71 research outputs found
Nuclear localization of Ī²-catenin in Sertoli cell tumors and other sex cordāstromal tumors of the testis: an immunohistochemical study of 87 cases
The diagnosis and subclassification of Sertoli cell tumors (SCT) of the testis are often challenging to general surgical pathologists because of the rarity of the tumors. Immunohistochemical study to date has limited diagnostic value. Nuclear localization of Ī²-catenin, which correlated closely with CTNNB1 gene mutation, was recently reported in SCTs. We investigated the utility of Ī²-catenin nuclear localization in diagnosing SCTs and differentiating them from other testicular sex cordāstromal tumors. Immunohistochemical staining for Ī²-catenin was evaluated in 87 cases of testicular sex cordāstromal tumor: 33 SCTs, not otherwise specified (SCT-NOS) (15 with benign and 18 with malignant features), 10 sclerosing SCTs (SSCT), 5 large cell calcifying SCTs (LCCSCT), 6 Sertoliāstromal cell tumors, 10 Leydig cell tumors, 7 juvenile granulosa cell tumors, 4 adult granulosa cell tumors, and 12 sex cordāstromal tumors, unclassified. Twenty-one of 33 (64%) SCT-NOS, 6 of 10 (60%) SSCTs, and 4 of 6 (67%) Sertoliāstromal cell tumors showed strong, diffuse Ī²-catenin nuclear staining. Nuclear Ī²-catenin positivity was more frequent in SCTs-NOS with benign features than in those with malignant features (93% and 39%, respectively, P=0.13) and, in the Sertoliāstromal cell tumors, occurred only in the Sertoli component. All 5 LCCSCTs and all other types of sex cordāstromal tumor were negative for Ī²-catenin nuclear staining. In conclusion, SCT-NOS and SSCT frequently show Ī²-catenin nuclear localization. Positive nuclear staining of Ī²-catenin is specific for SCT-NOS, SSCT, and Sertoliāstromal cell tumor among testicular sex cordāstromal tumors but has limited sensitivity (63%) in this group. The similar reactivity of SCT-NOS and SSCT provides additional support that these 2 variants are not distinct entities
Immunophenotypic Comparison of Testicular Sclerosing Sertoli Cell Tumors and Sertoli Cell Tumors Not Otherwise Specified
Testicular Sertoli cell tumors (SCTs) are rare, and most fall into the category of SCTānot otherwise specified (SCT-NOS). Only a few additional types of SCT are recognized. Sclerosing SCT (S-SCT), originally described in 1991, comprises a small fraction of SCTs and was considered a specific entity until the 2016 revision of the World Health Organization classification of nonāgerm cell tumors, where it was classified as a morphologic variant of SCT-NOS. In a recent study, differences in expression of PAX2/PAX8, inhibin, androgen receptor, and S100 protein between SCT-NOS and S-SCT were noted in a small number of cases. In this interinstitutional study, we compared the expression of these markers and Ī²-catenin in 11 cases each of SCT-NOS and S-SCT to determine if differences exist that could justify keeping a separate classification of these neoplasms. PAX2/PAX8 cocktail was the only marker that was significantly overexpressed in S-SCT. Expression of androgen receptors was strong in S-SCT and variable in SCT-NOS but did not reach statistical significance. Expression of Ī²-catenin was common in both, whereas inhibin was infrequent. The available material was insufficient for a conclusive evaluation of S100 protein expression. Overall, our results support the inclusion of S-SCT as a morphologic variant of SCT-NOS. Expression of PAX2/PAX8 in S-SCT may reflect an overactive epithelial-to-mesenchymal transition as has been shown in experimental models of acute and chronic seminiferous tubular injury and might be related to the process generating the stroma in these tumors
Primary Teratoma of the Lesser Sac: Lesser Sac Teratoma
Germ cell tumors predominantly involve the gonads but may rarely be found outside of the gonads, primarily in midline structures. We describe the case of a 27-year-old male with an asymptomatic 8ācm teratoma located within the lesser sac of his omentum. This is the fourth case of a teratoma located within the lesser sac of the omentum, which provides the opportunity to make some comparisons. Finally, we discuss some of the etiologic theories behind extragonadal germ cell tumors and how they relate to teratomas in the lesser sac
