Enhanced expression of parathyroid hormone-related protein in prostate cancer as compared with benign prostatic hyperplasia

Parathyroid hormone-related protein (PTHrP) has been shown to be the primary factor responsible for humoral hypercalcemia of malignancy. Recently PTHrP has been shown to be an early-response gene that may be involved in cellular proliferation or differentiation. In addition, PTHrP has been implicated in the pathogenesis of bone metastases. Bone metastases are a significant complication in patients with prostate cancer. We compared the expression of PTHrP by immunohistochemical staining using a monoclonal antibody directed against epitope between amino acids [53–64] in benign prostatic hyperplasia (BPH) with that in various stages of prostate cancer. Tissue sections were obtained on formalin-fixed paraffin-embedded blocks from BPH, well-differentiated prostate cancer, poorly differentiated prostate cancer, lymph node metastases (n = 15 each), and normal prostate (n = 2). In the normal prostate tissue there was no staining observed. In BPH, 13 of 15 tissue samples were positive for PTHrP immunoreactivity. An average of 33% of the cells stained positive with 1+ intensity. All samples from prostate cancer stained positive for PTHrP. In the samples from well-differentiated prostate cancer, an average of 87% of cells stained positive for PTHrP, whereas 100% of cells were positive in poorly differentiated and metastatic tumors. The intensity of staining was 3+ in well-differentiated tumors and 4+ in poorly differentiated tumors. Therefore, the expression of PTHrP is enhanced in prostate cancer as compared with BPH and is greater in poorly differentiated carcinoma as compared with the well-differentiated tumors. The role of PTHrP in the pathogenesis of prostate cancer deserves further study.     

Prostatic adenocarcinoma. Evaluation of immunoreactivity to monoclonal antibody B72.3

Monoclonal antibody B72.3 reacts with a tumor-associated glycoprotein designated TAG-72 that is expressed in many adenocarcinomas but not in normal tissues. The authors evaluated the immunoreactivity of B72.3 to benign, hyperplastic prostate, and to primary adenocarcinoma of the prostate to determine the frequency of TAG-72 production by benign and malignant prostatic epithelium. Focal cytoplasmic staining of gland cells was seen in 19 of 20 cases of glandular hyperplasia, and weak, homogeneous staining of secretions was seen in five cases. In contrast, 27 of the 35 (77%) adenocarcinomas studied showed at least focal intense staining of secretions, and 30 (86%) of the tumors showed some cytoplasmic immunostaining with B72.3. Positive staining occurred in all of the well-differentiated adenocarcinomas (100%) but was seen less often in moderately differentiated (82%) and poorly differentiated adenocarcinomas (58%). Because benign gland cells may express the TAG-72 antigen, immunohistochemistry results must be interpreted with caution and with regard to the overall morphologic pattern. Nonetheless, a positive B72.3 immunostain may be useful in identifying adenocarcinoma of the prostate, especially when an intense luminal reaction is found. A negative stain does not exclude the presence of adenocarcinoma, however.     

Patterns of expressions of transforming growth factor and epidermal growth factor receptor in squamous cell lesions of the urinary bladder.

AIM: To investigate the patterns of expression of transforming growth factor alpha (TGF-alpha) and epidermal growth factor receptor (EGFR) in squamous metaplasia and squamous cell carcinomas of the urinary bladder with and without schistosomiasis. METHODS: Immunohistochemical study of the expression of TGF-alpha and EGFR in squamous metaplasias (n = 12) and various grades of squamous cell carcinomas (n = 21) of the bladder with and without schistosomiasis. RESULTS: Focal cytoplasmic and membranous positivity for EGFR and TGF-alpha was seen in all cases of squamous metaplasia. The markers were diffusely coexpressed in a concordant pattern in areas of hyperplastic keratinising squamous metaplasia. A similar pattern of positivity was seen in verrucous carcinomas (n = 2) and well differentiated squamous carcinomas (n = 6). Progressive loss of differentiation was associated with increasing loss of EGFR staining while TGF-alpha staining was retained. Squamous cell carcinoma in situ (n = 2) showed focal positivity for TGF-alpha and EGFR. There were no differences in staining patterns between cases with and without schistosomiasis. CONCLUSIONS: The coexpression of TGF-alpha and EGFR by well differentiated squamous cell carcinomas and hyperplastic keratinising squamous metaplasia is consistent with the active regulatory role exerted by this autocrine loop. There is regional absence of expression of EGFR but not of TGF-alpha in squamous cell carcinomas of lesser differentiation, suggesting heterogeneity of such control in these tumours. The focal expression of the two markers in squamous cell carcinomas in situ indicates a possible second pathway of oncogenesis for less differentiated tumours. These observations may have important implications for the effectiveness of putative growth factor based treatments.     

