Carla Facco

Immunohistochemical pattern of hMSH2/hMLH1 in familial and sporadic colorectal, gastric, endometrial and ovarian carcinomas with instability in microsatellite sequences

Abstract. Alterations of DNA mismatch repair (MMR) genes are involved in carcinogenesis of sporadic and inherited human cancers characterised by instability of DNA microsatellite sequences (MSI). MSI tumours are usually identified using molecular analysis. In the present investigation, hMLH1 and hMSH2 immunohistochemistry was tested in order to evaluate the utility of this method in predicting MMR deficiency. Colorectal (72), gastric (68), endometrial (44) and ovarian (17) carcinomas were independently evaluated for familial history, histological type of tumour, MSI status and immunohistochemical results. Loss of expression of either hMLH1 or hMSH2 was observed in 51 of 55 (92.8%) MSI tumours, while 145 of 146 microsatellite stable (MSS) tumours expressed both the hMLH1 and hMSH2 gene products. Independently of tumour site, an overall agreement between immunohistochemical and molecular results was observed in 15 hereditary non-polyposis colorectal cancer-related tumours. Among sporadic tumours, only 2 of 60 colorectal and 2 of 66 gastric carcinomas, displaying MSI, expressed both hMLH1 and hMSH2 gene products. All 39 endometrial and 16 ovarian tumours presented a concordant molecular and immunohistochemical profile. These data show that immunohistochemistry is an accurate and rapid method to predict the presence of defective DNA MMR genes and to identify both sporadic and familial MSI tumours.

Ovarian metastases from colorectal carcinoma. Clinicopathologic profile, immunophenotype, and karyotype analysis.

Ovarian metastases from colorectal carcinoma frequently mimic primary ovarian carcinomas. The present study was performed to identify possible criteria helpful in differential diagnosis. Twenty-three ovarian metastases from colorectal carcinomas and 23 primary ovarian carcinomas were evaluated clinicopathologically and immunostained with antigastric M1 antigen, cathepsin E, CA125, vimentin, estrogen and progesterone receptors, cytokeratins 7 and 20, and alpha-inhibin antibodies. We performed a conventional and molecular cytogenetic study on 5 ovarian metastases from colorectal carcinoma using direct preparation, Q banding techniques, and fluorescence in situ hybridization. Integration of clinicopathologic, immunohistochemical, and cytogenetic features is helpful for the differential diagnosis of metastases of colorectal carcinomas from primary ovarian carcinomas. Bilaterality, extrapelvic spreading, high mitotic index, and cytokeratin 20 immunoreactivity, and lack of M1, CA125, and cytokeratin 7 immunoreactivity favor the diagnosis of ovarian metastases from colon carcinomas. The identification of 13q gain as a peculiar, sensitive, and specific marker of colorectal carcinomas seems relevant.

Genetic progression in sporadic endometrial and gastrointestinal cancers with high microsatellite instability.

This study selected a series of 136 MSI‐H (microsatellite instability at high frequency) gastric, colorectal, and endometrial carcinomas combining immunohistochemical analysis for hMLH1 or hMSH2 gene products and microsatellite study. The clinico‐pathological profile of all tumours was correlated with the overall instability rates at coding and non‐coding repeats, in order to clarify the role and the mutation timing of seven target genes (TGFβRII, IGFIIR, BAX, hMSH3, hMSH6, CHK1, and BRCA2) in the progression of an MSI‐H neoplasm. Regardless of the primary site, the results confirm a model of oncogenesis in which inactivation of hMLH1, or less frequently hMSH2, may initiate a pathway culminating in a progressive accumulation of frameshifts in coding region (CDR) microsatellites. Comparing gastrointestinal and endometrial tumours, significantly lower levels of microsatellite instability at both coding and non‐coding repeats were observed. Among gastric and colorectal tumours, the detection of small shortening within Bat‐26 and Bat‐25 markers defines a subgroup of MSI‐H gastrointestinal tumours invariably characterized by early stage at diagnosis. In these tumours, mutations of TGFβRII or BAX genes precede frameshifts in the other tested genes. The analysis of correlations between the mutational and clinico‐pathological profiles of advanced gastrointestinal tumours revealed that the higher levels of microsatellite instability at both coding and non‐coding repeats were not associated with a more advanced clinico‐pathological stage or a less favourable outcome. A significant association was observed between a low number of CDR frameshifts and the presence of lymph‐node metastasis in advanced gastrointestinal tumours. The existence of advanced MSI‐H tumours with more aggressive behaviour and a ‘mild mutator phenotype’ could be explained by hypothesizing an overlapping of different mechanisms of tumourigenesis, including both the mutator and the suppressor pathways; this should be tested by further studies. Copyright

Physical map of the D6S149-D6S193 region on chromosome 6Q27 and its involement in benign surface epithelial ovarian tumours

