Epithelioid Leiomyosarcoma of the Uterus: Modern Outcome-based Appraisal of Diagnostic Criteria in a Large Institutional Series.

Epithelioid leiomyosarcoma of the uterus is rare and poorly understood. Herein, we characterize a large institutional series of epithelioid leiomyosarcomas aiming to define outcome-determinant diagnostic pathologic features. We also retrieved epithelioid smooth muscle tumors of unknown malignant potential and evaluated a consecutive cohort of leiomyomas for epithelioid subtypes. Of a total of 1177 uterine leiomyosarcomas, 81 (7%) were categorized as epithelioid after review. Epithelioid leiomyosarcoma was strictly defined as having round to polygonal cells with visible pink cytoplasm and round to ovoid nuclei in ≥50% of the tumor volume. Average age was 55 years (range: 26 to 81 y). Median tumor size was 11 cm; tumor was >5 cm in 93% of subjects; 47% were stage 1 at presentation. An infiltrative tumor border was observed, grossly and/or microscopically, in 89% of cases; necrosis was noted in 80%, and vascular invasion in 47%. Mitotic count in 2.4 mm2 (totalling 10 high-power fields, each field 0.55 mm in diameter) ranged from 3 to 100 (median: 26). All cases had moderate, severe or highly pleomorphic atypia. All cases had 2 or 3 of the following: necrosis, at least moderate atypia and ≥4 mitoses in 2.4 mm2. Immunohistochemistry revealed frequent expression of smooth muscle markers including SMA (96%), desmin (95%), and caldesmon (81%). HMB45 and Melan-A were negative in 92% and 100% of cases, respectively. Estrogen and progesterone receptors were expressed by 65% and 54% of tumors, respectively. Follow-up information was available in 68 subjects (median: 23 mo, range: 1 to 254); cancer-related death occurred in 63%, and an additional 15% had recurrent or metastatic disease at last follow-up. Disease-specific survival was shorter in epithelioid leiomyosarcoma patients (median: 44 mo; 35% at 5-y) than in a matched cohort of nonepithelioid leiomyosarcoma (median: 55 mo; 46% at 5-y) (P=0.03). Three epithelioid smooth muscle tumors of unknown malignant potential were evaluated, all <5 cm in size and with atypia and/or irregular borders but mitotic count below the threshold for malignancy. Two of these had follow-up available, which was uneventful. Of 142 consecutive leiomyomas assessed, none had epithelioid morphology as defined. Epithelioid leiomyosarcoma is an aggressive neoplasm, sometimes with a remarkably low mitotic count. In the setting of an epithelioid smooth muscle tumor of the uterus, we postulate that the diagnosis of malignancy is made in the presence of ≥2 of the following: moderate or severe atypia, ≥4 mitoses/2.4 mm2 and tumor cell necrosis. In their absence, the finding of tumor size ≥5 cm, vascular invasion, infiltrative edges or atypical mitoses should be treated with caution, and designation as of at least uncertain malignant potential is warranted.

Adoptive Cell Transfer of Allogeneic Epstein-Barr Virus-Specific T Lymphocytes for Treatment of Refractory EBV-Associated Posttransplant Smooth Muscle Tumors: A Case Report.

Posttransplant smooth muscle tumors (PTSMTs) are rare Epstein-Barr virus (EBV)-associated neoplasms, mostly occurring after solid organ transplantation. Current therapeutic strategies include surgery and reduction of immunosuppressive medication. We describe for the first time a novel treatment approach for PTSMT by adoptive cell transfer (ACT) of EBV-specific T cells to a 20-year-old patient with a medical history of cardiac transplantation, posttransplant lymphoproliferative disease, and multilocular PTSMT. During ACT, mild cytokine release syndrome occurred, while no unexpected safety signals were recorded. We observed in vivo expansion of EBV-specific T cells and reduction of EBV viremia. Best response was stable disease after 4 months with reduction of EBV viremia and normalization of lactate dehydrogenase levels. ACT with EBV-specific T cells may be a safe and efficacious therapeutic option for PTSMT that warrants further exploration.

