Epigenomic tensor predicts disease subtypes and reveals constrained tumor evolution.

Understanding the epigenomic evolution and specificity of disease subtypes from complex patient data remains a major biomedical problem. We here present DeCET (decomposition and classification of epigenomic tensors), an integrative computational approach for simultaneously analyzing hierarchical heterogeneous data, to identify robust epigenomic differences among tissue types, differentiation states, and disease subtypes. Applying DeCET to our own data from 21 uterine benign tumor (leiomyoma) patients identifies distinct epigenomic features discriminating normal myometrium and leiomyoma subtypes. Leiomyomas possess preponderant alterations in distal enhancers and long-range histone modifications confined to chromatin contact domains that constrain the evolution of pathological epigenomes. Moreover, we demonstrate the power and advantage of DeCET on multiple publicly available epigenomic datasets representing different cancers and cellular states. Epigenomic features extracted by DeCET can thus help improve our understanding of disease states, cellular development, and differentiation, thereby facilitating future therapeutic, diagnostic, and prognostic strategies.

Significance of postmenopausal uterine leiomyomas: Focus on variants.

AIM: To investigate the differences in leiomyoma pathophysiology by patient age at the time of surgery and the possible significance of postmenopausal uterine leiomyomas, particularly variants. METHODS: We retrospectively reviewed data from 471 patients who underwent surgery for uterine leiomyomas and evaluated their clinical data. RESULTS: Overall, 441 (93.4%) women were premenopausal and 30 (6.4%) were postmenopausal. There were no differences in the frequency of the coexistence of ovarian steroid-dependent diseases among age groups. Common histopathological features were observed in most cases despite menopausal status; however, the incidence of variants among postmenopausal patients was high compared to that among premenopausal women (23.3% [7/30] vs 3.2% [14/441], respectively). Among the variant leiomyomas in postmenopausal patients, lipoleiomyomas comprised six. CONCLUSION: Although progesterone is known to play a vital role in promoting leiomyoma growth, it reportedly performs dual actions and does not always stimulate leiomyoma growth. Our study may support the idea that the dual action of progesterone is the primary reason for the surgical treatment required for uterine leiomyomas in the postmenopausal period. We also found that lipoleiomyoma might be the most common uterine leiomyoma variant requiring surgical treatment among postmenopausal women. Thus, we must consider the diagnosis of uterine lipoleiomyoma in postmenopausal women with uterine leiomyomas.

Benign and malignant pathology of the uterus.

The diagnosis of a uterine myoma size and location can be very precise when a 3D sonograph and knowledge are available. The majority of fibroids are asymptomatic, and expectant management is recommended. In young patients, fibroids cause infertility and in middle-aged women, abnormal uterine bleedings. Laparoscopic myomectomy is the preferred way of surgery for IM and SS fibroids, versus hysteroscopy for SM fibroids. In both cases, the size, number of fibroids and the surgeon's experience determine the limitations of the MIGS. Medical treatments provide only temporary tumor reduction and symptom alleviation. Leiomyosarcoma risk is higher in older women usually carrying fibroids larger than 8 cm. There are no other pathognomonic parameters ruling out a sarcoma. In case of suspected fibroid malignancy, the best treatment option is laparotomy and total hysterectomy. Myomectomy complications can be reduced when MIGS is performed by a surgeon with proper training and experience.

Perianal leiomyoma / Leiomioma de localização perianal

Abstract Leiomyomas are smooth muscle tumors and may occur in places where these fibers are present, while the anorectal location is rare. They are commonly incidental imaging findings and in most cases, patients are asymptomatic. The therapeutic recommendation is tumor resection and postoperative follow-up. Case report: a 38-year-old Black woman had, one year ago, a swelling in perianal right region, which showed slow and progressive growth. She denied bowel habit alterations, local pain, hematochezia, or tenesmus. Proctologic examination showed a fibroelastic, regular, mobile, painless nodule measuring 10 cm at its largest diameter in the right perianal region, next to the anal verge. The soft tissue ultrasound image identified a solid, hypoechoic, and discreetly vascularized nodule in the perianal, superficial right gluteal region that did not reach the adjacent muscles. A complete resection of perineal tumor was carried out in the ventral position. Histological and immunohistochemical analyses disclosed a leiomyoma with a positive finding for actin smooth muscle and negative for desmin. She is currently asymptomatic and undergoing outpatient follow-up.

