Breast lesions in reduction mammaplasty specimens: a histopathological pattern in 534 patients.

BACKGROUND: The prevalence of breast lesions (benign, precancerous and cancer lesions) in reduction mammaplasty (RM) specimens has rarely been reported in Europe and never in the Swiss population. METHODS: Personal and histopathological data from 534 female patients who underwent RM were reviewed. RESULTS: Benign and/or malignant lesions were detected in 76.2% of all patients. Benign breast lesions associated with an increased risk of developing breast cancer represented 2.8% of all lesions. Breast cancer in situ was identified in 5 (0.9%) patients. Patient age and previous history of breast cancer were risk factors for incidental breast cancer. CONCLUSION: The rate of incidental carcinoma in situ was higher for patients with breast cancer history. Probably due to preoperative breast cancer investigation, no occult invasive breast cancer was found in reduction mammary specimens. Therefore before RM, breast cancer evaluation should be considered for all patients, especially for those with breast cancer risk factors (e.g., patient age, personal history of breast cancer).

NANOG priming before full reprogramming may generate germ cell tumours.

Reprogramming somatic cells into a pluripotent state brings patient-tailored, ethical controversy-free cellular therapy closer to reality. However, stem cells and cancer cells share many common characteristics; therefore, it is crucial to be able to discriminate between them. We generated two induced pluripotent stem cell (iPSC) lines, with NANOG pre-transduction followed by OCT3/4, SOX2, and LIN28 overexpression. One of the cell lines, CHiPS W, showed normal pluripotent stem cell characteristics, while the other, CHiPS A, though expressing pluripotency markers, failed to differentiate and gave rise to germ cell-like tumours in vivo. Comparative genomic hybridisation analysis of the generated iPS lines revealed that they were genetically more stable than human embryonic stem cell counterparts. This analysis proved to be predictive for the differentiation potential of analysed cells. Moreover, the CHiPS A line expressed a lower ratio of p53/p21 when compared to CHiPS W. NANOG pre-induction followed by OCT3/4, SOX2, MYC, and KLF4 induction resulted in the same tumour-inducing phenotype. These results underline the importance of a re-examination of the role of NANOG during reprogramming. Moreover, this reprogramming method may provide insights into primordial cell tumour formation and cancer stem cell transformation.

[Trophoblastic diseases: a multidisciplinary approach, a first Swiss center]. / Maladies trophobtastiques: une prise en charge pluridisciplinaire, un premier centre suisse.

Trophoblastic diseases are rare and complex. The Center for trophoblastic diseases, the first in Switzerland, was founded in Geneva in January 2009 to formalize the collaboration between obstetricians-gynecologists, pathologists, geneticists, radiologists and oncologists. At the physician's request and with patient consent, an integrative diagnosis is proposed after centralized review of the histological slides, anti-p57KIP2 immunohistochemistry, and ploidy analysis by QF-PCR (Quantitative fluorescent polymerase chain reaction). The referring physician receives treatment and beta-hCG dosage recommendations. This pluridisciplinary diagnostic and therapeutic approach allows optimal surveillance and treatment of patients.

Diverse glandular pathologies coexist with high-grade squamous intraepithelial lesion in cyto-histological review of atypical glandular cells on ThinPrep specimens.

OBJECTIVE: To identify in cytology, high-grade squamous intraepithelial lesions with endocervical glandular extension in cases previously diagnosed as atypical glandular cells (AGC), analyse possible reasons for the diagnostic pitfall and document the frequency of glandular pathology coexisting with high-grade cervical intraepithelial lesion in histology. METHODS: Thirty-nine ThinPrep cervical smear (Pap) tests reported as AGC of undetermined significance and showing high-grade lesions on histology [cervical intraepithelial neoplasia (CIN) 2 or 3, endometrial or extrauterine adenocarcinoma] were reviewed retrospectively to identify the cases of high-grade squamous intraepithelial lesion with endocervical glandular extension, using the Bethesda 2001 system. Cyto-histological correlation was performed. RESULTS: A high frequency of diverse glandular pathologies coexisted with high-grade cervical intraepithelial lesions on histology. This included endocervical glandular extension in 63%, benign glandular pathology in 33% and pre-neoplastic or malignant glandular pathology (endocervical glandular dysplasia, adenocarcinoma in situ and metastatic breast carcinoma) in 17% cases. On cytology, the sensitivity was 40%, specificity was 80% and positive predictive value was 86% for endocervical gland extension in high-grade squamous intraepithelial lesions. CONCLUSIONS: Special efforts to recognize endocervical glandular extension in high-grade squamous intraepithelial lesions and glandular neoplasia coexisting with squamous intraepithelial lesions from the heterogeneous category of AGC can contribute to increasing the diagnostic accuracy. The identification of endocervical glandular extension on cervical cytology would alert the gynaecologist to perform a thorough assessment of the endocervix during colposcopy. This could also help to decide on the need to perform deeper conization rather than loop electrosurgical excision procedure to ensure negative margins when colposcopic biopsy shows CIN 2 or 3.

