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Endemic Kaposi Sarcoma

Kaposi sarcoma is a mesenchymal tumor possibly originating from the endothelial cells lining blood and lymphatic vessels. Human herpesvirus-8 (HHV-8) has been identified as one of its triggers, but an HHV-8 infection alone is insufficient to induce the development of the tumor. Other factors must play a role in cancerogenesis, and these factors presumably explain the distinct epidemiology and presentation of classical Kaposi sarcoma and endemic Kaposi sarcoma (EKS). The latter is mainly seen in African young adults and children. Therefore, EKS is also referred to as African Kaposi sarcoma or African endemic Kaposi sarcoma.


Presentation

The presentation of EKS is heterogeneous, and at least four variants should be distinguished [1] [2]:

  • Benign nodular tumors of the skin mimicking classical Kaposi sarcoma in morphology and growth behavior. Accordingly, these neoplasms slowly increase in pigmentation and size. They may initially appear as flat macules or raised, indurated papules, and gradually turn into nodules that are prone to bleeding and ulceration. These tumors generally develop on the lower extremities. Lymph node involvement is not to be expected.
  • Large, aggressive tumors of the skin that show invasive growth behavior and spread to the underlying soft tissues and bones. Cutaneous lesions preferentially develop on the arms and legs, and commonly take on an exophytic, fungating appearance. Visceral involvement is rare, but not unheard of.
  • Florid EKS with involvement of the skin, mucous membranes and/or viscera. Patients generally display multiple nodular lesions, which are distributed over the skin of the extremities. Gastrointestinal tumors may not provoke any symptoms or may interfere with the passage of food or function of stomach and bowel.
  • Fulminant lymphadenopathic EKS that rapidly spreads to lymph nodes and viscera. This variant primarily affects young children with a mean age of 3 years, but it may also be developed in late childhood or adolescence. These patients present with local or generalized lymphadenopathy, whereas cutaneous lesions are not usually observed.

EKS patients do not typically present symptoms of immunodeficiency, nor do laboratory analyses suggest an immunocompromised condition.

Chest Discomfort
  • This manifests as shortness of breath and chest discomfort due to compression of the lung by the collection of chyle. Drainage of milky-white pleural fluid suggests chylothorax that can be confirmed by pleural fluid examination.[sajhivmed.org.za]
Fishing
  • The deletion of chromosome 16 and Y was confirmed by interphase FISH on paraffin embedded sections. EKS had higher number of chromosomal abnormalities than AKS.[openarchive.ki.se]
  • The use of shark cartilage to treat KS derives from a popular belief that sharks and other cartilaginous fish (skates and rays) do not get cancer.[encyclopedia.com]
Productive Cough
  • Three months after completion of chemotherapy, he developed a worsened shortness of breath and productive cough. The whitish sputum was negative upon Ziehl-Neelsen smear.[sajhivmed.org.za]

Workup

The diagnosis of EKS is based on anamnestic data, clinical findings, and the microscopic analysis of tumor tissue obtained by biopsy or excision [3]. With regard to the latter, the examination of EKS tissue samples allows for the observation of proliferating spindle-shaped cells and newly formed vessels traversing the tumor. Besides spindle cells, there may be endothelial cells with vascular slits or polymorphic round cells with frequent mitoses and marked pleomorphism of cellular components. According to these observations, the following histological patterns may be distinguished: monocellular (mainly spindle cells), mixed (spindle cells and endothelial cells), and anaplastic (spindle cells and round cells) [4]. Regardless of the cellular composition, the extravasation of erythrocytes is frequently described, as is the presence of hemosiderin-laden macrophages and inflammatory infiltrates [5].

The detection of HHV-8 latency-associated nuclear antigen (LANA) by immunohistochemistry confirms the tentative diagnosis of Kaposi sarcoma [3], but it should be noted that neither histopathological nor immunohistochemical allow for the distinction of EKS and other types of Kaposi sarcoma [6]. Thus, further diagnostic measures should be taken to verify the immunocompetence of the patient: Demographic data may suggest EKS over classical Kaposi sarcoma, and a survey of the patient's medical history may argue against the iatrogenic type of the disease. To rule out epidemic Kaposi sarcoma, all patients should be tested for an infection with the human immunodeficiency virus (HIV) and the ensuing acquired immunodeficiency syndrome (AIDS).

If LANA staining yields negative results despite a strong suspicion of EKS, molecular biological studies should be realized to demonstrate the infection with HHV-8. Polymerase chain reaction has been shown to reliably detect HHV-8 in Kaposi sarcoma even in the absence of LANA expression [3]. Further steps should then be taken as described above.

Treatment

There are no specific guidelines for the management of EKS. The disease is treated like other types of Kaposi sarcoma are: The surgical resection or cryotherapy of superficial lesions may be combined with the administration of liposomal doxorubicin when the disease has spread to other organs. Due to the pivotal role of HHV-8 in the pathogenesis of EKS, antiviral treatment is also recommended. HHV-8 is sensitive to ganciclovir and foscarnet, but not to acyclovir [3].

