Human Pathology - Articles in Press

A novel t(6;13)(q15;q34) translocation in a giant cell reparative granuloma (solid aneurysmal bone cyst) - Corrected Proof

2012-01-27

Abstract: Aneurysmal bone cyst is a rapidly growing and locally aggressive lesion that commonly affects children and young adults. Initially regarded as a reactive process, primary aneurysmal bone cyst is now widely accepted as a neoplasm owing to recent findings of recurrent clonal chromosomal alterations, mostly t(16;17)(q22;p13). However, other infrequent chromosomal rearrangements have also been reported. Giant cell reparative granuloma, previously regarded as a nonneoplastic process and histologically indistinguishable from the solid variant of aneurysmal bone cyst, is frequently seen in the gnathic bones and the short tubular bones of the hands and feet. Here we present such a case of giant cell reparative granuloma (solid aneurysmal bone cyst) in the finger of a 63-year-old white man. Cytogenetic analysis revealed a novel alteration involving a reciprocal translocation between 6q and 13q, with a karyotype of 46,XY,t(6;13)(q15;q34),del(20)(q13.1).

An immunohistochemical comparison of cytokeratin 7, cytokeratin 15, cytokeratin 19, CAM 5.2, carcinoembryonic antigen, and nestin in differentiating porocarcinoma from squamous cell carcinoma - Corrected Proof

2012-01-27

Summary: The distinction of porocarcinoma from squamous cell carcinoma is clinically relevant but can often be a diagnostic dilemma. Current markers reported to be helpful in diagnosing porocarcinoma include carcinoembryonic antigen and cytokeratin 7; however, their expression has been demonstrated in 30% to 80% and 13% to 22% of squamous cell carcinoma cases, respectively. In this study, we assessed immunohistochemical expression of cytokeratin 7, cytokeratin 15, cytokeratin 19, CAM 5.2, carcinoembryonic antigen, and nestin in 67 cases (39 porocarcinomas and 28 moderately differentiated squamous cell carcinomas) to determine their use as histologic adjuncts. Expression of carcinoembryonic antigen, cytokeratin 19, cytokeratin 7, CAM 5.2, cytokeratin 15, and nestin was seen in 77%, 67%, 64%, 51%, 49%, and 13% of porocarcinomas, respectively; and in 57%, 18%, 26%, 32%, 30%, and 37% of squamous cell carcinomas, respectively. Of these, cytokeratin 19 was the most specific (specificity, 82%) in detecting porocarcinomas, and carcinoembryonic antigen was the most sensitive (sensitivity, 77%). By χ2 test, statistically significant P values (<.05) were observed for cytokeratin 7, cytokeratin 19, and nestin in the distinction of porocarcinoma from squamous cell carcinoma. However, in a logistic regression and stepwise selection for predicting a porocarcinoma, statistical significance was observed only for cytokeratin 19 (P = .0003). In conclusion, we found cytokeratin 19 to be a helpful marker in the distinction of porocarcinoma from squamous cell carcinoma, although a focal staining pattern can be seen in a third of cases. The diagnostic sensitivity and specificity appear to be significantly improved using a selected panel of immunohistochemical stains that include cytokeratin 7, cytokeratin 19, and nestin.

Importance of muscle light microscopic mitochondrial subsarcolemmal aggregates in the diagnosis of respiratory chain deficiency - Corrected Proof

2012-01-25

Summary: The purpose of this study was to evaluate relationships between subsarcolemmal mitochondrial aggregates and electron transport chain deficiencies in skeletal muscle with the objective of establishing an association between mitochondrial accumulation and electron transport chain complex deficiency. We conducted a large-scale, retrospective study to evaluate factors associated with subsarcolemmal mitochondrial aggregates (percent) in pediatric patients who received muscle biopsies for suspected respiratory chain disorders. Patients were included if they had histochemical stains for assessment of mitochondrial pathology and had biochemical testing for muscle electron transport chain complex activities. Significant positive bivariate correlations (n = 337) were found between subsarcolemmal mitochondrial aggregate percentage and electron transport chain complexes II, IV, I + III, and II + III activities. Evaluation showed that a cutoff value of > 2% subsarcolemmal mitochondrial aggregates had poor overall diagnostic accuracy (mean, 32%), compared with a < 5% cutoff (mean, 60%). To better evaluate the effects of subsarcolemmal mitochondrial aggregates percentages, patients were stratified according to lower one-third (group 1, n = 120 plus ties) and upper one-third (group 2, n = 115 plus ties) of subsarcolemmal mitochondrial aggregates values. Although only minor clinical and pathologic differences were observed, group 1 participants had significantly lower electron transport chain complex activities than group 2 for all enzymes except complex III. Logistic regression showed over 2-fold greater odds of deficiency for electron transport chain complexes I + III (P = .01) and II + III (P = .03) for group 1 participants compared with group 2. We conclude that, contrary to the previous > 2.0% subsarcolemmal mitochondrial aggregates cutoff for respiratory chain disorder, patients with a low subsarcolemmal mitochondrial aggregates percentage (≤4%) are significantly more likely to have electron transport chain complex deficiency than patients with increased subsarcolemmal mitochondrial aggregates percentage (≥10%). This morphological approach for assessment of mitochondrial proliferation may assist clinicians to select further testing to rule out an electron transport chain complex deficiency in children by other methods, including direct biochemical testing of electron transport chain complex activities, measurement of muscle coenzyme Q10 content, or evaluation for a mitochondrial DNA depletion syndrome.

Ectopic hepatic tissue presenting as right atrial mass - Corrected Proof

Lauren Xu, Jean Jeudy, Allen P. Burke — 2012-01-25

Summary: A 52-year-old woman had a well-circumscribed, mobile mass (1.8 × 1.7 cm) in the right atrium detected by echocardiography and confirmed by magnetic resonance imaging. Subsequent histologic evaluation of the mass revealed benign, ectopic hepatic tissue. Ectopic liver is a rare occurrence, and most frequent anatomical distribution of ectopic hepatic tissue is the region around the gallbladder. In exceptional cases, ectopic liver can be found within the thorax. The reported case demonstrates that ectopic liver should be included in the differential diagnosis of right atrial masses removed surgically.

