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Int J Clin Exp Pathol. 2011 April 30; 4(4): 421–429.
Published online 2011 April 23.
PMCID: PMC3093067

Multicentric hepatic EBV-associated smooth muscle tumors in an AIDS patient: a case report, investigation of mTOR activation and review of the literature


Epstein-Barr virus (EBV) - associated smooth muscle tumors (EBV-SMT) are a rare, recently recognized distinct group of mesenchymal tumors that develop exclusively in patients with immunosuppression. It is believed that tumorigenesis is, at least in part, through the activation of the Akt/mammalian target of rapamycin (mTOR) signal pathway. We describe the clinicopathologic and immunohistochemical features of a multifocal hepatic EBV-SMT in a 34-year-old acquired immunodeficiency syndrome (AIDS) patient and investigate the activation status of the mTOR signal pathway in this tumor. In addition, we provide a review of the literature on the clinicopathologic findings of hepatic EBV-SMT in adult AIDS patients, and discuss their biologies and possible therapeutic strategies.

Keywords: Smooth muscle tumor, HIV infection, acquired immunodeficiency syndrome, adult, Epstein-Barr virus, liver


Epstein-Barr virus (EBV)-associated smooth muscle tumors (EBV-SMT) are a recently recognized distinctive group of mesenchymal tumors that develop exclusively in patients with clinical immunosuppression, predominantly in human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS), and solid organ transplantation [1-2]. Since clonal EBV is consistently detected in these tumors but not in conventional smooth muscle tumors occurring outside the setting of immunosuppression, EBV virus is believed to play an essential role in the tumorigenesis of EBV-SMT [3]. The molecular mechanism by which EBV drives the smooth muscle transformation is unclear, however recent studies have suggested it is mediated, at least in part, through the activation of the Akt/ mammalian target of rapamycin (mTOR) signaling pathway [4].

In organ transplant recipients, EBV-SMT most often involve the lung, gastrointestinal tract, and liver [5]. In AIDS patients, visceral EBV-SMT, particularly those involving the liver are rare, and occur mostly in the pediatric population, with only eight cases reported thus far in adults [1, 6-12]. The predisposition to visceral EBV-SMT in the pediatric HIV- infected population may be related to myocyte immaturity, whereas in HIV-infected adults, a mature visceral smooth muscle tissue may possess resistance to EBV infection or neoplastic transformation [13].

Here we describe a new case of multifocal hepatic EBV-SMT in a 34-year-old AIDS patient and investigate the activation status of the mTOR signaling in this tumor. In addition, we provide a review of the literature on the clinicopathologic findings of hepatic EBV-SMT in adult AIDS patients, and discuss their biologies and possible therapeutic strategies.

Case Report

The patient is a 34-year-old man who was first diagnosed with HIV/AIDS in 2000. He presented to our hospital in May 2010 with generalized fatigue, right upper quadrant abdominal pain and watery diarrhea for 3 months. The patient was initially placed on a regimen of highly active antiretroviral therapy (HAART) using tenofovir/ emtricitabine combination and efavirenz, which were discontinued 5 years prior to admission due to the fact that he did not tolerate the medications. He had a history of Pneumocystis ji-roveci pneumonia, oral and genital herpes infections, and perianal abscess. On admission, physical examination was unrevealing. His CD4+ T cell count was 15 cells/ml and the plasma HIV-1 RNA viral load was 79,600 copies/ml. Liver function test showed elevated liver enzymes. The diarrhea was attributed to his chronic HIV infection and ultrasound of the abdomen revealed two hypoechoic lesions in the right and left hepatic lobes, measuring 1.9 cm and 2.0 cm in diameter, respectively. Follow-up abdominal computed tomography (CT) scan (Figure 1) showed five hypodense lesions, ranging from 0.9 to 2.3 cm in greatest dimension, with minimal peripheral arterial enhancement throughout the liver. No extrahepatic masses were appreciated on the CT of chest, abdomen, and pelvis and in an magnetic resonance imaging (MRI) of the brain. CT-guided percutaneous fine needle aspiration biopsy of the lesions in the right hepatic lobe was performed. The patient was restarted on HAART with tenofovir, emtricitabine, and darunavir/norvir combination, and his diarrhea improved after starting the antiretroviral therapy with the addition of loperamide. He was discharged and referred to the University of Texas MD Anderson Cancer Center for further management of his liver lesions. The patient was clinically stable, exhibiting viral suppression in the latest follow-up at 7 months after this presentation.

