Mixed epithelial and stromal renal tumour in a 12-year-old boy.

Mixed epithelial and stromal tumour of the kidney (MESTK) is a rare kidney neoplasm that occurs almost exclusively in perimenopausal women. Long-term oestrogen replacement appears to play a major role in its pathogenesis. Around 70 cases have been described in the international literature, none of which involve male children. Herein, we describe an atypical case of MESTK diagnosed in a 12-year-old prepubertal boy who presented with hematuria. Pathology and immunohistochemistry revealed a typical MESTK. The child was free of disease at 2-year follow up after a partial nephrectomy and tumour excision.

Kinetics of HER2/neu ECD in 45 patients treated with trastuzumab (Herceptin) between January 2001 and June 2005 at the Grenoble University Hospital.

UNLABELLED: The aim of this study was to evaluate the utility of HER2/neu ECD concentration as a marker of the efficacity of clinical response to Herceptin. PATIENTS AND METHODS: Iterative measurements of HER2/neu ECD (ELISA c-erbB2/c-neu Rapid Format Elisa kit QIA10 Calbiochem) concentrations in 45 patients treated with Herceptin between January 2001 and June 2005 at the Grenoble University Hospital. RESULTS: Changes in HER2/neu ECD concentrations were observed in 21 patients (47%). The baseline concentration was the concentration of circulating HER2/neu ECD before treatment with Herceptin. In 15 patients, the mean baseline concentration was 52 ng mL(-1) (extreme values 13-170), which normalized no later than at the time of the 3rd administration of Herceptin. Nine patients (60%) were still alive 5 years later (p<0.05). For 6 patients, the mean baseline concentration was 800 ng mL(-1) (extreme values 140-2000) which persisted and even increased during Herceptin therapy; fewer than 25% were alive 30 months later (p<0.05). In the case of the 24 patients whose HER2/neu ECD concentration remained <5 ng mL(-1), survival time was intermediate. CONCLUSION: The study confirmed the utility of HER2/neu ECD in predicting therapeutic response. However, as in the case of other circulating tumor markers, it is only useful when there is a variation in concentration. This marker should now be evaluated in multi-center studies covering a large number of homogeneous subjects.

Can the sentinel lymph node technique affect decisions to offer internal mammary chain irradiation?

PURPOSE: Identification of the sentinel lymph node (SLN) for small mammary tumours (cT1N0) sometimes leads to detection of internal mammary chain (IMC) drainage. This information is often ignored by physicians. The present study sought to determine the frequency with which an internal mammary SLN was identified by peritumoral injection of radioactive tracer, and then to determine the patients in whom identification of an internal mammary SLN could have an impact on the radiation treatment plan. MATERIALS: Between March 2002 and March 2008, 622 SLN biopsies performed in a cohort of 608 patients were analysed. Technetium-labelled nanocolloids were administered via three peritumoral injections, completed by a deep prepectoral injection, with the entire procedure performed under echographic guidance. RESULTS: The SLN was identified in 607 of the 622 patients, including 174 (28.7%) in the IMC. A total of 161 successful internal mammary biopsies were performed. Of the 622 patients, 18 showed SLN involvement in the IMC. In 7 of these patients, only the internal mammary SLN was affected. Prophylactic irradiation of the IMC was indicated in 376 patients, but only in 18 (4.8%) of these patients was there effectively IMC involvement; internal mammary SLN biopsy failed in 7 patients (1.9%). CONCLUSION: SLN detection by peritumoral injection, combined with the systematic removal of the internal mammary SLN, enabled the involvement of this region to be found in a nonnegligible number of patients. Such information should make it possible to personalize treatment for patients with stage cT1 mammary cancer and thereby avoid needless internal mammary radiation therapy in a large number of patients (93.4% in our study).

Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer.

Hepatoblastoma, the most common pediatric liver cancer, is tightly linked to excessive Wnt/beta-catenin signaling. Here, we used microarray analysis to identify two tumor subclasses resembling distinct phases of liver development and a discriminating 16-gene signature. beta-catenin activated different transcriptional programs in the two tumor types, with distinctive expression of hepatic stem/progenitor markers in immature tumors. This highly proliferating subclass was typified by gains of chromosomes 8q and 2p and upregulated Myc signaling. Myc-induced hepatoblastoma-like tumors in mice strikingly resembled the human immature subtype, and Myc downregulation in hepatoblastoma cells impaired tumorigenesis in vivo. Remarkably, the 16-gene signature discriminated invasive and metastatic hepatoblastomas and predicted prognosis with high accuracy.