Hepatocellular carcinomas show abnormal expression of fibronectin protein.

Fibronectin plays an important role in cell-to-cell adhesion, cell migration, and cell signaling. In the liver, fibronectin expression has been studied primarily as a component of the extracellular matrix, but little information is available on the expression of fibronectin protein in the neoplastic cells of hepatocellular carcinomas (HCCs). Twenty-four surgically resected HCCs were immunostained with fibronectin. Tumor and normal liver tissues were concurrently analyzed in all cases, and expression in the tumor was evaluated in comparison to the nonneoplastic liver. The average age at resection was 54 +/- 18 years for the 18 men and 6 women. Twenty-one of the cases were classic HCCs including 6 cases that were well differentiated, 12 cases moderately differentiated, and 3 cases poorly differentiated. The remaining 3 cases were moderately differentiated fibrolamellar carcinomas. In the normal liver, fibronectin labeled the sinusoids and weakly to moderately stained the cytoplasm of hepatocytes. In HCCs, 15/24 showed overexpression of fibronectin in the cytoplasm, 8/24 showed no change from the nonneoplastic liver, and one case showed decreased cytoplasmic staining. In addition, an abnormal membranous staining pattern was noted in 16/24 HCCs. In contrast to the HCCs, none of the three fibrolamellar carcinomas showed increased cytoplasmic or membranous staining. Excluding fibrolamellar carcinoma, increased cytoplasmic staining and/or an abnormal membranous staining was noted in 19/21 (90%) of HCCs. Fibronectin shows abnormal cytoplasmic and/or membranous staining in the majority of HCCs. The implications of fibronectin overexpression are uncertain but may reflect a critical step in tumor genesis.     

Immunohistochemical staining with MIB1, bcl2 and p16 assists in the distinction of cervical glandular intraepithelial neoplasia from tubo-endometrial metaplasia,endometriosis and microglandular hyperplasia

AIMS: Preinvasive endocervical glandular lesions, termed cervical glandular intraepithelial neoplasia, are increasing in incidence. The distinction of cervical glandular intraepithelial neoplasia from benign mimics, especially tubo-endometrial metaplasia, endometriosis and microglandular hyperplasia, can be difficult. This study investigates the value of immunohistochemical staining with MIB1, bcl2 and p16 in the distinction of cervical glandular intraepithelial neoplasia from these benign mimics. METHODS AND RESULTS: Immunohistochemical staining using the monoclonal antibodies MIB1, bcl2 and p16 was performed on cases of cervical glandular intraepithelial neoplasia (n = 21), tubo-endometrial metaplasia (n = 13), endometriosis (n = 7) and microglandular hyperplasia (n = 14). With tubo-endometrial metaplasia and microglandular hyperplasia staining with MIB1 was either negative or involved <10% of cells, while with cervical glandular intraepithelial neoplasia the majority of cases (86%) exhibited >10% positive cells. Two cases of endometriosis exhibited a MIB1 index of 10-30% while in the other cases <10% cells stained. With bcl2 the cells of microglandular hyperplasia were negative although there was staining of associated reserve cells in 43% of cases. All cases of tubo-endometrial metaplasia except one and all cases of endometriosis stained diffusely positive with bcl2. Cases of cervical glandular intraepithelial neoplasia were negative or exhibited focal staining. With p16 all cases of cervical glandular intraepithelial neoplasia exhibited diffuse strong positivity, generally involving 100% of cells, while all cases of microglandular hyperplasia were negative. Sixty-two percent of cases of tubo-endometrial metaplasia showed focal positivity, the remainder being negative. Cases of tubo-endometrial metaplasia were never diffusely positive with p16. In three cases of endometriosis there was staining of >50% of cells while the other cases were either focally positive or negative. CONCLUSIONS: A panel of antibodies, comprising MIB1, bcl2 and p16, is a useful adjunct to histology in distinguishing cervical glandular intraepithelial neoplasia from tubo-endometrial metaplasia, endometriosis and microglandular hyperplasia. Cases of cervical glandular intraepithelial neoplasia are diffusely positive for p16 and generally exhibit a high proliferation index with MIB1, while bcl2 is negative or, at most, focally positive. Tubo-endometrial metaplasia and endometriosis are characterized by strong diffuse positivity with bcl2 and a low proliferation index with MIB1 (although occasional cases of endometriosis show moderate proliferative activity). p16 is negative or exhibits focal positivity in tubo-endometrial metaplasia but in endometriosis there may be quite widespread positivity. Microglandular hyperplasia shows a low proliferation index with MIB1 and is negative for bcl2 and p16.     