The diagnostic utility of the GNAS mutation in patients with fibrous dysplasia: meta-analysis of 168 sporadic cases - Corrected Proof

2012-01-16

Summary: GNAS mutations have been implicated in the development of fibrous dysplasia and multiple endocrinopathies of the Albright-McCune syndrome. To investigate the diagnostic utility of GNAS mutations in patients with fibrous dysplasia, we performed mutational analyses of histologically confirmed fibrous dysplasia and conducted a meta-analysis of the literature. We collected 48 cases of fibrous dysplasia from 3 institutions from 2002 to 2011 and performed polymerase chain reaction and direct bidirectional sequencing of exons 8 and 9 of GNAS using paraffin-embedded tissues. We searched MEDLINE, PubMed, and the KoreaMed databases from 1997 to 2011 and included an additional 155 cases of fibrous dysplasia from 8 representative studies to conduct a meta-analysis. In our sample, 28 (58.3%) of 48 cases showed point mutations of codon 201 at exon 8. Twenty-five cases had a substitution of arginine at codon 201 for histidine (p.R201H), and 3 cases had a substitution for cysteine (p.R201C). One case had a new mutation at codon 224 (p.V224A). The incidence of GNAS mutations was significantly greater in cases that involved long bones than in cases that involved flat bones (P = .017) and was higher in polyostotic cases than in monostotic cases (P = .067). In meta-analysis, 9 studies and 203 patients were included. The overall positive rate of GNAS mutation in fibrous dysplasia was 71.9% (146/203). The major types of mutations were missense mutations such as R201H (66.4%) and R201C (30.8%). As a result, the detection of GNAS mutation could be a valuable adjunct to conventional histopathologic diagnosis of fibrous dysplasia.

Lysine-specific demethylase 1 (LSD1/KDM1A/AOF2/BHC110) is expressed and is an epigenetic drug target in chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma - Corrected Proof

Idriss M. Bennani-Baiti, Isidro Machado, Antonio Llombart-Bosch, Heinrich Kovar — 2012-01-16

Summary: Lysine-specific demethylase 1 (GeneID 23028), a flavin-dependent monoamine oxidoreductase and a histone demethylase, serves as an epigenetic coregulator of transcription. Lysine-specific demethylase 1 is up-regulated in neuroblastoma and in bladder, breast, colorectal, gastric, lung, and neuroendocrine cancers, and its overexpression drives the cell cycle of otherwise nontransformed human cells, suggesting oncogenic properties. Lysine-specific demethylase 1 was recently reported to be also overexpressed in several different mesenchymal tumors. We investigated lysine-specific demethylase 1 expression in over 500 sarcomas by gene expression profiling and tissue microarray-coupled immunohistochemical analyses and confirmed lysine-specific demethylase 1 overexpression in rhabdomyosarcoma and synovial sarcoma. We also show for the first time that lysine-specific demethylase 1 is also overexpressed in chondrosarcoma, Ewing's sarcoma, and osteosarcoma wherein it localizes in cell nuclei. We further show that a US Food and Drug Administration–approved drug that inhibits lysine-specific demethylase 1 also inhibits chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma cell growth in vitro. These data suggest that lysine-specific demethylase 1 plays a role in sarcoma pathology and that lysine-specific demethylase 1 inhibition strategies might represent a novel means to inhibiting growth of lysine-specific demethylase 1–overexpressing sarcomas.

Erratum to “Counting myenteric ganglion cells in histologic sections: an empirical approach” [Hum Pathol 2010;41:1097-1108] - Corrected Proof

Maya Swaminathan, Raj P. Kapur — 2012-01-16

In the abovementioned article, the authors have noted that the citation information for reference 39 is incorrect. The correct reference should be: Koletzko S, Jesch I, Faus-Kessler T, et al. Rectal biopsy for diagnosis of intestinal neuronal dysplasia in children: a prospective multicentre study on interobserver variation and clinical outcome. Gut 1999;44:85-861.

Silencing of homeobox B9 is associated with down-regulation of CD56 and extrathyroidal extension of tumor in papillary thyroid carcinoma - Corrected Proof

2012-01-06

Summary: Papillary thyroid carcinoma is the most common type of thyroid malignancy, and CD56, a neural cell adhesion molecule, is typically down-regulated in almost all cases of papillary thyroid carcinoma. Homeobox B9 is a transcription factor, belongs to the products of the homeobox transcription factor gene family, and has been known to regulate transcription of CD56 and to promote tumorigenicity and metastasis in some malignancies. In this study, we investigated the expression and relation of homeobox B9 to reduced expression of CD56 in papillary thyroid carcinomas and also a relationship between their expression and clinicopathologic parameters. Therefore, we performed CD56 and homeobox B9 immunohistochemical staining on 72 papillary thyroid carcinomas and Western blotting on 31 papillary thyroid carcinomas. CD56 protein staining revealed that it was reduced or absent in 65 papillary thyroid carcinomas (90.3%) and was related to silencing of homeobox B9 (77.8%) (P = .003). The loss of homeobox B9 expression was associated with extrathyroidal extension (P = .002), pathologic stage of tumor (P = .01), and age older than 45 years (P = .032). However, the CD56 staining did not reveal any significant relationship with clinicopathologic features (P > .05). In conclusion, reduced expression of CD56 is associated with homeobox B9 in papillary thyroid carcinomas. Furthermore, silencing of homeobox B9 is more common in older age and is linked to extrathyroidal extension and advanced pathologic stage of papillary thyroid carcinoma.

Oral extragonadal yolk sac tumor in a patient with Aicardi syndrome: putative origin and differential diagnosis - Corrected Proof

2012-01-06

Summary: We report, for the first time, a primary oral presentation of a germ cell yolk sac tumor in a 4-year-old girl with Aicardi syndrome. The diagnosis, differential diagnosis, and histogenesis are discussed.

Composite ganglioglioma/dysembryoplastic neuroepithelial tumor: a clinicopathologic study of 8 cases - Corrected Proof

Richard A. Prayson, Karl M. Napekoski — 2012-01-05

Summary: Ganglioglioma and dysembryoplastic neuroepithelial tumor are both low-grade glioneuronal neoplasms that most commonly occur in association with chronic epilepsy. Rare cases of tumors with composite features of ganglioglioma and dysembryoplastic neuroepithelial tumor have been reported. We retrospectively reviewed the clinicopathologic features of 8 composite tumors (7 were female; median age, 20 years). All patients had chronic epilepsy and had tumors in either the temporal or the frontal lobe. Six patients are currently seizure-free (follow-up: median, 90 months). All tumors were multinodular. Some nodules had distinct features of each tumor type (range, 5%-85% of the tumor). Seven tumors contained nodules with mixed features of both tumor types. Five of 7 evaluable tumors demonstrated adjacent focal cortical dysplasia (Palmini type I). Mitotic activity, vascular proliferation, or necrosis was not observed in any of the tumors. Three tumors demonstrated focal meningeal extension. Composite tumors commonly arise in the temporal lobe in young patients with chronic epilepsy; they appear to behave as a World Health Organization grade I neoplasm. Histologically, these multinodular tumors appear to maintain distinct areas with features of each tumor and foci where the 2 patterns are merged. A subset of composite tumors are associated with adjacent focal cortical dysplasia.

