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1.
Arch. argent. pediatr ; 118(3): e329-e332, jun. 2020. tab, ilus
Article in Spanish | LILACS, BINACIS | ID: biblio-1117357

ABSTRACT

Los tumores de los cordones sexuales y estromales son neoplasias poco frecuentes, que corresponden al 8 % de los tumores primarios del ovario. El tumor de los cordones sexuales con túbulos anulares del ovario es considerado un subtipo y es infrecuente. Puede presentarse de manera esporádica o asociado al síndrome de Peutz-Jeghers y tiene diferente comportamiento y características en cada situación.Se presenta el caso de una paciente adolescente con diagnóstico de tumor de los cordones sexuales con túbulos anulares del ovario asociado a síndrome de Peutz-Jeghers


Tumors of the sexual and stromal cords are rare neoplasms, corresponding to 8 % of primary ovarian tumors. The tumor of the sexual cords with annular tubules of the ovary is considered a subtype and is uncommon. It can occur sporadically or associated with Peutz-Jeghers Syndrome, having different behavior and characteristics in each situation.We present the case of an adolescent patient with a diagnosis of a tumor of the sexual cords with annular tubules of the ovary associated with Peutz-Jeghers Syndrome


Subject(s)
Humans , Female , Adolescent , Peutz-Jeghers Syndrome , Sex Cord-Gonadal Stromal Tumors/diagnosis , Ovary/pathology , Sex Cord-Gonadal Stromal Tumors/surgery , Neoplasms
2.
Arch Argent Pediatr ; 118(3): e329-e332, 2020 06.
Article in Spanish | MEDLINE | ID: mdl-32470276

ABSTRACT

Tumors of the sexual and stromal cords are rare neoplasms, corresponding to 8 % of primary ovarian tumors. The tumor of the sexual cords with annular tubules of the ovary is considered a subtype and is uncommon. It can occur sporadically or associated with Peutz-Jeghers Syndrome, having different behavior and characteristics in each situation. We present the case of an adolescent patient with a diagnosis of a tumor of the sexual cords with annular tubules of the ovary associated with Peutz-Jeghers Syndrome.


Los tumores de los cordones sexuales y estromales son neoplasias poco frecuentes, que corresponden al 8 % de los tumores primarios del ovario. El tumor de los cordones sexuales con túbulos anulares del ovario es considerado un subtipo y es infrecuente. Puede presentarse de manera esporádica o asociado al síndrome de Peutz-Jeghers y tiene diferente comportamiento y características en cada situación. Se presenta el caso de una paciente adolescente con diagnóstico de tumor de los cordones sexuales con túbulos anulares del ovario asociado a síndrome de Peutz-Jeghers.


Subject(s)
Ovarian Neoplasms/diagnosis , Peutz-Jeghers Syndrome/diagnosis , Sex Cord-Gonadal Stromal Tumors/diagnosis , Adolescent , Female , Humans , Ovarian Neoplasms/pathology , Peutz-Jeghers Syndrome/pathology , Sex Cord-Gonadal Stromal Tumors/pathology
3.
Virchows Arch ; 470(6): 695-701, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28349238

ABSTRACT

Insulin-like growth factor-1 receptor (IGF1R) plays a key role in cell growth and transformation. It is overexpressed in several solid tumors. This study evaluates IGF1R immunoexpression in penile squamous cell carcinoma (SCC). Four tissue microarrays were built from formalin-fixed, paraffin-embedded blocks of 112 penile SCC from Paraguay. Membranous IGF1R expression was evaluated by immunohistochemistry using two different approaches. An H-score was calculated in each spot (stain intensity by extent), and a median score per tumor was obtained. The second approach consisted of a score similar to the scoring system that was used for evaluating HER2 immunoexpression. For each case, the highest category obtained at any spot was used for statistical analyses. IGF1R expression was compared by histologic subtype, grade, and human papillomavirus (HPV) status. Median H-score was 22.5. The distribution of IGF1R expression by HER2 approach was as follows: 0 in 33.0% cases, 1+ in 46.4%, 2+ in 14.3%, and 3+ in 6.2%. IGF1R H-scores were associated with basaloid and warty/basaloid subtypes (p = 0.0026) and higher grade (p = 0.00052). Although weaker when using the HER2 approach, the association of IGF1R expression with subtype (p = 0.015) and grade (p = 0.015) remained significant. Furthermore, there was an association between IGF1R expression by HER2 approach and HPV status (p = 0.012). IGF1R was expressed in about two thirds of penile SCC cases, showing a strong positive association with histologic grade, subtype, and HPV status. Considering that grade is a predictor of outcome IGF1R expression may have prognostic relevance and could point to a potential role for IGF1R inhibitors in treating penile SCC.


Subject(s)
Biomarkers, Tumor/analysis , Carcinoma, Squamous Cell/pathology , Penile Neoplasms/pathology , Receptors, Somatomedin/biosynthesis , Carcinoma, Squamous Cell/virology , Humans , Immunohistochemistry , Male , Middle Aged , Neoplasm Grading , Papillomavirus Infections/complications , Penile Neoplasms/virology , Receptor, IGF Type 1 , Receptors, Somatomedin/analysis , Tissue Array Analysis
4.
Hum Pathol ; 54: 106-12, 2016 08.
Article in English | MEDLINE | ID: mdl-27085557

