Epstein-Barr Virus-Associated Smooth Muscle Tumor.
Epstein-Barr virus-associated SMT can occur in different locations and can manifest in multiple locations in the same patient. These lesions are considered to be independent primary lesions rather than metastatic disease when multiple tumors are encountered in the same patient. Also, the histopathologic features may vary considerably in different patients (see Table).
Epstein-Barr virus-associated SMT arises in different clinical settings related to immunosuppression, including (1) most commonly, HIV-associated SMT (HIV-SMT); (2) drug-related immunosuppression in posttransplant recipients (PT-SMT); and (3) congenital immunodeficiency disorder-associated SMT.
Authors have compared and analyzed the clinicopathologic features in different groups of patients, dividing them according to the underlying immune-deficient states. (6) A discussion and synopsis of the clinicopathologic features and treatment modalities is provided in this review.
Epstein-Barr virus-associated SMT is an uncommon soft tissue neoplasm affecting both adult and pediatric populations. The affected patients have one of the underlying diseases leading to immunodeficiency listed above. Though there is no significant sex bias, data analysis has revealed that there is a slight female preponderance. (6)
The clinical findings are related to the site of tumor manifestation. The main presentation in these patients is pain and organ dysfunction. The tumor tends to occur mainly in one location in most patients, but simultaneous occurrences in multiple sites have been reported. (7) There is a slight difference in the site predilection in the different subsets of patients.
Human immunodeficiency virus-SMT, which accounts for the majority of the reported cases so far, is most frequently encountered in the central nervous system, gastrointestinal tract and liver, skin, and larynx/lungs/pharynx. (6) A few cases occurring in the adrenal glands have been reported. (7) In contrast, PT-SMT occurs preferentially in the liver, (8) lungs/ larynx/pharynx, gut, spleen, and kidneys, sometimes in the brain, and rarely in the adrenal gland and the iris of the eye. (9) Very few cases of congenital immunodeficiency disorder associated SMT have been reported, and lungs/larynx are most frequently affected, followed by intracranial tumors, liver, adrenal, and spleen. (10-12)
The tumor may vary in size (0.7-21 cm), with a median size of 3.7 cm. The tumor shows a fascicular arrangement of relatively well-differentiated smooth muscle cells with brightly eosinophilic cytoplasm, and elongated, blunt-ended nuclei exhibiting variable atypia (Figure 1). There are 2 important defining and unique features. The first is the presence of variable numbers of intratumoral lymphocytes (Figure 1). The lymphocytic infiltrate is composed primarily of T cells. The second distinctive feature is so-called primitive round cell areas arising gradually or abruptly from the well-differentiated smooth muscle cells (Figure 2). (5) These features may vary considerably in different cases. In our case, the lesion was predominated by spindle cells (~95%), and the primitive round cell component contributed to the remaining 5% of the tumor area. The HIV-SMT subtype shows the most histologic variation, ranging from standard leiomyoma-like to leiomyosarcoma-like and even angioleiomyoma or myopericytoma-like features. In such cases, the detection of EBV in the tumor cells remains the mainstay for distinguishing them from conventional leiomyosarcoma.
The histologic features may show foci with variable areas of cellular atypia, mitotic activity, and necrosis. However, unlike in somatic SMT, where the malignant behavior and clinical outcome are predicted by the histologic features, the behavior of EBV-SMTs does not correlate well with their histologic features and apparent grade of lesion. (6,8) Some of the well-differentiated tumors devoid of mitoses and atypia have proven to be lethal. (3) Thus, it has been proposed that these tumors be designated as SMT of uncertain potential.
Immunohistochemically, these tumors exhibit a smooth muscle immunophenotype with positive staining for a smooth muscle actin, muscle-specific actin, and desmin. The extent of immunoexpression of these muscle markers may vary. (13,14) In our case, immunohistochemistry revealed positivity for smooth muscle actin (Figure 3); however, desmin was not expressed in the tumor cells.
Demonstration of EBV-encoded small RNA by in situ hybridization (EBER DNP RNA probe in situ hybridization, Roche Diagnostics, Mississauga, Ontario, Canada) shows nuclear positivity in the spindle cells (Figure 4). The other methods of EBV detection, such as EBV seropositivity and EBV DNA detection by polymerase chain reaction, may provide unreliable results and are unreliable for the diagnosis of EBV-SMT.
