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Primary mediastinal seminomas are unusual tumors that can present in a pure form or as part of a mixed germ cell tumor. Contrary to testicular seminomas, little is known about the expression of novel immunohistochemical markers in mediastinal seminomas. This study investigates the immunohistochemical features of these tumors with a focus on novel markers. Thirty-two cases of primary mediastinal seminomas were reviewed; and representative whole-tissue sections were selected for immunohistochemical studies using antibodies directed against high molecular weight cytokeratin 5/6 (CK5/6), low molecular weight cytokeratin (CAM5.2), octamer-binding transcription factor 3/4 (OCT3/4), spalt-like transcription factor 4 (SALL4), GATA binding protein 3 (GATA-3), sry-related HMG box 2 (SOX2), SOX17, human T cell leukemia/lymphoma 1 (TCL1), glypican 3, melanoma associated antigen C2 (MAGEC2), and paired box gene 8 (Pax8). The percentage of positive tumor cells as well as the intensity of staining was evaluated and scored. Thirty-one cases (97%) expressed SOX17, whereas 29 cases (91%) were positive for OCT3/4 and SALL4, respectively. Twenty-eight cases (88%) expressed MAGEC2 and CAM5.2, respectively. Two cases (6%) were positive for Pax8, and a single case (3%) was positive for TCL1. None of the cases stained with CK5/6, GATA-3, SOX2, or glypican 3. Similar to testicular seminomas, mediastinal seminomas show consistent expression of OCT3/4, SALL4, SOX17, and MAGEC2 and are negative for SOX2, glypican 3, GATA-3, and CK5/6. Pax8 positivity is only inconsistently identified in mediastinal seminomas. Contrary to their testicular counterparts, mediastinal tumors show diffuse expression of low-molecular-weight cytokeratin in up to 90% of cases and are commonly negative for TCL1. Although there is some immunohistochemical overlap between testicular and mediastinal seminomas, considerable differences also exist and should be acknowledged when dealing with these tumors., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Solitary fibrous tumor (SFT) is a rare spindle cell neoplasm that usually arising from the pleura, but has been reported in diverse extrapleural sites. Urogenital localization is rare, and only several cases of paratesticular SFT have been reported. In the present report, we present the case of a 61-year-old male suffering from a paratesticular SFT. A surgical excision of the lesion was performed. The tumor was well circumscribed and consisted of a mixture of bland spindle cells and dense collagen bands. Immunohistochemical studies showed positive reactivity for CD34, CD99 and vimentin, but stained negative for CD117, S100, SMA, HMB45, Desmin and CD68. All these clinicopathologic features are suggestive of the diagnosis of paratesticular SFT.

All malignant testicular germ cell tumors (TGCT) of adult men are preceded by an in situ stage (CIS) of protracted evolution. The adult CIS is well characterized, but there is debate on the phenotype of infantile CIS, its distinction from delayed maturation of germ cells and prognostic potential. A large series of 43 patients with Disorders of Sex Development (DSD) and dysgenetic testes (90% ranging from neonates to 12 years, mean age 4.7 years), was studied by quantifying dysgenetic features, degree of germ cell abnormalities/atypia (GCA), expression of OCT 3/4 (a pluripotency-undifferentiation marker), germ cell ploidy and evolution to CIS and invasive TGCT. Findings were compared with those of normal testes. The type of gonads present defined three groups of patients: bilateral testes (BT-DSD, n = 21), one testis and one streak gonad (CT-DSD, C for combined, n = 13), and ovarian-testicular combinations (OT-DSD, n = 9). There were 5 boys with infantile CIS, bilateral in 3 (total of 8 infantile CIS) and two patients with adult CIS, bilateral in one (total of 3 adult CIS). Two patients had bilateral seminomas one at 12-17 and the other at 23 years. Histological dysgenesis was significantly higher in CT-DSD (p < 0.05), that had only 1 CIS. The highest frequency of GCA was in BT-DSD (p < 0.05), which coincided with a total of 11CIS + Seminomas. In all patients, aneuploidy was significantly higher (63%) than diploidy (p < 0.02), and GCA were more frequent in aneuploid than in diploid samples (p < 0.02). All CIS and TGCT were OCT 3/4 positive. Finally, there was a significant association between the triad Aneuploidy + GCA + OCT 3/4 positivity and the incidence of CIS (Fisher Exact test p < 0.002, relative risk 7.0). The degree of testicular dysgenesis (derived from abnormal organization of Sertoli cells in fetal testicular cords) is inversely related to the incidence of CIS. Our data demonstrate that the combined use of OCT 3/4 expression, quantification of germ cell abnormalities-atypia and ploidy in dysgenetic testes can satisfactorily identify infantile CIS with high risk of malignant evolution and set it aside from delayed germ cell maturation with lower or nil neoplastic potential., (© 2014 American Society of Andrology and European Academy of Andrology.)

Four cases are reported meeting the criteria of a pediatric (i.e., Type I) testicular germ cell tumor (TGCT), apart from the age of presentation, which is beyond childhood. The tumors encompass the full spectrum of histologies of pediatric TGCT: teratoma, yolk sac tumor, and various combinations of the two, and lack intratubular germ cell neoplasia/carcinoma in situ in the adjacent parenchyma. The neoplasms are (near)diploid, and lack gain of 12p, typical for seminomas and non-seminomas of the testis of adolescents and adults (i.e., Type II). It is proposed that these neoplasms are therefore late appearing pediatric (Type I) TGCT. The present report broadens the concept of earlier reported benign teratomas of the post-pubertal testis to the full spectrum of pediatric TGCT. The possible wide age range of pediatric TGCT, demonstrated in this study, lends credence to the concept that TGCT should according to their pathogenesis be classified into the previously proposed types. This classification is clinically relevant, because Type I mature teratomas are benign tumors, which are candidates for testis conserving surgery, as opposed to Type II mature teratomas, which have to be treated as Type II (malignant) non-seminomas., (© 2014 American Society of Andrology and European Academy of Andrology.)

Purpose: Androgen receptor (AR) is a recognized immunohistochemical marker of prostate cancer. However, the sensitivity and specificity of AR for prostate cancer in the setting of other genitourinary neoplasms has not been rigorously studied., Methods: We employed tissue microarrays containing prostate carcinomas, urothelial carcinomas, renal cell carcinomas, and testicular neoplasms. Slides were stained immunohistochemically for AR., Results: Androgen receptor was positive in 95% of prostate carcinomas (n=230), but 19% of invasive urothelial carcinomas of the bladder (n=190) and 33% of non-invasive bladder urothelial carcinomas were also AR positive (N=107). Furthermore, 16% of renal pelvis urothelial carcinomas (n=43) were positive. Of primary renal cell carcinomas, 19% were AR positive (n=307). From a metastatic renal cell carcinoma cohort, 28% of metastases were AR positive (N=126). Six percent of non-teratomatous testicular germ cell tumors stained for AR (n=103)., Conclusions: Our data show that the sensitivity of AR immunohistochemistry for prostate cancer is 94.8%. However, the specificity of AR is only 81.4%, among our cohort of invasive genitourinary tumors. Thus, we find the specificity of AR suboptimal, yet AR may remain useful as a component of an immunostain panel.