Epstein-Barr Virus+ Smooth Muscle Tumors as Manifestation of Primary Immunodeficiency Disorders.

Epstein-Barr virus positive (EBV+) smooth muscle tumors (SMTs) constitute a very rare oncological entity. They usually develop in the context of secondary immunodeficiency caused by human immunodeficiency virus infection or immunosuppressive treatment after solid organ transplantation. However, in a small fraction of predominantly pediatric patients, EBV+ SMTs may occur in patients with primary immunodeficiency disorders (PIDs), such as GATA2 and CARMIL2 deficiency. In secondary immunodeficiencies and when the underlying condition can not be cured, the treatment of EBV+ SMTs is based on surgery in combination with antiretroviral and reduced or altered immunosuppressive pharmacotherapy, respectively. Importantly, without definitive reconstitution of cellular immunity, long-term survival is poor. This is particularly relevant for patients with EBV+ SMTs on the basis of PIDs. Recently, allogeneic hematopoietic stem cell transplantation resulted in cure of immunodeficiency and EBV+ SMTs in a GATA2-deficient patient. We propose that in the absence of secondary immunodeficiency disorders patients presenting with EBV+ SMTs should be thoroughly evaluated for PIDs. Allogeneic hematopoietic stem cell transplantation should be taken into consideration, ideally in the setting of a prospective clinical trial.

Lacrimal Sac Smooth Muscle Tumor of Uncertain Malignant Potential.

A 13-year-old male presented with recurrent left nasolacrimal duct obstruction following endoscopic dacryocystorhinostomy 4 years prior at an outside institution. The past medical history was significant for stage IV neuroblastoma, diagnosed at age 2, requiring surgical resection, induction chemotherapy, autologous bone marrow transplantation and radiation, currently in remission. Preoperative CT scan demonstrated a 2 cm ovoid mass centered in the left lacrimal fossa, consistent with dacryocystocele; however, a solid tumor could not be ruled out. Subsequent surgical exploration of the lacrimal sac revealed a friable, solid mass filling the lacrimal sac, and extending into the duct. The mass was grossly resected with preservation of the lacrimal drainage system and placement of indwelling silicone stents. Histopathology confirmed the diagnosis of smooth muscle tumor of uncertain malignant potential. The patient remained free of epiphora and showed no clinical or radiographic evidence of recurrence at 6 months of follow up.

Epstein-Barr virus-associated smooth muscle tumor of the cavernous sinus: a delayed complication of allogenic peripheral blood stem cell transplantation: case report.

Epstein-Barr virus (EBV)-associated smooth muscle tumors (SMTs) have recently been associated with primary and secondary immunodeficiencies. They are broadly divided into 3 subgroups: HIV-related, posttransplant, and congenital immunodeficiency. Subsequent to organ transplantation and acquired immunosuppression, a few cases of EBV-associated SMTs have been described in the liver, respiratory tract, and gastrointestinal system. To the authors' knowledge, intracranial involvement after peripheral blood stem cell transplantation has never been reported previously. The authors describe the case of a 65-year-old woman who presented with recent-onset painful ophthalmoplegia. She had a prior history of acute myelogenous leukemia requiring allogenic peripheral blood stem cell transplantation 2 years earlier, but she was in a remission phase. Imaging revealed a T1/T2 isointense, homogeneously enhancing lesion of the left cavernous sinus. A presumptive diagnosis of Tolosa-Hunt syndrome was made, and she was treated with steroids; however, her symptoms progressed quickly and repeat imaging revealed that the lesion was growing. To rule out leukemic deposits, a minimally invasive lateral orbitotomy extradural transcavernous approach was performed for biopsy sampling and debulking of the lesion. The biopsied tumor tissue was found to be infiltrative, grayish, firm, and moderately vascular. The final pathology results indicated an EBV-associated SMT of the cavernous sinus. Subsequently, the patient's steroid treatment was stopped and she had obtained partial symptomatic relief at her last follow-up visit, 3 months after surgery. EBV-associated SMT should be included in the differential diagnosis for intracranial and dural-based central nervous system lesions, especially in immunocompromised patients. Paradoxical response to steroids with worsening of symptoms is a hallmark of EBV-associated SMTs.

