Abstract: Signet-ring stromal tumor of the ovary is extremely rare, with only ten cases reported in the literature. We report on a case of signet-ring stromal tumor of the left ovary in a 54-year-old woman who presented with abdominal discomfort. Histologically, the tumor was composed of an admixture of spindle and round cells which contained a large cytoplasmic vacuole which displaced the nucleus, creating a signet-ring appearance. Numerous cells showed intracytoplasmic hyaline globules. Immunohistochemically, the tumor cells showed positivity for vimentin, actin, inhibin, and calretinin, thus confirming the ovarian stromal origin of the neoplasm. The patient remains free of disease one year and 9 months after surgery. Signet-ring tumor of the ovary is a rare variant of benign ovarian stromal neoplasm and should be distinguished from metastatic mucin-secreting signet-ring adenocarcinoma.

Abstract: OBJECTIVE: Pure squamous cell carcinoma (SCC) of the breast is a rare tumour and its clinical behaviour is not correctly known. The aim of the study is to evaluate the prevalence, epidemiological and clinical characteristics of the cases of SCC studied in our institution. STUDY DESIGN: The breast department's database was searched for patients diagnosed with breast SCC between September 1979 and June 2006. Pathological features, outcome aspects and prognosis were studied. All specimens were reviewed by our pathologist who performed inmunohistochemistry for hormone receptors. RESULTS: Eleven patients were identified (0.19%) between 5771 cases of breast cancer. Mean age was 64 (37-76) years and mean follow-up was 46 (6-216) months. Mean disease free survival (DFS) was 92 months (S.E.=33), with a 36% DFS rate at 5 years and the mean overall survival was 93 months (S.E.=34). Mean survival from the time recurrent disease was recognized was 9 (1-16) months. Tumours were hormone receptor negative. CONCLUSIONS: SCC of the breast is aggressive and often treatment-refractory. The role of different new chemotherapy regimens need to be explored.

Abstract: Epithelial-mesenchymal transition (EMT) is defined by the loss of epithelial characteristics and the acquisition of a mesenchymal phenotype. In carcinoma cells, EMT can be associated with increased aggressiveness, and invasive and metastatic potential. To assess the occurrence of EMT in human breast tumors, we conducted a tissue microarray-based immunohistochemical study in 479 invasive breast carcinomas and 12 carcinosarcomas using 28 different markers. Unsupervised hierarchical clustering of the tumors and statistical analysis showed that up-regulation of EMT markers (vimentin, smooth-muscle-actin, N-cadherin, and cadherin-11) and overexpression of proteins involved in extracellular matrix remodeling and invasion (SPARC, laminin, and fascin), together with reduction of characteristic epithelial markers (E-cadherin and cytokeratins), preferentially occur in breast tumors with the "basal-like phenotype." Moreover, most breast carcinosarcomas also had a basal-like phenotype and showed expression of mesenchymal markers in their sarcomatous and epithelial components. To assess whether basal-like cells have intrinsic phenotypic plasticity for mesenchymal transition, we performed in vitro studies with the MCF10A cell line. In response to low cell density, MCF10A cells suffer spontaneous morphologic and phenotypic EMT-like changes, including cytoskeleton reorganization, vimentin and Slug up-regulation, cadherin switching, and diffuse cytosolic relocalization of the catenins. Moreover, these phenotypic changes are associated with modifications in the global genetic differentiation program characteristic of the EMT process. In summary, our data indicate that in breast tumors, EMT likely occurs within a specific genetic context, the basal phenotype, and suggests that this proclivity to mesenchymal transition may be related to the high aggressiveness and the characteristic metastatic spread of these tumors.

Abstract: Pleomorphic lobular carcinomas (PLC) of the breast display histological features associated with classic invasive lobular carcinoma (ILC), yet they also exhibit more conspicuous nuclear atypia and pleomorphism, and an aggressive clinical behaviour. From a breast cancer progression perspective, it is unclear whether PLC is a variant of ILC or is a high-grade invasive ductal carcinoma (IDC) that has lost E-cadherin. The molecular features of 26 PLC were studied using immunohistochemistry [oestrogen receptor (ER), progesterone receptor (PR), HER2, p53 and E-cadherin], 0.9 Mb resolution, microarray-based comparative genomic hybridization (aCGH), fluorescent (FISH) and chromogenic (CISH) in situ hybridization and loss of heterozygosity. Comparative analysis was performed with aCGH data from PLC with classic ILC (16 cases) and high grade IDC (35 cases). PLCs were frequently ER- and PR-positive, E-cadherin-negative and occasionally HER2- and p53-positive. Recurrent copy number changes identified by aCGH included gains on 1q, 8q, 11q, 12q, 16p and 17q and losses on 8p, 11q, 13q, 16q and Xq. Highly recurrent 1q+ (100% of cases), 16p+ (93%), 11q- (53%) and 16q- (93%) and evidence of the der(1;16)/der(16)t(1;16) rearrangement, as detected by FISH, suggested that PLC had a 'lobular genotype'. Focal amplifications were evident at 8p12-p11, 8q24, 11q13.1-q14.1, 12q14, 17q12 and 20q13. Loss of BRCA2 was detected in 40% of PLC by LOH. Comparative analysis of aCGH data suggested the molecular features of PLC (ER/PR-positive, E-cadherin-negative, 1q+, 11q(-), 16p+ and 16q(-)) were more closely related to those of ILC than IDC, implicating an overlapping developmental pathway for these lobular tumour types. Molecular alterations found in PLC that are more typical of high-grade IDC than ILC (p53 and HER2 positivity, 8q+, 17q24-q25+, 13q(-) and amplification of 8q24, 12q14, 17q12 and 20q13) are likely to drive the high-grade and more aggressive biology of PLC.

Abstract: To date, only 16 cases of transitional cell carcinoma of the endometrium and endometrial carcinoma with transitional cell differentiation have been reported in the literature. We reviewed the clinicopathologic features of 5 cases of endometrial carcinoma with transitional cell differentiation. The mean age was 68 years, and all patients presented with postmenopausal bleeding. Macroscopically, the tumors were intracavitary and friable. Microscopically, the tumors were composed of tightly packed papillary structures with thin fibrovascular cores, resembling a transitional cell carcinoma of the urinary tract. One tumor showed exclusively transitional cell differentiation, whereas the remaining 4 neoplasms showed that the transitional cell carcinoma was admixed with a variable proportions of endometrioid adenocarcinoma. Four cases were in FIGO stage IB, whereas the remaining tumor infiltrated the uterine cervix (FIGO stage IIB). Immunoreactivity was typical of müllerian derivatives (cytokeratin 7 positive, cytokeratin 20 negative). p16 protein was positive in all cases, but human papillomavirus DNA was not detected in any of the tumors. None of the patients developed local recurrence or distant metastases, even though there are too few cases of transitional cell carcinoma of the endometrium reported to make any statistically valid conclusions about response to therapy and prognosis. Transitional cell carcinoma is an unusual variant of endometrial carcinoma, with distinctive histologic and immunophenotypic features. Identification of this variant broadens the morphological spectrum of epithelial neoplasms of the endometrium.

Abstract: Lysyl oxidase-like 2 (Loxl2) interacts with and stabilizes Snai1 transcription factor, promoting epithelial-mesenchymal transition. Either Loxl2 or Snai1 knock-down blocks tumor growth and induces differentiation, but the specific role of each factor in tumor progression is still unknown. Comparison of the gene expression profiles of the squamous cell carcinoma cell line HaCa4 after knocking-down Loxl2 or Snai1 revealed that a subset of epidermal differentiation genes was specifically up-regulated in Loxl2-silenced cells. In agreement, although both Loxl2- and Snai1-knockdown cells showed reduced in vivo invasion, only Loxl2-silenced cells exhibited a skin-like epidermal differentiation program. In addition, we show that expression of Loxl2 and Snai1 correlates with malignant progression in a two-stage mouse skin carcinogenesis model. Furthermore, we found that increased expression of both LOXL2 and SNAI1 correlates with local recurrence in a cohort of 256 human laryngeal squamous cell carcinomas. We describe for the first time that high levels of LOXL2 are associated with decreased overall and disease-free survival in laryngeal squamous cell carcinomas, lung squamous cell carcinoma, and lymph node-negative (N(0)) breast adenocarcinomas. Altogether, our results show that LOXL2 can be used as a new poor prognosis indicator in human squamous cell carcinomas promoting malignant transformation by both SNAI1-dependent and SNAI1-independent pathways.

Abstract: Use of tamoxifen for treatment and prevention of breast cancer is becoming increasingly common. Tamoxifen has been associated with increased risk of endometrial carcinoma, although the exact mechanism of action is unknown. The aim of our study was to seek a possible correlation between endometrial carcinoma, tamoxifen exposure and MSI, PTEN, beta-catenin and K-ras abnormalities. A group of 18 patients with endometrial carcinoma following treatment with tamoxifen were selected. A control group included 15 patients with endometrial carcinoma and associated ovarian hyperthecosis and one patient with endometrial carcinoma and adult granulosa cell tumor of the ovary, chosen because both conditions are associated with increased production of estrogen and increased risk of endometrial carcinoma development. The second control group included 27 randomly selected consecutive patients with endometrial carcinoma without identifiable associated conditions. Immunostaining for beta-catenin was performed on all cases; DNA was extracted and amplified by PCR with primers for beta-catenin, K-ras and PTEN genes. BAT-25 and BAT-26 were analyzed to assess for MSI. There were 16 endometrioid endometrial carcinomas, one mixed carcinoma and one clear cell carcinoma among patients in the tamoxifen group. All patients with ovarian hyperthecosis and adult granulosa cell tumor had endometrioid endometrial carcinoma. In the random control group, there were 26 endometrioid endometrial carcinomas and one carcinosarcoma. Immunohistochemical and mutational analysis for beta-catenin showed abnormalities in 4/11 (36%) and 3/10 (30%) informative cases in the tamoxifen group; 7/16 (44%) and 4/15 (27%) informative cases, respectively in the ovarian hyperthecosis group and 1/27 random control cases (4%) (P<0.05). Patients with tamoxifen exposure had more K-ras mutations and fewer PTEN mutations and MSI as opposed to controls, but the results were not statistically significant. In conclusion, there was a direct relationship between tamoxifen exposure and overexpression of beta-catenin oncoprotein, which is known to play a major role in the pathogenesis of estrogen-driven, type I endometrial adenocarcinoma.

