—  SPECIALTY CONFERENCE  —

Neuropathology

Case 5 - Epstein-Barr Virus-Associated Smooth Muscle Tumor (EBV-SMT)

Anthony T. Yachnis
University of Florida College of Medicine
Gainesville, FL





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History
A 37 year old HIV-positive African-American male presented with a six-month history of progressively worsening vision on the left and recent development of persistent bifrontal headaches. On examination, he was almost completely blind on the left. MRI revealed a 5.5 X 5.0 X 4.0 cm heterogeneously enhancing mass involving much of the left anterior cranial fossa, which extended to the right cerebral hemisphere and involved the skull base. There was significant mass effect and vasogenic edema of the adjacent brain.

The past medical history was significant for a diagnosis of AIDS two years prior to admission for which the patient was treated with Combivir, Viramune, and Azithromycin. About a year before the current admission, he presented with back pain of two weeks duration and was found to have a 10 cm mass involving the T6 and T7 vertebral bodies with cord compression at T7. Biopsy revealed a plasma cell neoplasm that was CD79a and CD138-immunoreactive and was lambda light-chain restricted by in situ hybridization. Radiation therapy produced marked reduction in size of this lesion with disappearance of circulating paraprotein.

A craniotomy was performed for resection and diagnosis of the intracranial tumor. Intra-operatively, it was noted to be entirely extra-axial and appeared to invade the floor of the anterior cranial fossa. The neoplasm was firm and somewhat elastic peripherally but softer and gelatinous internally and could be readily separated from the adjacent cerebral surface. A near total resection was performed, which provided diagnostic material.


Case 5 - Slide 1
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Case 5 - Figure 1 - Imaging studies (MRI) showing a large anterior cranial fossa lesion with contrast-enhancement (left image: T1-weighted after contrast) and peritumoral edema (right image: FLAIR-"Fluid attenuation inversion recovery").
Case 5 - Figure 2 - Low magnification view showing circumferential arrangement of tumor cells around a hyalinized blood vessel. The surrounding stroma presents an ischemic appearance. (H&E: Original magnification: X 250)
Case 5 - Figure 3 - A cellular area of the tumor showing scattered intratumoral capillaries. (H&E: Original magnification: X 250)

Case 5 - Figure 4 - High magnification showing spindle-shaped neoplastic cells with eosinophilic cytoplasm, inconspicuous cell borders, and elongated nuclei (some with blunt ends).
Case 5 - Figure 5 - An area of coagulation necrosis. (H&E: Original magnification: X 1000)

Case 5 - Figure 6 - Immunohistochemical stain for smooth muscle actin showing diffuse, strong reactivity of tumor cells. (Original magnification: X 500)
Case 5 - Figure 7 - In situ hybridization for EBER (Epstein-Barr virus-encoded early RNA) showing strong positivity for the anti-sense probe (left image) but no reaction with the sense (negative control) probe. (Original magnification: X 500)


Diagnosis:
Epstein-Barr virus-associated smooth muscle tumor (EBV-SMT)

Discussion:

Histologic findings : Low magnification study revealed cellular areas of tumor that were interrupted by prominent areas of eosinophilic, ischemic-appearing changes. In the latter areas, tumor cells were circumferentially arranged around hyalinized blood vessels. Fascicular arrangements of neoplastic cells were present and more cellular areas of tumor contained delicate capillaries. At higher magnification, tumor cells were spindle-shaped, having eosinophilic cytoplasm, indistinct cell borders, and elongated, blunt-ended nuclei, many with a single small nucleolus. There was only mild to focally moderate atypia. Areas of frank coagulation necrosis were present as well as other areas with degenerative or hyalinized ischemic-like change. Primitive-appearing round cells and intratumoral lymphocytes were not conspicuous by routine examination in this tumor. Overall, less than one mitosis per ten high power fields was counted.

Special studies : Tumor cells were strongly and diffusely immunoreactive for smooth muscle actin (SMA) and vimentin but negative for desmin, CD99, EMA, S-100, cytokeratin (AE1/AE3), and bcl-2. Tumor cells were negative for CD34, which was strongly reactive in intratumoral blood vessels. An acid-fast stain to exclude the possibility of a pseudosarcomatous reaction to a treatable mycobacterial infection was negative. However, in-situ hybridization to detect Epstein-Barr virus-encoded early RNA (EBER) was strongly positive in most tumor cell nuclei. These findings support and confirm the diagnosis of an Epstein-Barr virus-associated smooth muscle tumor (EBV-SMT).

EBV-SMT : The occurrence of unusual smooth muscle tumors in immunocompromised patients has been recognized since the early 1970's [1]. They were first identified in association with organ transplantation, and subsequently in patients with AIDS and inherited immunodeficiency syndromes. The association of Epstein-Barr virus infection was first reported in 1995 [2, 3]. Including a spectrum of smooth muscle tumors ranging from leiomyoma to leiomyosarcoma, such tumors tend to occur in atypical locations such as the lung, liver, spleen, bladder, heart, thyroid, and the nervous system [4, 5, 6, 7].