Beyond that, inhibitors of vascular endothelial growth factor and its receptor, mTOR inhibitors, and distinct immunomodulatory compounds have been applied to patients with Kaposi sarcoma. Ambiguous results have been reported, and neither of the aforementioned compounds is currently approved for the treatment of EKS [3].

Prognosis

The outcome depends on the characteristics of EKS, even if adequate treatment is provided. In this context, benign nodular EKS follows an indolent course and is associated with a good prognosis, while aggressive cutaneous tumors are usually fatal within 5-7 years [2]. Florid EKS is an aggressive, invasive, and rapidly progressive type of tumor. The outcome is often unfavorable, with mean survival times of 3-5 years [1]. Pediatric patients diagnosed with fulminant lymphadenopathic EKS have the poorest prognosis: The disease is universally fatal within a maximum of 3 years.

Etiology

HHV-8 or Kaposi sarcoma-associated herpesvirus, as it is also called, has been identified as the trigger of all types of Kaposi sarcoma. However, only a minor share of HHV-8 infected individuals does develop this type of cancer, so additional factors must be involved in the pathogenesis of the disease. A myriad of factors has been discussed in this context - genetic predisposition, climatic conditions, exposure to certain compounds in water and soils, hematophagous parasites, viral agents other than HHV-8, or non-viral pathogens -, but none could be identified as a key player in EKS development [5].

Epidemiology

In sub-Saharan Africa, the prevalence of HHV-8 is very high. It is transmitted horizontally, mainly via saliva and extensive, repeated contact between mother and child, or sexual partners [3]. The corresponding seroconversion rate is >80% in post-pubertal inhabitants [7].

Data collected before the HIV/AIDS epidemic, which has significantly altered the epidemiology of Kaposi sarcoma, indicated highest incidence rates in the Democratic Republic of the Congo, then Zaire, for Tanzania and Uganda. Here, the annual incidence of EKS was as high as 0.6%. High EKS prevalence has also been declared in Cameroon and Malawi, and in all these Central African countries, males seemed to be affected up to ten times more often than females [8]. More recent publications indicate male-to-female ratios of about 3 to 1, whereby the apparent change may be due to a higher detection rate in female patients [4]. Still, the older the patients, the more likely they are males.

In the pre-HIV/AIDS era, EKS may have accounted for up to 9% of all cases of cancer, and for about 56 and 34% of tumors in young boys and girls, respectively [4] [5]. Indeed, EKS incidence was found to peak in boys aged 5-9 years and in girls who were younger than 5 years [4]. It should be noted, though, that certain subtypes of EKS preferentially develop during mid-adulthood. This applies particularly to the more benign, cutaneous variants of the disease.

Updated information is difficult to obtain because of the high African prevalence of HIV/AIDS-related Kaposi sarcoma, which is not unequivocally distinguished from EKS in official reports. In any case, even the highest EKS prevalence rates are far below the prevalence of HHV-8. What's more, the geographical range of the herpesvirus includes large areas where EKS is hardly ever reported, such as the West African nations Gambia and Ivory coast [5]. Thus, there must be a factor in EKS distribution that has not yet been identified.

Sex distribution
Age distribution

Pathophysiology

EKS is a mesenchymal neoplasm that may derive from endothelial cells. However, tumor cells also display characteristics of pericytes, smooth muscle cells, dendritic cells, and macrophages, so their precise origin remains a matter of debate [3] [5]. Furthermore, Kaposi sarcoma has been characterized as a multifocal neoplasm, i.e., multiple lesions develop independently and are not metastases of a primary tumor [1]. This hypothesis is in agreement with a strong carcinogenic potential of HHV-8 and/or other triggers of the disease that may infect or affect numerous cells in the human skin and other organs. However, the pathophysiological events underlying EKS oncogenesis largely remain elusive.

HHV-8 employs a series of mechanisms to escape the human immune system, thus favoring the establishment of a lifelong latency in CD19+ B cells [3] [6]. The virus has been shown to inhibit autophagy and apoptosis, to modulate cytokine release and to suppress the actions of natural killer cells [3]. Upon exposure to interferon-γ, latently infected cells undergo lytic cycles, thereby generating new virus particles that infect other cells. However, neither the infection nor the lysis of a human cell induces its transformation. The proliferation of spindle cells has been related to the expression of viral interferon regulatory factor 1, viral G-protein-coupled receptor, and the ORF-K1 gene [9]. While viral interferon regulatory factor 1 suppresses the expression of interferon-inducible genes by the host, the viral G-protein-coupled receptor binds distinct chemokines. Finally, the K1 glycoprotein is an essential component of the virus' membrane. If and how these proteins interact, has yet to be clarified.