Abstract: AIMS: To determine whether basal-like phenotype and vimentin and/or laminin are related in both sporadic/familial (BRCA1 or BRCA2 mutated) tumours. METHODS: 230 non-familial and 28 hereditary node-negative invasive breast carcinomas were immunohistochemically analysed for oestrogen receptors (ER), progesterone receptors (PR), cytokeratin 5/6 (CK5/6), epidermal growth factor receptors (EGFR), Ki67, p53, vimentin and laminin, using tissue microarrays. Tumours were considered to have basal-like phenotype if they were ER negative and HER2 negative, but positive for CK5/6 and/or EGFR. RESULTS: In sporadic tumours, vimentin expression was found in 77.8% cases with basal-like phenotype and 15.5% of non-basal cases (p<0.001). In familial cases, vimentin was expressed in 83.3% basal-like cancers and 16.7% of non-basal tumours (p<0.001). Vimentin expression was more frequent in BRCA1 than BRCA2 mutation carriers. Vimentin expressing tumours were associated with poor prognosis (p = 0.012) among patients not receiving adjuvant chemotherapy and showed a trend for local recurrence or visceral but not bone metastasis (p = 0.021). Laminin expression was also related to basal-like phenotype in both sporadic/familial cases (p<0.001 and p = 0.007, respectively), but neither with prognosis nor recurrence pattern in sporadic cancers. CONCLUSIONS: Vimentin and laminin expression is associated with basal-like phenotype in breast cancer. Expression of vimentin and laminin is characteristic of BRCA1 associated tumours. Since vimentin and laminin staining is widely used by pathologists for diagnostic purposes, thus demonstrating the robustness of their specific antibodies, the immunohistochemical evaluation of these two molecules could be used in identification of basal-like breast tumours in both sporadic/familial cases.

Abstract: Recently, it has been shown that mice deficient in the proapoptotic protein prostate apoptosis response 4 (Par-4) are specifically prone to develop endometrial carcinomas. Based on this, we have examined here the possible role of Par-4 as a tumor suppressor gene in human endometrial cancer. Using cDNA arrays, quantitative reverse transcription-PCR, and immunohistochemistry, we detected Par-4 down-regulation in approximately 40% of endometrial carcinomas. This alteration was not associated with phosphatase and tensin homologue (PTEN), K-RAS, or beta-catenin mutations, but was more frequent among tumors showing microsatellite instability (MSI) or among tumors that were estrogen receptor positive. Mutational analysis of the complete coding sequence of Par-4 in endometrial cancer cell lines (n = 6) and carcinomas (n = 69) detected a mutation in a single carcinoma, which was localized in exon 3 [Arg (CGA) 189 (TGA) Stop]. Interestingly, Par-4 promoter hypermethylation was detected in 32% of the tumors in association with low levels of Par-4 protein and was more common in MSI-positive carcinomas. Par-4 promoter hypermethylation and silencing was also detected in endometrial cancer cell lines SKUT1B and AN3CA, and reexpression was achieved by treatment with the demethylating agent 5'-aza-2'-deoxycytidine. Together, these data show that Par-4 is a relevant tumor suppressor gene in human endometrial carcinogenesis.

Abstract: Tumours arising in BRCA1 mutation carriers and sporadic basal-like breast carcinomas have similar phenotypic, immunohistochemical and clinical characteristics. SOX2 is an embryonic transcription factor located at chromosome 3q, a region frequently gained in sporadic basal-like and BRCA1 germline mutated tumours. The aim of the study was to establish whether sox2 expression was related to basal-like sporadic breast tumours. Two hundred and twenty-six sporadic node-negative invasive breast carcinomas were immunohistochemically analysed for oestrogen receptor (ER), progesterone receptor (PR), CK5/6, EGFR, vimentin, HER2, ki67, p53 and sox2 using tissue microarrays. Tumours were considered to have basal-like phenotype if they were ER/HER2-negative and CK5/6 and/or EGFR-positive. Thirty cases of this series (13.7%) displayed a basal-like phenotype. Sox2 expression was observed in 16.7% of cases and was significantly more frequently expressed in basal-like breast carcinomas (43.3% in basal-like, 10.6% in luminal and 13.3% in HER2+ tumours, P<0.001). Moreover, Sox2 showed a statistically significant inverse association with ER and PR (P=0.001 and 0.017, respectively) and direct association with CK5/6, EGFR and vimentin (P=0.022, 0.005 and <0.001, respectively). Sox2 is preferentially expressed in tumours with basal-like phenotype and may play a role in defining their less differentiated/'stem cell' phenotypic characteristics.

Abstract: Phospholipid Hydroperoxide Glutathione Peroxidase (PHGPx) is the only known enzyme able to reduce lipid peroxides bound to cell membranes. Moreover it has been involved in apoptosis and can influence intracellular signaling. To investigate the possible relationship between PHGPx and human cancer we have quantified PHGPx expression levels by real-time quantitative PCR and immunohistochemistry in tissue samples of human breast invasive ductal carcinoma from 34 patients compared with their own controls of benign breast tissue. PHGPx expression levels were compared with the clinical and pathological data of these patients. The results showed that PHGPx expression levels are downregulated in poorly differentiated (grade 3) breast invasive ductal carcinoma (P = 0.0043). PHGPx expression levels decreased gradually with tumor grade from grade 1 to grade 3. We also found a downregulation of PHGPx in cases that showed p53 accumulation compared with cases without p53 immunostaining (P = 0.0011). PHGPx was also downregulated in cases without progesterone receptors (PR) immunostaining compared with cases with PR immunostaining (P = 0.0165). Grade 3, p53 immunostaining and absence of PR immunostaining are poor prognostic factors. These results suggest that PHGPx downregulation could be related with a poorer prognosis in breast invasive ductal carcinoma.

Abstract: The membrane-cytoskeleton crosslinker ezrin is associated with malignant progression and metastasis in human neoplasias. To study the role of ezrin in breast cancer, we first assessed ezrin expression in a panel of breast cancer cell lines by western blot and confocal microscopy. Western blot revealed no differences in total ezrin levels among these breast cell lines. However, immunofluorescence staining revealed that Estrogen receptor (ER)-positive, noninvasive and nontumorigenic cell lines concentrated ezrin at the apical surface, whereas invasive cell lines localized ezrin in motile structures (membrane ruffles and filopodia) but also had more diffuse cytoplasmic staining. We next studied ezrin expression in 509 breast carcinomas using tissue microarrays. Immunohistochemical staining for ezrin, p53, Ki-67, phospho-Akt, HER2, and hormonal receptors was performed. Ezrin staining in normal breast epithelium localized at the apical, but not lateral, cell surface, whereas, in most breast tumor cases (331, 70.3%), it localized in the cytoplasm. Complete membranous staining occurred in 89 (18.9%) samples, and apical staining was seen in 51 (10.8%) cases. There were significant positive associations between cytoplasmic ezrin localization and adverse tumor characteristics such as high grade, high level of Ki-67 expression, hormonal-receptor negativity, and lymph-node metastases. Apical ezrin staining was associated with favorable clinicopathological features and node-negative tumors. Membranous ezrin staining was associated with high grade, strong HER2 and p-Akt expression. In conclusion, the switch of ezrin localization from the apical membrane to either the complete membrane or to the cytoplasm is correlated with dedifferentiation and adverse features in invasive breast tumors and cancer cell lines.

Abstract: PURPOSE: Basal-like phenotype tumors are frequently found among BRCA1 germ-line mutated breast carcinomas. They are biologically aggressive and have a tendency towards visceral metastasis when untreated. Nevertheless, it has been suggested that they respond to chemotherapy better than other types of tumors. Fascin expression has been associated with lung metastasis in breast cancer. The aim of this study was to determine whether basal-like phenotype and fascin were related in both sporadic and familial tumors and with prognosis in node-negative sporadic breast cancers. EXPERIMENTAL DESIGN: 230 nonfamilial and 28 hereditary node-negative invasive breast carcinomas were immunohistochemically analyzed using tissue microarrays. Tumors that were estrogen receptor/HER2 negative and cytokeratin 5/6 and/or epidermal growth factor receptor positive were considered to have a basal-like phenotype. RESULTS: A basal-like phenotype was found in 11.9% of sporadic cancers. Among patients not receiving adjuvant chemotherapy, a basal-like phenotype was associated with poor prognosis (P = 0.001, log-rank test) whereas no such association was found in patients receiving it. Tumors with a basal-like phenotype showed local recurrence (17.4%) or visceral metastasis (13%) but not bone metastasis (P = 0.001). Fascin expression was observed in 25.1% of sporadic invasive breast carcinomas and was associated with the basal-like phenotype, but not with prognosis or recurrence pattern. Fascin was expressed in 83.3% and 16.7% BRCA1- and BRCA2-associated carcinomas, respectively (P = 0.048). CONCLUSIONS: Basal-like tumors had a tendency towards visceral metastasis and their prognosis was dependent on the use of postoperative chemotherapy. Although fascin expression was associated with the basal-like phenotype, it was not associated with their metastatic behavior. Fascin expression is frequent in BRCA1-associated tumors.

Abstract: The role of caveolin 1 (CAV1), a structural component of caveolae in breast cancer is controversial, although most studies suggest that it functions as a tumor-suppressor gene. In addition, some studies have identified CAV1 as a marker of myoepithelial cells. Since myoepithelial markers are frequently expressed in breast carcinomas with a basal-like phenotype, which are frequently occurring tumors in women with BRCA1 germline mutations, we evaluated whether CAV1 was associated with a basal-like phenotype in 509 sporadic and 47 hereditary BRCA1-/BRCA2-associated carcinomas. Immunohistochemistry was performed on tissue microarrays and cases were classified as having a basal-like-phenotype if they were estrogen-receptor- and HER2-negative but cytokeratin 5/6- and/or epidermal growth factor receptor-positive. In sporadic carcinomas, CAV1 expression was found in 21 out of 496 valuable cases (4.2%). A basal-like-phenotype was found in 53 out of 498 (10.6%) cases. A strong association was found between CAV1 expression and a basal-like-phenotype, since 52% of tumors that expressed CAV1 had this phenotype, compared with only 9% of CAV1-negative carcinomas (p<0.001). CAV1 was expressed in six (12.8%) familial cases, five of which had a basal-like-phenotype (p = 0.009). Moreover, these six CAV1-positive cases were BRCA1 tumors. The difference in the frequency of CAV1 expression between BRCA1- and BRCA2-associated tumors was statistically significant (p = 0.024). In conclusion, this study reports for the first time CAV1 expression in BRCA1 and BRCA2 hereditary breast cancer and identifies CAV1 as a marker associated with a basal-like-phenotype in both hereditary and sporadic breast cancer.

