Kaposi’s Sarcoma


Key Points

  • Kaposi's sarcoma is a multicentric, mostly oligoclonic neoplastic proliferation of endothelial cells that have been infected and transformed by human herpesvirus-8.

  • Four epidemiologic types of Kaposi's sarcoma are recognized: classic (typically found sporadically in elderly persons of Mediterranean descent), epidemic (AIDS-related), endemic (occurring in Africa), and iatrogenic (immunosuppression-associated, transplant-associated).

  • While there are numerous clinical variants, the typical lesions are well-demarcated, smooth purple macules, plaques and nodules that histologically show slit-like vascular channels and spindle-shaped tumor cells.

  • Clinical course varies from the development of few, indolent-growing cutaneous lesions to aggressive, life-threatening dissemination of tumors affecting skin, lymph nodes and systemic organs.

  • Treatment may be localized or systemic depending on the type, extent, complications, rate of progression, and organ invasion.

Introduction

Kaposi's sarcoma (KS) is a reactive, multifocal, multicentric, angiogenic neoplastic proliferation that is thought to originate from endothelial cells that are infected with the human herpesvirus-8 (HHV-8), also known as KS-associated herpesvirus (KSHV). Most cases present with lesions on the skin and/or mucous membranes, but, as the course progresses, tumors may also arise in the lymph nodes and visceral organs.

History

In 1872, Moritz Kaposi reported an ‘idiopathic multiple pigmented sarcoma of the skin’ which became known as ‘classic’ Kaposi sarcoma. In the 1950s, a more aggressive ‘endemic’ form of the malignancy, with a prevalence in equatorial and southern Africa as high as 200 times that of the classic type, was described in English language journals. An ‘iatrogenic’ KS variant was distinguished in the 1970s in transplant patients receiving immunosuppressive therapy. However, KS remained a relatively uncommon disease until 1981, when a virulent and disseminated ‘epidemic’ type associated with life-threatening opportunistic infections was described in men who have sex with men (MSM) and blood transfusion recipients.

Pathogenesis

In 1994, DNA sequences of a new human gammaherpesvirus (HHV-8) were identified in KS tissue examined by representational difference analysis. Since then, the virus has been detected in more than 90% of KS tumors and all four main types. The virus is recovered most often and in higher titers in saliva, suggesting that intimate sexual or asexual oral contact increases the risk of transmission. Less effective transmission occurs via blood and semen. Annually, only 0.03% of men and 0.015% of women over 50 years of age who are infected with HHV-8 develop classic KS. In contrast, the 10-year probability of developing KS for persons co-infected with HHV-8 and HIV is nearly 50%. Molecular diagnostic techniques comparing viral HHV-8 DNA of the tumors have demonstrated that at least 80% of the tumors arise independently from multiple cells.

Much remains to be learned about the mechanisms by which HHV-8 and co-factors, such as HIV, trigger KS lesions. HIV infection potentiates oncogenesis and increases the risk of developing KS lesions by up to a factor of 10,000. The viral–host interaction is complex and appears to involve HHV-8 infection of the cells with growth factors secreted by the spindle cells, mononuclear and endothelial cells. It is postulated that HHV-8 transforms a lymphatic or vascular endothelial cell or its precursor into a spindle cell, and then helps to sustain its unregulated proliferation by interacting with the multifunctional proangiogenic HIV-1 transcriptional transactivator (TAT) protein, inhibiting apoptosis, accelerating tumorigenesis in part by activating nuclear factor-kappa B, and stimulating angiogenesis by upregulating various angiogenic cytokines and growth factors, including vascular endothelial growth factor (VEGF). A number of cytokines stimulate KS spindle cell growth in vitro and possibly in vivo.

Clinical findings

Typically, KS lesions progress from well-demarcated, non-blanching, reddish to dark purple, oval or circular, ecchymotic-like macules or patches to firm, indurated papules, plaques or nodules that enlarge to measure several centimeters in length ( Fig. 16.1 ). These lesions may coalesce to form larger infiltrated plaques that cover large areas. In dark-skinned persons, the lesions are often brown ( Fig. 16.2 ). Less frequently, the initial lesions are plaques or subcutaneous nodules, or exophytic papules may be the initial disease manifestation ( Fig. 16.3 ). Several clinical and histological KS variants have been described ( Table 16.1 ).

