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Background: Conflicting results have been reported in studies evaluating the relationship between serum markers of iron overload, liver iron deposits, and HFE mutations (C282Y and H63D) in chronic hepatitis C patients, and also their impact on the response to therapy in these patients., Aim: To evaluate the role of HFE mutations in the severity of liver disease and in the response to therapy in chronic hepatitis C., Methods: Two hundred and sixty-four hepatitis C patients treated with standard interferon and ribavirin were divided into two groups according to type of antiviral response: sustained virological response (SVR) and nonresponse or relapse. We evaluated the relationship between HFE mutation and the type of antiviral response, clinical data, biochemical tests, liver histopathology, virological data, and HFE mutations., Results: Of the 264 patients, 88 (32.1%) had SVR whereas 67.9% had nonresponse or relapse. Liver iron deposits were observed in 49.2% of the patients. The factors associated with SVR were hepatitis C virus genotype 2 or 3, transferrin saturation value of 45% or less, and detection of the H63D mutation. HFE mutation was more frequent in patients with iron deposits, but without association with serum iron biochemistry or severity of liver disease. Steatosis was more frequent in patients with liver iron deposits. CONCLUSION THE: H63D mutation was an independent factor associated with SVR in chronic hepatitis C patients, as also were hepatitis C virus genotype 2 or 3 and transferrin saturation value of 45% or less. Moreover, the H63D mutation was associated with liver iron deposits.

Context: Although there is evidence that endometriosis results from basal endometrium dislocation, the underlying biology is not fully understood. One protein that plays an important role in regulating epithelial proliferation and differentiation is the 63-kDa membrane protein (p63), which is also a marker of basal and reserve cells in the female genital tract., Objective: To determine whether p63 is expressed differently in peritoneal endometriosis, endometriomas, and adenomyosis, as well as in deep endometriotic nodules of the rectovaginal septum and abdominal wall., Design: This study includes a prospective series of consecutive patients (Canadian Task Force classification II-2) from a tertiary care university hospital. Specimens collected from 83 patients (15 peritoneal endometriosis specimens, 22 endometrioma specimens, 36 adenomyosis specimens, and 10 rectovaginal septum/abdominal wall specimens) were evaluated. Diagnostic and operative laparoscopies or laparotomies were performed, and tissue samples were obtained. Immunohistochemistry was used to evaluate p63 expression., Results: Positivity for p63 was detected in 93.3% of the peritoneal endometriosis specimens, 81.8% of the endometrioma specimens, 36.1% of the adenomyosis specimens, and none of the rectovaginal/abdominal wall endometriosis specimens (P < .001). Distribution of p63 immunostaining in the positive specimens was homogeneous., Conclusions: Endometriotic lesions express p63 differently, and some retain the basal/reserve cell immunophenotype. Nevertheless, it remains unclear whether the lack of p63 expression in some lesions is related to the extent of the disease, to its clinical behavior, or to exacerbation of the accompanying symptoms.

Background: p63 and p16 have been described as stem-cell markers of squamous epithelium. In an attempt to obtain new insights into the pathogenesis of pterygium, this study aims to evaluate the relationship between p63 and p16 expression in primary and recurrent pterygia., Methods: Samples of primary (n=56) and recurrent (n=14) pterygia and normal bulbar conjunctival tissue (n=11) were submitted to immunohistochemical study to evaluate the expression of p63 and p16 in these tissues., Results: Most of the cells stained for p63 were located in the basal layer of the normal conjunctiva, in the lower two-thirds of the epithelium of primary pterygia, and throughout all epithelial layers of recurrent pterygia. In normal conjunctivae, p16 expression was rarely expressed. Primary and recurrent pterygium groups exhibited increased p16 expression, with cytoplasmic staining in the primary group, and cytoplasmic or nuclear staining in the recurrent group., Conclusion: The overexpression of p63 and p16 observed in the present study reinforces likelihood of involvement of these genes in the pathogenesis of pterygium, perhaps related to the intense cellular turnover with substitution of superficial epithelial cells by less differentiated forms. This loss of normal cellular differentiation of the epithelial layers could explain the high rates of recurrence overall in the recurrent pterygia.

