An unusual case of hepatic carcinosarcoma.

We report a rare case of a hepatic carcinosarcoma with rabdomyosarcomatous differentiation in its sarcomatous component. A 71-year old Caucasian female patient underwent a liver resection for a 4-cm lesion developed on an underlying HCV-related cirrhosis. Post-operative course was uneventful and the patient was discharged 5 days after surgery. At pathology, the tumor presented the features of hepatocellular carcinoma and rhabdomyosarcoma Three months later the patient experienced a liver recurrence, dying 2 months later for systemic disease. The reported case presents several peculiarities, i.e. the female gender, the HCV-related cirrhotic status, and the European origin of the patient. However, the outcome of our case confirms that this neoplasm pursues a highly aggressive course with poor prognosis.

Outcome after liver transplantation in patients with cirrhosis and hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is considered an optimal indication for liver transplantation (LT) because it may eliminate both the tumor and the underlying liver disease. The present study sought to compare cumulative survival, rate of HCC recurrence, and causes of death among patients with cirrhosis and HCC before and after the adoption of more restrictive criteria (Milan selection criteria) at the time of patient listing. Among 226 adult patients who received an elective liver transplantation between 1999 and 2005, 58 (27%) had a diagnosis of HCC at the time. The 38 patients who underwent transplantation for HCC in the period 1989 to 1998 were considered the "historical group." After LT (mean follow-up, 34 + 28 months), the cumulative survival rate was better among HCC versus non-HCC recipients (93% vs 71% at 1 year and 81% vs 67% at 3 years, respectively; P < .046), although the difference tended to attenuate after 5 years (66% vs 67%, respectively). Tumor recurrence (evaluated in patients surviving at least 3 months after LT) was observed in 10/31 in the historical group versus 4/53 among those who underwent transplantation after 1999. Among the causes of death, recurrence represented 50% in the old series and 23% in patients who underwent transplantation after 1999. Cumulative survival significantly improved among HCC patients who underwent transplantation after 1999 (93% vs 66% at 1 year and 81% vs 50% at 3 years; P < .00001). The 58 patients who underwent transplantation with a diagnosis of cirrhosis and concomitant HCC after 1999 showed even better survival than patients who underwent transplantation for end-stage liver disease without malignancy.

Predictive factors of outcome after liver transplantation in patients with cirrhosis and hepatocellular carcinoma.

Studies to define the optimal upper limits of tumor size and number as predictors of outcome after orthotopic liver transplantation (OLT) have yielded conflicting results. We analyzed 72 patients with cirrhosis and hepatocellular carcinoma (HCC) who underwent OLT over a 12-year period in a single center. Predictive factors for survival and tumor recurrence, according to the Milan criteria, were also examined. Our cohort included 60 men and 12 women of mean age 54 +/- 8 years and mean follow-up of 40 +/- 39 months. Origin of cirrhosis was postviral in 70% and Child class B or C in two thirds of patients. HCC was multifocal in 61%; about one fifth of patients had micro- or macrovascular involvement or positive nodes upon histologic examination. The cumulative size of the lesions was <3 cm in 17 patients; >3 to < or =5 cm in 28 patients; >5 to < or =8 cm in 14 patients; and >8 cm in 13 patients. According to the number and size of tumor nodules, 49 patients met the Milan criteria. During follow-up 25 patients died, 13 due to tumor recurrence. The 1- and 2-year survivals were 90% and 85% for patients who met the Milan criteria versus 57% and 51% for patients exceeding those limits (P = .006). A cumulative tumor size >8 cm was predictive of survival and tumor recurrence upon multivariate analysis. The adoption of Milan criteria for selection of cirrhotic patients has improved survival and reduced the rate of tumor recurrence. The evaluation of cumulative tumor size might further improve patient selection.

New placental factors: Between implantation and inflammatory reaction.