Figure 1
Contrast-enhanced computed tomography (CT) scan of the abdomen shows multiple hypodense lesions (arrow), 0.9 to 2.3 cm in maximal dimension, with minimal peripheral arterial enhancement throughout the liver.

Materials and methods

Bright field microscopy

Tissue was fixed in 10% formalin, embedded in paraffin, routinely processed, and stained with hematoxylin and eosin. Fite's acid fast stain and Warthin-Starry silver stain were also performed.

Immunohistochemical analysis

Formalin-fixed, paraffin-embedded sections of tissue were deparaffinized and rehydrated. Sections were stained with the primary antibodies against smooth muscle actin (SMA) (DAKO, Carpinteria, CA), desmin (DAKO), CD34 (Becton Dickinson, Franklin Lakes, NJ), CD31 (Novocastra, Newcastle upon Tyne, UK), human herpes virus 8 (HHV8) (Novocastra), S100 (DAKO), CD117 (DAKO), CD99 (DAKO), CD21 (DAKO), pan-cytokeratin cocktail (Novocastra), Ki-67 (DAKO), phosphorylated (p)-mTOR at ser-ine 2448 (Cell Signaling, Beverly, MA), p-Akt at serine 473 (Cell Signaling), and EBV latent membrane protein 1 (EBV-LMP1) (DAKO). Those incubated with anti-phosphospecific probes were incubated at 4°C, per the vendor's recommended procedure; all other primary antibodies were incubated at room temperature. Sections were then stained with the biotinylated secondary antibodies as previously described [14], and the antibody complexes were detected with the direct avidin-biotin-peroxidase method (Dako), using 3, 3'-diaminobenzidine as the chromogen and hematoxylin as the counter-stain. Positive and negative controls were run in parallel with the samples.

Chromogenic in situ hybridization for EBV-encoded small RNA 1 (EBER-1)

Formalin-fixed, paraffin-embedded sections of tissue were mounted on slides treated with 3-aminopropyltriethoxysilane, deparaffinized, digested with proteinase K, and dehydrated. The EBER-1 probe (Operon Technologies Inc, San Pablo, Ca), an oligonucleotide probe that detects a non-poly(A) RNA EBV transcript expressed in latently infected cells, was applied. The slides were incubated at 37°C for 1 hour before being washed with probe wash, developed with an in situ hybridization detection system (Biomeda, Foster City, CA), and counter-stained with hematoxylin.

Literature review

A literature search was performed from 1990 to February 2011 on PubMed using the search terms of “liver", “Epstein-Barr virus", “HIV infection", “acquired immunodeficiency syndrome", “smooth muscle tumor", “leiomyoma", “leiomyosarcoma", and “muscle neoplasms". All reported cases with diagnoses of EBV associated SMT in the liver were reviewed. Only cases of adult HIV-infected patients (> 18 years old) were included, excluding the pediatric cases. A total of 9 cases of intrahepatic EBV-SMT in adult AIDS patients, including our current case, fulfilled these criteria and were included in the review.


Microscopic and Immunohistochemical findings

On light microscopy (Figure 2), these hypercellular hepatic lesions are comprised of two cell populations: relatively monomorphic spindle cells arranged in short intersecting fascicles, and more primitive-looking oval to round cells that form separate nodules. The nuclei of the tumor cells are slightly hyperchromatic with delicate chromatin and inconspicuous nucleoli. The cytoplasm was deeply eosinophilic. There were mild to moderate nuclear atypia with a minimal mitotic activity of 1 mitotic figure per 10 high power fields. Focal single cell necrosis was seen. Additionally, some tumor cells were intimately related to the walls of small blood vessels, suggesting smooth muscle cells in the preexisting vessels as the potential origin of the lesions. The residual non-neoplastic hepatic parenchyma showed intact architecture with no evidence of cirrhosis.

Figure 2
Histologic features of EBV-SMT. A. The tumors contain two cell populations composed of spindle cells arranged in short fascicles and oval to round cells forming distinct nodules. B. The spindle cells have elongated blunt-ended nuclei and abundant eosinophilic ...

Immunohistochemical stains demonstrated that the tumor cells were diffusely positive for SMA, focally positive for desmin (Figure 3), and negative for CD34, CD31, HHV8, S100, CD117, CD99, and pan-cytokeratin. The proliferation marker Ki-67 highlighted only a few proliferating tumor cells (Figure 3). Fite's acid fast stain and Warthin-Starry stain failed to demonstrate the presence of mycobacteria or Bartonella henselae microorganisms, as are seen in the mycobacterial spindle cell pseudotumor and bacillary angiomatosis, respectively.

