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Twelve cases of metastatic tumors to the female breast are reported. Ten of them were incidentally discovered at autopsy; two cases were diagnosed ante mortem but one was misinterpreted as primary. The patients' mean age was 58 years. The metastasizing tumors included cutaneous malignant melanoma (four cases); ovarian, renal and gastric adenocarcinoma (two cases each); and individual cases of pulmonary and pancreatic carcinoma. The patients with melanoma were younger than the others (49.7 vs. 62.7 years). The results of the present study indicate that breast metastases, although rare, are not exceptional especially in large autopsy series. Their recognition in surgical material would result in more adequate treatment against the primary tumor, thereby avoiding unnecessary radical surgery to the breast.

The frequent association of HPV lesions with cytological and/or hystological alterations of CIN in the uterine portio and in the lower genital tract suggests their possible role in the genesis of precancerous lesions of the cervix. In the systematic cytological screening, condylomatous lesions present an incidence varying from 0.52% to 1.5%. With the aim of verifying the incidence rate of condylomatosis of the portio, in the population of the women followed in the Colpocytological Service of obstetrics and gynaecology (Institute for Childhood of Trieste), the authors have performed a retrospective analysis on 17273 colpocytological examinations and have found 72 cases (0.41%) with cytological and/or histological evidence of viral-cytopathic effect produced by HPV. These patients have undergone various treatments of this pathology and have performed a follow-up. In some patients 12 cases, treated only with antiflogistic therapy or no therapy, 50% of these has shown a complete regression of viral infection in the first control after 4 months. In these patients, it is suggestive to suppose that a good immunological reactivity has brought the patient to recovery. For that, in their next work, the Authors will investigate the immunological responsiveness of patients affected by HPV lesions of the cervix.

Metastases from mammary carcinoma represent the principal cause of exitus in 45% of subjects dead from this neoplasia. Also if they are not frequent, uterine metastases from mammary carcinoma are not very rare to find at the autopsy (2-15% as various Authors report). In this study, the Authors present 17 cases (1 bioptic and 16 autoptic cases) of uterine metastases from breast carcinoma. The histological examination confirms a more frequent involvement of the uterine corpus, with infiltration of the myometrium. When the endometrium is affected, generally the neoplasia infiltrates the stroma, preserving the glandular architecture. In one case, the uterine metastases was associated with a fibroleiomyoma. The clinical symptomatology (metrorrhagia in 3 of 17 cases) was poor because, as we have said above, generally the neoplasia infiltrates the myometrium.

Invasive endocervical adenocarcinoma represents on average 15% of cervical carcinomas and it is associated with the human papillomavirus infection high risk types 16 and 18 in most cases. Its detection has some special features compared to squamous cell carcinoma; glandular precancerous lesions are less known and only adenocarcinoma in situ is diagnosed by consensus among pathologists; adenocarcinoma in situ develops in the squamocolumnar junction by reserve cells but it is hard to be located by colposcopy in the endocervical canal or in the deep glandular recess. Sampling of endocervical cells requires brushes rather than an Ayre spatula. Cytological diagnosis of glandular cells abnormalities is based on the Bethesda System 2001 terminology which redefined endocervical cells abnormalities and also introduced the entity of adenocarcinoma in situ. This entity is characterized by specific morphological features, such as the radial arrangement of nuclei in the periphery, like "at the end of the feathers of a bird's wing"(feathering of cells), images of nuclei palissading or rosette without tumoral diathesis. Glandular cells abnormalities are rare and represent less than 0.1% of all smears and less than 5% of abnormal smears. By improving the collection and the interpretation of abnormal endocervical cells, cytological screening should allow the diagnosis of in situ adenocarcinoma and detection of invasive adenocarcinoma at a very early stage. This will lead to a decrease in mortality from endocervical adenocarcinoma, especially in young women.