Abstract:

Abstract: PURPOSE: Classic lobular carcinomas (CLC) account for 10% to 15% of all breast cancers. At the genetic level, CLCs show recurrent physical loss of chromosome16q coupled with the lack of E-cadherin (CDH1 gene) expression. However, little is known about the putative therapeutic targets for these tumors. The aim of this study was to characterize CLCs at the molecular genetic level and identify putative therapeutic targets. EXPERIMENTAL DESIGN: We subjected 13 cases of CLC to a comprehensive molecular analysis including immunohistochemistry for E-cadherin, estrogen and progesterone receptors, HER2/neu and p53; high-resolution comparative genomic hybridization (HR-CGH); microarray-based CGH (aCGH); and fluorescent and chromogenic in situ hybridization for CCND1 and FGFR1. RESULTS: All cases lacked the expression of E-cadherin, p53, and HER2, and all but one case was positive for estrogen receptors. HR-CGH revealed recurrent gains on 1q and losses on 16q (both, 85%). aCGH showed a good agreement with but higher resolution and sensitivity than HR-CGH. Recurrent, high level gains at 11q13 (CCND1) and 8p12-p11.2 were identified in seven and six cases, respectively, and were validated with in situ hybridization. Examination of aCGH and the gene expression profile data of the cell lines, MDA-MB-134 and ZR-75-1, which harbor distinct gains of 8p12-p11.2, identified FGFR1 as a putative amplicon driver of 8p12-p11.2 amplification in MDA-MB-134. Inhibition of FGFR1 expression using small interfering RNA or a small-molecule chemical inhibitor showed that FGFR1 signaling contributes to the survival of MDA-MB-134 cells. CONCLUSIONS: Our findings suggest that receptor FGFR1 inhibitors may be useful as therapeutics in a subset of CLCs.

Abstract: Alterations in the cadherin-catenin expression and activation of the Wnt signaling have been related to the pathology of ovarian carcinomas. Here, we evaluated the immunoreactivity of cadherins (E-, P-, and N-cadherin and cadherin-11) and catenins (alpha-, beta-, and gamma-catenin and p120) in 86 ovarian tumors. We found significant differences in the expression of all cadherins and catenins among the distinct histologic tumor types. Clear cell tumors were rarely N-cadherin- and P-cadherin-positive and showed reduced membranous expression in all the catenins; Serous carcinomas were frequently N-cadherin- and P-cadherin-positive, mucinous tumors strongly expressed E-cadherin and the catenins in the membrane, and endometrioid tumors characteristically expressed nucleocytoplasmic beta-catenin in most of the cases. We next studied whether allelic losses in the chromosomal regions containing various cadherin genes (16q22) or APC gene (5q21) occurred in ovarian tumors and observed a high frequency of loss of heterozygosity in 16q22 (78%) and 5q21 (33%) regions, but there were no differences among the tumor types analyzed. Finally, we also assessed the molecular alterations responsible for beta-catenin nuclear accumulation in endometrioid tumors by screening for mutations in AXIN1, AXIN2, APC, and KRAS genes. Mutations in KRAS were observed in 2 of 19 tumors, but no mutations were detected in AXIN1, AXIN2, or APC genes. Only beta-catenin gene mutations were associated with nuclear beta-catenin staining in these tumors. In conclusion, different cadherin-catenin expression patterns are associated with distinct histologic types. Oncogenic Wnt signaling plays a role only in endometrioid tumors, where beta-catenin mutations seem to be the main cause of its aberrant expression.

Abstract: PURPOSE: We sought to reproduce with quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) the results obtained with a 70-gene expression profile that has been described previously in breast cancer. PATIENTS AND METHODS: Frozen breast cancer samples from patients who were operated on were used to isolate tumor RNA. Ninety-six patients with stage I to II disease were included. Median age was 57 years (range, 27 to 80 years). Forty-eight patients had lymph node-negative and 48 lymph node-positive disease. qRT-PCR amplifications were performed and the results were correlated with clinical data. RESULTS: After a minimum follow-up of 5 years, 25 patients had a relapse. The gene profile divided patients into two groups with poor and good prognosis. Significant differences with regard to grade of differentiation, size and hormone receptors were seen between the two groups. The gene profile was significantly associated with relapse-free survival and overall survival in the whole group of 96 patients. Multivariate analysis showed that only lymph node status and gene profile were significantly correlated to overall survival. CONCLUSION: qRT-PCR reproduced the results obtained with microarrays for a prognostic gene profile in women with early-stage breast cancer.

Abstract: The aim of this study was to investigate selected proteomic markers of the metabolic phenotype of breast carcinomas as prognostic markers of cancer progression. For this purpose, a series of 101 breast carcinomas and 13 uninvolved breast samples were examined for quantitative differences in protein expression of mitochondrial and glycolytic markers. The beta-subunit of the mitochondrial H(+)-ATP synthase (beta-F1-ATPase) and heat shock protein 60 (Hsp60), and the glycolytic glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase and lactate dehydrogenase were identified by immunological techniques. Correlations of the expression level of the protein markers and of the ratios derived from them were established with the clinicopathological information of the tumors and the follow-up data of the patients. The metabolic proteome of breast cancer specimens revealed a pronounced shift towards an enhanced glycolytic phenotype concurrent with a profound alteration on the mitochondrial beta-F1-ATPase/Hsp60 ratio when compared with normal samples. Discriminant analysis using markers of the metabolic signature as predictor variables revealed a classification sensitivity of approximately 97%. Kaplan-Meier survival analysis showed that several of the proteomic variables significantly correlated with overall and disease-free survival of the patients. The expression level of beta-F1-ATPase per se allowed the identification of a subgroup of breast cancer patients with significantly worse prognosis. Multivariate Cox regression analysis indicated that tumor expression of beta-F1-ATPase is a significant marker independent from clinical variables to assess the prognosis of the patients. We conclude that the alteration of the mitochondrial and glycolytic proteomes is a hallmark feature of breast cancer further providing relevant markers to aid in the prognosis of breast cancer patients.

Abstract: INTRODUCTION: A number of findings suggest that cyclooxygenase-2 (COX-2) is overexpressed in breast tumours. However, there is a lack of consensus in the literature regarding the pattern of expression of this protein in invasive breast ductal carcinoma and in the adjacent non-tumour ductal epithelium. This study compares the expression of COX-2 mRNA and protein in breast ductal carcinoma relative to non-tumour breast tissue. MATERIAL AND METHODS: We analysed the expression of COX-2 mRNA by quantitative PCR, and COX-2 protein by immunohistochemistry in invasive ductal carcinoma as well as in non-tumour adjacent ductal epithelium from 34 breast biopsies diagnosed as being invasive ductal carcinoma. As control, we analysed expression of COX-2 protein by immunohistochemistry in surgically-resected benign breast lesions. RESULTS: Our results show that COX-2 mRNA and protein are overexpressed in non-tumour ductal epithelium compared with invasive ductal carcinoma. However, the pattern of the protein expression is different in tumour and non-tumour tissue: COX-2 protein is expressed predominantly in the membrane of the non-tumour ductal epithelium (including in benign breast lesions) while, in invasive ductal carcinoma cells, it is localised in the cytoplasm. CONCLUSIONS: The non-tumour ductal epithelium adjacent to invasive ductal carcinoma shows a higher COX-2 expression than does the invasive ductal carcinoma. However, the different localisation of the immunohistochemically-detected protein suggests a possible post-translational regulation of the protein.

Abstract: Squamous cell carcinoma of the pharynx and larynx (SCCPL) is a genetically complex disease and is frequently associated with nonrandom chromosomal alterations. Fifty primary SCC of the pharynx (oropharynx, n=11): see and hypopharynx, n=11) and larynx ( n=28) were examined for numerical aberrations of chromosomes 8, 9, 11, and 17 with a panel of chromosome-specific repetitive DNA probes by fluorescence in situ hybridization (FISH). DNA ploidy analysis was also performed by flow cytometry (FCM). Aneusomic copy numbers of chromosomes 8, 9, 11, and 17 were discovered in 66%, 68%, 68% and 78% of tumors, respectively. FCM showed abnormal DNA content in 74% of cases (mean DNA index=1.69). Polysomy was the main finding in both DNA-aneuploid and DNA-diploid tumors (64.5% of cases). Numerical aberrations of chromosomes 8 and 11 correlated to DNA ploidy by FCM (P< 0.05). Aneusomy was present in 69.23% of DNA-diploid tumors. Marked intratumoral and intertumoral chromosomal heterogeneity was noted between individual tumors, suggesting a notable heterogeneity in aneuploid and diploid cell populations. Interphase FISH can be used to study important cytogenetic changes which occur during the development of SCC of the pharynx and larynx.

Abstract: Accumulating evidences indicate that p120 catenin, a member of the E-cadherin (E-CD)/catenin adhesion complex, plays a role in tumor invasion. To establish the expression pattern of p120 in breast cancer, we analysed 326 breast tissue biopsies by tissue microarray. Most of the lobular tumors (88%) showed exclusive cytoplasmic localization, and 6% of them also had p120 nuclear staining. Cytoplasmic p120 strongly associated with complete loss of E-CD and beta-catenin not only in lobular carcinoma and its metastases but also in atypical lobular hyperplasias. In the latter, loss of heterozygosity of E-CD gene was also observed. Complete loss of E-CD and cytoplasmic and nuclear p120 staining was also observed in primary lobular cancer cell cultures generated by us. In ductal tumors, by contrast, reduction of p120 and E-CD in membrane was very common (57 and 53%, respectively), whereas cytoplasmic p120 staining was rarely seen. This simultaneous reduction of membranous E-CD and p120 was not associated with increased Src kinase activity. To demonstrate that cytoplasmic p120 localization was a consequence of the absence of E-CD, the endogenous E-CD was re-expressed in MDA-231 cells by 5-Aza-2'-deoxycytidine (5Aza) treatment. After treatment, p120 shifted from the cytoplasm to the membrane, where it colocalized with endogenous E-CD. Additionally, suppressing E-CD expression in Madin-Darby canine kidney cells by stable transfection of the transcriptional repressors Snail, E47 or Slug, provokes p120 cytoplasmic localization and p120 isoform switching. In conclusion, abnormal cytoplasmic and nuclear localization of p120, which are mediated by the absence of E-CD, characteristically occur in the early stages of lobular breast cancer and are maintained during tumor progression to metastasis. Consequently, p120 may be an important mediator of the oncogenic effects derived from E-CD inactivation, including enhanced motility and invasion, in lobular breast cancer.