Mantle cell lymphoma as a component of composite lymphoma: clinicopathologic parameters and biologic implications - Corrected Proof

2012-01-05

Summary: Composite lymphoma is a rare circumstance in which 2 or more distinct types of lymphoma occur in a single anatomical location. Although composite lymphoma has been increasingly identified with the advent of molecular genetic techniques, this topic has only rarely been a specific focus of the medical scientific literature. In this review, we focus on mantle cell lymphoma occurring as a major pathologic component of composite lymphoma and emphasize the clinicopathologic features of these tumors and associated biologic implications. To date, 26 cases of composite lymphoma including a component of mantle cell lymphoma have been previously published. Issues of clonal relatedness between the individual lymphoma components and emerging biologic implications as well as potential diagnostic pitfalls are evaluated.

Significance of E-cadherin, β-catenin, and vimentin expression as postoperative prognosis indicators in cervical squamous cell carcinoma - Corrected Proof

2012-01-05

Summary: Although early-stage cervical cancer can be treated by surgery, distant metastases can be life threatening. It has been a challenge to identify reliable biomarkers as indicators of metastasis or poor prognosis. We investigated the prognostic impact of vimentin, E-cadherin, and β-catenin expression measured by immunohistochemistry staining in samples from 135 patients with clinical stage I or II cervical squamous cell cancer and in normal cervical tissues from 55 patients who underwent hysterectomy for reasons other than neoplasia. Down-regulation of E-cadherin and β-catenin was positively related to histologic differentiation (P < .001), metastasis (P < .001), and recurrence (P < .001), whereas up-regulation of vimentin was inversely related to histologic differentiation, metastasis, and recurrence (P < .0001, .020, and .000, respectively). In univariate Cox regression analysis, high expression of E-cadherin or β-catenin was a positive prognostic indicator for overall survival (P < .001 and P < .001, respectively), whereas high expression of vimentin was a negative indicator (P < .001). In multivariate Cox regression analysis, high expression of E-cadherin was a positive prognostic indicator for overall survival (P = .002), whereas high expression of vimentin was a negative indicator (P = .034). The expression of E-cadherin and vimentin was associated with survival, and the 2 proteins were independent prognostic factors in univariate and multivariate analyses. The combination of a decrease of E-cadherin and an increase in vimentin might be a valuable survival indictor in cervical squamous cell cancer.

Foamy gland adenocarcinoma of the prostate: incidence, Gleason grade, and early clinical outcome - Corrected Proof

2012-01-05

Summary: Foamy gland carcinoma is a variant of prostatic acinar adenocarcinoma characterized by abundant foamy cytoplasm and often pyknotic nuclei. Limited data exist regarding outcome and the clinicopathologic attributes of this variant. We screened 477 radical prostatectomies for foamy gland carcinoma to determine the incidence, amount, and Gleason grade/score of foamy gland carcinoma within the prostate. Time until prostate-specific antigen biochemical recurrence after radical prostatectomy was compared for both foamy and control/nonfoamy cases. For validation of incidence, Gleason grade, and pathologic stage, a second series of 100 consecutive radical prostatectomies was screened for foamy gland carcinoma. Foamy gland carcinoma was found in 69 (14.5%) of 477 cases. The median Gleason score of the foamy component was 7, which was not significantly different from the Gleason score of the nonfoamy component within those cases or the 408 nonfoamy cases. The most common Gleason score was 7 (44/69). There was no difference between foamy gland and nonfoamy gland cases in recurrence rate (23% versus 22%) or the average time to prostate-specific antigen recurrence (130 versus 151 months). In the second series, foamy gland carcinoma was found in 23% of cases and had a median Gleason score of 7; and the most common Gleason score was 7 (11/23). Foamy gland carcinoma exists in a significant subset of prostatic carcinomas. This variant does not appear to harbor a different prognosis compared with usual acinar adenocarcinoma, but diagnostic recognition of foamy gland carcinoma is important because there is a Gleason grade 4 element in the majority of cases.

Factors associated with residual disease after initial breast-conserving surgery for ductal carcinoma in situ - Corrected Proof

Shi Wei, Christopher P. Kragel, Kui Zhang, Omar Hameed — 2012-01-05

Summary: Breast-conserving surgery with radiation therapy has become a standard treatment option in women with localized ductal carcinoma in situ. Re-excision is common in breast-conserving surgery, partly due to lack of consensus on what might constitute an adequate margin. In this study, we aimed to identify potential predictive factors for presence/absence of residual disease after initial breast-conserving surgery. Of 232 cases with a diagnosis of ductal carcinoma in situ without invasive carcinoma at initial biopsy between 2005 and 2009, 108 patients underwent breast-conserving surgery, of which 46 had re-excisions due to close margins (≤2 mm). The notable features significantly associated with ductal carcinoma in situ residuum (19/46; 41%) on univariate logistic regression analysis included the number of close margins, the percentage of sections with ductal carcinoma in situ, and the number of duct spaces with ductal carcinoma in situ (no. of ductal carcinoma in situ ducts) at close margins. Only the percentage of sections with ductal carcinoma in situ remained a significant factor associated with outcomes on multivariate analysis, whereas the number of ductal carcinoma in situ ducts at close margins held borderline predictive value (P = .054). Furthermore, logistic regression and classification and regression tree analysis using the 10-fold cross validation method revealed optimal predicting accuracy by using the 3 significant factors in univariate analysis. The final decision tree was constructed by using the number of ductal carcinoma in situ ducts at close margins and the percentage of sections with ductal carcinoma in situ. Thus, these 2 factors represent the most powerful predictors for residual disease on re-excision. Optimal discriminatory power for prediction of absence of residual disease was achieved with cutoffs of 18 ductal carcinoma in situ ducts at close margins and 51.3% sections with ductal carcinoma in situ.

