F R E P O R T S
Kaposi sarcoma (KS) is considered one of the most common neoplasms in HIV-positive pa- tients. Herein we report a case of an HIV-posi- tive man diagnosed 6 years prior who had never received highly active anti-retroviral therapy (HAART) who presented with anasarca and cu- taneous KS. The patient was found to have sig- nificant hypoalbuminemia in the setting of nor- mal renal and liver function. An esophagogas- troduodenoscopy (EGD) and fecal alpha-1 antit- rypsin assay revealed that the patient had a pro- tein-losing enteropathy secondary to gastroin- testinal involvement of KS. Additionally, a ver- tebral body biopsy of a lytic bone lesion found on computed tomography (CT) scan revealed osseous involvement of KS. Our patient pro- vides an interesting case of diffuse KS, a fairly uncommon presentation as many patients now receive HAART and osseous involvement is rare.
Kaposi sarcoma (KS) is considered one of the most common neoplasms in HIV-positive pa- tients. Since the advent of highly active anti- retroviral therapy (HAART) in the mid-1990s, there has been a significant decrease in both the risk of developing KS1as well as the incidence of this disease.2,3Numerous reports of AIDS-relat- ed KS illustrate its diffuse nature as it can in- volve the skin, lungs, gastrointestinal tract, liver, and spleen.4-9 In rare instance, KS can involve the bones.4
A 24-year-old Hispanic male with a six year his- tory of HIV who had never received HAART presented with increasing lower extremity swelling over the last three months. The swelling had spread to his thighs and inguinal region involving the scrotum, and it had pro- gressed to the point that he was unable to urinate.
He reported a history of intermittent fevers, dif- ficulty swallowing, hemoptysis, hematemesis, loose watery stools, and bright red blood per rec- tum. At the time of admission, his vitals were stable and he appeared cachectic. On physical exam, there was 3+ pitting edema in the lower
1University of California, Irvine School of Medicine, Irvine, CA
2Department of Medicine, Division of Hematology-Oncology, University of California, Irvine, Orange, CA
Lauren S. Marshall, MS1; Wilson Tong, MD2,3; Chaitali S. Nangia, MD2,3
Corresponding Author: Lauren S. Marshall, MS, University of California Irvine School of Medicine, 333 City Blvd W, Orange, CA 92868.
The authors claim no conflicts of interest or disclosures.
AMSRJ 2015; 2(1):81-87
extremities and flanks, scrotal edema, and mod- erate upper extremity edema. He had multiple red-purple plaques and nodules on his arms, chest, face, and inguinal region (Figure 1A), dif- fuse lymphadenopathy, and oral candidiasis.
Additionally, the patient reported that when he
was diagnosed with HIV he did not feel sick so he did not follow up with a physician for treat- ment.
His labs revealed a serum albumin of <1.0 g/dl and total protein of 4.0 g/dl while his BUN, crea-
Figure 1. Forearm and inguinal red-purple nodules and plaques. Biopsies were positive for Kaposi Sarcoma. Initial presentation (A) compared to last hospital admission (B) illustrates disease progression due to inability to tolerate HAART.