Objective: Although endometrial polyps likely originate from reserve cells in the basal layer, the underlying biology is not fully understood. One protein that plays an important role in regulating epithelial proliferation and differentiation is the 63-kd membrane protein (p63), which is also a marker of basal and reserve cells in the female genital tract. Our objective was to determine whether p63 is expressed differently in postmenopausal endometrial polyps than in the adjacent endometrium., Design: In this study, 36 specimens of endometrial polyps and 36 samples of the adjacent endometrium were obtained from postmenopausal women through hysteroscopic surgery performed in a tertiary-care university hospital. Immunohistochemistry was used to evaluate the expression of p63 in all samples., Results: The majority of endometrial polyp samples (94.4%) presented nuclear immunostaining for p63, whereas only 5.6% of adjacent endometrium samples were positive for p63 (P < 0.0001). Distribution of p63 immunostaining in the endometrial polyp samples was homogeneous., Conclusions: Our results provide evidence that a basal cell immunophenotype is maintained in the endometrial polyps seen in postmenopausal women, suggesting that p63 plays a role in the pathogenesis of such polyps.

Background: p63 helps regulate differentiation and proliferation in epithelial progenitor cells. Its expression is often higher in malignant tissue compared with normal tissue, and poorly differentiated carcinomas often show a larger number of p63-positive cells than well-differentiated tumors. The aim of the present study was to investigate the immunohistochemical expression of p63 in human cholangiocarcinomas (CC) and hepatocellular carcinomas (HCC)., Methods: Sixteen cases of CC and 37 cases of HCC were selected for the present study. Paraffin-embedded sections were submitted to immunohistochemical double-staining to identify p63 and cytokeratin 19., Results: p63 was diffusely expressed in 100% of CC, while it was negative in all HCC. In addition, cytokeratin 19, a marker for hepatic progenitor cells, was colocalized in all p63-positive cells., Conclusions: The nuclear immunostaining for p63 in all CC cases indicates that the p63 protein can act to promote neoplastic growth in bile duct epithelium, but it is not important for hepatocellular carcinogenesis. Co-localization of p63 and cytokeratin 19 in CC cells suggests that CC may be derived from undifferentiated progenitor cells (hepatic oval cells). Furthermore, p63 can be useful in the differential diagnosis between CC and HCC in biopsy samples.

Gestational trophoblastic diseases are a group of interrelated diseases of trophoblastic tissue that include partial hydatidiform mole, complete hydatidiform mole, invasive mole, choriocarcinoma, and placental site trophoblastic tumor. P63 is a p53 homologue that, in normal placentas, is expressed in the cytotrophoblast cells. The role of p63 in gestational trophoblastic diseases, however, merits further investigation. Immunohistochemistry with the p63 antibody (clone 4A4) was performed in formalin-fixed paraffin-embedded samples of hydropic abortion (n=10), partial hydatidiform mole (n=12), complete hydatidiform mole (n=12) and choriocarcinoma (n=5). P63 expression was quantitatively assessed as 0 (no stained cells), + (less than 10% positive cells), ++ (10-50% positive cells), and +++ (more than 50% positive cells). The intensity was scored as 0 (absence), + (weak), ++ (moderate), or +++ (strong). Statistical analysis was carried out by the Fisher test. In contrast to the other diagnoses, none of the choriocarcinomas analyzed exhibited p63-positive cells. There was no difference in distribution of p63 positive cells between hydropic abortion, partial hydatidiform mole, and complete hydatidiform mole. Concerning the intensity of immunostaining, there was difference only between partial hydatidiform mole and complete hydatidiform mole. According to our results, p63 might be useful to differentiate a choriocarcinoma from other gestational trophoblastic diseases. Besides, since the intensity of p63 expression was much stronger in partial hydatidiform mole and complete hydatidiform mole than in hydropic abortion, this feature may be helpful in distinguishing these two diagnoses in challenging cases.

