Sacrococcygeal teratomas: clinico-pathological characteristics and isochromosome 12p status.

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.

Loss of PTEN expression is associated with increased risk of recurrence after prostatectomy for clinically localized prostate cancer.

PTEN (phosphatase and tensin homolog on chromosome 10) is one of the most frequently lost tumor suppressor genes in human cancers and it has been described in more than two-thirds of patients with advanced/aggressive prostate cancer. Previous studies suggest that, in prostate cancer, genomic PTEN loss is associated with tumor progression and poor prognosis. Thus, we evaluated whether immunohistochemical PTEN expression in prostate cancer glands was associated with higher risk of recurrence, using a nested case-control study that included 451 men who recurred and 451 men who did not recur with clinically localized prostate cancer treated by radical prostatectomy. Recurrence was defined as biochemical recurrence (serum prostate-specific antigen >0.2 ng/ml) or clinical recurrence (local recurrence, systemic metastases, or prostate cancer-related death). Cases and controls were matched on pathological T stage, Gleason score, race/ethnicity, and age at surgery. Odds ratios of recurrence and 95% confidence intervals were estimated using conditional logistic regression to account for the matching factors and to adjust for year of surgery, preoperative prostate-specific antigen concentrations, and status of surgical margins. Men who recurred had a higher proportion of PTEN negative expression (16 vs 11%, P=0.05) and PTEN loss (40 vs 31%, P=0.02) than controls. Men with markedly decreased PTEN staining had a higher risk of recurrence (odds ratio=1.67; 95% confidence intervals 1.09, 2.57; P=0.02) when compared with all other men. In summary, in patients with clinically localized prostate cancer treated by prostatectomy, decreased PTEN expression was associated with an increased risk of recurrence, independent of known clinicopathological factors.

[Tumor of the sexual cords with ovarian annular tubules associated with Peutz-Jeghers syndrome in adolescence: a case report]. / Tumor de los cordones sexuales con túbulos anulares ováricos asociado a síndrome de Peutz-Jeghers: reporte de un caso en la adolescencia.

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.

Strong association of insulin-like growth factor 1 receptor expression with histologic grade, subtype, and HPV status in penile squamous cell carcinomas: a tissue microarray study of 112 cases.

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.

Overexpression of Insulin-like Growth Factor-1 Receptor Is Associated With Penile Cancer Progression.

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.

Global 5-Hydroxymethylcytosine Levels Are Profoundly Reduced in Multiple Genitourinary Malignancies.

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.

High-resolution telomere fluorescence in situ hybridization reveals intriguing anomalies in germ cell tumors.

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.

Immunohistochemical expression of ARID1A in penile squamous cell carcinomas: a tissue microarray study of 112 cases.

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.

Human papillomavirus infection and immunohistochemical p16(INK4a) expression as predictors of outcome in penile squamous cell carcinomas.

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.

Utility of uroplakin II expression as a marker of urothelial carcinoma.

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.

¹8F-DCFBC PET/CT for PSMA-Based Detection and Characterization of Primary Prostate Cancer.

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.

Tumor de los cordones sexuales con túbulos anulares ováricos asociado a síndrome de Peutz-Jeghers: reporte de un caso en la adolescencia / Tumor of the sexual cords with ovarian annular tubules associated with Peutz-Jeghers syndrome in adolescence: a case report

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

Comprehensive profile of GATA binding protein 3 immunohistochemical expression in primary and metastatic renal neoplasms.

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.

ARID1A immunohistochemistry improves outcome prediction in invasive urothelial carcinoma of urinary bladder.

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.

Insulin-like growth factor-1 receptor overexpression is associated with outcome in invasive urothelial carcinoma of urinary bladder: a retrospective study of patients treated using radical cystectomy.

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.

Determination of the nonlethal margin inside the visible "ice-ball" during percutaneous cryoablation of renal tissue.