RBC 3.59 million/mcl (L) Sodium 131 mEq (L)
Hemoglobin 8.2 g/dl (L) Potassium 3.6 mEq/L
MCV 73.6 fL (L) BUN 13 mg/dl
Additional Studies Cr 0.6 mg/dl
CD4 27 cells/mm3 (L) Albumin <1.0 g/dl (L)
HIV viral load 19,743 copies/ml (H) Total protein 4.0 g/dl (L)
PT 11.2 sec AST 27 IU/L
INR 1.05 ALT 16 IU/L
UPCRa 0.2 mg protein/mg Cr Alkaline phosphatase 101 IU/L α-1 antitrypsinb 252 mg/dl (H) Total bilirubin 0.3 mg/dl Stomach corpus biopsy: 0 genomic alterationsc
Abnormal results: H= High, L= Low
aUrine protein: creatinine ratio: nephrotic >3 mg protein/mg creatinine
bFecal alpha-1 antitrypsinassay: normal <54 mg/dl
cFoundationOne Heme (Foundation Medicine, Inc., Cambridge, MA) next-generation
sequencing: DNA sequencing of 405 genes and 31 introns and RNA sequencing of 265 genes to identify genomic alterations in cancer-related genes
CBC= complete blood count; CMP= comprehensive metabolic panel; RBC= red blood cell count; MCV= mean corpuscular volume; PT= prothrombin time; INR= international normalized ratio; UPCR= urine protein: creatinine ratio; BUN= blood urea nitrogen; Cr= creatinine;
AST= aspartate transaminase; ALT= alanine transaminase.
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tinine, and liver function tests were all within normal limits. His CD4 cell count was 27 cells/
mm3with an HIV viral load of 19,743 copies/ml (Table 1). Additionally, the patient was severely anemic but would not accept blood transfusion as he was a Jehovah’s Witness. Skin biopsies of red-purple lesions on the forearm and inguinal region were positive for KS. In order to ascer- tain the extent of this patient’s KS for cancer staging, a CT scan of the chest, abdomen, and pelvis was performed. It showed multiple low-
density lesions in the liver and spleen, small bowel wall edema, and multifocal osseous lytic lesions in the spine and ribs which were concern- ing for lymphoma (Figure 2). Due to this patien- t’s hypoalbuminemia and anemia, liver and spleen biopsies were not performed, but they were suspected to be KS. An inguinal lymph node core needle biopsy was found to have spin- dle tumor cells positive for HHV-8, SMA, and CD34 and negative for S100 and desmin, consis- tent with KS (Figure 3).
Figure 2. CT scans demonstrating low-density lesions in the liver and spleen (A) and lytic vertebral lesions (B).
Figure 3. Inguinal lymph node core needle biopsy with demonstration of slit-like spaces. Immunohistochemistry staining showed cells positive for HHV-8 (A) at 20x magnification and negative for S100 (B) at 10x magnification. Not shown are cells that stained positive for SMA and CD34 and negative for desmin. These findings are consistent with the diagnosis of Kaposi sarcoma. Courtesy of Deepty Bhansali, MD.
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Based on the patient’s history of hemoptysis and hematemesis, he underwent an EGD and was empirically started on fluconazole for treatment of oral candidiasis. A stomach corpus biopsy (Figure 4) was positive for KS and there was no evidence of esophageal candidiasis. As fecal al- pha-1 antitrypsin levels have been shown to be an adequate measure for protein loss through the gastrointestinal tract and are significantly ele- vated in cases of KS,10-14the elevated level ob- tained (252 mg/dl) was consistent with a pro- tein-losing enteropathy. The patient also had sputum cultures positive for Klebsiella pneumo- nia and blood cultures positive for Campylobac- ter jejunii. These findings in addition to the dif- fuse involvement of KS were suspected as likely causes for his presenting complaints of he- matemesis, hemoptysis, and bright red blood per rectum.
In order to investigate the cause of the lytic bone lesions found on CT (Figure 2), the patient un- derwent bone marrow and vertebral body biop- sies. Both biopsies were negative for lym- phoma, while the vertebral biopsy was positive for KS. Based on the above findings demon- strating diffuse KS, the patient was started on a regimen of pegylated liposomal doxorubicin at
20 mg/m2in addition to HAART consisting of darunavir, ritonavir, emtricitabine, and teno- fovir.