Uterine smooth muscle tumors of uncertain malignant potential: analysis of diagnoses and therapies illustrated by two case reports.

Uterine smooth muscle tumors of uncertain malignant potential, or STUMP, form a rare group of tumors that fall neither into the benign nor malignant categories. Two cases are reported, describing diagnosis, known prognostic factors, and therapy. In contrast to leiomyomas and leiomyosarcomas, many uncertainties still exist concerning prognosis and postoperative management of STUMP, because of their rarity. Diagnosis is usually not made preoperatively, but by postoperative anatomo-pathological examination. There are histological and immunohistochemical factors that could be associated with a worse prognosis, but scientific evidence is insufficient. Most cases show a low risk of recurrence, although individual risk is unpredictable. Recurrences mostly occur after a long disease-free interval. A conservative approach with strict long-term clinical follow-up is therefore indicated. Further research must be conducted to identify surgical procedures that have a higher risk for recurrence. After a laparoscopy, where the specimen was morcellated, the possibility of peritoneal spread and the difficulty in examining section margins, need to be taken into account. Further treatment therefore needs to be individualized.

Rare Presentations of Epstein-Barr Virus--Associated Smooth Muscle Tumor in Children.

Epstein-Barr virus (EBV) has oncogenic potential and has been implicated in the etiology of a wide range of malignancies. Certain EBV-driven neoplasms, such as smooth muscle tumors (SMTs), manifest typically in immunocompromised patients. In children, these neoplasms have been encountered in the setting of primary immune disorders, specifically severe combined and common variable immunodeficiency syndromes. Human immunodeficiency virus infection and posttransplant immunosuppression, in particular liver and kidney transplantation, likewise increase the risk in the pediatric population. The location of these neoplasms appears related to the type of immunodeficiency: in acquired immunodeficiency syndrome they are frequently located intracranially or intraspinally, whereas after transplant they usually involve the liver or lung. We report 2 distinct cases of EBV-related SMT, unique through their coassociated immunosuppressive state or location: the 1st occurred in a patient with immunodeficiency secondary to NEMO gene mutation following hematopoietic stem cell transplantation; the 2nd developed in the orbit after heart transplant.

Epstein-Barr Virus associated primary intracranial smooth muscle tumor in HIV positive patient: case report and review of the literature.

The authors report a case of HIV-positive patient with primary intracranial smooth muscle tumor Evidence of Epstein-Barr Virus (EB V) infection in this tumor is proven by in situ hybridization for EBV-encoded RNA (EBER). Review of the literature shows that the occurring of smooth muscle tumor at intracranial site is extremely rare and most cases are HIV-infected patient. It also shows an association with EBV infection.

[Primary smooth muscle tumor in the male reproductive system: a report of 5 cases and review of the literature].

OBJECTIVE: To systematically study the clinical diagnosis and treatment of smooth muscle tumor in the male reproductive system. METHODS: We analyzed the ultrasonographic features, pathological findings, treatment strategies and postoperative follow-up results of 5 male patients with smooth muscle tumor in the reproductive system, and reviewed other relevant literature. RESULTS: Compared with leiomyoma, leiomyosarcoma exhibited stronger mixed echoes than the testis at ultrasonography, typical mitotic phase (> or = 2/10 HP) of tumor cells at HE staining, and significant expressions of HIF-1alpha and Glut-1 at immunohistochemistry. No relapse was observed in the 2 cases of leiomyoma during the 10-year follow-up after simple tumor resection, nor were recurrence and metastasis in another 3 cases of leiomyosarcoma during the first year after radical surgery without combined radio- and chemo-therapy. CONCLUSION: Primary smooth muscle tumor of the male reproductive system is difficult to be diagnosed. Ultrasonography can help to preliminarily screen leiomyosarcoma. For those with possible leiomyosarcoma, preoperative MRI and intraoperative frozen sectioning examinations are recommended for the possibility of lymphatic metastasis. Postoperative radiotherapy and chemotherapy should be chosen cautiously for those confirmed with leiomyosarcoma by pathological examination.