A detailed long range restriction map of the region defined by markers D6S149 and D6S193 on chromosome 6q27 has been constructed. This was achieved by YAC cloning and contig assembling of the same region. Seven YAC clones were found to span the almost 1000 Kb region flanked by the two markers which on the genetic map resulted to be 1.9 cM apart. With some of the characterized YAC clones we undertook a molecular cytogenetic analysis of 20 benign ovarian tumors. The rationale for this was the recent mapping to a region of chromosome 6q27, flanked by markers D6281 and D6S133, of a locus for the SV40-mediated immortalization of human cells (SEN6 gene). Noteworthy we found that the the D6S149-D6S193 region (comprised in the larger D6S281-D6S133 physical interval) was altered in all samples analysed adding support to the occurrence of a immortalization step in this type of tumors.

Sinonasal mucosal melanoma: A 12-year experience of 58 cases

Sinonasal mucosal melanoma is a rare malignancy with poor prognosis.

Genetic and cytogenetic observations among different types of ovarian tumors are compatible with a progression model underlying ovarian tumorigenesis

In this report we present the characterization of ovarian neoplasms including benign tumors, borderline tumors, and invasive carcinomas in order to assess whether a sharing of cytogenetic abnormalities is present in all three types of tumors. A cohort of 114 newly diagnosed and untreated ovarian epithelial tumors were analyzed by cytogenetic and molecular cytogenetic approaches with probes specific for chromosome 6. Three groups of chromosome abnormalities were identified: the first group included abnormalities common to all tumor classes (losses of chromosomes 6, 8, 10, 11, 15, 16, 17, 18, 19, 20, 21, 22, and X; gains of chromosomes 1, 3, 5, and 12; 6q24 approximately qter deletions); the second group presented specific abnormalities present in malignant but not in benign tumors (losses of chromosomes 2, 7, 13, and 14; gains of chromosome 4 and chromosome markers); and the last group included abnormalities unique to invasive carcinomas (loss of chromosome 4; gains of chromosomes 2, 7, 8, 9, 10, 16, 17, 18, 19, 20, and 21; 6q16 approximately q24 deletions; rearrangements of 3p, 3q, 13q, and 21q regions). The presence of shared chromosomal alterations in all three types of ovarian neoplasms investigated in this report seems therefore to suggest a progression model for these types of tumors.

Primary serous papillary adenocarcinoma of the vagina: a case report.

The first reported case of vaginal serous papillary adenocarcinoma (VSPA) in a 61-year-old woman is presented. The woman had a mass in the upper posterior vaginal wall that was 2.5 cm in maximal dimension and was treated with a radical hysterectomy with bilateral salpingo-oophorectomy, lymphadenectomy, and subtotal vaginectomy, followed by radiation therapy. The ovaries, fallopian tubes, cervix, endometrium, and peritoneum did not show primary or secondary neoplastic involvement. The patient died because of recurrent disease in the form of widespread peritoneal metastases 30 months postoperatively. Microscopically, the tumor was similar to serous papillary adenocarcinoma of the ovary (OSPA). Immunohistochemical studies showed positive staining for CA 125, CA19.9, DUPAN-2, and TAG-72, and negative staining for CEA. Cytogenetic analysis showed chromosome 6 abnormalities similar to those found in OSPA. These results suggest that VSPA is a clinically aggressive primary tumor sharing morphological and cytogenetic analogy with OSPA.

Treatment strategies for primary early-stage sinonasal adenocarcinoma: A retrospective bi-institutional case-control study

To investigate different treatment strategies for primary early‐stage (pT1‐T2) sinonasal adenocarcinomas.

Role of endoscopic surgery in the management of sinonasal and skull base schwannomas.

The purpose of this study was to report our experience with the endoscopic management of sinonasal schwannomas, analyzing the advantages, limitations, and outcomes of the technique.

Endoscopic Treatment of Ewing Sarcoma of the Sinonasal Tract.

AbstractThe extra-skeletal form is an unusual type of Ewing sarcoma (ES) arising from soft tissue and in the literature there are reports of less than 50 patients describing the tumor in the paranasal sinuses and skull base. The histological diagnosis is crucial to plan the correct treatment and the molecular confirmation is mandatory in equivocal patients. A multimodality treatment with chemotherapy, surgery and radiotherapy improved the outcomes of these diseases during the last decades and a free-margin resection with the endoscopic transnasal technique is one of the most recent ways to manage these pathologies in selected patients, reducing the morbidities of the external approaches and preserving the quality of life of the patient.Here, the authors present the first patient of primary sinonasal ES free from disease after 5 years of follow-up and treated with an endoscopic endonasal approach and a second patient of sinonasal metastases of ES treated with and endoscopic transnasal approach.