ABSTRACT

Testicular germ cell tumor (TGCT) is the most common malignancy of young men. Most patients are completely cured, which distinguishes these from most other malignancies. Orchiectomy specimens (n=76) were evaluated using high-resolution (single-cell discriminative) telomere-specific fluorescence in situ hybridization (FISH) with simultaneous Oct4 immunofluorescence to describe telomere length phenotype in TGCT neoplastic cells. For the first time, the TGCT precursor lesion, germ cell neoplasia in situ (GCNIS) is also evaluated in depth. The intensity of the signals from cancerous cells was compared to the same patient's reference cells-namely, healthy germ cells (defined as "medium" length) and interstitial/somatic cells (defined as "short" telomere length). We observed short telomeres in most GCNIS and pure seminomas (P=.006 and P=.0005, respectively). In contrast, nonseminomas displayed longer telomeres. Lesion-specific telomere lengths were documented in mixed tumor cases. Embryonal carcinoma (EC) demonstrated the longest telomeres. A fraction of EC displays the telomerase-independent alternative lengthening of telomeres (ALT) phenotype (24% of cases). Loss of ATRX or DAXX nuclear expression was strongly associated with ALT; however, nuclear expression of both proteins was retained in half of ALT-positive ECs. The particular distribution of telomere lengths among TGCT and GCNIS precursors implicate telomeres anomalies in pathogenesis. These results may advise management decisions as well.


Subject(s)
Biomarkers, Tumor/genetics , Carcinoma in Situ/genetics , In Situ Hybridization, Fluorescence , Neoplasms, Germ Cell and Embryonal/genetics , Seminoma/genetics , Telomere/genetics , Testicular Neoplasms/genetics , Adaptor Proteins, Signal Transducing/analysis , Adult , Biomarkers, Tumor/analysis , Carcinoma in Situ/chemistry , Carcinoma in Situ/pathology , Carcinoma in Situ/surgery , Co-Repressor Proteins , DNA Helicases/analysis , Fluorescent Antibody Technique , Humans , Male , Molecular Chaperones , Neoplasms, Germ Cell and Embryonal/chemistry , Neoplasms, Germ Cell and Embryonal/pathology , Neoplasms, Germ Cell and Embryonal/surgery , Nuclear Proteins/analysis , Octamer Transcription Factor-3/analysis , Seminoma/chemistry , Seminoma/pathology , Seminoma/surgery , Telomere/chemistry , Telomere Homeostasis , Telomere Shortening , Testicular Neoplasms/chemistry , Testicular Neoplasms/pathology , Testicular Neoplasms/surgery , X-linked Nuclear Protein , Young Adult
5.
Urology ; 92: 51-6, 2016 Jun.
Article in English | MEDLINE | ID: mdl-26905033

ABSTRACT

OBJECTIVE: To evaluate insulin-like growth factor-1 receptor (IGF1R) expression in penile cancer and its association with oncologic outcomes. METHODS: Tissue microarrays were constructed from 53 patients treated at our institution. Expression of IGF1R was evaluated using a Her2-like scoring system. Overexpression was defined as 1+ or greater membranous staining. Association of IGF1R expression with pathologic features was assessed with comparative statistics, and association with local recurrence, progression to nodal or distance metastases, or death was assessed with Kaplan-Meier survival analysis and Cox proportional hazard regression models. RESULTS: Overall, IGF1R overexpression was seen in 33 (62%) cases. With a median follow-up of 27.8 months, IGF1R overexpression was associated with inferior progression-free survival (PFS) (P = .003). In a multivariable model controlling for grade, T stage, perineural invasion, and lymphovascular invasion, IGF1R expression was independently associated with disease progression (hazard ratio 2.3, 95% confidence interval 1.1-5.1, P = .03. Comparing patients without IGF1R overexpression to those with overexpression, 5-year PFS was 94.1% vs 45.8%. CONCLUSION: IGF1R overexpression was associated with inferior PFS in penile cancer. Drugs that target IGF1R and downstream messengers may have a therapeutic benefit in patients that exhibit IGF1R overexpression.


Subject(s)
Penile Neoplasms/etiology , Penile Neoplasms/pathology , Receptor, IGF Type 1/biosynthesis , Aged , Disease Progression , Humans , Male , Middle Aged , Retrospective Studies
6.
PLoS One ; 11(1): e0146302, 2016.
Article in English | MEDLINE | ID: mdl-26785262

ABSTRACT

Solid tumors are characterized by a plethora of epigenetic changes. In particular, patterns methylation of cytosines at the 5-position (5mC) in the context of CpGs are frequently altered in tumors. Recent evidence suggests that 5mC can get converted to 5-hydroxylmethylcytosine (5hmC) in an enzymatic process involving ten eleven translocation (TET) protein family members, and this process appears to be important in facilitating plasticity of cytosine methylation. Here we evaluated the global levels of 5hmC using a validated immunohistochemical staining method in a large series of clear cell renal cell carcinoma (n = 111), urothelial cell carcinoma (n = 55) and testicular germ cell tumors (n = 84) and matched adjacent benign tissues. Whereas tumor-adjacent benign tissues were mostly characterized by high levels of 5hmC, renal cell carcinoma and urothelial cell carcinoma showed dramatically reduced staining for 5hmC. 5hmC levels were low in both primary tumors and metastases of clear cell renal cell carcinoma and showed no association with disease outcomes. In normal testis, robust 5hmC staining was only observed in stroma and Sertoli cells. Seminoma showed greatly reduced 5hmC immunolabeling, whereas differentiated teratoma, embryonal and yolk sack tumors exhibited high 5hmC levels. The substantial tumor specific loss of 5hmC, particularly in clear cell renal cell carcinoma and urothelial cell carcinoma, suggests that alterations in pathways involved in establishing and maintaining 5hmC levels might be very common in cancer and could potentially be exploited for diagnosis and treatment.