Figure 16.1, Characteristic purple papules and plaques on the toes of a man with KS.

Figure 16.2, Reddish brown KS papules on the groin.

Figure 16.3, Exophytic, pyogenic granuloma-like KS resembles bacillary angiomatosis.

Table 16.1
Morphologic Variants of Kaposi's Sarcoma
Anaplastic: Rare histologic phenotype with marked cytologic atypia, numerous mitoses, a propensity for acral locations, and a high degree of aggressiveness and local invasion.
Bullous: Tense blister(s) within KS tumor plaques that histologically show subepidermal or intraepidermal edema.
Ecchymotic: Bluish or purplish bruise-like KS lesion characterized by vast extravasation of red blood cells.
Exophytic: Well-demarcated, smooth-surfaced, red papules and nodules above the surface of the skin.
Intravascular: Rare type in which spindle cell proliferation is limited to intravenous areas.
Lymphangiomatous: Invasion of lymphatics by tumors producing cutaneous lymphedema. This variant typically occurs in the lower extremities and results in gross swelling with cobblestoning violaceous papules, nodules and occasionally bullae that may ulcerate.
Hyperkeratotic: Verrucous indurated plaques associated with chronic lymphedema, with markedly thickened stratum corneum, verruciform epidermal acanthosis, and often fibrosis in the upper dermis.
Keloidal: Firm, thick, rubbery nodules which histologically show dense, hyalinized collagen, usually seen in African-Americans.
Lymphangiectactic: Pseudoblister-like nodules with large, dilated ectatic lymphatic vessels.
Lymphadenopathic: Enlarged palpable lymph nodes from KS invasion.
Lymphangioma-like: Also known as lymphangiomatous or cavernous KS, this rare type is characterized by a proliferation of wide, irregular anastomosing channels lined by a monolayer of plump sarcoma cells separating the collagen bundles. The spaces contain frothy, pale eosinophilic fluid rather than erythrocytes. A pseudo-bullous appearance, considered a clinical hallmark of this type, occurs in about half of the cases.
Micronodular: Minute, unencapsulated nodules of proliferating spindle cells in the reticular dermis.
Pyogenic granuloma-like: An exophytic KS variant consisting of bright red, friable polypoid papules or nodules which may bleed, erode, ulcerate or crust. These lesions are often misdiagnosed clinically as bacillary angiomatosis.
Telangiectatic: Lesion studded with numerous telangiectasias on their surface. An uncommon variant is a well-demarcated patch of spider telangiectasias that eventually becomes a solid purple plaque.

Clinical variants

Classic KS

This type of KS characteristically develops in middle-aged or elderly men living in or descending from the Mediterranean basin and Eastern or Southern Europe. While the highest incidences have been found in Sardinia (29.2 per million in men and 19.6 per million in women) and Sicily (30.1 per million in men and 5.4 per million in women), cases of classic KS have been reported from every continent except Antarctica. The male-to-female gender ratio is approximately 3:1, although ratios as high as 15:1 have been calculated in some populations. Less than 8% of cases present before the age of 50 and cases in adolescents and young adults are rare.

An elevated risk of classic KS, independent of HHV-8 infection, has been reported in patients with low absolute lymphocytes, including low CD4 + and CD8 + T cells. Other reported risk factors include exposure to southern Italian volcanic soil, living in areas contaminated with arthropods, chronic leg edema, diabetes mellitus, and reduced numbers of B cells. In men, multivariate analysis has demonstrated an elevated KS risk with the use of topical corticosteroids, infrequent bathing, and a history of asthma or of allergy. Recent studies have indicated that classic KS is promoted by interleukin-13 (IL-13) and haplotypes of the IL-8 receptor-beta genes. Notably, the risk of developing KS may be decreased by cigarette smoking in men – by approximately 20% for each 10 pack-years reported, sevenfold with more than 40 pack-years, and 80% overall in current smokers.