Abstract: Cyclin D1 is frequently overexpressed in human neoplasias by gene rearrangement and amplification. In addition, Ras, PTEN and beta-catenin appear to modulate cyclin D1 levels. Since the causes of cyclin D1 overexpression are poorly understood in EC, we investigated whether or not this alteration is due to cyclin D1 gene amplification or to RAS, PTEN and beta-catenin mutation. We analyzed cyclin D1 expression in 18 AEHs, 65 EECs and 27 NEECs by immunohistochemistry as well as CCND1 gene amplification by FISH. In EECs, mutations in K-RAS, PTEN, beta-catenin and CCND1 were studied by PCR-SSCP and sequencing and MSI was evaluated by analyzing BAT-25 and BAT-26 microsatellites. Contingency tests were used to evaluate the relationships between variables. Cyclin D1 overexpression was not observed in AEHs but was present in 13.8% of EECs and 11.2% of NEECs (p = 0.031). CCND1 amplification was more frequent in NEECs (26.3%) than in EECs (2.1%) (p = 0.002). In EECs, cyclin D1 overexpression was not associated with mutations in K-RAS, PTEN or beta-catenin. However, in EECs with beta-catenin mutations, cyclin D1 was expressed mainly by cells expressing beta-catenin in the cytoplasm and nucleus but not in those with membranous expression. Finally, cyclin D1 overexpression was associated with MSI (p = 0.047). The molecular alterations associated with cyclin D1 overexpression differ in the 2 clinicopathologic types of EC. Cyclin D1 overexpression is associated with gene amplification in NEECs and with nucleocytoplasmic expression of beta-catenin and MSI in EECs.

Abstract:

Abstract: Deoxynucleoside analogs are used in the treatment of a variety of solid tumors. Their transport across the plasma membrane may determine their cytotoxicity and thus nucleoside transporter (NT) expression patterns may be of clinical relevance. Lack of appropriate antibodies for use in paraffin-embedded biopsies has been a bottleneck to undertake high-throughput analysis of NT expression in solid tumors. Here we report the characterization of 2 new antibodies raised against the low-affinity equilibrative NTs, hENT1 and hENT2, suitable for that purpose. These 2 antisera, along with a previously characterized antibody that specifically recognizes the high-affinity Na-dependent concentrative NT, hCNT1, have been used to analyze, using a tissue array approach, NT expression in gynecologic cancers (90 ovarian, 80 endometrial and 118 uterine cervix carcinomas). Human CNT1 was not detected in 33% and 39% of the ovarian and uterine cervix carcinomas, respectively, whereas hENT1 and hENT2 expression was significantly retained in a high percentage of tumors (91% and 96% for hENT1, 84% and 98% for hENT2, in ovarian and cervix carcinomas, respectively). Only a few endometrial carcinomas (15%) were found to be negative for hCNT1, but they all retained hENT1 and hENT2 expression. In ovarian cancer, the loss of all 3 NT proteins was a more common event in the clear cell histologic subtype than in the serous, mucinous and endometrioid histotypes. In uterine cervix tumors, the loss of expression of hCNT1 was significantly associated with the adenocarcinoma subtype. In summary, hCNT1 was by far the isoform whose expression was most frequently reduced or lost in the 3 types of gynecologic tumors analyzed. Moreover, NT expression is related to the type of gynecologic tumor and its specific subtype, hCNT1 protein loss being highly correlated with poor prognosis histotypes. Since hCNT1, hENT1 and hENT2 recognize fluoropyrimidines as substrates, but with different affinities, this study anticipates high variability in drug uptake efficiency in solid tumors.

Abstract: Carcinoma with osteoclast-like giant cells (OCGC) is an uncommon neoplasm characterized by giant cells, prominent vascularization, haemorrhage and areas of cribriform epithelial growth with moderate atypia. Multinucleated giant cells (MGC) have been described in several other breast lesions raising an interesting differential diagnosis, mainly with benign disorders. Due to its rarity few cases have been described cytologically. We retrospectively reviewed 13 fine needle aspiration samples from nine patients with this variant of carcinoma. Nine corresponded to breast tumours and four to axillary, liver, subcutaneous and mediastinal metastatic lesions. The expression of CD68 by giant cells was evaluated immunocytochemically in six cases. All patients had a complete pathological study of the breast neoplasm. Smears showed a double component of epithelial and giant cells. Epithelial clusters were predominantly of intermediate size with irregular contours. Most were cohesive but others showed cellular dissociation with scarce to moderate cellular pleomorphism. Giant cells had well defined, deeply stained cytoplasm and round to elongated morphology. Two metastatic cases were devoid of them. Haemosiderin-laden macrophages were common in smears from breast tumours. In the six cases tested CD68 was expressed in MGC. Cytological features of mammary carcinoma with OCGC correlate closely with the histological ones. Most cases are clearly recognizable as malignant but in others cytological atypia may be minimal, mimicking a benign lesion. In difficult cases the presence of haemosiderin-laden macrophages and the histiocytic nature of the MGC are helpful diagnostic features.

Abstract: Head and neck squamous cell carcinoma (HNSCC) represents 6% of all cancers. The overall 5-year survival rate for patients with this type of cancer is among the lowest of the major cancer types and has not improved dramatically during the last decade. The pathological staging, in particular the nodal stage, is the most important factor in HNSCC. The lack of progress in head and neck oncology emphasizes the importance of molecular genetic studies to define alterations that may correlate with tumor behavior. The molecular alterations observed in HNSCC are mainly due to oncogene activation and tumor suppressor gene inactivation, leading to deregulation of cell proliferation. These alterations include gene amplification and overexpression of oncogenes such as ras, myc, EGFR and cyclin D1, and mutations and deletions leading to p16 and TP53 tumor suppressor genes inactivation. This article reviews the molecular changes commonly observed in HNSCC. The biological function of these markers and the potential clinical application are discussed. Advances in the understanding of the molecular basis of HNSCC will help in the identification of new molecular markers that could be used for a more accurate diagnosis and assessment of prognosis and may open the way for novel approaches to treatment and prevention.

Abstract: BACKGROUND: Solid papillary carcinoma of the breast (SPCB) is a distinctive form of papillary carcinoma that tends to occur in older women and usually has a favorable prognosis. CASES: We report the cytologic and histologic findings in four cases of SPCB. All but one of the patients were elderly women (mean age, 66 years). Three patients presented with breast masses, and one patient presented with a breast mass and nipple discharge. Cytology demonstrated moderately to highly cellular smears with irregular groups of predominantly monolayered epithelium composed of small, polygonal or cuboidal cells with eosinophilic cytoplasm and rounded, eccentrically placed nuclei. Papillalike clusters with thin, fibrovascular cores were also observed. Immunocytochemical expression of synaptophysin was present in two cases. The diagnosis of SPBC was subsequently confirmed histologically and immunohistochemically. CONCLUSION: The FNA of SPCB displays some features that may be helpful in its correct identification preoperatively.

Abstract: Multiple pulmonary leiomyomatous hamartomas (MPLHs) are extremely rare lesions. We present a case of MPLHs associated with a bronchogenic cyst in a symptomless, 46-year-old man. Previously, MLPHs have been reported to occur in men; therefore, not all cases of MPLHs represent metastases from a uterine smooth muscle tumor. Because these lesions represent a tumorlike overgrowth of normal tissue, we think that leiomyomatous hamartoma is an appropriate term to designate this entity. The possible influence of inflammatory cell mediators in the pathogenesis of MPLHs remains speculative.

Abstract: Abnormal expression of cadherins and catenins plays a critical role in the initiation and progression of multiple human tumours. This study aimed to evaluate the immunoreactivity of E- and P-cadherin, beta- and gamma-catenin, and p120ctn in premalignant and malignant endometrial lesions and to correlate their membranous expression with clinicopathological features. In addition, we examined whether or not LOH and promoter hypermethylation of the CDH1 gene were associated with E-cadherin expression and clinicopathological variables. Finally, we studied the frequency of beta-catenin mutations in premalignant endometrial lesions. Immunohistochemical staining was performed in 21 atypical endometrial hyperplasias (AEHs), 95 endometrioid carcinomas (EECs), and 33 non-endometrioid carcinomas (NEECs). Reduced E-cadherin expression was observed in 57.8% of the cases, being more frequent in NEECs (87.1%, p = 0.001) and carcinomas of more advanced stage (85.7% of stage III-IV carcinomas, p = 0.01). LOH of CDH1 gene was found in 57.1% of NEECs but only in 22.5% of EECs (p = 0.011) and showed a trend towards association with reduced E-cadherin expression (p = 0.089). CDH1 promoter hypermethylation was found in 21.2% of endometrial carcinomas but was not associated with clinicopathological or immunohistochemical variables. Reduced expression of beta- and gamma-catenin and p120ctn was found in 76.1%, 94.3%, and 63.6% of the cases, respectively, being more frequent in lesions with reduced E-cadherin expression. In addition, beta-catenin, but not gamma-catenin or p120ctn expression, was associated with the histology of the lesion, since it was reduced in 35% of AEHs, 80.3% of EECs, and 96.9% of NEECs (p = 0.000). Mutations in exon 3 of the beta-catenin gene, associated with beta-catenin nuclear expression, were detected in 3 (14.0%) AEH, a frequency similar to that previously reported in this series of ECs. Finally, upregulation of P-cadherin was observed in 28.6% of cases. This alteration was associated with the histology of the lesion, since it was found in 9.5% of AEHs, 27.7% of EECs, and 46.2% of NEECs (p = 0.021).