The pathogenesis of these rare tumors and the role of EBV in the tumorigenesis is poorly understood. Two EBV strains primarily infect humans: types 1 and 2 (formerly types A and B). These 2 strains differ in their biologic properties, epidemiology, and geographic distribution. Type 1 has greater transforming ability and has been identified in immunocompetent patients with EBV-positive Hodgkin lymphoma and Burkitt lymphoma, whereas type 2 is pathogenic primarily in immunodeficient patients. The virus is transmitted by close contact, frequently through saliva, and EBV uses the CD21 receptor on the surface of B cells to gain entry into cells. Though limited data are available for strain typing in EBV-SMT, EBV type 2 has been detected. (5)
The progenitor cell for EBV-SMT is thought to be derived from an aberrant myogenous vascular smooth muscle cell. (15) Normal smooth muscle cells have been shown to express the CD21 receptor (15) or a protein with a related, cross-reactive epitope. (16) In support of this theory, tumor cells in EBV-related SMT express CD21. (4,16) These observations have led to the proposal of a model suggesting that
EBV infects the smooth muscle cells directly by attaching to CD21 and thereby facilitating and promoting replication within these cells. (17) However, in cases of PT-SMT, examination for CD21 has yielded negative results, suggesting an alternative, as yet unidentified route of EBV integration. (3,18,19) In such cases, fusion of smooth muscle cells with an infected B cell prior to tumor proliferation has been postulated. (13)
Overexpression of myc, a proto-oncogene, has been demonstrated in some in EBV-SMT. (16) Upregulation of myc proto-oncogene leads to increased cell proliferation. However, no further rearrangement or translocation of myc has been shown, suggesting that EBV itself may elicit increased myc expression. In addition, the Akt/mTOR pathway is considered to play a significant role in the proliferation of smooth muscle cells. Activation of mTOR has been shown to be triggered by LMP2A, (19,20) which is a latency membrane protein expressed by EBV. Activation of this pathway has been demonstrated in PT-SMT21 and HIV-SMT. (22) These associations suggest that EBV plays a pivotal and critical role in tumor formation and growth. (8)
Clonal analysis of multifocal EBV-SMT has indicated that individual tumors in a given patient contain distinct EBV-insertion events. (4,5) As EBV infection is an early event in SMT associated with immunosuppression, this observation suggest that multifocal SMT represents independent primary lesions rather than metastases.
The major differential diagnosis considered for a spindle cell lesion in an immunosuppressed individual includes Kaposi sarcoma (KS) and mycobacterial spindle cell pseudotumor. Kaposi sarcoma is a low-grade vascular tumor associated with human herpesvirus 8. It predominantly involves mucocutaneous sites but other anatomic locations can be involved as well. Well-developed KS (tumors) consists of fascicles of spindle-shaped tumor cells often admixed with a variable chronic inflammatory infiltrate composed of lymphocytes, plasma cells, and dendritic cells. Various histologic subtypes have described, including anaplastic, hyperkeratotic, lymphangioma-like, bullous, telangiectatic, ecchymotic, keloidal, pyogenic granuloma-like, micronodular, intravascular, glomeruloid, and pigmented KS, as well as KS with sarcoidlike granulomas and, importantly, KS with myoid nodules. (22) Kaposi sarcoma shows immunoreactivity for vascular markers CD31 and CD34 and is negative for smooth muscle-related antigens. Epstein-Barr virus-associated SMT can resemble KS histologically in view of the presence of intratumoral lymphocytes and spindle-shaped cells; however, the negative staining for endothelial markers (CD31 and CD34) and positivity for desmin along with demonstration of EBV in tumor cells by in situ hybridization helps in clinching the diagnosis. Mycobacterial spindle cell pseudotumor shows numerous acid-fast bacilli within the spindle cells and thus can be differentiated from EBV-SMT on this basis.
Other differential diagnosis that needs to be excluded in pertinent cases is myopericytoma, as the EBV-SMT may exhibit some myopericytoma-like features. Myopericytoma is a benign perivascular myoid tumor composed of oval to short fusiform cells with a striking multilayered concentric growth around the vessels. The immunophenotype shows myoid features with positive staining for a smooth muscle actin, caldesmon, and desmin. The index of suspicion should be high in immunocompromised patients and a positive staining for EBV-encoded small RNA in situ hybridization, helps in distinguishing the EBV-SMT from this tumor.
