Soft tissue

Smooth muscle

Epstein-Barr virus associated smooth muscle tumor


Editorial Board Member: Farres Obeidin, M.D.
Borislav A. Alexiev, M.D.

Last author update: 26 January 2024
Last staff update: 26 January 2024

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PubMed Search: Epstein-Barr virus associated smooth muscle tumor

Borislav A. Alexiev, M.D.
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Cite this page: Alexiev BA. Epstein-Barr virus associated smooth muscle tumor. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/softtissueebv.html. Accessed May 19th, 2024.
Definition / general
Essential features
  • Neoplasm with smooth muscle differentiation
  • Clinical history of immunosuppression
  • Positivity for Epstein-Barr virus encoded small RNA (EBER) transcripts by in situ hybridization
  • Fascicles of spindled cells with eosinophilic cytoplasm and elongated nuclei; a second population of round, more primitive appearing smooth muscle cells in a subset of cases
  • Tumor infiltrating lymphocytes; the lymphocytic infiltrate is composed primarily of T cells
Terminology
  • Not recommended: AIDS associated EBV positive smooth muscle tumor, EBV associated posttransplant smooth muscle tumor
ICD coding
  • ICD-O: 8897/1 - smooth muscle tumor of uncertain malignant potential
  • ICD-11: 2F7Y & XH00B4 - neoplasms of uncertain behavior of other specified site & smooth muscle tumor, NOS
Epidemiology
  • Wide age range (1 - 66 years), with a slight female predominance
  • Most cases occur in 1 of 3 main settings (Am J Surg Pathol 2006;30:75, Head Neck Pathol 2021;15:1162, Front Immunol 2018:9:368)
    • Immunodeficiency due to HIV / AIDS
    • Immunodeficiency after transplantation of a solid organ or hematopoietic stem cells
    • Congenital or primary immunodeficiency (least commonly)
  • Most primary immunodeficiency patients with EBV associated smooth muscle tumors are children (88%)
  • 68% of posttransplant and 72% of HIV / AIDS patients are adults
  • In the posttransplant EBV SMT group, they present as late complications (median: 48 months; range: 5 - 348 months) (Front Immunol 2018:9:368)
Sites
  • EBV SMT can occur anywhere in the body, including sites unusual for sporadic leiomyomas and leiomyosarcomas
  • Posttransplant EBV SMTs most commonly involve the liver (56%), followed by the lungs (31%) and gastrointestinal tract (15%) (Pathobiology 2013;80:297)
  • In patients with HIV, EBV SMTs have a particular predilection for the intra-axial or extra-axial CNS (41% of cases)
  • EBV SMTs can occur at single or multiple sites synchronously or metachronously and may grow continuously (Front Immunol 2018:9:368)
Pathophysiology
  • Pathogenesis appears to be related to infection and transformation of smooth muscle cells by EBV (Patholog Res Int 2011;2011:561548)
  • Having entered a smooth muscle cell, it is unclear how EBV infection causes neoplastic transformation with clonal proliferation
  • Majority of HIV EBV SMTs are positive for complement receptor 2 (CR2 or CD21) that is bound by EBV during B cell infection, while a substantial number of EBV SMTs resulting from organ transplantation associated immunosuppressive treatment and all analyzed cases of EBV SMTs arising from primary immunodeficiency disorders are CD21 negative (Front Immunol 2018:9:368)
  • EBV generally achieves a latency type III-like pattern in EBV SMTs (i.e., cells are positive for EBV nuclear antigen 2 [EBNA2], EBNA3 and late membrane protein 1) (Front Immunol 2018:9:368)
  • MYC overexpression and AKT-mTOR pathway activation appear as the main mediators of EBV SMT proliferation (Clin Cancer Res 2009;15:5350, Clin Transplant 2013;27:E462)
  • Epigenetic alterations may play an important role in tumorigenesis as recurrent copy number gains were found in histone deacetylases (Mod Pathol 2023;36:100127)
Etiology
  • EBV infection in the setting of T lymphocyte immunosuppression
  • EBV SMTs usually develop in the context of secondary immunodeficiency caused by human immunodeficiency virus infection or immunosuppressive treatment after solid organ transplantation (Front Immunol 2018:9:368, Am J Surg Pathol 2006;30:75, Head Neck Pathol 2021;15:1162)
  • In a small fraction of patients (mostly pediatric), EBV associated smooth muscle tumors may occur with primary immunodeficiency disorders, such as GATA2 and CARMIL2 deficiency (Front Immunol 2018:9:368)
Clinical features
  • Clinical manifestation of EBV SMTs is unspecific and mainly depends on the tumor localization, the tumor size and the particular organ displacement or disruption (Front Immunol 2018:9:368)
Diagnosis
  • EBV SMTs are suspected in the context of secondary immunodeficiency and primary immunodeficiency
  • No pathognomonic radiological picture
  • Biopsy with histopathology, immunohistochemistry and EBER in situ hybridization are mandatory to formally establish the diagnosis (Eur J Cancer 2014;50:2417)
Radiology description
Radiology images