After the patient was discharged, he was read- mitted a total of five times over a period of four months for severe Clostridium difficile colitis and spontaneous bacterial peritonitis. He also experienced significant nausea, vomiting, and progressive dysphagia that prevented him from taking all of his medications as prescribed. An EGD revealed an esophageal web, which likely developed as a result of his vomiting and iron- deficiency anemia. The triad of dysphagia, iron deficiency anemia, and esophageal webs is also known as Plummer-Vinson syndrome, a rare condition of unknown etiology that typically af- fects middle-aged Caucasian women and is treated with iron supplementation and mechani- cal dilation.15
In order to improve medication adherence, all HAART medications were transitioned to liquid forms. Despite these changes, he was only able to take his medications sporadically as he con- tinued to have odynophagia and was not a candi- date for an esophageal dilation procedure to treat the esophageal web. After starting HAART, the patient achieved viral suppression with an unde- tectable viral load, but when he was no longer able to take his medications his viral load in- creased to 2043 copies/ml with a CD4 count of 57 cells/mm3. Abacavir was added to his initial regimen given the rise in his viral load and histo- ry of medication nonadherence while a genotype study was pending.
Unfortunately, his health continued to deterio- rate and within the span of four months he only received a total of four treatments of doxoru- bicin that were administered off schedule. It was noted that the cutaneous KS became much more extensive (Figure 1B) during this time. In order to determine if the progression of this patient’s disease was due to a more virulent form of KS,
Figure 4. EGD demonstrating abnormal mucosa with erythematous and purpuric lesions throughout the stomach. Courtesy of John G.
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a genomic analysis of the KS lesion from the stomach corpus biopsy was performed. This study found 0 mutations in over 400 cancer-re- lated gene sequences surveyed, which suggests that this patient’s disease worsened as a result of his inability to tolerate his medications. After his last hospitalization, he and his family decid- ed to discontinue HAART and chemotherapy, and he went home on hospice care.
KS was once a commonly encountered AIDS- defining illness prior to the widespread avail- ability of HAART.1-3 In fact, between 2001-2005 the number of cases of KS dropped by 84% compared to 1991-1995 when HAART was in its early stages.16 Important risk factors for developing KS include a delay in starting HAART and a low CD4 count, the latter being the most significant.17 In addition to the cuta- neous, gastrointestinal, and osseous KS de- scribed in this case, KS can also involve the lungs, liver, and spleen.4-9
The patient presented with anasarca and severe hypoalbuminemia with a serum albumin level of
<1 g/dl. Hypoalbuminemia can be caused by decreased hepatic synthesis or abnormal excre- tion in the urine; however, patient’s liver func- tion tests, BUN, creatinine, and urine studies were normal (Table 1). Therefore, alternate causes including a protein-losing enteropathy were considered.
Gastrointestinal involvement of KS may cause hemorrhage, diarrhea, occlusion, perforation, and a protein-losing enteropathy.13One way to diagnose a protein-losing enteropathy is to mea- sure levels of fecal alpha-one antitrypsin.10-14Al- pha-one antitrypsin is a protease inhibitor with a molecular weight similar to albumin. When it leaks into the intestine, it is neither degraded nor reabsorbed.10,12Therefore, it is an intact protein
when excreted into the stool, and elevated levels of fecal alpha-one antitrypsin are a reliable indi- cator of protein-losing enteropathies.10-14 Our patient had significantly elevated fecal alpha- one antitrypsin levels at 252 mg/dl. The stomach corpus biopsies taken during the EGD (Figure 4) were positive for KS, which confirmed that the protein-losing enteropathy was due to KS in- volvement. Albumin loss in the gastrointestinal tract is due to a disruption of the vascular en- dothelium by KS.13Additional factors that likely contributed to this patient’s hypoalbuminemia include malnutrition and cancer cachexia.14 Therefore, the patient’s initial symptoms of anasarca and bloody diarrhea were attributed to gastrointestinal KS.