Glypican 3 is a membrane-bound heparan sulfate proteoglycan, which has recently been identified as a marker for liver cancer and germ cell malignancies. Individuals with loss-of-function mutations for the glypican 3 gene exhibit Simpson-Golabi-Behmel syndrome, a rare X-linked overgrowth disorder. Expression of glypican 3 mRNA and protein is normally silenced in most adult organs and may reappear during malignant transformation. In the past few years, immunohistochemical and molecular characteristics of glypican 3 in hepatocellular carcinoma have been elucidated. More recently, glypican 3 has been emerging as a new diagnostic marker for germ cell tumors and especially testicular and ovarian yolk sac tumors. However, in other tumors such as renal cell carcinomas, squamous cell carcinomas, and melanomas, studies disagree on the level of glypican 3 expression. Finally, there is the controversial notion of glypican 3 as a tumor suppressor gene. In this review article, we update current knowledge on glypican 3 expression in normal and neoplastic tissues, evaluate its utility as a tumor marker in clinical practice, and explore its role as a novel oncofetal protein with clinical implications. Our focus is on the diagnostic value of glypican 3 in germ cell tumors and other neoplasms in addition to hepatocellular carcinoma. In conclusion, glypican 3 has been proven to be a useful immunohistochemical marker in distinguishing yolk sac tumors, choriocarcinomas, and Wilms tumors from other malignancies histologically mimicking these primitive tumors. Clinically, we recommend that glypican 3 be used as part of a panel of markers in subtyping testicular germ cell tumors.

In this article, we discuss advances in our knowledge of the pathology of signet ring stromal cell tumor and related signet ring cell lesions of the ovary and a single case of signet ring stromal cell tumor of the testis. We divide ovarian signet ring cell lesions into 3 categories that reflect differences in their pathogenesis and histologic appearance. With 1 exception, all authentic cases of signet ring stromal cell tumor have been unilateral. Cases of ovarian signet ring stromal cell tumor from the literature can arise in 2 ways. The majority of cases arise multifocally from fibroma, whereas the remainder likely arise directly from the ovarian stroma. In difficult cases, immunocytochemistry provides improved diagnostic accuracy in distinguishing signet ring stromal cell tumor and its mimics from Krukenberg tumor. The most useful antibodies in this regard are epithelial membrane antigen and vimentin.

Somatic-type malignancies (SMs) in patients with testicular germ cell tumors (GCT) are rare and mostly attributed to "transformation" of teratoma, although yolk sac tumor (YST) origin has also been proposed. We studied 124 cases of "SM" of testicular GCT origin from 106 patients to evaluate their morphology, immunohistochemical features (especially the utility of SALL4), and relationship to YST. Primitive neuroectodermal and nephroblastomatous tumors were excluded because of prior studies. Patients ranged in age from 15 to 68 years (mean, 33 y). The tumors ranged from 0.7 to 30 cm (mean, 7.6 cm) and involved the retroperitoneum (64%), abdomen/pelvis (10%), lung (10%), mediastinum (6%), supraclavicular region/neck (4%), testis (4%), and thigh (1%). Most initial diagnoses were sarcomas (n=68) or carcinomas (n=51). On review and immunohistochemical analysis, 7 of 45 adenocarcinomas were reclassified as glandular YSTs (GYST) on the basis of glypican-3 (GPC3) and/or α-fetoprotein positivity and scant/absent reactivity for EMA and CK7. These occasionally (29%) had subnuclear and sometimes supranuclear vacuoles (endometrioid-like), whereas adenocarcinomas were more frequently mucinous (17%) or enteric-type (11%) than endometrioid-like (9%). Both expressed CDX2 frequently (83% and 63%, respectively). MUC protein 2, 4, 5, and 6 expression was more common in adenocarcinomas (7% to 36%) than in GYSTs (0% to 20%) but was infrequent. Both were often positive for SALL4, BerEP4, and MOC31; all were negative for TTF-1. On follow-up (GYST: range, 23 to 169 mo; mean, 81mo; adenocarcinoma: range, 1 to 170 mo; mean, 55 mo), 50% and 33% of patients with GYST and adenocarcinoma, respectively, died of disease. We reclassified 26 of 76 sarcomatoid tumors as sarcomatoid YSTs (SYST) on the basis of positive reactivity for both AE1/3 and GPC3. These tumors often had spindled and epithelioid cells in a fibromyxoid stroma. SYSTs were often (60%) SALL4 positive, whereas sarcomas were all negative. On follow-up (SYST: range, 1 to 259 mo; mean, 62 mo; sarcoma: range, 1 to 327 mo; mean, 70 mo), 50% and 29% of patients with SYST and sarcoma, respectively, died of disease, with most mortality occurring in those with high-grade tumors. We conclude that, on the basis of a panel of immunoreactivities, a significant number of "SMs" in testicular GCT patients are more accurately classified as either GYSTs or SYSTs. Ambiguous glandular tumors should be evaluated for GPC3, α-fetoprotein, CK7, and EMA reactivity and sarcomatoid ones for GPC3, AE1/3, and SALL4 reactivity.

Objective: The oncoprotein, gankyrin, is known to facilitate cell proliferation through phosphorylation and degradation of retinoblastoma protein. In the present study, we evaluated the expression of gankyrin and phosphorylated retinoblastoma protein in human testis and testicular germ cell tumors., Methods: The effects of suppression of gankyrin by locked nucleic acid on phosphorylation status of retinoblastoma and cell proliferation were analyzed using western blot analysis and testicular tumor cell line NEC8. The expressions of gankyrin, retinoblastoma and retinoblastoma protein were analyzed in 93 testicular germ cell tumor samples and five normal human testis by immunohistochemistry. The retinoblastoma protein expression was determined using an antibody to retinoblastoma protein, Ser795., Results: Gankyrin was expressed in NEC8 cells as well as a normal human testis and testicular tumors. Suppression of gankyrin by locked nucleic acid led to suppression of retinoblastoma protein and cell proliferation in NEC8 cells. Immunohistochemistry of normal testis showed that gankyrin is expressed dominantly in spermatocytes. In testicular germ cell tumors, high expressions of gankyrin and phosphorylated-retinoblastoma protein were observed in seminoma and embryonal carcinoma, whereas the expressions of both proteins were weak in histological subtypes of non-seminoma. Growing teratoma and testicular malignant transformation tissues expressed phosphorylated-retinoblastoma protein strongly, but gankyrin faintly., Conclusion: Gankyrin is dominantly expressed in normal spermatocytes and seminoma/embryonal carcinoma, and its expression correlates well with retinoblastoma protein expression except in the growing teratoma and testicular malignant transformation cases. These data provide new insights into the molecular mechanisms of normal spermatogenesis and pathogenesis of testicular germ cell tumors., (© 2014 The Japanese Urological Association.)

Malignant mesotheliomas of the testis arise from the tunica vaginalis, formed from the evagination of the abdominal peritoneum into the scrotum. It is an extremely rare tumor representing 0.3% to 5% of all malignant mesotheliomas. We presented an interesting case of 68-year-old male with swelling and slightly painful in the right scrotum. Histologically, the lesion were composed of small tubular, microcystic, gland lined by flattened epithelioid cells and vague signet ring cells set in a myxofibrous stroma, which is resemblance to adenomatoid tumor. But the tumor cells showed significant atypical cytologic morphology and invaded into spermatic cord tissue, which indicated the diagnosis of malignant tumor. Immunohistochemistry study showed positive expression of CK, CK5/6, CK7, Calretinin, D2-40 and Vimentin which indicated the diagnosis of malignant mesothelioma. This case of mesothelioma should be classified as epithelial in type. To our knowledge, the mesothelioma of the tunica vaginalis testis with adenomatoid tumor-like microscopic features is very rare.

