients in Arabia.[36]

In Zambia, Kaposi sarcoma represents up to 25% of childhood cancers and has an average male-to-female ratio of 1.76:1, with male predominance higher in children older than 5 years (2.5:1) than in children younger than 5 years (1.4:1).

Clinical manifestations and therapeutic response in men and women with AIDS-associated KS in Uganda differed between men and women.[37] At presentation, the median CD4 T-cell count was significantly lower in women than men, with women more likely than men to initially develop Kaposi sarcoma of the face and hard palate and more likely to develop lesions on the lower extremity. In addition, women were less likely than men to demonstrate clinical improvement.

Age

Age distribution depends on the type of Kaposi sarcoma.

In the United States and Europe, traditional Kaposi sarcoma has a peak incidence between 40-70 years, with a wide range of up to 89 years.

Young men with KS-AIDS who are engage in sex with men also show a wide age range but tend to be much younger, averaging 20-40 years at age of onset.

For endemic Kaposi sarcoma in Uganda, the incidence in boys and girls was approximately the same in childhood (birth to 14 y), with a small peak in girls younger than 5 years and boys aged 5-9 years. Subsequently, a progressive rise in incidence peaked in women aged 25-29 years and in men aged 35-39 years.

Clinical classification of Kaposi sarcoma may be the best prognosticator, comparing localized nodular disease, locally aggressive disease, and generalized Kaposi sarcoma.

Cutaneous skin testing for anergy may correlate with clinical disease type and prognosis.

Prognosis appears to correlate with the CD4 count.

Localized nodular Kaposi sarcoma has the best prognosis, with few deaths directly attributable to Kaposi sarcoma.

Locally aggressive Kaposi sarcoma has an intermediate prognosis.

The authors do not disagree with an old African estimate of a 3-year survival rate of 64%. Generalized Kaposi sarcoma, the form seen most commonly in patients with KS-AIDS, has a 3-year survival rate closer to 0% without therapy.

The low level of access to antiretroviral drugs in HIV-infected patients explains the morbidity and mortality from AIDS-associated Kaposi sarcoma in much of Africa, including Togo.[38]

Seventy children with Kaposi sarcoma and HIV infection were evaluated in South African hospitals.[39] The mortality was high despite use of antiretrovirals and cytostatics, with 32 patients surviving only 4 months on average; 10 were lost to follow-up, and 28 were alive, with an average follow-up of 16 months.

Significant morbidity and mortality has been seen in those with Kaposi sarcoma IRIS.[40, 41]

Mortality/morbidity

Patients with traditional Kaposi sarcoma (KS) tend to die with Kaposi sarcoma rather than of Kaposi sarcoma. Patients with KS-AIDS usually die from associated opportunistic infections or from gastrointestinal Kaposi sarcoma with hemorrhage. The mean survival rate of patients with KS-AIDS has been approximately 15-24 months, although the introduction into the United States of apparent immune system reconstitution using highly active antiretroviral therapy (HAART) has extended survival substantially. Kaposi sarcoma also may be fatal as a result of gut perforation, cardiac tamponade, massive pulmonary obstruction or, rarely, brain metastases.

In Kaposi's original description, death usually ensued within 3 years and was linked to fever, diarrhea, and hemoptysis. Inanition may be an important factor, and death may ensue as a result of bulky tumor obstructing the bronchi or larynx.

Patients with AIDS-related Kaposi sarcoma often have widespread visceral Kaposi sarcoma, although Kaposi sarcoma limited to the skin also is common.

Patients with iatrogenic Kaposi sarcoma tend to have gut bleeding resulting from Kaposi sarcoma, although termination or reduction of immunosuppression often, but not always, results in regression of Kaposi sarcoma.

Kaposi sarcoma (KS) is a neoplasm that often manifests with multiple vascular nodules in the skin and other organs.

Although true metastases appear to occur, a multifocal origin is most common.

The pattern of Kaposi sarcoma is variable, with a course ranging from indolent (only skin manifestations) to fulminant (extensive visceral involvement).