Resumo Os leiomiomas são tumores da musculatura lisa podendo ocorrer nos locais onde essas fibras estão presentes, sendo rara a localização anorretal. Na maioria dos casos os pacientes são assintomáticos, sendo comumente achados de exame de imagem. A recomendação terapêutica é a ressecção tumoral e o seguimento pós-operatório. Relato do caso: mulher, 38 anos, negra. Há um ano, apresentou abaulamento em região perianal direita, de crescimento lento e progressivo. Negava alteração do hábito intestinal, dor local, hematoquezia, puxo ou tenesmo. Ao exame proctológico, apresentava nodulação fibroelástica, regular, móvel, indolor, com 10 cm de diâmetro em região perianal à direita, próxima à borda anal. Realizou ultrassonografia de partes moles que identificou imagem nodular, sólida, hipoecogênica e discreta vascularização em parte superficial perianal e glútea direita, não envolvendo musculatura adjacente. Foi submetida à ressecção completa do tumor via perineal, em posição ventral. O laudo histológico e imuno-histoquímico revelou leiomioma, com achado positivo para actina de músculo liso e negativo para desmina. Atualmente está assintomática, em seguimento ambulatorial.

Clinical limitations of the International Federation of Gynecology and Obstetrics (FIGO) classification of uterine fibroids.

OBJECTIVE: To determine the reproducibility of classifying uterine fibroids using the 2011 International Federation of Gynecology and Obstetrics (FIGO) staging system. METHODS: The present retrospective cohort study included patients presenting for the treatment of symptomatic uterine fibroids at the Gynecology Fibroid Clinic at Mayo Clinic, Rochester, USA, between April 1, 2013 and April 1, 2014. Magnetic resonance imaging of fibroid uteri was performed and the images were independently reviewed by two academic gynecologists and two radiologists specializing in fibroid care. Fibroid classifications assigned by each physician were compared and the significance of the variations was graded by whether they would affect surgical planning. RESULTS: There were 42 fibroids from 23 patients; only 6 (14%) fibroids had unanimous classification agreement. The majority (36 [86%]) had at least two unique answers and 4 (10%) fibroids had four unique classifications. Variations in classification were not associated with physician specialty. More than one-third of the classification discrepancies would have impacted surgical planning. CONCLUSION: FIGO fibroid classification was not consistent among four fibroid specialists. The variation was clinically significant for 36% of the fibroids. Additional validation of the FIGO fibroid classification system is needed.

The role of T1 perfusion-based classification in magnetic resonance-guided high-intensity focused ultrasound ablation of uterine fibroids.

OBJECTIVE: To comparatively evaluate the role of magnetic resonance (MR) T1 perfusion-based time-signal intensity (SI) curves of fibroid tissue and the myometrium in classification of fibroids for predicting treatment outcomes of high-intensity focused ultrasound (HIFU) treatment. METHODS: The fibroids of 74 women who underwent MR-HIFU treatment were classified into group A (time-SI curve of fibroid lower than that of the myometrium) and group B (time-SI curve of fibroid equal to or higher than that of the myometrium). Non-perfused volume (NPV) ratios immediately after treatment and fibroid volume reduction ratios and symptom severity scores (SSS) at the 6-month follow-up were retrospectively assessed. RESULTS: The immediate NPV ratios in groups A and B were 95.3 ± 6.3% (n = 62) and 63.8 ± 11% (n = 12), respectively. At the 6-month follow-up, the fibroid volume reduction ratios in groups A and B were 0.52 ± 0.14 (n = 50) and 0.07 ± 0.14 (n = 11), with the corresponding improvement in mean transformed SSS being 0.86 ± 0.14 and 0.19 ± 0.3, respectively. No serious adverse effects were reported. CONCLUSIONS: Our novel classification method could play an important role in classifying fibroids for predicting the immediate outcomes of HIFU treatment. KEY POINTS: • MRI is an important modality for outcome prediction in HIFU treatment • Patient selection is a significant factor for achieving high NPV ratio • NPV ratio is very strongly correlated with T1 perfusion-based classification • T1 perfusion-based classification is a strong predictor of treatment outcome.

