Genomic profile analysis of leiomyomas with bizarre nuclei and fumarate hydratase deficient leiomyomas: Strengths, weaknesses, and limitations of array-CGH interpretation.

A close relationship has been demonstrated between genomic complexity and clinical outcome in uterine smooth muscle tumors. We studied the genomic profiles by array-CGH of 28 fumarate hydratase deficient leiomyomas and 37 leiomyomas with bizarre nuclei (LMBN) from 64 patients. Follow-up was available for 46 patients (from three to 249 months, mean 87.3 months). All patients were alive without evidence of disease. For 51 array-CGH interpretable tumors the mean Genomic Index (GI) was 16.4 (median: 9.8; from 1 to 57.8), significantly lower than the mean GI in LMS (mean GI 51.8, p < 0.001). We described three groups: (1) a group with FH deletion (24/58) with low GI (mean GI: 11 vs. 22,4, p = 0.02), (2) a group with TP53 deletion (17/58) with higher GI (22.4 vs. 11 p = 0.02), and (3) a group without genomic events on FH or TP53 genes (17/58) (mean GI:18.3; from 1 to 57.8). Because none of these tumors recurred and none showed morphological features of LMS we concluded that GI at the cut-off of 10 was not applicable in these subtypes of LM. By integration of all those findings, a GI <10 in LMBN remains a valuable argument for benignity. Conversely, in LMBN a GI >10 or alteration in tumor suppressor genes, should not alone warrant a diagnosis of malignancy. Nine tumors were tested with Nanocind CINSARC® signature and all were classified in low risk of recurrence. We propose, based on our observations, a diagnostic approach of these challenging lesions.

Uterine smooth muscle tumors of uncertain malignant potential (STUMP): A retrospective study in a single center.

OBJECTIVE: Uterine smooth muscle tumors of uncertain malignant potential (STUMP) is a heterogeneous group of tumors with histological and biological diversity that cannot be defined as a benign leiomyoma or malignant leiomyosarcoma. The study aims to investigate the diagnostic methods, treatment management and prognosis of STUMP patients in a 13-year period. STUDY DESIGN: We retrospectively reviewed the clinicopathologic information of 31 STUMP patients in Peking University People's Hospital. Statistical analyses were conducted to compare the difference of clinical characteristics between the women in myomectomy group and those in hysterectomy group. RESULTS: The most common clinical presentation was menstrual disorder. The tumors were mainly manifested as hypoechoic, non-cystic nodules with low blood flow signal by pelvic doppler ultrasonography. Most tumors carried Ki-67 index ranging from 10% to 30%. Immunohistochemical markers such as ER, PR, p16 and Desmin was positively expressed in tumors. At the first operation, 21 cases underwent myomectomy and 10 cases underwent hysterectomy. The patients in myomectomy group were younger than those in hysterectomy group. In the follow-up period, two cases experienced a relapse in the form of STUMP within 36 months. One case died of cardiovascular accident while the other cases were alive. Six of 21 women in myomectomy group desired pregnancy and two healthy live births were recorded. CONCLUSION: The diagnosis of STUMP primarily depends on histopathologic features. Fertility-sparing surgery may be a treatment selection for patients with fertility desire. Patients with STUMP, especially in the case of myomectomy, should be informed of recurrence risk and monitored closely.

Hereditary leiomyomatosis and renal cell carcinoma syndrome associated uterine smooth muscle tumors: Bridging morphology and clinical screening.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant familial syndrome that results from germline mutation in the fumarate hydratase (FH) gene and is associated with an increased risk for smooth muscle tumors of the uterus and skin and renal cell carcinoma. HLRCC associated RCC develop in up to 25% of patients, often presenting in the fourth decade and are high stage, aggressive tumors with poor clinical outcome. Most women with HLRCC develop large and bulky uterine smooth muscle tumors (USMT) in the second to third decade, thus presenting the ideal opportunity for early detection of HLCC to enable timely implementation of surveillance for their RCC risk. However, the concept of screening women with USMT for HLRCC is challenging given that HLRCC is rare but USMT are common. In addition, FH deficiency in USMT can also result from sporadic FH gene aberrations, unrelated to HLRCC, further complicating any potential screening process. Recent studies show that tumor morphology can be used to identify FH deficiency in USMT and thereby direct patients to formal genetic counseling. The low magnification clues of staghorn shaped blood vessels and alveolar pattern should prompt for high magnification examination for eosinophilic cytoplasmic inclusions and oval nuclei containing prominent eosinophilic macronucleoli surrounded by a halo. Additional clues include Schwannoma-like growth and chain-like distribution of the tumor cells. Although immunostains exist for FH and 2SC, their role is limited in the presence of well-developed FH deficient morphology. The prevalence of germline pathogenic mutation in FH among women with USMT with FH deficient morphology is as high as 50% in some studies, with somatic FH mutation accounting for the remainder. Therefore, morphologic evaluation of USMT for features of FH deficiency can serve as a screening tool for HLRCC syndrome by triaging patients to formal hereditary risk assessment.