Kaposi sarcoma also may arise primarily in the oral mucosa, lymph nodes, and/or viscera without skin involvement. See the image below.

Kaposi sarcoma initially may be evident in any organ of the body.

Chronic lymphedema may precede Kaposi sarcoma.

Professor Ruocco's term isotopic response applies to the occurrence of Kaposi sarcoma with new cutaneous nodules at the site of other, unrelated, and already healed skin diseases.[42]

Although primary penile Kaposi sarcoma is uncommon in HIV negative men, one should consider this possibility when treating nonspecific penile lesions.[43] A minimal penile lesion with nondistinctive clinical features may be the exclusive manifestation of Kaposi sarcoma. In addition, it may appear as a skin-colored nodule suggestive of a primary squamous cell carcinoma.[44] Clearly, in both cases, histologic evaluation is mandated to establish the diagnosis. Disseminated Kaposi sarcoma may also involve the penis.[45]

Vitiligo and other autoimmune disorders are sometimes evident in patients with AIDS Kaposi sarcoma. Rarely, vitiligo has been observed developing around nodules of Kaposi sarcoma.[46]

Kaposi sarcoma (KS) is described in 3 forms including localized nodular, locally aggressive, and generalized Kaposi sarcoma. Kaposi sarcoma typically occurs in these 3 forms and in 6 stages including patch, plaque, nodular, exophytic, infiltrative, and lymphadenopathic. Oral involvement may also be evident, in some quite prominent.[47, 26]

Cutaneous Kaposi sarcoma usually begins as discrete red or purple patches that are bilaterally symmetric and initially tend to involve the lower extremities.

Patches become elevated, evolving into nodules and plaques.

Nodules may be spongy to the touch and show on dermatoscopic examination a bluish-red coloration with a rainbow pattern.[48] A homogeneous or structured vascular pattern is evident in most nodular Kaposi sarcoma.

See the images below.

Kaposi sarcoma also occurs as a large infiltrating mass or as multiple cone-shaped friable tumors. These 2 variants, termed locally aggressive Kaposi sarcoma, may adhere firmly to underlying anatomic structures including bone. Rarely, Kaposi sarcoma may resemble pyogenic granuloma clinically.[49, 50, 51]

See the images below.

Early Kaposi sarcoma may appear as violaceous patches (patch stage Kaposi sarcoma), which occasionally resemble large junctional melanocytic nevi or may appear as irregular-shaped patches similar to the nevus flammeus.

More commonly, Kaposi sarcoma is evident as violaceous plaques or nodules on the lower extremities. The nodules tend to enlarge into dome-shaped tumors.

Cutaneous Kaposi sarcoma rarely may be infiltrative or exophytic. To the authors' knowledge, infiltrative Kaposi sarcoma has not been described outside of Africa. Exophytic Kaposi sarcoma may erode downward into bone.

Although rare, isolated osseous Kaposi sarcoma with osteolytic bone changes has been described.[52]

Lymphadenopathic Kaposi sarcoma may demonstrate skin lesions.

At times, a Köbner phenomenon appears evident, with nodules at sites of trauma.

A few unusual varieties of Kaposi sarcoma also exist.

Telangiectatic Kaposi sarcoma is an eruption of pink translucent nodules with prominent telangiectasia.

Ecchymotic Kaposi sarcoma appears as periorbital ecchymoses. Histologically, there is a large amount of extravasated red blood cells, no evidence of amyloidosis, and a dermis containing foci of proliferating moderately atypical spindle cells, vascular slits, erythrophagocytosis, and other features of Kaposi sarcoma. On the trunk, lesions often follow skin tension lines.

See the image below.

Keloidal Kaposi sarcoma is evident as somewhat brown-to-violaceous keloidal nodules. Histologically, these are Kaposi sarcoma nodules with a keloidal component.

Cavernous Kaposi sarcoma is a rare type of locally aggressive Kaposi sarcoma characterized by cutaneous tumors that histologically resemble cavernous hemangiomas; however, the endothelial cells and their nuclei are large and prominent, bulging into the cavity.

