Classic Kaposi sarcoma

                              Dr. KS Dhillon

Introduction

Kaposi sarcoma (KS) is an indolent angio-proliferative spindle-cell tumor. It is derived from endothelial and immune cells infected with human herpes virus type 8 (HHV-8; also known as Kaposi sarcoma herpes virus [KSHV]). HHV-8 is the causative agent of KS. It is present in 95-98% of all cases [1]. There are 4 types of KS [2]:

• Epidemic (AIDS related)

• Iatrogenic (immunosuppressant therapy related)

• Classic, or sporadic

• Endemic (African)

• Nonepidemic

Nonepidermic KS occurs in men who have sex with men but have no evidence of HIV infection or immunodeficiency. These cases present in an indolent cutaneous form that resembles classic KS [3,4,5].

All types of KS have in common an infection with HHV-8. However, each has a distinct clinical course which is likely due to other factors, such as the extent and type of immune suppression [6]. The presentation of KS can range from minimal mucocutaneous disease to extensive organ involvement.

KS was first described in 1872 as a rare disease in Eastern European men. In the 1950s, an endemic form of KS was one of the most common neoplasms observed in central Africa, affecting men, women, and children. The cases in children occur due to maternal-child transmission of HHV-8 through saliva [6]. 

A surge in KS cases occurred just prior to the identification of the AIDS epidemic in the early 1980s. In the USA, AIDS-related KS is the most common KS presentation. The risk of KS in people living with HIV from 2009-2012 was 500-fold higher than for the US general population. KS accounts for 12% of cancers in people living with HIV. There are between  765 to 910 new cases per year in the US [7,8,9].

Following the AIDS epidemic, the incidence of KS in Africa increased markedly. From 1968 to 1970, KS accounted for 6.6% of all cancers occurring in men. From 1989 to 1991, KS became the most commonly reported cancer in men [10,11].

Iatrogenic KS cases have also increased. This is due to the greater use of immunosuppression in medical practice, especially in the post-transplant setting and treatment of autoimmune diseases [9].

Pathophysiology

In 1994 Kaposi sarcoma human herpes virus (KSHV) was discovered. This led to rapid progress in understanding the disease’s pathophysiology. Different epidemiologic and clinical presentations of the disease could be related to modifiable risk factors, such as uncontrolled HIV infection and immunosuppressive medications used in transplantation. 

Kaposi sarcoma is caused by an excessive proliferation of spindle cells that have an endothelial cell origin. The tumors are predominantly composed of KSHV genomic material with immunohistochemical markers of lymphoid, spindle, and endothelial cells. 

The cell of origin remains unknown. Increased endothelial factor VIIIa antigen, spindle cell markers such as smooth muscle alpha-actin, and macrophage markers such as PAM-1, CD68, and CD14 expressed by the spindle cells have been observed. The spindle cells proliferate in a background of reticular fibers, collagen, and mononuclear cells such as macrophages, lymphocytes, and plasma cells. They tend to be vascular, involving either the reticular dermis or the entire thickness of the dermis.

KSHV contains a large genome that has more than 85 antigenically competent genes. Immunofluorescent assays and an enzyme-linked immunoassay (ELISA) to major antigens have been developed to measure antibodies to KSHV. Seropositivity is more than 50% in sub-Saharan Africa, 20-30% in Mediterranean countries, and less than 10% in most of Europe, Asia, and the United States. The prevalence of KS is higher in men who have sex with men, Amerindians in South America, and certain ethnic groups in China. 

Previous molecular studies suggested that Kaposi sarcoma originates from a single-cell clone rather than a multifocal origin. More recent data showed that nearly 80% of the tumors arose independently from multiple cells. A few Kaposi sarcomas originate from a single cell. Kaposi sarcoma can independently occur at multiple sites. 

Human herpes virus 8 (HHV-8) genomic sequences have been identified by polymerase chain reaction in more than 90% of all types of Kaposi sarcoma lesions. The current belief is that HHV-8 must be present for the disease to develop. It can be transmitted in saliva. 