Cytology of benign multicystic peritoneal mesothelioma in peritoneal washings.

OBJECTIVE: To describe the cytological aspect of peritoneal washings in benign multicystic peritoneal mesothelioma (BMPM). METHODS: Three peritoneal washing specimens stained by standard cytological and histological procedures and analysed by light microscopy. RESULTS: The specimens showed an abundance of monomorphous mesothelial cells devoid of atypia or mitoses. The mesothelial cells were calretinin positive. They also showed numerous squamous metaplastic cells arranged in flat sheets or isolated cells. The background contained some inflammatory cells. CONCLUSION: The combination of cytology of the peritoneal washing, histology (cell block and surgical specimen) and clinical history allow differentiation of BMPM from other cystic lesions (cystic lymphangioma and malignant mesothelioma).

Outcome of uterine clear cell carcinomas compared to endometrioid carcinomas and poorly-differentiated endometrioid carcinomas.

OBJECTIVES: Our aim was to compare the survival between patients with clear cell carcinoma (CC) and patients with endometrioid carcinoma (EC). METHODS: Through the population-based Geneva Cancer Registry, we identified 1,380 resident women diagnosed with uterine cancer between 1970 and 2000. We excluded those with papillary serous endometrial carcinoma and uterine sarcomas. We categorized patients as CC (n = 32, 2.8%) or EC (n = 1,145, 97.2%). Uterine cancer-specific survival rates were calculated by Kaplan-Meier analysis. We used Cox proportional hazards analysis to compare uterine cancer mortality risks between groups, and adjusted these risks for other prognostic factors. RESULTS: CC patients presented with a more advanced stage at diagnosis than EC patients (p = 0.002). Compared to women with EC, women with CC had a significantly greater risk of dying from their disease (hazard ratio [HR] 2.9, 95% confidence interval (95% CI) 1.7-4.9). After adjustment for age, stage and adjuvant chemotherapy, the risk of dying from uterine cancer was still significantly higher for CC patients (HR 2.0, 95% CI 1.2-3.4). By univariate analysis, the risk of dying of endometrial cancer was not significantly higher in CC patients than in patients with poorly-differentiated EC (HR 1.3, 95% CI 0.7-2.3). CONCLUSION: This population-based investigation shows that patients with CC have a poorer outcome than those with EC. Studies to determine the role of adjuvant treatment in CC patients are needed.

[New treatments for renal cell carcinoma: hope and limits]. / Nouveautés thérapeutiques dans le cancer du rein: espoirs et questions.

Metastatic renal cell carcinoma remains a main therapeutic challenge in oncology. Interferon-alpha and Interleukin-2 have been the sole available drugs for decades. Allogeneic bone marrow transplantation is an interesting but experimental therapeutic approach. The von Hippel-Lindau disease is a rare genetic disorder predisposing to the development of renal cell carcinoma. Its molecular elucidation paves the way for novel therapeutic approaches based, mainly but not exclusively, on the inhibition of angiogenesis.

Yolk sac tumours of the ovary: an update.

AIMS: Yolk sac tumours of the ovary (YST), also called endodermal sinus tumours (EST) are rare and highly malignant tumours of utmost importance occurring in children and young adults. In the past, outcome was very poor and the disease was almost always fatal. With the refinement of chemotherapeutic regimens in the last several decades, survival rates have improved dramatically and fertility preserving surgery has become possible. The aim of this review is to provide the reader with an analysis of the available literature and a rational approach to patient management. METHODS: We performed a literature search in the PubMed database and the reference lists of relevant articles concerning yolk sac tumours of the ovary. FINDINGS AND CONCLUSION: There are no randomised studies relating to the management of YST of the ovary. The available literature is composed of retrospective reviews and case reports that span several decades. Prognosis nowadays is good in stage I and II but still comparable to that of ovarian epithelial cancer in stage III and IV. The overall good prognosis is due to the fact that most of ovarian YST are diagnosed at an early stage where 5years survival reaches 95%. Appropriate surgical treatment for patients where fertility needs to be preserved consists in laparotomy with unilateral salpingo-oophorectomy, peritoneal cytologic studies, omentectomy, multiple peritoneal and abdominal biopsies and resection of all visible disease. Three courses of BEP (bleomycin, etoposide, cisplatin) is the current standard therapy and four courses is recommended in case of bulky residual disease after surgery. Serum alpha-feto-protein (AFP) is a useful marker for the diagnosis and management of YST.

p53 as a potential predictive factor of response to chemotherapy: feasibility of p53 assessment using a functional test in yeast from trucut biopsies in breast cancer patients.

