Importance and determinants of Gleason score undergrading on biopsy sample of prostate cancer in a population-based study.

BACKGROUND: In this population-based study, we investigated the degree of concordance between Gleason scores obtained from prostate biopsies and those obtained from prostatectomy specimens, as well as the determinants of biopsy understaging. METHODS: We considered for this study all 371 prostate cancer patients recorded at the Geneva Cancer Registry diagnosed from 2004 to 2006 who underwent a radical prostatectomy. We used the kappa statistic to evaluate the Gleason score concordance from biopsy and prostatectomy specimens. Logistic regression was used to determine the parameters that predict the undergrading of the Gleason score in prostate biopsies. RESULTS: The kappa statistic between biopsy and prostatectomy Gleason score was 0.42 (p < 0.0001), with 67% of patients exactly matched, and 26% (n = 95) patients with Gleason score underestimated by the biopsy. In a multi-adjusted model, increasing age, advanced clinical stage, having less than ten biopsy cores, and longer delay between the two procedures, were all independently associated with biopsy undergrading. In particular, the proportion of exact match increased to 72% when the patients had ten or more needle biopsy cores. The main limitation of the study is that both biopsy and prostatectomy specimens were examined by different laboratories. CONCLUSIONS: The data show that concordance between biopsy and prostatectomy Gleason scores lies within the classic clinical standards in this population-based study. The number of biopsy cores appears to strongly impact on the concordance between biopsy and radical prostatectomy Gleason score.

Plasmablastic lymphoma clinically presenting in the urinary tract.

Plasmablastic lymphoma is a high-grade B-cell lymphoma that poses major diagnostic problems and carries an extremely poor prognosis. This tumor was first described in the oral cavity of HIV+ patients but has since been identified in other sites and in seronegative patients. We describe 2 cases of plasmablastic lymphoma of the urinary tract that both presented with hydronephrosis. One occurred in an HIV+ patient and harbored a MYC translocation; the other, in an HIV- patient with no translocation detected.

Young patients with endometrial cancer: how many could be eligible for fertility-sparing treatment?

OBJECTIVES: To assess the characteristics of young women with endometrial carcinoma, and evaluate those potentially eligible for conservative therapy. METHODS: We identified women diagnosed with endometrial cancer between 1970 and 2005 at the population-based Geneva Cancer Registry (n=1365). We classified patients into two age groups (< or =45 and >45 years old). Differences in demographic, tumor, diagnostic and treatment characteristics were tested with chi square. Kaplan-Meier analysis was used to calculate survival from endometrial cancer and the log-rank test to analyze differences in survival between the two groups. RESULTS: The young group comprised 44 (3.2%) women and the old group 1321 (96.8%) women. Synchronous ovarian malignancies were found in six patients (14%) in the young group, compared with 23 (2%) in the old group (P<0.001). Tumor stage was also different between the two groups, principally because of more stage II among the young (P=0.012). Histological tumor type, grade and specific endometrial cancer 5-year survival did not significantly differ between the two groups. According to final histopathologic evaluation, eight patients from the young group had FIGO stage IA, grade I disease, i.e. may have been eligible for fertility-sparing treatment, corresponding to an incidence rate of 0.3/100,000. CONCLUSION: No significant difference regarding tumor characteristics and survival between young and older patients was observed, except stage of disease and rate of synchronous ovarian malignancy. Conservative approach is a meaningful quality of life goal for patients with cancer, but only suitable for a limited number of patients.

Increased risk of second cancer among patients with ovarian borderline tumors.

OBJECTIVES: Several studies have demonstrated a higher risk of colorectal and breast cancers subsequent to invasive ovarian cancer. Such risk has not been investigated for ovarian borderline tumors. We aim to evaluate the risk of subsequent cancer occurrence among patients with borderline ovarian tumors in a population-based setting. METHODS: We identified 171 patients with a diagnosis of borderline ovarian tumors recorded at the Geneva Cancer Registry, Switzerland. We calculated age and period standardized incidence ratios (SIR) of second tumor occurrence by dividing the number of observed cases by the number of expected cases in the cohort, using cancer incidence rates of the general female population. RESULTS: The risk of developing second cancer was 1.85-fold (95% Confidence Interval [CI]: 1.10-2.92, n=16) higher among women with borderline ovarian tumors compared to that expected in the general population. The excess of risk primarily concerned colorectal cancer (SIR: 3.97, CI: 1.38-12.95, n=5) and breast cancer (SIR: 2.09, CI: 0.84-4.31, n=7), but the latter result was not statistically significant (p=0.09). The increased risk of developing second cancer was mainly observed among patients diagnosed with ovarian borderline tumors occurring before the age of 50. These results were not explained by surveillance bias or by metastasis from one site to another. CONCLUSION: Women with ovarian borderline tumors have an increased risk of developing secondary cancer, particularly colorectal cancer. These results point to potential common risk factors for these tumors and ask for close surveillance of patients with borderline ovarian tumors.