Factors that are thought to contribute to the development of Kaposi sarcoma in individuals infected with HHV-8 and HIV include an abnormal cytokine milieu associated with HIV infection.

Kaposi sarcoma may be caused by HHV-8 (KSHV) with stimulation by autocrine and paracrine growth factors secreted by the spindle cells. Coinfection with HIV may create a more aggressive course. The risk of Kaposi sarcoma development is amplified 500-10,000 times in patients coinfected with KSHV and HIV. 

Cofactors

Kaposi sarcoma develops in only a small percentage of HHV-8 seropositive individuals. This points to the importance of other factors. Some of these may be genetic. Individuals with certain polymorphisms in the MDM2 gene, which is involved in the function of the tumor suppressor protein p53, may be at increased risk for Kaposi sarcoma.

Some agents may either stimulate or inhibit the development of Kaposi sarcoma. This depends on the presence of influences such as genetic predisposition, environmental factors, drug intake, or lymphatic system disorders. There is a high prevalence of Kaposi sarcoma in areas where quinine and its derivatives are widely used for the treatment of malaria. The high prevalence may partly be attributable to the immunosuppressant effect of those drugs. However, quinolones are also known to have several effects that could inhibit Kaposi sarcoma development.  Angiotensin-converting enzyme (ACE) inhibitors also induce Kaposi sarcoma in some and inhibit it in others.

Transmission

KSHV is largely transmitted via saliva. It is also associated with sexual risk factors. These may just be a surrogate for close contact. Heterosexual risk factors do not play a role in transmission. Transmission by blood or blood products can occur. Transmission of KSHV may occur during solid organ donation. In solid organ transplant recipients, the incidence of Kaposi sarcoma may be higher in those who are seropositive as compared to those who are seronegative. [57]

Etiology

Etiologic factors for KS include the following:

• Iatrogenic immunosuppression (including corticosteroids)

• Coinfection with  HIV and HHV-8 

• Elevated expression of numerous cytokines and angiogenic growth factors, including tumor necrosis factor alpha, interleukin-6, basic fibroblast growth factor, HIV-tat protein, and oncostatin M

Epidemiology

Before HIV came into existence, Kaposi sarcoma was common in central Africa and prevalent in Mediterranean countries and the Middle East. It rarely occurred in other areas of the world. In Africa, the annual incidence of Kaposi sarcoma is very high. It is at 37.7 per 100,000 in men and 20.5 per 100,000 in women. 

In Europe, the highest rates of classic Kaposi sarcoma are in Ragusa Sicily with 30.1 cases per million in men and 5.4 cases per million in women. In  Sardinia, there are 24.3 cases per million in men and 7.7 cases per million in women.

A meta-analysis of the worldwide epidemiology of Kaposi sarcoma found the following incidence rates per 100,000 person-years:

• General population: 1.53 

• HIV-infected persons: 481.54 

• HIV-infected MSM:1397.11 

• HIV-infected children: 52.94 

• Transplant recipients: 68.59 

Kaposi sarcoma was rare before the AIDS epidemic. Between the years of 1975 and 1980, only 19 cases occurred in men aged 20-54 years in the USA. Just before 1980, at the beginning of the AIDS epidemic, 40-50% of men who had sex with men, who had AIDS, developed Kaposi sarcoma.

The incidence of Kaposi sarcoma reached its peak in 1989 among white men aged 20-54 years. It was the most common AIDS-associated neoplasm. Since than its incidence has dramatically declined.

The incidence and severity of Kaposi sarcoma has lessened following the introduction of highly active antiretroviral therapy. This reduction has been attributed to restoration of the immune system by these drugs. 

In the USA, AIDS-related Kaposi sarcoma occurs primarily in homosexual and bisexual men, as well as in the female sexual partners of bisexual men.