Lymphangiomalike Kaposi sarcoma is a rare variant in which dilated vascular spaces produce a bullous-appearing eruption, typically on the lower legs. The lesions are easily compressible and appear clinically to be fluid-filled. The vascular channels are lined by banal-appearing endothelial cells permeating the dermis in the absence of spindle cell proliferation. Oral lymphangioma-like Kaposi sarcoma may also occur.[53]

Occasionally, Kaposi sarcoma may be first evident as a cutaneous horn.[54]

The most common complications include secondary malignancy and secondary infections. In particular, secondary infection occurs with the KS-AIDS group of patients. A relatively common clinical concern is to distinguish Kaposi sarcoma from opportunistic infection and lymphoma.

In patients with classic Kaposi sarcoma, lymphoma develops in approximately 35%, usually after a number of years.

Kaposi sarcoma may produce clinical problems including edema from impaired lymphatic draining (sometimes resulting in pain), difficulty ambulating, friability of cutaneous nodules, or secondary localized skin infection.

The immune reconstitution inflammatory syndrome (IRIS) when antiretroviral therapy commences may involve Kaposi sarcoma as the disorder that flares.[55] A study from Chicago of 260 patients calculated the incidence of IRIS as occurring in 11% of them.[40] Kaposi sarcoma IRIS was documented in 29% of these patients, perhaps reflecting the visibility of progressing Kaposi sarcoma in these patients.

Serum glucose levels may reflect an increased incidence of diabetes mellitus in patients with classic Kaposi sarcoma (KS). Ketoacidosis is unusual in these patients.

Immunohistochemical detection of human herpes virus-8 latent nuclear antigen-1 has been claimed as useful in the diagnosis of Kaposi sarcoma.[62]

Hemogram in nonimmunosuppressed patients with Kaposi sarcoma tends to be within normal limits, but occasionally, monocytosis or eosinophilia has been noted. Eosinophilia is seen especially in African patients and patients who are homosexual, in whom parasitosis may be common.

In KS-AIDS, cytopenia of 1 or more cell lines is frequent.

Anemia, if present, may result from gastrointestinal bleeding or may be associated with an autoimmune hemolytic anemia or a hematologic malignancy.

Assays for HHV-8 have been challenging. At present, no universally accepted method exists.

Polymerase chain reaction often is used but may have false-positive results because of its high susceptibility to contamination.

Methods based on both lytic and latent-phase viral antigens remain promising.

Computed tomography (CT) may be valuable, especially abdominal CT scans in patients with AIDS.[63] In AIDS-related Kaposi sarcoma, early lymphatic and hepatosplenic involvement may be evident. Consider CT-directed fine needle aspiration to provide tissue confirmation, since lymphomas and atypical mycobacterial and other infections may appear similar.

Consider endoscopic and conventional radiographic studies; however, these modalities may miss gastrointestinal Kaposi sarcoma, while selective angiography may demonstrate Kaposi sarcoma.

Radionucleotide scans may be useful in demonstrating visceral Kaposi sarcoma and associated lymphoma.

With lung nodules, the distinction between Kaposi sarcoma, lymphoma, and/or opportunistic infection may be challenging.

In both adults and children with pulmonary Kaposi sarcoma, chest radiography shows perihilar and lower zone involvement.[64] Pleural effusions appear to be more common on radiographs in children.

The cell of origin in Kaposi sarcoma remains a subject of dispute, although the following tests may be useful:

• Ultrastructural and immunohistochemical testing favor the endothelial cell.

• The presence of factor VIII–related antigen, human leukocyte antigen DR (HLA-DR), von Willebrand factor, and the lectin Ulex europaeus I (which all are markers for endothelial cells) is highly suggestive.

• Reactivity with 2 monoclonal antibodies (EN4 and PAL E) implies that Kaposi sarcoma is derived from endothelium of lymphatic origin; however, Kaposi sarcoma spindle cells express CD34 antigen, a glycoprotein expressed by endothelial cells of small blood vessels (but not those of lymphatic origin).