Two novel classification systems for uterine fibroids and subsequent uterine reconstruction after myomectomy.

OBJECTIVE: Laparoscopic approaches are the gold standard surgical treatment for intramural and subserous fibroids, whereas submucosal myomas can be treated via hysteroscopy. Removal of intramural myomas often requires a subsequent reconstruction of the uterine wall that ranges from single- to multiple-layer sutures to complex reconstructions. Several classification systems are currently used to characterize uterine fibroids, all of which focus on the assessment of submucosal fibroids during hysteroscopic myomectomy. There are no classification systems for the comprehensive localization of fibroids or for uterine reconstruction after myomectomy. Therefore, the aim of this study was to validate a new scoring system developed by our group to classify uterine leiomyoma as well as a standardized assessment scoring system for uterine reconstruction after surgical myomectomy. METHODS/PATIENTS: To validate the uterine fibroid and uterine reconstruction classification systems, a retrospective review of 136 patients undergoing surgical myomectomy and uterine reconstruction at a single tertiary institution was performed. The age of the patient, duration of surgery, number, size, and location of excised fibroids, number of uterine incisions, level of uterine reconstruction, desire for future pregnancies, pre- and postoperative hemoglobin concentrations, duration of postoperative hospitalization, and operating surgeon were obtained by medical chart review. For each patient, a specific fibroid score and the level of uterine reconstruction were determined according to the classification systems. Correlations between the uterine fibroid and reconstruction scores, as well as between the classification scores and perioperative parameters, were analyzed. RESULTS: The newly developed classification system for uterine fibroids incorporates the number, location, and size of myomas, as well as the number of uterine incisions required for myomectomy. The uterine reconstruction scoring system comprises four levels of reconstruction, ranging from no reconstruction to advanced reconstruction. Outcomes from 136 patients showed a correlation between uterine fibroid and uterine reconstructive scores. High fibroid scores were correlated with higher levels of reconstruction. Both scoring systems showed associations with the duration of surgery, intraoperative blood loss, and days of hospitalization. CONCLUSIONS: This study presents the first scoring system for uterine fibroids that incorporates all possible fibroid locations and a standardized assessment of uterine reconstruction. Scoring systems were validated in a large cohort, and a correlation was identified between uterine fibroid and uterine reconstruction scores. In daily clinical practice, this scoring system allows a better planning of surgery, specifically of the estimated duration of surgery, blood loss, and time of hospitalization.

Follow-up study of symptomatic submucous fibroids after hysteroscopic myomectomy.

PURPOSE OF INVESTIGATION: This study aimed to estimate the effectiveness of hysteroscopic myomectomy for symptomatic submucous uterine fibroids and to identify prognostic factors for persistent or recurrent symptoms. MATERIALS AND METHODS: A total of 237 patients who underwent hysteroscopic myomectomy were divided into three groups according to the classification of the European Society for Gynaecological Endoscopy: Type 0 (n=116), Type I (n=97), and Type II (n=24). Medical records and videotape records of all patients were retrospectively reviewed. RESULTS: Improvement of symptoms was achieved in 100% of Types 0 and I, and 66.7% of Type II. The five-year cumulative symptom-free rates after hysteroscopic myomectomy were 96.7% ± 1.9%, 87.8% 6.7%, and 44.5% ± 12.7% in Types 0, I, and II, respectively. The mean symptom-free periods were 46.2 ± 2.6, 47.7 ± 2.7, and 24.7 ± 6.3 months in Types 0, I, and II, respectively. Logistic regression analysis showed that co-existence of other myomas and Type II were independent prognostic factors for recurrence of symptoms. CONCLUSION: Type I fibroids are a good indication for hysteroscopic myomectomy. In Type II, some patients feel that their symptoms improve, but this curative effect could be temporary.

