Pulmonary Medicine

HIV-Associated Kaposi Sarcoma

What every physician needs to know:

Kaposi sarcoma (KS) is a multifocal, low-grade vascular tumor that may involve the skin, the mucosa, and the viscera.

KS is caused by infection with Kaposi sarcoma herpes virus/human herpes virus-8 (KSHV/HHV-8). In HIV-infected persons, KS is an AIDS-defining illness. KS is currently the most prevalent malignancy that patients with AIDS encounter worldwide. AIDS-associated KS is an aggressive tumor of endothelial origin that typically manifests with multifocal skin lesions and visceral organ involvement. KS may affect the trachea, the lungs, the endobronchial tract, the pleura, and the intrathoracic lymph nodes. Bronchopulmonary KS may be difficult to diagnose because symptoms and imaging findings are non-specific and because endobronchial lesions may be patchy and missed by bronchoscopy and transbronchial biopsy.

Prior to highly active antiretroviral therapy (HAART), pulmonary KS was a fatal disease, and patients lived on average of four to six months after initial diagnosis. With effective HAART and control of HIV viremia, the majority of patients respond favorably to systemic chemotherapy and have a survival rate comparable to that of AIDS-KS patients who do not have pulmonary involvement.

Classification:

KS can be divided into four clinical-epidemiological types:

  • AIDS-associated (epidemic) KS

  • Classic KS, which is not associated with HIV infection and which affects mainly men between forty and seventy years of age who are of Mediterranean, Eastern European, or Jewish origin

  • Iatrogenic KS, which is associated with immunosuppression from drugs or after solid organ transplantation

  • African KS, which is endemic largely in sub-Saharan Africa and affects predominantly black Africans

Are you sure your patient has Kaposi sarcoma? What should you expect to find?

The majority of HIV-infected patients with KS present with skin lesions. Patients with pulmonary KS can present with asymptomatic findings on chest x-ray or with symptoms such as shortness of breath, fever, cough, hemoptysis (which may be massive), stridor (when endobronchial lesions are present), bloody or chylous effusions, and chest pain.

Even in the absence of symptoms, the clinical suspicion of KS in a patient with HIV infection should be heightened by the presence of hilar adenopathy, diffuse interstitial infiltrates, or prominent parenchymal nodularity on radiographic imaging. This suspicion should be particularly high for the HIV-infected patient with a CD4+ cell count of less than 50 cells/ul and poorly controlled HIV replication. Rarely, patients have pulmonary KS even in the absence of obvious cutaneous disease.

Beware: there are other diseases that can mimic Kaposi sarcoma.

The presence of comorbidities in the setting of HIV infection, particularly opportunistic infections (i.e., mycobacterial and fungal infections) may mimic pulmonary KS and/or complicate the interpretation of chest imaging findings.

How and/or why did the patient develop Kaposi sarcoma?

HIV acts in a synergistic fashion with HHV8, resulting in more aggressive and widespread KS disease. Visceral KS occurs in roughly 20-30 percent of patients with AIDS-associated KS, and pulmonary KS occurs in up to 10 percent of patients with AIDS-associated KS. Pulmonary KS is almost always preceded by mucocutaneous or visceral KS.

Which individuals are at greatest risk of developing Kaposi sarcoma?

Viral Infection

HHV-8 infection alone is usually insufficient for the development of KS. The presence of KS also depends upon some degree of host immune dysfunction, such as progressive immunodeficiency caused by HIV infection. Although AIDS-associated KS can be seen at any CD4+ cell count, pulmonary KS is invariably diagnosed in HIV-positive patients with low CD4+ T-cell counts and poorly controlled HIV infection. KS occurs around 20,000 times more often in AIDS patients who have not had HAART than in the general population.

However, despite the introduction of HAART, the incidence for KS among people with AIDS remains substantial. KS remains the single most common AIDS-defining neoplasm, although the incidence has fallen roughly 90 percent since the widespread availability of HAART. Among individuals with HIV-HHV8 coinfection, HHV8 viremia identifies a subgroup of patients with extremely high risk for developing KS.

Age and Gender.

AIDS-associated KS can affect patients of all ages, but it occurs most commonly in adults and most often in men.

Flares

KS lesions may flare (so-called KS exacerbation) as a result of an immune reconstitution inflammatory syndrome (IRIS) following HAART, after corticosteroids, and with rituximab therapy.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Biopsy

A biopsy of a lesion can provide a definitive diagnosis of KS. In the context of known HIV infection and the finding of characteristic raised and errythematous endobrochial lesions, a biopsy may not be required, particularly if there is concern that the lesion will bleed post-procedure. KS tends to grow along the intrapulmonary septa and to concentrate around small tubular airways and blood vessels. Histopathological examination will show a proliferation of spindled tumor cells associated with abnormal vessels and variable chronic inflammatory cells ( Figure 1 and Figure 2).

Figure 1.

Lung tissue showing Kaposi sarcoma infiltrating in the interstitium and alveolar spaces filled with edema and fibrin (H&E stain, magnification x100).

Figure 2.

