Are You Confident of the Diagnosis?
What you should be alert for in the history
Kaposi’s sarcoma is characterized by the appearance of purplish, reddish-blue, or dark brown/black macules, plaques, or nodules on the skin. With classic Kaposi’s sarcoma, the lesions most commonly appear on the lower extremities (Figure 1).
There are four types of Kaposi’s sarcoma:classic (sporadic), endemic (African), immunosuppression related and acquired immunodeficiency syndrome (AIDS) associated. In the cutaneous presentation is most often on the distal lower extremities the classic Kaposi’s and the immunosuppression related variety. In the endemic and AIDS-associated varieties, the disease is more often disseminated and aggressive, but invariably has cutaneous manifestations.
Visceral involvement, including the gastrointestinal tract and regional lymph nodes, is less common in the classic variety but more likely in the other subtypes. There are at least ten different morphologic variants of the cutaneous lesions of Kaposi’s sarcoma.
Characteristic findings on physical examination
The skin lesions may appear as a plaque, patch, nodule, exophytic infiltrative, or lymphadenopathy. The lesions may appear cavernous and lymphangioma-like, and produce chronic lymphedema in the lower extremities. These lesions may consist of compressible nodules that appear as fluid-filled cysts, or they can coalesce and anastomose in networks, producing areas of extensive raised plaques.
Regional lymphadenopathy in the inguinal nodes may be present but does not influence prognosis or treatment options in patients with classic Kaposi’s.
Expected results of diagnostic studies
Immunohistochemical staining of the biopsies can also be useful to detect the presence of LANA-1 (latency-associated nuclear antigen) within the spindle cells (Figure 2, Figure 3).
Radiological studies are rarely necessary to evaluate potential metastatic disease sites in patients with classic Kaposi’s. Gastrointestinal involvement rarely complicates cases of classic Kaposi’s, except those with extensive skin involvement of the lower extremities. Patients with Kaposi’s related to endemic, immunosuppression, and AIDS are much more likely to have extensive disease involvement that is extracutaneous.
Involvement of the oral cavity occurs in approximately a third of patients with AIDS-related Kaposi’s, and in 15% of cases, it is the initial presentation of this disease. The palate is the most commonly affected area, followed by the gingiva. Intraoral lesions can be easily traumatized, causing pain, bleeding, ulceration, and secondary infection. Oral lesions may interfere with nutrition and speech, and are often a major reason for treating patients urgently.
Evaluation of gastrointestinal involvement should be performed by endoscopic examination, as these lesions are rarely seen radiologically. Gastrointestinal lesions may be asymptomatic, or can cause weight loss, abdominal pain, nausea, vomiting, upper or lower gastrointestinal bleeding, malabsorption, intestinal obstruction, or diarrhea.
Pulmonary involvement is common in AIDS-related Kaposi’s, usually presenting as shortness of breath, fever, cough, hemoptysis, or chest pain (or patients may be asymptomatic).
Radiological findings are variable, and include infiltrates and densities, effusions, and adenopathy. Diagnosis of pulmonary involvement with Kaposi’s sarcoma is usually made by bronchoscopy, by observing cherry-red raised lesions on the endobronchial surface.
Since a number of other organs can be involved by Kaposi’s computed tomography (CT) and magnetic resonance imaging (MRI) scans are usually needed to evaluate organ involvement including involvement of the lymph nodes, liver, pancreas, cardiovascular system, , testes, bone marrow, bone, or skeletal muscle.
Staging and prognosis are established by determining CD4 count, human immunodeficiency virus (HIV) viral load, and the presence of human herpes virus 8 (HHV-8) DNA. The most commonly used staging system developed by the AIDS clinical trial group separates patients into good and poor risk categories according to extent of tumor, immune status, and severity of illness. These factors were much more important in the period before highly active retroviral therapy. Since the introduction of highly active retroviral therapy, the incidence of and prognosis for Kaposi’s have improved substantially in all risk categories.
The diagnosis of classic Kaposi’s sarcoma is suspected based on the appearance and location of the lesions. Lesions located on the lower extremities can be mistaken for changes due to peripheral vascular disease or venous stasis.