Kaposi sarcoma (KS) tends to demonstrate increased spindle cells with vascular slits and vascular structures with a predominance of endothelial cells. Extravasated erythrocytes and hemosiderin-laden macrophages often are evident. Some spindle cells may show nuclear pleomorphism. Early Kaposi sarcoma may resemble granulation tissue with a diffuse chronic inflammatory infiltrate and capillaries dilated and increased in number. This pattern also is seen in lymph nodes and viscera.

Histopathologic classification is based on relative contribution of spindle cells, fibrosis, and nuclear pleomorphism, sometimes divided into 3 histopathologic forms, which include (1) a mixed form with an equal amount of spindle cells, vascular clefts, and capillaries, (2) a mononuclear type with 1 cell type predominating, and (3) an anaplastic form with cellular pleomorphism and numerous mitotic figures. In 2007, intravascular Kaposi sarcoma was recognized as a morphological variant of Kaposi sarcoma that seems to be unassociated with an increased risk of aggressive behavior.[65]

Cutaneous Kaposi sarcoma probably evolves through the early inflammatory or patch stage, progresses to the nodular stage, and then, to the late proliferative or plaque stage. The authors believe that the glomeruluslike vascular formations in early patch stage Kaposi sarcoma and in some later lesions may reflect the histogenesis of Kaposi sarcoma. The late plaque stage shows diffuse involvement of the dermis, exhibiting the histologic features of the nodular stage. The lesions may resolve, with involution of the vascular components and formation of scar tissue, or, occasionally, they become extremely pleomorphic and invade deeper tissues. Histologic variants have been recently emphasized.[66] The angiomatous variant demonstrates neoplastic vessel staining with podoplanin, which is not noted with preexisting vessels.[67]

Kaposi sarcoma specimens may be stained for iron and HHV-8.[68] Iron staining of dermal tissue may suggest Kaposi sarcoma. Immunohistochemical stains for HHV-8 should be positive in most typical Kaposi sarcoma. Iron staining and immunohistochemical HHV-8 staining in combination may be reliable markers for Kaposi sarcoma compared with interstitial granuloma annulare.

The lymphadenopathy in Kaposi sarcoma may show marked follicular hyperplasia and hypervascularity, nonspecific inflammation in regional lymph nodes that drain ulcerated Kaposi sarcoma, and lymphomas or actual lymph node Kaposi sarcoma, with or without cutaneous involvement. More than 1 of these processes may be evident in the same node. The authors view localized lymphadenopathic Kaposi sarcoma as a type of localized nodular Kaposi sarcoma. Kaposi sarcoma in nodes shows the typical proliferation of spindle cells separated by slitlike spaces containing red blood cells and is accompanied by marked follicular hyperplasia and plasmacytic infiltration. The earliest changes occur in the subcapsular and trabecular sinuses, with extension into the entire node and, later, the perinodal tissues. Kaposi sarcoma of lymph nodes may be localized or generalized. The lymphocytic, plasmacytic, and immunoblastic proliferation may simulate a lymphoma.

The electron microscopy and immunohistochemical features of Kaposi sarcoma may be important. Staining with CD34, factor VIII–related antigen, the lectin Ulex europaeus I, and HLA-DR antigen may be useful to support or confirm the diagnosis of Kaposi sarcoma. The authors prefer CD34 antigen, which is expressed by Kaposi sarcoma cells, and find it helpful in distinguishing Kaposi sarcoma from pseudo-Kaposi sarcoma (acroangiodermatitis).

 

See the images below.

