cyclin-d1 and Leiomyosarcoma

Diagnostic criteria, biological behavior, and treatment approaches of leiomyosarcomas (LMS) may differ according to the origin of the tumor. This is important in terms of patient's management, especially in tumors located in the peritoneum and retroperitoneal sites. In our study, we aimed to demonstrate the immunophenotypic characteristics of uterine and extra-uterine LMS using a large antibody panel, and to determine whether they potentially play a role in the differences among these tumor groups. Between 2006 and 2018, 29 uterine and 42 extra-uterine primary LMS were included in this study. Using tissue samples taken from the areas that best represented the tumor, an immunohistochemical study was performed on the blocks prepared by tissue micro-array method with estrogen and progesterone receptor (PR), WT-1, SMA, desmin, caldesmon, calponin, p16, p53, MDM2, CDK4, bcl-2, cyclin D1, fascin, EMMPRIN, FOXM1, c-erb-B2, c-Myc, PAX8, and CD117. Staining results of uterine and extra-uterine LMS were evaluated with these 20 antibodies. In uterine LMS compared with extra-uterine LMS, estrogen receptor (48% vs. 12%), PR (62% vs. 21%), desmin (79% vs. 50%), and EMMPRIN (69% vs. 45%) staining rate was detected higher. In extra-uterine LMS, caldesmon (88% vs. 69%), c-Myc (33% vs. 10%), and cyclin D1 (52% vs. 28%) were stained higher than uterine LMS (p < 0.05). No significant staining difference was detected with other antibodies. We concluded that estrogen receptor, PR, desmin, EMMPRIN, caldesmon, c-Myc, and cyclin D1 antibodies may help to determine primary origin of the tumor in LMS cases.

Topics: Basigin; Biomarkers, Tumor; Calmodulin-Binding Proteins; Cyclin D1; Desmin; Female; Humans; Leiomyoma; Leiomyosarcoma; Receptors, Estrogen; Uterine Neoplasms

To study the morphologic features, immunophenotype and significance of expression of JAZF1-SUZ12 and YWHAE-FAM22 fusion genes in endometrial stromal sarcoma (ESS).. Fifty-three cases of ESS were retrieved and the pathologic features were reviewed. Immunohistochemical study for estrogen receptor, progesterone receptor, CD10, cyclin D1, smooth muscle actin, desmin and H-caldesmon were carried out using tissue microarray technology. Reverse transcription-polymerase chain reaction (RT-PCR) was applied for detection of expression of JAZF1-SUZ12 and YWHAE-FAM22 fusion genes in 47 cases of ESS and 12 cases of other spindle cell neoplasia in uterus (including 2 cases of undifferentiated sarcoma, 3 cases of leiomyosarcoma, 3 cases of leiomyoma, 4 cases of adenosarcoma and 2 cases of uterine tumor resembling ovarian sex cord tumor).. The 53 cases of ESS studied included 43 cases of low-grade ESS and 10 cases of high-grade ESS. As for low-grade ESS, in addition to the classic morphologic features, smooth muscle differentiation was present in 7 cases (16.3%), sex cord-like differentiation in 2 cases (4.7%), rhabdoid differentiation in 1 case (2.3%), clear cell changes in 1 case (2.3%) and schwannoma-like palisading pattern in 1 case (2.3%). As for high-grade ESS, sex cord-like differentiation (1 case), mucinous microcystic changes (1 case) and focal clear cell changes (1 case) were also observed. The expression rate of estrogen receptor, progesterone receptor, CD10, cyclin D1, smooth muscle actin, desmin and H-caldesmon was 86.0%, 81.4%, 74.4%, 2.3%, 23.3%, 23.3% and 4.7% in low-grade ESS, respectively, and was 1/10, 6/10, 6/10, 7/10, 1/10, 1/10 and 0 in high-grade ESS, respectively. RNA extraction was successful in 47 cases of ESS, including 39 cases of low-grade ESS and 8 cases of high-grade ESS. The positive rate of JAZF1-SUZ12 fusion gene was 30.8% (12/39) in low-grade ESS. The positive rate of YWHAE-FAM22 fusion gene was 12.5% (1/8) in high-grade ESS. The 14 control cases were all negative for JAZF1-SUZ12 and YWHAE-FAM22 fusion genes.. As uncommon pathologic pattern may occur in both low-grade ESS and high-grade ESS, detection of JAZF1-SUZ1 and YWHAE-FAM22 fusion genes by RT-PCR would be helpful in diagnosis and differential diagnosis of ESS, especially for those tumors which lack typical morphologic features.