Subject(s)
Carcinoma, Renal Cell/genetics , Cytosine/analogs & derivatives , DNA Methylation , Kidney Neoplasms/genetics , Urogenital Neoplasms/genetics , 5-Methylcytosine/analogs & derivatives , Adult , Aged , Aged, 80 and over , Cytosine/metabolism , Female , Humans , Male , Middle Aged
7.
J Nucl Med ; 56(7): 1003-1010, 2015 Jul.
Article in English | MEDLINE | ID: mdl-26069305

ABSTRACT

UNLABELLED: We previously demonstrated the ability to detect metastatic prostate cancer using N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-(18)F-fluorobenzyl-L-cysteine ((18)F-DCFBC), a low-molecular-weight radiotracer that targets the prostate-specific membrane antigen (PSMA). PSMA has been shown to be associated with higher Gleason grade and more aggressive disease. An imaging biomarker able to detect clinically significant high-grade primary prostate cancer reliably would address an unmet clinical need by allowing for risk-adapted patient management. METHODS: We enrolled 13 patients with primary prostate cancer who were imaged with (18)F-DCFBC PET before scheduled prostatectomy, with 12 of these patients also undergoing pelvic prostate MR imaging. Prostate (18)F-DCFBC PET was correlated with MR imaging and histologic and immunohistochemical analysis on a prostate-segment (12 regions) and dominant-lesion basis. There were no incidental extraprostatic findings on PET suggestive of metastatic disease. RESULTS: MR imaging was more sensitive than (18)F-DCFBC PET for detection of primary prostate cancer on a per-segment (sensitivities of up to 0.17 and 0.39 for PET and MR imaging, respectively) and per-dominant-lesion analysis (sensitivities of 0.46 and 0.92 for PET and MR imaging, respectively). However, (18)F-DCFBC PET was more specific than MR imaging by per-segment analysis (specificities of 0.96 and 0.89 for PET and MR imaging for corresponding sensitivity, respectively) and specific for detection of high-grade lesions (Gleason 8 and 9) greater than 1.0 mL in size (4/4 of these patients positive by PET). (18)F-DCFBC uptake in tumors was positively correlated with Gleason score (ρ = 0.64; PSMA expression, ρ = 0.47; and prostate-specific antigen, ρ = 0.52). There was significantly lower (18)F-DCFBC uptake in benign prostatic hypertrophy than primary tumors (median maximum standardized uptake value, 2.2 vs. 3.5; P = 0.004). CONCLUSION: Although the sensitivity of (18)F-DCFBC for primary prostate cancer was less than MR imaging, (18)F-DCFBC PET was able to detect the more clinically significant high-grade and larger-volume tumors (Gleason score 8 and 9) with higher specificity than MR imaging. In particular, there was relatively low (18)F-DCFBC PET uptake in benign prostatic hypertrophy lesions, compared with cancer in the prostate, which may allow for more specific detection of primary prostate cancer by (18)F-DCFBC PET. This study demonstrates the utility of PSMA-based PET, which may be used in conjunction with MR imaging to identify clinically significant prostate cancer.


Subject(s)
Cysteine/analogs & derivatives , Fluorodeoxyglucose F18 , Positron-Emission Tomography , Prostatic Neoplasms/diagnostic imaging , Tomography, X-Ray Computed , Aged , Antigens, Surface/chemistry , Biomarkers, Tumor/chemistry , Biopsy , Glutamate Carboxypeptidase II/chemistry , Humans , Hypertrophy , Immunohistochemistry , Magnetic Resonance Imaging , Male , Middle Aged , Neoplasm Metastasis , Prostatectomy , Sensitivity and Specificity
8.
Hum Pathol ; 46(5): 761-6, 2015 May.
Article in English | MEDLINE | ID: mdl-25776029

ABSTRACT

ARID1A, a member of the chromatin remodeling genes family, has been suggested as a novel tumor suppressor gene in gynecologic malignancies. However, its role in penile cancer has yet to be determined. This study assesses the immunohistochemical expression of ARID1A in penile squamous cell carcinoma (SCC) and its association with pathologic features, human papillomavirus (HPV) status, and previously reported mammalian target of rapamycin pathway markers in the same cohort. Four tissue microarrays were constructed from 112 cases of formalin-fixed, paraffin-embedded penile SCC from Paraguay. Each tumor was sampled 3 to 12 times. ARID1A expression was evaluated by immunohistochemistry using a polyclonal rabbit anti-ARID1A (BAF250A) antibody. An H score was calculated in each spot as the sum of expression intensity (0-3+) by extent (0%-100%). Median H score per case was used for statistical analysis. ARID1A expression was observed in all cases, ranging from 3% to 100% of tumor cells (median, 95%). In 96 cases (86%), ARID1A expression was observed in 90% or more tumor cells. HPV DNA was detected in 20 (38%) of 52 analyzed samples. There was a significant trend of association between ARID1A and histologic grade. ARID1A expression was not associated with histologic subtype (P = .61) or HPV status (P = .18). ARID1A expression decreased with decreasing levels of PTEN expression (P = .01). ARID1A was expressed in penile SCC, in most cases at high levels. A significant trend of association was found between histologic grade and ARID1A expression, with lower ARID1A expression, lower histologic grades, and decreased PTEN expression.