Oral Kaposi sarcoma biopsy specimens from 135 cases were placed into 1 of 7 categories based on the predominant pattern of growth[69] : solid, lymphangiomalike, telangiectatic, desmoplastic, lymphangiectatic, ecchymotic, and anaplastic. Some had coexistent pathology, mainly superimposed candidiasis, but also a few had cytomegalovirus and nonnecrotizing granulomatous inflammation. With oral Kaposi sarcoma, some believe that HHV-8 immunohistochemistry is strongly advisable to confirm the diagnosis, although obtaining this immunohistochemistry study may be a challenge in resource-poor countries.[70]

Stage the patient's disease and note any extracutaneous involvement. Staging this multicentric disorder has been a challenge.[71]

The AIDS Clinical Trials Group classification by Krown et al[72] in 1989 uses the following 3 categories, although the tumor/immune/system/systemic (TIS) illness grading method has limitations:

• Tumor (T) - Good or bad risk signs (good when Kaposi sarcoma is confined to skin and/or lymph nodes and/or demonstrates minimal oral disease)

• Immune system (I) - CD4 cell levels equal to or greater than 150/µL (good risk) versus less than 150/µL (poor risk)

• Systemic illness (S) - Good or poor risk

Another classification formula developed by Mitsuyasu in 1987[73] divides Kaposi sarcoma into the following 4 stages:

• Stage I - Localized nodular Kaposi sarcoma in elderly men in North America and Europe

• Stage II - Localized, invasive, and aggressive Kaposi sarcoma (mostly seen in Africa)

• Stage III - Disseminated mucocutaneous Kaposi sarcoma in African children and patients who are homosexual

• Stage IV - Stage III with visceral involvement

In 1984, the authors originally proposed and currently prefer the following classification system (including new recommended modifications):

• Stage I represents localized nodular Kaposi sarcoma, with more than 15 cutaneous lesions or involvement restricted to 1 bilateral anatomic site, and few, if any, gut nodules.

• Stage II includes both exophytic destructive lesions and locally infiltrative cutaneous lesions as locally aggressive Kaposi sarcoma.

• Stage III (generalized lymphadenopathic Kaposi sarcoma) has widespread lymph node involvement, with or without skin lesions, but with no visceral involvement.

• Stage IV (disseminated visceral Kaposi sarcoma) has widespread Kaposi sarcoma, usually progressing from Stage II or Stage III, with involvement of multiple visceral organs.

The authors modify each stage as follows:

• A: Associated opportunistic infection(s) is evident.

• B: Patient is HIV-I seropositive.

• C: Cutaneous anergy or other evidence of severe immunodeficiency is present.

Treating patients with advanced Kaposi sarcoma often requires a team approach, as follows:

• Medical oncologists often administer systemic chemotherapy.

• Radiation oncologists tend to favor radiotherapy options.

• Infectious diseases/HIV specialists may be needed for HIV and opportunistic infections.

Reducing the HHV-8 infection rate prevents Kaposi sarcoma development.

Suggestions have been made that some antiherpetic agents, particularly foscarnet, may lower the HHV-8 infection rate.

Screening transplant recipients for HHV-8 infection may be beneficial.[74, 75, 76, 77, 78] Testing donors and recipients for HHV-8 is difficult, as there are no validated commercial serology kits available; however, limited HHV-8 antibody testing is available through some US reference laboratories and the US Centers for Disease Control and Prevention.[79] Many US donors originate from groups at high risk of HHV-8 transmission to recipients.

Use of the highly active anti-HIV therapy (ie, HAART) appears to significantly reduce the risk of developing new Kaposi sarcoma.[35]

Careful follow-up monitoring is essential for patients with Kaposi sarcoma (KS).

The authors' preference often is the Klein[80] regimen of weekly outpatient intravenous vinblastine titered against white cell count levels to avoid falling below 4000/µL. The authors recommend intralesional injections of vinblastine for persistent cutaneous nodules and intraarterial vinblastine in certain settings for locally aggressive Kaposi sarcoma (KS). Systemic vinblastine (3.5-10 mg IV weekly with, at times, 1 intralesional injection of 0.1 mg) usually is best for both the patient with classic Kaposi sarcoma and, occasionally, patients with KS-AIDS. Treatment of classic Kaposi sarcoma may also be accomplished with topical imiquimod.[81] Limited experience in Kaposi sarcoma in renal transplant recipients suggested it may be beneficial in at least some of them.[82]