Derivation of the first Swiss human embryonic stem cell line from a single blastomere of an arrested four-cell stage embryo.

PRINCIPLES: Human embryonic stem cells (hESC) hold enormous potential for regenerative medicine. So far, the majority of hESC lines have been derived from the isolated inner cell mass (ICM) of blastocysts of variable quality, and several of them from low-grade embryos. Moreover, most of the lines have been obtained in media containing animal components such as foetal bovine serum. We aimed to derive hESC lines in xeno-free conditions using spare embryos frozen in Switzerland before 2001. METHODS: In cooperation with Swiss IVF centres we collected up to 199 donated embryos frozen between 1988 and 2000 at different stages of development. RESULTS: Embryo quality at thawing showed wide variability, reduced quality and low survival upon culture. Using early arrested embryos (n=46), we report here the first Swiss hESC line, called CH-ES1, derived from a single blastomere of an arrested four-cell-stage embryo. Despite its polyploidy, already present at the third passage, CH-ES1 expressed ESC markers of pluripotency and differentiated into all three germ layers in embryoid bodies in vitro and in teratomas in vivo. CONCLUSIONS: As the destruction of viable developing embryos, even spare ones, raises serious ethical concerns, deriving hESC lines from arrested embryos may be an alternative approach to avoid embryo destruction. However, given the reduced derivation efficiency they should not be considered a unique and/or selective source of hESC lines.

Reclassification and analysis of clinical significance of atypical glandular cells on ThinPrep using Bethesda 2001: Geneva experience.

BACKGROUND: The category "atypical glandular cells" (AGC) in The Bethesda System (TBS) 2001 represents equivocal glandular atypia. The objective was to determine the clinical significance of diagnosing AGC using new TBS 2001 on Thin-Prep. There is scant information on the diagnosis of AGC and its outcome on ThinPrep using TBS 2001. METHODS: 174 "ThinPrep" Pap tests reported as atypical glandular cells of unknown significance (AGUS) using TBS 1991 during the period (2001-2004) were reclassified using AGC subcategories of TBS 2001. Follow-up histology was correlated with AGC subcategories of TBS 2001 and in women <40 and >or=40 years of age. RESULTS: The mean AGC rate significantly decreased from 0.7% to 0.3%. (p <0.02). The frequency of clinically significant lesions on followup was higher with AGC diagnosis (51%, 21/41) than AGUS diagnosis (36%, 37/103). It was significantly higher for atypical endocervical cells favouring neoplasia (AEC-FN) (67%, 4/6) and AGC with concurrent squamous intraepithelial lesions (SIL) (67%, 8/12) than for the atypical endocervical cells, not otherwise specified (AECNOS) subcategory (12.5%, 2/16). All clinically significant lesions were high grade squamous intraepithelial lesions (HSIL) in women <40 years but in women >or=40 years, the majority (70%) were glandular. In categories atypical glandular cells favouring neoplasia (AGC-FN) and atypical endometrial cells (AEMC) all women had clinically significant glandular lesions. CONCLUSIONS: AEC-FN, AGC-FN, AEMC and AGC with concurrent SIL subcategories represented high risk diagnoses. The sequence of further investigations may vary by age and presence of postmenopausal bleeding.

Paget disease of the breast: findings at magnetic resonance imaging and histopathologic correlation.