Characterization of the leiomyomatous variant of myofibroblastoma: a rare subset distinct from other smooth muscle tumors of the breast.

Mammary myofibroblastoma is a benign spindle cell tumor that can show variable morphologic patterns and lines of differentiation. Myofibroblastoma belongs to a family of CD34-positive tumors with similar morphology that show a deletion of 13q14, which includes RB1 and FOXO1A genes. A subset of these tumors demonstrates distinct smooth muscle differentiation. We aimed to characterize 4 cases of the leiomyomatous variant of myofibroblastoma arising in the breast by clinicopathological, immunohistochemical, and molecular means. All 4 examples arose in women aged 41 to 62 years (median, 46.5 years). Tumors ranged in size from 1.7 to 2.5 cm (median, 2.2 cm). Morphologically, all tumors were characterized by bundles of smooth muscle cells with elongated cigar-shaped nuclei and eosinophilic cytoplasm. All 4 tumors showed diffuse positive staining with desmin, caldesmon, smooth muscle actin, estrogen receptor, and Bcl-2. CD34 staining was diffusely positive in 2 cases, was weak and patchy in 1 case, and was negative in 1 case. Two (50%) of 4 tumors showed deletion of RB1 by fluorescence in situ hybridization. Loss of Rb staining was seen in 1 tumor with RB1 deletion by fluorescence in situ hybridization, whereas intact Rb staining was observed in 1 nondeleted case studied. In conclusion, this rare variant of myofibroblastoma is a distinct subgroup of tumors among an already uncommon category of (smooth muscle) breast tumors. Some reported examples of "parenchymal leiomyoma" may represent the leiomyomatous variant of myofibroblastoma.

Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers.

Uterine leiomyomas are common benign smooth muscle tumors that impose a major burden on women's health. Recent sequencing studies have revealed recurrent and mutually exclusive mutations in leiomyomas, suggesting the involvement of molecularly distinct pathways. In this study, we explored transcriptional differences among leiomyomas harboring different genetic drivers, including high mobility group AT-hook 2 (HMGA2) rearrangements, mediator complex subunit 12 (MED12) mutations, biallelic inactivation of fumarate hydratase (FH), and collagen, type IV, alpha 5 and collagen, type IV, alpha 6 (COL4A5-COL4A6) deletions. We also explored the transcriptional consequences of 7q22, 22q, and 1p deletions, aiming to identify possible target genes. We investigated 94 leiomyomas and 60 corresponding myometrial tissues using exon arrays, whole genome sequencing, and SNP arrays. This integrative approach revealed subtype-specific expression changes in key driver pathways, including Wnt/ß-catenin, Prolactin, and insulin-like growth factor (IGF)1 signaling. Leiomyomas with HMGA2 aberrations displayed highly significant up-regulation of the proto-oncogene pleomorphic adenoma gene 1 (PLAG1), suggesting that HMGA2 promotes tumorigenesis through PLAG1 activation. This was supported by the identification of genetic PLAG1 alterations resulting in expression signatures as seen in leiomyomas with HMGA2 aberrations. RAD51 paralog B (RAD51B), the preferential translocation partner of HMGA2, was up-regulated in MED12 mutant lesions, suggesting a role for this gene in the genesis of leiomyomas. FH-deficient leiomyomas were uniquely characterized by activation of nuclear factor erythroid 2-related factor 2 (NRF2) target genes, supporting the hypothesis that accumulation of fumarate leads to activation of the oncogenic transcription factor NRF2. This study emphasizes the need for molecular stratification in leiomyoma research and possibly in clinical practice as well. Further research is needed to determine whether the candidate biomarkers presented herein can provide guidance for managing the millions of patients affected by these lesions.