KS involvement of the bone is uncommon. A literature review by Caponetti et al.4found 66 case reports of musculoskeletal KS, and of these 27 were AIDS-related osseous KS. Osseous in- volvement is usually due to spread from an adja- cent area and very rarely is it the primary site of KS.4,7It is best visualized with magnetic reso- nance imaging (MRI) as a CT scan can miss cor- tical lesions or adjacent soft tissue tumor. Typi- cally these lesions are osteolytic, and similar ap- pearing lesions in the differential diagnosis in- clude bacillary angiomatosis, mycobacterial spindle cell pseudotumor, pyogenic granuloma, arteriovenous malformation, hemangioen- dothelioma, metastatic solid tumors, and an- giosarcoma.4,5 The pattern of involvement in AIDS patients typically includes the axial skele- ton with the skull, vertebra, pelvis, ribs, and ster- num being most commonly involved in order of reported incidence.4Although many patients re- port bone pain, patients reported minimal to no symptoms in case reports of extensive osteolytic lesions.4 Di Bella et al.5reviewed 11 cases of vertebral AIDS-related KS, and found that these patients were men between the ages of 25-37 years with CD4 counts <200 cells/mm3, and the majority also had cutaneous involvement.
Caponetti et al.4found that in the cases of AIDS- DISCUSSION
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related KS, CD4 counts ranged from 0-128 cells/
mm3. A literature review of 11 cases of vertebral KS by Isenbarger et al.6 found that 36% of pa- tients also had involvement of the gastrointesti- nal tract.
The treatment for KS in HIV-positive individu- als can vary. For those already diagnosed with KS, initiating HAART is associated with an overall prolonged survival rate.18The staging of the KS is also important as it can help guide therapeutic management of the patient. The AIDS Clinical Trials Group classification19 stages KS based on extension of the tumor (T), CD4 count reflecting the degree of immunosup- pression (I), and systemic signs (S). Given this patient’s widespread tumor burden (T1), CD4 count of less than 150 (I1), tumor-associated edema, and involvement of the viscera and oral candidiasis (S1), his KS was classified as T1-I1- S1. A study by El Ameri et al.20found that in T1 stage KS, a CD4 count <200 cells/µl and plasma positive for HHV8 DNA were associated with a poor prognosis, defined as death or initiation of chemotherapy to treat KS. In addition to HAART, patients with extensive KS may bene- fit from chemotherapy.9,21,22Currently, pegylat- ed liposomal doxorubicin (PLD) and daunoru- bicin citrate liposome (DNX) are the first-line systemic therapies for advanced AIDS-related KS.9,22In a study by Martin-Carbonero et al.,21 PLD added to HAART was associated with a 76% response rate compared to 20% with HAART alone. As our patient was untreated for many years, he eventually developed dissemi- nated KS involving bone, which is not often seen. Furthermore, the inability to tolerate HAART was seen as a major factor that led to the progression of his disease. Overall, this patien- t’s case illustrates the array of complications that can develop without appropriate initiation of HAART as well as the difficulties in managing medication side effects and diagnostic chal- lenges encountered in patients with advanced AIDS.
• AIDS patients with Kaposi sarcoma may present with disseminated disease if not on HAART.
• In patients with Kaposi sarcoma and hy- poalbuminemia, consider gastrointestinal involvement and a protein-losing enteropa- thy in the differential. Protein loss in the stool can be detected using a fecal alpha-1 antitrypsin assay as this protein is neither de- graded nor secreted in the gastrointestinal tract.
• Although rare, Kaposi sarcoma can be a cause for lytic bone lesions in AIDS patients, and it is best visualized with MRI. The dif- ferential diagnosis also includes bacillary angiomatosis, mycobacterial spindle cell pseudotumor, pyogenic granuloma, arteri- ovenous malformation, hemangioendothe- lioma, metastatic solid tumors, and an- giosarcoma.
• Management of medication side effects and identifying means to improve adherence are equally as important as prescribing the appropriate treatment.
The authors would like to thank the patient for allowing his case to be presented for educational purposes. The authors appreciate the photo- graphic contributions of John G. Lee, MD, and Deepty Bhansali, MD, to this manuscript.
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