Purpose: Intratubular germ cell neoplasia is a precursor to testicular germ cell cancer. The condition is characterized by large germ cells with large nuclei with a hyperchromatic, coarse chromatin pattern, large prominent nucleoli and abundant pale cytoplasm. In prepubertal boys these cells are located centrally and peripherally mixed with normal cells in the seminiferous tubules. We evaluated the impact of adult intratubular germ cell neoplasia marking immunohistochemistry in screening for intratubular germ cell neoplasia in boys with cryptorchidism., Materials and Methods: Histology sections of 236 testicular biopsies were retrieved from 170 boys 1 month to 15 years old operated on for cryptorchidism (excluding disorders of sex development). Specimens were incubated with primary antibodies, including anti-placental-like alkaline phosphatase, anti-Oct3/4, anti-C-kit and anti-D2-40 receptor., Results: A 1-year, 1-month-old boy had intratubular germ cell neoplasia and all positive markers. The prevalence of placental-like alkaline phosphatase positive staining of germ cells in testicular biopsies was 98% in boys younger than 1 year, 82% in those 1 to less than 2 years old, 74% in those 2 to less than 3 years old and 60% in those 3 to 15 years. Similarly the prevalence of C-kit positive staining was 71% in boys younger than 1 year, 49% in those 1 to less than 2 years, 16% in those 2 to less than 3 years and 34% in those 3 to 15 years. Placental-like alkaline phosphatase negative germ cells did not express any of the other described antigens. In none of the 116 testes from boys older than 1 year and 7 months were any Oct3/4 or D2-40 positive germ cells identified. Up to that age 33% and 8% of biopsies were Oct3/4 and D2-40 positive, respectively., Conclusions: Adult intratubular germ cell neoplasia/cancer immunohistochemical markers cannot be used alone for intratubular germ cell neoplasia screening in male infants with cryptorchidism because positive immunohistochemistry is commonly seen within this age group, when most orchiopexies are performed. It is generally not plausible that intratubular germ cell neoplasia originates during fetal development in patients with cryptorchidism., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

The Sertoli cell tumor (SCT) of the testis is a sex cord stromal tumor, usually sporadic, rarely associated with genetic syndromes. Much remains unclear about the molecular genetic changes involved in SCT and its histogenesis. Recently, nuclear β-catenin immunostaining has been reported in a case of bilateral SCT, but the molecular basis of the aberrant nuclear β-catenin expression remains uncertain. In the present study, β-catenin immunohistochemical assay and mutational analysis of exon 3 of the CTNNB1 gene by direct sequencing were performed in 14 SCTs, 2 of which had an unfavorable clinical course. Immunohistochemical study showed that β-catenin was located in the cytoplasm of tumor cells in 4 cases (28.6%) and in both the nuclei and the cytoplasm in the remaining 10 cases (71.4%). β-Catenin mutations were detected in 10 of the 14 patients (71.4%) under evaluation. Ten of 10 mutation-carrying cases showed strong nuclear and diffuse cytoplasmic β-catenin immunoreactivity. Seven of the 8 CTNNB1-mutated tumors tested for cyclin D1 displayed diffuse immunoreactivity in the nuclei of tumor cells. We conclude that CTNNB1 exon 3 mutations are likely to be involved in the pathogenesis of male SCT with nuclear accumulation of β-catenin and affect the expression of cyclin D1.

Although well recognized in the literature, the contemporary clinicopathologic data regarding choriocarcinoma (CC) as a pure or the predominant component of a testicular germ cell tumor (GCT) are limited. Herein, we present a series of pure CC and predominant CC in mixed GCT of the testis obtained from a single oncology institution. A comprehensive histologic review of 1010 orchiectomies from 1999 to 2011 yielded 6 (0.6%) pure CC and 9 (0.9%) mixed GCT cases with a predominant CC component. Patients' ages ranged from 20 to 39 years (median 29 y). All patients had markedly elevated serum β-hCG levels (median 199,000 IU/mL) at presentation. All tumors were unilateral and involved the right (9/15) and left (6/15) testis. The mean tumor size was 6.5 cm (range, 1.5 to 8 cm). Histology was similar for pure CCs and the CC component of mixed GCTs. CC commonly showed expansile hemorrhagic nodular cysts surrounded by variable layers of neoplastic trophoblastic cells (mononucleated trophoblasts and syncytiotrophoblasts). The syncytiotrophoblasts usually covered columns of mononucleated trophoblasts and occasionally formed plexiform aggregates and pseudovillous protrusions. Immunohistochemical stains suggested a mixture of cytotrophoblasts (p63+, HPL&#95;) and intermediate trophoblasts (p63-, HPL weak +/-) in the columns of mononucleated cells. In the 9 mixed GCTs, CC comprised 50% to 95% (7/9 were ≥80% CC) of the tumor; 7 were combined with 1, and 2 were combined with 2 other GCT components. The non-CC components included teratoma (5/9), seminoma (2/9), yolk sac tumor (2/9), and embryonal carcinoma (2/9). Lymphovascular invasion, spermatic cord invasion, and tunica vaginalis invasion were present in 15/15, 5/15, and 1/12 cases, respectively. In mixed GCTs, these locally aggressive features were attributed to the CC component, except in 1 tumor in which it was also exhibited by the embryonal carcinoma component. Lymphovascular invasion was multifocal to widespread in 73% of tumors. The stages of the 15 tumors were: pT2 (10), pT3 (5); NX (1), N1 (4), N2 (5), N3 (5); and M1a (2) and M1b (13). Distant organ metastasis mostly involved the lungs (11) and liver (10). Follow-up information was available in 14 patients, all of whom received cisplatin-based chemotherapy. All 6 pure CC patients were dead of disease (range, 6 to 14 mo, median 9.5 mo). Follow-up of 8 patients with predominant CC (range, 10 to 72 mo, median 27 mo) showed that 5 died of the disease, and 1 was alive with disease and 2 were alive with no evidence of disease at 60 and 72 months of follow-up, respectively; these latter 2 patients were the only ones with M1a disease on presentation. This series confirms the proclivity for high-stage presentation including presence of distant metastasis, hematogenous spread, and poor outcome of testicular CC. Mixed GCT with a predominant CC component has similar tendency for high-stage presentation, marked elevation of serum β-hCG levels, and aggressive behavior compared with pure CC. This study also showed that distant metastasis by CC when only involving the lungs (M1a) may not be uniformly fatal with chemotherapy. The mononucleated trophoblastic columns in testicular CC appear to be a mixture of cytotrophoblasts and intermediate trophoblasts, similar to that described in gestational CC.

Aims and Background: This paper deals with the clinical significance of the immunohistochemical expression of MAGE-A1, MAGE-A3/4 and NY-ESO-1 antigens in patients with non-small cell lung cancer (NSCLC)., Methods and Study Design: The study included 80 patients with NSCLC (40 with adenocarcinoma, 40 with squamous cell carcinoma) who had undergone surgery. MAGE-A1 and MAGE-A3/4 antigen expression was determined by an immunohistochemical method using the monoclonal antibody 57B, and NY-ESO-1 antigen expression was determined with the addition of the B9.8.1.1 antibody. The expression of these antigens was compared with the clinicopathological features of the tumors and the survival of the patients., Results: MAGE-A1, MAGE-A3/4 and NY-ESO-1 were expressed in 17.3%, 44.4% and 18.5% of NSCLC patients, respectively. A statistically higher immunohistological expression rate of MAGE-A3/4 was found in squamous cell carcinoma (P <0.001) and a significantly higher amount of tumor necrosis was observed in tumors with MAGE-3 expression (P = 0.001), but no correlation with positive lymph nodes was found. There was a statistically significant correlation between MAGE-A1 expression in adenocarcinoma and the presence of tumor necrosis (P = 0.05). Furthermore, there was a significant correlation between NY-ESO-1 expression and positive lymph nodes in adenocarcinoma, but not in squamous cell carcinoma. No statistically significant difference in patient survival was found with regard to tumor type and the observed histopathological characteristics except tumor size. Statistically significantly better survival was found in the group of patients with adenocarcinomas who had positive expression of MAGE-A3/4 (P = 0.012)., Conclusions: This study demonstrated that the expression of MAGE-A3/4 antigen might be a valuable prognostic factor regarding survival in patients with NSCLC.