Loss of heterozygosity of the PTCH gene in ameloblastoma - Corrected Proof

2012-01-05

Summary: Ameloblastoma is a locally aggressive benign neoplasm derived from odontogenic epithelium, with high recurrence rates. Alterations in the Sonic Hedgehog signaling pathway, including PTCH gene mutations, have been associated with the pathogenesis of some odontogenic tumors. The purpose of the present study was to assess loss of heterozygosity at the PTCH locus in ameloblastoma. Twelve ameloblastomas were included, and loss of heterozygosity was assessed by using 3 microsatellite markers D9S252, D9S127, and D9S287 and 3 single-nucleotide polymorphisms rs112794371, rs111446700, and rs357564, all located at the PTCH gene locus. Furthermore, we investigated GLI1 and GLI2 transcription levels by quantitative reverse transcription polymerase chain reaction in 8 ameloblastomas and, concomitantly, PTCH protein levels by immunohistochemical analysis. Loss of heterozygosity at 9q21.33-9q.31 was detected in 4 (40.0%) of 10 informative cases of ameloblastoma. All 8 analyzed samples expressed GLI1 messenger RNA and 7 cases GLI2 messenger RNA. Interestingly, loss of heterozygosity at the PTCH locus was not correlated with GLI1 or GLI2 transcription levels, nor was there any correlation with PTCH protein expression. In conclusion, our findings suggest that loss of heterozygosity in the PTCH region may be relevant to the pathogenesis of ameloblastoma but may target a different gene than PTCH.

HMGA gene rearrangement is a recurrent somatic alteration in polypoid endometriosis - Corrected Proof

2012-01-05

Summary: The pathogenesis of endometriosis is unclear, and several genetic, endocrine, immune, and environmental agents have been evaluated with no putative causative factors identified. Here, we show somatic genetic alterations involving HMGA1 (6p21) and HMGA2 (12q15) in 3 cases of polypoid endometriosis. The lesions involved the small bowel mesentery and perirectal soft tissue in 1 case and the posterior vaginal fornix and sigmoid colon serosa in 2 other cases, respectively. All had a polypoid configuration with cystically dilated irregular glands and fibrotic stroma, containing thick-walled vessels. Conventional cytogenetic analysis of 1 case showed 46,XX,t(5;12)(q13;q15) in all metaphases. Fluorescence in situ hybridization studies confirmed the balanced rearrangement of HMGA2. HMGA1 rearrangements were present in 2 additional cases. Rearrangements were exclusively found in the stromal component but not in the glandular component. These findings suggest that HMGA rearrangements likely contribute to the pathogenesis of endometriosis. However, additional studies are needed to better define the biologic role of this genetic alteration.

Serotonin expression in pancreatic neuroendocrine tumors correlates with a trabecular histologic pattern and large duct involvement - Corrected Proof

2012-01-05

Summary: Pancreatic neuroendocrine tumors with prominent stromal fibrosis are often clinically, radiographically, and grossly indistinguishable from ductal adenocarcinoma. We recently described a small series of fibrotic pancreatic neuroendocrine tumors that express serotonin. To understand better the relationship between histopathologic patterns and serotonin expression, we reviewed 361 pancreatic neuroendocrine tumors to identify those with prominent stromal fibrosis exceeding 30% of total tumor area. We identified 52 cases and immunolabeled these neoplasms with antibodies to serotonin and Ki-67. Two predominant histologic subtypes were identified: 14 (26.9%) of 52 had a trabecular or trabecular-glandular cellular pattern with interspersed fibrosis, whereas 38 (73.1%) of 52 had solid architecture. Of the 52, 14 (26.9%) pancreatic neuroendocrine tumors showed at least focal serotonin immunoreactivity. Tumors with predominantly trabecular architecture were significantly more likely to express serotonin than those with solid architecture (P < .01). Only 2 of 34 pancreatic neuroendocrine tumors with fibrosis less than 30% of total tumor area expressed serotonin. The 14 serotonin-expressing tumors were less likely to have lymph node metastases (P = .016) and more likely to involve large pancreatic ducts (P < .01) than were the 38 serotonin-negative tumors. The serotonin-expressing tumors were also found in a younger patient population (P < .01). There was no significant association of serotonin immunoreactivity with Ki-67 proliferation index, tumor size, or distant metastases. Our data demonstrate a strong correlation between trabecular architecture and serotonin immunoreactivity in pancreatic neuroendocrine tumors with stromal fibrosis. Serotonin-expressing tumors are also less likely to have lymph node metastases and more likely to involve large pancreatic ducts.

Human epithelial growth factor receptor 2 (HER2) status in primary and metastatic esophagogastric junction adenocarcinomas - Corrected Proof

2012-01-04

Summary: Differences in human epithelial growth factor receptor 2 dysregulation in primary solid tumors and metastases may (at least partially) explain human epithelial growth factor receptor 2–targeted therapeutic inconsistencies. Human epithelial growth factor receptor 2 status was tested in a series of 47 radically treated consecutive esophagogastric junction adenocarcinomas (male/female, 38/9; mean age, 67.9 years) in both primary cancers and paired synchronous nodal metastases. None of the patients received neoadjuvant therapy. For each case, 2 nonadjacent tissue samples from primary esophagogastric junction adenocarcinoma and 2 different metastatic nodes were considered (188 tissue samples in all). Human epithelial growth factor receptor 2 status was assessed by immunohistochemistry (PATHWAY-HER2/neu [4B5]; Ventana Medical Systems, Milan, Italy) and dual chromogenic in situ hybridization (duoCISH; DAKO, Glostrup, Denmark). Immunohistochemistry staining scores were nil in 22 tumors (47%), 1 (21%) in 10, 2 (13%) in 6, and 3 (19%) in 9. Human epithelial growth factor receptor 2 gene amplification (25.5%) was associated with more differentiated phenotype (Fisher exact test, P = .039) and advanced tumor stage (Fisher exact test, P = .015). Significant agreement was observed between human epithelial growth factor receptor 2 protein expression (immunohistochemistry) and human epithelial growth factor receptor 2 gene's amplification (chromogenic in situ hybridization) (κ = 0.84, P < .001). Both immunohistochemistry and chromogenic in situ hybridization documented an excellent intratumor agreement in human epithelial growth factor receptor 2 status (κ = 0.75, P < .001; κ = 0.88, P < .001, respectively). Human epithelial growth factor receptor 2 status was comparable in primary versus metastatic nodal cancers by both immunohistochemistry and chromogenic in situ hybridization (Cohen Φ, both P < .001). In esophagogastric junction adenocarcinomas, human epithelial growth factor receptor 2 status (as assessed by immunohistochemistry and/or chromogenic in situ hybridization) is virtually unaffected by intratumor variability; it is consistent with findings in nodal metastases, and it reliably identifies patients with esophagogastric junction adenocarcinoma eligible for anti–human epithelial growth factor receptor 2 therapy.