Bacillary angiomatosis is a rare infection caused by the Bartonella species, which are gram-negative bacilli that are readily treated with antibiotics. Lesions due to this infection usually present as numerous small red-purple papules that may expand into larger exophytic lesions and become friable. The rash may be associated with fevers, chills, malaise, headache, and anorexia. Bacillary angiomatosis can infect both immunocompromised and immunocompetent patients.
Bacillary angiomatosis was described in the 1980s and found to be associated with AIDS at presentation. This condition may simulate Kaposi’s in patients with AIDS by its dermatological presentation and systemic spread; however, this disorder responds to antibiotics, including oral erythromycin as well as other antibiotics. Anti-tuberculosis medications are also effective. Bacillary angiomatosis is treatable and curable, but it may also be life-threatening, if undiagnosed.
Other rare infections that may produce similar and confusing nodular violaceous skin lesions include S. schenckii (sporotrichosis) and M. marium. Biopsy of these skin lesions allows a definitive diagnosis to be made. Biopsies demonstrate typical histological features under standard microscopy. Additional studies, including polymerase chain reaction, can be performed on obvious skin lesions to detect amplified HHV-8 DNA sequences.
Who is at Risk for Developing this Disease?
There are four subgroups of Kaposi’s sarcoma:
1. Classic Kaposi’s is characteristically seen in older men of Mediterranean and Jewish origin.
2. Endemic or African Kaposi’s is found in all parts of equatorial Africa, particularly in sub-Saharan Africa, and is not associated with immunodeficiency.
HHV-8, also known as Kaposi’s-sarcoma-associated herpes virus (KSHV), is necessary but not sufficient for the development of Kaposi’s sarcoma. A secondary factor results in a reactivation of this virus, which is important in the pathogenesis of Kaposi’s and the distinctive and largely unexplained geographic distributions of classic Kaposi’s.
3. Immunosuppression due to transplantation, particularly solid organ transplant, is a risk factor for Kaposi’s sarcoma. Patients receiving immunosuppressive agents are not at risk for developing Kaposi’s; thus it appears that the immunological derangements that occur in patients with solid organ transplants and in those on immunosuppressive agents is a distinctive risk factor for Kaposi’s.
4. AIDS-related Kaposi’s (epidemic KS) is associated with HIV and severe immunosuppression with low CD4 counts. Kaposi’s sarcoma in patients with HIV defines AIDS. Treatment with highly active retroviral therapy not only helps control Kaposi’s disease, but also has been associated with a marked reduction in the incidence of Kaposi’s in patients on highly active retroviral therapy.
What is the Cause of the Disease?
Kaposi’s sarcoma is a low-grade vascular tumor associated with infection with HHV-8 also known as KSHV. These vascular tumors primarily develop in the skin and lower extremities in classic Kaposi’s sarcoma and remain confined to the lower extremities, causing lymphedema and disfigurement.
Classic Kaposi’s patients are not immunosuppressed, and their disease involves chronic lower extremity edema due to this invasive tumor. This tumor rarely metastasizes distantly, other than to local regional nodes.
Endemic Kaposi’s follows a similar pattern, with lower extremity involvement, but generally is more aggressive and can disseminate to distant organs, unlike classic Kaposi’s.
Immunosuppression-related Kaposi’s occurs during immunosuppression for solid tumor organs. Lesions usually present in the skin and lower extremity, but are much more likely to disseminate. The control and progression of the lesions, both locally and with dissemination, are related to the ability to restore the immune system by eliminating or changing immunosuppressive agents.
AIDS-related Kaposi’s is a much more aggressive and widely disseminated disease, causing significant morbidity and mortality. The degree of immunosuppression is directly correlated with the risk of developing Kaposi’s sarcoma and treatment with highly active retroviral therapy; the resultant restoration of the immune system has reduced the incidence of Kaposi’s and provided an improved outcome.
Systemic Implications and Complications
Patients with AIDS-associated Kaposi’s or immunosuppression-mediated Kaposi’s who are treated with corticosteroids are more likely to have exacerbation of existing Kaposi’s lesions and progression of their lesions. Patients with Kaposi’s who are on corticosteroids also have a higher incidence of opportunistic infections.
Patients with AIDS-associated Kaposi’s that arises during immunosuppression are also at risk for other malignancies. Non-Hodgkin’s lymphoma is a common second malignancy in patients on immunosuppression. Non-Hodgkin’s lymphoma is a complication for patients with HIV-AIDS and for solid organ transplant patients that are being treated with immunosuppressive agents.