Epstein-Barr virus-associated smooth muscle tumors in a composite tissue allograft and a pediatric liver transplant recipient.

Epstein-Barr virus (EBV) is known to establish latent infections in B-lymphocytes that can cause lymphoproliferative disorders particularly in immunocompromised patients. More recently, the development of rare EBV-associated smooth muscle tumors has been reported in transplant recipients. We herein describe 2 new cases of EBV-associated post-transplant smooth muscle tumors (EBV-PTSMT), including the first in a facial composite tissue graft recipient. Among the striking features shared by these 2 patients were their young ages, the fact that they were naïve for EBV before the transplantation, that they developed a post-transplant lymphoproliferative disorder before the diagnosis of EBV-PTSMT, and that they responded favorably to reduction of immunosuppression. Radiological and histologic features of EBV-PTSMT are shown. Finally, pathophysiology and therapeutic management of EBV-PTSMT are discussed based on a comprehensive review of the literature.

Uterine smooth muscle tumors of uncertain malignant potential: diagnostic challenges and therapeutic dilemmas. Report of 2 cases and review of the literature.

Morphologically, there exist variants of uterine smooth muscle tumors that cannot be clearly interpreted and classified as benign or malignant. Because their behavior and clinical prognosis is also uncertain, the World Health Organization has termed these "smooth muscle tumors of uncertain malignant potential" (STUMP). Herein we describe 2 cases, present a review of the literature, and highlight the diagnostic challenges and therapeutic dilemmas associated with uterine STUMP in myomectomy specimens from women who wish to maintain or enhance their fertility. The clinical course of residual STUMP remains speculative.

["STUMP" (smooth muscle tumour of uncertain malignant potential), a tumour of the uterus in pregnancy--a diagnostic and therapeutic challenge]. / "STUMP" (smooth muscle tumor of uncertain malignant potential), ein Uterustumor in der Schwangerschaft, eine diagnostische und therapeutische Herausforderung.

We present the case of a preterm birth in the 27 (th) week of gestation, probably due to a chorionamnionitis, with the coincidental finding of a STUMP (smooth muscle tumour of uncertain malignant potential). The STUMP is a rare tumour entity characterised by smooth muscle cells which is difficult to classify by means of histology. The WHO classification of mesenchymal tumours allocates STUMP as an intermediate tumour between a benign leiomyoma and a malignant leiomyosarcoma. If histological criteria of malignancy are not fulfilled because the type of necrosis is in doubt or the interpretation of mitotic figures is ambiguous and the tumour cannot reliably be classified as a leiomyoma, it is classified as a STUMP. Compared to malignant leiomyosarcoma, STUMP has a superior prognosis, but the biological potential of the tumour remains unclear; lymphogenic and haematogenic dissemination seems possible even after a long period of time. STUMP represents a challenge in diagnosis and treatment recommendations. We present the first description of a case of STUMP during pregnancy, raising the question of whether the histological finding in tumours of the uterus during pregnancy are important.

Successful medical treatment of EBV smooth muscle tumor in a renal transplant recipient.

EBV is associated with various malignancies in patients with acquired or induced immune impairment. EBV-SMT is very uncommon in immunocompromised patients, and a kidney localization has been described only anecdotally. We report the case of a 17-yr-old kidney transplant recipient diagnosed as having an EBV-SMT inside the renal graft, which was successfully managed by minimizing isolated immunosuppression.