OBJECTIVES: The purpose of this article is to describe magnetic resonance imaging (MRI) findings in patients with Paget disease of the breast and to evaluate mammography and MRI of the breast in the diagnosis of associated breast cancer. MATERIALS AND METHODS: Nine patients with biopsy-proven Paget disease of the nipple underwent preoperative mammography and MRI of the breast to evaluate underlying breast cancer. All patients underwent subsequent surgery. The patients' charts and imaging studies were retrospectively reviewed. Imaging findings were correlated to results of histopathology. RESULTS: Histopathology confirmed Paget disease of the nipple in all 9 patients and diagnosed associated ductal carcinoma in situ (DCIS) in the retroareolar lactiferous ducts in 8 of 9 patients (88%). MRI showed abnormal nipple enhancement in these 8 patients with an ill-defined thickened nipple-areolar complex. DCIS elsewhere in the breast was diagnosed in 4 of 9 patients (45%) corresponding to nonfocal enhancement in all 4 patients at MRI of the breast (100%). CONCLUSIONS: Paget disease of the breast associated with underlying DCIS can be diagnosed at MRI of the breast and therefore impact management decisions.

[The therapeutic dilemma of the early invasive bladder cancer]. / Le dilemme thérapeutique du stade micro-invasif du cancer de la vessie.

Transitional tumours of the bladder are classically divided in superficial (lesions of the mucosa and the submucosa) and invasive (infiltrating the detrusor) cancers. However, the recurrence and progression rate of submucosal urothelial cancers is highly variable. Therefore, management of such neoplasias is very challenging, some patients requiring a cystectomy, whereas others can be managed less invasively with endoscopic resection eventually associated with intravesical chemotherapy. We review herein the prognostic factors which help us to orientate our patients. We also emphasize the importance of the subclassification of the micro-invasive stage, and its practicability, which is reliable and simple, as opposed to the general belief.

Immunohistochemical profile of high-grade urothelial bladder carcinoma and prostate adenocarcinoma.

The differential diagnosis between poorly differentiated prostate adenocarcinoma (PAC) involving the bladder and high-grade urothelial bladder cancer (UC) with prostate extension can be very challenging. The aim of this study is to evaluate the use of a panel of antibodies to distinguish the poorly differentiated forms of these two tumors. We evaluated a series of 40 PAC cases (Gleason's grade >/= 8) and 45 (G3) UC cases obtained from transurethral endoscopic resection material. Immunohistochemical analysis was performed using the following antibodies: prostate acid phosphatase (PAP), prostate-specific antigen (PSA), uroplakin III (UP), thrombomodulin (TM), cytokeratin (CK) 7, and CK20. PAC expressed PSA and PAP in 34 and 38 cases, respectively. The sensitivity and specificity of expressing at least 1 marker (PSA+ or PAP+) is 95% and 100%, respectively. All UC cases were negative for both markers. UC expressed UP and TM in 27 and 22 cases, respectively. In addition, 36 of 45 cases stained positively for at least 1 marker (UP + or TM +) with specificity and sensitivity of 80% and 100%, respectively. All cases of PAC were negative for both markers. Twenty-eight UC cases were CK7+/CK20 +, and 4 PAC cases stained positively for both markers. On the other hand, 29 PAC cases and 4 UC cases were CK7-/CK20-. We concluded that PSA, PAP, UP, and TM are very useful markers in differentiating poorly differentiated UC from PAC. Finally, when all 4 markers (PAP, PSA, UP, and TM) were negative, CK7 and CK20 appeared of no major use in making the differential diagnosis.

[Optical diagnosis of cervical dysplasia]. / Diagnostic optique des lésions dysplasiques du col utérin.

Cervix cancer is a curable disease when diagnosed at an early stage. Screening of cervical lesions by cytology and colposcopy with in situ staining has allowed for substantial progress in early diagnosis and consequently the cure of cervix cancer. Nevertheless, because of its low specificity, this approach generally implies repetitive tissue sampling and, thus a relative long time before the treatment of the lesions. Furthermore, the cost of preparation and analysis of biopsy samples is sufficiently high to represent a burden for industrialized countries and a virtual impossibility for the developing world. To overcome these problems, various biophotonic methods using optical fibers have been developed to allow for detection of cervical epithelial anomalies in a specific, fast and non-invasive way. This process, known as "optical biopsy", is based on the measurement of light-tissue interactions, which are analysed by various mathematical and data processing methods, to provide information on the metabolism and morphology of epithelial tissue. Currently investigated methods can be distinguished according to the type of signal used to probe the tissue (fluorescence, reflectance), the depth of analysed tissue (surface analysis, confocal imaging, tomography), the analysis modalities (spectral measurements or imaging), and the use of additive molecules (contrasting or photosensitizing agents, inorganic fluorophores). While most of the methods remain experimental, constant progress in the understanding of the mechanisms of light behavior in biological environments as well as advances in optical fibers technology, will make a number of these methods soon available for clinical practice to contribute efficiently to the reduction of biopsy number and cost of cervical screening.