The subtype of Kaposi’s sarcoma will dictate the extent of clinical workup. For example, patients with classic Kaposi’s do not require any extensive radiological surveillance. On the other hand, patients with AIDS-related Kaposi’s will need very careful attention to various organs, and will require radiological studies, especially an endoscopic evaluation including careful oral and dental evaluations.
Chest x-rays are useful for screening for pulmonary lesions; bronchoscopy should be reserved for patients with abnormal radiographs or respiratory symptoms. Visceral disease is much more likely in patients with low CD4 counts (CD4 counts of 200 or less are usually associated with a higher risk of developing Kaposi’s and also with more aggressive and extensive disease at the time of presentation).
Testing stool for occult blood is a good screen for gastrointestinal involvement and endoscopy should be reserved for patients who have positive occult blood or have gastrointestinal symptoms.
Treatment options will vary according to the subtype of Kaposi’s.
CLASSIC KAPOSI’S SARCOMA
-observation of asymptomatic lesions
-topical allotretinoin cream
-laser (pulsed-dye laser)
-systemic chemotherapy (peglyated doxorubicin)
AFRICAN KAPOSI’S SARCOMA
African Kaposi’s sarcoma can be treated with the same approach used for patients with classic Kaposi’s.
-withdrawal of immunosuppressive agents
-systemic chemotherapy (peglyated doxorubicin)
AIDS-ASSOCIATED KAPOSI’S SARCOMA
-highly active antiretroviral treatment
-intralesional chemotherapy (vincristine or bleomycin)
-laser ablation—pulsed dye laser
-systemic chemotherapy (liposomal anthracycline)
AIDS-associated Kaposi’s sarcoma patients who receive highly active retroviral therapy and develop immune reconstitution inflammatory syndrome and progressive Kaposi’s within weeks after initiation of highly active retroviral therapy should be treated with chemotherapy (vincristine, bleomycin, adriamycin, or paclitaxel based) during this phase.
Optimal Therapeutic Approach for this Disease
Treatment options will vary according to the subtype of Kaposi’s.
Classic Kaposi’s sarcoma can be treated with surgical excision of small isolated lesions. If there is extensive skin involvement, then radiation therapy is the treatment of choice.
The goal of therapy is to alleviate symptoms, including reducing lymphedema, improving the function of lower extremities, decreasing the size of cutaneous lesions, and preventing progression. Patients with limited disease involvement may be observed without active therapy. Asymptomatic patients and those who do not have impairment of ambulation (if lower extremity edema can be managed with compressive stockings) may be observed without active therapy.
Patients with a limited volume of disease causing bleeding or cosmetic disfigurement can be treated with local therapy; radiation therapy, excision, cryotherapy, and laser ablation are useful, depending on the number of sites and the extent of involvement, as well as clinician and patient preference.
Patients with bulky disease that cannot be managed with local modalities should be considered for systemic therapy and first-line preference given to pegylated liposomal doxorubicin. African Kaposi’s can be treated with the same approach used for patients with classic Kaposi’s.
The recommendation is to initially diagnose the suspicious skin lesion and classify the subtype of Kaposi’s sarcoma. As indicated above, the various subtypes of Kaposi’s sarcoma will have different natural histories of disease. Once a diagnosis has been established, the patient can be referred to a medical oncologist and infectious disease specialist. For patients with a solid organ transplant who are on immunosuppression, the treatment decisions are usually difficult and require a balance of maintaining immunosuppression for the transplanted organ and controlling and eradicating the Kaposi’s sarcoma.
Immunosuppression-mediated Kaposi’s can often respond to withdrawal of the immunosuppressive agents used to control graft-versus-host disease. These maneuvers can often result in complete responses and remissions. Case reports have described regression of Kaposi’s sarcoma in patients treated with the mTOR inhibitor rapamycin (sirolimus), suggesting that this approach (rather than using an alternative immunosuppressive agent in transplant-associated Kaposi’s) may be much more rational and applicable to transplant patients.
Systemic chemotherapy with pegylated liposomal doxorubicin as a first-line therapy, followed by other second-line agents, can be used to control the disease in patients where immunosuppression cannot be altered.
