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ARTICLE

Final Diagnosis: Disseminated Kaposi Sarcoma With Tonsillar and Pulmonary Involvement

FEB 20, 2019 | ERIN TUTTLE, MD; REBECCA HOPPE, MD; ALEXANDER CUBBERLEY, MD; GINNY MARMOLEJOS, MD; ANITA KO, MD

HISTORY OF PRESENT ILLNESS:

A 29-year-old Brazilian man was sent to the emergency department (ED) for an incidental finding of a pneumothorax. The pneumothorax was discovered on a CT scan ordered by his ear, nose, and throat (ENT) physician to evaluate a left necrotic tonsillar mass. Five months prior, he presented at an outside hospital with a dry cough and was found to have pneumocystis pneumonia (PCP), HIV (CD4 count, 23 c/mm3; viral load unknown), and syphilis. He was treated successfully with trimethoprim-sul­famethoxazole and antiretroviral therapy (ART), and single-tablet tenofovoir alafenamide/emtricit­abine/elvitegravir/cobicistat was initiated at that time. Three months later, he had his initial occur­rence of a tonsillar lesion, which progressed to a mass the following month. In addition to seeing an ENT specialist, he had been following up with a provider at a city health center where his antiretroviral therapy was subsequently switched to single-tablet abacavir/lamivudine/ dolutegravir. Upon arrival in the ED, a chest tube was placed and the patient was admitted to the hospital where the infectious disease, ENT, pulmonary, and hematology-oncology teams were all consulted.

PAST MEDICAL HISTORY:

The patient was diagnosed with HIV, PCP, and syphilis 5 months prior. He had no surgical history.

MEDICATIONS:

Abacavir/lamivudine/dolutegravir (Triumeq, ViiV Healthcare) and trimethoprim-sulfamethoxazole for PCP prophylaxis.

EPIDEMIOLOGICAL HISTORY:

The patient was born in Brazil and is currently in the United States to attend school. He had no travel history except to Brazil (none recently) and no pets. He lives alone. He denies any recent sexual activity, but stated he has sex with women only. He also denied any tobacco, alcohol, or drug use.

PHYSICAL EXAM:

The patient’s vital signs were within normal limits. He was awake and alert and not in acute distress. On oral inspection, he had a large dark red lesion on his left palatine tonsil. His neck was supple, and he had bilateral bulky cervical lymphadenopathy. His heart sounds were regular, with normal S1 and S2. He had coarse breath sounds bilaterally, but louder over the right lung with normal work of breathing. He had a left-sided chest tube. His abdomen was soft with no rebound or guarding. His complete neurological exam was nonfocal.

STUDIES:

On admission, the patient’s labs were significant for a CD4 count of 154. His HIV viral load was not tested.

Rapid plasma reagin was positive at 1:4. A hepatitis C virus (HCV) antibody test was positive, and his HCV viral load was undetectable. Urine gonorrhea and chlamydia tests were negative by nucleic acid amplification testing. His chemistries and comprehensive blood count were unimpressive.

A head-and-neck CT scan showed an exophytic, heterogeneously enhancing left palatine tonsillar mass and incidentally found a moderate to large left apical pneumothorax. Further imaging with CT of the chest revealed a multilobar dense alveolar consolidation with areas of soft tissue attenuation and numerous surrounding flame-shaped nodular opacities with perilymphatic distribution.

DIAGNOSTIC PROCEDURES AND RESULTS:

Tonsillectomy with biopsy was performed, showing numerous unoriented irregular fragments of red-purple, soft, glistening to cauterized tissue admixed with a blood clot measuring 3.5 x 2.8 x 1.4 cm in aggregate, consistent with Kaposi sarcoma (KS). Immunohistochemical stains for CD34, CD31, and HHV8 were positive, confirming the KS diagnosis. Ki67 immunostaining showed 50% positive staining. Bronchoscopy was unrevealing for endobronchial lesions; however, it showed friable mucosa with erythema. Bronchoalveolar lavage (BAL) was negative for Pneumocystis jirovecii, acid fast bacilli, or fungal infection. Absolute CD4 count of 154 cells μ/L (16%) and serum HHV-8 polymerase chain reaction were positive. Additionally, herpesvirus 8 IgG antibody was positive 1:>320.