The trophoblast invasion is a dynamic changes in cell-cell and cell matrix interaction and it create in the endometrio a reaction similar to the inflammatory reaction. In the recent past most of the investigator in this field had focus on the mediator of this process especially on cytokine and on vasoactive agent. We have studied the inducible isoform of nitric oxide synthase (iNOS), adrenomedullin (AM), fatty acid synthase (FAS), and S-100 protein. Several evidences had lead our choice: the two first factors are essentially local mediator of vasospasm which works in synergy during the inflammatory reaction, but the AM I addition stimulates the DNA synthesis and cell proliferation of Swiss 3T3 fibroblasts, induces the cell cycle progression from G0 to G1 phase and the malignant cell lines express AM mRNA and mRNA for its receptor and the pattern of distribution of ir-AM and its mRNA during murine development is similar to that of other growth factors (TGFb isoforms, PDGF, FGF, IGF 1 and 2); Fatty acid synthase (FAS) is a major biosynthetic enzyme of intracellular fatty acid synthesis, its expression and activity is enhanced in proliferative tissues, such as malignant cells; S-100 is an acid calcium binding protein present in central nervous system where it is in mainly concentrated in the glial cells, astrocytes, Schwann cells, and neurons. It regulates several functions such as cell-cell communication, cell growth, cell structure, energy metabolism, contraction, and intracellular signal transduction. Recently the appearance in blood of S100 in preterm infants has been used as a marker of brain damage in perinatal period. The iNOS, AM, S100 and FAS are localized in both decidual and trophoblastic cells in early pregnancy, but we found that changes in iNOS, S100, AM, and FAS are different in spontaneous abortion (SA) versus voluntary pregnancy termination (VPT). Considering the VPT as non pathologic pregnancy, this difference may reflect functional modifications of placental tissues. Our result shown that AM and NO are increased in VPT vs SA showing that when the process of implantation is on course we found an higher expression that we have during the inflammatory reaction. [Table: see text]

Immunohistochemical expression of human erythrocyte glucose transporter and fatty acid synthase in infiltrating breast carcinomas and adjacent typical/atypical hyperplastic or normal breast tissue.

To evaluate the immunohistochemical expression of GLUT1, human erythrocyte glucose transporter 1, and fatty acid synthase (FAS), 66 human breast carcinomas and adjacent peritumoral tissue were studied. GLUT1 and FAS were expressed in 53 and 61 carcinomas, in 17 and 14 typical/atypical hyperplastic tissues, and in 16 and 13 tissues adjacent to tumor normal breast tissue, respectively. Statistical analysis revealed association between invasive carcinomas, invasive carcinomas with in situ component and GLUT1 immunostaining. GLUT1 staining was associated with tumor grade, FAS with tumor stage, and GLUT1 and FAS coexpression with tumor grade. Controls expressed no immunostaining. GLUT1 and FAS are new markers involved in the biologic activities of cancer cells. GLUT1 and FAS coexpression may indicate increased use of energy by the neoplastic cells correlated with poorly differentiated features and aggressive behavior. The innovative finding that GLUT1 and FAS are observed in mammary carcinoma adjacent nonneoplastic tissues may suggest a role in detecting initial phases of breast carcinogenesis.

[Malignant phyllode tumor of the breast with features of intraductal carcinoma]. / Tumore filloide maligno della mammella con aspetti di carcinoma intraduttale.

Malignant phyllode tumor is a rare biphasic breast tumor consisting of a malignant mesenchymal component and an epithelial component that is usually benign. We report an unusual case of a malignant phyllode tumor of the breast with neoplastic features of both the epithelial and stromal components. The patient was a 39-year-old woman with family history for breast carcinoma. Grossly, the excised tumor was a 9 x 7 x 5.5 cm gray lobulated mass with infiltrative margins and necrotic-hemorrhagic areas. Histologically the tumor consisted mainly of neoplastic mesenchyme with non invasive comedo, cribriform and micropapillary features of the ducts. Three months after the excision of the neoplastic mass, the patient developed an infiltrating ductal carcinoma of the opposite breast. Hereditary and bilateral tumors are commonly associated with germline mutations. Tissue from both neoplasms however did not express either BRCA1 or BRCA2 mutations.