Modelling and rescuing neurodevelopmental defect of Down syndrome using induced pluripotent stem cells from monozygotic twins discordant for trisomy 21.

Down syndrome (trisomy 21) is the most common viable chromosomal disorder with intellectual impairment and several other developmental abnormalities. Here, we report the generation and characterization of induced pluripotent stem cells (iPSCs) derived from monozygotic twins discordant for trisomy 21 in order to eliminate the effects of the variability of genomic background. The alterations observed by genetic analysis at the iPSC level and at first approximation in early development illustrate the developmental disease transcriptional signature of Down syndrome. Moreover, we observed an abnormal neural differentiation of Down syndrome iPSCs in vivo when formed teratoma in NOD-SCID mice, and in vitro when differentiated into neuroprogenitors and neurons. These defects were associated with changes in the architecture and density of neurons, astroglial and oligodendroglial cells together with misexpression of genes involved in neurogenesis, lineage specification and differentiation. Furthermore, we provide novel evidence that dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) on chromosome 21 likely contributes to these defects. Importantly, we found that targeting DYRK1A pharmacologically or by shRNA results in a considerable correction of these defects.

A pelvic mass on ultrasonography and high human chorionic gonadotropin level: not always an ectopic pregnancy.

A 24-year-old patient with 7-week amenorrhoea consulted for vaginal bleeding without abdominal pain. Ultrasonography revealed a 7 × 4 cm solid right pelvic mass. There was no visible intrauterine gestational sac. The serum ß-human chorionic gonadotropin (ß-hCG) level was 11 998 IU/l. Emergency laparoscopy was performed for a presumptive diagnosis of ectopic pregnancy. At laparoscopy, the right ovary was enlarged with a non-haemorrhagic 7 × 4 cm solid lesion, which was resected. The histological diagnosis was a dysgerminoma with immunohistochemistry showing nests of syncytiotrophoblastic cells, which were the origin of the hCG production. There was no pregnancy, either intrauterine or ectopic. There was no evidence of metastasis from the dysgerminoma on the positron-emission tomography scanner. The patient underwent a second procedure for surgical staging of this ovarian germ-cell tumour. This ovarian dysgerminoma was staged FIGO 1A, and the patient did not receive adjuvant therapy. There was no recurrence at the last 8-month follow-up.

Frozen section in axillary sentinel lymph nodes for diagnosis of breast cancer micrometastasis.

BACKGROUND: Sentinel lymph node (SLN) biopsy plays a major role in the surgical management of primary breast cancer. The aim of this study was to assess the diagnostic accuracy of the assessment of axillary frozen sections of SLNs for micrometastasis diagnosis. PATIENTS AND METHODS: This study focused on 278 SLNs from 149 patients. Each lymph node was fully analyzed by frozen section. After fixation, serial sections were cut and stained by hematoxylin and eosin (HE) and for pan-cytokeratins by immunohistochemistry (IHC). RESULTS: Tumor cells were detected in 63 SLNs, 41 on frozen sections and 22 on controls. Of these 63 positive SLNs, 42 contained metastases, 10 contained micrometastases and 11 contained isolated tumor cells. The specificity and positive predictive value of SLN frozen sections for micrometastasis was 100%. The sensitivity was 83.3% for metastasis, 40% for micrometastasis; the false-negative rate was 16.7% for metastasis and 60% for micrometastasis. CONCLUSION: Analysis of frozen section of SLNs is an accurate method for metastasis detection, allowing concurrent axillary dissection when positive. The protocol for SLN analyses described herein shows good sensitivity for micrometastasis detection.

Magnetic resonance imaging to identify risk of lymph node metastasis in patients with endometrial cancer.

OBJECTIVE: To assess the value of magnetic resonance imaging (MRI) to identify endometrial cancer patients at risk of lymph node metastasis. METHODS: Retrospective review of data from 108 patients with clinical stage I endometrial cancer who underwent preoperative MRI and were treated surgically. Patients at risk of lymph node metastasis were defined as those who had more than 50% myometrial infiltration or cervical invasion. Preoperative MRI reports were compared with final pathologic results. RESULTS: The mean age of the patients was 69.5 years and most patients had endometrioid cancer. On final pathologic analysis, 59 patients had deep myometrial infiltration or cervical invasion. For diagnosis of deep myometrial infiltration, cervical invasion, or both, MRI sensitivity and specificity were 56% and 85%; 47% and 83%; and 67% and 77%, respectively. CONCLUSION: MRI has limited value in identifying patients with endometrial cancer who are at risk of lymph node metastasis. Minimally invasive laparoscopic lymph node staging should be undertaken when it is feasible.