Most examples affecting the nervous system have been classified as leiomyosarcomas based on conventional histologic criteria [8, 9, 10, 11, 12, 13, 14, 15], although leiomyomas affecting the spinal cord in immunosuppressed patients have also been reported [16, 17]. Intracranial EBV-SMTs tend to arise as extra-axial neoplasms of the skull base and most appear to have some association with the dura, including dural venous sinuses [7]. One intra-axial tumor arose in the basal ganglia of a child [18]. Multifocal neoplasms of this type have involved several organ systems including the nervous system [4, 19, 20]

In order to compare the extent to which EBV-SMTs resemble classic smooth muscle neoplasms, Deyrup and colleagues [4] recently examined the clinicopathologic features of 29 EBV-SMT from 19 patients (12 males and 7 females). Tumors arose in adults (mean age: 39 years) with a history of organ transplantation (n=10), AIDS (n=8), or steroid therapy (n=1) and were located in soft tissue, lungs, liver, spleen, extradural regions, tonsil, vocal cords, gall bladder, urinary bladder, adrenal, pleura, bone, and spinal cord. Multifocal tumors were present in seven cases. Histologically, appearances were those of a well-differentiated smooth muscle tumor with mild to, at most, moderate pleomorphism, and generally less than three mitoses per ten high power fields (<3/10 HPF). Although occasional tumors had areas of necrosis and/or myxoid change, high grade sarcoma histology was not observed. Of note, the authors identified the presence of primitive round cell areas and a variable lymphocytic infiltrate in this series of EVB-SMT, which are not considered to be typical of more conventional smooth muscle tumors [4]. Although many of these neoplasms presented features suggestive of a low grade malignancy by conventional histology, only one patient died of tumor (three died of other causes). This study emphasized that the clinicopathologic features of EBV-SMT are quite different from sporadic leiomyosarcoma, which overall has a much worse prognosis.

In another disparity from conventional smooth muscle tumors, which tend to arise from organs containing large amounts of smooth muscle (such as the uterus), EBV-SMTs are believed to arise from the smooth muscle of blood vessels. Hence, early infection of vascular smooth muscle by EBV has been suggested to occur in studies where clonal expansion of smooth muscle cells infected with EBV was demonstrated [2, 4, 21]. The linear EBV genome becomes circular upon entering an infected cell such that the number of long terminal repeats (LTR) of this genome becomes non-random. Clonality analysis can thus be determined in the tumor by studying the LTR region of EBV. Deyrup and colleagues [4] performed such an analysis in several individuals with multifocal EBV-SMTs and found that the number of LTRs varied both between different patients and between multifocal neoplasms in the same patient. From the latter observation, they concluded that multifocal disease most likely results from multiple infection events rather that by metastasis from a primary site. This would be supported by the better prognosis for patients with EBV-SMT compared with conventional leiomyosarcoma.

Differential Diagnosis : The differential diagnosis includes tumors arising in the anterior cranial fossa (ACF) that may have a dural attachment. Tumors of this intracranial compartment may grow quite large before becoming symptomatic because of the paucity of symptoms referable to the anterior frontal lobes. Although meningiomas account for the majority of such lesions, other less common entities may occasionally be encountered. It should be mentioned here that intracranial benign and malignant smooth muscle tumors of the more typical type rarely arise in non-immunocompromised patients and are not typically EBV-associated [7]. Tumors of the hemangiopericytoma/solitary fibrous tumor group may present as dural-based tumors. Immunohistochemical staining for CD34 may be useful for this differential diagnosis. Hematologic malignancies such as extramedullary myeloid tumors ("granulocytic sarcomas") or MALT-like lymphomatous processes may sometimes present as dural-based lesions. Intracranial nerve sheath tumors present most commonly as CP-angle schwannomas arising from the vestibular branch of the eighth cranial nerve but can arise from other cranial nerves. Nerve sheath tumors do not typically present in the anterior cranial fossa. Small blue cell tumors such as rhabdomyosarcomas in children or esthesioneuroblastomas may present as anterior skull base masses and rare examples of mesenchymal chondrosarcoma and synovial sarcoma could occasionally be encountered in this location. Finally, in the setting of immunosupression, the possibility of a pseudosarcomatous reaction to Mycobacterium avium-intracellulare (MAI) should be considered in any unusual spindle cell lesion [22].

References:
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  2. McClain KL, Leach CT, Jensen HB, Joshi VV, Pollock BH, Parmley RT, DiCarlo FJ, Chadwick EG, Murphy SB. Association of Epstein-Barr virus with leiomyosarcoma in young people with AIDS. N Engl J Med 1995;332:12-18.

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

  4. Deyrup AT, Lee VK, Hill CE, Cheuk W, Toh HC, Kesavan S, Chan EW, Weiss SW. 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;30:75-82.

  5. Anguita J, Rico ML, Palomo J, et al. Myocardial Epstein-Barr virus-associated cardiac smooth muscle neoplasm arising in a cardiac transplant recipient. Tranplantation 1998;66:400-401.

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

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  18. Kumar S, Santi M, Vesina G, Rosser T, Chandra RS, Keating R. Epstein-Barr virus-associated smooth muscle tumor of the basal ganglia in an HIV+ child: case report and review of the literature. Pediatr Dev Pathol 2004;7:198-203.

  19. Boudjemaa S, Boman F, Guigonis V, Boccon-Gibod L. Brain involvement in multicentric Epstein-Barr virus-associated smooth muscle tumors in a child after kidney transplantation. Virchows Arch 2004;444:387-391.

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