Expression of Organic Anion Transporting Polypeptides in an H-Ras 12V Transgenic Mouse Model of Spontaneous Hepatocellular Carcinoma

PurposeExpression of organic anion transporting polypeptides (OATPs) 1B1/1B3 in hepatocellular carcinoma (HCC) induces a paradoxical enhancement of gadoxetic acid on liver magnetic resonance imaging (MRI). We examined the expression profile of OATPs with regard to tumor differentiation in a genetically modified H-Ras 12V mouse model of spontaneous HCC that undergoes multistep hepatocarcinogenesis with minimal inter-individual variation.Materials and MethodsTumor nodules were harvested from transgenic H-Ras 12V mice. Hematoxylin and eosin-stained slides were examined for tumor differentiation and high-grade pathological components (tumor necrosis, thickened trabeculae, or vascular invasion). Immunohistochemistry of OATP 1B1/1B3 was performed, and OATP expression was assessed.ResultsWe examined well-differentiated HCCs (n=59) in which high-grade pathological components were absent (n=49) or present (n=10). Among the well-differentiated HCCs without high-grade pathological components (n=49), OATP expression was negative, weak positive, and moderate positive in 23, 17, and nine cases, respectively. Among the well-differentiated HCCs with high-grade pathological components (n=10), OATP expression was negative, weak positive, and moderate positive in one, two, and seven cases, respectively. The ratio of positive OATP 1B1/1B3 expressing tumors was higher in HCCs with high-grade pathological components than in those without high-grade pathological components (p=0.004).ConclusionOur findings support those of previous clinical studies that have reported the frequent appearance of gadoxetic acid-enhanced MRI in moderately differentiated HCC.     

Primary liver carcinoma arising in people younger than 30 years

Primary liver carcinomas in children and young adults are uncommon and poorly described. We examined primary liver carcinomas in people younger than 30 years and performed immunostains for markers of biliary (cytokeratin [CK] 7, CK19, CD56) and hepatocellular (HepPar) differentiation. We found 23 primary liver carcinomas were found: 13 hepatocellular carcinomas (HCCs), 9 fibrolamellar carcinomas (FLCs), and 1 cholangiocarcinoma. Most HCCs showed compact (n = 7) or trabecular (n = 4) growth patterns. The Edmondson grades were as follows: 1, 3 tumors; 2, 8 tumors; and 3, 2 tumors). All HCCs and FLCs were HepPar(+). All FLCs and 7 of 9 HCCs were CK7(+). In contrast, a control group of 65 adult HCCs showed less CK7 positivity (24 [37%]; P = .03). CK19 was positive in 2 HCCs and CD56 in 1 HCC. No chronic background liver disease was seen, although 3 cases showed foci of altered hepatocytes. HCCs are the most common primary liver carcinoma in children and young adults followed by FLCs. They are morphologically similar to adult HCC, but more likely to be CK7(+).     

Identification of a 1-cM region of common deletion on 4q35 associated with progression of hepatocellular carcinoma.

To identify the location of one or more of the putative tumor suppressor genes (TSG) on chromosome arm 4q that may be involved in hepatocellular carcinoma (HCC), we examined 96 primary HCCs for their patterns of allelic loss at 39 microsatellite marker loci distributed along this chromosome arm. Allelic loss at one or more loci was observed in 71 (74%) HCCs. Detailed deletion mapping identified two distinct commonly deleted regions; one was located within a 1-cM interval flanked by D4S1534 and D4S2929 at 4q21-22, the other in the 1-cM interval flanked by D4S2921 and D4S2930 at 4q35. Of the tumors for which clinical data were available, allelic loss at 4q35 was more frequent in poorly or moderately differentiated tumors than in well-differentiated tumors (3/15, 20%, vs. 14/21, 67%, P = 0.008); in tumors larger than 2 cm in size (2/11, 18%, vs. 34/62, 55%, P = 0.046); and in tumors that arose from liver cirrhosis as opposed to HCCs arising from chronic hepatitis (25/42, 60%, vs. 9/27, 33%, P = 0.048). The association of allelic losses on 4q35 with larger tumor size and aggressive histological type implies that loss or inactivation of TSG located within the 1-cM interval of 4q35 identified here contribute to progression of HCCs.     