Background Three novel polyomaviruses have been recently discovered: KI, WU and MC polyomaviruses. Their role in human pathology is debated while tissue tropism and site of latency remain unknown. Objective To test the hypothesis that KI, WU and MC polyomaviruses can infect human tonsils. Study design Archival paraffin-embedded tonsils from 91 patients affected by different tonsil diseases were screened by polymerase chain reaction to detect viral DNA of KIV, WUV, MCV, BKV and JCV. Phylogenetic and evolutionary analysis of the identified polyomaviruses was carried out. Results Of the 91 tested specimens, 11 contained KIV DNA (12%), 4 WUV DNA (4.4%), 5 BKV DNA (5.5%). MCV and JCV were not detected. Phylogenetic analysis showed that KIVs identified in tonsils fall into a clade distinct from that containing KIVs isolated from respiratory secretions, respiratory tissue and feces. Moreover, four positively selected sites (4.5% of t-Ag sites) were found under strong positive selection ( ω = 11.4), with posterior probabilities above 0.99. All the sites were located in the N-terminal region of the small t antigen. Conclusions The results suggest that the novel KI and WU polyomaviruses can infect human tonsils. Future studies are needed to define their role in tonsil diseases.

Objective To evaluate the 67-kd laminin receptor (67LR) in cervical cancer and its molecular links to oncogenic HPV types. Study Design As part of the HPV-PathogenISS Study, a series of 150 squamous cell carcinomas (SCCs) and 152 carcinoma in situ (CIN) lesions were examined using immunohistochemical staining for LR67 and tested for HPV using polymerase chain reaction (PCR) with 3 primer sets (MY09/11, GP5 + /GP6 + , SPF). Follow-up data were available for all SCC patients, and 67 GIN lesions had been monitored with serial PCR for HPV clearance/persistence after cone treatment. Results 67LR expression increased in parallel with increasing grade of CIN (p = 0.0001), with the most dramatic up-regulation upon the transition from CIN 2 to CIN 3 and further to SCC. This increased expression was associated with CIN 3/cancer at OR 17.04 (95% CI 7.28-39.87). The seemingly significant association of 67LR with high-risk HPV (HR-HPV) detection (OR 2.20, 95% CI 1.27-3.80) was due to confounding by the histologic grade (Mantel-Haenszel common OR = 1.118, 95% CI 0.576-2.168). Using performance indicators, 67LR expression was of little value as a marker of HRHPV type, and it did not predict clearance/persistence of HR-HPV after treatment of CIN. Similarly, 67LR expression was not an independent prognostic factor in cervical cancer. Conclusion In cervical carcinogenesis, both integrin- and nonintegrin-type LRs (67LR) probably have functions complementary to each other, mediating transient early and stable adhesions, respectively. Up-regulated 67LR expression is significantly associated with progression from CIN 2 to CIN 3 as a marker of cell proliferation. 67LR is probably orchestrated by mechanisms independent of HR-HPV oncoproteins, which seem to be more closely associated with integrin-type laminin receptors.

Summary We report a case of inflammatory fibrosarcoma occurring in a 49 year-old man, that manifested with distinct multinodular masses in the mesentery. Histologically, the lesion was characterized by spindle fibroblast-like cells, histiocytes, pool of lymphocytes and eosinophils, abundant fibrous to hyaline stroma, and numerous “ganglion” cells. Of special interest was the presence of large multinucleated tumor cells which displayed optically clear nuclei and prominent nucleoli, bearing a deceitful resemblance to the diagnostic Reed Sternberg cells of Hodgkin's disease. The differential diagnosis between the two conditions rests on the evaluation of the appropriate clinical background, as well as on an in-depth assessment of the basic pathologic features. Immunohistochemical reactivity of spindle and ganglion cells for actin along to complementary negativity for CD15, and CD30 further assists in separating the two conditions.