Abstract: The causes and functional consequences of E-cadherin (E-CD) loss in breast cancer are poorly understood. E-CD loss might act in concert with alterations in the APC/beta-catenin pathway to permit oncogenic beta-catenin signaling. To test this hypothesis, we have analyzed the presence of genetic and epigenetic alterations affecting E-CD (CDH1), APC and beta-catenin (CTNNB1) genes and the immunohistochemical expression of E-CD, beta- and gamma-catenin in a series of 46 infiltrating lobular breast carcinomas (ILCs). Since 80% of ILCs featured complete loss of E-CD expression, we analyzed the molecular alterations responsible for E-CD inactivation in these tumors. We found that 10 of 46 (22%) cases harbored mutations in CDH1, including 1 case with 2 different mutations (1 of which was germline). CDH1 was also inactivated by loss of heterozygosity (LOH; 30/41, 73%) and promoter hypermethylation (19/46, 41%). Interestingly, LOH and mutations were also detected in the corresponding in situ lesions of the ILCs, implying that these alterations are early events in lobular cancer tumorogenesis. Additionally, the presence of a polymorphism in the CDH1 promoter was found to be inversely correlated with CDH1 mutations, but not with E-CD levels. We next examined whether alterations in the APC/beta-catenin pathway also occurred in the same series of ILCs. Although no CTNNB1 or APC mutations were detected, promoter methylation (25/46, 52%) and LOH (7/30, 23%) of APC were found. Moreover, methylation of APC and CDH1 occurred concordantly. However, beta- and gamma-catenin were severely reduced or absent in 90% of these tumors, implying that alterations in CDH1 and APC genes do not promote beta-catenin accumulation in ILC. These molecular alterations were not associated with microsatellite instability. In summary, several different mechanisms (mutations, LOH, methylation) are involved in the frequent CDH1 inactivation in invasive and in situ lobular breast cancer. The same tumors also show genetic and epigenetic alterations of APC gene. However, altered CDH1 and APC genes do not promote beta-catenin accumulation in this tumor type.

Abstract: Endometrial carcinoma (EC) comprises at least two types of cancer: endometrioid carcinomas (EECs) are estrogen-related tumors, which are frequently euploid and have a good prognosis. Nonendometrioid carcinomas (NEECs; serous and clear cell forms) are not estrogen related, are frequently aneuploid, and are clinically aggressive. We used cDNA microarrays containing 6386 different genes to analyze gene expression profiles in 24 EECs and 11 NEECs to identify differentially expressed genes that could help us to understand differences in the biology and clinical outcome between histotypes. After supervised analysis of the microarray data, there was at least a 2-fold difference in expression between EEC and NEEC in 66 genes. The 31 genes up-regulated in EECs included genes known to be hormonally regulated during the menstrual cycle and to be important in endometrial homeostasis, such as MGB2, LTF, END1, and MMP11, supporting the notion that EEC is a hormone-related neoplasm. Conversely, of the 35 genes overexpressed in NEECs, three genes, STK15, BUB1, and CCNB2, are involved in the regulation of the mitotic spindle checkpoint. Because STK15 amplification/overexpression is associated with aneuploidy and an aggressive phenotype in other human tumors, we used fluorescence in situ hybridization to investigate whether STK15 amplification occurred in ECs. We found that STK15 was amplified in 55.5% of NEECs but not in any EECs (P <or= 0.001). We confirmed this result in an independent series of ECs included in a tissue microarray in which breast and ovarian cancer samples showed an incidence of STK15 amplification of 15 and 18%, respectively (P <or= 0.001). This study demonstrated the usefulness of cDNA microarray technology for identifying differences in gene expression patterns between histological types of EC and implies that alteration of the mitotic checkpoint is a major mechanism of carcinogenesis in NEECs.

Abstract: Cyclin E overexpression occurs in a subset of endometrial carcinomas (ECs), but the molecular mechanisms underlying this alteration remain to be established. The present study has analysed amplification of the cyclin E gene (CCNE) and mutation in hCDC4, the gene coding for the F-box protein, which tags phosphorylated cyclin E for proteosomal degradation, to ascertain whether these alterations might be responsible for cyclin E overexpression in ECs. Cyclin E and p53 expression was studied by immunohistochemistry in eight atypical endometrial hyperplasias (AEHs), 51 endometrioid endometrial carcinomas (EECs), and 22 non-endometrioid endometrial carcinomas (NEECs). CCNE amplification was analysed by fluorescence in situ hybridization (FISH). Mutations in exons 2-11 of the hCDC4 gene were screened by PCR-SSCP-sequencing. Finally, the polymorphic marker D4S1610 was used to assess loss of heterozygosity (LOH) in the hCDC4 gene. Cyclin E overexpression was found in 26/81 (32%) cases and was associated with the histological type of the lesion, since it was not found in any AEHs but was present in 27% of EECs and 54.5% of NEECs (p=0.035). Cyclin E overexpression was associated with histological grade (p=0.011) and p53 immunostaining in EECs (p=0.033). CCNE amplification was found in 6 of 37 (16%) ECs examined. There was a significant association between CCNE amplification and the histological type of the lesion, since five (83%) of the six cases with amplification were NEECs (p=0.008). One EEC harboured an hCDC4 mutation: a CGA to CAA (Arg/Gln) change at codon 479. In addition, D4S1610 LOH was found in 7 of 23 (30%) informative cases analysed, but no correlation with cyclin E overexpression was found. However, the tumour with hCDC4 mutation also showed LOH. This is the first study demonstrating that cyclin E overexpression is associated with gene amplification in ECs, these alterations being more frequent in NEECs. Although hCDC4 exhibits a low mutation frequency in ECs overexpressing cyclin E, it seems to function as a tumour suppressor gene that is involved in endometrial carcinogenesis.

Abstract: Scarce data are available regarding the molecular mechanisms implicated in paclitaxel resistance. There is controversial data about beta-tubulin mutations role in paclitaxel resistance. We have conducted this trial to address the influence of beta-tubulin mutations in paclitaxel resistance in advanced non-small cell lung cancer (NSCLC). A group of 15 patients were biopsied and diagnosed of stages IIIB and IV NSCLC. Tumor specimens were used for DNA isolation and exon 4 of HM40 beta-tubulin isotype was amplified and automatically sequenced, using both intronic and exonic primers. Next, the chemotherapy schedule consisted of weekly paclitaxel (100 or 150 mg/m(2) x 6) followed 2 weeks later by cisplatin 100 mg/m(2) on day 1, gemcitabine 1000 mg/m(2) on days 1 and 14, and vinorelbine 25 mg/m(2) on days 1 and 14, every 28 days. Using exonic primers, gene sequence alterations were found in 13/15 (87%) patients, including transitions (codons 180 and 182) and one silent transversion (codon 195). Also, three transversions (codons 231, 234, and 235) were found in all patients and controls. All alterations disappeared when sequenced with intronic primers. Our results suggest that point mutations demonstrated with exonic primers but not with intronic ones are probably due to beta-tubulin pseudogenes present in advanced NSCLC specimens. Even so, when these beta-tubulin pseudogenes are found there is a clear relation with clinical response. Although these changes could be relevant in paclitaxel resistance, this observation must be proven in future clinical trials to resolve "the tubulin dilemma".

Abstract: Alterations in the mismatch repair genes (hMLH1 and hMSH2) play an important role in the development of microsatellite instability in sporadic endometrial cancer. Tissue microarray technology allows molecular profiling of tumor samples at the DNA, RNA, and protein levels. We analyzed hMLH1 and hMSH2 expression by immunohistochemistry in a group of atypical endometrial hyperplasias (n = 10), endometrioid endometrial carcinomas (n = 58), and nonendometrioid endometrial carcinomas (n = 27) on tissue microarray. The results were correlated with microsatellite instability status as evaluated by BAT-25 and BAT-26. Overall, 29.4% of lesions showed microsatellite instability. Loss of nuclear hMLH1 and hMSH2 protein expression was seen in 22.3% and 6.5% of cases, respectively. Immunohistochemistry for hMLH1 and hMSH2 showed lack of protein expression in 64% and 16.6% of microsatellite instability-positive endometrial lesions, respectively. Taken together, hMLH1 or hMSH2 protein expression was absent in 18 of 24 microsatellite instability-positive cases (75% sensitivity). A high level of concordance was found between immunohistochemistry for hMLH1 and hMSH2 and microsatellite instability status evaluated by BAT-25 and BAT-26 (kappa value of 0.7). Of the 57 cases found to be microsatellite instability negative, 53 showed normal expression of both proteins (93% specificity). The observed predictive value of absence of expression of hMLH1 for predicting microsatellite instability-positive status was 82%. The predictive value of normal expression of both proteins for predicting microsatellite instability-negative status was 90%. These results are consistent with those previously reported in whole tissue sections. Therefore, immunohistochemical analysis of hMLH1 and hMSH2 expression on tissue microarray provides an accurate technique for screening for tumors with microsatellite instability. Tissue microarrays represent an ideal approach for comparing different diagnostic or predictive markers with one another in consecutive tissue microarray sections.

Abstract: Cyclin D1 is frequently overexpressed in human neoplasias by gene rearrangement and amplification, but no mutations in the CCND1 gene have so far been reported. However, in vitro mutagenesis of CCND1 has shown that substitutions affecting threonine 286 residue produced cyclin D1 nuclear accumulation, by interfering with protein degradation and induced neoplastic transformation in murine fibroblasts. To test whether similar genetic changes may occur in vivo, we analysed a series of 60 endometrioid endometrial carcinomas (EECs) for cyclin D1 expression and gene amplification by immunohistochemistry and FISH, respectively. Two of 17 carcinomas showing cyclin D1 expression in more than 5% of neoplastic cells, but without gene amplification, were found to harbor single-base substitutions in CCND1 that changed proline 287 into threonine and serine, respectively. Both cases expressed cyclin D1 in more than 50% of neoplastic cells. Additionally, seven tumors with cyclin D1 overexpression of an independent series of 59 EECs were also analysed, and a 12-bp in-frame deletion that eliminated amino acids 289-292 was detected in one case with cylin D1 expression in more than 50% of neoplastic cells. In contrast, no mutations of the CCND1 gene were detected in a set of breast carcinomas with cyclin D1 overexpression without gene amplification. In summary, our data indicate that mutations of CCND1, which probably render the protein insensitive to degradation, represent a previously unreported mechanism of cyclin D1 overexpression in human tumors in vivo.