Assessment of the predictive value of p53 requires the testing of large numbers of samples from patients enrolled in prospective phase III clinical trials. The goal of this study was to determine whether p53 status can be determined by p53 yeast functional assay using the limiting amounts of material that can typically be obtained in prospective phase III trials (particularly when chemotherapy is given before surgery). All patients presenting with a clinically palpable tumour which could be considered large enough to perform a trucut biopsy (> or =2 cm breast tumour) were eligible for this study. Two trucut biopsies and one incisional biopsy were performed on the surgical specimens (mastectomy or tumourectomy). Samples were snap frozen and cryostat sections were taken for histology and p53 testing. Thirty patients were included. Three samples out of 90 failed to give any p53 PCR products, probably because these samples contained almost entirely fibrous tissue. Of the 87 samples that could be tested, the incisional and trucut biopsies results were fully concordant in every case. p53 could be defined in 97% of patients by double trucut biopsy. Eight out of 30 tumours tested were mutant for p53 (27%). p53 status can be reliably determined by yeast assay from single frozen sections of trucut biopsies. Histological examination before p53 testing is essential to exclude cases where the p53 result may reflect only the status of the normal cells in the biopsy.

Telomerase RNA as a detection marker in the serum of breast cancer patients.

Tumor-derived circulating DNA has been found in the plasma of cancer patients. Alterations include decreased strand stability, mutations of oncogenes or of tumor suppressor genes, microsatellite alterations, and hypermethylation of several genes. RNA has also been found circulating in the plasma of normal subjects and cancer patients. Tyrosinase mRNA has been extracted from the serum of melanoma patients and subjected to RT-PCR. Moreover, the presence of cell-free EBV-associated RNA has been reported in the plasma of patients with nasopharyngeal carcinoma. Human telomerase comprises two RNA subunits, telomerase RNA template (hTR) and its catalytic component, telomerase reverse transcriptase protein (hTERT). Expression of these subunits correlates with telomerase activity. Using RT-PCR, we investigated whether these RNA subunits were present in the serum of 18 patients with breast cancer, 2 patients with benign breast disease, and 21 normal subjects. The presence of amplifiable RNA was confirmed in all tissue and serum samples using RT-PCR of glyceraldehyde-3-phosphate dehydrogenase RNA. hTR was found in 17 of 18 tumors (94%) and 5 of 18 serum samples (28%). hTERT was also detected in 17 of 18 tumors (94%) and in 4 of 16 available serum samples (25%). hTR and hTERT were undetectable in tissues and sera taken from 2 patients with benign disease and in the sera of 21 normal subjects. We conclude that RNA is detectable in the serum of breast cancer patients and that tumor-derived mRNA can be extracted and amplified using RT-PCR, even in patients with localized disease. This may have implications for cancer diagnosis and follow-up in the future.

Tumor necrosis factor/cachectin and lymphotoxin gene expression in lymph nodes from lymphoma patients.

We investigated the mRNA content for tumor necrosis factor (TNF)/cachectin and lymphotoxin (LT) in tumoral tissues of a prospective series of 35 non-Hodgkin's (NHL) and 23 Hodgkin's (HL) lymphomas, to assess their postulated contribution to systemic symptoms. Total RNAs were extracted from diagnostic tissue specimens and submitted to Northern blot analysis, using specific TNF and LT cRNA probes. High amounts of TNF mRNA were found exclusively in NHL (12/35). The majority (9/12) of these were low grade B-cell NHL, which contained a uniform population of malignant cells. In contrast, abundant LT mRNA production was detected in most HL (21/23) and in 19 of 35 NHL. The highest LT mRNA levels were observed in high grade NHL and in lymphocytic predominant subtypes of HL specimens. A significant correlation was found between TNF/cachectin and LT gene expression in NHL and the presence of constitutional symptoms. The biologic and prognostic implications of these preliminary findings are presently unknown, but they demonstrate that lymphoma tissues sharing common histologic features are highly heterogeneous in their ability to synthesize cytokines susceptible to playing a role in the growth control of malignant cells. These results suggest that the evaluation of TNF/cachectin and LT production in lymphomas may help to elucidate the mechanisms of tumoral fever and cachexia.

Histiocytic necrotizing lymphadenitis or Kikuchi's disease. Anatomo-clinical study of 4 cases.