Immunohistochemical study of fatty acid synthase in ovarian neoplasms.

In order to evaluate the prognostic significance of fatty acid synthase (FAS), the key enzyme in fatty acid biosynthesis, in ovarian benign and malignant tumors 98 patients with ovarian masses were immunohistochemically evaluated. Histologic features of the lesions and expression for FAS were statistically associated with clinical data and disease-free survival over a 5-year follow-up period. The mean age of patients was 65 years. TNM surgical stages were I in 31.8%, II in 28.2% and III in 40% of cases. The 5-year disease-free survival of the 85 malignant common epithelial ovarian tumors was 47.1% while 35.3 of patients died with active disease. Seventy-eight (79.6%) out of 98 cases expressed FAS in the neoplastic epithelial cells and 42 (42.9%) in the non-neoplastic stromal cells. Statistical analysis revealed FAS expression and stage of the disease to be significantly correlated to recurrence and survival rates only in the malignant common epithelial tumors. Moreover, multivariate analysis showed FAS expression (p=0.05) and tumor stage (p=0.03) to be independent prognostic predictors. FAS is a reliable predictor of recurrence and disease-free survival in common epithelial ovarian tumors along with neoplastic stage. Clinical data, other histologic subtypes and grading were not statistically significant.

Orbital osteoclastoma of apparent extraskeletal origin in a pagetic patient: a case report.

A large mass in the right orbit, causing proptosis, ptosis of the right upper eyelid, and limitation to eye movements, was surgically removed from a 51-year-old woman suffering from Paget's bone disease (PBD). Histologically, a giant cell tumor of the bone (osteoclastoma) was diagnosed. No bony involvement was apparent either operatively, microscopically, or on preoperative computed tomographic scans. The neoplasm has not recurred in a 3-year follow-up. In addition to the fact that osteoclastoma complicating PBD is rare, the extraskeletal origin of the tumor is a matter of interest and can be tentatively explained by an unusually powerful systemic stimulus acting on circulating osteoclast precursors. HUM PATHOL 31:1527-1531.

Histological findings in the eyelids of AIDS patients.

PURPOSE: The eyelids of 15 AIDS patients (17 specimens) were examined histologically at postmortem. METHODS: Formalin-fixed, paraffin-embedded and haematoxylin-eosin stained sections were examined by conventional light microscopy. The presence of calcific deposits was confirmed by special stains and elemental analysis (X-ray energy dispersive spectroscopy). RESULTS: 6 cases had abnormal microscopical findings. In two cases deposits of calcium oxalates were observed in the wall of dermal blood vessels and in epithelial cells of sweat and sebaceous glands, respectively. Precipitates of calcium phosphate were observed in the superficial substantia propria of the palpebral conjunctiva in an additional patient. Other histological findings in the remaining three patients included flat warts, an unusual elastotic degeneration of the forniceal palpebral conjunctiva and more common lesions (chalazion, Demodex folliculorum infestation of the eyelashes, trichilemmal cyst). CONCLUSION: The presence of microscopical lesions in nearly half of this small series demonstrates that the eyelids may be affected subclinically in AIDS patients.

Immunohistochemical study of fatty acid synthase, Ki67, proliferating cell nuclear antigen, and p53 expression in hyperplastic parathyroids.

Patients with secondary hyperparathyroidism following chronic renal disease frequently develop hyperplastic parathyroids. Hyperplastic parathyroids have an increased number of chief cells, a decreased amount of stromal fat, and a nodular or diffuse histologic pattern. Hyperplastic parathyroids may also express higher proliferative activity compared with controls. We evaluated the morphologic features and immunohistochemical expression of fatty acid synthase (FAS), Ki67, proliferating cell nuclear antigen, and p53 protein in 78 hyperplastic parathyroids from 20 patients with secondary hyperparathyroidism. Twenty normal parathyroids incidentally removed during nonneoplastic thyroid surgery were used as controls. Our results showed that hyperplastic glands overexpress FAS (P =.06). Statistical analysis also revealed a significant association between FAS and p53 protein (P =.006) and between FAS and hyperplastic glands with a predominant nodular pattern (P =.02). Hyperplastic parathyroids from patients with chronic renal failure strongly express FAS. Fatty acid synthase may therefore be a potential biological indicator of highly proliferating parathyroid cells.