Contributed by Borislav A. Alexiev, M.D.
Cervical spine MRI

Cervical spine MRI



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CT and PET scans

CT and PET scans

Prognostic factors
  • Prognosis is mainly dependent on the condition of the individual patient's immune system
  • Most EBV SMTs do not metastasize
  • Adverse prognosis is mainly related to comorbidities associated with immunosuppression but not with the extent of histological atypia or tumor size (Pathobiology 2013;80:297)
  • EBV SMTs do not correlate well with their histologic features and apparent grade of lesion, unlike somatic smooth muscle tumors (Arch Pathol Lab Med 2016;140:718)
    • It has been proposed that these tumors be designated as smooth muscle tumors of uncertain potential
  • Poor prognosis is mainly associated with intracranial manifestation and nonresectable tumors
Case reports
Treatment
  • Surgery or reduced immunosuppression are the main therapeutic approaches and both provide comparable overall survival rates (Am J Transplant 2012;12:1908)
  • Other therapies are chemotherapy and palliative radiation
Clinical images

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Endobronchial mass

Endobronchial mass

Right arytenoid lesion

Right arytenoid lesion

Gross description
Gross images

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Liver nodules

Liver nodules

Frozen section description
  • Intersecting fascicles of spindled cells with ample eosinophilic cytoplasm and elongated nuclei (Arch Pathol Lab Med 2016;140:718, Am J Surg Pathol 2006;30:75, Head Neck Pathol 2021;15:1162)
  • In ~50% of cases, a second population of round appearing cells may be seen
  • Cytological atypia is mild to moderate but can be marked in HIV positive patients
  • Tumor infiltrating lymphocytes
  • Low mitotic activity
  • Tumors in HIV positive patients may show higher mitotic activity or necrosis
Microscopic (histologic) description
  • Fascicular arrangement of relatively well differentiated smooth muscle cells with brightly eosinophilic cytoplasm and elongated, blunt ended nuclei exhibiting variable atypia (Arch Pathol Lab Med 2016;140:718, Am J Surg Pathol 2006;30:75, Head Neck Pathol 2021;15:1162)
  • There are 2 important defining and unique features
    • Presence of variable numbers of intratumoral lymphocytes; the lymphocytic infiltrate is composed primarily of T cells
    • Presence of so called primitive round cell areas (round, oval and epithelioid) arising gradually or abruptly from the well differentiated smooth muscle cells
    • These features may vary considerably in different cases
  • Subset of these tumors exhibits a hemangiopericytoma-like pattern
  • Vesicular nuclei with small nucleoli
  • Moderate increased cellularity, lack of nuclear pleomorphism and low mitotic rate
  • Focal areas of necrosis may be present
  • Histopathologic features may vary considerably in terms of cellular atypia, mitotic activity and necrosis, with no correlation to the clinical behavior (Arch Pathol Lab Med 2016;140:718)
  • HIV / AIDS EBV associated smooth muscle tumor 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
Microscopic (histologic) images