Primary breast lymphomas.

The diagnosis, prognostic factors, and optimal management of primary breast lymphomas (PBL) is difficult. Seven patients recorded at the Geneva Cancer Registry between 1973-1998 were reviewed. Five patient had diffuse large B-cell lymphoma, one a follicular lymphoma and one a MALT-lymphoma. All patients had clinical and radiological findings consistent with breast cancer and underwent mastectomy, which is not indicated in PBL. Diagnosis should be established prior to operative interventions, as fine needle aspiration missed the diagnosis for one patient and intra-operative frozen sections for 3 patients in our study. Five-year and 10-year overall survivals were 57% and 15%, respectively. Of the 3 patients who died from PBL, 2 had tumors that were Bcl-2 positive but Bcl-6 negative. All 3 surviving patients have positive Bcl-2 and Bcl-6 immunostaining, which could be important prognostic factors if confirmed by a larger study.

Diagnosis of vulvar lesions by non-invasive optical analysis: a pilot study.

A procedure that could allow an early in vivo and non-invasive detection of vulvar lesions would be extremely useful. We tested an innovative optical method (Optiprobe), which uses a harmless, visible light source for the in vivo, on-line detection of minimal alterations in the structure of vulvar epithelium. A group of 3 female volunteers without gynecological symptoms were first screened to evaluate optical properties of normal vulvar tissue. Next, a group of 16 patients undergoing gynecological examination for vulvar lesions was evaluated by the Optiprobe at suspected sites before these sites were biopsied for histological analysis. Adjacent, non-involved sites were also measured to provide internal controls. Histological analysis of the biopsies identified one case that did not show obvious alterations, 4 cases of high-grade vulvar intraepithelial neoplasia (VIN), 5 cases of vulvitis, and 6 cases of lichen sclerosis (LS).The optical properties of the VIN cases were significantly different from those of controls, due to a decrease in the absorption spectra and an increase in the scattering spectra. In contrast, a significant increase in the absorption spectra and a decrease in the scattering spectra were observed in the cases of vulvitis. In the LS cases, the absorption spectra were as in controls, whereas the scattering spectra were significantly decreased. We conclude that the Optiprobe provides a useful tool for a rapid and non-invasive detection of vulvar alterations. The method should contribute to reduce the number of biopsies and to facilitate the long-term follow-up of vulvar lesions.

Histopathological study of breast cancer and normal breast tissue after magnetic resonance-guided cryotherapy ablation.

BACKGROUND: Cryotherapy ablation is a minimally invasive procedure being investigated as an alternative to conventional surgery. There are few reports in breast cancer. AIM: Evaluate the histopathology of tumoral and normal breast tissue after cryotherapy. METHODS: Eleven patients with clinically <2.0cm and ultrasound visible tumors were studied. Invasive carcinoma was documented by preoperative mammography, magnetic resonance imaging and biopsies. Cryotherapy needles were inserted in the tumor under magnetic resonance guidance and deep freezed with a CRYO-HIT TM System-3. Lumpectomy was performed within 4-5 weeks following cryoablation and submitted for pathological examination including immunostaining of keratins. RESULTS: The tumoral response after cryoablation was variable. In 4 cases there was no viable invasive carcinoma left and focal DCIS only in 2. In 6 cases, residual invasive carcinoma of various size was present with DCIS inside or outside the cryozone. One case could not be evaluated because the cryozone was adjacent to the tumor due to technical problems. Histologically, the normal breast parenchyma of the cryozone showed dense fibrosis, fat necrosis, xanthogranulomatous reaction, endovascular fibrosis and haemorrhages in all cases. The positive immunostaining of keratins revealed remnants of cytoskeleton of carcinomatous cells in the necrotic areas without any viable tumoral cells on routine stains. Skin ulceration and/or necrosis were observed in five patients. CONCLUSIONS: Cryotherapy allows tumor destruction of variable extent in breast carcinomas <2.0cm in diameter. Immunostaining of keratins is useful to identify cytoskeleton remnants of tumor cells in devitalized areas.