Subject(s)
Carcinoma, Squamous Cell/metabolism , Nuclear Proteins/metabolism , Penile Neoplasms/metabolism , Transcription Factors/metabolism , Chromatin Assembly and Disassembly/genetics , DNA-Binding Proteins , Humans , Immunohistochemistry/methods , Male , Nuclear Proteins/genetics , Penile Neoplasms/pathology , Prognosis , Tissue Array Analysis/methods
9.
Hum Pathol ; 46(4): 532-40, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25661481

ABSTRACT

Approximately 50% of penile squamous cell carcinomas (SCC) are associated with high-risk human papillomavirus (HR-HPV) infection. We evaluated the correlation of p16(INK4a) expression and HR-HPV with clinicopathological features and outcome in a cohort of patients with penile SCC. Two tissue microarrays were constructed from 53 invasive penile SCC at our hospital. p16(INK4a) expression was assessed by immunohistochemistry (CINtec Kit). High-risk human papillomavirus status was assessed by in situ hybridization (INFORM HPV III family 16 probe B cocktail). High-risk human papillomavirus was detected in 8 cases (15%), and p16(INK4a) overexpression was found in 23 cases (44%). Both markers showed a significant association with histologic subtype (P = .017 and P = .01, respectively) and lymphovascular invasion (P = .015 and P = .015, respectively). Regarding outcome analyses, neither HPV infection nor p16(INK4a) overexpression significantly predicted overall survival or cancer-specific survival using Cox proportional hazards regression model. High-risk human papillomavirus positivity and p16(INK4a) overexpression were significantly associated with histologic subtype and presence of lymphovascular invasion. Human papillomavirus status was not predictive of outcome in our cohort.


Subject(s)
Carcinoma, Squamous Cell/metabolism , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Papillomavirus Infections/metabolism , Penile Neoplasms/metabolism , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/analysis , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/virology , Humans , Immunohistochemistry/methods , Male , Middle Aged , Neoplasm Invasiveness , Papillomavirus Infections/complications , Papillomavirus Infections/pathology , Penile Neoplasms/pathology , Penile Neoplasms/virology , Predictive Value of Tests , Prognosis
10.
Hum Pathol ; 46(1): 58-64, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25449628

ABSTRACT

Uroplakins are markers of terminally differentiated urothelium. Uroplakin II (UPII) is a newly described sensitive marker for urothelial carcinoma (UC). The expression profile of UPII in different types of UC and its utility in the diagnostic setting are needed. We evaluated UPII expression in bladder tissue microarrays, including urothelial neoplasm of low malignant potential (n = 8), low-grade papillary UC (n = 72), noninvasive high-grade papillary UC (n = 77), UC in situ (n = 27), and invasive high-grade UC (INVUC) (n = 122). UPII expression in 52 breast carcinomas and 38 high-grade prostate adenocarcinomas was also assessed. UPII expression was compared with GATA binding protein 3 (GATA3) and estrogen receptor for its role in facilitating the differential diagnosis of the above 3 types of malignancy. UPII labeling was seen in 83.0% of UC overall, including 95.7% of noninvasive UC and 65.6% of INVUC. UPII labeling was not found in any breast and prostate carcinomas. In comparison, GATA3 labeling was seen in 91.6% of all UCs, including 96.4% of noninvasive UCs and 85.1% of INVUC, with stronger intensity and extent compared with UPII (P < .005). GATA3 labeled 2 (5%) of 38 high-grade prostate adenocarcinoma. Estrogen receptor nuclear labeling was seen in 13.0% of UCs and 12.5% of prostate carcinomas. UPII was highly specific (100%) but only moderately sensitive for UC and can therefore be a potentially useful marker to identify urothelial lineage and help distinguish UC from prostate cancer or, in conjunction with GATA3, from metastatic breast cancer.


Subject(s)
Biomarkers, Tumor/analysis , Carcinoma/chemistry , Urinary Bladder Neoplasms/chemistry , Uroplakin II/analysis , Urothelium/chemistry , Adenocarcinoma/chemistry , Adenocarcinoma/pathology , Biopsy , Breast Neoplasms/chemistry , Breast Neoplasms/pathology , Carcinoma/pathology , Diagnosis, Differential , Female , GATA3 Transcription Factor/analysis , Humans , Immunohistochemistry , Male , Neoplasm Grading , Neoplasm Invasiveness , Predictive Value of Tests , Prostatic Neoplasms/chemistry , Prostatic Neoplasms/pathology , Receptors, Estrogen/analysis , Tissue Array Analysis , Urinary Bladder Neoplasms/pathology , Urothelium/pathology
11.
Hum Pathol ; 45(11): 2233-9, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25175170

ABSTRACT

AT-rich interactive domain 1A (ARID1A) is tumor suppressor gene that interacts with BRG1 adenosine triphosphatase to form a SWI/SNF chromatin remodeling protein complex. Inactivation of ARID1A has been described in several neoplasms, including epithelial ovarian and endometrial carcinomas, and has been correlated with prognosis. In the current study, ARID1A expression in urothelial carcinoma (UC) of the bladder and its association with clinicopathological parameters and outcome are addressed. Five tissue microarrays were constructed from 136 cystectomy specimens performed for UC at our institution. Nuclear ARID1A staining was evaluated using immunohistochemistry. An H-score was calculated as the sum of the products of intensity (0-3) multiplied by extent of expression (0%-100%). Average H-score per case was used for statistical analysis. ARID1A expression was categorized in low and high using Youden index to define the cut point. ARID1A expression significantly increased from normal to noninvasive UC to invasive UC. For both tumor progression and cancer death, Youden index yielded an H-score of 288 as the optimal cut point for ARID1A expression. Low ARID1A expression showed a tendency for lower risk of tumor progression and cancer mortality. Adding ARID1A expression to pathologic features offers a better model for predicting outcome than pathologic features alone. Low ARID1A expression was more frequently seen in earlier stage disease. There was a tendency for low ARID1A expression to predict better outcome. More importantly, the findings indicate that adding ARID1A expression to pathologic features increases the goodness of fit of the predictive model.