Histiocytic necrotizing lymphadentis (HNL) is an uncommon clinical and histologic entity, essentially diagnosed in Japan since 1972. The clinical picture is usually characterized by cervical lymphadenopathy and fever, females being more often affected. Leukopenia and elevated erythrocyte sedimentation rate are frequent. The etiology is still unknown, but a viral origin is most likely. The clinical course is always favorable without treatment, except in one case. The histological picture, with necrotic foci surrounded by histiocytes, immunoblasts, small T lymphocytes and plasmacytoid monocytes (so-called plasmacytoid T cells), is characteristic. Nevertheless, HNL may be mistaken for malignant lymphoma both clinically and histologically. We report 4 cases of HNL. One of these presented severe leukothrombopenia; the serum of this patient significantly suppressed the maturation of granulocytic precursor cells in the bone marrow.

Alpha-smooth muscle actin, a differentiation marker of smooth muscle cells, is present in microfilamentous bundles of pericytes.

alpha-Smooth muscle (alpha-sm) actin, an isoform typical of smooth muscle cells (SMC) and present in high amounts in vascular SMC, was demonstrated in the cytoplasm of pericytes of various rat and human organs by means of immunocytochemistry at the electron microscopic level. In SMC and pericytes, alpha-sm actin was localized in microfilament bundles, strengthening the assumption that it is the functional isoform in these cell types and supporting the assumption that pericytes exert contractile functions.

Hyperprealbuminemia, euthyroid hyperthyroxinemia, Zollinger-Ellison-like syndrome and hypercorticism in a pancreatic endocrine tumour.

Prealbumin, one of the main thyroxine transport proteins, has recently been shown to be a valuable immunohistochemical marker of neuroendocrine tumours. We report the case of a multisecretory pancreatic endocrine tumour whose prealbumin secretion was so high that it produced a peak on routine serum protein electrophoresis and induced a euthyroid hyperthyroxinemia. The maximal binding capacity of prealbumin for thyroxine was indeed markedly increased, whereas its affinity for this hormone was normal. The tumour was associated with gastric hyperacidity and hypergastrinemia thereby evoking a Zollinger-Ellison syndrome. The secretin stimulation test and gastrin tumoural immunohistochemistry were, however, negative. We suggest that the concomitant tumoural production of gastrin-releasing peptide was responsible for the gastric hyperacidity and hypergastrinemia. This hormone probably also accounted for a moderate hypercorticism.

[Malignant lymphoma of parotid origin mimicking Melkersson-Rosenthal syndrome]. / Lymphome malin à point de départ parotidien mimant un syndrome de Melkersson-Rosenthal.

The Melkersson-Rosenthal syndrome is classically described as the association of a unilateral tumefaction, a facial hemiparesia and of a furrowing of the tongue. Granulomatous blepharitis is an unusual localisation of the facial tumefaction, and chronic periocular oedema may represent a difficult differential diagnosis. The reported case has erroneously been diagnosed as a Melkersson-Rosenthal syndrome and further showed to be a parotid gland involvement of a systemic malignant lymphoma.

Characterization of stromal cells with myoid features in lymph nodes and spleen in normal and pathologic conditions.

Stromal cells with myoid features were identified in rat or human lymph nodes and spleen in normal and pathologic conditions, using antibodies to desmin, alpha-smooth muscle actin, and smooth muscle myosin. In normal lymph nodes, myoid cells (MCs) were present in the superficial and deep paracortex as well as in the medulla, and absent in lymphoid follicles. In the spleen, they were numerous in the red pulp, less abundant in periarteriolar lymphocyte sheaths of the white pulp, and absent in lymphoid follicles. On double immunostaining, alpha-smooth muscle actin and smooth muscle myosin were coexpressed with desmin only in the deep paracortex and parafollicular areas of the lymph nodes, as well as in the MCs of the periarteriolar lymphocyte sheaths and marginal zone of the spleen; the remaining MCs expressed only desmin. When examined by means of electron microscopy, MCs showed a dendritic shape and cytoplasmic bundles of microfilaments with dense bodies scattered between them. When compared with normal conditions, MCs showed changes of distribution and number in several pathologic situations. Additional findings were 1) staining of pericytes surrounding high endothelium venules of lymph nodes with alpha-smooth muscle actin antibodies in man and rat and with desmin antibodies in rats; 2) staining of endothelial cells in these venules with desmin antibodies in rats. It is concluded that a subset of reticular cells in lymph nodes and spleen, as well as pericytes and endothelial cells in high endothelium venules display cytoskeletal features suggesting a myoid differentiation and function.