A scanning transmission microscopy and energy-dispersive X-ray microanalysis of idiopathic ocular calcification and oxalosis in AIDS patients.

In a series of 98 consecutive eyeballs enucleated at postmortem from 86 patients dying with AIDS, the incidence of calcium deposits was 14 and 18.6%, respectively, for oxalates and calcium hydroxyapatite. The calcific eyes were examined by scanning electron microscopy (SEM) coupled with energy-dispersive X-ray microanalysis to confirm the elemental nature of the precipitates. Transmission electron microscopy was used in 2 of the cases with oxalosis. Oxalates with a free end exhibited a plate-like shape at SEM and appeared acicular at TEM, due to the reduced thickness of ultrathin sections. Crystals that were embedded in tissues such as the sclera or degenerate detached retinal tissue formed either spherules or plates at SEM. No clear relationship with intracellular structures could be found at TEM, possibly due to postmortem autolysis phenomena. Calcium hydroxyapatite deposits appeared at SEM as fine granules distributed over the collagen fibers of the corneal and conjunctival stroma and the scleral lamellae, but were also present intracellularly, both in the nucleus and cytoplasm of epithelial cells.

Primary non-Hodgkin's lymphoma of the liver.

The clinicopathological features of a rare case of primary non-Hodgkin's hepatic lymphoma (PHL) are described and compared to those of the other 76 cases reported in the world literature. PHL is mainly a disease of Caucasian, middle-aged males and, in approximately half of the reported cases, was associated with other diseases involving depression or chronic stimulation of the immune system. Right upper abdominal and epigastric pain with loss of weight are the most common presenting symptoms. The tumour is usually a single large mass involving both hepatic lobes and is almost invariably composed of lymphocytes reacting with B-cell markers. Most tumours are of intermediate or high grade according to the classification of the Working Formulation for Clinical Usage. No correlation is apparent between gross appearance of PHL (massive or nodular) and grade of severity. Chemotherapy or radiotherapy alone appears to be ineffective, while relatively good results can be obtained with combination modalities.

Fatty acid synthase (FAS) predictive strength in poorly differentiated early breast carcinomas.

AIMS AND BACKGROUND: Many normal and human cancer tissues express fatty acid synthase (FAS), the major enzyme required for endogenous fatty acid biosynthesis. Strong expression of FAS seems to be associated with a poor prognosis. This study examines the strength of FAS and other common markers of relapse in poorly differentiated breast carcinoma. MATERIALS AND METHODS: Fifty-one patients with poorly differentiated ductal infiltrating breast carcinomas were followed up for more than 10 years. Immunohistochemical detection of FAS was associated with morphological features of the tumors, with immunohistochemical expression of c-erbB-2, cathepsin D, estrogen and progesterone receptor status and with DNA ploidy in order to detect a statistical correlation. RESULTS: The chi-square test revealed a correlation between FAS and peritumoral lymphatic vessel invasion (PLVI) (P = 0.001). Univariate analysis showed that FAS was correlated with disease-free survival (DFS) (P = 0.0001). Other prognosticators associated with DFS were PLVI (P = 0.002), estrogen (P = 0.008) and progesterone receptor status (P = 0.007). Bivariate analysis showed that FAS was a further prognostic discriminant of DFS within the ER, PgR and PLVI subsets. DISCUSSION: FAS is a reliable prognosticator of recurrence in poorly differentiated early breast carcinomas. Association of FAS with PLVI may be useful to plan a correct follow-up in patients with breast neoplasms.

Inflammatory pseudotumour of the liver--evidence for malignant transformation.

A case of inflammatory pseudotumour of the liver is reported, and evidence is presented for its subsequent evolution into malignant non-Hodgkin's lymphoma. Such postulated malignant transformation challenges the assumption that hepatic inflammatory tumours are entirely benign lesions.