Evaluation of a manual ELISA kit for determination of HER2/neu in serum of breast cancer patients.

BACKGROUND: Our aim was to conduct an analytical validation in a routine laboratory setting of the cerb-B2/c-neu ELISA assay kit from Calbiochem used to measure the extracellular domain (ECD) of HER2/neu in the serum of breast cancer patients. MATERIALS AND METHODS: The evaluation was based on three different production lots used in a routine laboratory setting. The reference value was based on a population of 217 patients with breast cancer not overexpressing HER2. RESULTS: The detection limit, below that given by the manufacturer, was 0.34 ng ml(-1) and the quantification limit was 0.90 ng ml(-1). Reproducibility and repeatability were at least 95%, precision coefficients of variation varied between 6 and 8.5% and trueness measured by dilution tests and the standard additions method varied between 97 and 107%. The threshold was estimated at 5 ng ml(-1). CONCLUSION: This technique presents satisfactory levels of accuracy for routine laboratory use.

First case report of a fetal synovial sarcoma confirmed by molecular detection of SYT-SSX fusion gene transcripts.

Synovial sarcomas are aggressive malignant soft tissue tumors typically observed in adolescents and young adults. They are often characterized by the chromosomal translocation t(X;18)(p11.2;q11.2), which results in the expression of SYT-SSX fusion transcripts. We describe the first case of synovial sarcoma observed in a human fetus. The tumor occurred in the left upper arm and led to intrauterine fetal demise during gestational week 31. Grossly, the tumor measured 10 x 8 x 8 cm, appeared pinkish in color, and developed in the soft tissues of the left arm surrounding the humerus. Histologically, this large tumor showed a dense proliferation of homogeneous spindle cells with some necrotic areas. The positive detection of the SYT-SSX1 fusion transcripts with reverse-transcription polymerase chain reaction in formalin-fixed and paraffin-embedded tissue confirmed the synovial sarcoma diagnosis.

Tubulocystic carcinoma of the kidney: a new entity among renal tumors.

Tubulocystic carcinoma is a tumor entity, which is not yet included in the WHO-classification of renal tumors. We report a series of 11 cases of this tumor, 6 of which were examined in by immunohistochemistry using a panel of five antibodies (CK7, CK34betaE12, CK19, CD10 and P504S). All patients were men. Each had renal tumor stage of pT1N0M0, with a diameter of 1.7 to 7 cm (mean, 3.3 cm). None of the patients presented with recurrence or metastases. Grossly, tumors were microcystic masses with a bubble-wrap appearance. Histological features included cysts and small tubules, separated by delicate septa and lined by flat to columnar or hobnail cells. The cyst and tubule epithelium showed immunohistochemical characteristics of both proximal and distal tubules. Tubulocystic carcinoma is a distinctive kidney tumor, with noteworthy macroscopic and microscopic characteristics, which can be distinguished from other cystic kidney tumors, including cystic nephroma, multilocular cystic renal cell carcinoma and some solid tumors with extensive cystic changes. More cases are needed to ascertain its prognosis. Tubulocystic carcinoma should be considered as a new subtype of renal cell carcinoma in the next revision of the WHO classification.

Nuclear localization of protein kinase CK2 catalytic subunit (CK2alpha) is associated with poor prognostic factors in human prostate cancer.

Many genomic abnormalities have been identified in various subsets of prostate cancer, but until now, few genes have been associated with the progression of this cancer. High activity of protein serine/threonine kinase CK2 has been observed in various solid tumours and this alteration has been linked both to growth-related functions and to suppression of cellular apoptosis. Here, we provide the first evidence for a strong association between a nuclear localization of CK2alpha, evaluated by immunohistochemistry, and poor prognostic factors in a retrospective cohort of 131 human prostate adenocarcinomas. Nuclear CK2alpha localization is significantly correlated with higher Gleason score, more locally advanced disease (cT3-T4) and more perineural or lymphatic invasion (p<0.0019 to 0.046). In contrast, despite a strong trend, no significant relationship was found between higher initial PSA and nuclear CK2alpha localization. Thus, this previously undescribed molecular heterogeneity is the first step in defining CK2 as both a potential biomarker and a promising target in human prostate cancer.

Prospect for anti-HER2 receptor therapy in breast cancer.