Clinically, the patient appeared to have disseminated KS in the setting of paradoxical immune reconstitution inflammatory syndrome (IRIS). Chest imaging indicated pulmonary KS, with the characteristic flame-shaped nodules, although BAL was negative. He was discharged 6 days after admission, with outpatient hema­tology–oncology follow-up for port placement to begin doxorubicin therapy for treatment of disseminated KS caused by IRIS.

DISCUSSION:

KS, first described in 1872 by Moriz Kaposi, is a multicentric neoplasm that presents as vascular tumors of the skin, mucus membrane, and viscera.1 KS is the most common neoplasm associated with HIV infection. It predominantly affects the skin in 80% to 90% of cases and is the most common initial manifestation. Visceral organs can also be affected. Visceral KS most frequently affects the lungs and gastrointestinal (GI) tract; however, it has been documented in almost every visceral site.

There are 4 clinical types of KS: classic, endemic, transplant-related, and AIDS-associated. AIDS-associated KS, the most prevalent form, is associated with infection from HHV-8, also known as the KS-associated herpesvirus.1 The mechanism of transmission of HHV-8 is not well understood, although it is possible the virus could be sexually trans­mitted, as it is seen almost exclusively in men who have sex with men.2 KS, an AIDS-defining illness, can be seen at any stage of HIV infection, even if the CD4 count is normal3; however, incidence is highest among patients with CD4 counts <200.4 KS is typically seen in patients with a low CD4 count (<150 c/mm3) and a high viral load (>10,000 c/mL); however, more recent study findings are showing increased incidence in patients with CD4 counts >350 c/mm3.5 Treatment always consists of antiretroviral therapy and can include systemic chemotherapy.

Initial manifestations of AIDS-associated KS include erythema­tous, violaceous cutaneous lesions (macular, papular, or nodular) involving the face, oral mucosa, upper trunk, and lower extremities, with increasing involvement of visceral organs, including lymph nodes, GI tract, and lungs as the disease progresses.6 Pulmonary involvement is preceded by skin lesions 80% of the time and presents as shortness of breath.3 Other pulmonary manifestations include dyspnea, fever, cough, hemoptysis, and chest pain. Radiographic findings are nonspecific and demonstrate pleural effusion, lymph­adenopathy, and nodules, as well as interstitial and alveolar infil­trates. Dyspnea, cough, hemoptysis, stridor, nodular infiltrates, pleural effusion, low diffusion capacity, and absence of arterial desaturations are more likely to be due to pulmonary KS than to opportunistic infections.7 However, among persons at high risk for AIDS, the etiology of spon­taneous pneumothorax has been more commonly associated with Pneumocystis carinii infections.7
Clinical diagnosis alone is not suffi­cient for KS; it requires tissue exam­ination for confirmation. Pulmonary KS diagnosis is made based on phys­ical exam findings, CT features, and endobronchial lesions. Classical CT chest findings show hilar densities along peribronchovascular path­ways and a nodular pattern accompanied by pleural effusions.8 Bronchoscopy and BAL are often performed in HIV-infected patients with pulmonary symptoms and parenchymal abnormali­ties on imaging. Endobronchial lesions appear violaceous or bright red and are macular and papular, often located at airway bifurca­tions. Transbronchial biopsies are not common, as hemorrhage can occur in up to 30% of patients.9

The mainstay of treatment is antiretroviral therapy, although there are no definitive treatment guidelines. In the majority of cases, antiretroviral therapy alone will cause regression of lesions; however, KS has also been known to appear as a form of IRIS. Antiretroviral therapy with chemotherapy is indicated in visceral disease, rapid progression of disease, or disseminated skin or mucosal involve­ment. If there is a single lesion, then radiation or cryotherapy may be introduced. For extensive or disseminated disease, interferon alpha or chemotherapy is considered. The response rate of initial therapy is dependent on CD4 count. If the count is >150 cells/mm3, then inter­feron alpha is given; otherwise, treatment is with chemotherapy. The response rate for interferon alpha in patients with CD4 <150 c/mm3 is less than 10%. The US Food and Drug Administration has approved 4 chemotherapy agents for treatment that have been shown to have activity against KS: liposomal daunorubicin, liposomal doxorubicin, vinblastine, and paclitaxel.10 In patients with pulmonary KS, the median survival time has increased from 4 months to 1.6 years due to the initiation of antiretroviral therapy.11 Patients presenting with KS already on antiretroviral therapy typically have a less aggressive presentation compared with those not receiving treatment.