Abstract: Solitary fibrous tumor (SFT) is an uncommon tumor initially reported in the pleura but recently described in other sites of the body. We report a SFT of the skin that presented as painless nodule located in the right cheek in a 56-year-old woman. Histologically, the tumor was composed of spindle-shaped cells arranged in a patternless pattern of short and narrow fascicles with interspersed bundles of thick collagen, and numerous blood vessels with a focally hemangiopericytoma-like appearance. Immunohistochemically, the tumor cells strongly expressed vimentin, CD34 and bcl-2. The lesion was excised and the patient remains well at 16-month follow-up. This case presented some diagnostic difficulty because of its unusual location, and had to be distinguished from other superficial soft tissue tumors. Recognition of SFT in the skin is important to avoid possible confusion with a variety of spindle cell neoplasms with different biologic potential.

Abstract: Sixty cases of uterine adenomatoid tumors (ATs) are reported. All except four were incidental findings in hysterectomy specimens, three of these being discovered preoperatively as large multicystic tumors. ATs were classified into two distinctive macroscopic patterns: small, solid tumors and large, cystic ones. The 56 small, solid ATs ranged from 0.2 to 3.5 cm, (average 2.1 cm); 48 were nodular and 8 diffuse. The four large, cystic tumors ranged from 7 to 10 cm. Inflammation occurred in 65% of the tumors, and a smooth muscle reaction, identified by an increased Ki-67 index, was present in most cases. Both types were histologically similar except for the presence of short papillae in cystic tumors, which also showed serosal involvement. Both were immunoreactive for cytokeratins, calretinin, HMBE-1, and vimentin. Estrogen and progesterone nuclear receptors and EMA were negative. These tumors represent a spectrum ranging from small and solid to large and cystic ATs in the female genital tract, whereas outside the genital tract they are morphologically similar to multicystic mesothelioma. Although a reactive origin for ATs often seems plausible, especially when inflammation is present, their neoplastic nature should not be ignored.

Abstract:

Abstract: BACKGROUND: Kaposiform hemangioendothelioma is an uncommon vascular tumor initially reported to occur exclusively in children. METHODS: The presentation, pathologic evaluation, and management of an unusual case of kaposiform hemangioendothelioma is presented and discussed. RESULTS: A 27-year-old HIV-negative man was initially seen with a reddish nodule located in the outer third of the external auditory canal. Histologically, the tumor was composed of spindle-shaped cells arranged in short fascicles associated with small endothelial-like vascular spaces, similar in appearance to Kaposi's sarcoma. The lesion was locally excised but recurred 1 month later; then radiation therapy was performed. The patient remains well at 5-year follow-up. CONCLUSIONS: Recognition of kaposiform hemangioendothelioma is important to avoid possible confusion with a variety of vascular neoplasms with different biologic potential. This case presented some diagnostic difficulty because of the age of the patient and the unusual location of the lesion and had to be mainly distinguished from Kaposi's sarcoma.

Abstract: Bronchocentric granulomatosis is a non-specific necrotizing granulomatous reaction in the bronchi and bronchioles. In asthmatic patients, bronchocentric granulomatosis is considered a hypersensitivity reaction to intrabronchial fungi. However, in non-asthmatic patients the possible etiology has not been identified.We report the case of a 46-year-old woman with bronchocentric granulomatosis associated with pulmonary hydatidosis. The likely immuno-pathogenic mechanisms leading to bronchial lesions are briefly discussed.

Abstract: The activation of the APC/beta-catenin signalling pathway due to beta-catenin mutations has been implicated in the development of a subset of endometrial carcinomas (ECs). However, up to 25% of ECs have beta-catenin nuclear accumulation without evidence of beta-catenin mutations, suggesting alterations of other molecules that can modulate the Wnt pathway, such as APC, gamma-catenin, AXIN1 and AXIN2. We investigated the expression pattern of beta- and gamma-catenin in a group of 128 endometrial carcinomas, including 95 endometrioid endometrial carcinomas (EECs) and 33 non-endometrioid endometrial carcinomas (NEECs). In addition, we evaluated the presence of loss of heterozygosity and promoter hypermethylation of the APC gene and mutations in the APC, beta- and gamma-catenin, AXIN1, AXIN2, and RAS genes, and phospho-Akt expression. No APC mutations were detected but LOH at the APC locus was found in 24.3% of informative cases. APC promoter 1A hypermethylation was observed in 46.6% of ECs, and was associated with the endometrioid phenotype (P=0.034) and microsatellite instability (P=0.008). Neither LOH nor promoter hypermethylation of APC was associated with nuclear catenin expression. Nuclear beta-catenin expression was found in 31.2% of EECs and 3% of NEECs (P=0.002), and was significantly associated with beta-catenin gene exon 3 mutations (P<0.0001). beta-catenin gene exon 3 mutations were associated with the endometrioid phenotype, and were detected in 14 (14.9%) EECs, but in none of the NEECs (P=0.02). gamma-catenin nuclear expression was found in 10 ECs; it was not associated with the histological type but was associated with more advanced stages (P=0.042). No mutations in gamma-catenin, AXIN1 and 2 genes were detected in this series. Neither RAS mutations nor phospho-Akt expression, which were found in 16 and 27.6% of the cases, respectively, were associated with beta-catenin nuclear expression. Our results demonstrated a high prevalence of alterations in molecules of the APC/beta-catenin pathway, but only mutations in beta-catenin gene are associated with aberrant nuclear localization of beta-catenin.

Abstract: To study the cost-benefit of the histological examination of tonsilar samples, we evaluated 567 cases (547 routine and 20 nonroutine cases) of patients under 14 years of age, operated between 1st January 1996 and 30th November 2000. There were 2 routine cases (0.3%), and 6 nonroutine cases (30%) with a diagnosis different to follicular hyperplasia. In this way, our clinical preoperative sensitivity was 75% and specificity 97%. The average cost per case at our Centro to study the tonsilar samples was 30$. We conclude that the histological examination of tonsilar specimens is economically worth only in nonroutine cases, although additional factors (e.g. training of residents of Pathology and the quality control of the institution must be taken into consideration.

Abstract: We report a rare case of dyspnea due to enlargement of the epiglottis in a severely immunocompromised patient. The child underwent a previous tracheostomy at another hospital because of respiratory distress under the diagnosis of acute epiglottitis. The patient was subsequently decannulated without incident. One year later, the child developed a new episode of dyspnea with inspiratory stridor. A new tracheostomy was neccessary, and a biopsy specimen of the enlarged epiglottis was taken to confirm the diagnosis of graft-vs-host disease. The therapeutic measures in these situations are discussed below, and a review of the current literature concerning the etiology and management of epiglottic enlargement is performed.

Abstract: Objective: To assess the incidence and characteristics of post-transplant lymphoproliferative disease (PTLD) in tonsils of the liver transplanted children. Methods: All patients under 14 years of age recipients of a liver transplant at the institution and operated on for tonsillectomy under suspicion of malignancy were included in this study. Results: Seven patients underwent surgery on their tonsils under suspicion of PTLD. One case of B-cell lymphoma, and three cases of polymorphic diffuse B-cell hyperplasia were found. This represents an incidence of 1.4% of PTLD in the tonsils of the 283 pediatric liver transplants performed at the hospital. Conclusion: The incidence of PTLD in tonsils after liver transplantation is very low at the institution. However, it is very important to follow-up allograft recipients for early diagnosis of this entity.

Abstract: To identify potential risk factors related to complications after thyroidectomy, a study was designed that included 675 patients. Recurrent laryngeal nerve (RLN) paralysis, hypocalcemia, serohematoma, wound infection, and postoperative hemorrhage were evaluated. The rate of paralysis of the RLN was calculated on nerves at risk for hypocalcemia (n = 890) in patients undergoing bilateral procedures or unilateral procedures if they had previously undergone a contralateral operation (n = 321). Multivariate analysis was used to identify the relationships between the variables included in the study. All statistical tests received the same level of significance of 0.05. Permanent hypocalcemia occurred in 2.2% of the patients, whereas unilateral paralysis of the RLN developed in 0.9%. Mortality was 0.1% in this series. The RLN paralysis had a significant relationship with preoperative diagnosis of malignancy (P < 0.03). Likewise, hypocalcemia was related to sex and surgical procedure (P < 0.03). Serohematoma was linked with age (P < 0.001), and hemorrhage was associated with previous radiation of the neck (P < 0.03).

Abstract: BACKGROUND: Primary uterine osteosarcoma is extremely rare, with only 15 cases reported in the literature. CASE: A 41-year-old woman presented with abnormal vaginal bleeding due to a large tumor arising from the uterine corpus. Histologically, the tumor showed the features of a malignant mesenchymal neoplasm with osteoid formation and lacked an epithelial component. Immunohistochemical and ultrastructural studies showed no evidence of epithelial differentiation. The tumor was excised and the patient received chemotherapy and radiation therapy postoperatively, but the tumor recurred locally at the 8-month follow-up. CONCLUSION: Osteosarcoma as a primary uterine tumor is exceedingly rare and should be distinguished from carcinosarcoma, which shows different macroscopic and histologic features. Prognosis of this neoplasm is very poor with an average life expectancy of 5 months.

Abstract: OBJECTIVE: To evaluate the diagnostic accuracy and pitfalls of fine needle aspiration (FNA) cytology in the initial evaluation of Hodgkin's disease (HD) and to assess the influence of the pathologist's experience by comparing the results during two periods. STUDY DESIGN: A total of 170 cytodiagnoses of HD were reviewed and compared with those on the final histopathologic report. Thirty-three cases of HD with a previous, different cytologic diagnosis were also selected. In all the cases under study, FNA was performed as part of the initial diagnostic approach. From a practical perspective, diagnostic errors were divided into major or minor according to the consequences on patient management. RESULTS: Fifteen cytologic diagnoses of HD were followed by a different histologic diagnosis after lymph node biopsy. In 33 cases of HD an erroneous cytologic diagnosis was given prior to biopsy. The sensitivity of the series was 82.4% (86.1% excluding nonrepresentative cases). The positive predictive value reached 91.2%. Sensitivity varied from 79.3% in the first period (1982-1990) to 84.9% in the second (1991-1999) (83.3% and 88.2%, respectively, excluding nonrepresentative cases). Similarly, the positive predictive value increased from 89% to 92.8%. Diagnostic errors with important consequences for patient management diminished from 14 in the first period to 5 in the second. CONCLUSION: Cytology offers a rapid and accurate approach not only for the diagnosis of recurrent HD but also for its initial recognition. These results increase the capacity of FNA as a first-level diagnostic technique in the screening of lymphadenopathies.