Anti-EGFR antibody efficiently and specifically inhibits human TSC2-/- smooth muscle cell proliferation. Possible treatment options for TSC and LAM.

BACKGROUND: Tuberous sclerosis complex (TSC), a tumor syndrome caused by mutations in TSC1 or TSC2 genes, is characterized by the development of hamartomas. We previously isolated, from an angiomyolipoma of a TSC2 patient, a homogenous population of smooth muscle-like cells (TSC2(-/-) ASM cells) that have a mutation in the TSC2 gene as well as TSC2 loss of heterozygosity (LOH) and consequently, do not produce the TSC2 gene product, tuberin. TSC2(-/-) ASM cell proliferation is EGF-dependent. METHODS AND FINDINGS: Effects of EGF on proliferation of TSC2(-/-) ASM cells and TSC2(-/-) ASM cells transfected with TSC2 gene were determined. In contrast to TSC2(-/-) ASM cells, growth of TSC2-transfected cells was not dependent on EGF. Moreover, phosphorylation of Akt, PTEN, Erk and S6 was significantly decreased. EGF is a proliferative factor of TSC2(-/-) ASM cells. Exposure of TSC2(-/-) ASM cells to anti-EGFR antibodies significantly inhibited their proliferation, reverted reactivity to HMB45 antibody, a marker of TSC2(-/-) cell phenotype, and inhibited constitutive phosphorylation of S6 and ERK. Exposure of TSC2(-/-) ASM cells to rapamycin reduced the proliferation rate, but only when added at plating time. Although rapamycin efficiently inhibited S6 phosphorylation, it was less efficient than anti-EGFR antibody in reverting HMB45 reactivity and blocking ERK phosphorylation. In TSC2(-/-) ASM cells specific PI3K inhibitors (e.g. LY294002, wortmannin) and Akt1 siRNA had little effect on S6 and ERK phosphorylation. Following TSC2-gene transfection, Akt inhibitor sensitivity was observed. CONCLUSION: Our results show that an EGF independent pathway is more important than that involving IGF-I for growth and survival of TSC(-/-) ASM cells, and such EGF-dependency is the result of the lack of tuberin.

Multifocal Epstein-Barr virus-associated smooth muscle tumor in adults with AIDS: case report and review of the literature.

OBJECTIVES: The aim of this study was to provide a systematic review of Epstein-Barr virus-associated smooth muscle tumors (EBV-SMT) in human immunodeficiency virus (HIV)-infected adults, focusing on clinical and histopathologic features and outcome. METHODS: A literature search was performed using Medline, Embase and the Cochrane Library. RESULTS: We reviewed 35 cases including our case of a patient with a progressive multifocal EBV-SMT. Patients were mainly men (n = 24) with a mean age of 35.5 years. Median CD4 count was 21/mm(3). Main locations were brain (n = 12), liver (n = 8), spinal cord (n = 7) and adrenal gland (n = 6). The tumors were multifocal in 34% of cases, whereas analysis of clonality showed different clones in tumors from different sites. Treatment included removal surgery in 17 cases and/or radiotherapy in 9 and therapeutic abstention in 4. Mean follow-up after diagnosis was 12.3 months. Nine patients died during this period essentially from opportunistic infection and only 2 from the disease. CONCLUSION: EBV-SMT should be added to the list of virally induced tumors in severely immunocompromised HIV-infected adults. Multifocality of independent tumor clones, especially in liver, brain, spinal cord and adrenal gland, and a slow disease progression seem to be the key features of these tumors, the treatment of which remains poorly defined.

Expression of p16 protein in patients with uterine smooth muscle tumors: an immunohistochemical analysis.