Topics: 14-3-3 Proteins; Co-Repressor Proteins; Cyclin D1; DNA-Binding Proteins; Endometrial Neoplasms; Female; Humans; Leiomyosarcoma; Neoplasm Proteins; Polycomb Repressive Complex 2; Recombinant Proteins; Sarcoma, Endometrial Stromal; Tissue Array Analysis; Transcription Factors

Endometrial stromal sarcoma (ESS) characterized by YWHAE-FAM22 genetic fusion is histologically higher grade and clinically more aggressive than ESS with JAZF1-SUZ12 or equivalent genetic rearrangements, hence it is clinically important to recognize this subset of ESS. To identify diagnostic immunomarkers for this biologically defined ESS subset, we compared gene expression profiles between YWHAE-FAM22 ESS and JAZF1-rearranged ESS. These studies showed consistent upregulation of cyclin D1 in YWHAE-FAM22 ESS compared with JAZF1-SUZ12 ESS. Immunohistochemically, the high-grade round cell component of all 12 YWHAE-FAM22 ESS demonstrated diffuse (≥70%) moderate to strong nuclear cyclin D1 staining, and this diffuse positivity was not seen in 34 ESSs with JAZF1 and equivalent genetic rearrangements or in 21 low-grade ESS with no demonstrable genetic rearrangements. In a series of 243 non-ESS pure uterine mesenchymal and mixed epithelial-mesenchymal tumors, only 2 of 8 undifferentiated endometrial sarcomas with nuclear uniformity and 1 of 80 uterine leiomyosarcomas demonstrate diffuse cyclin D1 immunoreactivity. Both cyclin D1-positive undifferentiated endometrial sarcomas showed diffuse strong CD10 staining, which is consistently absent in the high-grade round cell component of YWHAE-FAM22 ESS. The low-grade spindle cell component of YWHAE-FAM22 ESS showed a spatially heterogenous cyclin D1 staining pattern that was weaker and less diffuse overall. Our findings indicate that cyclin D1 is a sensitive and specific diagnostic immunomarker for YWHAE-FAM22 ESS. When evaluating high-grade uterine sarcomas, cyclin D1 can be included in the immunohistochemical panel as an indicator of YWHAE-FAM22 ESS.

Topics: Biomarkers, Tumor; Cell Nucleus; Cyclin D1; Endometrial Neoplasms; Female; Gene Rearrangement; Humans; In Situ Hybridization, Fluorescence; Leiomyosarcoma; Neoplasm Proteins; Oncogene Proteins, Fusion; Polycomb Repressive Complex 2; Sarcoma, Endometrial Stromal; Tissue Array Analysis; Transcription Factors; Up-Regulation