Multiple Primary Leiomyomas in the Right Ventricle: A Rare Form of Leiomyoma.

A case of multiple benign leiomyomas in the right ventricle of a 47-year-old woman is presented. Multiple lesions were revealed at different locations in the right ventricle; 1 lesion extended into the right pulmonary artery. Histologic examination showed benign leiomyomas arising from the tunica media of the intramyocardial vessels. Also, the primary origin of the cardiac tumors is demonstrated by the evidence that no leiomyoma was found in the genital system 30 months after the cardiac operation. To our knowledge, this is the first case report of multiple primary cardiac leiomyomas in a premenopausal woman. The midterm prognosis after complete resection is good.

[Leiomyomatous renal cell carcinoma : Controversy around a new entity]. / Leiomyomatöses Nierenzellkarzinom : Kontroverse um eine neue Tumorentität.

While clear cell, papillary and chromophobic renal cell carinoma (RCC) represent the most common malignant renal neoplasms, the evaluation and classification of rare renal carcinomas has currently come into focus. One of these is the leiomyomatous RCC, which shows morphologic similarities to clear cell RCCs, however exhibiting additional, atypical smooth muscle differentiation. We report the clinical case of a patient simultaneously presenting with leiomyomatous and papillary RCC and discuss new tumor entities of RCC.

An immunohistochemical analysis of stathmin 1 expression in uterine smooth muscle tumors: differential expression in leiomyosarcomas and leiomyomas.

The oncogenic phosphatidylinositol 3-kinase-AKT-mammlian target of rapamycin pathway (PI3K-AKT-mTOR) pathway is known to be activated in uterine smooth muscle tumors, and Stathmin 1 (STMN1) expression has been identified as a marker of PI3K-AKT-mTOR pathway activation. We hypothesized that STMN1 may have some diagnostic utility and explored how well STMN1 expression correlated with histologic classifications of uterine smooth muscle tumors into benign and malignant groupings. 84 smooth muscle tumors were assessed for STMN1 expression by immunohistochemistry. These included spindle cell leiomyosarcoma (n=32), conventional spindle cell leiomyomas (n=30), atypical (symplastic) leiomyoma (n=5), cellular leiomyoma (n=7), smooth muscle tumor of uncertain malignant potential (n=4), mitotically active leiomyomas (n=2), benign metastasizing leiomyoma (n=3), and cotyledonoid dissecting leiomyoma (n=1). All spindle cell leiomyosarcomas were positive (32/32 positive; 100%) as compared with conventional leiomyomata (11/30; 37%) (P<0.0001). The average immunohistochemical score (0-12+, reflective of intensity and extent) for leiomyosarcomas was 8.7 (±1.43) whereas the conventional leiomyomata average score was 1.6 (±1.07) (P<0.0001). This difference in scores was reflected in the patterns of expression: leiomyosarcomas were predominantly strongly and diffusely positive whereas leiomyomata were predominantly weakly, albeit diffusely positive when expression was present. The sensitivity of STMN1 expression for leiomyosarcomas was 100%. However, the specificity was found to be only 55% (CI=43-68%). The negative and positive predictive values for leiomyosarcomas were 100% and 52% respectively. The odds ratio (OR) for any STMN1 expression in predicting a spindle cell leiomyosarcoma diagnosis from this dataset was highly significant (OR=144, P=0.0006). Thirteen non-smooth muscle tumors that involved the uterus all showed at least focal STMN1 immunoreactivity. In summary, STMN1 is a highly sensitive marker for leiomyosarcoma but is suboptimally specific for diagnostic purposes. The 100% negative predictive value for leiomyosarcoma may offer some diagnostic utility in a small sample, since the absence of STMN1 immunoreactivity in a putative leiomyosarcoma is a strong argument against this diagnostic possibility.