Subject(s)
Carcinoma, Transitional Cell/pathology , Nuclear Proteins/metabolism , Transcription Factors/metabolism , Urinary Bladder Neoplasms/pathology , Urothelium/pathology , Adult , Aged , Aged, 80 and over , Carcinoma, Transitional Cell/metabolism , Carcinoma, Transitional Cell/surgery , Cystectomy , DNA-Binding Proteins , Disease Progression , Female , Humans , Immunohistochemistry , Male , Middle Aged , Prognosis , Treatment Outcome , Urinary Bladder Neoplasms/metabolism , Urinary Bladder Neoplasms/surgery , Urothelium/metabolism , Urothelium/surgery
12.
Urology ; 83(6): 1444.e1-6, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24713135

ABSTRACT

OBJECTIVE: To assess the insulin-like growth factor-1 receptor (IGF1R) expression in urothelial carcinoma (UC) and its prognostic role in relation to clinicopathologic parameters. METHODS: A total of 100 cases of invasive UC were evaluated using tissue microarrays. Membranous IGF1R staining was evaluated using immunohistochemistry. A scoring method analogous to that of HER2 expression in breast carcinoma was used, and the highest score was assigned in each tumor. IGF1R was considered overexpressed in cases with score≥1. RESULTS: We found IGF1R overexpression in 62% of invasive UC. IGF1R overexpression was associated with race (P=.04) and pT category (P=.03). Median follow-up was 29 months (range, 0.5-212). Progression rate was 60%, and overall mortality and cancer-specific mortality rates were 69% and 51%, respectively. In invasive UC, IGF1R overexpression was significantly associated with overall mortality and cancer-specific mortality (Mantel Cox P=.0002 and P=.006, respectively). IGF1R overexpression was associated with increased hazard ratios (HRs) for overall mortality (HR=2.63, P=.001) and cancer-specific mortality (HR=2.45, P=.01), independently and after adjusting for clinicopathologic features and treatment modalities. CONCLUSION: We found IGF1R overexpression in 62% of bladder UC. More importantly, IGF1R overexpression was a significant predictor of overall mortality and cancer-specific mortality, suggesting its potential role as a prognosticator in UC of bladder.


Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Transitional Cell/metabolism , Carcinoma, Transitional Cell/mortality , Carcinoma, Transitional Cell/surgery , Receptor, IGF Type 1/metabolism , Urinary Bladder Neoplasms/metabolism , Adult , Aged , Aged, 80 and over , Biopsy, Needle , Cohort Studies , Disease-Free Survival , Female , Humans , Immunohistochemistry , Male , Middle Aged , Predictive Value of Tests , Proportional Hazards Models , Retrospective Studies , Risk Assessment , Survival Analysis , Treatment Outcome , Urinary Bladder Neoplasms/mortality , Urinary Bladder Neoplasms/surgery
13.
Hum Pathol ; 45(2): 244-8, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24315206

ABSTRACT

Transcription factor GATA binding protein 3 (GATA3) has been suggested as a marker of urothelial carcinoma of the bladder and upper urinary tract. Its expression in primary and metastatic renal tumors has not been fully determined. We evaluated GATA3 expression in 47 oncocytomas, 196 primary renal cell carcinomas (RCCs) (71 clear cell, 53 papillary, 21 Xp11.2, 33 chromophobe RCCs, and 18 collecting duct carcinomas [CDC]), and 43 unrelated metastatic RCCs (41 clear cell and 2 Xp11.2 RCC). GATA3 nuclear expression was evaluated in tissue microarrays built from archival tissues using immunohistochemistry. Intensity (0 to 3+) and extent (percentage) of expression were assessed. Several cutoff values (>0%, >5%, and >10%) were evaluated to indicate GATA3 positivity. Among oncocytomas, 9 (19%) of 47 had some degree of nuclear GATA3 expression with median extent of 0% (0%-100%). When using either 5% or 10% cutoff values, 5 (11%) of 47 oncocytomas were positive. In primary RCCs, 6 (3%) of 196 had some degree of nuclear expression with a median extent of 0% (0%-100%). When using either 5% or 10% cutoff values, 2 cases remained positive (1%) (Xp11.2 and CDC). All metastatic RCCs were negative. We found an overall lack of GATA3 expression in primary and metastatic RCCs. GATA3 is expressed in a minority of oncocytomas, Xp11.2-RCC, and CDC. Given GATA3 positivity in upper urinary tract urothelial carcinoma, our findings support a role for GATA3 in the differential diagnosis of primary renal masses and a utility in the interrogation of metastatic tumors of unknown primary in the presence of a renal mass.