Neck subcutaneous nodule as first metastasis from broad ligament leiomyosarcoma: a case report and review of literature.

BACKGROUND: Leiomyosarcoma usually develops in the myometrium and is characterized by a high recurrence rate, frequent hematogenous dissemination, and poor prognosis. Metastasis is usually to lungs, liver, and bone, and occasionally to the brain, but seldom to the head and neck region. Primary leiomyosarcoma very rarely arises in the broad ligament. CASE PRESENTATION: A 54-year old woman presented to the otolaryngology department with a mass in the right posterior region of the neck 4 years after surgery for a primary leiomyosarcoma of the right broad ligament. The neck mass was removed and found to be a metastatic leiomyosarcoma. Leiomyosarcoma localizations in lungs and liver were absent. Morphological examination showed both the primary and the secondary leiomyosarcomas to have features of low-grade tumors. One year after excision of the neck mass, the patient presented with tachycardia. Echocardiography detected two intracardiac nodules suggestive of metastatic tumors. Chemotherapy was administered; the disease has been stable since then. CONCLUSIONS: We report the first case of broad ligament leiomyosarcoma with the neck subcutaneous region being the first site of secondary involvement. We speculate that the Batson venous plexus might have been the pathway of dissemination.

Reasons to Reconsider Risk Associated With Power Morcellation of Uterine Fibroids.

Our insights into the molecular pathogenesis of uterine smooth muscle tumors have improved significantly. Accordingly, in the present review, we advocate a more refined risk assessment for patients considering surgical removal of fibroids or hysterectomy, respectively, requiring morcellation. For this procedure, the risk estimates given for the iatrogenic spread of a previously unexpected malignancy considerably vary among different studies. Nearly all previous studies conducted retrospectively refer to the risk of a patient having an unexpected malignancy at the time of surgery. We feel that, more appropriately, risk should refer to the number of tumors because, as a rule, every single nodule arises independently and, thus, carries an independent risk of being malignant or not. Furthermore, whether so-called parasitic fibroids carry an underestimated risk of stepwise malignant transformation is discussed.

Examination of the use of needle biopsy to perform laparoscopic surgery safely on uterine smooth muscle tumors.

The warning statement issued by the United States Food and Drug Administration against the use of laparoscopic power morcellators prompted a discussion about the methods of preoperative diagnosis of uterine myometrial lesions. Since 1994, transcervical needle biopsies have been performed to differentiate between uterine leiomyomas and leiomyosarcomas. Needle biopsies are also useful for performing laparoscopic surgery on uterine smooth muscle tumors with histopathological safety. In the present study, data from hematoxylin and eosin (HE)-stained specimens obtained by transcervical needle biopsies from 331 patients with smooth muscle tumors and high intensity regions on T1 weighted images (WI) and/or T2WI from magnetic resonance imaging (MRI) scans were retrospectively examined. From a total of 10 patients with moderate or severe cytological atypia, 4 exhibited smooth muscle tumors of uncertain malignant potential and 6 exhibited leiomyosarcomas. The final diagnosis in 3 patients with ≥10 mitotic figures/high-power field was leiomyosarcoma. A total of 5 patients with coagulative tumor cell necrosis exhibited final diagnoses of leiomyosarcoma. Patients without cytological atypia, mitotic figures or coagulative tumor cell necrosis were not diagnosed with either leiomyosarcomas or smooth muscle tumors of uncertain malignant potential. The present study revealed that laparoscopic surgery is safe when HE-stained specimens obtained by transcervical needle biopsy from areas of high intensity on an MRI scan are negative for all three criteria assessed-cytological atypia, mitotic figures and coagulative tumor cell necrosis.

Atypical Uterine Smooth Muscle Tumors: A Retrospective Evaluation of Clinical and Pathologic Features.

BACKGROUND: Clinical characteristics combined with new biomarkers help discriminate between atypical uterine smooth muscle tumors (AUSMT) and leiomyosarcomas (LMS). PATIENTS AND METHODS: We retrospectively collected a series of leiomyomas (LM), AUSMT, and LMS. Estrogen receptors (ER), progesterone receptors (PR), p16, Ki-67, and p53 expression were assessed by immunohistochemistry. For AUSMT patients, immunohistochemistry evaluations were performed at the time of diagnosis and at recurrences. RESULTS: A total of 27 cases of AUSMT, 22 LM, and 31 LMS were identified. The expression of ER and PR decreased from LM to LMS (ER+: LM 95.5%, AUSMT 88.9%, LMS 41.9%, p < 0.001; PR+: LM 100%, AUSMT 88.9%, LMS 38.2%, p = 0.002). By contrast, p16 and p53 expression increased (p16+: LM 4.5%, AUSMT 40.7%, LMS 45.2%, p = 0.004; p53: LM 9.1%, AUSMT 33.3%, LMS 58.1%, p = 0.001). At a median follow-up of 33.47 months, 40.7% of patients with AUSMT experienced recurrent disease, 6 patients relapsed as AUSMT and 5 as LMS. In univariate analysis was observed that ER status (p = 0.027) and p53 expression (p = 0.015) predicted risk of relapse. CONCLUSIONS: Treatment of AUSMT should be centralized in dedicated centers. International collaborations are needed to optimize research strategy, which may lead to the identification of new useful biomarkers and to improvement in the clinical management of this rare disease.

