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EBV-Associated Smooth Muscle Tumor

EBV-associated smooth muscle tumor is a smooth muscle tumor associated with EBV infection, usually in the setting of immunosuppression.

Symptoms & Causes

Introduction

EBV-associated smooth muscle tumor is a rare tumor linked to Epstein-Barr virus infection, often seen in immunosuppressed individuals.

Reference
WHO Classification of Tumours Editorial Board. Soft tissue and bone tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2020 [cited 2024 09 11]. (WHO classification of tumours series, 5th ed.; vol. 3). Available from: https://tumourclassification.iarc.who.int/chapters/33.

Related Terminology
Not recommended: AIDS-associated EBV-positive smooth muscle tumor; EBV-associated posttransplant smooth muscle tumor; smooth muscle tumor in immunocompromised patient.

Subtype(s)
None

Symptoms

Presenting features may be nonspecific (pain) or related to the site of involvement: neurological symptoms with intra-axial or extra-axial CNS tumors; bleeding, abdominal pain, obstruction, and perforation when involving the gastrointestinal tract; and cyanosis, fever, and lung infections with endobronchial lesions.

Localization

EBV-associated smooth muscle tumors can occur anywhere in the body, including sites unusual for sporadic leiomyomas and leiomyosarcomas. HIV-associated smooth muscle tumors have a particular predilection for the intra-axial or extra-axial CNS (41% of cases), whereas posttransplant smooth muscle tumors most commonly involve the liver (56%; the donor liver in liver transplant recipients and the native liver in recipients of other solid organs), followed by the lungs (31%) and gastrointestinal tract (15%); they have also been reported in kidney, lung, and heart allografts. Tumors are multicentric in 71%, 54%, and 29% of primary immunodeficiency, posttransplant, and HIV-positive patients, respectively.

Epidemiology

Occurring over a wide age range (1–66 years) and with a slight female predominance, most cases occur in one of three main settings: immunodeficiency due to HIV/AIDS, immunodeficiency after transplantation of a solid organ (63% kidney, 15% heart, 12% liver) or hematopoietic stem cells, and (least commonly) congenital or primary immunodeficiency. Most primary immunodeficiency patients (88%) with EBV-associated smooth muscle tumors have been children; reported adult primary immunodeficiency patients had GATA2 deficiency. In contrast, 68% of posttransplant and 72% of HIV/AIDS patients are adults. Tumors are found several months to years after the onset of the patient’s immunodeficiency syndrome or transplantation. The epidemiology is similar to that of the immunodeficiency-associated lymphoproliferative disorders, which are frequently EBV-positive, although they tend to occur as a later consequence than the EBV-positive lymphoproliferative disorders observed in a subset of smooth muscle tumor patients (particularly in children in the posttransplant and primary immunodeficiency settings). Rarely, these tumors are associated with iatrogenic immunosuppression for autoimmune disease. If these tumors are encountered outside of any of these settings, a thorough immunological work-up and close follow-up for opportunistic infections are warranted.

Etiology

The etiology involves EBV infection in the setting of T-lymphocyte immunosuppression.

Diagnosis & Treatment

Staging

Not clinically relevant

Pathogenesis

During latent infection, as many as 10 of the nearly 100 genes in the EBV genome are expressed, another mechanism to evade T-cell immune surveillance. The latency pattern remains controversial and is perhaps unique to this entity, although many authors describe a type III–like pattern with positivity for EBV-encoded small RNA (EBER), EBNA2, and LMP1 despite somewhat inconsistent EBNA2 results and absence of LMP1 from most posttransplant and some HIV-associated cases. MYC overexpression and AKT/mTOR pathway activation appear to be main mediators of EBV-induced smooth muscle tumor proliferation. Tumor multicentricity is related to multiple infection events, with viral episomal analysis showing independent viral clones rather than dissemination or metastasis of a single clone, which is far less common. Furthermore, short tandem repeat (STR) analysis has revealed that posttransplant smooth muscle tumors can be derived from either recipient or donor.

Macroscopic Appearance

Tumors range from subcentimeter to > 20 cm, with white to grey cut surfaces, a firm to rubbery consistency, and well-circumscribed to infiltrative borders.

Histopathology

The tumor is composed of intersecting fascicles of spindled cells with ample eosinophilic cytoplasm and elongated nuclei; in about half of cases, a second population of round, more primitive-appearing smooth muscle cells is seen. A subset of these tumors exhibit a haemangiopericytoma-like pattern. Cytological atypia is usually mild to moderate but can be marked in HIV-positive patients, whose tumors also show higher mitotic activity and/or necrosis. An intratumoral T-lymphocytic infiltrate is common and usually sparse but can be more pronounced. Neoplastic cells are diffusely positive for SMA and h-caldesmon. Desmin is sometimes positive but expression is usually focal. EBER is consistently positive.

Cytology

Not clinically relevant

Prognosis and Prediction

Prognosis is mainly dependent on the condition of the individual patient’s immune system. Most of these tumors do not metastasize. Intracranial posttransplant smooth muscle tumors (but not HIV/AIDS-associated or primary immunodeficiency–associated smooth muscle tumors) have an adverse prognosis. Some posttransplant cases respond to reduced immunosuppression, which partially restores immune function, and complete resolution of EBV-associated smooth muscle tumors has been reported in a patient with GATA2 deficiency after hematopoietic stem cell transplantation.

Clinical Features

Diagnostic Molecular Pathology

Diagnostic molecular pathology involves demonstration of EBV, usually by in situ hybridization for EBER.

Essential and Desirable Diagnostic Criteria

Essential: clinical history of immunosuppression; neoplasm with smooth muscle differentiation; positivity for EBER transcripts by in situ hybridization.

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