Juvenile Granulosa Cell Tumors of the Testis: A Clinicopathologic Study of 70 Cases with Emphasis on Its Wide Morphologic Spectrum
The clinical and pathologic features of 70 juvenile granulosa cell tumors (JGCTs) of the testis are presented. The patients were from 30 weeks gestational age to 10 years old; 60 of 67 (90%) whose ages are known to us were 6 months old or younger. Sixty-two underwent gonadectomy, 6 wedge excision, and 2 only biopsy. Twenty-six tumors were left sided and 22 right sided. Six occurred in an undescended testis and 2 in dysgenetic gonads. The most common presentation was a testicular mass (65%), followed by an āenlarging testisā (25%). Six of 14 patients in whom it was measured had āelevatedā serum Ī±-fetoprotein (AFP), likely physiologically, and 1 had gynecomastia. The tumors measured 0.5 to 5 cm (mean, 1.7 cm; median, 1.5 cm) and were most commonly well circumscribed and typically yellow-tan; approximately 2/3 had a cystic component, whereas 1/3 were entirely solid. Microscopic examination typically showed a lobular growth, punctuated in 67 cases by variably sized and shaped follicles containing material that was basophilic (21%), eosinophilic (44%), or of both characters (35%); 3 lacked follicles. In nonfollicular areas, the tumor cells typically grew diffusely but occasionally had a corded arrangement (26%) or reticular appearance (29%). The stroma was either fibrous or fibromyxoid; hemorrhage associated with hemosiderin-laden macrophages was focally seen in 16%. The tumor cells were mostly small to medium sized with round to oval nuclei containing inconspicuous nucleoli and moderate to abundant, but occasionally scant, pale to lightly eosinophilic, sometimes vacuolated, cytoplasm; nuclear grooves were infrequent (6%). Focal columnar morphology was seen in 27% of the tumors. Mitoses were plentiful in 37%, and apoptosis was prominent in 46%. Intratubular tumor was seen in 43% and entrapped seminiferous tubules in 70%. Lymphovascular invasion was present in 2 cases, rete testis involvement in 4, and necrosis in 1. Rare features/patterns included: regressed tumor with hyalinization and prominent blood vessels (13%), papillary growth (4%), basaloid morphology (1%), spindle cell predominance (1%), microcystic foci (1%), adult granulosa cellālike (1%) patterns, and hyaline globules (1%). Inhibin (16/18), calretinin (8/9), WT1 (6/7), FOXL2 (12/12), SF-1 (12/12), and SOX9 (6/11) were positive, whereas SALL4 and glypican-3 were consistently negative in the neoplastic granulosa cells. Only 1 of 10 tumors was focally positive for Ī±-fetoprotein. JGCT is a rare neoplasm with a wide morphologic spectrum that also occurs rarely in undescended testes and dysgenetic gonads. The solid and reticular patterns may pose diagnostic challenges, but the lobular appearance and follicular differentiation are characteristic. Immunohistochemical stains may aid in its distinction from other tumors of young male individuals, particularly yolk sac tumor, a neoplasm that peaks at a somewhat later age. Twenty-four patients with follow-up, including 4 of 6 patients treated with wedge resection/biopsy, had no evidence of disease (2 to 348 mo; mean, 83 mo; median, 61 mo). One additional patient was alive at 260 months, but the disease status is unknown. The benign clinical course of all cases of JGCT with follow-up, despite often frequent mitotic activity, supports testis sparing surgery when technically feasible
Pathologic Risk Factors for Higher Clinical Stage in Testicular Seminomas
Introduction
Testicular seminomas require accurate staging for effective management. 20% are metastatic at presentation while 80% are clinical stage I, requiring only orchiectomy and surveillance. Tumor size, rete testis invasion, hilar soft tissue invasion, and lymphovascular invasion have been shown to incur a higher risk of metastasis and recurrence in clinical stage I seminomas, with little congruence between studies.
Materials and Methods
We reviewed 211 cases of testicular seminomas and recorded patient age, tumor size, lymphovascular invasion and rete testis, hilar soft tissue, epididymis, spermatic cord, tunica albuginea, and tunica vaginalis involvement. A univariate and multivariate analysis was performed comparing clinical stage I to advanced clinical stage patients (stages II and III) in reference to these factors.