Immunohistochemical expression of fatty acid synthase, apoptotic-regulating genes, proliferating factors, and ras protein product in colorectal adenomas, carcinomas, and adjacent nonneoplastic mucosa.

The normal mucosa-adenoma-carcinoma sequence in colon pathology provides an attractive model of tumor progression. The role of tumor suppressor genes, oncogenes, and proliferative markers in tumorogenesis has evolved considerably in the last decade. By immunohistochemistry means, we have studied p53, bcl-2, c-myc, p21-ras, ki67, and fatty acid synthase (a fatty-acid-synthesizing enzyme) in normal, dysplastic, and neoplastic mucosa. The results were correlated with clinicopathological features and overall survival (OS). Formalin-fixed, paraffin-embedded archival material from 100 nonconsecutive adenomas and 100 adenocarcinomas (ADCs), including adjacent-to-tumor nonneoplastic mucosa (ANNM), from patients with a 5-year follow-up period were studied. Negative controls were obtained from colon resections for nonneoplastic disease. Fatty acid synthase was associated with ADC (P = 0.0001). p53 protein was associated with high-grade dysplasia adenoma (AHGD), ADC (P = 0.0001), and pT stage (P = 0.003). bcl-2 was associated with adenomas with low-grade dysplasia (P = 0.009); c-myc was associated with ANNM (P = 0.005) and pT stage (P = 0.006). p21-ras was associated with AHGD (P = 0.0001) and ANNM (P = 0.01). Ki67 was associated with AHGD (P = 0.02) and ADC (P = 0.0001). Univariate analysis on neoplastic tissue revealed histological grade, pT stage, pN stage, p21-ras, and p53 to be significant markers of OS; p21-ras, p53, and c-myc were reliable markers when evaluated on ANNM. Multivariate analysis revealed pT stage, pN stage, and p21-ras to be independent prognosticators of OS on ADC; p21-ras and c-myc staining in the ANNM were correlated with worse survival (OS). We suggest that the evaluation in concert of clinicopathological data and immunohistochemical markers on both normal and abnormal colon tissue provides an attractive model of tumor progression; moreover, it may give important messages about the prediction of survival.

Ocular, cerebral and systemic interrelationships of cytomegalovirus infection in a post-mortem study of AIDS patients.

PURPOSE: Eighty-six post-mortems of AIDS patients were reviewed microscopically and the presence of cytomegalovirus (CMV) infection in the viscera, brain and eye was recorded. METHODS: Immunohistochemical stains and in situ hybridisation with a CMV probe were performed. RESULTS AND CONCLUSION: CMV infection was observed in 63% of the cases. Visceral, cerebral and ocular involvement were overall 49%, 33% and 29%, respectively. The visceral form with no concomitant ocular and/or cerebral infection was the main cause of death (31%) in the 54 CMV-infected patients. Although CMV retinitis occurred mostly (20%) as a component of systemic disease, in 13% of the CMV-infected patients the eyes only were involved, while there were no cases with CMV limited to the brain. In the absence of systemic involvement, 9% of the cases showed concomitant ocular and cerebral infection, but because we failed to observe CMV optic neuritis without ocular involvement, retrograde viral spread from the brain through the optic nerve appears to be an infrequent mechanism of CMV retinitis.

Levels of expression of hRPB11, a core subassembly subunit of human RNA polymerase II, affect doxorubicin sensitivity and cellular differentiation.