Figure 3
A Immunohis-tochemical stain for smooth muscle actin produces strong diffuse cytoplasmic staining in the tumor cells. B. The tumor cells show focal immunoreactivity for desmin. C. EBER in situ hybridization produces strong distinct nuclear staining in ...

EBV analysis

EBV was studied by chromogenic in situ hybridization using EBER1 oligonucleotides. The nuclei of the tumor cells showed strong positivity for EBER-1 in greater than 95% of the cells, indicating latent EBV viral infection (Figure 3). There was no in situ hybridization signal in the nuclei of the adjacent hepatocytes. Immunohisto-chemical stain of EBV-LMP1 was negative in tumor cells. CD21, the EBV receptor on B lymphocytes, could not be detected in the tumor cells by immunostaining. Polymerase chain reaction (PCR) analysis of the patient's plasma failed to detect the presence of EBV DNA. A diagnosis of EBV-associated smooth muscle tumor with uncertain malignant potential was made.

Studies on Akt/mTOR signal pathway

The chromogenic signals for p-Akt (serine 473) and p-mTOR (serine 2448) were both primarily localized in the nuclei of the tumor cells. Moderate to strong nuclear staining of p-Akt and p-mTOR was observed in > 90% of tumor cells, indicating constitutive activation of the mTOR signaling in this EBV-related tumor (Figure 4).

Figure 4
Expression of p-Akt at serine 473 (A) and p-mTOR at serine 2448 (B) in the current case of hepatic EBV-SMT.


The clinicopathologic findings of the current and 8 previously reported cases of hepatic EBV-SMT occurring in HIV-infected adults are summarized in Tables 1 and and2.2. The male to female ratio was 8: 1, and 8 of 9 patients were in their third decade of life. Hepatic EBV-SMT were detected from 48 to 120 months (mean 96 months) after the diagnosis of HIV infection. CD4 cell count at the initial presentation ranged from 2 to 150 cells/ul (mean 39 cells/ul; median 18 cells/ul). Plasma HIV RNA levels were extremely variable ranging from < 400 to 796,000 copies/ml. The hepatic tumors can be single or multiple, with a maximal diameter varying greatly between 0.9 cm and 14.0 cm. Follow-up information was available in eight patients. Five patients were alive: one patient (case 9) underwent resection of the liver tumors and had no recurrence 8 months post surgery, whereas the remaining four receiving no treatment were alive with persistent liver tumors at least 7, 7, 11, and 12 months after presentation. Three patients died. Of note, only one patient (case 8) died of EBV-SMT nine months following diagnosis, whereas the other two died of opportunistic infections. This patient (case 8) had a very high tumor burden with SMT involving multiple organs including the liver, lungs, gallbladder, and spinal cord. Regarding microscopic features, mitotic activity was documented in 7 of 9 cases, with virtually all 7 cases having less than 3 mitoses per 10 high power fields. Focal necrosis was present in 2 cases.

Together, the observations in these 9 cases suggest that hepatic EBV-SMT usually present as relatively well-differentiated tumors in adult HIV patients. The natural evolution of these tumors appears to be slow, and even in the face of multiple lesions, death in these patients is only occasionally due to the direct effects of EBV-SMT. Accordingly, it is very important to distinguish hepatic EBV-SMT from the non-EBV-related primary or metastatic leiomyosarcomas that occur in the liver, which typically pursue a far more aggressive clinical course and may potentially necessitate different clinical management [15-16].

EBV-SMT has many unique biological and his-tologic features that are rarely seen in the non-EBV-related SMT. These include occurrence exclusively in immunosuppressed patients, frequent multifocal involvement at very uncommon sites, presence of dual cell populations composed of not only the typical spindle-shaped cells but also primitive-appearing oval to round cells, hemangiopericytoma-like vascular pattern, variable intratumoral T lymphocytes, only mild to moderate nuclear atypia, and consistently sparse mitotic activity [11], [17]. The presence of multifocal masses, as seen in our patient, certainly raises the concern for malignancy and metastases. However, previous molecular analysis of different tumors in a given patient have shown that each tumor is derived from a different clone and therefore, represents multiple independent primaries rather than metastases from a single tumor [11], [2], [1]. Clonal analysis was not performed in the current case. Immunohistochemical stain for SMA and EBER in situ hybridization are diffusely positive in all EBV -SMT examined thus far, and are currently used as the most sensitive and reliable markers for the diagnosis of EBV-SMT. Expression of desmin is variable in EBV-SMT.