Characteristic violaceous, purple or brown macules or patches evolve into papules, plaques, or deep-seated indurated nodules. The tumors gradually grow horizontally and vertically, coalescing into larger plaques or nodules and occasionally become hyperkeratotic. Although lesions may develop over any other part of the body, especially the upper legs, face, and trunk, the most frequently involved location is the lower extremities, commonly the ankles and soles ( Fig. 16.4 ). The lesions typically present on a single extremity but in time the distribution often becomes bilateral and multifocal.

Figure 16.4, Classic KS involving the ankle and foot.

The course of classic KS is usually chronic, indolent and protracted, and only rarely acute, rapidly progressive, or characterized by rapidly enlarging tumors after periods of relative quiescence. Over 2 years, only 34% of 39 untreated asymptomatic patients remained progression-free. However, most cases survive 10 to 15 years after diagnosis, dying of unrelated causes. In one study, only 2% of 438 patients with classic KS died of disseminated disease after 4.8 years, although 14% died of second malignancies and 22% died of other unrelated medical conditions. In a smaller series, only one of 41 patients died from KS after 10 years of observation.

The most common complications are edema, ulceration and bleeding. The tumors are disfiguring and those on the soles or oral cavity become especially painful. Lymphatic obstruction eventuates in gross lymphedema. Tumor ulceration increases the risk of cellulitis and sepsis. Oral mucosal lesions are rare, but lymph node and gastrointestinal lesions occur more commonly than previously appreciated. In one report, tumors were found endoscopically in the gastrointestinal tract (all on the stomach, 27% on the esophagus and 11% on the duodenum) in 82% of classic-KS patients, and in another study 23% had regional lymph node involvement. Intestinal involvement may produce nausea, vomiting, abdominal cramps, weight loss, and anemia from chronic bleeding. Based on lesion distribution and disease progression a classification system for staging classic KS has been proposed ( Table 16.2 ).

Table 16.2
Clinical Staging for Classic Kaposi Sarcoma
Stage 1 (maculonodular) * : Small macules and papules are confined to lower extremities
Stage 2 (infiltrative) * : Plaques, sometimes associated with nodules, present mainly on the lower extremities
Stage 3 (florid) : Widespread plaques and nodules, many ulcerated, predominantly localized on the lower extremities
Stage 4 (disseminated) : Tumors on various areas of the body beyond the extremities

* Slow rate of progression, fewer complications, low incidence of visceral involvement.

More rapid progression, greater risk of systemic involvement, and significant functional impairment.

Up to a third of classic KS cases develop a second primary malignancy, often non-Hodgkin lymphoma. There are conflicting data on the risk of other malignancies, either before or following a diagnosis of classic KS. Although some studies have reported an association, particularly with non-Hodgkin lymphoma and other lymphohematopoietic malignancies, larger, population-based studies have failed to document higher rates of these or other types of cancer. On the other hand, a population-based study from Israel found higher rates of KS in individuals, especially immigrants from the Soviet Union and Poland, previously diagnosed with lymphoma, leukemia and breast cancer. It remains to be determined whether cancer-induced immunosuppression predisposes persons from HHV-8 endemic areas to develop classic KS. Treatment is palliative and administered to halt disease progression, decrease edema, and enhance function. Unfortunately, there are few prospective, well-designed classic-KS trials to assist the clinician to select a best practice approach. Localized radiotherapy to individual tumors is particularly valuable in the elderly, whose shorter life expectancy precludes the probability of severe chronic radiation dermatitis. Other therapies, including cryotherapy, intralesional vinblastine and laser or surgical destruction for localized cutaneous disease, and chemotherapy or interferon for symptomatic progressive skin or systemic disease, have been effectively used.

Epidemic (AIDS-related) KS

The development of epidemic KS tumors represents recognizable stigmata that publicly reveal the person's HIV status and are considered by many patients to be the most dreaded complication of HIV infection. Tumors may arise on any body region, including the face, hands, anogenital area and mucous membranes (see Chapter 19 ). On the trunk, the lesions often follow Langer's cleavage lines ( Fig. 16.5 ). Oral lesions develop in a third of cases and may be the presenting site in about 15%, with the hard palate being the most commonly involved oral cavity area followed by the soft palate, gingiva, uvula, pharynx, and tongue ( Fig. 16.6 ). While mucocutaneous lesions are usually the presenting manifestation, lymphatic and visceral tumors may precede those on the skin. Lymph node involvement is frequent but only detected on autopsy in many cases.