In Africa the Kaposi sarcoma occurs in heterosexual men and women with equal frequency. Kaposi sarcoma occurs primarily in men, with a male-to-female ratio of 10-15:1.

AIDS-related Kaposi sarcoma generally occurs in young to middle-aged adults between the ages of 20-54 years.  Classic Kaposi sarcoma usually occurs in patients aged 50-70 years.  African Kaposi sarcoma occurs in younger people between the age of 35-40 yrs.

Clinical presentation

Lesions in KS can involve the skin, lymph nodes, oral mucosa, and visceral organs. Most of the patients present with cutaneous disease. The visceral disease can occasionally precede cutaneous manifestations.

Cutaneous lesions in patients with KS can be characterized as follows:

• Cutaneous lesions typically are concentrated on the lower extremities and the head and neck region but can occur at any location.

• Lesions can have papular, nodular, macular, or plaque-like appearances.

• Nearly all the lesions are palpable and nonpruritic.

• The size of the lesions may range from several millimeters to several centimeters in diameter.

• Lesions may assume a pink, red, brown, or violaceous color and can be difficult to distinguish in dark-skinned individuals.

• Lesions can be discrete or confluent. They typically appear in a linear, symmetrical distribution, along the Langer lines

• Mucous membrane involvement is common. The lesions can appear on the palate, gingiva, and conjunctiva.

Lesions in the gastrointestinal tract can occur anywhere in the tract. The lesions are usually asymptomatic and clinically indolent. The following signs and symptoms can be present:

• Odynophagia (pain on swallowing), dysphagia

• Nausea, vomiting, and pain in the abdomen

• Hematemesis, hematochezia (fresh blood in stool), melena

• Bowel obstruction

Pulmonary lesions can be an asymptomatic radiographic finding. Signs and symptoms can include the following:

• Chest pain

• Cough

• Dyspnea

• Hemoptysis

Classic Kaposi sarcoma

Classic Kaposi sarcoma has a more indolent course than AIDS-related KS. It progresses over 10-15 years or more, with gradual enlargement of cutaneous lesions. Over the years there is development of new lesions.

Diagnosis

Laboratory studies

For patients with HIV infection CD4 lymphocyte counts and plasma HIV viral-load studies can be performed. 

Imaging studies

Chest radiographic findings are variable and nonspecific in patients with KS. They may include any of the following:

• Interstitial infiltrates

• Diffuse reticulonodular infiltrates

• An isolated pulmonary nodule

• Pleural effusions

• Hilar or mediastinal lymphadenopathy

Thallium and gallium scans can help differentiate pulmonary KS from infection. Pulmonary KS lesions usually demonstrate intense thallium uptake and no gallium uptake. Infection is often gallium avid and thallium negative.

Procedures

A punch biopsy can be carried out. Typical histologic findings in KS include the following:

• Extravasated red blood cells.

• Proliferation of spindle cells

• Prominent, slitlike vascular spaces

Bronchoscopy, esophagogastroduodenoscopy (EGD) or colonoscopy may be required for diagnosis. 

Management

Antiretroviral therapy

Highly active antiretroviral therapy (HAART) is necessary for optimal control of HIV infection in patients with KS. HAART can be tried as the sole modality for the treatment of nonvisceral disease. For visceral disease, chemotherapy can be added.

Local therapy

Local therapies can be used for palliation of locally advanced symptomatic disease or in individuals who have cosmetically unacceptable lesions. Local therapies include:

• Cryotherapy

• Radiation therapy

• Laser therapy

• Intralesional vinca alkaloid therapy

• Topical retinoids

• Surgical excision

Immunomodulation 

Immunomodulation with interferon-alfa has clinical activity in KS. It may be mediated by its antiangiogenic, antiviral, and immunomodulatory properties.

Combination therapy

Combination therapy with drugs such as actinomycin D, bleomycin, and vincristine produces higher response rates than does single-agent therapy such as doxorubicin. Time to progression and overall survival rates, however, are similar.