Prevention

Due to considerable knowledge gaps regarding the etiology and pathophysiology of EKS, few recommendations can be given to prevent the development of this tumor:

  • The prevention of infection with HHV-8 may be beneficial, but is hardly feasible: Although few habitants of endemic areas know whether they have been exposed to the virus, the majority comes into contact with the pathogen before reaching adulthood [7]. In immunocompetent patients, HHV-8 may not cause any symptoms or trigger a self-limiting disease with non-specific symptoms, so that the infection generally goes unnoticed [10]. Furthermore, the low incidence of EKS among people infected with HHV-8 does not justify extensive antiviral treatment.
  • The benefits of a general strengthening of the immune system are questionable, since EKS has not yet been related to any type of immunodeficiency.

Summary

EKS has first been described in the 1950s, when it was characterized as an endemic disease affecting young black men in equatorial Africa [1]. It is one of several types of Kaposi sarcoma that are universally recognized:

  • The disease is named after Moritz Kaposi, who described what's currently referred to as classical Kaposi sarcoma.
  • Furthermore, patients who are administered immunosuppressive drugs are predisposed to the development of Kaposi sarcoma. This type of the disease is called iatrogenic Kaposi sarcoma.
  • Kaposi sarcoma is a common manifestation of AIDS. Due to the wide dissemination of this type of neoplasm among HIV-positive individuals, HIV/AIDS-related Kaposi sarcoma is also referred to as epidemic Kaposi sarcoma.
  • A fifth type of Kaposi sarcoma has been described more recently. It affects men who have sex with men but who are HIV-negative and don't show any symptoms of immunodeficiency [6].

There are major differences in the epidemiology and clinical presentation of these variants, and they are associated with more or less favorable outcomes. However, they are histopathologically indistinguishable and have all been related to infections with HHV-8. It is highly likely that additional factors are involved in the pathogenesis of the disease, and it's these unknown factors that are speculated to account for the aforementioned differences.

Patient Information

Kaposi sarcoma is a multifocal neoplasm primarily affecting the skin. However, lymph nodes, mucous membranes, and viscera may also be involved. It is triggered by infection with human herpesvirus-8 and, presumably, by as-of-yet unknown additional factors. The epidemiology and clinical presentation of Kaposi sarcoma are highly heterogeneous, so that distinct types of the disease have been defined. One of these types is endemic Kaposi sarcoma (EKS). It is widely distributed in Central Africa and is usually diagnosed in boys and girls under the age of 10, and in mid-aged men. Whereas other types of Kaposi sarcoma are associated with immunodeficiency, those developing EKS are immunocompetent.

EKS may follow a chronic, indolent course, or manifest as fulminant lymphadenopathic disease. Intermediate variants of EKS comprise large, aggressive tumors of the skin that generally spread to the underlying tissues, and florid EKS with cutaneous, mucous membrane, and visceral involvement. The outcome varies according to the type of EKS: Patients with indolent EKS have a favorable prognosis, but fulminant lymphadenopathic EKS is universally fatal within 3 years, even if adequate treatment is provided.

References

Article

  1. Friedman-Kien AE, Saltzman BR. Clinical manifestations of classical, endemic African, and epidemic AIDS-associated Kaposi's sarcoma. J Am Acad Dermatol. 1990; 22(6 Pt 2):1237-1250.
  2. Hengge UR, Ruzicka T, Tyring SK, et al. Update on Kaposi's sarcoma and other HHV8 associated diseases. Part 1: epidemiology, environmental predispositions, clinical manifestations, and therapy. Lancet Infect Dis. 2002; 2(5):281-292.
  3. Schneider JW, Dittmer DP. Diagnosis and Treatment of Kaposi Sarcoma. Am J Clin Dermatol. 2017; 18(4):529-539.
  4. Buonaguro FM, Tornesello ML, Buonaguro L, et al. Kaposi's sarcoma: aetiopathogenesis, histology and clinical features. J Eur Acad Dermatol Venereol. 2003; 17(2):138-154.
  5. Simonart T. Role of environmental factors in the pathogenesis of classic and African-endemic Kaposi sarcoma. Cancer Lett. 2006; 244(1):1-7.
  6. Vangipuram R, Tyring SK. Epidemiology of Kaposi sarcoma: review and description of the nonepidemic variant. Int J Dermatol. 2018.
  7. Dittmer DP, Damania B. Kaposi sarcoma-associated herpesvirus: immunobiology, oncogenesis, and therapy. J Clin Invest. 2016; 126(9):3165-3175.
  8. Cook-Mozaffari P, Newton R, Beral V, Burkitt DP. The geographical distribution of Kaposi's sarcoma and of lymphomas in Africa before the AIDS epidemic. Br J Cancer. 1998; 78(11):1521-1528.
  9. Hengge UR, Ruzicka T, Tyring SK, et al. Update on Kaposi's sarcoma and other HHV8 associated diseases. Part 2: pathogenesis, Castleman's disease, and pleural effusion lymphoma. Lancet Infect Dis. 2002; 2(6):344-352.
  10. Sarmati L. HHV-8 infection in African children. Herpes. 2004; 11(2):50-53.

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Last updated: 2019-07-11 20:54