Background/aim: Recently, a novel circulatory system, the primo vascular system (PVS), was found to be a potent metastatic route of cancer cells. The aim of the current work is to demonstrate that cancer cells injected into the testis migrate through the primo vessel (PV)., Materials and Methods: NCI-H460 cells labeled with fluorescent nanoparticles (FNP) or green fluorescent protein (GFP) gene transfection were injected into testicular parenchyma in 24 rats. After 24 hours of injection, the abdominal cavity was investigated via a stereomicroscope, to detect the PVS, and the samples were analyzed histologically with 4',6-diamidino-2-phenylindole (DAPI) and hematoxylin and eosin., Results: Injected cancer cells were detected inside the PVS distributed on the abdominal organs. Some were detected inside intestinal parenchyma into which the attached primo vessels (PVs) entered., Conclusion: The results supported the fact that the PVS may be a novel migration path of cancer cells, in addition to the lymphatic and hematogenous routes., (Copyright © 2013. Published by Elsevier B.V.)

TCam-2 cells are the main in vitro model for investigations into seminomatous tumors. However, despite their widespread use, questions remain regarding the cells' homogeneity and consequently how representative they are of seminomas. We assess the TCam-2 cell line using routine and novel authentication methods to determine its homogeneity, identify any cellular sub-populations and resolve whether any changes could be due to generational differentiation. TCam-2, embryonal carcinoma cells (2102EP) and breast cancer cell (MCF7) lines were assessed using qRT-PCR, immunocytochemistry, flow cytometry and short tandem repeat analyses. Raman maps of individual cells (minimum of 10) and single scan spectra from 200 cells per culture were obtained. TCam-2s displayed the characteristic marker gene expression pattern for seminoma, were uniform in size and granularity and short tandem repeat analysis showed no contamination. However, based only on physical parameters, flowcytometry was unable to differentiate between TCam-2 and 2102EPs. Raman maps of TCam-2s comprised three equally distributed, distinct spectral patterns displaying large intercellular single spectral variation. All other cells showed little variation. Principal component, cluster and local spectral angle analyses indicated that the TCam-2s contained two different types of cells, one of which comprised two subgroups and was similar to some 2102EP cells. Protein expression corroborated the presence of different cells and generational differences. The detailed characterization provided by the Raman spectra, augmented by the routine methods, provide substantiation to the long-held suspicion that TCam-2 are not homogeneous but comprise differing cell populations, one of which may be embryonal carcinoma in origin.

Extracardiac rhabdomyomas, which currently are classified into fetal, adult, and genital types, are rare. We have identified 7 cases of a distinct morphologic variant of rhabdomyoma that affects mainly young men in the paratesticular region, seen in consultation between 2001 and 2011. The 7 male patients were adults (median age 24 y) and presented with tumors in paratesticular soft tissue (4 left-sided, 3 right-sided). Grossly, the median tumor size was 4.5 cm (range, 2.0 to 12 cm), and lesions were well circumscribed with a uniform tan-white cut surface. Microscopically, these rhabdomyomas were characterized by bundles of large well-differentiated skeletal muscle cells with copious eosinophilic cytoplasm that were variably round, polygonal, and occasionally strap shaped. The tumor cells were set in a dense hyalinized collagenous stroma, often with adjacent prominent lymphoplasmacytic aggregates. Tumor cells had round, occasionally vesicular, nuclei (sometimes binucleate or multinucleate) with small or inconspicuous nucleoli. All tumors lacked nuclear atypia and necrosis. Mitotic activity was virtually absent, although 1 tumor showed a count of 1 per 50 HPF. All tumors were diffusely positive for desmin, 4/4 were diffusely positive for fast myosin, and 1/1 examined was positive for myf-4. All patients were treated by local excision (5 with positive margins). Four patients with known follow-up data had no evidence of tumor recurrence or disease progression (median follow-up time 8.5 mo). The clinical course as determined thus far is benign, similar to other types of rhabdomyoma. However, this rare paratesticular subset of rhabdomyomas appears to be morphologically distinct from rhabdomyomas at other locations and appears to represent a separate variant.

Background: Spermatocytic seminoma is a rare testicular germ cell tumor of old men. Accounting for 1-4% of all seminomas, spermatocytic seminomas have distinct pathogenesis, histological features, immunohistochemical profile and comparatively benign clinical behavior which distinguishes them from other germ cell tumors, especially classic seminoma., Aims: The purposes of our study were to assess the patient demographics, pathological features and to evaluate the utility of CD 117 immunostain along with other immunohistochemical stains in distinguishing Spermatocytic seminomas from classic seminomas., Material and Methods: All spermatocytic seminomas patients diagnosed during 1992 to 2013 at Section of Histopathology, Department of Pathology and Microbiology, Aga Khan University hospital were included. Patient characteristics, histological details and follow-up data of few patients were available. CD 117 expression was determined by immunohistochemistry., Results: Total 16 cases of Spermatocytic seminomas were reviewed. Median age was 60 years and average tumor size was 10.4 cms. Microscopically, all of the 16 cases showed presence of edema and absence of lymphocytic infiltrate and intratubular germ cell neoplasia. Cytoplasmic glycogen was negative in all 13 cases, PLAP immunostain was negative in all 12 cases, while CD 117 was positive in all 8 cases, where applied., Conclusion: CD 117 is of limited utility in differentiating the spermatocytic seminoma from classic seminoma as it is expressed in significant number of spermatocytic seminomas. However, different histological features, PAS special stain and PLAP immunostain are significantly helpful in distinguishing these two entities.

We herein report the case of a right-sided testicular fibrothecoma in a 17 year old male and review the pertinent literature relatable to this rare, benign lesion., Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7738283021019280.

Paratesticular liposarcoma is a rare neoplasm, described in single case studies or components of larger studies, as histologically well-differentiated liposarcoma (WDL) and dedifferentiated liposarcoma (DL). However, leiomyosarcomatous differentiation is an extremely rare occurrence in WDL and DL. We report a case of leiomyosarcomatous differentiation in a 77-year-old man. The patient presented with a painless right scrotal mass. Magnetic resonance imaging showed a large mass along the right spermatic cord. The resected mass, measuring 17.5 × 12 × 5 cm, was composed of a high-grade pleomorphic undifferentiated sarcomatous component with necrosis. Atypical smooth muscle differentiation was also detected. Additional tumor sampling revealed the presence of a WDL component. Immunohistochemical analysis of the pleomorphic sarcomatous component showed positive staining for MDM2 and CDK4, and negative staining for alpha smooth muscle actin (αSMA) and desmin. The smooth muscle component was positive for αSMA and desmin, and negative for MDM2 and CDK4. Extension from primary retroperitoneal sarcoma was not proved. We diagnosed of DL with leiomyosarcomatous differentiation., Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1484291498104021.