Renal leiomyoma: a contemporary multi-institution study of an infrequent and frequently misclassified neoplasm.

Renal leiomyoma is an exceptionally rare benign mesenchymal tumor of the kidney predominantly arising in proximity of the renal capsule or pelvis. Its rarity and nonspecific clinical and imaging features may lead to radical or partial nephrectomy on the basis of preoperative suspicion of renal cell carcinoma. The diagnosis of renal leiomyoma is challenging because of the histologic overlap with lipid-poor angiomyolipoma (AML). We conducted a multi-institution study to characterize renal leiomyoma in greater detail. We collected and reviewed 24 cases diagnosed initially as renal leiomyoma in 10 institutions from North America, Canada, and Europe. Immunohistochemical expression of desmin, HMB-45, estrogen receptor (ER), progesterone receptor (PR), and cathepsin K was evaluated. Upon central review, 9 tumors were classified as renal leiomyoma, whereas the remaining were reclassified as AML (n=13), myolipoma (n=1), and medullary fibroma (n=1). All renal leiomyomas were solitary and occurred in female patients (mean age 63 y; range, 44 to 74 y). Tumor size ranged from 0.6 to 7.0 cm (mean 2.9 cm); 7 originated from the renal capsule or the subcapsular area and 1 from a large vessel in the renal sinus. All leiomyomas were diffusely positive for desmin and negative for HMB-45 and cathepsin K; 6/9 (67%) showed diffuse ER and PR expression, and 1 case showed focal ER positivity only. Renal leiomyoma should be included in the histologic differential diagnosis of solid renal masses, particularly in perimenopausal women. The main differential diagnosis is with lipid-poor AML, and cathepsin K plays a key role in distinguishing these 2 lesions.

Uterine fibroid: common features of widespread tumor (Review article).

Leiomyoma is the most frequent benign monoclonal tumor (cells behave identically in culture) of the female reproductive system. It affected almost 50% of childbearing age women, deteriorating the quality of life and may cause infertility. The unique features of this pathology is the absence of detailed understanding of pathogenic mechanisms and continuous morbidity among any age groups. Despite the huge amount of articles and studies related to leiomyoma, review pretend to depict herein actual and non-trivial information. This review assemble a versatile description of medical and biological aspects of leiomyomas. Explanation of genetic, molecular, pathophysiological mechanisms of uterine fibroid growing predetermine marked clinical symptoms of pathology. Mentioned model systems show multivariation of leiomyomas in human and animals. Review gives an opportunity analyze separate facets and collect it in one deep understanding of leiomyomas.

Genomics of uterine leiomyomas: insights from high-throughput sequencing.

Uterine leiomyomas are benign smooth-muscle tumors of extremely low malignant potential. Early work utilizing classical cytogenetics revealed that a subset of uterine leiomyomas harbor recurrent chromosomal rearrangements, such as translocations affecting the HMGA2 gene. Our understanding of the genetics of many tumor types has deepened remarkably with the emergence of next-generation sequencing technologies. Exome sequencing identified that the majority of leiomyomas display highly specific MED12 mutations. Further studies suggest that these MED12 hotspot mutations are also frequent in breast fibroadenomas, but not in other human tumors. Whole-genome sequencing showed that a subset of leiomyomas display complex chromosomal rearrangements resembling chromothripsis. These were formed in a single event of chromosomal breakage and random reassembly involving one or a limited number of chromosomes. Although most leiomyomas have been shown to arise independently, these studies also revealed that distinct nodules within a uterus may display identical genetic changes indicating a common clonal origin. A minority of leiomyomas were also found to display deletions within the COL4A5-COL4A6 genes, leading to upregulation of the adjacent gene IRS4. The findings derived from high-throughput sequencing combined with previous knowledge have led to an emerging molecular classification of leiomyomas, suggesting that there are several distinct pathogenic pathways involved in leiomyoma formation. The evidence points to at least 4 molecular subclasses: leiomyomas with MED12 mutation, FH inactivation, HMGA2 overexpression, and COL4A6-COL4A5 deletion. Elucidating the molecular pathogenesis of leiomyomas should be relevant for developing treatments for this very common disease.