We have previously shown that the human RNA polymerase II subunit 11 (hRPB11) is among the proteins specifically downregulated upon Doxorubicin (Dox) treatment of human cancer cell lines, and that Dox resistant clones derived upon drug selection express about 20% of the protein present in the original parental cell line. Given the prominent role that this subunit appears to have in eukaryotic cells, and the fact that its deletion causes lethality in yeast, we wanted to test the effect of the reintroduction of parental cell line levels of this subunit in Dox resistant colon cancer cells (LoVoDX). Stable transfectants of LoVoDX expressing parental (LoVoH) levels of hRPB11 showed a reduced sensitivity to the drug without changing the response of these cells to other chemotherapeutic agents, confirming a specific inverse correlation between cellular Dox sensitivity anti-hRPB11 levels of expression. In addition we show here that the levels of expression of this same RNA polymerase II subunit directly affect cellular differentiation, reducing the rate of cell proliferation, clonogenicity and increasing the expression of E-cadherin, a marker of epithelial cell differentiation. As expected from cells with these characteristics, upon in vivo administration of these clones in nude mice, we detected a significant reduction in the size and time of appearance of the primary tumors and overall metastatic capability. Finally, the role played by hRPB11 in regulating the transcription of specific genes is underlined by transient transfection experiments that show transactivation of the E-cadherin promoter by this protein.

DNA/protein flow cytometry as a predictive marker of malignancy in dysplasia-free Barrett's esophagus: thirteen-year follow-up study on a cohort of patients.

Intestinal metaplasia identifies Barrett's esophagus (BE) and is associated with an increased risk for esophageal adenocarcinoma. Dysplasia occurs as an intermediate step. However, progression from metaplasia to neoplasia without the demonstration of dysplasia has been described. The role of dual-parameter flow cytometry (FC) as a predictor of neoplastic risk in dysplasia-free cases was evaluated. DNA/protein FC and histology were performed on 362 samples from 30 dysplasia-free BE patients, followed up since 1985 once every 1-2 years. Nine cases were aneuploid, five of which (group IV) were frankly aneuploid; in the other four cases (group III), aneuploidy was detectable by dual-parameter analysis only. Twenty-one patients were diploid. Twelve (group II) also had an abnormally high G1-phase protein content compared to group I (nine patients), which were diploid with a low-moderate protein content. In three patients of group IV an adenocarcinoma in situ was diagnosed, after 5, 6, and 10 years, respectively. In two patients of group III, a low- and a high-grade dysplasia were observed at 3 and 6 years follow-up, respectively. One patient of group I first acquired a high protein content, then an aneuploid DNA content, and then progressed to adenocarcinoma (12 years). None of the still diploid patients (17 cases) have progressed to dysplasia or cancer compared with 6 of 13 presently aneuploid patients (P < 0.01). In conclusion, DNA/protein FC is a marker of increased malignant potential and thus may be used to detect patients at higher risk in dysplasia-free BE and assist in understanding the various stages of malignant transformation in long-term follow-up studies.

Differential expression of IGF-I and IGF-II in eutopic and ectopic endometria of women with endometriosis and in women without endometriosis.

PROBLEM: Factors regulating the development, growth, and differentiation of endometrial cells of endometriotic lesions are poorly understood. To investigate the paracrine-autocrine regulation of ectopic endometrial cell growth, the expression of IGF-I and IGF-II were studied. METHOD: Tissue specimens of eutopic and ectopic endometria were obtained from eight patients with endometriosis at laparoscopy and from the endometria of 14 women without endometriosis as controls. They were tested for the expression of IGF-I and IGF-II by immunohistochemical analysis. RESULTS: Immunohistochemical study for IGF-I in controls showed a more intense staining during the proliferative phase both in stromal and epithelial cells. In eutopic endometria of women with endometriosis a reduction in the staining was observed, whereas in epithelial cells of fibrotic peritoneal adhesions an intense immunostaining for IGF-I was observed. Immunohistochemical study of IGF-II in controls showed a more intense staining during secretory phase both in stromal and epithelial cells. In eutopic endometria of women with endometriosis, a reduction in the staining was observed, whereas in epithelial cells of fibrotic peritoneal adhesions an intense immunostaining for IGF-I was observed. Immunohistochemical study of IGF-II in controls showed a more intense staining during secretory phase both in stromal and epithelial cells. In eutopic endometria of women with endometriosis, a reduction in the staining was observed, whereas in epithelial cells of ovarian lesions and fibrotic peritoneal adhesions, no immunostaining for IGF-II was observed. CONCLUSIONS: In endometriosis there is an alteration of mechanisms regulating cell proliferation and differentiation.