A 19-year-old male Caucasian, without prior medical history, noticed a painless right testicular mass. Physical examination revealed neither gynecomastia nor abnormal skin pigmentation. Serum alpha-fetoprotein, β-HCG and testosterone levels were normal. Sonography depicted an intratesticular diffusely hyperechoic lesion with acoustic shadowing. The patient underwent right orchiectomy. Histology revealed a benign large cell calcifying Sertoli cell tumour. This tumour is rare and may be associated with genetic abnormalities., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Benign intratesticular spindle cell lesions are rare. Herein, we report the morphology, immunohistochemical characteristics, and prognosis of 16 cases of testicular fibrothecoma. The mean age at diagnosis was 44 years (16 to 69 y). Of 15 patients with information, 14 presented with a palpable testicular mass and 1 with heaviness in the scrotum. Medical histories included bilateral orchidopexy as a child (n=1) and testicular atrophy receiving testosterone replacement (n=1). The average size was 1.8 cm (median 2 cm; range, 0.5 to 7.6 cm). All cases were intratesticular, although 13 were abutting the tunica albuginea with others centered on the rete testis (n=2), or were indeterminate on biopsy (n=1). Eleven cases were relatively well circumscribed, although not encapsulated, with 1 being infiltrative and 4 not evaluable. Four tumors showed entrapment of seminiferous tubules. Half of the fibrothecomas showed a mixed storiform pattern and short fascicles, with 6 storiform only and 2 short fascicles only. One half of the tumors were very hypercellular. Cases were equally split between having plumper ovoid as opposed to spindled pointed nuclei, with all cases lacking prominent nucleoli. Eleven cases had 0 to 2 mitoses per 10 HPF, 3 had 4 to 5 mitoses per 10 HPF, and 2 had 9 to 10 mitoses per 10 HPF. Collagen deposition either in bands or investing single cells ranged from none to extensive, with 10/16 cases having at least a moderate amount. Immunohistochemical positivity was as follows: inhibin (11/13, patchy to diffuse); calretinin (5/9); Melan-A (4/4); pan keratin (5/8); BCL2 (3/4); CD34 (3/8); S100 (4/8); muscle-specific actin (4/4); and desmin (5/8). Patients were followed up for a mean of 71.8 months (range, 3 to 144 mo). All were well with no evidence of disease. Of the 2 men with 9 to 10 mitoses per 10 HPF, 1 died of other causes 5 years and 8 months later, and the other had no evidence of disease at 4 years and 10 months after surgery. In summary, testicular fibrothecomas are rare with somewhat variable histology and can have worrisome histologic features such as minimal invasion into surrounding testis, high cellularity, and increased mitotic rate. Their immunoprofile is variable and typically not diagnostic. Despite some worrisome histologic features, they appear uniformly benign in their behavior.

Sertoliform cystadenoma of the rete testis represents an uncommon benign tumour. They appear in patients from 26 to 62 years of age. We describe a case of a 66-year-old man with a tumour in the area of the epididymal head. The tumour markers were not increased. Under the assumption of a malignant testicular tumour an inguinal orchiectomy was performed. The cut surface of this tumour was of grey/white color and showed small cysts. The tumour consisted of two compartments. The epithelial like tumour cells showed a sertoliform growth pattern and cystic dilatations. In between the tumour cells repeatedly actin expressing sclerotic areas could be recognized as the second tumour component. Proliferative activity was not increased. Immunohistochemically the tumour cells were positiv for inhibin, S-100, and CD 99. Alpha feto protein (AFP), human chorionic gonadotropin (ß-HCG) and placental alkaline phosphatase (PLAP) as well as synaptophysin, epithelial membrane antigene (EMA), and BCL-2 were not expressed. As far as we know this is the sixth reported case of this tumour. Because of the benign nature of this tumour the correct diagnosis is important for the intra- and postoperative management. Here we present a case of this rare tumour and discuss potential differential diagnosis., Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1956026143857335.

Background: Leiomyomas are benign tumours that originate from smooth muscles. They are often seen in the uterus, but also in the renal pelvis, bladder, spermatic cord, epididymis, prostate, scrotum or the glans penis. Leiomyomas of the tunica albuginea are extremely rare., Case Presentation: A 59-year-old white male has noted an asymptomatic tumour on the right side of his scrotal sac for several years. This tumour has increased slowly and caused local scrotal pain. An inguinal incision was performed, in which the hypoplastic testis, the epididymis and the tumour could be easily mobilized. Macroscopically the tumour showed a solid round nonencapsulated whorling cut surface. Histologically the diagnosis of a leiomyoma was made., Conclusion: We report here a very interesting and rare case of a leiomyoma of the tunica albuginea. Leiomyomas can be a possible differential diagnosis in this area., Virtual Slides: http://www.diagnosticpathology.diagnomx.eu/vs/2585095378537599.

Recent studies have suggested that mRNAs transcribed from cancer/testis genes might be used as biomarkers of cancer cells migrating through the bloodstream. Using RT-PCR we evaluated the expression of several cancer/testis mRNAs (MAGEA1-6, GAGE1-8, NY-ESO-1, SSX1, 2, and 4, XAGE1 and MAGEC1) in primary tumors and peripheral blood samples of colorectal cancer patients. The detection rate of at least one of the transcripts was 95% (37/39 samples) for primary tumors and 81% (52/64 samples) for the peripheral blood. Moreover, selected mRNAs were detectable in cellular fraction of the peripheral blood at all stages the disease (14 out of 14 cases), whereas in extracellular fraction of plasma were found only at stages III and IV. Obtained data open a possibility of early diagnosis of colorectal cancer in people at high risk by peripheral blood analysis.

Testicular spermatocytic seminoma (SS) is a rare tumor type predominantly found in elderly men. It is thought to originate from spermatogonia and shows cytological and genetic heterogeneity. In this study, we performed for the first time a comprehensive analysis of epigenetic modifications in a series of 36 SS samples. We assessed by immunohistochemistry tumor DNA methylation levels, the expression of methyltransferases DNMT3A, DNMT3B and DNMT3L as well as levels of histone modifications H3K9me2, H3K27me3, H3K4me1, H3K4me2/3, H3K9ac, and H2A.Z. We did not identify any epigenetic marks that matched the pattern of the supposed cell-of-origin, the spermatogonia, and found no correlation between specific marks and the size of the SS cells. The emerging epigenetic picture of SS is a heterogeneous "salt-and-pepper"-like pattern, with neighboring cells displaying very variable levels of epigenetic marks. We conclude that SS cells display apparent epigenetic heterogeneity and instability, with loss of the organized manner typical for normal germ cell maturation in the adult testis, likely due to the lack of regulatory signals from the absent somatic cell niche., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We report 2 cases of localized, microscopic diffuse large B-cell lymphoma (DLBCL) that were detected incidentally within pseudocysts. In case 1, the neoplasm was identified within a 26-cm, 860-g adrenal gland pseudocyst. In case 2, the neoplasm was detected within a 9-cm, 90-g paratesticular pseudocyst. In both cases, the neoplastic cells were large, had a nongerminal center B-cell immunophenotype, and were positive for Epstein-Barr virus (EBV)-encoded RNA detected by in situ hybridization. The most appropriate classification of these tumors using current World Health Organization classification is uncertain. The best fit seems to be DLBCL associated with chronic inflammation (DLBCL-CI), defined as DLBCL arising in the context of long-standing chronic inflammation and associated with EBV infection, with the prototype for this category being pyothorax-associated lymphoma. This term has been used by others in the literature for tumors similar to the cases reported here. However, in the 2 cases we report chronic inflammation was not a prominent feature, and the inflammatory cells that were present showed little relationship to the lymphoma cells. The findings in these cases have led us to question the role of chronic inflammation in pathogenesis. Perhaps the closed space of the pseudocyst, by preventing a cytolytic response to EBV-infected cells, results in local immunodeficiency that may be most important for pathogenesis. We also have concerns about using the term DLBCL-CI for these tumors. Perhaps the cases we report and the few other similar cases reported previously deserve their own category in a future version of the World Health Organization classification.