Contributed by Borislav A. Alexiev, M.D.
Moderate increased cellularity

Moderate increased cellularity

Spindle cell proliferation

Spindle cell proliferation

Blunt ended nuclei

Blunt ended nuclei

Low degree of atypia

Low degree of atypia


Intratumoral lymphocytes

Intratumoral lymphocytes

Smooth muscle actin

Smooth muscle actin

EBER ISH

EBER ISH

CD3

CD3

Positive stains
Electron microscopy description
  • Spindle cells with abundant cytoplasmic aggregates of actin microfilaments, including fusiform dense bodies and attachment plaques (Sarcoma 2008:2008:859407)
  • Cytoplasmic organelles are mainly represented by mitochondria, while rough endoplasmic reticulum cisternae are sparse
  • In studies in which electron microscopy was performed, no nuclear viral particles were detected (Patholog Res Int 2011;2011:561548)
Electron microscopy images

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Spindle cells with microfilaments

Spindle cells with microfilaments

Molecular / cytogenetics description
  • Overall copy number alteration profile is closer to leiomyoma
  • Recurrent copy number gain of oncogenes, such as RUNX1, CCND2 and ETS2 (Mod Pathol 2023;36:100127)
  • Epigenetic alterations may play an important role in tumorigenesis as recurrent copy number gains were found in histone deacetylases
Molecular / cytogenetics images

Images hosted on other servers:
Ideograms

Ideograms

Unsupervised hierarchical clustering

Unsupervised hierarchical clustering

Copy number alteration score

Copy number alteration score

Enrichment plots

Enrichment plots

Sample pathology report
  • C4 / C5 intradural tumor, resection:
    • EBV associated smooth muscle tumor (see comment)
    • Comment: The patient is a 35 year old woman, status post-kidney pancreas transplant. She presented with back pain and right upper extremity weakness and was found to have an intradural extramedullary lesion at C4 - C5 measuring 2.5 x 1.5 x 1.0 cm. She underwent C3 - C6 posterior cervical fusion with intradural tumor resection.
    • Histologic sections of the intradural mass show a moderately cellular lesion composed of spindle cells with eosinophilic cytoplasm and elongated, blunt ended vesicular nuclei with small nucleoli. Mitotic activity is low (2 mitoses/10 high power fields). There is no tumor necrosis. An intratumoral lymphocytic infiltrate is present.
    • The spindle cells are positive for smooth muscle actin and h-caldesmon and negative for all other markers analyzed (keratin AE1 / AE3, SOX10, desmin, ALK1, CD30, MyoD1). In situ hybridization for EBER shows strong diffuse positivity in the spindle cells.
    • The findings are consistent with an EBV associated smooth muscle tumor in a posttransplant setting.
Differential diagnosis
  • Mycobacterial spindle cell pseudotumor (Head Neck Pathol 2023;17:782):
    • Monotonous, spindle cell population in a vaguely storiform arrangement mixed with a heavy infiltrate of neutrophils and sparse lymphocytes
    • Spindle cell population stains strongly and diffusely for CD68 and is negative for muscle markers
    • Ziehl-Neelsen stain discloses numerous intracytoplasmic acid fast bacilli
    • EBER negative
  • Inflammatory myofibroblastic tumor (Diagn Pathol 2023;18:105):
    • Spindle cells are arranged in fascicular or haphazard patterns, accompanied by admixtures of inflammatory infiltrate with an abundance of plasma cells and lymphocytes in a hyalinized or myxoid background
    • Variable expression of smooth muscle markers, CD34 and MDM2
    • > 50% of inflammatory myofibroblastic tumors contain rearrangements of the anaplastic lymphoma kinase (ALK) gene on chromosome 2p23, resulting in the aberrant expression of ALK chimeric protein by IHC
    • ROS1 and RET rearrangements in rare cases of ALK negative inflammatory myofibroblastic tumor (Am J Surg Pathol 2015;39:957)
    • EBER negative
  • Inflammatory leiomyosarcoma / rhabdomyoblastic tumor (Genes Chromosomes Cancer 2022;61:653):
    • Morphologic and immunohistochemical features show overlap of smooth and skeletal muscle phenotypes
    • Sheets and fascicles of variably pleomorphic tumor cells showing spindled and epithelioid to rhabdoid morphology and a prominent histiocyte rich inflammatory infiltrate
    • Calcospherites (psammomatous calcifications) are a striking feature in the majority of cases
    • May show immunopositivity for some combination of smooth muscle actin, desmin and h-caldesmon, although h-caldesmon was absent in 1 cohort of 13 patients (Mod Pathol 2021;34:758)
    • Expression of MyoD1
    • Characteristic genetic finding is a near haploid loss of heterozygosity
    • EBER negative
  • Leiomyoma (Mod Pathol 2014;27:S17):
    • Histologically indistinguishable from EBV associated smooth muscle tumor in most cases
    • Rare in visceral organs outside uterus
    • Prominent intratumoral lymphocytic infiltrate, a characteristic feature of EBV associated smooth muscle tumor, is rarely seen
    • EBER negative
  • Angioleiomyoma (Mod Pathol 2014;27:S17):
    • Bundles of bland, well differentiated smooth muscle cells and intervening variably sized blood vessels
    • Most commonly in the subcutis or dermis of extremities; rare in visceral organs
    • Histologic variations include adipocytic metaplasia, prominent hyalinization / calcification and degenerative atypia
    • Prominent intratumoral lymphocytic infiltrate, a characteristic feature of EBV associated smooth muscle tumor, is rarely seen
    • EBER negative
  • Myopericytoma, including myofibroma (J Clin Pathol 2006;59:67):
    • Myopericytomas are nodular or lobular neoplasms composed of cytologically bland, oval to spindle shaped, myoid cells with characteristic multilayered, concentric growth around numerous small blood vessels
    • Myofibromas are nodular, well circumscribed neoplasms characterized by a distinctive biphasic growth pattern; the center of the lesion is composed of immature appearing, plump, spindled cells associated with hemangiopericytoma-like vasculature, whereas the periphery of the lesion contains nodules and fascicles of variable hyalinized myoid cells
    • Prominent intratumoral lymphocytic infiltrate, a characteristic feature of EBV associated smooth muscle tumor, is rarely seen
    • EBER negative
  • Leiomyosarcoma (Mod Pathol 2014;27:S17):
    • Focal pleomorphism is common even in low grade tumors with low mitotic activity
    • TP53 / p53 germline mutations
    • EBER negative
Board review style question #1