Uterine leiomyomas with bizarre nuclei: a clinicopathologic study of 59 cases.

Leiomyoma with bizarre nuclei (LM-BN) is an uncommon tumor with histologic features (mononucleated or multinucleated bizarre cells that may have a diffuse distribution, prominent nucleoli, and karyorrhectic nuclei that may mimic atypical mitoses) that often causes confusion with leiomyosarcoma. Fifty-nine LM-BNs were collected from our consultation files over the years 2000 to 2011. Features recorded included patient age, therapy, tumor size, border, gross appearance, density and distribution of BN, mitotic count, karyorrhectic nuclei, prominent nucleoli, cells with conspicuous dense eosinophilic cytoplasm (rhabdoid-like), vascular changes and type of vasculature, and presence of necrosis and its nature. Follow-up information was obtained for all patients. Patients ranged in age from 25 to 75 (average 45) years (11 patients between 25 and 35 y, 20 between 36 and 45 y, 22 between 46 and 55 y, and 6 between 56 and 75 y). Forty-two underwent hysterectomy and 17 myomectomy. For 51 tumors gross findings were known. Forty (78%) had a solid white and whorled cut surface and 11 (22%) a yellow appearance. Five (10%) neoplasms showed prominent cystic degeneration, and hemorrhage and/or necrosis was seen in 9 (18%). Forty-five LM-BNs had a pushing margin with the surrounding myometrium, whereas 1 showed irregular borders. Margins could not be ascertained in the slides available in 13 cases. Twenty-eight (48%), 19 (32%), and 12 (20%) LM-BN showed low, intermediate, and high BN density. Eighteen (30%) tumors showed diffuse, 26 (44%) showed multifocal, and 15 (26%) had focal BN distribution. Mitotic counts ranged from 0 to 7/10 high-power fields (HPF) (average 1 to 2/10 HPF). Thirty-seven (63%) had <2/10 HPF, 19 (32%) had 2 to 5 mitoses/10 HPF, and in 3 tumors (5%) mitotic counts were 6, 7, and 7/10 HPF (2 with focal and 1 with diffuse BN). All but 4 LM-BNs showed karyorrhectic nuclei, striking in 12 neoplasms, mimicking atypical mitoses. Nineteen (32%) LMs had prominent eosinophilic nucleoli surrounded by a clear halo. Ischemic necrosis was detected in 21 (36%) LM-BN. Rhabdoid-like cells were noted in 24 (41%) tumors. All patients had no evidence of recurrence, ranging from 1 to 13 years (overall average 6 y; in patients with myomectomy 6.3 y with a range of 2.6 to 11 y). Our results corroborate that LM-BN is associated with a favorable outcome even in those patients only treated by myomectomy and highlights that a conservative approach can be undertaken in these patients, as many of them are of reproductive age. Because of the favorable outcome, the term LM-BN is preferable to alternative terminology including "atypical leiomyoma."

Missense mutations in exon 2 of the MED12 gene are involved in IGF-2 overexpression in uterine leiomyoma.