OBJECTIVE: The study was designed to determine the distance between the visible "ice-ball" and the lethal temperature isotherm for normal renal tissue during cryoablation. METHODS: The Animal Care Committee approved the study. Nine adult swine were used: three to determine the optimum tissue stain and six to test the hypotheses. They were anesthetized and the left renal artery was catheterized under fluoroscopy. Under MR guidance, the kidney was ablated and (at end of a complete ablation) the nonfrozen renal tissue (surrounding the "ice-ball") was stained via renal artery catheter. Kidneys were explanted and sent for slide preparation and examination. From each slide, we measured the maximum, minimum, and an in-between distance from the stained to the lethal tissue boundaries (margin). We examined each slide for evidence of "heat pump" effect. RESULTS: A total of 126 measurements of the margin (visible "ice-ball"-lethal margin) were made. These measurements were obtained from 29 slides prepared from the 6 test animals. Mean width was 0.75 ± 0.44 mm (maximum 1.15 ± 0.51 mm). It was found to increase adjacent to large blood vessels. No "heat pump" effect was noted within the lethal zone. Data are limited to normal swine renal tissue. CONCLUSIONS: Considering the effects of the "heat pump" phenomenon for normal renal tissue, the margin was measured to be 1.15 ± 0.51 mm. To approximate the efficacy of the "gold standard" (partial nephrectomy, ~98 %), a minimum margin of 3 mm is recommended (3 × SD). Given these assumptions and extrapolating for renal cancer, which reportedly is more cryoresistant with a lethal temperature of -40 °C, the recommended margin is 6 mm.

Immunohistochemical expression of SALL4 in hepatocellular carcinoma, a potential pitfall in the differential diagnosis of yolk sac tumors.

SALL4 is a transcription factor that serves as a marker of yolk sac tumor. Yolk sac tumor and hepatocellular carcinoma share histologic, serologic, and immunohistochemical features. Previous studies have shown lack of SALL4 expression in hepatocellular carcinoma, suggesting utility in this differential diagnosis. Sixty-nine samples of hepatocellular carcinoma were retrieved from surgical pathology archives and used to construct 9 tissue microarrays. A germ cell tumor tissue microarray containing 10 yolk sac tumors was used for comparison. Extent, intensity, and pattern of nuclear SALL4 expression were assessed in each spot. Mean percentage of expression was calculated for each tumor and used during analysis. Optimal discriminatory extent of expression cutoff was determined by receiver operating characteristic curve analysis. Other potential discriminatory markers including Hep Par1 were also evaluated. Forty-six percent (32/69) of hepatocellular carcinoma and all yolk sac tumors revealed at least focal expression of SALL4. A unique punctuate/clumped pattern of nuclear staining was present in 94% (30/32) of hepatocellular carcinoma, whereas all yolk sac tumors displayed a diffuse finely granular nuclear staining pattern. A 25% extent of SALL4 expression cutoff was found to be optimal for the distinction of yolk sac tumor from hepatocellular carcinoma yielding a sensitivity of 100%, specificity of 92.8%, and a positive predictive value of 66.6% for yolk sac tumor diagnosis. The addition of Hep Par1 increased the specificity (99%) and positive predictive value (90%). This is the first report of SALL4 expression in hepatocellular carcinoma. Our finding should be taken into consideration in the differential diagnosis of hepatocellular carcinoma and yolk sac tumor. The unique punctuate/clumped pattern seen in hepatocellular carcinoma cases could be of further discriminatory value.

Dysregulation of mammalian target of rapamycin pathway in plasmacytoid variant of urothelial carcinoma of the urinary bladder.

Plasmacytoid urothelial carcinoma is a rare but aggressive variant of bladder cancer with no clear therapeutic guidelines. Dysregulation of the mammalian target of rapamycin (mTOR) pathway has been linked to oncogenesis in conventional bladder cancer. Several antineoplastic agents targeting mTOR pathway are currently available. This study assesses mTOR pathway status as well as c-myc and p27 expression. We retrieved 19 archival cases of plasmacytoid urothelial carcinoma from two institutions. Whole tissue sections were evaluated for immunoexpression of phosphatase and tensin homolog (PTEN), phosphorylated mTOR, phosphorylated protein kinase B (AKT), phosphorylated S6, c-myc, and p27. We evaluated intensity (0 to 3+) and extent (0%-100%) of expression for all markers. An H score was calculated as the sum of products of intensity and extent for each marker and used during analysis. In addition, PTEN loss was defined as absence of expression in >10% of tumor cells. We encountered PTEN loss in 28%. Higher H score for nuclear phosphorylated AKT and a lower H score for phosphorylated S6 was encountered in muscle invasive tumors compared to non-muscle invasive tumors (P = .007 and P = .009, respectively). Although a trend for negative prognostic impact on overall survival for higher phosphorylated mTOR expression was noted (P = .051), markers expression levels failed to predict survival in our cohort. We found dysregulation of mTOR pathway members in urinary bladder plasmacytoid urothelial carcinoma, suggesting that the use of mTOR pathway inhibitors might be beneficial for patients with this aggressive tumor.

The role of GATA binding protein 3 in the differential diagnosis of collecting duct and upper tract urothelial carcinomas.

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.

Activation of mammalian target of rapamycin signaling pathway markers in minute adenocarcinoma of the prostate.

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.