The clinicopathologic findings of the current and 8 previously reported cases of hepatic EBV-SMT occurring in HIV-infected adults are summarized in and . 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
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
]. 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
]. 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
]. 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
]. 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
]. 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
]. 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.