MANAGEMENT AND PROGNOSIS
Different treatment modalities have been described for EBV-SMT, including chemotherapy, surgical resection, antiviral therapy, and reduced immunosuppression. However, given the rarity and uncertain behavior of these tumors, no fixed approach has been described to treat these tumors.
In PT-SMT, surgery and/or reduced immunosuppression remain the main therapeutic approaches and provide comparable results. (16) Sirolimus, which is an mTOR/Akt signal inhibitor, shows therapeutic benefits; however, it's not clear if it alone is responsible for disease stability. As suppression of tumor neoangiogenesis is used as a potential target for therapy in several neoplasms including sarcomas, antiangiogenic molecules are being tried in these patients, although somewhat unsuccessfully. (13)
A review of the literature has revealed that HIV-SMT has the poorest prognosis among the 3 subtypes. (6) Also, patients succumb to infectious complications in most cases rather than local tumor progression, especially in HIV and posttransplant patients. It is interesting to note that although HIV-SMTs most commonly occur in the brain, posttransplant patients who develop intracranial EBV-SMTs are associated with poor prognosis. (6)
Epstein-Barr virus-associated SMTs are rare soft tissue spindle cell neoplasms that occur in immunosuppressed individuals. There is a slight female preponderance for all subtypes and they can be seen in pediatric as well as adult patients. Histologic features and behavior are variable in HIV-SMT and immunosuppression-associated complications are more relevant and important for predicting outcome than tumor morphologic characteristics. Therapeutic strategies target the tumor location as well as the etiology of immunosuppression.
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Accepted for publication June 1 9, 2015.
From the Department of Pathology, Laboratory Medicine Program, University Health Network and University of Toronto, Toronto, Ontario, Canada.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Runjan Chetty, FRCPath, Department of Pathology, 11th Floor, Eaton Wing, Toronto General Hospital, 200 Elizabeth St, Toronto, ON M5G 2C4, Canada (email: firstname.lastname@example.org).
Please Note: Illustration(s) are not available due to copyright restrictions.
Caption: Figure 1. Spindle cells with histologic features in keeping with a smooth muscle tumor: elongated slender blunt-ended nuclei and eosinophilic cytoplasm. Also noted are a scattering of intralesional lymphocytes (hematoxylin-eosin, X400).
Caption: Figure 2. In areas the lesion is characterized by rounder, more primitive-appearing smooth muscle cells (hematoxylin-eosin, X400).
Caption: Figure 3. The tumor cells show strong staining for actin (anti-actin, X400).
Caption: Figure 4. Epstein-Barr-encoded RNA in situ hybridization highlights the presence of Epstein-Barr virus within the nuclei of the spindle cells (X400).
Literature Review From 2012 to Present Age y/ Source, y Sex Location Shaw et al, (11) 12/F Bilateral adrenal 2012 masses Kazmi et al, (14) 8/F Adrenal, small bowel, 2014 lung, brain Conrad et al, (23) 27/M Liver 2013 Conrad et al, (23) 1/F Left colon 2013 Lohan et al, (24) 37/M Paraspinal 2013 Lohan et al, (24) 55/F Extra-axial with 2013 dural attachment Takei et al, (25) 27/M Brain 2013 Ibebuike et al, (26) 37/M Brain 2012 Dominelli et al, (27) 38/F Tonsil, lung, trachea 2014 Underlying Immunodeficient Source, y Size State Shaw et al, (11) 21 X 12 X 11 cm and Natural killer cell 2012 6 X 5 X 4.5 cm deficiency Kazmi et al, (14) 0.9-2.5 cm Post-renal transplant 2014 Conrad et al, (23) NS Composite tissue 2013 allograft Conrad et al, (23) 5-mm nodule Liver transplant 2013 Lohan et al, (24) NS HIV positive 2013 Lohan et al, (24) NS Post-renal transplant 2013 Takei et al, (25) 2.6 X 4.0 X 3.3 cm Nil, immunocompetent 2013 Ibebuike et al, (26) 4.8 X 4.6 X 5.2 cm HIV positive 