Histopathology of Kaposi sarcoma tumor showing fascicles of spindled cells and associated abnormal vessels filled with red blood cells (H&E stain; magnification x200)

Immunohistochemical studies can be diagnostically helpful in demonstrating that the lesional cells are of lymphatic endothelial origin (D2-40, CD31, CD34 positive) and that they are infected with HHV8 (LNA-1 positive). Coexisting lung disease and infection (e.g., CMV) may be present.

Cytology

Bronchoalveolar lavage fluid may show alveolar hemorrhage. Pleural effusions may be bloody or chylous in appearance and (infrequently) contain ameboid-appearing KS tumor cells.

HHV-8

Testing for HHV-8 DNA in serum and pulmonary samples (e.g., bronchoalveolar lavage) is sensitive and specific but not routinely available.

What imaging studies will be helpful in making or excluding the diagnosis of Kaposi sarcoma?

Radiographic findings are variable, and they can include nodular, interstitial, and/or alveolar infiltrates, pleural effusion, hilar and/or mediastinal adenopathy, or (rarely) an isolated lung nodule. The radiologic findings of pulmonary KS associated with IRIS are similar to those described in patients with KS without any flare. Imaging studies can be used to document the extent of KS and changes following therapy. The presence of comorbidities like infection or other malignancy may complicate the interpretation of imaging findings.

Chest x-rays

(Figure 3 and Figure 4) Conventional radiology can be used to visualize KS lung lesions although CT and MRI are generally more useful. A chest roentgenogram is useful to screen for pulmonary KS in patients with respiratory symptoms. Many patients, especially those with local endobronchial KS, may have normal chest radiographs.

Figure 3.

Chest x-ray showing bilateral and scattered reticulonodular densities most prominent in right lower and mid-lung fields that are due to pulmonary Kaposi sarcoma. (Reproduced with permission from Pantanowitz L et al. Overview of Kaposi sarcoma. In: Kaposi sarcoma: A model of oncogenesis. Pantanowitz L et al. (eds). 2010. Research Signpost.)

Figure 4.

Another chest radiograph demonstrating extensive bilateral reticulonodular infiltrates of Kaposi sarcoma confirmed by biopsy. (Reproduced with permission from O'Mahony D et al. Imaging techniques for Kaposi sarcoma. In: Kaposi sarcoma: A model of oncogenesis. Pantanowitz L et al. (eds). 2010. Research Signpost.)

Several chest radiograph findings of pulmonary KS have been described as including bilateral reticulonodular infiltrates, homogeneous infiltrates, non-loculated pleural effusions, pneumothorax, and lymphadenopathy. Because KS proliferates mainly in the interstitium and peribronchial or perivascular lymphatics, bilateral reticulonodular infiltrates are frequently seen in the perihilar area and lower lung fields. Mediastinal lymphadenopathy is uncommon with KS, but when it is present, it can be used to distinguish KS from pneumocystis infection.

CT scan

( Figure 5 and Figure 6) ACT-scan is slightly better than radiography for identifying thoracic KS. KS is usually thallium-avid and gallium-negative, whereas infections are usually gallium-avid and thallium-negative. Typical appearances of thoracic KS include nodules (solitary or multiple), bronchovascular infiltrates, interlobular septal thickening, areas of consolidation, ground-glass opacities, tumoral masses, pleural effusions, and lymphadenopathy.

Figure 5.

Pulmonary Kaposi sarcoma shown on CT scan of the chest. Note bilateral thickening of lymphovascular areas.(Reproduced with permission from Pantanowitz L et al. Overview of Kaposi sarcoma. In: Kaposi sarcoma: A model of oncogenesis. Pantanowitz L et al. (eds). 2010. Research Signpost.)

Figure 6.

Chest CT with characteristic Kaposi sarcoma peri-hilar bronchovascular infiltrates. (Reproduced with permission from O'Mahony D et al. Imaging techniques for Kaposi sarcoma. In: Kaposi sarcoma: A model of oncogenesis. Pantanowitz L et al. (eds). 2010. Research Signpost.)

While none of these findings are specific, the combination of poorly defined nodules, fissural nodularity, and a bronchovascular distribution of perihilar opacities on CT is highly suggestive of pulmonary KS. High-resolution CT may help demonstrate interlobular septal thickening and thickening of bronchovascular bundles, reflecting the bronchocentric distribution of KS.

"Flame-shaped" nodules/masses associated with a halo of ground glass attenuation have been described. Air-space disease and lymphadenopathy that are due to KS are much more common on CT in children than in adults. Lytic lesions of the sternum and thoracic spine or soft tissue masses may be encountered, but rarely.

MRI

MRI signal abnormalities that are suggestive of pulmonary KS include irregular increased signal intensity in T1-weighted images with markedly reduced signal intensity on T2-weighted images and significant enhancement of KS lesions after gadolinium administration.

PET scan

Published data on the role of PET scans for KS is limited. The few published reports indicate the KS exhibit's markedly increased FDG uptake.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of Kaposi sarcoma?

Pulmonary function tests are not of diagnostic value for KS. However, patients with bronchopulmonary KS, especially those with extensive lesions, may have variable abnormal lung function studies (such as reductions in FEV1 and FVC).