Subject(s)
Biomarkers, Tumor/biosynthesis , Carcinoma, Renal Cell/secondary , GATA3 Transcription Factor/biosynthesis , Kidney Neoplasms/metabolism , Adenoma, Oxyphilic/metabolism , Adenoma, Oxyphilic/pathology , Adult , Aged , Aged, 80 and over , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Female , Humans , Kidney Neoplasms/pathology , Male , Middle Aged , Retrospective Studies
14.
Mod Pathol ; 27(4): 562-8, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24051698

ABSTRACT

The biological behavior of teratomas is highly variable, and morphologic features alone are insufficient to predict their clinical course. Prognostic factors that influence behavior include the following: patient sex, age, anatomic site, coincident neoplasm, and cytogenetic abnormalities. Gonadal teratomas have been well-characterized; postpubertal testicular teratomas are commonly associated with isochromosome 12p (i12p) and considered to nearly always carry a potential for malignant behavior, whereas ovarian and prepubertal testicular teratomas are i12p negative and predominantly benign in behavior. For extragonadal sites, such as sacrum and coccyx, clinical characteristics and i12p status are yet to be adequately characterized. As part of this study, we identified 19 sacrococcygeal teratomas in our surgical pathology archives from 1990 to 2012. Clinical records and slides were reviewed to confirm the original diagnosis. Gains in chromosome 12p, including i12p status were assessed in representative paraffin sections by fluorescence in situ hybridization. Our cases included 16 mature sacrococcygeal teratomas (11 prepubertal and 5 postpubertal) and three immature saccrococygeal teratomas (all prepubertal). Among mature teratomas, the average tumor size was larger in adults compared with prepubertal patients. A higher number of adult cases were recurrences (80% vs 21%), but only pediatric recurrences were managed with postoperative chemotherapy. All examined tumors were negative for i12p. 100% survival was documented in our cohort with a median follow-up of 6 years. We present a large series of sacrococcygeal teratomas and the first series to examine postpubertal adults at this anatomic site. All tumors lacked chromosome 12p gains, including i12p. Both pre- and postpubertal sacrococcygeal teratomas had a favorable outcome regardless of age or sex.


Subject(s)
Biomarkers, Tumor/genetics , Chromosomes, Human, Pair 12 , Isochromosomes , Sacrum , Spinal Neoplasms/genetics , Teratoma/genetics , Adult , Child, Preschool , Female , Genetic Predisposition to Disease , Humans , In Situ Hybridization, Fluorescence , Infant , Infant, Newborn , Male , Middle Aged , Phenotype , Spinal Neoplasms/pathology , Spinal Neoplasms/therapy , Survival Analysis , Teratoma/pathology , Teratoma/therapy , Treatment Outcome
15.
Hum Pathol ; 44(12): 2668-76, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24074531

ABSTRACT

Upper tract urothelial carcinoma (UTUC) accounts for 5% to 10% of all urothelial carcinomas. Despite many shared features, key clinical and molecular genetic differences between upper tract and bladder urothelial carcinomas are becoming apparent. We have previously demonstrated alterations of mammalian target of rapamycin (mTOR) pathway in bladder carcinoma with a potential impact on biological behavior. In the current study, we evaluated the expression status and prognostic significance of mTOR pathway members in UTUC. Archival formalin-fixed and paraffin-embedded tissues from 99 primary UTUCs were retrieved from one of the authors' institution. Tissue microarrays were constructed with triplicate tumor samples and paired nonneoplastic urothelium. Tissue microarrays were analyzed using immunohistochemistry for mTOR pathway members: PTEN, phos-AKT, phos-mTOR, phos-S6, phos-4EBP1, and related markers p27 and c-MYC; correlation with clinicopathologic parameters and outcome was performed. We found significantly lower expression of PTEN, phos-AKT, phos-mTOR, phos-S6, phos-4EBP1, p27, and c-MYC in UTUC compared with paired benign urothelium (P < .0005). We found a strong positive correlation between PTEN and phos-AKT. Moderate correlation was observed between phos-mTOR and phos-S6, PTEN and p27, phos-AKT and p27, phos-S6 and p27, phos-mTOR and c-MYC, phos-S6 and c-MYC, and p27 and c-MYC. None of the evaluated biomarkers were associated with increased hazard ratios for tumor recurrence or for cancer-specific mortality, when adjusting for relevant clinicopathologic variables. Dysregulation of the mTOR pathway was observed in UTUC compared with normal urothelium, implicating a potential pathogenic role in tumor development. In our cohort, expression of the evaluated biomarkers had no prognostic value.


Subject(s)
Carcinoma/metabolism , Signal Transduction/physiology , TOR Serine-Threonine Kinases/metabolism , Urinary Bladder Neoplasms/metabolism , Urologic Neoplasms/metabolism , Urothelium/metabolism , Aged , Aged, 80 and over , Biomarkers, Tumor/metabolism , Carcinoma/pathology , Disease Progression , Female , Humans , Male , Middle Aged , Phosphorylation , Prognosis , Urinary Bladder Neoplasms/pathology , Urologic Neoplasms/pathology , Urothelium/pathology
16.
Hum Pathol ; 44(12): 2760-7, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24134931

ABSTRACT

The penile urethra has a distinctive morphology not yet fully characterized by immunohistochemistry. In addition, both urothelial and squamous cell carcinomas have been reported in the penile urethra, and the distinction between these 2 tumors might be difficult. The purposes of this study are to assess the histology and immunohistochemical profile (CK20, CK7, p63, and GATA3) of the penile urethra and to assess the usefulness of Trans-acting T-cell-specific transcription factor (GATA3) and human papillomavirus detection in distinguishing urothelial versus squamous cell carcinomas. Normal penile urethra was evaluated in 11 total penectomies. The penile urethra was lined by 2 cell layers: a superficial single layer of CK7+, CK20-, and p63- columnar cells and a deep stratified layer of CK7-, CK20-, and p63+ cubical cells. Both layers were GATA3+, supporting urothelial differentiation. In addition, 2 tissue microarrays and 6 surgical specimens of primary tumors of the penile urethra (3 urothelial and 3 squamous cell carcinomas) were evaluated for GATA3 expression. In the tissue microarrays, 22 of 25 upper tract urothelial carcinomas and 0 of 38 penile squamous cell carcinomas were GATA3+. In the surgical specimens, GATA3 was positive in all urothelial carcinomas and negative in all squamous cell carcinomas. Human papillomavirus was detected in 2 of 3 squamous cell carcinomas and in 0 of 3 of the urothelial carcinomas. In conclusion, the penile urethra is covered by epithelial cells that are unique in morphology and immunohistochemical profile. In addition, our study suggests that GATA3 and human papillomavirus detection are useful markers for distinguishing urothelial carcinomas from squamous cell carcinomas of the penile urethra.