Yolk sac tumors may exhibit numerous patterns. One that has received little attention overall, yet is not uncommon, is a solid pattern, which is especially prone to misinterpretation, usually as seminoma, in biopsy specimens from metastatic or mediastinal sites. This distinction is of critical importance as the 2 tumors are treated differently. To determine features useful in the diagnosis of solid yolk sac tumor we reviewed 52 germ cell tumors (28 testicular primaries, 21 metastases from the testis, and 3 mediastinal primaries) that had a yolk sac tumor component with foci of solid growth, defined as a sheet-like arrangement of tumor cells occupying >2 mm and with no or only rare microcysts. Solid yolk sac tumor was almost always associated with other patterns, most commonly microcystic/reticular (75%), glandular (35%), and myxoid (25%). The solid foci consisted of sheets of cells with usually abundant cytoplasm that was mostly (85%) pale to clear and frequently had intercellular basement membrane deposits (75%), rare microcysts (67%), significant nuclear pleomorphism (65%), and hyaline globules (65%). In 2 cases (4%), the cells were small with scant cytoplasm (blastema-like variant). A myxoid background (39%), lymphocytic infiltrate (17%), and an appliqué pattern (8%) were sometimes observed. On immunostaining, AE1/AE3 cytokeratin and glypican 3 provided the most intense and diffuse reactivity for solid yolk sac tumor, whereas α-fetoprotein was negative in 38%. CD117 stained 59%, whereas only rare cells in 1 case (3%) were weakly reactive for podoplanin; OCT3/4 was uniformly negative. We conclude that solid yolk sac tumor can generally be recognized by careful morphologic evaluation, especially its association with other yolk sac tumor patterns, the presence of intercellular band-like deposits of basement membrane, occasional microcysts, nuclear pleomorphism, intracellular hyaline globules, and usual absence of lymphocytes. In difficult cases a concise immunohistochemical panel consisting of AE1/AE3, glypican 3, and OCT3/4 distinguishes solid yolk sac tumor from other neoplasms. α-fetoprotein stains are commonly negative or weak and focal in solid yolk sac tumor and cannot be solely relied on for diagnosis. Common CD117 positivity in solid pattern yolk sac tumors makes it an unreliable discriminator between yolk sac tumor and seminoma.

Sertoli cell tumor is a potential histologic mimic of other tumors, such as seminoma due to similar histology and overlapping clinical presentation. Sclerosing Sertoli cell tumor is a rare sex cord stromal tumor variant, with 16 cases reported in the English literature. We present an unusual case of sclerosing Sertoli cell tumor in a 33-year-old Caucasian male, which was negative or weakly reactive using immunohistochemical markers typically positive in Sertoli cell tumors. The tumor was positive for cytokeratin AE1/AE3, CAM 5.2, vimentin, CD56, CK8, synaptophysin and S100, and negative for inhibin, calretinin, WT1, CD99, CD117, CK5/6, CK7, chromogranin A, placental alkaline phosphatase, neuron specific enolase, D2-40, smooth muscle actin, Melan-A, epithelial membrane antigen and carbonic anhydrase IX. This is the second reported case of a Sertoli cell tumor with reactivity limited to neuroendocrine markers and the first such case of the sclerosing variant. A literature review of sclerosing Sertoli cell tumor, including English and non-English literature, is described. Our case highlights that expected immunohistochemical markers may be negative, and awareness of antigenically unreactive tumors is needed to avoid confusion between Sertoli cell tumor and other entities., (Copyright © 2011 Elsevier GmbH. All rights reserved.)

Adenomatoid tumors are rare benign neoplasms thought to be of mesothelial origin. Although most reported cases arise from the epididymis, rare cases have been reported in the spermatic cord, testicular tunica, ejaculatory ducts, prostate, and suprarenal recess. We describe a 4.5-year-old boy who presented with a relatively asymptomatic right testicular mass that was resected and confirmed to be adenomatoid tumor of the testis by histopathology. Because of its rarity, the clinical and histopathologic aspects are discussed., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Aspects of the biopsy of the testis from the pathologist's point of view are discussed. Direct enzyme-histochemical staining for alkaline phosphatase (dAP) on frozen sections of biopsies taken during operation is a useful diagnostic tool to aid surgeons in testis-sparing surgery. Biopsy of the contralateral testis for the diagnosis of carcinoma in situ (CIS) in patients with a testicular germ cell tumour is not standard of care in most countries because of the high rate of negative biopsies. Based on risk factors for germ cell tumours, i.p. microlithiasis, a patient population is defined in which the rate of CIS in the contralateral biopsy is about 25%. It is reiterated that the diagnosis of CIS in testicular biopsies requires expertise, and should not be carried out without immunohistochemistry for markers for CIS. As OCT3/4 is increasingly used as marker, it is important to be aware that it may be false-negative in biopsies fixed in Bouin's or Stieve's fixative. Preliminary results are presented on a series of biopsies from cryptorchid testes in infants and children allowing the definition of morphological and immunohistochemical criteria for delayed maturation of gonocytes and pre-CIS., (© 2011 The Authors. International Journal of Andrology © 2011 European Academy of Andrology.)

Second- to fourth-digit length ratio, 2D:4D, is a marker of testosterone level during foetal life that was found associated with sperm concentration or testosterone levels in some studies, but not in others, a difference possibly related to the way the ratio is assessed. In this study, 2D:4D was assessed in 122 men partners of pregnant women and in 71 testicular cancer patients using a new method based on direct measurements of finger lengths. In addition, we investigated the association between 2D:4D, birth weight, testicular volume, semen quality and time to pregnancy. A validation study of the method demonstrated high reliability and reproducibility. Neither digit lengths nor 2D:4D significantly differed in both groups of men. We found a significant negative association between 2D:4D and birth weight in testicular cancer patients. In fertile men, 2D:4D was associated with testicular volume (r=-0.36, p<0.001), total sperm number (r=-0.18, p=0.04) and time to pregnancy (r=0.24, p<0.02). In addition, participants with a history of epididymal cyst had a significantly higher 2D:4D than those without cysts. In conclusion, all significant findings indicate that the human male reproductive function is negatively related to 2D:4D. However, 2D:4D for testicular cancer patients does not point to a hormonal imbalance during foetal life as the common cause for developing germ-cell cancer. Such results obtained, thanks to an easy, direct and reliable method for measuring finger lengths, suggest the usefulness of this new tool in fertility studies as well as for studying men with developmental disorders of the reproductive tract., (© 2010 The Authors. International Journal of Andrology © 2011 European Academy of Andrology.)

We report a case of intratesticular endometrioid papillary cystadenocarcinoma. A 73-year-old man was admitted for a painless right scrotal swelling. Ultrasonography and computed tomography revealed a large cystic mass in the right testis. Right scrotum puncture revealed xanthochromic fluid with negative cytology. Three months later, follow-up computed tomography showed enlargement of the cystic mass. Right high orchiectomy was performed because a testicular malignancy was suspected. The pathological diagnosis was endometrioid papillary cystadenocarcinoma, and the cells were strongly positive for the estrogen and progesterone receptors. Testicular neoplasms resembling common ovarian-type epithelial tumors are very rare. This is the first report of endometrioid papillary cystadenocarcinoma of the testis.

Adult testicular granulosa cell tumors are rare sex cord-stromal tumors of which only 28 have been previously reported. As compared with their ovarian counterparts, these tumors may follow a more aggressive course because the proportion of malignant cases is higher. To date, there are no clinical or pathologic features that definitively predict malignancy. We reviewed all prior case reports for features that may predict their malignant potential. Tumor size greater than 5.0 cm is the only feature statistically associated with malignancy. Mitotic count, tumor necrosis, patient age, and the presence of gynecomastia do not, at present, predict benign versus malignant behavior.