Although the authors prefer low-dose vinblastine, a number of other chemotherapeutic agents may be effective. Drugs with proven efficiency include vincristine, vinblastine, dacarbazine, doxorubicin, and actinomycin D. Alkylating agents (eg, cyclophosphamide, chlorambucil, bleomycin, doxorubicin, etoposide) also may be of value. Multiagent intravenous chemotherapy, rather than single agent usage, is preferred by some for disseminated aggressive Kaposi sarcoma. No particular combination regimen has been established yet. The combination of doxorubicin, bleomycin, vinblastine, and dacarbazine may be effective.

Alternating vincristine and vinblastine in patients with KS-AIDS can be both effective and well tolerated, but leukopenia and a propensity to opportunistic infections makes aggressive chemotherapy difficult. Patients with KS-AIDS usually succumb either to disseminated Kaposi sarcoma or to an intervening opportunistic infection within 3 years of diagnosis, regardless of the form of therapy (except with HAART [highly-active antiretroviral therapy]). All of these therapies (except low-dose vinblastine) are significantly immunosuppressive and, perhaps, accelerate the disease. Combining chemotherapy for Kaposi sarcoma with chemotherapy for HIV is an attractive option. Interferon also may be used in this way. Thus, the combination of zidovudine, interferon, and low-dose intravenous vinblastine may be used for patients with KS-AIDS.

Experimental treatments for Kaposi sarcoma and HHV-8 infections are myriad. Many come under the rubric of immunotherapy, pioneered for Kaposi sarcoma by Klein in the early 1960s. Other agents (in addition to interferon) used for immunomodulation include bovine-thymic extracts, thymosin, Imreg-l, thalidomide, endothelial growth factor inhibitor (SU5416), human chorionic gonadotropin, isoprinosine, thymopoietin, monoclonal antibodies to T-suppressor (T8) cells, BCG vaccine, cord factor, and topically administered halofuginone, an angiogenesis inhibitor that inhibits collagen type-I and matrix metalloproteinases (MMPs).[83]  There may be a role for checkpoint inhibitors.[84]

The value of recombinant interferon alfa and other modalities may depend on the pretreatment immune status of the patient as the best predictor of response. The degree of reduction in the helper-inducer T-cell (T4) subpopulation as manifested in the T4:T8 ratio may correlate highest with prognosis and be a good measure of immune status for this purpose. Thalidomide therapy may be of value in non-AIDS–related Kaposi sarcoma; in 2 of 3 patients, complete remission was achieved after 12 months of treatment.[85]

In iatrogenic Kaposi sarcoma, cessation of immunosuppressive therapy may be the most effective treatment. Patients on immunosuppressive therapy, specifically corticosteroids and cytotoxic drugs, may have partial or complete regression when therapy is discontinued. If possible, immunosuppressive medication doses should be reduced or discontinued before beginning specific therapy for iatrogenic Kaposi sarcoma. Sirolimus has the advantage of decreased risk of malignancies, including Kaposi sarcoma, associated with its use compared with other immunosuppressants, namely calcineurin inhibitors, and possibly Kaposi sarcoma regression.[86, 87] Everolimus may offer similar advantages.[88]

In some patients, KS-AIDS may resolve clinically with the use of HAART. Resolution of conjunctival Kaposi sarcoma after use of HAART alone has been described.[89] Antiviral therapy with foscarnet may not only reduce progression of Kaposi sarcoma in patients, but may lower its occurrence substantially in patients with HIV disease.

Patients with KS-AIDS, the most common tumor in Zimbabwe, were randomized and evaluated for the effectiveness of supportive care versus 3 intervention approaches, namely oral etoposide, a 3-drug combination, and radiotherapy, using quality of life as the primary measure of success.[90] No patient used antiretroviral therapy. Oral etoposide resulted in a significantly better quality of life and may represent a pragmatic approach to treating epidemic Kaposi sarcoma in an environment where antiretroviral drugs are not universally available.