Immunohistochemical expression profile of β-catenin, E-cadherin, P-cadherin, laminin-5γ2 chain, and SMAD4 in colorectal serrated adenocarcinoma - Corrected Proof

2012-01-03

Summary: The immunohistochemical expression of cell adhesion molecules in colorectal serrated adenocarcinoma is still unknown. The immunostaining patterns of β-catenin, E-cadherin, P-cadherin, laminin 5γ2, and SMAD4 and their relationship to survival were studied in different tumor areas, namely, tumor center and invasive front, the latter comprising tumor bud and non–tumor bud clusters, as described in a previous study of 66 serrated adenocarcinomas and matched conventional carcinomas. Compared with conventional carcinomas, serrated adenocarcinomas showed significantly reduced nuclear β-catenin, membranous E-cadherin, and nuclear SMAD4 but an increased cytoplasmic expression of laminin-5γ2 at the invasive front that was particularly pronounced in the tumor buds. E-cadherin loss at the invasive front was identified as an independent prognostic factor for a poorer outcome in serrated adenocarcinoma. Serrated adenocarcinoma shows a distinct immunohistochemical profile at the invasive front compared with conventional carcinoma, which may account for its less favorable outcome. The lower frequency of nuclear β-catenin in SAC, especially in right-sided tumors, suggests that molecular mechanisms other than the canonical Wnt/β-catenin pathway may have a role in tumor bud formation.

PIK3CA mutations in endometrial carcinomas in Chinese women: phosphatidylinositol 3′-kinase pathway alterations might be associated with favorable prognosis - Corrected Proof

2012-01-03

Summary: The aim of this study was to determine the clinicopathological impact of PIK3CA mutations and phosphatidylinositol 3′-kinase pathway alterations in endometrial cancers in Chinese women. The PIK3CA mutation status was analyzed by sequencing in 94 tumors. The status of phosphatase and tensin homolog, p-(Ser/Thr)AKT, human epidermal growth factor receptor 2, p53, and estrogen and progesterone receptor was assessed in 102 tumors using immunohistochemistry. Biomarker status was correlated with clinicopathologic variables and with patient survival. We found that 28 mutations occurred in the helical domain encoded by exon 9 of PIK3CA and 16 occurred in the kinase domain (exon 20). Mutations of both exons were more common in low-grade than in high-grade endometrioid carcinomas, and the correlation between exon 9 mutation and lower grade was statistically significant (P = .045). In univariate analysis, phosphatidylinositol 3′-kinase pathway activation (defined as PIK3CA mutation and/or phosphatase and tensin homolog loss) was associated with a favorable prognosis (P = .034) and showed an increased predictive power when combined with expression of p-AKT, the phosphatidylinositol 3′-kinase pathway downstream effector (P = .022). In multivariate analysis, phosphatidylinositol 3′-kinase pathway activation was not an independent predictor of disease-free survival (P = .091). Interestingly, in the estrogen receptor–negative subgroup, the phosphatidylinositol 3′-kinase pathway alteration was significantly related to prolonged patient survival (P = .048), whereas this association was not present in the estrogen receptor–positive subgroup (P > .05). Our findings suggest that phosphatidylinositol 3′-kinase pathway alteration might have a favorable prognostic impact on endometrial cancers in Chinese women. Furthermore, the function of the phosphatidylinositol 3′-kinase pathway might be affected by estrogen receptor status.

Thyroid paraganglioma. Report of 3 cases and description of an immunohistochemical profile useful in the differential diagnosis with medullary thyroid carcinoma, based on complementary DNA array results - Corrected Proof

2012-01-03

Summary: Thyroid paraganglioma is a rare disorder that sometimes poses problems in differential diagnosis with medullary thyroid carcinoma. So far, differential diagnosis is solved with the help of some markers that are frequently expressed in medullary thyroid carcinoma (thyroid transcription factor 1, calcitonin, and carcinoembryonic antigen). However, some of these markers are not absolutely specific of medullary thyroid carcinoma and may be expressed in other tumors. Here we report 3 new cases of thyroid paraganglioma and describe our strategy to design a diagnostic immunohistochemical battery. First, we performed a comparative analysis of the expression profile of head and neck paragangliomas and medullary thyroid carcinoma, obtained after complementary DNA array analysis of 2 series of fresh-frozen samples of paragangliomas and medullary thyroid carcinoma, respectively. Seven biomarkers showing differential expression were selected (nicotinamide adenine dinucleotide dehydrogenase 1 alpha subcomplex, 4-like 2, NDUFA4L2; cytochrome c oxidase subunit IV isoform 2; vesicular monoamine transporter 2; calcitonin gene-related protein/calcitonin; carcinoembryonic antigen; and thyroid transcription factor 1) for immunohistochemical analysis. Two tissue microarrays were constructed from 2 different series of paraffin-embedded samples of paragangliomas and medullary thyroid carcinoma. We provide a classifying rule for differential diagnosis that combines negativity or low staining for calcitonin gene-related protein (histologic score, <10) or calcitonin (histologic score, <50) together with positivity of any of NADH dehydrogenase 1 alpha subcomplex, 4-like 2; cytochrome c oxidase subunit IV isoform 2; or vesicular monoamine transporter 2 to predict paragangliomas, showing a prediction error of 0%. Finally, the immunohistochemical battery was checked in paraffin-embedded blocks from 4 examples of thyroid paraganglioma (1 previously reported case and 3 new cases), showing also a prediction error of 0%. Our results suggest that the comparative expression profile, obtained by complementary DNA arrays, seems to be a good tool to design immunohistochemical batteries used in differential diagnosis.

