BACKGROUND: Uterine smooth muscle tumors (USMTs) constitute a group of histologic, genetic, and clinical heterogeneous tumors that include at least 6 major histologically defined tumor types: leiomyoma (ULM), mitotically active leiomyoma (MALM), cellular leiomyoma (CLM), atypical leiomyoma (ALM), uncertain malignant potential (STUMP), and leiomyosarcoma (LMS). Apart from ULM and LMS, the nature of these variants is not well defined. METHODS: A total of 167 cases of different USMT variants were collected, reviewed, and diagnostically confirmed based on the World Health Organization and Stanford schemes. These included 38 cases of LMS, 18 cases of STUMP, 42 cases of ALM, 22 cases of CLM, 7 cases of MALM, and 40 cases of ULM. Molecular analysis included selected microRNAs (miRNAs), oncogenes, and tumor suppressors that are highly relevant to USMT. RESULTS: Overall, 49% (17/35) of LMS cases and 7% (1/14) of STUMP cases died due to their USMT, but no deaths were attributed to ALM. miRNA profiling revealed that ALM and LMS shared similar miRNA signatures. P53 mutations and PTEN deletions were significantly higher in LMS, ALM, and STUMP compared with other USMT variants (P <.01). In contrast, MED12 mutations were extremely common in ULM and MALM (>74%) but were significantly less common (<15%) in CLM, ALM, STUMP, and LMS (P <.01). CONCLUSION: Six types of USMT have different gene mutation fingerprints. ALM shares many molecular alterations with LMS. Our findings suggest that ALM may be a precursor lesion of LMS or have similar genetic changes during its early stage. Cancer 2014;120:3165-77.

BACKGROUND:In urine cytology, the diagnosis of atypia is subjective and clinical management based on these results can be difficult to determine. In this study, the authors determined the percentage of atypical urine diagnoses that progressed to positive cytology or surgical pathology results over an 11-year period. METHODS: In a retrospective review of the authors' institution, 1320 atypical urine cytology diagnoses were identified in specimens from 851 patients obtained from January 2000 through December 2010. All subsequent pathology reports were reviewed to determine which patients developed positive cytology/surgical pathology diagnoses. In total, 4106 cytology and surgical pathology specimen reports were reviewed. RESULTS: At the authors' institution, 1320 of 16,299 of urine cytology specimens (8.1%) were diagnosed as atypical during the 11-year period. Overall, 271 of 1320 initial atypical urine specimens (21%) progressed to positive cytology or surgical pathology results with a mean time to progression of 155 days. Of the cases that progressed to malignancy, 118 were high-grade urothelial carcinoma and 92 were low-grade urothelial carcinoma. CONCLUSIONS: The rate of atypia in urine specimens at this institution was 8.1%. Of the specimen types, atypia was the most common in urinary diversion specimens (16%) and the least common in upper tract cytology (3.8%). When diagnosed as atypical, upper tract specimens had the highest percentage of progression to high-grade carcinoma. Therefore, the authors concluded that the diagnosis of atypia in this specimen group has higher clinical significance and should be managed more aggressively. Cancer (Cancer Cytopathol) 2013;121:387-91.

Leiomyoma with bizarre nuclei (LM-BN), is a variant of uterine smooth muscle tumor with atypical histologic features. Although some LM-BN share several significant genetic alterations with leiomyosarcoma, including p16 and p53, the underlying tumorigenesis of LM-BN remains largely unknown. As we previously reported, LM-BN can be divided into 2 subtypes, type I and type II, based on different nuclear features. Type I LM-BN have similar histologic features as uterine smooth muscle tumors with fumarate hydratase (FH) alterations. In this study, we examined FH expression and FH mutations in 77 LM-BN (40 type I cases and 37 type II cases). FH expression was examined by immunohistochemistry using S-(2-succino)-cysteine antibodies (2SC, a protein modification associated with FH inactivation and subsequent fumarate accumulation) and FH antibodies (FH gene products). Seventy-two LM-BN tumors underwent Sanger sequencing to detect FH mutations. We found that 51% (39/77) of LM-BN showed FH alterations detected by immunohistochemistry with both 2SC and FH. Mutational analysis showed that 21% (15/72) of LM-BN harbored FH gene mutations. Further analysis revealed that 85% (34/40) of those with FH alterations were type I LM-BN while 19% (7/37) were type II LM-BN. Our findings suggest that over half of histologically diagnosed LM-BN may be related to FH alterations or FH mutations and the majority of these have the characteristic histologic features of type I LM-BN.

Uterine smooth muscle tumors (USMTs) consist of a group of histologically heterogeneous and clinically diverse diseases ranging from malignant leiomyosarcoma (LMS) to benign leiomyoma (ULM). The genetic alterations in LMS are complex, with some genetic alterations present in both LMS and other atypical histologic variants of USMT. In this study, we reviewed 119 USMTs with a diagnosis of LMS, smooth muscle tumor of uncertain malignant potential, atypical leiomyomas/leiomyoma with bizarre nuclei, and cellular leiomyoma, as well as 46 ULMs and 60 myometrial controls. We selected 17 biomarkers highly relevant to LMS in 4 tumorigenic pathways including steroid hormone receptors (estrogen receptor [ER] and progesterone receptor [PR]), cell cycle/tumor suppressor genes, AKT pathway markers, and associated oncogenes. ER and PR expression was significantly lower in LMS than smooth muscle tumor of uncertain malignant potential, atypical leiomyomas/leiomyoma with bizarre nuclei, cellular leiomyoma, and ULM (P < .01). Sixty-five percent of LMSs showed complete loss of ER, and 75% of LMSs showed complete loss of PR. All cell cycle genes were differentially expressed in different types of tumor, but significant overlap was noted. More than 75% of LMSs had Ki-67 index greater than 33%, and only 5% in all other types of USMT. Expression of the selected oncogenes varied widely among different types of USMT. PR positivity and p53 had a borderline association with progression-free survival (P = .055 for PR and P = .0847 for p53). Furthermore, high PR expression was significantly associated with a longer overall survival (P = .0163, hazard ratio 0.198). Cell proliferative indices (Ki-67) and sex steroid hormone receptors were the most valuable markers in differentiating LMS from other USMT variants.

Atypical leiomyoma (ALM) is a rare variant of uterine smooth muscle tumors. Several recent studies have suggested that ALM has distinct, but also heterogeneous, histologic and molecular features, yet little is known about the biology and histogenesis of ALM. Some have even postulated whether the atypical histologic features represent true atypia or simply degenerative changes. In this study, we analyzed the cytologic features of 60 ALM cases and found that ALM could be further divided into two subtypes, type I and type II, based primarily on nuclear features. Type I ALM showed round or oval nuclei, distinct and smooth nuclear membranes, prominent nucleoli with perinucleolar halos, and open coarse chromatin. Type II ALM showed elongated or spindled nuclei, irregular nuclear membranes, pinpoint or no nucleoli, and dark smudgy chromatin. There were also architectural differences between type I and type II ALM. Type I ALM often showed diffuse atypia within the tumor while the atypia in type II ALM was patchy, surrounded by usual-type leiomyoma. The two subtypes also differed when we compared the immunohistochemical and molecular patterns. Type II tumors showed significantly higher rates of immunoreactivity for p16, p53 and HMGA2 and showed MED12 mutations more frequently than the type I counterparts. Our findings suggest that the type I and type II subtypes of ALM may arise from two different pathways. Type I tumors may be related to fumarate hydratase mutations while type II ALM appear to arise in a background of usual-type leiomyomas.