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Epstein-Barr Virus-Associated Smooth Muscle Tumor.

Epstein-Barr virus (EBV)-associated smooth muscle tumor (SMT) is an uncommon neoplasm typically manifesting in immunodeficient individuals. The association between SMT and immunosuppression was first described in 1970 by Pritzker et al. (1) Subsequently, Chadwick et al (2) reported SMT in human immunodeficiency virus (HlV)-infected children and asserted the association between HIV and these rare neoplasms. It was only in 1995 that in 2 simultaneous publications (3,4) the clear association with EBV was linked. A detailed pathologic and molecular characterization of this tumor/entity was first described by Deyrup et al. (5)

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.

CLINICAL FEATURES

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)

HISTOPATHOLOGIC FEATURES

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.

PATHOGENESIS

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.

DIFFERENTIAL DIAGNOSIS

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)

CONCLUSION

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.

References

(1.) Pritzker KP, Huang SN, Marshall KG. Malignant tumours following immunosuppressive therapy. Can Med Assoc J. 1970; 103(13):1362-1365.

(2.) Chadwick EG, Connor EJ, Hanson IC, et al. Tumors of smooth-muscle origin in HIV-infected children. JAMA. 1990; 263(23):3182-3184.

(3.) Lee ES, Locker J, Nalesnik M, et al. The association of Epstein-Barr virus with smooth-muscle tumors occurring after organ transplantation. N Engl J Med. 1995; 332(1):19-25.

(4.) McClain KL, Leach CT, Jenson HB, et al. Association of Epstein-Barr virus with leiomyosarcomas in children with AIDS. N Engl J Med. 1995; 332(1):12-18.

(5.) Deyrup AT, Lee VK, Hill CE, et al. Epstein-Barr virus-associated smooth muscle tumors are distinctive mesenchymal tumors reflecting multiple infection events: a clinicopathologic and molecular analysis of 29 tumors from 19 patients. Am J Surg Pathol. 2006; 30(1):75-82.

(6.) Hussein K, Rath B, Ludewig B, Kreipe H, Jonigk D. Clinico-pathological characteristics of different types of immunodeficiency-associated smooth muscle tumours. Eur J Cancer. 2014; 50(14):2417-2424.

(7.) Suankratay C, Shuangshoti S, Mutirangura A, et al. Epstein-Barr virus infection-associated smooth-muscle tumors in patients with AIDS. Clin Infect Dis. 2005; 40(10):1521-1528.

(8.) Jossen J, Chu J, Hotchkiss H, et al. Epstein-Barr virus-associated smooth muscle tumors in children following solid organ transplantation: a review. Pediatr Transplant. 2015; 19(2):235-243.

(9.) Yu L, Aldave AJ, Glasgow BJ. Epstein-Barr virus-associated smooth muscle tumor of the iris in a patient with transplant: a case report and review of the literature. Arch Pathol Lab Med. 2009; 133(8):1238-1241.

(10.) Reyes C, Abuzaitoun O, De Jong A, Hanson C, Langston C. Epstein-Barr virus-associated smooth muscle tumors in ataxia-telangiectasia: a case

report and review. Hum Pathol. 2002; 33(1):133-136.

(11.) Shaw RK, Issekutz AC, Fraser R, et al. Bilateral adrenal EBV-associated smooth muscle tumors in a child with a natural killer cell deficiency. Blood. 2012; 119(17):4009-4012.

(12.) Tulbah A, Al-Dayel F, Fawaz I, Rosai J. Epstein-Barr virus-associated leiomyosarcoma of the thyroid in a child with congenital immunodeficiency: a case report. Am J Surg Pathol. 1999; 23(4):473-476.

(13.) Purgina B, Rao UN, Miettinen M, Pantanowitz L. AIDS-related EBV-Associated smooth muscle tumors: a review of 64 published cases. Pathol Res Int. 2011; 2011:561548.

(14.) Kazmi SA, Aizenberg MR, Harper JL, et al. Multifocal histologically malignant Epstein-Barr virus-associated smooth muscle tumor in a pediatric transplant patient with an indolent course. Int J Surg Pathol. 2014; 22(2):186-189.

(15.) Jonigk D, Laenger F, Maegel L, et al. Molecular and clinicopathological analysis of Epstein-Barr virus-associated posttransplant smooth muscle tumors. Am J Transplant. 2012; 12(7):1908-1917.

(16.) Jenson HB, Montalvo EA, McClain KL, et al. Characterization of natural Epstein-Barr virus infection and replication in smooth muscle cells from a leiomyosarcoma. J Med Virol. 1999; 57(1):36-46.

(17.) Tetzlaff MT, Nosek C, Kovarik CL. Epstein-Barr virus-associated leiomyosarcoma with cutaneous involvement in an African child with human immunodeficiency virus: a case report and review of the literature. J Cutan Pathol. 2011; 38(9):731-739.

(18.) Rougemont AL, Alfieri C, Fabre M, et al. Atypical Epstein-Barr virus (EBV) latent protein expression in EBV-associated smooth muscle tumours occurring in paediatric transplant recipients. Histopathology. 2008; 53(3):363-367.

(19.) Moody CA, Scott RS, Amirghahari N, et al. Modulation of the cell growth regulator mTOR by Epstein-Barr virus-encoded LMP2A. J Virol. 2005; 79(9):5499-5506.

(20.) Ong KW, Teo M, Lee V, et al. Expression of EBV latent antigens, mammalian target of rapamycin, and tumor suppression genes in EBV-positive smooth muscle tumors: clinical and therapeutic implications. Clin Cancer Res. 2009; 15(17):5350-5358.

(21.) Shen Q, Feng W, Long MS, et al. Multicentric hepatic EBV-associated smooth muscle tumors in an AIDS patient: a case report, investigation of mTOR activation and review of the literature. Int J Clin Exp Pathol. 2011; 4(4):421-429.

(22.) Radu O, Pantanowitz L. Kaposi sarcoma. Arch Pathol Lab Med. 2013; 137(2):289-294.

(23.) Conrad A, Brunet AS, Hervieu V, et al. Epstein-Barr virus-associated smooth muscle tumors in a composite tissue allograft and a pediatric liver transplant recipient. Transpl Infect Dis. 2013; 15(5):182-186.

(24.) Lohan R, Bathla G, Gupta S, et al. Epstein-Barr virus (EBV)-related smooth muscle tumors of central nervous system--a report of two cases and review of literature. Clin Imaging. 2013; 37(3):564-568.

(25.) Takei H, Powell S, Rivera A. Concurrent occurrence of primary intracranial Epstein-Barr virus-associated leiomyosarcoma and Hodgkin lymphoma in a young adult. J Neurosurg. 2013; 119(2):499-503.

(26.) Ibebuike KE, Pather S, Emereole O, et al. Epstein-Barr virus-associated smooth muscle tumour presenting as a parasagittal brain tumour. J Clin Neurosci. 2012; 19(11):1589-1591.

(27.) Dominelli GS, Jen R, Park K, et al. Tracheal Epstein-Barr virus-associated smooth muscle tumour in an HIV-positive patient. Can Respir J. 2014; 21(6):334-336.

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: runjan.chetty@gmail.com).

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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