WT-1 assists in distinguishing ovarian from uterine serous carcinoma and in distinguishing between serous and endometrioid ovarian carcinoma

AIMS: It has been suggested that WT-1 is helpful in distinguishing a primary ovarian serous carcinoma (OSC) from a primary uterine serous carcinoma (USC). Since both neoplasms are often disseminated at diagnosis and since USC often spreads to the ovary and vice versa, it may be difficult to ascertain the primary site. This is important, since adjuvant therapies for OSC and USC may differ. WT-1 staining patterns also differ between OSC and ovarian endometrioid carcinoma and so it is possible that WT-1 may assist in the distinction of these two neoplasms, which is sometimes problematic, especially with poorly differentiated tumours. This study aims to document the value of WT-1 in these settings. Cases of ovarian borderline serous tumour, primary peritoneal serous carcinoma (PPSC) and uterine endometrioid carcinoma were also studied. METHODS AND RESULTS: Cases of OSC (n = 38), USC (n = 25) (in five of these cases there was also a component of endometrioid adenocarcinoma), ovarian endometrioid carcinoma (n = 13), uterine endometrioid carcinoma (n = 7), ovarian borderline serous tumour (n = 16) and PPSC (n = 6) were stained with WT-1. Cases were scored on a scale of 0-3, depending on the percentage of positive cells. The intensity of staining was scored as weak, moderate or strong. There was positive nuclear staining of 36 of 38 (94.7%) OSC with WT-1. In most OSC (68.4%), >50% of cells stained positively and staining was usually strong. Five of 25 (20%) USC were positive with only two cases exhibiting staining of >50% of cells. All primary ovarian and uterine endometrioid carcinomas were negative. All PPSC were positive, usually with diffuse strong immunoreactivity. Fourteen of 16 borderline serous tumours exhibited positivity with WT-1. CONCLUSIONS: WT-1 is useful in distinguishing OSC (characteristically diffuse strong nuclear positivity) from USC (characteristically negative). However, rarely OSC is negative and occasional cases of USC are positive. WT-1 may also be helpful in differentiating poorly differentiated OSC from poorly differentiated ovarian endometrioid carcinoma.     

CD10 expression in pancreatic endocrine tumors: correlation with prognostic factors and survival

CD10 is a cell surface metalloprotease expressed by a variety of hematopoietic and solid tumors. Immunohistochemical expression of CD10 was examined in 91 pancreatic endocrine tumors (PETs) included in tissue microarrays and representing various stages of tumorigenesis as well as in 10 normal pancreas tissues. The results were correlated with histoprognostic factors, namely, Ki-67 index and microvascular density. Thirty PETs (33%) presented positive cytoplasmic staining, and in 7 cases (8%), membranous staining also was observed. Stromal CD10 positivity was observed in 29 PETs (32%). In nontumoral pancreatic tissue, the islets were consistently negative. Epithelial cytoplasmic expression of CD10 increased with World Health Organization classification: CD10 was detected in 12% of benign tumors, 29% of tumors of uncertain prognosis, 38% of well-differentiated carcinomas, and 86% of poorly differentiated carcinomas. Membranous expression of CD10 correlated with poor differentiation (P = .0004). Expression of CD10 also correlated significantly with a high proliferative index (P = .020), low microvascular density (P = .043), large tumor size (P = .023), and presence of metastasis (P = .013). Expression was associated with poorer survival (P = .017). No statistical relation was observed between stromal CD10 expression and any of the histopathologic criteria examined. In conclusion, CD10 is expressed in a subset of PETs and correlates with histopathologic indicators of poor outcome, suggesting a role for this molecule in tumorigenesis and prognostic analysis.     

Nuclear translocation of survivin in hepatocellular carcinoma: a key to cancer cell growth?