Background. Although Papanicolaou cytology represents the most effective technique to prevent and detect precancerous conditions of the uterine cervix, its false-negative yield is still a reason of concern among pathologists and gynecologists. Methods. Because histologic control is one of the best ways to assess the accuracy of cytology diagnosis, the authors have investigated 1000 women who had cervical smears and tissue sampling obtained during the same colposcopic evaluation between 1987 and 1990. Results. Out of 1000 cases (average age, 34.6 years; range, 14–80 years), 918 had adequate, 62 had less than optimal, and 10 had unsatisfactory samples. Cytology unsatisfactory and less than optimal cases as well as inadequate histology cases have been disregarded from all calculations. After histologic comparison, confirmed negatives were 622 of 918 (67.8%). Cytologic diagnoses of cervical intra-epithelial neoplasia (CIN) I were 96, of CIN II were 44, of CIN III, inclusive of carcinoma in situ, were 39, and of invasive carcinoma were 2. Atypical cases were 56. The overall sensitivity was 76.3%, with group sensitivity rates increasing directly with CIN grade. Positive predictive value was 80.2%. Specificity was 93.0%, and negative predictive value was 91.3%. False-negatives were 59 of 681 (8.7%), basically due to sampling errors. Among true-positives, there was 1 category discrepancy in 30 cases (mostly undercalled or overcalled CIN II) and 2 category discrepancies in 4 cases. Conclusions. Cervical cytology has an overall accuracy close to that reported in studies employing indirect control methods, such as patient follow-up. Higher sensitivity rates emerged for CIN II, CIN III, and cervical carcinoma. Our figures of sensitivity and specificity may represent a useful reference source for future studies dealing with quality control in cervical cytopathology.

Comprehensive multivariate models were used to disclose whether any of our previously analyzed 13 markers would be independent predictors of intermediate end point markers in cervical carcinogenesis. The expression of the following biomarkers, E-cadherin, extracellular signal-regulated kinase 1, 67-kd laminin receptor (LR67), matrix metalloproteinase 2, tissue inhibitor of metalloproteinase 2, nuclear factor-kappaB, nm23-H1, p16, proliferating cell nuclear antigen, survivin, human telomerase reverse transcriptase, topoisomerase 2alpha, and vascular endothelial growth factor (VEGF) C in 150 cervical cancer (CC) and 152 cervical intraepithelial neoplasia (CIN) lesions were determined immunohistochemically. Multivariate models were constructed to test predictive power of the markers for 3 outcomes: (1) high-grade CIN, (2) high-risk human papillomavirus (HR-HPV), and (3) CC survival. Performance indicators were calculated and compared by the areas under receiver operating characteristic (ROC) curve. Three marker panels were identified consisting of 5 independent predictors of CIN2 (E-cadherin, extracellular signal-regulated kinase 1, LR67, topoisomerase 2alpha, and VEGF-C), 3 predictors of HR-HPV (survivin, p16, and human telomerase reverse transcriptase), and 2 predictors of CC survival (nm23-H1 and tissue inhibitor of metalloproteinase 2). In predicting CIN2, the best balance between sensitivity (SE) and specificity (SP) was obtained by combining the 2 most powerful predictors in panel 1 (VEGF-C and LR67), giving the area under ROC curve, 0.897 (95% confidence interval [CI], 0.847-0.947); odds ratio, 86.27 (95% CI, 19.71-377.47); SE, 86.0%; SP, 93.3%; positive predictive value (PPV), 99.1%; and negative predictive value (NPV), 43.1%. In a hypothetical screening setting (10,000 women; CIN2 prevalence, 1%), this marker combination should theoretically detect CIN2 with 86.0% SE, 100% SP, 99.1% PPV, and 99.6% NPV, area under ROC curve of 0.930 (95% CI, 0.909-0.951), and odds ratio, 29998.0 (95% CI, 7,879.0-37,338.0). Combining 2 markers (LR67 and VEGF-C) enables accurate detection of high-grade CIN in a clinical setting. However, testing the performance of this marker combination in a screening setting necessitates their analysis in cytological samples.