2012 Dominelli et al, (27) 8 mm-1.5 cm HIV positive 2014 Associated Clinical Source, y Disease Radiologic Findings Shaw et al, (11) Nil NS; mass identified 2012 on CT scan Kazmi et al, (14) Nil MRI brain- 2014 enhancing, complex, hemorrhagic extra- axial masses in the right frontal- temporal and right frontal areas measuring 2.5 cm and 0.9 cm in greatest dimension Conrad et al, (23) EBV-positive high-grade CT, multiple 2013 B-cell lymphoma hypodense lesion with annular contrast enhancement Conrad et al, (23) Polymorphic EBV-driven NS 2013 SMT in tonsils and cervical nodes Lohan et al, (24) Nil MRI, intradural 2013 extramedullary mass in the thecal sac posteriorly at the T6 vertebra, isointense to mildly hyperintense on T2- weighted images, isointense on T1- weighted images, and depicted intense uniform enhancement on postcontrast sequences Lohan et al, (24) Nil MRI, extra-axial 2013 with a dural attachment to the lesser wing of the sphenoid, isointense to mildly hyperintense to the grey matter on T2- weighted images and isointense on T1- weighted images; intense homogenous postcontrast enhancement Takei et al, (25) Hodgkin lymphoma MRI, 2.6 X 4.0 X 2013 3.3-cm homogeneously enhancing intra-axial tumor with marked surrounding edema, extending into the corpus callosum and deep white matter, in the anteromedial aspect of the right frontal lobe Ibebuike et al, (26) Nil MRI, right frontal 2012 lobe mass (measuring 4.8 X 4.6 X 5.2 cm) with irregular rim enhancement and an enhancing solid component invading the superior sagittal sinus Dominelli et al, (27) Nil CT scan, polypoid 2014 tracheal mass from 8 mm to 1.5 cm in diameter, an increase in the right tonsil mass to 1.1 cm and a left upper lobe nodule measuring 11 mm Source, y Histologic Findings Mitosis Shaw et al, (11) Elongated spindle NS 2012 cells with eosinophilic cytoplasm were present along with inflammatory cells, including lymphocytes and histiocytes; hemangiopericytoma- like pattern seen Kazmi et al, (14) Spindle to round Variable, 1-15/ 2014 cells forming 10 HPF irregular short fascicles and small sheetlike areas Conrad et al, (23) NS Low mitotic 2013 activity, NS Conrad et al, (23) NS Moderate mitotic 2013 activity Lohan et al, (24) Compact NS 2013 proliferation of spindle cells with elongated, blunt- ended nuclei and ample eosinophilic cytoplasm, arranged in short intersecting fascicles, EBV- positive by EBER- ISH Lohan et al, (24) Interlacing Low mitosis 2013 fascicles of mild to (<1/10 HPF) moderately pleomorphic atypical spindle cells with ample eosinophilic cytoplasm, mild to moderate increase in cellularity, and few to no areas of necrosis Takei et al, (25) Variable Brisk mitosis 2013 hypercellularity; (23/10 HPF) areas of tumor cells with increased nuclear to cytoplasmic ratio and multiple foci of tumor necrosis Ibebuike et al, (26) Variably cellular 0/10 HPF 2012 spindle cell neoplasm with degenerative changes Dominelli et al, (27) Well-circumscribed Up to 20/10 2014 mass composed of HPF tightly packed fascicles of mildly atypical short spindle cells with scattered intratumoral lymphocytes, no necrosis Patient Source, y Survival Shaw et al, (11) >26-mo 2012 follow-up Kazmi et al, (14) >36-mo 2014 follow-up Conrad et al, (23) >15 mo 2013 Conrad et al, (23) >48 mo 2013 Lohan et al, (24) NS 2013 Lohan et al, (24) NS 2013 Takei et al, (25) NS 2013 Ibebuike et al, (26) >3 mo 2012 postoperation Dominelli et al, (27) > 6-mo follow-up 2014 Abbreviations: CT, computerized tomography; EBER-ISH, Epstein-Barr- encoded RNA in situ hybridization; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; HPF, high-power field; MRI, magnetic resonance imaging; NS, not specified; SMT, smooth muscle tumor.
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|Author:||Dekate, Jyoti; Chetty, Runjan|
|Publication:||Archives of Pathology & Laboratory Medicine|
|Date:||Jul 1, 2016|
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