Context: p63 is a recently described p53 homologue. Despite structural homology, they have different activities., Objectives: To obtain new insights into the role of p63 in normal and neoplastic breast tissue and to verify the possible association between p63 and p53 in breast carcinomas., Design: Immunohistochemistry in 85 breast carcinomas using p63, smooth muscle actin (1A4), p53, estrogen receptor, and progesterone receptor. The p63-positive cases were submitted to a double-immunolabeling study using p63 with 1A4, cytokeratin 7, and 34betaE12. Clinical data were retrieved from medical files., Results: p63, like 1A4, stained a single and continuous layer surrounding normal breast ductal and alveolar epithelium. In carcinomas, p53 was expressed in 21.17% of carcinomas, whereas p63 was expressed only in poorly differentiated ductal carcinomas (11.76% of cases). p63-positive cells coexpressed 1A4 and 34betaE12, but not cytokeratin 7. Expression of p63 correlated with pathologic staging, tumor size, histologic grading, nodal metastasis, and estrogen receptor negativity., Conclusions: p63 is a specific myoepithelial cell marker in normal breast tissue and is expressed in a minority of breast carcinomas, being seen only in grade III ductal carcinomas. In ductal carcinomas, malignant p63-positive cells have an immunophenotype similar to that of myoepithelial cells, suggesting that these cells originate from a primary progenitor cell that underwent divergent differentiation to ductal and myoepithelial cells during clonal expansion. Our study argues against a direct role in mammary tumorigenesis. However, p53 is rarely coexpressed with p63, suggesting that p63 could act indirectly as an oncogene by inhibiting p53. This hypothesis could also explain why p63 correlated with several other indicators of poor prognosis.

P63, a p53 homologue, is considered to be a marker of myoepithelial cells in breast tissue. This study was carried out to determine the sensitivity of p63 in detecting myoepithelial cells in DCIS and to compare the results obtained with smooth-muscle actin (1A4) in an attempt to verify the reliability of p63 as a possible marker of microinvasion in breast carcinoma. Fifteen DCIS of the breast were submitted to immunohistochemical analysis with anti-p63 and 1A4 antibodies and to a double immunolabeling study using p63 with 1A4. The double immunolabeling study showed that the same cells positive for p63 were also positive for 1A4. The three cases of DCIS with micro-invasion were negative for p63 and 1A4 in the foci of invasiveness. P63 staining was continuous in five of twelve cases of DCIS without microinvasion, being focal and discontinuous in 6 cases and completely negative in one case. Smooth-muscle actin staining was continuous in nine of twelve cases, including the five cases positive for p63. Smooth-muscle actin was focal and discontinuous in only two cases, which were also discontinuous for p63. The DCIS negative for p63 was also negative for 1A4. In conclusion, our results confirm the data of literature that p63 is a specific marker of myoepithelial cells in breast tissue. However, p63 is not as sensitive as 1A4 in staining myoepithelial cells and lack of p63 expression cannot be used as a reliable marker of invasiveness in ductal carcinoma in situ of the breast.

It has been proposed that iron overload may adversely affect liver disease outcome. The recent identification of 2 mutations in the HFE gene related to hereditary haemochromatosis (Cys282Tyr and His63Asp) provided an opportunity to test whether they are associated with hepatic iron accumulation and the activity and severity of liver disease in hepatitis C virus (HCV) infection. We investigated the prevalence of HFE mutations in 135 male patients with chronic HCV hepatitis, and correlated genotype distribution with different parameters of iron status and the activity and severity of liver disease. Of these 135 patients, 6 (4.4%) carried Cys282Tyr and 32 (23.7%) carried His63Asp, frequencies which were similar to those observed in healthy controls. Serum iron levels and transferrin saturation (but not ferritin levels or liver iron content) were significantly higher in carriers than in non-carriers of HFE mutations. No difference was observed in serum ALT, AST and GGT levels between carriers and non-carriers. Finally, scores for necroinflammatory activity and fibrosis in the liver were significantly higher in HFE carriers than in non-carriers. Patients with chronic HCV infection carrying HFE mutations tend to present more evident body iron accumulation and a higher degree of necroinflammatory activity and fibrosis in the liver. HFE gene mutations might be an additional factor to be considered among those implicated in the determination of a worse prognosis of the liver disease in chronic HCV infection., (Copyright 2000 S. Karger AG, Basel)