Survivin is a recently described anti-apoptosis protein and regulator of cell division. Its expression and localization in hepatocellular carcinoma (HCC) and in normal liver tissue has not been fully elucidated. We examined the expression of survivin, Fas, proliferating cell nuclear antigen (PCNA), and apoptosis in 47 specimens of hepatocellular carcinoma (HCC) and surrounding nonmalignant hepatic tissues. To further determine the relationship between survivin expression and cell proliferation and apoptosis, we performed double immunostaining for survivin and PCNA TUNEL staining in the same HCC specimens. Positive immunostaining for survivin was present in 35 of 47 (74%) HCCs. Twenty-two of 35 survivin-positive HCCs (63%) showed punctate nuclear staining in HCC cells, and the remaining 13 showed predominant cytoplasmic staining. In contrast, nonmalignant hepatocytes showed only cytoplasmic staining. HCC cells had significantly higher PCNA-labeling and apoptotic indices compared with the case of nonmalignant hepatic tissue (P<0.001). Furthermore, nucleus-positive HCC specimens for survivin showed the highest PCNA labeling index. The nuclear localization of survivin in HCC cells correlated with tumor cell de-differentiation with the exception of the HepG2 cell line. Survivin expression was inversely associated with apoptosis and was strongly associated with Fas expression (P=0.01). All 4 HCC cell lines examined showed survivin expression and punctate nuclear localization. Our results indicate that survivin is localized to the cytoplasm in quiescent nonmalignant liver cells to suppress apoptosis and translocates into the nucleus in HCC cells. In conclusion, translocation of survivin from the cytoplasm to the nucleus may constitute an important regulatory mechanism for cell proliferation and differentiation in HCC.     

CD10 and calretinin staining of endocervical glandular lesions,endocervical stroma and endometrioid adenocarcinomas of the uterine corpus: CD10 positivity is characteristic of,but not specific for,mesonephric lesions and is not specific for endometrial stroma

AIMS: In the female genital tract CD10 has been used to assist in the evaluation of mesenchymal tumours of the uterus and in determining whether endometrial stroma is present. CD10 positivity has also been shown in cervical mesonephric remnants and this antibody has been suggested as a useful immunohistochemical marker of mesonephric lesions in the female genital tract. Calretinin has also been shown to be positive in mesonephric lesions. In this study the specificity of these two antibodies in evaluating cervical and uterine glandular lesions and the value of CD10 in determining whether stroma is endometriotic or not were investigated. METHODS AND RESULTS: Cases of cervical tubo-endometrial metaplasia (TEM) (n = 11), microglandular hyperplasia (MGH) (n = 10), endometriosis (n = 8), mesonephric remnants/hyperplasia (n = 12), endocervical adenocarcinoma, usual type (n = 15), mucinous variant of minimal deviation adenocarcinoma (MDA) (n = 7) and mesonephric adenocarcinoma (n = 3) were stained with antibodies against CD10 and calretinin. Nine cases of endometrial adenocarcinoma of endometrioid type were also stained. In all the cervical cases normal endocervical glands were negative with both antibodies except for one case with strong positive luminal staining with CD10. All cases of TEM, MGH and endometriosis were negative with CD10 and calretinin except for focal staining with CD10 in one case each of MGH (cytoplasmic staining) and endometriosis (luminal staining). Most usual endocervical adenocarcinomas were negative with both antibodies, although one exhibited focal cytoplasmic staining with calretinin and five exhibited limited luminal positivity with CD10. All MDAs were negative with both antibodies. Ten of 12 mesonephric remnants/hyperplasia showed luminal positivity with CD10 and one exhibited cytoplasmic and nuclear staining with calretinin. Two of three mesonephric adenocarcinomas showed luminal positivity with CD10 and nuclear and cytoplasmic positivity with calretinin. Seven of nine endometrial adenocarcinomas were positive with CD10 (four cytoplasmic, two membranous and cytoplasmic, one luminal and cytoplasmic) and three with calretinin (two cytoplasmic, one nuclear and cytoplasmic). Positive staining of endometriotic stroma with CD10 was present in all endometriosis cases but normal cervical stroma was also strongly positive, especially around glands. Endometriotic stroma and cervical stroma were negative with calretinin. CONCLUSIONS: We conclude that most endocervical glandular lesions, including mesonephric remnants/ hyperplasia, are negative with calretinin. However, the focal nuclear and cytoplasmic positivity with calretinin in two of three mesonephric adenocarcinomas suggests that this may be a useful indicator of a mesonephric origin of a cervical adenocarcinoma. Most mesonephric remnants/hyperplasias exhibit luminal positivity with CD10, although this is not invariable and staining is usually focal. Positive luminal staining of a benign endocervical glandular lesion with CD10 may help confirm mesonephric remnants. Although positive staining with CD10 was found in two of three mesonephric adenocarcinomas, the observed immunoreactivity of several conventional cervical adenocarcinomas limits the diagnostic value of CD10 in confirming a mesonephric origin for an adenocarcinoma. Since all cervical MDAs were negative with CD10, positivity with this antibody may be of value in distinguishing mesonephric hyperplasia from MDA, although this distinction rarely necessitates immunohistochemistry. Most endometrial adenocarcinomas of endometrioid type stain with CD10 and thus positivity with this antibody is not specific for a mesonephric origin of an endometrial adenocarcinoma. Positivity of normal cervical stroma limits the value of CD10 staining in confirming a diagnosis of cervical endometriosis.     