Figure 16.5, Epidemic KS plaques along the Langer's lines on the back.

Figure 16.6, Bluish-red tumors on the palate of a man with AIDS-associated KS.

Untreated HIV-infected persons with KS usually die of other opportunistic infections. However, death may be caused by complications from internal organ involvement, including respiratory failure, gut perforation, cardiac tamponade, and brain metastasis. The course of pulmonary KS may be slowly progressive or aggressive, especially in profoundly immunocompromised persons, requiring prompt treatment. Pulmonary tumors present with bronchospasm, cough, dyspnea and/or hemoptysis. The gastrointestinal tract (stomach, colon) is the most commonly involved organ (40% at initial presentation, 80% at autopsy) but the lesions are frequently asymptomatic and may not influence prognosis. Other organs (heart, adrenal glands, urethra, bone, brain) are rarely involved. Low CD4 counts and elevated HIV-1 viral loads are independently poor prognostic factors for the development of epidemic KS ( Fig. 16.7 ).

Figure 16.7, Disseminated KS in a profoundly immunocompromised HIV-infected man.

Previous to the introduction of antiretroviral therapy, as many as 40% of HIV-infected men who have sex with men (MSM) developed KS, in contrast to 3% of heterosexual injection drug users, 3% of transfusion recipients, 3% of women or children, and 1% of hemophiliacs. With the introduction of highly active antiretroviral therapy, the KS incidence in the HIV French Hospital Database decreased from 32 cases/1000 person-years in 1993 to 3 cases/1000 person-years after 1999. Among HIV-infected women, the incidence of KS is 15-fold lower than in HIV-infected men, but the disease is often more aggressive, with higher rates of lymph node and visceral involvement and poorer survival than in men, even after adjustment for CD4 lymphocyte counts. The development of classic KS is associated with high HHV-8 lytic and latent antibody titers.

Since KS is a multicentric disease, conventional cancer staging has been a challenge and not found to be clinically valuable. No system has been universally accepted for clinical staging, but the AIDS Clinical Trials Group classification, which is based on immune status, extent of tumor involvement, and presence of systemic illnesses, is used for clinical studies of AIDS-associated KS and has been associated with survival ( Table 16.3 ).

Table 16.3
The AIDS Clinical Trials Group Classification
T (tumor) status
  • T 0 (good risk): Localized tumor confined to skin and/or lymph nodes and/or minimal non-nodular oral disease limited to the palate

  • T 1 (poor risk): Widespread KS tumors and presence of one of the following:

    • Disease-induced edema

    • Extensive oral KS: nodular or extrapalatal

    • Visceral lesions in organs other than lymph nodes

I (immune system) status
  • I 0 (good risk): CD4 cell count is ≥ 200 (or 150 or 100) cells per μL

  • I 1 (poor risk): CD4 cell count ≤ 200 cells per μL

S (systemic illness) status
  • S 0 (good risk): No systemic illness, no history of opportunistic infections (OI) or thrush, Karnofsky performance status score ≥70 and absence of the following B symptoms:

  • Unexplained fever

  • Night sweats

  • More than 10% involuntary weight loss

  • Diarrhea persisting more than 2 weeks

  • S 1 (poor risk): OI or thrush, presence of B symptoms and/or Karnofsky performance status score ≤70

Non-epidemic gay-related KS in MSM

KS develops at a higher rate than in the general population in MSM without evidence of HIV infection or immunodeficiency. The lesions most commonly appear on the extremities or genitalia, but in contrast to the epidemic type, the extent of disease is limited and the prognosis is good. Patients are younger than those with the classic variant. However, these patients may have a higher risk of developing lymphoproliferative neoplasms (Castleman disease, follicular lymphoma and Burkitt lymphoma).

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