Patients with AIDS-associated Kaposi’s who develop either limited or advanced Kaposi’s sarcoma should initially be treated with highly active retroviral therapy. For patients who have limited disease-causing symptoms or cosmetic disfigurement, local therapy rather than systemic therapy, in addition to highly active retroviral therapy, is the recommended approach. The treatment approach for local regional disease, including intralesional chemotherapy, surgery, cryotherapy, and laser ablation should be reserved for patients with small lesions.
Patients with larger lesions or bulky local regional disease should receive radiation therapy.
Patients with extensive cutaneous disease and symptomatic visceral involvement or local cutaneous disease unresponsive to local measures should receive systemic chemotherapy with the recommended liposomal anthracycline.
AIDS-associated Kaposi’s sarcoma patients who receive highly active retroviral therapy and develop immune reconstitution inflammatory syndrome and progressive Kaposi’s within weeks after initiation of highly active retroviral therapy should be treated with chemotherapy during this phase.
Classic Kaposi’s sarcoma requires the identification of the appropriate patient subgroup, namely older males of Mediterranean or Jewish ancestry. The lesions are typically extensive, involving the lower extremities, and treated with local regional control efforts. Laboratory studies need to be ordered to rule out HIV infection, and CD4 counts should be monitored. Radiological studies such as CT scans should be ordered only if there are symptoms and concern about organ involvement. There is no role for routine radiological surveillance.
African Kaposi’s sarcoma presents in a fashion similar to classic Kaposi’s, with lower extremity involvement; however, this disease tends to be more aggressive and infiltrative. Laboratory studies need to be ordered to rule out HIV infection, and CD4 counts should be monitored. Radiological studies, including CT scans and pulmonary and GI endoscopy, should be considered, especially in patients with symptoms and in those with extensive disease involvement.
AIDS-associated Kaposi’s sarcoma is a much more aggressive and widespread disease. Routine radiological surveillance and pulmonary and GI endoscopic studies should be performed. Physical examination should include a careful oral and dental evaluation. Laboratory studies include monitoring of viral load and CD4 counts.
Kaposi’s sarcoma that develops in patients with solid organ transplants is established once a positive skin biopsy is obtained. Radiological surveillance should include CT scans and endoscopic surveillance of the pulmonary system and GI tract. Laboratory studies will include monitoring of the immune system and viral serology, including HIV testing. Treatment decisions will be made by collaboration between the medical oncologist and transplant physician.
Unusual Clinical Scenarios to Consider in Patient Management
One must be vigilant for the possibility of secondary malignancies, most notably non-Hodgkin’s lymphoma.
Patients may be at risk for the immune reconstitution syndrome after the commencement of highly active antiretroviral therapy.
What is the Evidence?
Gill, PS, Wernz, J, Scadden, DT. “Randomized phase 3 trial of liposomal doxorubicin in AIDS related Kaposi's sarcoma”. JClini Oncol. vol. 14. 1996. pp. 2353(Nice study on the use of systemic chemotherapy for AIDS-related Kaposi's sarcoma)
Leidner, RS, Aboulafia, DM. “Recrudescent Kaposi's sarcoma after initiation of HAART: manifestation of immune reconstitution syndrome”. AIDS Patient Care STDS. vol. 19. 2005. pp. 635(Kaposi's sarcoma manifests after the start of HAAART. Mechanisms and theories are discussed.)
Gallafent, JH, Buskin, SE, De Turk, PB, Aboulafia, DM. “Profile of patients with Kaposi's sarcoma in the era of highly active retroviral therapy”. JClini Oncol. vol. 23. 2005. pp. 1253(Characterization of patients with Kaposi's, with special focus on those undergoing antiretroviral therapy)
Gill, PS, Loureiro, C, Bernstein-Singer, M. “Clinical effects of glucocorticoids on Kaposi's sarcoma related to acquired immunodeficiency syndrome”. Ann Intern Med. vol. 110. 1989. pp. 937(Short paper on corticosteroids for the treatment of Kaposi's in patients with AIDS .)
Fenig, E, Brenner, B, Rakowsky, E. “Classic Kaposi's sarcoma: experience at Rabin Medical Center in Israel”. Am J Clin Oncol. vol. 21. 1998. pp. 498(Wonderful review of the classical form of Kaposi's sarcoma. Discussion deals with etiology, pathogenesis, epidemiology, and therapy.)
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