Simple tumor profile chart based on cell kinetic parameters and histologic grade is useful for estimating the natural growth rate of hepatocellular carcinoma

Thirty-four untreated hepatocellular carcinomas (HCCs) with known growth rates were classified into 5 groups on a tumor profile chart based on their doubling time (DT), Ki-67-positive index (Ki-67-PI), apoptotic index (Apo-I), and histologic grade. The slow-growing HCCs (DT > 100 days) consisted of well-differentiated tumors with slight cell kinetic imbalance and were divided into groups A and B. Group A had Apo-I values <3%, and most tumors had Ki-67-PI values <10%, whereas group B had Apo-I values of 3 per thousand to 10 per thousand and Ki-67-PI values of 10% to 20%. The HCCs with intermediate growth rates, which had Ki-67-PI values similar to those of the tumors in group B, were divided into groups C and D based on differences in cell kinetics: group C consisted of well-differentiated tumors, most of which had Apo-I values <3 per thousand, and group D consisted of moderately or poorly differentiated tumors with Apo-I values between 10 per thousand and 20 per thousand. The rapidly growing tumors (DT < 50 days, group E) had higher Ki-67-PI values than other groups and a wide range of Apo-I values. Rapidly growing tumors were mostly moderately or poorly differentiated, with a large cell kinetic imbalance in favor of cell production. This grouping system is useful for approximating the growth rate of HCCs in a clinical setting, even when only histologic parameters are available.     

Cytodiagnosis of hepatocellular carcinoma in fine-needle aspirates of the liver: its differentiation from reactive hepatocytes and metastatic adenocarcinoma

Fine-needle aspiration (FNA) cytology is a useful tool for diagnosis of primary malignancies and metastatic lesions of the liver. However, well-differentiated hepatocellular carcinoma (HCC) may resemble benign/reactive hepatocytes, and less differentiated HCC may simulate poorly differentiated adenocarcinoma, leading to difficulties in interpretation of aspirates from liver. To determine the subtle cytomorphological features which can differentiate these lesions, ultrasound-guided FNA smears from 86 cases of liver malignancy were subjected to detailed cytologic assessment. These included 20 cases of HCC, 38 cases of metastatic adenocarcinoma, and 28 cases of benign/reactive hepatocytes. The important features for separating HCC or well-differentiated HCC from benign/reactive hepatocytes were excessive cellularity, trabecular pattern vs. thin cords of hepatocytes, nuclear pleomorphism, atypical stripped nuclei, and macronucleoli (P < 0.001 to < 0.0001). The most significant features for differentiating HCC from metastatic adenocarcinoma were trabecular growth pattern, hepatocytic cells vs. columnar/cuboidal cells, eosinophilic granular cytoplasm, lipid vacuoles, bile pigments, and atypical stripped nuclei (P < 0.001 to < 0.0001). The cytomorphological features which may distinguish poorly differentiated HCC from poorly differentiated adenocarcinoma were polygonal (hepatocytic) cells, eosinophilic granular cytoplasm and lipid vacuoles in HCC, and columnar/cuboidal cells and acinar/glandular formation in adenocarcinoma (P < 0.05 to < 0.001). Diagn. Cytopathol. 1999;21:370-377.     