Apoptotic protease activating factor-1 (APAF-1) is a key regulator gene of apoptosis, located downstream from p53. Loss of APAF-1 expression is associated with chemorefractory malignant melanoma and neuronal cell differentiation. In order to make clear the function of APAF-1 in the carcinogenesis of germ cell tumors, we evaluated the expression levels of APAF-1 and several apoptosis and differentiation markers by immunohistochemistry in formalin-fixed paraffin-embedded samples from 43 cases of testicular germ cell tumor (TGCT) and six specimens of normal testis tissue. Expression of cleaved caspase-3, Oct-3/4, and Ki-67 were also examined by immunohistochemistry to evaluate apoptotic reactivity, tumor differentiation, and proliferation activity, respectively. APAF-1 was downregulated in two TGCT cell lines by siRNA transfection, and subsequent expression of the Ki-67 and Oct-3/4 genes and differentiation markers of three embryonic germ layers including keratin16 (KRT16) for ectoderm, vimentin (VIM) for mesoderm and GATA4 for endoderm were then tested. No significant relationship was found between APAF-1 expression and apoptotic activity in TGCTs. Expression of APAF-1, Oct-3/4, and Ki-67 was significantly higher in seminomas than in non-seminomas. In TGCTs, higher APAF-1 expression was correlated with higher proliferation (high Ki-67) and a lower degree of differentiation (high Oct-3/4). Interestingly, the expression of APAF-1 gradually decreased in accordance with tumor differentiation (seminoma and embryonal carcinoma > teratoma). Downregulation of APAF-1 in TGCT cell lines resulted in a decrease of Ki-67 and Oct-3/4 and an increase of VIM and KRT16 gene expression. These data show that higher expression of APAF-1 is related to an undifferentiated state in the TGCT pathway., (© 2010 Japanese Cancer Association.)

Tumor lysis syndrome has been observed in patients with bulky, treatment-sensitive tumors, in particular hematological malignancies, especially after medical treatment (chemotherapy, corticosteroids, radiation, hormonal agents, and biological response modifiers). Tumor lysis syndrome has been observed also in solid malignancies and it very rarely occurs spontaneously. Tumor lysis syndrome-associated metabolic abnormalities include hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia and uremia. Severe hypoglycemia is another rare metabolic disorder, uncommonly associated with solid malignancies. The case described here is peculiar for the abrupt onset of these two rare conditions in a patient with a metastatic germ cell tumor.

Podoplanin, a 38-kd membrane glycoprotein of podocytes, is the human homologue of mouse protein, aggrus, a 44-kd sialoglycoprotein; the latter has recently been reported in testicular seminomas but not in embryonal carcinomas, suggesting that it may be a specific marker for seminomas. The physiologic role of podoplanin has yet to be determined and its function in tumors is not well characterized. In this study we investigate the utility of podoplanin expression in the diagnosis of testicular germ cell tumors. Sixty-eight cases of testicular mixed germ cell tumors were analyzed using a polyclonal antibody and compared to the results for OCT3/4. Stained sections were graded semiquantitatively as follows: negative (no expression), 1+ (mild intensity), 2+ (moderate intensity), 3+ (intense staining). Diffuse cytoplasmic expression of podoplanin with membrane accentuation was seen in the seminoma component of all cases. Lymphocytes and interstitial cells were negative. In mixed germ cell tumors, podoplanin identified small clusters of seminoma cells lying adjacent to nonseminomatous components. Focal staining was present in one third of cases of choriocarcinoma. There was no significant staining of any nontrophoblastic, nonseminomatous elements. In contrast to OCT3/4, podoplanin does not stain embryonal carcinoma. The availability of a marker for seminoma will enable better recognition and distinction from embryonal carcinoma, particularly in nongonadal sites. The identification by podoplanin of seminoma cells lying adjacent to foci of embryonal carcinoma gives credence to the hypothesis that the latter arise from seminomas as part of a process of "differentiation.", (Copyright © 2010 Elsevier Inc. All rights reserved.)

Sclerosing rhabdomyosarcoma (SRMS) is an infrequent variant of rhabdomyosarcoma characterized by extensive intercellular hyaline fibrosis. We report the case of a 37 year-old male with a 9 x 6 cm SRMS on the right elbow. Histologically, the tumor showed an abundant extracellular hyaline matrix with extratumoral vascular emboli and microscopic foci of fusocellular embryonal rhabdomyosarcoma (FRMS) separated by a fibrotic band from the sclerosing areas. One year later the patient presented with a right intratesticular tumor of 1.2 x 0.8 cm, which was reported as pure FRMS. Immunohistochemically, SRMS was positive only for MyoD1 and Vimentin and negative for Myogenin and Desmin. Both the elbow emboli with the extratumoral foci of FRMS and the intratesticular tumor were positive for Myogenin, MyoD1, Vimentin and Desmin. Using fluorescent in situ hybridization (FISH), the SRMS and the FRMS tumor cells of the elbow and the FRMS tumor cells of the testis were found to be negative for FOXO1A translocation in chromosome 13. PCR chimeric transcriptional products PAX3-FKHR and PAX7-FKHR were not found. Six months following testicular resection, the patient died of multiple metastases in the mediastinum, lung and right thigh.

Background: Human seminoma is classified as classical seminoma (SE) and spermatocytic seminoma (SS). Human SE is known to be more malignant and metastasizing more frequently than SS. Tumor angiogenesis is highly related with tumor progression and metastasis, with microvessel density (MVD) being an important parameter of metastatic potential. Canine seminoma is not yet well-established as SE or SS type including correlation with angiogenesis. We classified canine SE and SS, and then compared them to tumor associated vessels., Methods: Twenty-three cases of canine seminomas (2 intratubular, 9 diffuse, and 12 intratubular/diffuse seminomas showing both intratubular and diffuse patterns) were classified as SE or SS by immunohistochemistry (IHC) using monoclonal antibody against PLAP and by PAS stain. The histopathological data were then compared to see if there was a correlation with SE or SS. Angiogenesis of seminomas were evaluated by immunohistochemical assay using polyclonal antibody against Von Willebrand factor (vWF) and by calculating the means of MVD, vessels area and perimeters using computerized image analysis. Statistical Package for Social Sciences (SPSS) program was used for various statistical analyses., Results: The numbers of PLAP+/PAS+ canine SEs were 8/23 (34.8%) and PLAP-/PAS- SSs were 15/23 (61.2%). All SE cases (8/8, 100%) were intratubular/diffuse types. SS types included 2 intratubular (2/15, 13.3%), 9 diffuse (9/15, 60%), and 4 intratubular/diffuse (4/15, 26.7%) types. MVD and vascular parameters in SEs were significantly higher than in SSs, showing the highest value in the intratubular/diffuse type. Seminomas observed with neoplastic cells invasion of vessels presented higher perimeter and area values than seminomas without conformed neoplastic cells invasion., Conclusion: In this study, we demonstrated a positive relationship between canine SE and tumor angiogenesis. Furthermore, we also showed that a tumor cells invasion of vessels were a correlated vascular parameter. Although metastasis of canine seminomas has rarely been reported, our results support that canine SE could have high metastatic potential similar to the human counterpart. Further studies are required to clarify the relationship between canine SE and clinical data with metastatic factors.

Primary testicular lymphomas display mostly aggressive diffuse large cell B-cell lymphomas, which could be further subclassified into germinal center B-cell-like and an activated B-cell phenotype via immunohistochemistry. A retrospective analysis of primary testicular lymphomas diagnosed at the Institute of Pathology, Salzburger Landeskliniken (SALK) between January 1997 and December 2008 was done. Immunohistochemical staining and complete clinical data evaluation was carried out and linked to overall survival time. We found 18 cases of primary testicular lymphoma diagnosed in elderly patients showing no side predilection and having an aggressive clinical behavior with short overall survival independent of treatment. The lymphomas could for the most be classified into diffuse large cell B-cell lymphomas [15/18 (83.3%)] showing a non-significant prevalence of activated B cell phenotype [9/15 (60%)] compared to the germinal centre phenotype [6/15 (40%)]. Two of the cases were mantle cell lymphomas consisting of the infrequent pleomorphic subtype. The survival analysis revealed no significant difference for any of the investigated antigens. Primary testicular lymphomas are for the most DLBCL, but subtype classification reveal molecular heterogeneity inside this lymphoma entity. A distinction between those subtypes is necessary because of different clinical behavior and treatment.