Cytotoxic agents

There are several single cytotoxic agents for AIDS-related KS. These include:

• Paclitaxel (Taxol) or oral etoposide (VePesid)

• Liposomal doxorubicin (Doxil)

• Liposomal daunorubicin (DaunoXome)

Liposomal technology has now resulted in higher response rates with less myelotoxicity and cardiac toxicity for liposomal doxorubicin and liposomal daunorubicin [12, 13, 14].

Prognosis

AIDS-related Kaposi sarcoma tends to have an aggressive clinical course. In other forms of KS the clinical course is less agressive. Morbidity can occur from extensive cutaneous, mucosal, or visceral involvement. In patients receiving antiretroviral therapy, the disease has a more indolent clinical course or may regress spontaneously. The most common causes of morbidity include cosmetically disfiguring cutaneous lesions, lymphedema, pulmonary involvement, or gastrointestinal involvement. The most common cause of mortality is pulmonary involvement with uncontrolled pulmonary hemorrhage.

References

1. Antman K, Chang Y. Kaposi's sarcoma. N Engl J Med. 2000 Apr 6. 342(14):1027-38.

2. PDQ Adult Treatment Editorial Board. Kaposi Sarcoma Treatment (PDQ®): Health Professional Version. 2018 July 27.

3. Friedman-Kien AE, Saltzman BR, Cao YZ, et al. Kaposi's sarcoma in HIV-negative homosexual men. Lancet. 1990 Jan 20. 335(8682):168-9.

4. Vangipuram R, Tyring SK. Epidemiology of Kaposi sarcoma: review and description of the nonepidemic variant. Int J Dermatol. 2018 Jun 11. 

5. Denis D, Seta V, Regnier-Rosencher E, Kramkimel N, Chanal J, Avril MF, et al. A fifth subtype of Kaposi's sarcoma, classic Kaposi's sarcoma in men who have sex with men: a cohort study in Paris. J Eur Acad Dermatol Venereol. 2018 Jan 29.

6. Mesri EA, Cesarman E, Boshoff C. Kaposi's sarcoma and its associated herpesvirus. Nat Rev Cancer. 2010 Oct. 10 (10):707-19.

7. Robbins HA, Pfeiffer RM, Shiels MS, Li J, Hall HI, Engels EA. Excess cancers among HIV-infected people in the United States. J Natl Cancer Inst. 2015 Apr. 107 (4).

8. Yarchoan R, Uldrick TS. HIV-Associated Cancers and Related Diseases. N Engl J Med. 2018 Mar 15. 378 (11):1029-1041. 

9. Curtiss P, Strazzulla LC, Friedman-Kien AE. An Update on Kaposi's Sarcoma: Epidemiology, Pathogenesis and Treatment. Dermatol Ther (Heidelb). 2016 Dec. 6 (4):465-470.

10. Stein ME, Spencer D, Ruff P, Lakier R, MacPhail P, Bezwoda WR. Endemic African Kaposi's sarcoma: clinical and therapeutic implications. 10-year experience in the Johannesburg Hospital (1980-1990). Oncology. 1994 Jan-Feb. 51 (1):63-9. 

11. Wabinga HR, Parkin DM, Wabwire-Mangen F, Mugerwa JW. Cancer in Kampala, Uganda, in 1989-91: changes in incidence in the era of AIDS. Int J Cancer. 1993 Apr 22. 54 (1):26-36.

12. Northfelt DW, Dezube BJ, Thommes JA, et al. Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi's sarcoma: results of a randomized phase III clinical trial. J Clin Oncol. 1998 Jul. 16(7):2445-51.

13. Stewart S, Jablonowski H, Goebel FD, et al. Randomized comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AIDS-related Kaposi's sarcoma. International Pegylated Liposomal Doxorubicin Study Group. J Clin Oncol. 1998 Feb. 16(2):683-91. 

14. Gill PS, Wernz J, Scadden DT, et al. Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi's sarcoma. J Clin Oncol. 1996 Aug. 14(8):2353-64.