At present, how EBV infects and transforms the myocytes is largely unknown. Immunostaining for CD21, the EBV receptor on B lymphocytes and epithelial cells [18], was negative in the current case, similar to the findings of other investigators [7-8]. In contrast, McClain et al reported strong staining of CD21 in all 6 cases of EBV-SMT in HIV-infected children [1] , [19]. These discrepancies may reflect different antibodies utilized in immunohistochemistry or lower expression of CD21 in some cases that is below the threshold of technique sensitivity. Alternatively, EBV may enter the myocytes via other routes, such as fusion with EBV-infected lymphocytes [20-21]. Recently, a novel EBV receptor was identified in EBV-associated gastric carcinoma cells [22], raising the possibility that EBV-SMT tumor cells may similarly express a receptor protein that is distinct from CD21. EBV-LMP1 has clearly established transforming properties [23-24]. However, reports on LMP1 expression in EBV-SMT are equivocal, with negative immunostaining observed in the vast majority of cases, including the present case, focal faint reactivity in three cases, and detection by reverse transcriptase-polymerase chain reaction (RT-PCR) but not by immunohistochemistry in two cases [25], [11], [26]. Thus, the role of LMP1 in EBV-SMT remains to be determined.

Due to the relative rarity, the malignant potential of EBV-SMT is uncertain, revealing neither the benign behavior of leiomyomas nor the apparently aggressive behavior of leiomyosa rco-mas. Accordingly, optimal treatment for EBV-SMT aside from surgery is yet to be determined. Currently, complete surgical resection remains the mainstay therapy and has been shown satisfactory results, as in case 9 of our review [27]. Chemotherapy and radiotherapy appear to be ineffective in these tumors. Improvement of immune status, which is effective in the treatment of EBV-related posttransplant lymphopro-liferative disease, might also improve the outcome of EBV-SMT in AIDS patients [10].

The mammalian target of rapamycin (mTOR) has a central role in the regulation of cell growth [28]. Various growth factors and nutrients activate mTOR via multiple signaling pathways, which in turn stimulate protein synthesis by phosphorylating key translation regulators such as ribosomal S6 kinase and eukaryote initiation factor 4E binding protein 1 [29]. High levels of dysregulated mTOR activity are associated with many human diseases, including tumorigenesis. Studies by Sodhi [30] and Stallone [31] et al revealed that activation of the Akt/mTOR signal pathway played an essential role in AIDS-related Kaposi sarcoma's tumorigenesis, and sirolimus, an mTOR inhibitor, blocked the progression of Kaposi sarcoma. Very recently, overactivation of the Akt/mTOR signaling was also detected in EBV-SMT [4]. In one transplant patient, sirolimus induced complete remission of EBV-SMT in the liver [32]. Interestingly, Wittek et al published data demonstrating a close relationship between cultured Kaposi sarcoma cells from AIDS patients and leiomyoblasts [33]. In our case, the Akt-mTOR signal pathway is consti-tutively activated and more importantly the expression is mainly nuclear. The nuclear subcom-partmentalization of p-mTOR (Ser 2448) and its putative downstream effector, p-Akt (Ser 473) more likely reflects mTOR complex 2 (mTORC2) activation, which is less responsive to inhibition by rapamycin (sirolimus) [34]. The mechanism of rapamycin antitumorigenic effect in such cases needs further study. Specifically, further studies are needed to investigate the possible etiologic relationship between EBV-SMT and Kaposi sarcoma, to examine additional therapeutic molecular strategies aimed at inhibiting this Akt/mTOR pathway, and to search for other alternative explanations for the efficacy of sirolimus in EBV-SMT cases.

In conclusion, we have described a case of multicentric hepatic EBV-SMT affecting an adult patient with AIDS and examined the activation of the mTOR signal pathway in this tumor. A review of the literature suggests that the behavior of such tumors appears far less aggressive than the non-EBV- related primary or metastatic leiomyosarcomas involving the liver. Given the increased incidence and prolonged survival of AIDS patients, hepatic EBV-SMT are expected to be encountered more frequently in the future. This case demonstrates that EBV-SMT need to be included in the differential diagnoses of liver mass(es) in HIV-infected patients and that SMA immunohistochemistry and EBER in situ hybridization are the most useful ancillary studies.


We thank Richard A. Breckenridge, Pamela K. Johnston, and the histology technologists at the Lyndon B Johnson General Hospital for their technical assistance, and Bheravi Patel for her secretarial and graphic support.


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