Background: The urokinase plasminogen activating system (uPAS) is implicated in neoplastic progression and high tissue levels of uPAS components correlate with a poor prognosis in different human cancers. Despite that, relative few studies are available on the expression and function of the uPAS components in human seminomas. In the present study we characterized the expression of the urokinase plasminogen activator (uPA), its cognate receptor (uPAR) and the uPA inhibitors PAI-1 and PAI-2 in normal human testis and seminomas., Methods: The expression of the above genes was evaluated by means of quantitative RT-PCR, western blot, zymographic analysis and immunohistochemistry., Results: Quantitative RT-PCR analysis of 14 seminomas demonstrated that uPA and uPAR mRNAs were, with respect to control tissues, increased in tumor tissues by 3.80 +/- 0.74 (p < 0.01) and 6.25 +/- 1.18 (p < 0.01) fold, respectively. On the other hand, PAI-1 mRNA level was unchanged (1.02 +/- 0.24 fold), while that of PAI-2 was significantly reduced to 0.34 +/- 0.18 (p < 0.01) fold. Western blot experiments performed with protein extracts of three seminomas and normal tissues from the same patients showed that uPA protein levels were low or undetectable in normal tissues and induced in tumor tissues. On the same samples, zymographic analysis demonstrated increased uPA activity in tumor tissue extracts. Western blot experiments showed that also the uPAR protein was increased in tumor tissues by 1.83 +/- 0.15 fold (p < 0.01). The increased expression of uPA and uPAR was further confirmed by immunohistochemical staining performed in 10 seminomas and autologous uninvolved peritumoral tissues. Finally, variation in the mRNA level of PAI-1 significantly correlated with tumor size., Conclusions: We demonstrated the increased expression of uPA and uPAR in human seminomas with respect to normal testis tissues, which may be relevant in testicular cancer progression.

Necrotic testicular tumors are relatively frequent and can present a significant diagnostic challenge. Because of differing treatments for seminomas versus nonseminomas, accurate diagnosis is critical. Eleven totally (n=9) or almost totally (n=2) necrotic testicular tumors were retrieved from our consult files. The submitting pathologists favored benign processes in 4 cases, Leydig cell tumor in 1, and lymphoma in 1. The cases were evaluated for histologic features and, when material was available, by immunostaining with 7 antibodies: keratin (AE1/AE3), OCT4, placental alkaline phosphatase, alpha-fetoprotein (AFP), CD117, CD30, and S100. Only distinct reactivity in a cellular distribution in the necrotic zone was considered positive; nuclear reactivity alone was scored for OCT4 and membrane reactivity for CD117 and CD30. Mean patient age was 35 years (range 16-63). Mean tumor size was 19 mm (range 7-53). All patients presented with unilateral testicular masses (6 right, 5 left); 2 also had acute pain. The combination of histologic features, immunostains and, in 1 case, serum AFP permitted classification of 8 tumors (4 seminomas, 3 embryonal carcinomas, 1 yolk sac tumor). Three were not classifiable. The necrotic seminomas lacked associated coarse intratubular calcifications and were positive for OCT4 (4/4) and CD117 (3/3) but negative for keratin (0/4) and CD30 (0/4). The necrotic embryonal carcinomas had associated coarse intratubular calcifications and were positive for keratin (2/3), OCT4 (2/2), and CD30 (3/3). OCT4 stained 1 unclassifiable tumor, which lacked other specific markers. We did not find placental alkaline phosphatase, AFP, and S100 stains useful, although S100 did highlight tumor "ghost" cells in 1 case. Other features in most cases included intratubular germ cell neoplasia (6/11), tubular atrophy/hyalinization (10/11), tumor "ghost" cells (10/11), scar (9/11), and inflammation (10/11). Of the 5 patients with available follow-up, 3 were free of disease at 1, 5, and 8 years after orchiectomy (2 necrotic seminomas and 1 germ cell tumor, unclassified). One patient with yolk sac tumor (age 63 y) developed widespread metastases after 15 months and died of disease. The final case was initially misinterpreted as "testicular infarction, no malignancy" and 16 months later the patient developed a large retroperitoneal seminoma. Most totally necrotic testicular tumors can be placed into clinically important groups by assessment for coarse intratubular calcifications and staining reactions for keratin, OCT4, CD117, and CD30.

Background: We describe 6 cases of a poorly recognized vascular neoplasm that can simulate angiosarcoma., Design: Cases of a rare vascular tumor with a proclivity for the genitourinary tract encountered in our consultation material were prospectively collected between the year 1999 and 2008. Follow-up information was obtained when possible., Results: There were 6 tumors from 4 men (66%) and 2 women, ranging in age from 49 to 75 years (median, 59.5) involving the kidney and renal hilum (4, 66%) and testis (2). Tumors ranged from 1.3 to 1.7 cm (median, 1.6 cm) and were grossly well-marginated with a hemorrhagic mahogany spongy appearance. Microscopically, at low power they had a loosely lobulated architecture and were associated with a medium-caliber vessel (5/6, 83%). Most kidney (3/4, 75%) tumors showed minor extensions into adjacent adipose tissue. At higher magnification, the tumors consisted of anastomosing sinusoidal capillary-sized vessels with scattered hobnail endothelial cells within a framework of nonendothelial supporting cells. There was a minimal inflammatory backdrop consisting of lymphocytes but not plasma cells or acute inflammation. Mitoses were absent (5/6, 83%) or rare (1 case; in supporting cells). There was mild cytologic atypia in one of the cases but no multilayering of endothelial cells in any case. Vascular thrombi were typical (5/6, 83%) and the lesions had zones of central sclerosis with focal necrosis (5/6, 83%). Two (33%) tumors featured prominent extra-medullary hematopoiesis and 2 tumors (33%) had striking hyaline globules reminiscent of those seen in Kaposi's sarcoma. Immunohistochemistry was available on some cases and the lesions stained with CD34, CD31, and FVIII but not human herpes virus type 8, keratin AE1/3, epithelial membrane antigen, HMB45, placental alkaline phosphatase, or human chorionic gonadotropin. In all but one submitted consultation, the possibility of angiosarcoma had been raised based on the anastomosing vascular pattern. On follow-up, there were no recurrences or metastases in 5 cases (range: 8 to 36 mo; median 12 mo, mean 15 mo), and 1 patient was lost to follow-up., Conclusions: Anastomosing hemangioma of the genitourinary tract is a rare neoplasm displaying some overlapping features of both sinusoidal hemangioma and hobnail hemangioma of soft tissue and skin. However, in our opinion, it is a unique neoplasm with a proclivity for the kidney. Its anastomosing appearance can lead to concern for angiosarcoma but, despite small numbers and limited follow-up in our series, evidence to date supports that the lesion is benign.

Background: Rhabdomyosarcoma is the most common soft tissue sarcoma of children < 15 years of age., Case: We report a case of a paratesticular rhabdomyosarcoma diagnosed by fine needle aspiration (FNA) in an 18-year-old man with enlargement of the right testis. The FNA material revealed mainly isolated small to median-sized malignant cells with various shapes. Among these, large rhabdomyoblasts were observed. Some neoplastic cells showed longitudinal striations. Immunocytochemistry was strongly positive against vimentin and desmin, and results for cytokeratins, smooth muscle antibody, epithelial-membrane antigen, S-100 and neuron-specific enolase were negative. Histologic examination of the surgical specimen was in agreement with the FNA findings., Conclusion: FNA is a safe and accurate procedure, without implications, that could be used in the outpatient setting, allowing a preliminary, preoperative diagnosis, even for soft tissue tumors.