Subject(s)
Carcinoma, Squamous Cell/diagnosis , Carcinoma, Transitional Cell/diagnosis , GATA3 Transcription Factor/metabolism , Urethra/metabolism , Urethral Neoplasms/diagnosis , Urothelium/metabolism , Aged , Biomarkers, Tumor/metabolism , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Carcinoma, Transitional Cell/metabolism , Carcinoma, Transitional Cell/pathology , Diagnosis, Differential , Humans , Male , Middle Aged , Penis/metabolism , Penis/pathology , Tissue Array Analysis , Urethra/pathology , Urethral Neoplasms/metabolism , Urethral Neoplasms/pathology , Urothelium/pathology
17.
Hum Pathol ; 44(12): 2651-7, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24071011

ABSTRACT

Differential diagnosis of collecting duct carcinoma (CDC) from invasive upper tract urothelial carcinoma (UTUC) can be challenging. PAX8 and p63 are 2 markers often used in this setting. GATA binding protein 3 (GATA3) is a marker of urothelial differentiation. We investigated GATA3 expression in CDC and UTUC and its use in this differential. Eighteen CDC and 25 UTUC cases were used to build 2 tissue microarrays. GATA3, p63, and PAX8 nuclear expression was evaluated using standard immunohistochemistry. Staining intensity and percentage of positive cells were assessed. Sensitivity, specificity, and positive and negative predictive values of the markers and their combination were also evaluated. We found GATA3 positivity in 22 (88%) of 25 UTUCs and 1 (6%) of 18 CDCs. The median GATA3 extent of expression was higher in UTUC than in CDC (74% versus 0%, P = .00). We found p63 positivity in 23 (92%) of 25 UTUCs and 2 (11%) of 18 CDCs. PAX8 was positive in 3 (12%) of 25 UTUCs and all (100%) CDCs. GATA3 sensitivity and specificity for UTUC were 88% and 94%, respectively. p63 sensitivity and specificity for UTUC were 92% and 89%, respectively. The p63+/PAX8- profile showed higher sensitivity for UTUC than did the GATA3+/PAX8- profile (80% versus 76%). Both showed a specificity of 100% for UTUC. GATA3+ or p63+/PAX8- sensitivity and specificity for UTUC were 84% and 100%, respectively. Immunohistochemical expression of GATA3 was higher in UTUC, suggesting a potential role for distinguishing UTUC from CDC. Adding this marker to the combination panel of p63 and PAX8 might improve its performance in the diagnosis of epithelial neoplasms involving the renal sinus.


Subject(s)
Carcinoma, Renal Cell/diagnosis , GATA3 Transcription Factor/metabolism , Kidney Neoplasms/diagnosis , Urologic Neoplasms/diagnosis , Urothelium/pathology , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/metabolism , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Diagnosis, Differential , Female , Humans , Immunohistochemistry , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Male , Middle Aged , PAX8 Transcription Factor , Paired Box Transcription Factors/metabolism , Sensitivity and Specificity , Transcription Factors/metabolism , Tumor Suppressor Proteins/metabolism , Urologic Neoplasms/metabolism , Urologic Neoplasms/pathology , Urothelium/metabolism
18.
Urology ; 82(5): 1083-9, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24035134

ABSTRACT

OBJECTIVE: To asses the mammalian target of rapamycin (mTOR) pathway in minute prostatic adenocarcinoma on the basis of the previously reported role of phosphatase and tensin homolog (PTEN) inactivation and mTOR pathway activation as a negative prognosticator in prostatic cancer. METHODS: Tissue microarrays were constructed from 42 consecutive radical prostatectomy specimens with minute prostatic adenocarcinoma. Standard immunohistochemistry analysis for mTOR pathway members PTEN, phos-S6, phos-4E-BP1, phos-mTOR, phos-AKT, p27, and ERG was performed. For all markers, histologic expression score was calculated as the sum of intensity × extent of expression. In addition, for PTEN, presence of "markedly decreased" expression (any focal absence of expression) was also assessed. Expression status of all biomarkers was compared between tumor and paired benign tissue. Intercorrelation among markers was also performed. RESULTS: PTEN expression was seen in all 36 evaluable minute prostatic adenocarcinoma. Cytoplasmic phos-S6 was present in 32 of 36 tumors (89%). phos-S6 expression levels were higher in tumors compared with paired benign tissue (P = .007). Cytoplasmic and nuclear phos-4E-BP1 was present in all 34 evaluable tumors. phos-4E-BP1 was significantly higher in cancer compared with normal tissue (P <.0001). Only a minority of tumors demonstrating higher phos-S6 expression and phos-4E-BP1 (2 of 32 and 2 of 34, respectively) had associated "markedly decreased" PTEN expression. CONCLUSION: We found evidence of activation of mTOR pathway in minute prostatic adenocarcinoma that appears to be unrelated to "markedly decreased" PTEN expression. The latter finding suggests an alternative signaling mechanism controlling mTOR activation in minute prostate carcinoma.