Paclitaxel and pegylated liposomal doxorubicin were compared in a randomized trial evaluating their efficacy and toxicity.[91] Treatment with both produced significant improvements in pain and swelling in patients with advanced, symptomatic, HIV-associated Kaposi sarcoma. Three fourths of patients had also received highly active antiretroviral therapy.

Antiretroviral therapy for childhood HIV-associated Kaposi sarcoma is not always possible in resource-poor areas. Special recommendations exist for use where only minimal requirements for treatment are available.[92] Randomized controlled studies of chemotherapy for Kaposi sarcoma in children are lacking.

The programmed cell death protein-1 humanized antibody, pembrolizumab, has shown promising anti-tumor activity for classic or endemic Kaposi sarcoma with an acceptable safety profile.[93]

Class Summary

Chemotherapy agents inhibit cell growth and proliferation. Vincristine 2 mg IV alternating with vinblastine 0.1 mg/kg IV qwk is effective. Doxorubicin, an anthracycline, is used effectively as ABV combination (doxorubicin A=anthracycline [20 mg/m2 IV], B=bleomycin [10 U/m2 IV], V=vincristine [1.4 mg/m2 IV q2wk]). The combination may produce alopecia, neuropathy, neutropenia, nausea and vomiting, oral erosions, or palmoplantar erythrodysesthesia.

Vinblastine (Alkaban-AQ, Velban)

Vinblastine is an important vinca alkaloid, which is the salt of a common flowering herb, the periwinkle Vinca rosea. It inhibits microtubule formation, which, in turn, disrupts the formation of the mitotic spindle, causing cell proliferation to arrest at metaphase.

Vincristine (Oncovin, Vincasar PFS)

Vincristine is the salt of a common flowering herb, the periwinkle Vinca rosea. Its mechanism of action is uncertain. It may involve a decrease in reticuloendothelial cell function or an increase in platelet production.

Bleomycin (Blenoxane)

Bleomycin is a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus and freely soluble in water. It is a glycopeptide antibiotic that inhibits DNA synthesis. It is used for palliative measures in the management of several neoplasms.

Doxorubicin (Adriamycin, Rubex)

Doxorubicin is a cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces peucetius var caesius. It inhibits topoisomerase II and produces free radicals, which may cause the destruction of DNA. The combination of these 2 events can in turn inhibit the growth of neoplastic cells.

Daunorubicin (Cerubidine, DaunoXome)

Daunorubicin inhibits DNA and RNA synthesis by intercalating between DNA base pairs.

Paclitaxel (Taxol)

Paclitaxel's mechanisms of action are tubulin polymerization and microtubule stabilization.

Interferon alfa 2b (Interferon alfa-2b, Intron A)

Interferon alfa-2b is a protein product manufactured by recombinant DNA technology. The mechanism of antitumor activity is not understood clearly; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. It is an effective option for patients with more extensive cutaneous disease that is not rapidly progressive in whom no need exists for a rapid reduction in lesions and in whom overall functional status is relatively good.

Class Summary

Retinoids decrease cohesiveness of abnormal hyperproliferative keratinocytes and may reduce the potential for malignant degeneration. They modulate keratinocyte differentiation and have been shown to reduce the risk of skin cancer formation in renal transplantation patients.

Alitretinoin topical

Alitretinoin topical is a 0.1% gel. It is a topical treatment for cutaneous lesions. Alitretinoin is a naturally occurring endogenous retinoid. It inhibits the growth of Kaposi sarcoma by binding to retinoid receptors.

Class Summary

Antiviral agents are active against HHV-8 and represent an important potential intervention and prevention option.

Foscarnet (Foscavir)

Use of this medication appears to be linked to a decreased risk of developing Kaposi sarcoma. Foscarnet is an organic analog of inorganic pyrophosphate that inhibits replication of known herpesviruses, including CMV, HSV-1, and HSV-2. It inhibits viral replication at pyrophosphate-binding site on virus-specific DNA polymerases.