“Intrafollicular neoplasia” of nodular lymphocyte predominant Hodgkin lymphoma: Description of a hypothetic early step of the disease - Corrected Proof

Antonino Carbone, Annunziata Gloghini — 2012-01-03

Summary: The 2008 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues has addressed the problem of intrafollicular neoplasia/“in situ” lesion for follicular lymphoma. The concept of intrafollicular neoplasia has also been proposed for other lymphomas in which the putative normal counterpart of the tumor cell is located in the germinal center or the mantle zone or the marginal zone of the follicle. However, unlike in situ follicular lymphoma, the precise histologic definition of this early lesion for other lymphomas is still lacking. When applied to nodular lymphocyte predominant Hodgkin lymphoma, another germinal center–derived lymphoma, “intrafollicular neoplasia” may be regarded as a neoplasia at an early stage of development, such as in situ follicular lymphoma. Interestingly, this early lesion can be observed in lymph nodes that otherwise show the most common nodular involvement by nodular lymphocyte predominant Hodgkin lymphoma. The recognition of intrafollicular neoplasia is based on the identification of typical, strongly stained BCL6+, lymphocyte predominant tumor cells located within altered follicles with a recognizable germinal center. Lymphocyte predominant tumor cells, surrounded by rosetting PD1+ T cells, reside in an environment reminiscent of a secondary follicle. Intrafollicular neoplasia in nodular lymphocyte predominant Hodgkin lymphoma is correctly identifiable based on immunohistochemical recognition of the CD23+ meshwork of follicular dendritic cells surrounded by an outer zone containing immunoglobulin D+ B cells. This immunoarchitectural pattern, highlighting the intrafollicular involvement by the neoplasia, is of great utility for diagnosis. An appropriate immunohistochemical characterization for diagnosis should include lymphocyte predominant (BCL6 and CD20) and microenvironmental (CD23, immunoglobulin D, and PD1) cell markers.

Loss of nuclear expression of Krüppel-like factor 4 is associated with poor prognosis in patients with oral cancer - Corrected Proof

2012-01-03

Summary: Krüppel-like factor 4 is not only involved in cell proliferation but also affects cell differentiation and extracellular matrix production via positive and negative regulation of the expression of a wide range of genes. To our knowledge, little information is available regarding the role of Krüppel-like factor 4 in oral squamous cell carcinoma. In this study, we investigated the associations between Krüppel-like factor 4 expression and clinical parameters of oral cancer using immunohistochemical assays in 215 surgical specimens. Compared with positive nuclear Krüppel-like factor 4 expression, we observed that negative nuclear Krüppel-like factor 4 expression was significantly associated with an advanced cancer stage (P = .046), a high tumor recurrence rate (P = .009), and a worse 3-year survival rate in patients with oral cancer (P = .046). Nuclear expression of Krüppel-like factor 4 was shown to have an inverse relationship with Ki67 expression (P = .046). Patients with negative nuclear expression of Krüppel-like factor 4 had significantly worse overall survival rates as defined by the log-rank test (P = .014). Patients with oral cancer with negative nuclear Krüppel-like factor 4 expression in tumor cells had poor prognoses and a 2.5-fold higher death risk. Compared with disease stage (P = .025), negative nuclear Krüppel-like factor 4 expression (P = .006) was an independent prognostic factor. Our results revealed that the loss of nuclear expression of Krüppel-like factor 4 is significantly associated with aggressive clinical manifestations and might be an adverse survival factor.

On being a pathologist: a brief chronicle of an academic surgical pathologist - Corrected Proof

Jorge Albores-Saavedra — 2012-01-03

I was born in a small rural town of approximately 400 people named La Concordia (The Concord) in Chiapas, a southeastern state of Mexico. My father jokingly used to tell me that a better name for the town would be La Discordia (The Discord) because of trivial matters that the inhabitants often argued and fought over, perhaps because they had few things to keep busy. At that time, La Concordia did not have electricity, potable water, sewage, or medical services. Every year, a medical student in the final year of medical school came to do social service, a requirement for graduation. When I was finishing high school, during my winter vacation, I met Francisco Garcia Gonzales, a senior medical student who was doing his 1-year social service in La Concordia. He was a charismatic highly cultivated young medical student who provided excellent basic medical services and, as a result, gained the respect of the community. He was a firm believer in preventive medicine and vaccinated all children and most adults against small pox. We became friends, and soon I was also his admirer. He influenced me so much that, at that early age, I decided I wanted to be a doctor like him.

High density of tryptase-positive mast cells in patients with renal cell carcinoma on hemodialysis: correlation with expression of stem cell factor and protease activated receptor-2 - Corrected Proof

2011-12-28

Summary: Patients on hemodialysis are at higher risk of renal cell carcinoma probably because of inflammatory and immune system disorders. The aim of this study was to clarify the pathologic roles of 2 phenotypes of mast cells, mast cell tryptase and mast cell chymase, and their correlation with stem cell factor and protease-activated receptor 2 in patients with renal cell carcinoma on hemodialysis. The densities of mast cell tryptase and mast cell chymase and expressions of stem cell factor and protease-activated receptor 2 were examined in 35 patients with hemodialysis-renal cell carcinoma and 39 with non–hemodialysis-renal cell carcinoma who were diagnosed and treated in our hospital. Protein expression was examined by immunohistochemistry. The proliferation index represented the number of Ki-67–positive cells. There were no significant differences in clinicopathologic features between the 2 groups. Mast cell tryptase densities in intratumoral (8.3 per high-power field) and peritumoral areas (8.7 per high-power field) were higher in hemodialysis-renal cell carcinoma than non–hemodialysis-renal cell carcinoma (2.7 and 5.3 per high-power field). No such significant correlations were detected in mast cell chymase. In hemodialysis-renal cell carcinoma, intratumoral mast cell tryptase density correlated with the proliferation index (P = .039 and P = .008, respectively) and also with stem cell factor and protease-activated receptor 2 expression. Our results emphasize the important roles of mast cell tryptase in cancer cell proliferation and recurrence in hemodialysis-renal cell carcinoma. Stem cell factor and protease-activated receptor 2 seem to up-regulate mast cell tryptase functions in these patients. The results suggest collaborative effects of stem cell factor, mast cell tryptase, and protease-activated receptor 2 on the malignant potential of hemodialysis-renal cell carcinoma.

Assessment of the prognostic significance of endoglin (CD105) in clear cell renal cell carcinoma using automated image analysis - Corrected Proof

2011-12-28

Summary: The behavior of clear cell renal cell carcinoma can be difficult to predict. Angiogenesis has proven to be a useful prognostic indicator in different malignancies. Endoglin (CD105) is a new marker of angiogenesis found to have prognostic utility in various tumors. Here, we provide the first automated digital assessment of intratumoral microvascular density in clear cell renal cell carcinoma using endoglin and CD31 and assess their utility as predictors of clinical outcome. Both endoglin and CD31 expression showed association with advanced tumor stage (P = .025 and P = .011, respectively). There was a significant correlation between CD31 and tumor grade (P = .034). Kaplan-Meier survival curves showed that patients with higher endoglin expression had significantly shorter progression-free survival (P = .010). Patients with higher CD31 expression tended to have a worse prognosis, although this was not statistically significant (P = .082). In univariate analysis using endoglin as a continuous variable, increased endoglin was strongly associated with reduced survival (hazard ratio, 1.74; 95% CI, 1.39-2.18; P = <.001). CD31 also correlated with poor outcomes (hazard ratio, 1.52; 95% CI, 1.24-1.86; P = .001). There was no correlation between CD31 and endoglin expression (r = −0.090, P = .541). Receiver operating characteristic analysis showed the area under the curve to be 0.749 for endoglin and 0.550 for CD31. In conclusion, increased endoglin and CD31 expression are associated with a higher tumor stage and decreased progression-free survival. Our automated approach overcomes many limitations of manual quantification. Advances in digital assessment of immunohistochemical markers can be helpful in standardizing the evaluation of tumor biomarkers.