Which of the following is true for EBV associated smooth muscle tumors?

  1. Most occur in the setting of congenital or primary immunodeficiency
  2. Posttransplant tumors most commonly involve the gastrointestinal tract
  3. In patients with HIV, EBV associated smooth muscle tumors have a particular predilection for the intra-axial or extra-axial CNS
  4. Radiological imaging can establish the diagnosis of EBV associated smooth muscle tumors
  5. Most HIV / AIDS patients with EBV associated smooth muscle tumor are children
Board review style answer #1
C. In patients with HIV, EBV associated smooth muscle tumors have a particular predilection for the intra-axial or extra-axial CNS. Answer A is incorrect because EBV associated smooth muscle tumors rarely occur in the setting of congenital or primary immunodeficiency. Answer B is incorrect because posttransplant tumors most commonly involve the liver. Answer D is incorrect because radiological imaging cannot establish the diagnosis of EBV associated smooth muscle tumors as there are no pathognomonic findings. Answer E is incorrect because most HIV / AIDS patients with EBV associated smooth muscle tumors are adults (72%).

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Reference: Epstein-Barr virus associated smooth muscle tumor
Board review style question #2
Which of the following is true for EBV associated smooth muscle tumors?

  1. Poor prognosis is mainly associated with intracranial manifestation and nonresectable tumor
  2. Most EBV associated smooth muscle tumors do metastasize
  3. Adverse prognosis is mainly related to histological atypia
  4. Malignant behavior and clinical outcome are predicted by the histologic features
  5. Chemotherapy and palliative radiation are the main therapeutic approaches
Board review style answer #2
A. Poor prognosis is mainly associated with intracranial manifestation and nonresectable tumor. Answer B is incorrect because most EBV associated smooth muscle tumors do not metastasize. Answer C is incorrect because adverse prognosis is mainly related to comorbidities associated with immunosuppression but not with the extent of histological atypia or tumor size. Answer D is incorrect because unlike in somatic smooth muscle tumors, where the malignant behavior and clinical outcome are predicted by the histologic features, the behavior of EBV associated smooth muscle tumors does not correlate well with their histologic features and apparent grade of lesion. Answer E is incorrect because surgery or reduced immunosuppression are the main therapeutic approaches and both provide comparable overall survival rates.

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Reference: Epstein-Barr virus associated smooth muscle tumor
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