The carcinogenesis process is characterized, in part, by the dysfunction of cellular communication pathways, such as the one involving HER2. HER2 is a member of the EGF receptor family, which participates in cell growth and proliferation. HER2 may be overexpressed in 15 to 30% of breast cancer cases and is associated with poor prognosis, shortened overall survival and shorter time to disease progression. Furthermore, an increasing number of studies have demonstrated the relevance of HER2 serum concentrations (sHER2, extracellular domain released into blood by proteolysis) as a predictive marker of resistance to chemotherapy in HER2-overexpressing metastatic breast cancer. The determination of HER2 overexpression/ amplification in the diagnosis of relapse of breast cancer is currently a routine procedure. Immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) techniques, which are used to detect HER2 expression in the tumor, are improving constantly, and other parallel techniques such as chromogenic in situ hybridization (CISH) are starting to emerge. sHER2 concentrations can be measured using ELISA techniques, which can be automated. All of these procedures still need to be standardized. The discovery of a monoclonal antibody (4D5) that can inhibit the growth and proliferation of cells overexpressing HER2 led to the development of trastuzumab. Like 4D5, trastuzumab recognizes an epitope on the extracellular domain of HER2. Moreover, trastuzumab is also able to stimulate antibody-dependent cellular toxicity (ADCC). It is administered alone or in combination (with navelbine, taxol, carboplatin...) in patients with metastatic breast cancer overexpressing HER2. Other active antibodies have since been discovered, as well as other specific molecules, such as tyrosine kinase inhibitors which will undoubtedly find a place in the therapeutic arsenal used in breast cancer, especially to avoid the emergence of resistance to treatment.

Prospect for anti-her2 receptor therapy in breast cancer.

The carcinogenic process is characterized, in part, by the dysfunction of cellular communication pathways, such as the one involving HER2. HER2 is a member of the EGF receptor family, which participates in cell growth and proliferation. HER2 may be overexpressed in 15 to 30% of breast cancer cases and is associated with poor prognosis, shortened overall survival and shorter time to disease progression. Furthermore, an increasing number of studies have demonstrated the relevance of HER2 serum concentrations (sHER2, extracellular domain released into the blood by proteolysis) as a predictive marker of resistance to chemotherapy in HER2-overexpressing metastatic breast cancer. The determination of HER2 overexpression/ amplification in the diagnosis of relapse of breast cancer is currently a routine procedure. Immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) techniques, used to detect HER2 expression in the tumor, are improving constantly and other parallel techniques such as chromogenic in situ hybridization (CISH) are emerging. sHER2 concentrations can be measured using ELISA techniques, which can be automated. All of these procedures still need to be standardized. The discovery of a monoclonal antibody (4D5) that can inhibit the growth and proliferation of cells overexpressing HER2 led to the development of trastuzumab. Like 4D5, trastuzumab recognizes an epitope on the extracellular domain of HER2. Moreover, trastuzumab is also able to stimulate antibody-dependent cellular toxicity (ADCC). It is administered alone or in combination (with navelbine, taxol, carboplatin, etc.) in patients with metastatic breast cancer overexpressing HER2. Other active antibodies have since been discovered, as well as other specific molecules, such as tyrosine kinase inhibitors which will undoubtedly find a place in the therapeutic arsenal used in breast cancer, especially to avoid resistance to treatment.

[Breast carcinoma with predominant neuroendocrine differentiation]. / Adénocarcinome mammaire avec composante neuroendocrine majoritaire.

Neuroendocrine differentiation can be identified in a subset of human breast carcinomas, either as scattered cells or as a predominant neuroendocrine component. We report a case of an invasive breast carcinoma largely composed of neuroendocrine cells. Eight years after a left mammary lumpectomy for a pT2N1MO SBR III invasive ductal carcinoma, a 67-years-old woman presented with a metastastic neuroendocrine sternal mass. To establish a relationship between mammary carcinoma and bone metastasis, histological slides of both the breast tumor and axillary lymph nodes were reviewed, and an immunohistochemical study was performed. They showed that: a) the mammary carcinoma was composed of a majority of small and large neuroendocrine cells synaptophysin +, NCAM+, chromogranin - (80%), associated with 2 other differentiated non endocrine components, one of metaplastic squamous carcinoma (10%) and the other of ductal carcinoma (10%); b) 4 axillary lymph nodes were involved by the ductal component which contained few NCAM + but synaptophysin - cells; c) Estrogen and progesterone receptors and HER2 were negative in the breast tumor and the metastatic nodes. We discuss the histogenesis of composite mammary carcinomas with neuroendocrine differentiation, the outcome of each component and the prognostic relevance of such a diagnosis.

Fibrinogen mediates bladder cancer cell migration in an ICAM-1-dependent pathway.