What diagnostic procedures will be helpful in making or excluding the diagnosis of Kaposi sarcoma?

Bronchoscopy

(Figure 7) Pulmonary symptoms and/or an abnormal chest x-ray can be further evaluated with bronchoscopy. Because the bronchoscopic appearance of pulmonary KS is quite characteristic, a biopsy that may provoke bleeding is rarely needed. Although bronchoscopic and radiographic findings correlate fairly well, patients who have KS documented by bronchoscopy may sometimes have normal chest x-rays. On bronchoscopic examination, nodular or flat, bluish-red to purple or bright red discolorations may be observed in the mucosa. Some KS lesions may actively bleed. Bronchoscopy can also help exclude other etiologies, such as infection.

Figure 7.

Bronchoscopy showing a Kaposi sarcoma nodule (top of the image). (Reproduced with permission from Pantanowitz L et al. Overview of Kaposi sarcoma. In: Kaposi sarcoma: A model of oncogenesis. Pantanowitz L et al. (eds). 2010. Research Signpost.)

Biopsy

A tissue biopsy can provide a definitive diagnosis of KS, but biopsy of the upper tracheobronchial tree may be associated with significant bleeding, and the diagnostic yield of transbronchial biopsies is low because of the patchy distribution of the lesions. KS lesions are usually multifocal and do not tend to involve the actual mucosa. Open lung biopsy is diagnostically more helpful, but these biopsies are not absolutely sensitive.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of Kaposi sarcoma?

Tissue biopsy is often required to distinguish KS from its mimics.

If you decide the patient has Kaposi sarcoma, how should the patient be managed?

Treatment goals include symptom palliation, prevention of KS progression, and abatement of pulmonary compromise.

Antiretroviral therapy

Optimal control of HIV infection using antiretrovial therapy (i.e., HAART) is a key component in the treatment of AIDS-associated KS. Therefore, most--if not all--HIV+ patients with known KS should receive antiretroviral therapy, assuming access to such therapy is available. Protease inhibitor (PI)- and non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART regimens and newer regimens that incorporate integrase inhibitors all appear to be equally effective in protecting against KS.

Chemotherapy

Indications for systemic chemotherapy include widespread skin involvement, extensive oral KS, marked symptomatic edema, rapidly progressive disease, and KS flare in addition to pulmonary KS. Currently, liposomal anthracyclines and taxanes are the backbone of systemic cytotoxic therapy against KS.

Liposomal anthracyclines, which are used as the first-line treatment for KS, include pegylated liposomal doxorubicin (20 mg/m2 every three weeks) or liposomal daunorubicin (40 mg/m2 every two weeks). Taxanes, such as paclitaxel 100 mg/m2 every two to three weeks, have proven efficacy as second-line treatment for KS. Vinorelbine and gemcitabine may be effective for AIDS-related KS in patients who have failed other therapies.

Experimental therapy

Novel therapies include thalidomide and its derivative, lenolidamine; COL-3; anti-herpes therapy; and imatinib (Gleevec).

Radiation therapy

Low-dose external beam radiation therapy may help shrink centrally located lesions that contribute to airway compromise.

Surgery

Surgical intervention is not usually a feasible option because of the multifocal nature of KS lesions. There is little published experience with endobronchial stents and laser surgery for palliation of pulmonary KS, but they may be beneficial.

Pleural effusion

Pleural effusions that are due to KS are hard to manage, and they respond poorly to chemical pleurodesis and radiation therapy. In addition to early systemic therapy to treat pleural KS, repeated therapeutic thoracentesis, chest tube drainage, and talc pleurodesis have been utilized in the management of pleural effusions.

Therapeutic response

A complete response is defined by a normal chest x-ray, direct bronchoscopy revealing complete disappearance of KS lesions in the tracheobronchial tree, and resolution of all other sites of KS disease.

What is the prognosis for patients managed in the recommended ways?

Compared to other cancers, the prognosis for patients with KS is related to factors other than tumor burden itself, such as the host's underlying immunologic status and the presence of other comorbidities, such as opportunistic infection.

Without HAART

Prior to the introduction of HAART, a diagnosis of AIDS-associated KS was associated with a median survival of twelve to eighteen months. For the subset of patients with pulmonary KS, survival was on the order of four to six months after initial diagnosis, and patients most often died from pulmonary complications.

With chemotherapy

Despite relatively good results with chemotherapy, patients with pulmonary KS still do not have significantly long survival rates.

With HAART

Effective antiretroviral therapy is associated with a reduction in the incidence of AIDS-related KS and a regression in the size and number of existing lesions. HAART also prolongs the time to treatment failure in KS. Patients who are managed with HAART and chemotherapy have the best chance of achieving a complete remission, although rare instances of complete responses with HAART alone have been reported.

What other considerations exist for patients with Kaposi sarcoma?

Apart from treating the patient's KS disease, optimal control of their HIV infection, maintaining adequate caloric intake, prophylaxis against opportunistic infections, and screening for non-AIDS defining cancers like lung carcinoma are equally important.

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