Results
We found that tumor size (p=0.02), vascular invasion (p=0.02), and invasion of rete testis stroma (p=0.01), epididymis (p=0.02), spermatic cord (p=0.047), and hilar soft tissue (p=0.04) were predictors of higher clinical stage at the univariate level. However, multivariate analysis showed that only tumor size and vascular invasion remained significant (p=0.008 and 0.032, respectively). A tumor size of 4 cm was the size cutoff found to be significant.
Discussion
Tumor size and vascular invasion are the strongest predictors of higher clinical stage in testicular seminomas. Our univariate data suggests that rete testis and hilar soft tissue invasion relate to higher clinical stage. However, neither of these factors were found to be independent risk factors at multivariate analysis. Therefore, this study supports tumor upstaging based only upon size and vascular invasion
DOG1 immunohistochemical staining of testicular biopsies is a reliable tool for objective assessment of infertility
Testicular biopsy may be a component of the work-up of male infertility. However, no reliable diagnostic tools are available for objective quantitative assessment of spermatogenic cells. It is well known that MAGE-A4 is selectively expressed in spermatogonia and our group has previously demonstrated that DOG1 differentially stains germ cells. Therefore, we performed DOG1 and a double stain cocktail (DOG1 and 57b murine monoclonal anti-MAGE-A4) immunohistochemical stains on 40 testicular infertility biopsies (10 each with active spermatogenesis, Sertoli cell-only, hypospermatogenesis, and maturation arrest), 25 benign seminiferous tubules from radical orchiectomies, and 5 spermatocytic tumors (ST). In biopsies/resections with active spermatogenesis, DOG1 stained spermatocytes and spermatids and was absent in spermatogonia, while MAGE-A4 stained spermatogonia and primary spermatocytes (weak). In hypospermatogenesis, DOG1 highlighted decreased spermatocytes/spermatids and MAGE-A4 highlighted decreased spermatogonia. DOG1 staining confirmed decreased to absent spermatocytes in maturation arrest and MAGE-A4 staining established the presence of preserved spermatogonia in all cases. All STs were negative for DOG1 and positive for MAGE-A4, while all Sertoli cell-only cases were negative for DOG1 and the double stain cocktail. In conclusion, we confirmed that DOG1 is expressed in spermatocytes and spermatids and MAGE-A4 highlights primarily spermatogonia. Usage of these stains facilitates confirmation of maturation arrest, assessment of the percentage of testis involvement in hypospermatogenesis and identification of mixed patterns. Finally, this study supports that the differentiation of STs is more closely related to spermatogonia than the more mature spermatocytes
Comparison of Biomarker Expression between Proximal and Distal Colorectal Adenomas: The Tennessee-Indiana Adenoma Recurrence Study
It is unclear if proximal and distal traditional adenomas present with differences in molecular events which contribute to cancer heterogeneity by tumor anatomical subsite. Participants from a colonoscopy-based study (n=380) were divided into subgroups based on the location of their most advanced adenoma: proximal, distal, or āequivalent both sidesā. Eight biomarkers in the most advanced adenomas were evaluated by immunohistochemistry (Ki-67, COX-2, TGFĪ²RII, EGFR, Ī²-catenin, cyclin D1, c-Myc) or TUNEL (apoptosis). After an adjustment for pathological features, there were no significant differences between proximal and distal adenomas for any biomarker. Conversely, expression levels did vary by other features, such as their size, villous component, and synchronousness. Large adenomas had higher expression levels of Ki-67(P<0.001), TGFĪ²RII (P<0.0001), c-Myc (P<0.001), and cyclin D1 (P<0.001) in comparison to small adenomas, and tubulovillous/villous adenomas also were more likely to have similar higher expression levels in comparison to tubular adenomas. Adenoma location is not a major determinant of the expression of these biomarkers outside of other pathological features. This study suggests similarly important roles of Wnt/Ī²-catenin and TGF-Ī² pathways in carcinogenesis in both the proximal and distal colorectum
Molecular Genetic Evidence for the Independent Origin of Multifocal Papillary Tumors in Patients with Papillary Renal Cell Carcinomas
Abstract
Purpose: In patients with papillary renal cell carcinoma, it is not uncommon to find two or more anatomically distinct and histologically similar tumors at radical nephrectomy. Whether these multiple papillary lesions result from intrarenal metastasis or arise independently is unknown. Previous studies have shown that multifocal clear cell renal cell carcinomas express identical allelic loss and shift patterns in the different tumors within the same kidney, consistent with a clonal origin. However, similar clonality assays for multifocal papillary renal cell neoplasia have not been done. Molecular analysis of microsatellite and chromosome alterations and X-chromosome inactivation status in separate tumors in the same patient can be used to study the genetic relationships among the coexisting multiple tumors.