The MUC13 cell surface mucin is highly expressed by human colorectal carcinomas

Mucins are complex mucosal glycoproteins that can be highly expressed by adenocarcinomas, having diagnostic, therapeutic, and biological significance. MUC13 encodes a cell surface membrane-anchored mucin expressed in the normal gastrointestinal tract, trachea, and kidney as well as colorectal, esophageal, gastric, pancreatic, and lung cancers. MUC13 protein expression was determined immunohistochemically in 99 sporadic colorectal cancers, assessing proportion of tumor cells stained, stain intensity, and localization. In normal colon, intense apical membrane and variable cytoplasmic MUC13 staining was present in both goblet and columnar cells, with strongest reactivity in the upper crypts and surface epithelium. All cancers showed staining of most tumor cells, being most conspicuous in the apical membranes of gland spaces. Left-sided tumors had a higher overall proportion of MUC13-positive tumor cells than right-sided tumors (P < .05), and high staining intensity was more frequent in adenocarcinomas (81%) than mucinous tumors (50%) (P < .05). Poorly differentiated and late-stage tumors were more likely to have high-intensity cytoplasmic staining (P < or = .025). Basolateral cell membranes were stained in 24% of cases, being more common in poorly differentiated tumors (55%) than well or moderately differentiated tumors (16%) (P < or = .001). Partial or full circumferential MUC13 staining was frequently observed in areas of tumor budding. Although MUC13 immunoreactivity was not predictive of patient outcome, there was a trend toward poorer outcome in patients with tumors showing basolateral MUC13. In summary, MUC13 was expressed abundantly by all colorectal cancers, with the highest expression in more poorly differentiated tumors.     

Cd44: a marker of squamous differentiation in adenosquamous neoplasms

OBJECTIVE: To test the hypothesis that CD44 standard (CD44[s]) and its other variants, CD44v6 and CD44v7-8, might be useful markers of squamous differentiation in epithelial tumors. DESIGN: We studied expression of CD44(s), CD44v6, and CD44v7-8 using immunohistochemistry in human tumors that had squamous differentiation, glandular differentiation, or both arising in the colon, stomach, esophagus, lung, pancreas, gallbladder, or uterus/cervix, as well as in adjacent nonneoplastic tissues. Formalin-fixed, paraffin-embedded archival tissue specimens of 33 adenosquamous tumors were used. All were stained with monoclonal antibodies against a conserved portion of CD44(s) and its variants, CD44v6 and CD44v7-8, using the avidin-biotin peroxidase method. RESULTS: CD44(s) and its variants consistently and strongly stained areas of tumors with well-developed squamous differentiation. These markers also consistently and strongly stained normal squamous mucosa. Reactivity for CD44 and its variants was lacking in normal glandular type epithelium and in adenocarcinomas composed entirely of well-differentiated mucin-producing glands. Areas of well-differentiated carcinoma, both squamous and adenocarcinoma, were consistent with respect to both extent and intensity of staining. Staining in lymph nodes was similar to that in the primary tumors, with well-differentiated squamous foci being consistently positive, well-differentiated mucin-producing adenocarcinoma foci consistently negative, and poorly differentiated foci showing variable staining. Although staining was less intense with the variants, it followed the same staining pattern as found for CD44(s). No differences in the extent or intensity of staining were identified in the metastatic versus primary tumor foci, nor was any difference identified between superficial and deeply invasive areas of primary tumors. CONCLUSIONS: Our study shows that CD44(s) and its variants are good markers of squamous epithelial differentiation in several types of normal epithelium and tumors, and that these markers can identify areas of well- to moderately differentiated elements in adenosquamous neoplasms. However, poorly differentiated tumors show an inconsistent staining pattern with CD44, such that it cannot be used as a reliable and practical marker of squamous differentiation in poorly differentiated neoplasms.     