IRIS-KS is seen with improvement of immune status by a decrease in the viral load and an increase in CD4 count after initiating antiretroviral therapy, with the greatest risk of development within the first 3 months. There is no difference in initial presentation or location of involvement in those with AIDS-associated KS compared with IRIS-KS. Early initi­ation of chemotherapy with continuation of antiretroviral therapy remains the most effective treatment for reducing mortality.12 With the increase in HIV awareness and increased use of antiretroviral therapy, the incidence of KS has signifi­cantly declined, increasing the likelihood of alternative diagnoses in patients with pulmonary symptoms that resemble KS.
Dr. Tuttle is a current PGY-2 resident in the department of internal medicine at Drexel University College of Medicine/Hahnemann University Hospital and is interested in pursuing a career in pulmonary critical care. 

Dr. Hoppe is a current PGY-2 resident in the department of internal medicine at Drexel University College of Medicine/Hahnemann University Hospital and is interested in critical care and infectious diseases. 

Dr. Cubberley is a current PGY- 2 resident in the department of internal medicine at Drexel University College of Medicine/ Hahnemann University Hospital and is interested in pursuing a career in cardiology. 

Dr. Marmolejos is a pulmonary critical care fellow at Drexel University College of Medicine. She completed her internal medicine residency at Morristown in New Jersey. 

Dr. Ko is an assistant professor of medicine and director of the Sleep Medicine Fellowship program at Drexel University College of Medicine. She completed her pulmonary critical care fellowship at Drexel University College of Medicine. 

References:
1.         Dezube BJ. Clinical presentation and natural history of AIDS-related Kaposi's sarcoma. Hematol Oncol Clin North Am. 1996 Oct;10(5):1023-9.
2.         Martin JN, Ganem DE, Osmond DH, Page-Shafer KA, Macrae D, Kedes DH. Sexual transmission and the natural history of human herpesvirus 8 infection. N Engl J Med. 1998 Apr 2;338(14):948-54. doi: 10.1056/NEJM199804023381403.
3.         Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrison's Principles of Internal Medicine. 19th ed. New York, NY: McGraw Hill Education; 2015.
4.         Lodi S, Guiguet M, Costagliola D, et al. Kaposi sarcoma incidence and survival among HIV-infected homosexual men after HIV seroconversion. J Natl Cancer Inst. 2010 Jun 2;102(11):784-92. doi: 10.1093/jnci/djq134.
5.         Crum-Cianflone NF, Hullsiek KH, Ganesan A, et al. Is Kaposi's sarcoma occurring at higher CD4 cell counts over the course of the HIV epidemic? AIDS. 2010 Nov 27;24(18):2881-3. doi: 10.1097/QAD.0b013e32833f9fb8.
6.         Meduri GU, Stover DE, Lee M, Myskowski PL, Caravelli JF, Zaman MB. Pulmonary Kaposi's sarcoma in the acquired immune deficiency syndrome. Clinical, radiographic, and pathologic manifestations. Am J Med. 1986 Jul;81(1):11-8.
7.         Floris C, Sulis ML, Bernascani M, Turno R, Tedde A, Sulis E. Pneumothorax in pleuropulmonary Kaposi’s sarcoma related to acquired immunodeficiency syndrome. Am J Med. 1989 Jul;87(1):123-4.
8.         Miller RF, Tomlinson MC, Cottrill CP, Donald JJ, Spittle MF, Semple SJ. Bronchopulmonary Kaposi's sarcoma in patients with AIDS. Thorax. 1992 Sep;47(9):721-5.
9.         Rohrmus B, Thoma-Greber EM, Bogner JR, Röcken M. Outlook in oral and cutaneous Kaposi’s sarcoma. Lancet. 2000 Dec 23-30;356(9248):2160. doi: 10.1016/S0140-6736(00)03503-0.
10.      Letang E, Naniche D, Bower M, Miro JM. Kaposi sarcoma-associated immune reconstitution inflammatory syndrome: in need of a specific case definition. Clin Infect Dis. 2012 Jul;55(1):157-8; author reply 158-9. doi: 10.1093/cid/cis308.
11.      Palmieri C, Dhillon T, Thirlwell C, et al. Pulmonary Kaposi sarcoma in the era of highly active antiretroviral therapy. HIV Med. 2006 Jul;7(5):291-3. doi: 10.1111/j.1468-1293.2006.00378.x.
12.      Wolff SD, Kuhlman JE, Fishman EK. Thoracic Kaposi sarcoma in AIDS: CT findings. J Comput Assist Tomogr. 1993 Jan-Feb;17(1):60-2.

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