Experimental Design: We examined specimens from 21 patients who underwent radical nephrectomy for renal cell carcinoma. All patients had multiple separate papillary lesions (ranging from 2 to 5). Eighteen patients had multiple papillary renal cell carcinomas. Seven had one or more papillary renal cell carcinomas with coexisting papillary adenomas. Genomic DNA samples were prepared from formalin-fixed, paraffin-embedded tissue sections using laser-capture microdissection. Loss of heterozygosity assays were done for six microsatellite polymorphic markers for putative tumor suppressor genes on chromosomes 3p14 (D3S1285), 7q31 (D7S522), 9p21 (D9S171), 16q23 (D16S507), 17q21 (D17S1795), and 17p13 (TP53). X-chromosome inactivation analyses were done on the papillary kidney tumors from three female patients. Fluorescence in situ hybridization analysis was done on the tumors of selected patients showing allelic loss at loci on chromosome 7 and/or chromosome 17.
Results: Twenty of 21 (95%) cases showed allelic loss in one or more of the papillary lesions in at least one of the six polymorphic markers analyzed. A concordant allelic loss pattern between each coexisting kidney tumor was seen in only 1 of 21 (5%) cases. A concordant pattern of nonrandom X-chromosome inactivation in the coexisting multiple papillary lesions was seen in two of three female patients. A discordant pattern of X-chromosome inactivation was seen in the tumors of the other female patient. Fluorescence in situ hybridization showed that the majority of tumors analyzed had gains of chromosomes 7 and 17. Two patients had one tumor with chromosomal gain and another separate tumor that did not.
Conclusion: Our data suggest that, unlike multifocal clear cell renal cell carcinomas, the multiple tumors in patients with papillary renal cell carcinoma arise independently. Thus, intrarenal metastasis does not seem to play an important role in the spread of papillary renal cell carcinoma, a finding that has surgical, therapeutic, and prognostic implications
Multidisciplinary clinic approach improves overall survival outcomes of patients with metastatic germ-cell tumors
Background
To report our experience utilizing a multidisciplinary clinic (MDC) at Indiana University (IU) since the publication of the International Germ Cell Cancer Collaborative Group (IGCCCG), and to compare our overall survival (OS) to that of the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program.
Patients and methods
We conducted a retrospective analysis of all patients with metastatic germ-cell tumor (GCT) seen at IU from 1998 to 2014. A total of 1611 consecutive patients were identified, of whom 704 patients received an initial evaluation by our MDC (including medical oncology, pathology, urology and thoracic surgery) and started first-line chemotherapy at IU. These 704 patients were eligible for analysis. All patients in this cohort were treated with cisplatināetoposide-based combination chemotherapy. We compared the progression-free survival (PFS) and OS of patients treated at IU with that of the published IGCCCG cohort. OS of the IU testis cancer primary cohort (nā=ā622) was further compared with the SEER data of 1283 patients labeled with ādistantā disease. The KaplanāMeier method was used to estimate PFS and OS.
Results
With a median follow-up of 4.4āyears, patients with good, intermediate, and poor risk disease by IGCCCG criteria treated at IU had 5-year PFS of 90%, 84%, and 54% and 5-year OS of 97%, 92%, and 73%, respectively. The 5-year PFS for all patients in the IU cohort was 79% [95% confidence interval (CI) 76% to 82%]. The 5-year OS for the IU cohort was 90% (95% CI 87% to 92%). IU testis cohort had 5-year OS 94% (95% CI 91% to 96%) versus 75% (95% CI 73% to 78%) for the SEER ādistantā cohort between 2000 and 2014, P-valueā<0.0001.
Conclusion
The MDC approach to GCT at high-volume cancer center associated with improved OS outcomes in this contemporary dataset. OS is significantly higher in the IU cohort compared with the IGCCCG and SEER ādistantā cohort
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