The role of fibroblast growth factor 2 in patients with uterine smooth muscle tumors: an immunohistochemical study.

OBJECTIVE: Fibroblast growth factor 2 (FGF-2) is considered to be a potent stimulator of angiogenesis and seems therefore to play an important role in the growth of tumors. We compared the immunohistochemical profile of FGF-2 in patients with uterine leiomyomas, smooth muscle tumors of uncertain malignant potential (STUMP) and leiomyosarcoma (LMS). Furthermore, we tried to clarify the prognostic role of FGF-2 in uterine leiomyosarcoma. STUDY DESIGN: FGF-2 expression was investigated by immunohistochemistry from paraffin-embedded tissue in 26 patients with leiomyoma, in 24 cases with STUMP and in 21 patients with LMS. The immunohistochemical profile of these 3 tumor entities was compared and regarding LMS correlated with different clinicopathologic parameters. RESULTS: FGF-2 was expressed in 85% of leiomyomas, in 88% of STUMP and in 57% of LMS. Significant differences regarding the frequency of FGF-2 expression were observed between leiomyoma and LMS as well as between STUMP and LMS (p<0.05). In uterine LMS FGF-2 expression was statistically more frequent in cases with high histological grade (p<0.05). Furthermore, FGF-2 positive tumors demonstrated a statistically significant higher rate of recurrence disease and tumor progression (p=0.005). Disease free as well as overall survival was significantly shortened in patients with FGF-2 positive compared to FGF-2 negative tumors (p<0.05). CONCLUSION: The significant correlation between FGF-2 expression and high histological grade indicates that FGF-2 might work as a negative predictive factor. Higher rates of recurrence disease as well as shortened disease free and overall survival among FGF-2 positive LMS support the potential role as prognosticator for poor clinical outcome.

Patterns of Chromosomal Abnormalities that Can Improve Diagnosis of Uterine Smooth Muscle Tumors.

BACKGROUND/AIM: Compared to leiomyomas, smooth muscle tumors of uncertain malignant potential (STUMP), and leiomyosarcomas (LMS) originating from the Muellerian duct are very rare. Their molecular pathogenesis remains poorly understood. The present article aims at performing genetic analyses of these tumors that may help assist histopathological examination. MATERIALS AND METHODS: Ten tumors (four STUMP and six LMS) were investigated by copy number arrays. RESULTS: Two tumors, both classified as STUMP were shown to carry MED12 mutations with one of them presenting with a detectable copy number alteration. All other tumors had multiple copy number changes with a clear predominance of losses. Five chromosomal arms (1p, 13q, 14q, 16q, 22q) were affected by overlapping lost segments in at least four tumors including two cases with biallelic losses of the retinoblastoma gene locus. CONCLUSION: Besides the general presence of copy number alterations and particular genetic alterations, heterogeneity and ongoing karyotypic evolution indicate malignancy or approaching malignancy.

Value of counting positive PHH3 cells in the diagnosis of uterine smooth muscle tumors.

The diagnosis of uterine smooth muscle tumors including leiomyosarcomas (LMS), smooth muscle tumors of uncertain malignant potential (STUMP), bizarre (atypical) leiomyoma (BLM), mitotically active leiomyoma (MAL) and leiomyoma (LM) depends on a combination of microscopic features, such as mitoses, cytologic atypia, and coagulative tumor cell necrosis. However, a small number of these tumors still pose difficult diagnostic challenges. The assessment of accurate mitotic figures (MF) is one of the major parameters in the proper classification of uterine smooth muscle tumors. This assessment can be hampered by the presence of increased number of apoptotic bodies or pyknotic nuclei, which frequently mimic mitoses. Phospho-histone H3 (PHH3) is a recently described immunomarker specific for cells undergoing mitoses. In our study, we collected 132 cases of uterine smooth muscle tumors, including 26 LMSs, 16 STUMPs, 30 BLMs, 30 MALs and 30 LMs. We used mitosis specific marker PHH3 to count mitotic indexes (MI) of uterine smooth muscle tumors and compared with the mitotic indexes of hematoxylin and eosin (H&E). There is a positive correlation with the number of mitotic figures in H&E-stained sections and PHH3-stained sections (r=0.944, P<0.05). The ratio of PHH3-MI to H&E-MI has no statistically significant difference in each group except for LMs (P>0.05). The counting value of PHH3 in LMSs have significantly higher than STUMPs, BLMs, MALs and LMs (P<0.001) and the counting value of PHH3 is 1.5±0.5 times of the number of mitotic indexes in H&E. To conclude, our results show that counting PHH3 is a useful index in the diagnosis of uterine smooth muscle tumors and it can provide a more accurate index instead of the time-honored mitotic figure counts at a certain ratio.