Abstract: Pilomatrix carcinoma, the malignant variant of pilomatrixoma, is a rare entity. The authors report on six patients with pilomatrix carcinoma and review the pertinent literature. The lesions showed a predilection for elderly individuals (mean age, 61 years) with a male:female ratio of 5:1, and they presented as dermal or subcutaneous tumors located on the head and neck (5 neoplasms) and chest (1 neoplasm). Tumors varied in size from 0.6 cm to 2.5 cm (mean, 1.78 cm). None of the lesions recurred after wide local excision. On scanning magnification, all tumors showed the architectural features of a malignant neoplasm (asymmetry and poor circumscription, presence of several markedly sized and variably shaped basaloid aggregations, and ulceration). The tumors were composed of pleomorphic basaloid cells with prominent nucleoli and frequent atypical mitoses accompanied by central areas with keratotic material, shadow cells, and foci of necrosis. The tumor nests were surrounded by a desmoplastic stroma and infiltrated the adjacent tissues. Vascular or perineural infiltration was not observed. In one case, the basaloid cells contained abundant melanin pigment in their cytoplasms. Pilomatrix carcinoma is a neoplasm of low-grade malignancy that should be distinguished from the conventional pilomatrixoma and its variants (aggressive pilomatrixoma and proliferating pilomatrixoma), matricoma, and basal cell carcinoma with matrical differentiation. Clinicians and pathologists should be aware of the occurrence of pilomatrix carcinoma because of its potential for distant metastases.

Abstract: BACKGROUND: Crohn's disease confined to the vermiform appendix is rare. In our study, the incidence was 0.2% of all patients diagnosed with Crohn's disease at La Paz University Hospital, Madrid, Spain, in 20 years. METHODS: Here we review the clinical records of 10 patients with isolated appendiceal Crohn's disease. RESULTS: Preoperative diagnosis was acute appendicitis in all 10 cases, and all patients underwent appendectomy. Postoperative complications were limited to an enterocutaneous fistula in 1 patient. There was no evidence of recurrence during a mean follow-up period of 14.5 years (range 2 to 25 year). CONCLUSIONS: We conclude that Crohn's disease when confined to the appendix is less aggressive than in other sections of the intestine, with a low recurrence rate and incidence of postoperative fistula.

Abstract:

Abstract: We have immunohistochemically investigated P-cadherin (P-CD) expression in a series of 210 infiltrating ductal carcinomas (IDC) in an attempt to assess the biological and prognostic relevance of P-CD in patients harboring IDCs. Although only 74/210 (35%) of IDCs expressed P-CD in >5% of tumor cells (P-CD-positive carcinomas), categorical analyses revealed that P-CD-positive IDCs were larger (26 +/- 21 cm versus 22 +/- 11 cm, P =.0568), of higher histological grade (P =.0001), and had more lymph node metastases (P =.0327) than P-CD-negative breast carcinomas. In addition, P-CD-positive tumors were negative for estrogen (P =.0001) and progesterone receptors (P =.0001) and showed reduced E-cadherin expression (P =.0276) more frequently than P-CD-negative tumors. Univariate analysis carried out in 171 patients demonstrated that P-CD expression was also an indicator of poor prognosis (chi(2) = 8.292, P =.004), extent of lymph node metastasis (chi(2) = 20.854, P =.0000), histological grade (chi(2) = 12.908, P =.0016), and negative progesterone receptors (chi(2) = 4.116, P =.042). However, only histological grade and nodal metastases emerged as independent prognostic markers in the multivariate analysis. These results suggest that although P-CD expression may be involved in the progression of IDCs, its value as an independent prognostic factor remains to be established.

Abstract: A study was designed to assess the usefulness of postoperative radiotherapy (RT) in patients with surgically treated laryngeal and hypopharyngeal cancer with histologically proven positive neck nodes. Patients underwent operation between 1984 and 1995, with functional neck dissection (FND) being part of the treatment in all cases. The selection criteria included squamous cell carcinoma, negative margins for the primary tumor, and no previous treatment. For evaluation purposes, patients were divided into 2 groups: surgery alone versus surgery with postoperative RT. Eighty-three patients fulfilled the inclusion criteria and entered the study. All but 1 of the patients were men. The mean age was 58 years (range, 35 to 77 years). A multivariate analysis was used to analyze the prognostic parameters selected by univariate analysis, eg, age, alcohol, tumor location, T and N stages, and presence or absence of extracapsular spread and a desmoplastic pattern. Postoperative RT was not selected by univariate analysis as a prognostic factor, but was included in the multivariate analysis in order to assess its impact on survival and recurrence rates. Using the statistical method of multivariate analysis, we could not find evidence of a benefit to survival or local recurrence rates with postoperative RT in this series. Patients younger than 55 years and those with extracapsular spread had a decreased survival rate and a higher neck recurrence rate, irrespective of the treatment method.

Abstract: A 63-year-old man presented a polypoid tumor in the laryngeal space involving the right pyriform fossa. The patient underwent a total laryngectomy with bilateral functional neck dissection, and the diagnosis of sarcomatoid carcinoma with malignant fibrous histiocytoma-like stroma was established. The tumor showed an uncommon behavior, with distant metastases to the brain and to the subcutaneous tissue of the abdominal wall. The patient died 1 year after the development of the metastases. Despite its polypoid pattern of growth, sarcomatoid carcinoma of the larynx may behave very aggressively. It is important for clinicians to be aware of the possibility of distant subcutaneous and brain metastases in sarcomatoid tumors of the laryngeal space. If such metastases develop, the prognosis is ominous, with an average life expectancy of 3 months.

Abstract: The influence of extracapsular spread (ECS) and a desmoplastic pattern (DP) of metastatic cervical lymph nodes in patients with laryngeal cancer is presented. The study includes 128 patients surgically treated between 1984 and 1992 for squamous cell carcinoma of the larynx with pathologically proven lymph node metastasis. The results were studied from 2 major standpoints: survival and recurrence. The 3-year survival rates were as follows: patients without ECS 73.4%, and with ECS 28.9% (p < .001); patients without a DP 76.9%, and with a DP 43.3% (p < .03). Also, the 3-year recurrence rates in the neck showed significant differences: patients without ECS 10.7%, and with ECS 49.6% (p < .001); patients without a DP 10%, and with a DP 31.6% (p = .1142). Postoperative radiotherapy did not appear to improve the outcome.

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Abstract: OBJECTIVE: To study the cytomorphologic features of malignant peripheral nerve sheath tumor (MPNST), including the epithelioid cell variant, and to establish differential diagnostic features with benign neurogenic tumors and other sarcomas. STUDY DESIGN: Cytologic smears from primary, recurrent and metastatic tumors in 10 patients with MPNST were reviewed. Three patients had neurofibromatosis 1 (NF1), and in two others the tumor arose from a preexisting neurofibroma. Immunocytochemical evaluation of S-100 protein was performed in four cases. A complete pathologic study was available in all cases. To assess the validity of morphologic recognition, a blinded study, including eight cases of spindle MPNST among smears from histologically proven schwannomas, synovial sarcomas, leiomyosarcomas, malignant fibrous histiocytomas and liposarcomas, was performed. RESULTS: Neurogenic differentiation was recognizable in four cases (differentiated), while the other four (anaplastic) were indistinguishable from other pleomorphic sarcomas. The presence of elongated, slender, often wavy nuclei and less commonly a delicate, fibrillary metachromatic stroma were features suggestive of nerve sheath differentiation. Other cytologic, as well as clinical, features permitted their identification as malignant. Two cases of epithelioid MPNST disclosed large, polygonal to plasmocytoid tumor cells without specific cytologic features. S-100 immunoexpression was positive in two of the four cytologic samples tested. CONCLUSION: Although no morphologic findings are specific to MPNST, the above-mentioned cytologic features may suggest, in differentiated cases, its neurogenic differentiation. On the basis of morphologic features alone, the diagnosis of anaplastic and epithelioid MPNST is not possible, and immunocytochemical and ultrastructural studies are necessary. A specific cytodiagnosis is possible in recurrences, metastases and cases of NF1 or a preexisting neurofibroma.

Abstract: A 71-year-old woman presented with a six month history of constipation and abdominal discomfort, with anal bleeding during the last days. Ultrasonography and CT-scan of the abdomen showed a large heterogeneous mass that was located in the splenic region, but the nature and origin of the tumour could not be clearly established preoperatively. The clinical diagnosis was of abdominal tumour with colonic and splenic involvement, and a left hemicolectomy and splenectomy were performed. Pathologic examination revealed a primary angiosarcoma of the spleen with penetration and fistulization of the tumour into the large bowel. The patient received adjuvant radiation therapy, but she died of extensive metastastic disease from her primary angiosarcoma of the spleen nine months after surgery. In summary, splenic angiosarcoma is very difficult to diagnose preoperatively. This highly aggressive neoplasm has an overall poor prognosis, specially if it is associated with rupture and haemoperitoneum. As this case highlights, unusual forms of rupture may lead to atypical clinical presentations, increasing even more the difficulty in the diagnosis.

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Abstract: In order to assess the main complications following surgical treatment of thyroid neoplasms, a prospective-historical study was made in 145 patients operated between 1985 and 1997. Permanent hypocalcemia was encountered in 3.3% of our cases, and unilateral nerve injury in 2.2%, with 0.7% of fatal complications. The remain complications evaluated include: serohematoma, postoperative bleeding, and wound infection. To sum up, surgery of the thyroid neoplasms is a relatively safety procedure. The incidence of complications is similar to the surgical treatment of the remainder thyroid diseases.