Fibrinogen (fg), present in tumor matrices, has been demonstrated to be determinant in metastatic potential. We have recently shown that fg/ICAM-1 interactions are involved in leukocyte migration across endothelial cell monolayers. Using bladder transitional cell carcinoma as a model, we will show in this study that bladder high grade tumor cell lines express ICAM-1, and that this expression induces an fg-mediated migration. This phenomenon was dependent on ICAM-1/fg interaction as well as RhoA activity. ICAM-1 was concentrated in focal adhesion plaques when tumor cells were allowed to adhere on immobilized fg, suggesting a role in cell migration. The addition of fg induced a 3- to 6-fold enhancement of bladder tumor cell migration through HUVEC monolayers. This process was inhibited by an anti-ICAM-1 antibody blocking fg binding, demonstrating that ICAM-1/fg interaction was involved in the extravasation process. Finally, immunohistological studies revealed that the expression of ICAM-1 was closely associated with an infiltrative histological phenotype.

[Testicular Leydig cell hyperplasia in children]. / Hyperplasie à cellules de Leydig du testicule chez l'enfant.

INTRODUCTION: Leydig cell hyperplasia (LCH) of the testis is rarely described in children. The authors report a case of incidental discovery of LCH on ultrasound examination. CASE REPORT: The authors report the case of a 9-year-old boy presenting with isolated and painless increased volume of the left testis, with no clinically palpable mass. Scrotal ultrasound revealed an echogenic mass, 12 mm in diameter, with a solid appearance and several hypoechoic areas, without calcification, situated in the lower pole of the testis. Tumour markers and gonadotropin axis hormonal assessment were normal. On surgical exploration, the testis had a macroscopically normal appearance; opening of the tunica albuginea revealed the lesion and enucleation was performed. Histological examination confirmed the presence of LCH, 5 mm in diameter. The postoperative course was uneventful. Physical examination and scrotal ultrasound have remained normal with a follow-up of two years. DISCUSSION: The authors recall the characteristics of LCH, which usually presents, in children, in the form of signs of precocious puberty or more rarely by gynaecomastia. The lesion is rarely palpable. Scrotal ultrasound reveals a homogeneous mass with several hypoechoic nodules. An endocrine assessment must always be performed (frequent elevation of LH). Surgery should be as conservative as possible (enucleation-resection). Histological diagnosis may be difficult.

[Should liver biopsy be systematic during surgery for ulcerative colitis?]. / Faut-il réaliser une biopsie hépatique per-opératoire systématique chez tous les malades opérés pour rectocolite hémorragique?

AIM: The aim of this study was to evaluate the prevalence of primary sclerosing cholangitis and other histological liver abnormalities in patients operated on for ulcerative colitis and to discuss the advantages of performing a systematic liver biopsy during surgery. METHODS: From 1996 to 2001, 21 consecutive patients underwent a restorative proctocolectomy or a reoperation after proctocolectomy for ulcerative colitis. These patients systematically underwent liver biopsy during the procedure. RESULTS: One patient presented with primary sclerosing cholangitis (4.7%). This patient was clinically and biologically asymptomatic. Four patients had steatosis, 8 had non specific inflammation such as small duct cholangitis and 8 had normal liver biopsy. As a result medical treatment was adapted and close surveillance of the live was begun. CONCLUSION: Peroperative liver biopsy identify primary sclerosing cholangitis or other liver diseases in an early diagnosis and help evaluate their stage in order to start appropriate treatment.

Chordoid glioma of the third ventricle: a report of two new cases, with further evidence supporting an ependymal differentiation, and review of the literature.