The aim of this study was to investigate the expression of cell cycle regulators p53, p16, cyclin-D1, and retinoblastoma (Rb) gene protein in leiomyosarcoma of the peripheral soft in order to identify expression profiles potentially useful for clinical prognostic purposes.. A tissue microarray representing 70 localized leiomyosarcomas of the limbs and limb girdles was created with 3 representative cores from each tumor. Immunohistochemical staining was performed for p53, p16, cyclin-D1, and Rb using standard techniques. Staining was scored as either absent-low (<20% of neoplastic cells) or moderate-diffuse (≥20%). Outcome analysis was performed for local recurrence-free survival (LFS), metastatic disease-free survival (MDFS), and disease-specific survival (DSS).. Kaplan-Meier analysis of survival revealed that no single alteration of the factors examined was associated with outcome, but tumors showing concomitant alteration of p16 and p53 were characterized by reduced MDFS and DSS (P = 0.01 and P < 0.001, respectively). In addition, patients who received adjuvant therapy consisting of radiotherapy alone or radiotherapy and chemotherapy had a better DSS than those receiving surgery alone or surgery and chemotherapy (P = 0.05). In multivariate analysis, altered p16/p53 remained the only parameter predictive of MDFS and DSS (P = 0.048, hazard ratio [HR] = 2.488, 95% confidence interval [95% CI] 1.006-5.116; P = 0.043, HR = 2.498, 95% CI 1.029-5.909, respectively).. Accumulation of cell cycle alterations represents a prognostic indicator in localized soft tissue leiomyosarcoma, and in particular altered p16/p53 expression is associated with an unfavorable prognosis. This may help the clinical management of patients with leiomyosarcomas.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p16; Female; G1 Phase; Humans; Immunoenzyme Techniques; Leiomyosarcoma; Male; Middle Aged; Neoplasm Proteins; Neoplasm Staging; Prognosis; Retinoblastoma Protein; S Phase; Soft Tissue Neoplasms; Tissue Array Analysis; Tumor Suppressor Protein p53

Second nonocular malignancies develop with increased incidence in patients with hereditary retinoblastoma. Osteosarcoma is by far the most common type with an incidence of up to 50%, followed by soft tissue sarcomas. Visceral leiomyosarcoma is extremely rare and only 2 cases have been reported in the past 2 decades, one in the liver and another one in the urinary bladder, both of which developed after cyclophosphamide therapy. Here we report a case of vesical leiomyosarcoma that was diagnosed in a 49-year-old woman 47 years after the diagnosis of a hereditary retinoblastoma. The patient's retinoblastoma was treated with unilateral enucleation without adjuvant radiation or chemotherapy. We believe that this is the first report of vesical leiomyosarcoma occurring in a patient with retinoblastoma without a prior history of radiation or chemotherapy. This report is significant not only because of the rarity of vesical leiomyosarcoma as a second nonocular tumor in retinoblastoma patients, but also because of the infrequency of vesical leiomyosarcoma in general. We also investigated the potential molecular pathogenesis of the leiomyosarcoma.

Topics: Actins; Adult; Cyclin D1; Cystectomy; Desmin; Eye Neoplasms; Female; Hematuria; Humans; Hysterectomy; Leiomyosarcoma; Neoplasms, Second Primary; Ovariectomy; Retinoblastoma; Retinoblastoma Protein; Survivors; Tomography, X-Ray Computed; Tumor Suppressor Protein p53; Urinary Bladder Neoplasms

To evaluate the significance of p16, cyclin D1 and pRb expression in human soft tissue leiomyosarcoma (LMS) and the relationship among these three proteins.. 42 cases of LMS were studied for p16, cyclin D1 and pRb expression with immunohistochemical method.. The total abnormality percentage of p16, cyclin D1 and pRb expression in all 42 cases of LMS was 97.6%. The negative rate of p16 and pRb protein expression was 35.7% and 47.6% respectively, and the overexpression rate of cyclin D1 was 57.1%. Overexpression of cyclin D1 was also noticed in 55% leiomyomas. In the 20 cases of LMS which were pRb negative, 19 cases were moderately or strongly positive and one faintly positive for p16. Contrastly, in the 15 cases of LMS negative to p16, 12 cases were moderately or strongly positive and 3 cases faintly positive for pRb. Higher rates of loss of pRb protein were observed in the low-differentiated group than in the high-differentiated one.. (1) The abnormality of p16-cyclin-pRb pathway is highly related to the pathogenesis of LMS. (2) Loss of p16 or pRb and/or overexpression of cyclin D1 may be involved in the pathogenesis of LMS. (3) There is a negative reciprocity between p16 and pRb protein expression in LMS. (4) Overexpression of cyclin D1 is a common molecular alteration that may occur in the early stage. (5) Expression of pRb is inversely related to the differentiation degree of LMS. (6) The expression of the 3 proteins studied has no relation to tumor location, recurrence, invasion or metastasis.

Topics: Biomarkers, Tumor; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p16; Female; Humans; Immunohistochemistry; Leiomyosarcoma; Male; Retinoblastoma Protein