Uterine leiomyoma (UL), the most common benign tumour found in females, is associated with many recurrent genetic aberrations, such as translocations, interstitial deletions and specific germline mutations. Among these, mutations affecting exon 2 of the mediator complex subunit 12 (MED12) gene are commonly detected in the majority of ULs. Mutational analysis of the MED12 gene, performed on 36 UL samples, revealed that 12 leiomyomas (33.4%) exhibited heterozygous missense mutations in codon 44 of exon 2 of the MED12 gene, four leiomyomas (11.1%) showed internal in-frame deletions, and two leiomyomas (5.5%) exhibited deletions involving intron 1-exon 2 junction, which caused a predicted loss of the splice acceptor. No mutations were detected in uterine myometrium (UM) and pseudocapsule (PC) samples, including those from women with a MED12 mutation in UL. These data showed that the PC is a healthy tissue that surrounds the UL to maintain UM integrity. Analysis of insulin-like growth factor 2 (IGF-2) and collagen type IV alpha 2 (COL4A2) mRNA expression levels in the same set of ULs revealed that only those with MED12 missense mutations expressed significantly higher levels of IGF-2 mRNA. In contrast, MED12 gene status does not appear to affect mRNA expression levels of the COL4A2 gene. On the basis of this finding, we suggest that the MED12 status stratifies the ULs into two mutually exclusive pathways of leiomyoma genesis, one with IGF-2 overexpression and the other with no IGF-2 activation. The occurrence of IGF-2 overexpression could be therapeutically targeted for the non-surgical treatment of leiomyomas.

[Uterine fibroids]. / Une pathologie qui reste strictement bénigne. Fibromes utérins.

The uterine fibroid is a benign tumour. The prevalence, in all the population, is 50% for european women and 80% for black women. 30% of fibroids are symptomatic. The new FIGO classification gives 7 positions (0 to 7), submuccus (0, 1, 2), interstitial (3, 4, 5), subserous (6, 7). Diagnosis is performed by 2D and 3D ultrasound which could be associated by hysterosonography. Hysteroscopy and MRI could be proposed. Hysterectomy is the main treatment, if possible by vaginal or laparoscopic way. Conservative treatment (myomectomy) could be realized by hysteroscopic, laparoscopic way or laparotomy for patients who desire to preserve fertility. Arteries embolisation is an alternative to hysterectomy or myomectomy for patients without desire of pregnancy. Preoperative treatments by GnRH agonist or SPRM like ulipristal acetate treat anaemia, decrease the myoma volume and could modify the therapeutic strategy.

Smooth muscle tumors of soft tissue and non-uterine viscera: biology and prognosis.

Smooth muscle tumors are here considered an essentially dichotomous group composed of benign leiomyomas and malignant leiomyosarcomas. Soft tissue smooth muscle tumors with both atypia and mitotic activity are generally diagnosed leiomyosarcomas acknowledging potential for metastasis. However, lesions exist that cannot be comfortably placed in either category, and in such cases the designation 'smooth muscle tumor of uncertain biologic potential' is appropriate. The use of this category is often necessary with limited sampling, such as needle core biopsies. Benign smooth muscle tumors include smooth muscle hamartoma and angioleiomyoma. A specific category of leiomyomas are estrogen-receptor positive ones in women. These are similar to uterine leiomyomas and can occur anywhere in the abdomen and abdominal wall. Leiomyosarcomas can occur at any site, although are more frequent in the retroperitoneum and proximal extremities. They are recognized by likeness to smooth muscle cells but can undergo pleomorphic evolution ('dedifferentiation'). Presence of smooth muscle actin is nearly uniform and desmin-positivity usual. This and the lack of KIT expression separate leiomyosarcoma from GIST, an important problem in abdominal soft tissues. EBV-associated smooth muscle tumors are a specific subcategory occurring in AIDS or post-transplant patients. These tumors can have incomplete smooth muscle differentiation but show nuclear EBER as a diagnostic feature. In contrast to many other soft tissue tumors, genetics of smooth muscle tumors are poorly understood and such diagnostic testing is not yet generally applicable in this histogenetic group. Leiomyosarcomas are known to be genetically complex, often showing 'chaotic' karyotypes including aneuploidy or polyploidy, and no recurrent tumor-specific translocations have been detected.