OBJECTIVE: The loss of cell cycle control is a critical step in the development of neoplasia. The p16 protein has been identified as a tumor suppressor protein, which binds specifically to the cyclin-dependent kinase CDK-4, inhibiting the catalytic activity of the CDK4-cyclin D complex, and thereby acts as a negative cell cycle regulator. In the present study, we compared the expression of p16 protein in cases with leiomyoma, uterine smooth muscle tumor of uncertain malignant potential (STUMP), and leiomyosarcoma (LMS). METHODS: P16 expression was investigated by immunohistochemistry from paraffin-embedded tissue in 26 patients with leiomyoma, in 24 patients with STUMP, and in 21 patients with LMS. RESULTS: P16 was expressed in 12% of leiomyomas, in 21% of STUMP, and in 57% of LMS. A statistically significant difference regarding the frequency of p16 protein expression was observed between LMS and STUMP (P < 0.05) as well as between LMS and leiomyoma (P < 0.05), but not between STUMP and leiomyoma (P > 0.05). Likewise, the staining intensity did significantly differ between LMS and leiomyoma and between LMS and STUMP (P < 0.05), but no statistical significant difference was observed between STUMP and leiomyoma (P > 0.05). No statistically significant correlation between p16 expression and clinical stage, age, vascular space involvement, and recurrence disease could be found in patients with LMS (P > 0.05). Additionally, the overall survival did not significantly differ between p16-positive and p16-negative cases (P > 0.05). CONCLUSIONS: We found that p16 was more frequently and more strongly expressed in LMS compared to STUMP and leiomyoma. We therefore concluded that p16 might play an important role in sarcomagenesis. Furthermore, p16 might be a useful immunohistochemical marker, which could help to distinguish cases of smooth muscle tumors in which histologic features are ambiguous or borderline, but the use of p16 in a diagnostic setting should await further clinical studies and clarification of the mechanisms.

Bcl-2 receptor expression in patients with uterine smooth muscle tumors: an immunohistochemical analysis comparing leiomyoma, uterine smooth muscle tumor of uncertain malignant potential, and leiomyosarcoma.

OBJECTIVE: Bcl-2 protein is an apoptosis-inhibiting gene product that prevents the normal course of apoptotic cell death in a variety of cells. Additionally, bcl-2 can promote cell replication by reducing the requirement for growth factors. This protein seems, therefore, to play an important role in the growth of tumors. Our aim was to investigate the different expression of bcl-2 in uterine leiomyomas, smooth muscle tumors of uncertain malignant potential (STUMP), and leiomyosarcomas (LMS). Furthermore, the correlation between bcl-2 expression and various clinicopathologic parameters in leiomyosarcomas was assessed to evaluate its prognostic value. METHODS: This study included 26 cases of leiomyoma, 22 cases of STUMP, and 21 cases of LMS of the uterus. Bcl-2 expression was investigated by immunohistochemistry from paraffin-embedded tissue. The immunohistochemical findings were compared and correlated with different clinicopathologic parameters. Clinical information, including follow-up data, was obtained from the database of the Department of Gynecology and Obstetrics. RESULTS: Bcl-2 was present in 12 of 21 LMS, eight of 22 STUMP, and 20 of 25 leiomyomas. Significant differences regarding the frequency of bcl-2 expression and the staining intensity were observed between LMS and leiomyoma as well as between STUMP and leiomyoma (P <.05) but not between LMS and STUMP (P >.05). Regarding the outcome of uterine LMS, patients with bcl-2 positive tumors showed less vascular space involvement and longer overall survival (P <.05). CONCLUSION: Bcl-2 was expressed more frequently and more strongly in leiomyomas compared with LMS and STUMP. Regarding the outcome of uterine LMS, patients with bcl-2-positive tumors showed less vascular space involvement and longer overall survival. The stronger bcl-2 expression in benign leiomyomas and the better clinical outcome of bcl-2-positive LMS indicate that this protein seems to act as a good prognostic factor. Further studies including larger numbers of patients are necessary to establish bcl-2 as a routine marker for improved prognosis in malignant uterine smooth muscle tumors.