Abstract: OBJECTIVE: To quantify immunocompetent cell (IC) density for different testicular tumors and antibodies and to verify if the results of the comparisons depend on the antibody used. STUDY DESIGN: T-lymphocytes were studied with CD3 and UCHL1 antibodies and macrophages with MAC387 and CD68 in 43 patients with seminomas, mature teratomas, immature teratomas and embryonal carcinomas of the testis. Counts were expressed as number of IC per square millimeter. RESULTS: Use of different antibodies produced significant differences in the IC cell number; moreover, in the case of macrophages, the tumor type sequence by increasing cell number was different according to the antibody used. CONCLUSION: These results suggest the existence of a statistical interaction between the type of tumor and antibody.

Abstract: Congenital diaphragmatic Bochdalek hernia is rarely seen in adults. It may present with jejunal perforation and strangulation. In a 28-year-old man presenting with nausea and vomiting, absence of respiratory murmur at auscultation, loops of small intestine with air-fluid levels were radiographically visualized in the left hemithorax. Surgery revealed 1.5-m of herniated jejunum with three perforations and necrotic areas, 40 cm of which was resected. The patient remains well ten years postoperatively.

Abstract: OBJECTIVE: To report a case of paraganglioma localized in the organ of Zuckerkandl and to discuss its diagnosis, treatment and outcome. METHODS/RESULTS: A 37-year-old female presented with a periumbilical mass and pain that radiated to the lumbar region for the past three months. Abdominal US and CT disclosed a well vascularized mass lying adjacent to the aorta, 1 cm from its bifurcation. At laparotomy, an 8 x 10 cm tumor was discovered at the aortic bifurcation that displaced the left ureter and included the inferior mesenteric artery. Pathological analysis of the surgical specimen revealed a paraganglioma. CONCLUSION: Extra-adrenal paraganglioma should be taken into account in the differential diagnosis of retroperitoneal masses, particularly those adjoining the abdominal aorta.

Abstract: A 75-year-old woman presented with a four month history of a slowly growing tumour on the distal portion of the third finger of her left hand. The lesion suggested clinically an inflammatory process or an epidermoid carcinoma. The finger was amputated through the proximal interphalangeal joint. Microscopic examination showed an acral-lentiginous melanoma, subungual type (Clark level V). No elective lymph node dissection was done, and no prophylactic chemotherapy was given. The patient remains free of disease eight months after operation. Clinicians should be aware of this rare lesion, which may mimic other benign or malignant conditions.

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Abstract: BACKGROUND: Chondroid syringomas are benign uncommon tumours of controversial histogenesis that most often affect the head and neck region and usually measure > 3 cm in greatest dimension. Objective: To describe the clinical features, histology, and differential diagnosis of an unsually large axillary chondroid syringoma. METHODS: A 64-year-old man presented with a painless, subcutaneous tumour measuring 8 3 7 3 6.5 cm on his right axilla, which had been growing slowly for several years. The tumour was completely excised under local anesthesia. No recurrence of the tumour has been observed 12 months after surgery. RESULTS: Histological examination showed cords, nests, and tubuloglandular structures composed of well-differentiated tumour cells embedded in a hyalinized stroma with abundant chondroid matrix, and the diagnosis of chondroid syringoma was established. No features suggesting malignancy were observed. CONCLUSION: As this case shows, chondroid syringoma may reach a large size, and it should be included in the differential diagnosis of slowly growing solid nodules in the skin or subcutis.

Abstract: We describe a 12-year-old patient with a primary pulmonary mass in the left upper lung. The diagnosis of inflammatory pseudotumour was suspected preoperatively. After pathological examination and complete clinical evaluation, a diagnosis of malignant primary pulmonary fibrous histiocytoma was established. This is a very uncommon primary neoplasm of the lung and to our knowledge only five paediatric cases have been reported. Because of the rarity of these sarcomas and histological similarities to benign inflammatory pseudotumour, care must be taken to avoid confusion between the two disorders particularly in intra-operative frozen sections. Conclusion: Primary malignant fibrous histiocytoma of the lung is an uncommon tumour that should be considered in the differential diagnosis of pulmonary neoplasms of childhood. The histological diagnosis can be difficult due to the similarities with inflammatory pseudotumour.

Abstract: OBJECTIVES: a) To provide a clinicopathological profile of Hürthle cell neoplasms (HCT) in our experience. b) To evaluate if there are any differences in the clinical or morphological features between three HCT categories: benign, malignant and indeterminate. c) To examine the role of the clinical and morphological features in predicting the behavior of these neoplasms. METHODS: We reviewed the clinical reports of all patients with a histological diagnosis of HCT at our Hospital between 1981 and 1996. The final study group consisted of 25 cases. The neoplasms were divided into three categories on the basis of presence and degree of capsular and vascular invasion, marked nuclear atypia, tumour necrosis and pattern of growth. A series of clinical parameters were evaluated. RESULTS: Of the 25 tumors, 52% were morphologically classified as benign, 8% as indeterminate and 40% as malignant. Follow-up ranged from 10 months to 14.8 years or until death (average 3.8 years). There were four local recurrences (20%), three in the malignant group (30%) and one in the benign group (7.6%) (p = 0.15). One patient presented metastases and died because of tumor during the follow-up. Apart from capsular and vascular invasion and some aspects of therapy, no significant differences were found in the clinical and histological parameters analyzed between the three histological groups or between the groups with or without recurrence. CONCLUSION: We did not find any clinical or morphological parameter which can predict recurrence among these tumors. Our study further establishes the controversial issues surrounding the biological behavior of Hürthle cell neoplasms.

Abstract: We describe a case of Menke's disease with severe neurological involvement, convulsive crises and characteristic hair anomalies (scanty, fragile, macroscopically hypopigmented and microscopically kinked) which led to rapid diagnosis. Vascular abnormalities with elongated, twisted arteries, skeletal abnormalities (more wormian cranial bones than usual, lateral spurs of metaphyses) and vesicle diverticuli. Electron microscopy of skeletal muscle showed concentrically laminated bodies, possibly of mitochondrial origin. Respiratory chain enzyme activity was normal. The patient died at the age of two and a half. On necropsy, histological abnormalities characteristics of the illness were seen (loss of neurones in the granular layer of the cerebellum, the neurones of Purkinje had thickening of the dendrites which spread out in the form of a weeping willow, reduplication and fragmentation of the internal elastic layer of muscle arteries). In the cortex of the cerebellum mega-mitochondria with electron-dense bodies, were seen on electron microscopy. This is the first case of Menke's disease described in the Spanish literature which includes pathology and electron microscope studies.

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Abstract: AIMS: To describe a case of rhabdomyomatosis of the lung unassociated with other external or visceral malformations in a newborn infant. METHODS AND RESULTS: A 26 weeks gestation newborn male with no relevant medical or family history presented a well-circumscribed solid area in the posterior mediastinum occupying the upper lobe of the right lung. The possibility of neuroblastoma or an extralobar pulmonary sequestration were excluded after laboratory and arteriographic studies. No visceral anomalies were found. At the age of 9 months the patient underwent a partial lobectomy, and he is free of disease 39 months after surgery. Histological examination demonstrated the presence of numerous bundles of striated fibres arranged haphazardly in the pulmonary interstitium in a background of a type-II congenital cystic adenomatoid malformation-like morphology of the resected lung. CONCLUSION: The presence of striated muscle fibres in the lung not necessarily represents a lethal congenital malformation. As this case shows, rhabdomyomatosis of the lung can affect a single pulmonary lobe, and resection of the affected lung parenchyma may be curative. It is important for pathologists to be aware of this entity, although it is exceptional, and to include it in the differential diagnosis of pulmonary masses in the newborn lung.

Abstract: OBJECTIVE: To investigate the diagnostic sensitivity and prognosis predicting of DNA image cytometry in colorectal carcinoma. STUDY DESIGN: We studied the ploidy status and other DNA cytometric parameters in 68 patients with colorectal carcinoma. In addition, clinical-histologic and follow-up information was collected for at least five years. RESULTS: DNA histograms were available in all cases, showing a diploid DNA distribution pattern in 6 (8.8%), tetraploid in 21 (30.9%), hyperdiploid in 20 (29.4%) and hypertetraploid in 21 (30.9%). The differences in the correlation study between cytometric parameters and pathologic features were not statistically significant. Ploidy status and DNA malignancy grade were individually related to five-year survival (P < .005 and P < .05). CONCLUSION: The data show that DNA image cytometry can provide valuable prognostic information on colorectal carcinomas and may prove useful in guiding adjuvant therapy in these patients.

Abstract: We report a solitary fibrous tumor of the abdominal cavityt that presented as a encapsulated mass attached to the mesentery in a 33-yr-old man. Histologically, the lesion showed a disorganized arrangement of spindle cells in a collagenous background and prominent vascular channels of varying size. Tumor cells showed immunohistochemical reactivity for vimentin only. Cytokeratins and CD34 were negative. This report further extends the anatomic range of solitary fibrous tumor, a neoplasm that must be included in the differential diagnosis of well-defined abdominal masses. The behavior of this mesenteric solitary fibrous tumor has been benign.

Abstract: Primary adenocarcinomas of the oral cavity in minor salivary glands are distinctive lesions which can be subclassified according to their growth patterns or histomorphology. Polymorphous low-grade adenocarcinoma (PLGA) of minor salivary tissue has been recognized as a distinct entity. We report an unusual case of PLGA of the tongue. Only a few previous cases have been reported in the English literature. The treatment is discussed and a review of the current literature concerning this tumour is included.

Abstract: A 15-year-old boy with the characteristic features of the naevoid basal cell carcinoma syndrome presented with a retroperitoneal mass. The tumour showed morphological features of a still ill-defined variant of fetal rhabdomyoma, characterized by well-differentiated nerve fibres admixed with immature striated muscle cells, similar to neuromuscular choristoma. Four cases of fetal rhabdomyoma and naevoid basal cell carcinoma syndrome have been previously reported. The behaviour of this tumour has been benign, although a complete excision was impossible due to its close relation with abdominal vascular trunks.

Abstract: An adrenal gland leiomyoma was incidentally found at autopsy in a 2-year-old boy with acquired immunodeficiency syndrome (AIDS). Smooth muscle neoplasms have been described in pediatric AIDS and affect mainly the tracheobronchopulmonary, gastrointestinal, and hepatobiliary systems. An association between Epstein-Barr virus (EBV) and smooth muscle tumors in patients with AIDS has been described. This case is the first leiomyoma to be reported in the adrenal gland of a child with AIDS. EBV genome was demonstrated in the tumor by polymerase chain reaction.