Subject(s)
Adenocarcinoma/metabolism , Gene Expression Regulation, Neoplastic , PTEN Phosphohydrolase/metabolism , Prostate/metabolism , Prostatic Neoplasms/metabolism , TOR Serine-Threonine Kinases/metabolism , Biomarkers, Tumor/metabolism , Cohort Studies , Gene Expression Profiling , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Male , Prostatectomy , Signal Transduction , Tissue Array Analysis
19.
Int J Surg Pathol ; 21(4): 352-7, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23564700

ABSTRACT

OBJECTIVE: To assess the pathologic characteristics and prognostic significance of periprostatic lymph node (LN) metastasis of prostate cancer. The latter was performed by comparing biochemical recurrence (BCR)-free survival in cases of periprostatic LN metastasis versus matched patients showing pelvic LN metastasis. METHODS AND MATERIALS: We identified 15 patients who underwent radical prostatectomy in our institution (1984-2011) showing positive periprostatic and negative pelvic LN with available follow-up information (group 1). These patients were matched 1:2 to patients with positive pelvic LN (group 2) for pertinent clinicopathologic parameters. RESULTS: Main locations of positive periprostatic LN were posterior base and mid posterolateral. Overall higher rate of positive margins, smaller LN, and metastasis size were encountered in group 1 compared with group 2. At 5 years postprostatectomy, 69% of patients in group 1 were free of BCR, whereas 26% of those in group 2 remained BCR free, suggesting that patients with periprostatic node metastasis appeared to have a lower risk of BCR. However, the difference was not statistically significant (P = .072). The same was true when adjusted for the effect of prostate-specific antigen, surgical margin status, size of LNs, size of metastasis, age, and year of surgery. CONCLUSION: Patients with periprostatic node metastasis may have a lower risk of BCR compared with those with metastasis to pelvic LN. Future analysis of larger cohorts will help establish the biologic significance of prostate cancer metastasis to periprostatic LN.


Subject(s)
Adenocarcinoma/mortality , Adenocarcinoma/secondary , Prostatic Neoplasms/mortality , Prostatic Neoplasms/pathology , Adenocarcinoma/surgery , Aged , Disease-Free Survival , Humans , Kaplan-Meier Estimate , Lymphatic Metastasis/pathology , Male , Middle Aged , Prognosis , Proportional Hazards Models , Prostate-Specific Antigen/blood , Prostatectomy/mortality , Prostatic Neoplasms/surgery
20.
Cell Cycle ; 12(7): 1058-70, 2013 Apr 01.
Article in English | MEDLINE | ID: mdl-23435205

ABSTRACT

Urothelial cell carcinoma (UCC) is the second most common genitourinary malignant disease in the USA, and tobacco smoking is the major known risk factor for UCC development. Exposure to carcinogens, such as those contained in tobacco smoke, is known to directly or indirectly damage DNA, causing mutations, chromosomal deletion events and epigenetic alterations in UCC. Molecular studies have shown that chromosome 9 alterations and P53, RAS, RB and PTEN mutations are among the most frequent events in UCC. Recent studies suggested that continuous tobacco carcinogen exposure drives and enhances the selection of epigenetically altered cells in UCC, predominantly in the invasive form of the disease. However, the sequence of molecular events that leads to UCC after exposure to tobacco smoke is not well understood. To elucidate molecular events that lead to UCC oncogenesis and progression after tobacco exposure, we developed an in vitro cellular model for smoking-induced UCC. SV-40 immortalized normal HUC1 human bladder epithelial cells were continuously exposed to 0.1% cigarette smoke extract (CSE) until transformation occurred. Morphological alterations and increased cell proliferation of non-malignant urothelial cells were observed after 4 months (mo) of treatment with CSE. Anchorage-independent growth assessed by soft agar assay and increase in the migratory and invasive potential was observed in urothelial cells after 6 mo of CSE treatment. By performing a PCR mRNA expression array specific to the PI3K-AKT pathway, we found that 26 genes were upregulated and 22 genes were downregulated after 6 mo of CSE exposure of HUC1 cells. Among the altered genes, PTEN, FOXO1, MAPK1 and PDK1 were downregulated in the transformed cells, while AKT1, AKT2, HRAS, RAC1 were upregulated. Validation by RT-PCR and western blot analysis was then performed. Furthermore, genome-wide methylation analysis revealed MCAM, DCC and HIC1 are hypermethylated in CSE-treated urothelial cells when compared with non-CSE exposed cells. The methylation status of these genes was validated using quantitative methylation-specific PCR (QMSP), confirming an increase in methylation of CSE-treated urothelial cells compared to untreated controls. Therefore, our findings suggest that a tobacco signature could emerge from distinctive patterns of genetic and epigenetic alterations and can be identified using an in vitro cellular model for the development of smoking-induced cancer.


Subject(s)
DNA Methylation , Genome, Human , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Smoking , Carcinoma, Transitional Cell/metabolism , Carcinoma, Transitional Cell/pathology , Cell Cycle Proteins , Cell Line , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Transformation, Neoplastic/drug effects , DCC Receptor , Down-Regulation/drug effects , Forkhead Box Protein O1 , Forkhead Transcription Factors/metabolism , Humans , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Plant Extracts/pharmacology , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , Nicotiana/chemistry , Transcription Factors/genetics , Transcription Factors/metabolism , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Up-Regulation/drug effects , Urinary Bladder Neoplasms/metabolism , Urinary Bladder Neoplasms/pathology
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