Telomerase activation and telomere maintenance are essential for cell immortalization and represent a rate-limiting step in cancer progression. The E6 oncoprotein of high-risk human papillomavirus (HPV) is known to activate telomerase, but its expression in CIN lesions and its prognostic value in cervical cancer (CC) are still incompletely understood. As part of our HPV-PathogenISS study, a series of 150 CCs and 152 CIN lesions were examined using immunohistochemical (IHC) staining for hTERT (telomerase reverse transcriptase), and tested for HPV using PCR with three primer sets (MY09/11, GP5(+)/GP6(+), SPF). Follow-up data were available from all SCC patients, and 67 CIN lesions had been monitored with serial PCR for HPV after cone treatment. Expression of hTERT was increased in parallel with the grade of CIN, with major up-regulation upon transition to CIN3 (OR 18.81; 95% CI 8.48-41.69; P = 0.0001). Positive hTERT expression was 90% specific indicator of CIN, with 98.7% PPV, but suffers from low sensitivity (57.5%) and NPV (14.3%). hTERT expression was also significantly associated to HR-HPV with OR 3.38 (95% CI 1.90-6.02; P = 0.0001), but this association was confounded by the histological grade (Mantel-Haenszel common OR = 1.83; 95% CI 0.92-3.79; P = 0.086). Expression of hTERT did not predict clearance/persistence of HR-HPV after treatment of CIN, and it was not a prognostic predictor in cervical cancer in univariate or multivariate survival analysis. It was concluded that up-regulation of hTERT was closely associated with HR-HPV, due to activation by the E6 oncoprotein. hTERT is a late marker of cervical carcinogenesis, significantly associated with progression to CIN3. Theoretically, a combination of hTERT assay (showing high SP and PPV) with another test showing high SE and high NPV (e.g. Hybrid Capture 2 for HPV), should provide an ideal screening tool capable of high-performance detection of CIN lesions.

Almost all cervical cancers are human papillomavirus (HPV)-positive. Some aspects of HPV carcinogenesis, such as factors involved in the transformation process and the mono- or polyclonal origin of the carcinogenic process, need to be defined. The latter aspect is addressed in our study. Cervical samples were collected from 102 patients with squamous cell carcinoma. The HPV positivity was established by PCR analysis performed using consensus and specific primers for the L1 and E6/E7 regions, respectively. Eighty-seven samples were positive for the L1 gene and 5 for the E6/E7 genes. Overall, 92 samples contained segments of HPV-DNA (90.2%). HPV-16 was most frequently found either alone or associated with other genotypes (63%). All genotypes identified as a single infection, except HPV-73, belonged to the high-risk HPV group. Among multiple infections, the HPV-31+54 couple was the most frequent. The presence of two genotypes in a primary tumor raises the question of their distribution in a single tumor cell. We attempted to answer this question by comparing the HPV patterns in primary tumors and metastases, considering that metastases derive from cell clones released from the primary tumor. The HPV patterns of primary tumors and metastases overlapped in most patients, even when primary tumors contained a double genotype, thus suggesting that single tumor cells may contain multiple HPV genotypes.

Records of necropsies performed at the Institute of Pathological Anatomy and Histology of the University of Trieste during the period December 1 1971-December 31 1977 have been reviewed. Cases with a necropsy diagnosis of pleural tumor or lung sarcoma were reexamined. Twenty-six cases were accepted as definite diffuse pleural mesothelioma. Occupational history was indicative of asbestos exposure in 22 cases, with 12 patients having worked in shipyards. The high incidence of diffuse pleural mesothelioma in the Province of Trieste is emphasized.

The expression of nuclear proteins high mobility group (HMG) I and HMGY was investigated in intraepithelial and invasive lesions of the uterine cervix. Human carcinoma cell lines C-41, ME-180, and CaSki were used for testing protein expression in neoplastic cells from the cervix. Morphological grading of the dysplasias (CIN 1, CIN 2, and CIN 3) and invasive carcinomas from formalin-fixed paraffin-embedded samples parallels the degree of nuclear immunostaining obtained using a polyclonal antibody raised against the amino-terminal region of HMGI(Y) proteins. The immunostaining obtained with HMGI(Y) antibody was compared with that observed using the antibody Ki-67, and the results were similar. We suggest the use of HMGI(Y) antibody in clinical oncology as a useful marker of intraepithelial lesions and invasive carcinomas.

Four cases of small cell carcinoma characterized by a striking involvement of the pleural sheets were investigate. Histologically, the tumors were composed of small epithelial cells, expressing carcinoembryonic antigen and occasionally neuroendocrines markers. Our findings indicate that small cell carcinoma should be added to the group of pseudomesothelioma.