The Wnt/β-catenin pathway drives increased cyclin D1 levels in lymph node metastasis in papillary thyroid cancer - Corrected Proof

2011-12-28

Summary: We examined the expression of cyclin D1 in conjunction with β-catenin and the phosphorylated inactive form of glycogen synthase kinase 3β (GSK-3β) in benign, nonneoplastic thyroid tissue as well as papillary thyroid carcinoma primary tumors and nodal metastases. We aim to unravel the regulation of cyclin D1 and determine if this cell cycle protein is a useful biomarker for metastatic disease. It is clear that expression of cyclin D1 (P < .0001), β-catenin (P < .0001), and inactive form of GSK-3β (P < .0001) are significantly higher in papillary thyroid carcinoma primary tumors than in corresponding benign, nonneoplastic tissue thyroid specimens. Interestingly, β-catenin and cyclin D1 expressions in papillary thyroid carcinoma are correlated (P = .025), implying that β-catenin is a factor driving higher levels of cyclin D1 consistent with previous cell models linking Wnt/β-catenin signaling and cyclin D1 expression. Conversely, inactive form of GSK-3β expression does not correlate with cyclin D1 (P = .52) or β-catenin expression (P = .54). We also did not observe any relationship between tumor size and marker expression. Comparing papillary thyroid carcinoma primary tumors with or without nodal metastases, we did not see any differences in expression of inactive form of GSK-3β (P = .95), β-catenin (P = .14), or cyclin D1 (P = .46). However, in papillary thyroid carcinoma lymph node specimens, the up-regulation of cyclin D1 (P = .0083) was highly significant compared with primary tumors. pGSK-3β and β-catenin expression did not vary between primary tumors and nodal specimens. In conclusion, we have demonstrated that expression of cyclin D1 is linked to nodal metastases and that cyclin D1 levels are regulated by Wnt/β-catenin signaling. GSK pathway–mediated regulation of β-catenin or cyclin D1 expression does not appear operative in papillary thyroid carcinoma.

Extracutaneous Merkel cell carcinomas harbor polyomavirus DNA - Corrected Proof

Dario de Biase, Moira Ragazzi, Sofia Asioli, Vincenzo Eusebi — 2011-12-28

Summary: Merkel cell carcinoma is a neuroendocrine tumor, with characteristic morphological and immunohistochemical features. Originally reported as primary carcinoma of skin, it has been described in numerous other sites such as lymph nodes, oral cavity, breast, vaginal walls, and salivary glands. Recent studies have revealed in cutaneous Merkel cell carcinomas a clonally integrated polyomavirus, named Merkel cell polyomavirus. The aim of the present study was to verify the presence of Merkel cell polyomavirus in 5 cases of primary Merkel cell carcinomas of lymph nodes and 1 case of parotid gland to investigate similarities or differences among Merkel cell carcinomas from various sites. Cases studied were 5 primary Merkel cell carcinomas in lymph nodes, 1 in the parotid gland, and 12 in the skin. Twelve cases of primary and metastatic small cell carcinoma of the lung were also investigated. Immunohistochemistry for keratin 20, chromogranin, synaptophysin, and thyroid transcription factor 1 was performed in all cases. Viral DNA was studied using polymerase chain reaction assay and the products evaluated in agarose gel and sequenced. Cytokeratin 20 and Merkel cell polyomavirus were detected in all cases of primary Merkel cell carcinoma irrespective of their site of origin. On the contrary, all cases of pulmonary small cell carcinoma were negative for both Merkel cell polyomavirus and cytokeratin 20. It appears that cutaneous and extracutaneous Merkel cell carcinomas share similar histologic, immunohistochemical, and molecular features. This is further evidence that Merkel cell carcinomas are a multiorgan carcinoma and that Merkel cell polyomavirus might play a role in the pathogenesis of this neoplasm.

Cytogenetic and molecular genetic study on glioblastoma arising in granular cell astrocytoma: a case report - Corrected Proof

2011-12-28

Summary: Granular cell astrocytoma is a rare infiltrative malignant glioma with prominent granular cell change. Granular cell astrocytomas are biologically aggressive compared with conventional infiltrating astrocytomas of similar grades, but their genetic alterations are poorly known. We report a case of glioblastoma arising in granular cell astrocytoma and its genetic and molecular features. Histologically, the tumor not only showed features typical of granular cell astrocytoma but also demonstrated frequent mitoses, pseudopalisading necrosis, and vascular endothelial hyperplasia, compatible with glioblastoma. Array-based comparative genomic hybridization and focused molecular genetic analyses demonstrated gain of chromosome 7; losses of chromosome 1p, 8p, 9p, 10, 13q, and 22q; amplification of epidermal growth factor receptor (EGFR); and homozygous deletion of CDKN2A as well as isocitrate dehydrogenase 1 (IDH1) mutation and MGMT promoter methylation. Our results indicate that glioblastomas arising in granular cell astrocytoma share common molecular genetic features with conventional glioblastoma; however, the coexistence of EGFR amplification, homozygous deletion of CDKN2A, loss of chromosome 10, and IDH1 mutation seems to be unique.