Primary breast carcinomas with neuroendocrine features: Clinicopathological features and analysis of tumor growth patterns in 36 cases

Primary breast carcinoma with neuroendocrine features (NEBC) is an uncommon tumor. In the classification of WHO 2012, these tumors were categorized as: 1- neuroendocrine tumor, well-differentiated; 2- neuroendocrine carcinoma, poorly differentiated/small cell carcinoma; and 3- invasive breast carcinoma with neuroendocrine differentiation. In this study, we reviewed NEBC except poorly differentiated/small cell carcinoma variant in order to define the morphological growth patterns and cytonuclear details of these tumors. All breast surgical excision materials between 2007 and 2016 were re-evaluated in terms of neuroendocrine differentiation. Thirty-six cases showing positive staining for synaptophysin and/or chromogranin A in ≥50% of tumor cells were included in the study. All cases were female with a mean age of 67.4. Mean tumor diameter was 26 mm. Multifocality was noted in 5 cases. Grossly, they were mostly infiltrative mass lesions. T stages, identified in 34 cases, were as follows: 13 cases with pT1; 19 pT2 and 2 pT3. We described schematically 4 types of patterns depending on predominant growth pattern, except one case: 1) Large-sized solid cohesive groups (6 cases), 2) Small- to medium-sized solid cohesive groups with trabeculae/ribbons and glandular structures (6 cases), 3) Mixed growth patterns (20 cases), 4) Invasive tumor with prominent extracellular and/or intracellular mucin (3 cases). The tumor cells were mostly polygonal-oval with eosinophilic/eosinophilic-granular cytoplasm. The nuclei of tumor cells were mostly round to oval with evenly distributed chromatin. Only 5 cases showed high grade nuclear and histological features. Molecular subtypes of the cases were as follows: 33 luminal A, 2 luminal B, and 1 triple negative. NEBC should come to mind when a tumor display one of the morphological patterns described above, composed of monotonous cells with mild to moderate nuclear pleomorphism and abundant eosinophilic/eosinophilic granular or clear cytoplasm, especially in elderly patients.     

Expression of HNF-1α and HNF-1β in various histological differentiations of hepatocellular carcinoma

Hepatic nuclear factor 1 (HNF-1) regulates genes in a hepatocyte-specific manner. It has been previously reported that the ratio of HNF-1α and HNF-1β mRNA is related to histological differentiation hepatocellular carcinoma (HCC). In this study, the expression levels of the HNF-1α and HNF-1β proteins were analysed relatively and quantitatively in various histologically differentiated HCC and surrounding non-cancerous tissues, and HNF-1α binding activity for the AT element of the B domain of the human α-fetoprotein enhancer was examined. Western blot analysis demonstrated that HNF-1α protein was expressed at a higher level in well-differentiated HCC tissues than in the surrounding non-HCC tissues; on the other hand, the HNF-1α protein was expressed at lower levels in moderately and poorly differentiated HCCs than in the surrounding non-HCC tissues. The levels of HNF-1β expression in well-differentiated and poorly differentiated HCCs were similar to and higher than those found in the respective surrounding non-cancerous portions. In binding assays, HNF-1 binding activity was high in well-differentiated HCC and lower in moderately and poorly differentiated HCCs. Most well-differentiated HCC cases showed immunohistochemical expression of HNF-1α. These findings show that poor histological differentiation of HCC correlates with decreases in the level and activity of HNF-1α proteins. © 1998 John Wiley & Sons, Ltd.     

Ultrastructural features of solid/trabecular areas in differentiated thyroid carcinoma

The presence of areas exhibiting a solid/trabecular pattern of growth within an otherwise differentiated thyroid carcinoma represents a source of controversy as regards its proper classification and biologic and prognostic significance. The aim of the current study was to investigate the ultrastructural features of solid/trabecular areas in differentiated thyroid carcinoma and to compare those features with the submicroscopic profile of differentiated, poorly differentiated (insular), and undifferentiated (anaplastic) variants of thyroid cancer. The study series included differentiated carcinoma with solid/trabecular areas (3 cases), conventional papillary carcinoma (4 cases), follicular variant of papillary carcinoma (4 cases), poorly differentiated (insular) carcinoma (3 cases), and undifferentiated (anaplastic) carcinoma (3 cases). It was found that the solid/trabecular areas in differentiated carcinoma and poorly differentiated (insular) carcinoma share similar ultrastructural features and overall retain, even if attenuated, many of the submicroscopic attributes of differentiated carcinomas. In particular, nests of neoplastic cells were observed showing a highly developed cytosecretory apparatus and the presence of numerous abortive/rudimentary follicles, and intercellular and intracellular (intracytoplasmic) lumina/canaliculi of variable morphology. The study supports the hypothesis that the solid/trabecular areas do not merely represent an architectural pattern but rather should be regarded as the expression of a process of reduced differentiation similar to that of poorly differentiated (insular) carcinoma.