Epstein-Barr virus-associated smooth muscle tumor (EBVSMT)
EBVSMT occurs mainly in immunocompromised patients, either in the setting of solid organ transplantation or with HIV/AIDS . Typically, the disease has an indolent course, is locally invasive, and is rarely the cause of death . The pathogenesis of EBVSMT is related to the infection and neoplastic transformation of smooth muscle cells by EBV with clonal expansion. However, the exact mechanism of tumorigenesis is still unclear. It has been reported that these tumors tend to be multifocal with the propensity to arise in virtually any anatomical location . The clinicopathological features of EBVSMT in relation to their biological behavior and management remains to be fully elucidated. The CNS is a common site, and patients with these tumors often present with significant neurologic symptoms. EBVSMT should be included in the clinical differential diagnosis for an intracranial or spinal mass arising in a patient with AIDS. Within the CNS, EBVSMT may be dural, epidural, or extradural. Rare cases involved the basal ganglia and pontine cistern . EBVSMT appears to arise when patients exhibit severe immunosuppression due to their underlying HIV infection .
Histologically, EBVSMT demonstrates interlacing fascicles of mild to moderately pleomorphic spindle to oval cells with ample eosinophilic cytoplasm. Some cases described a second population of small round cells with a primitive appearance . Other features that have been described include a hemangiopericytic pattern with staghorn-like vessels and chronic inflammatory cells including intratumoral T lymphocytes. Most cases are positive for smooth muscle markers. However, negativity or focal staining for desmin can be encountered in a significant number of cases . The use of other muscle markers, including h-caldesmon, SMA, and SMMHC should be added in such cases. Positivity for EBER is detected in nearly all cases. As a result, EBER in situ hybridization should be performed on any smooth muscle tumor arising in an immunocompromised patient. Classical leiomyosarcomas and leiomyomas arising in immunocompetent patients have not demonstrated an association with EBV.
The differential diagnosis of a spindle cell lesions arising in the setting of HIV infection includes Kaposi sarcoma (KS) and spindle cell pseudotumor (SCP). KS is positive for vascular markers such as CD31, CD34, or factor VIII and negative for muscle markers. KS is positive for LNA-1, whereas EBVSMT is not. In mycobacterial SCP, numerous acid-fast bacilli can be identified within the spindle cells, using Ziehl-Neelsen stain. Histoplasma- and Cryptococcus-SCP are rarely reported. Histochemical staining with Gomori-methenamine silver stain and mucicarmine are helpful. Also, unlike SMT, mycobacterial-and fungal SCP are CD68 positive. Other entities that should be considered in the differential diagnosis of EBVSMT include schwannoma, meningioma, tanycytic ependymoma (TE), hemangiopericytoma (HPC), inflammatory myofibroblastic tumor (IMT), and follicular dendritic cell (FDC) sarcoma. EBVSMT should be distinguished from schwannoma. Schwannomas have wavy nuclei with nuclear palisading and hyalinized blood vessels. Immunostaining can help to provide a definitive diagnosis. S100 protein is diffusely positive in schwannoma and negative in EBVSMT. A dural-based EBVSMT must be distinguished from a meningioma. Meningioma demonstrates whirling, round-to-oval nuclei, some with intranuclear inclusions, eosinophilic cytoplasm and indistinct cytoplasmic borders. Meningioma can be separated from EBVSMT as it is usually positive for EMA, but negative for myoid markers. TE should be distinguished from EBVSMT. Radiologically, the reported TE are almost always intramedullary lesions. TE consisted of monotonous proliferation of long spindle cells with eosinophilic cell processes; focally forming perivascular pseudorosettes. TE is positive for GFAP but negative for myoid markers. EBVSMT may be mistaken for HPC. Focal HPC-like blood vessels can be observed in EBVSMT. Unlike EBVSMT, HPC is positive for CD34 and negative for EBER as well as myoid markers. Like EBVSMT, IMT can be observed in CNS and associated with EBV in a small subset of cases. Histologically, IMT composed of plump spindle cells with prominent plasma cells. As EBVSMT, IMT may show immunoreactivity for SMA. However, IMT often express SMA with "tram-track" pattern rather than dense cytoplasmic staining of EBVSMT. Other myoid markers (desmin, h-caldesmon) are typically negative in IMT. Expression of ALK is also useful which show positive result in IMT. Finally, FDC sarcoma is a rare tumor arising from FDC and shows a predilection for nodal sites. CNS involvement is very rare. Like EBVSMT, an association with EBV has been observed in a subset of these sarcomas. FDC can be distinguished from EBVSMT by immunolabeling for FDC markers CD23 and CD35. CD21 should be interpreted with caution because it can be observed in both diseases.
In summary, EBVSMT is a rare disease that occurs in immunocompromised patients. It is important to recognize this disease because it is different in clinical presentation and radiological differential diagnosis. Clinical history of immunocompromised status and unusual locations raise the possibility of disease. As pathologists may not always know the clinical history of immunosuppression, it may be wise to include EBVSMT in the differential diagnosis of any smooth muscle tumor occurring in uncommon sites.
ACKNOWLEDGMENTS: To Dr. Siriwan Tangitgamol for manuscript preparation.
Contributed by Kongsak Loharamtaweethong, MD; Bhakawat Chiamtrakool, MD; Sukrit Viriyasakultong, MD