The term chordoid glioma of the third ventricle was first used to describe a rare and slowly growing neoplasm of uncertain histogenesis, with chordoid appearance, occurring preferentially in middle-aged women. Herein we report two additional examples of this novel entity together with a literature review based on the 25 cases previously published. Our review fully confirms the strikingly stereotyped clinical, neuroradiologic, and pathologic features of this unique tumor. The female/male ratio was 1.7:1, and the age range was 24-70 years (mean 44.9 years). In all 27 cases imaging findings were similar showing a well-defined mass (mean 2.8 cm in largest dimension), ovoid in shape, hyperdense on CT scans, with uniform and intense contrast enhancement, arising in the hypothalamic/suprasellar/third ventricular region. Histologically, the main consistent characteristics were cords and clusters of epithelioid cells within an abundant mucinous and often vacuolated background. Mitoses were sparse or absent and anaplastic features, endothelial proliferation, and necrosis were not identified. Lymphoplasmacytic infiltrates with Russell bodies were frequent throughout the tumor and its interface with adjacent brain parenchyma. Most of the tumor cells revealed a strong and diffuse expression of vimentin and glial fibrillary acidic protein. Additionally, the vast majority of tumors showed focal coexpression of cytokeratins, CD34, S-100 protein, and epithelial membrane antigen; the MIB-1 labeling indices were uniformly low. Surprisingly for a glioma assigned WHO grade II, the 19 patients with an available but short follow-up (mean 22.5 months; range 6-68 months) experienced a rather poor outcome (three recurrences and seven deaths), probably reflecting the anatomic site of the neoplasm that precludes a complete surgical excision rather than its histologic composition. Ultrastructural examination of 10 cases demonstrated findings in line with a glial derivation and a putative ependymal origin such as cytoplasmic intermediate filaments, microvilli, intermediate junctions or desmosomes, and focal basal lamina formation. In our case no. 1, and for the first time in this tumor, we observed sparse and abnormal cilia in an aberrant juxtanuclear location, a further argument for considering chordoid glioma as a subtype of ependymoma. However, a better understanding of the biologic behavior and histogenesis of this distinctive clinicopathologic entity needs to be investigated with a larger series. Nevertheless, taking into account its strikingly consistent anatomic localization, its unique histopathologic and immunohistochemical profile, in conjunction with the most recent and convincing ultrastructural arguments, we suggest that chordoid glioma of the third ventricle could be better classified as chordoid ependymoma of the lamina terminalis area.

Detection of N-myc amplification by FISH in immature areas of fixed neuroblastomas: more efficient than Southern blot/PCR.

N-myc amplification is a major prognostic factor in neuroblastomas and is systematically investigated by Southern blot or polymerase chain reaction (PCR). A retrospective study of N -myc amplification has been carried out using fluorescence in situ hybridization (FISH) in 97 fixed neuroblastomas. For each tumour, FISH was performed on the area that contained the most immature neuroblasts. Among these 97 neuroblastomas, 16 were amplified and 12 were not interpretable. FISH was not interpretable in six cases. All neuroblastomas with N-myc amplification detected by Southern blot/PCR were amplified with FISH, except three that were not interpretable. Four tumours that were not interpretable in Southern blot/PCR contained more than five copies of N-myc by FISH: one was aneuploid and three were truly amplified, containing more than ten copies of N-myc. Among these three patients, two died in a short time of their tumours. Ten cases were not amplified by Southern blot/PCR and showed more than five copies by FISH: four were aneuploid and two showed heterogeneous amplification, with a few cells clearly amplified whereas most were not. Four cases were amplified, of which two patients died of their tumours. This study confirms that when applied to the most immature areas of fixed neuroblastomas, FISH displayed a higher sensitivity than molecular techniques (p < 0.001) and could detect heterogeneous amplification. FISH could therefore become an important complementary procedure in assessing prognosis in neuroblastomas.

Surgical pathology of drug-resistant partial epilepsy. A 10-year-experience with a series of 327 consecutive resections.

Herein we reviewed the histopathological findings in 327 consecutive surgical specimens from patients with pharmaco-resistant epilepsy (PRE). Three major pathological groups (78.3% of all cases) were identified: Ammon's horn sclerosis (85 cases as an isolated lesion plus 18 as one part of a dual pathology), tumors (94 cases), and malformations (77 cases). Tumors, often associated with cortical dysplasias (CDs), were all of low histological grade and included 61 dysembryoplastic neuroepithelial tumors (DNTs), 29 gangliogliomas, and 4 pleomorphic xanthoastrocytomas (PXAs). Among the malformations were observed 52 CDs, 13 cavernomas, 8 cortical tubers, and 4 cysts. The remaining findings consisted of 16 scars (mostly post-traumatic) and 4 Rasmussen's encephalitis. Fifty-one (15.6%) specimens contained non-specific changes, and histological samples from 215 patients with presurgical implantation of electrodes revealed iatrogenic changes. All these figures are in agreement with the most recent and comparable series, and confirm the high incidence of DNTs that appear clearly as the most common tumoral entity in PRE. Our data also support the hypothesis of a close histogenetic relationship between DNT, ganglioglioma, and PXA, with a putative common origin from pluripotential progenitor CD34 positive cells of the subpial granular layer. As for CDs, our study confirms the clinical relevance of two main subtypes: severe CD (or Taylor's type CD) with neuronal cytomegaly and balloon cells, and non-Taylor's type CDs with a better outcome. Eventually, this series demonstrates that most patients have significant histopathological lesions, among which, aspects that are relevant to the diagnostic surgical pathologist are highlighted [published with a complete image database on CD-Rom].