Overexpression of astrocyte-elevated gene-1 is closely correlated with poor prognosis in human non–small cell lung cancer and mediates its metastasis through up-regulation of matrix metalloproteinase-9 expression - Corrected Proof

2011-12-28

Summary: Expression of astrocyte-elevated gene-1, a novel oncoprotein, is elevated in multiple cancers and plays a vital role in tumor cell growth, invasion, angiogenesis, and progression to metastasis. However, the functional significance of astrocyte-elevated gene-1 in non–small cell lung cancer still remains unclear. Our present study showed that the markedly up-regulated expression of astrocyte-elevated gene-1 was observed in non–small cell lung cancer cell lines and tissues at the level of both transcription and translation. Simultaneously, ectopic expression or small interfering RNA silencing of astrocyte-elevated gene-1 markedly enhanced or inhibited the invasive ability of non–small cell lung cancer cells, respectively. At the molecular level, we also revealed that the function of astrocyte-elevated gene-1 in promoting metastasis was associated with the activation of matrix metalloproteinase-9 expression. Consistent with these observations, immunostaining analysis revealed a significant positive correlation between astrocyte-elevated gene-1 and matrix metalloproteinase-9. Moreover, subcutaneous xenografts of non–small cell lung cancer cells engineered to express astrocyte-elevated gene-1 were highly invasive compared with the parental cells and expressed a high level of matrix metalloproteinase-9. In archival non–small cell lung cancer specimens, high astrocyte-elevated gene-1 expression correlated significantly with clinical staging (P = .048), differentiation (P = .023), and lymph node metastasis (P = .032). The overall survival time in patients with high astrocyte-elevated gene-1 expression was notably shorter than that in patients with low astrocyte-elevated gene-1 expression (P < .001). Taken together, our results indicate that astrocyte-elevated gene-1 plays a crucial role in the carcinogenesis and aggressiveness of non–small cell lung cancer, promoting its metastasis by modulating matrix metalloproteinase-9 expression and leading to a poor clinical prognosis.

Utilization of fluorescence in situ hybridization with cytokeratin discriminators in TOP2A assessment of chemotherapy-treated patients with breast cancer - Corrected Proof

2011-12-28

Summary: Tumor biomarkers increasingly provide information for predicting outcomes with chemotherapeutic regimens (personalized medicine). Topo2A is a DNA helicase targeted by anthracyclines, cytotoxic therapeutics used in both adjuvant and palliative treatments of breast cancer. TOP2A gene amplification/deletion is implicated in response to anthracycline-based chemotherapy. We describe an approach for analyzing formalin-fixed, paraffin-embedded breast tumors on tissue microarrays with TOP2A fluorescence in situ hybridization coupled with cytokeratin immunofluorescence to target tumor cells. Stained tissue from patient specimens was imaged and analyzed using Metafer/Metacyte (Metasystems, Waltham, MA, USA), including customized image classifiers. TOP2A/CEN17 ratios of 2.0 or greater (amplified) and 0.8 or less (deleted) were observed for 10.0% and 6.1% of the patients, respectively. Patient outcomes for adjuvant chemotherapy (cyclophosphamide-epirubicin-fluorouracil, cyclophosphamide-methotrexate-fluorouracil, no chemotherapy) were evaluated. No statistical significance was achieved for clinical end points regarding TOP2A status in anthracycline-treated patients. However, patients with TOP2A aberrations receiving methotrexate-based therapy exhibited a significant decrease in 5-year distant disease-free survival and breast cancer–specific overall survival, especially for patients with TOP2A deletions (disease-free survival: hazard ratio, 5.31 [P = .001], and breast cancer–specific overall survival: hazard ratio, 6.45 [P ≤ .001]). No significant differences were seen in patients included in the no-chemotherapy group. Topo2A protein levels were assessed by immunohistochemistry with no correlative statistical relevance to immunofluorescence/fluorescence in situ hybridization–based prognosis for cyclophosphamide-epirubicin-fluorouracil or cyclophosphamide-methotrexate-fluorouracil groups. Interestingly, aberrant (under)expressing patients in the no-chemotherapy group exhibited better 5-year distant disease-free survival (hazard ratio, 0.39; P = .004), trending toward more favorable breast cancer–specific overall survival (hazard ratio, 0.61; P = .11). Our results indicate a strategy by which fluorescence in situ hybridization scoring targeted to cytokeratin-positive tumor cells may provide a tool for added precision and efficiency in TOP2A evaluation from tumor tissue.

Morphology and prognostic value of tumor budding in rectal cancer after neoadjuvant radiotherapy - Corrected Proof

Changzheng Du, Weicheng Xue, Jiyou Li, Yong Cai, Jin Gu — 2011-12-28

Summary: Tumor budding is an acknowledged prognostic marker in colorectal cancer. This study was conducted to investigate the morphology and prognostic significance of budding in rectal cancer after neoadjuvant radiotherapy. Surgical specimens from 96 consecutive patients who underwent neoadjuvant radiotherapy and curative resection were retrieved to assess budding and other clinicopathologic factors. The morphology and prognostic significance of postirradiation tumor budding were closely associated with tumor regression grade. In the tumor regression grade 1 group, tumor budding presented as “false budding” and did not have a significant association with prognosis. In the tumor regression grade 2 and 3 groups, budding was observed surrounded by radiation-induced fibrosis and large populations of infiltrating inflammatory cells, and budding intensity was significantly associated with histologic differentiation, ypN stage, and lymphovascular invasion (P < .05). Moreover, the low-grade budding subgroup showed a significantly higher rate of 5-year disease-free survival than the high-grade budding subgroup (87.5% versus 55.6%, P < .0001). Multivariate analysis showed that pretreatment serum carcinoembyronic antigen, tumor regression grade, and tumor budding were the major independent factors affecting long-term disease-free survival. In conclusion, postirradiation budding has distinct morphology and prognostic significance in rectal cancer after neoadjuvant radiotherapy.

Reduced nuclear and ectopic cytoplasmic expression of lysyl oxidase–like 2 is associated with lymph node metastasis and poor prognosis in esophageal squamous cell carcinoma - Corrected Proof

2011-12-28

Summary: Lysyl oxidase family members have various roles in cancer progression. The aim of this study was to investigate their expression and clinical significance in esophageal squamous cell carcinoma. We examined messenger RNA expression of lysyl oxidase family members including lysyl oxidase and lysyl oxidase–like proteins (lysyl oxidase L) in 10 esophageal squamous cell carcinoma cell lines and 83 pairs of tumor samples by quantitative real-time polymerase chain reaction. All except lysyl oxidase L3 were expressed at high levels in esophageal squamous cell carcinoma, but only lysyl oxidase L2 was associated with lymph node metastasis (P = .034). We examined lysyl oxidase L2 protein further by immunohistochemistry staining in 178 surgically resected esophageal squamous cell carcinoma tissue samples. The protein manifested decreased nuclear expression and increased cytoplasmic expression. Moreover, these 2 events both had significant correlation with the presence of lymph node metastasis (P = .001 and P < .001). Overall survival rates of the patients with esophageal squamous cell carcinoma with decreased nuclear expression or increased cytoplasmic expression of lysyl oxidase L2 were significantly lower than those of the patients with esophageal squamous cell carcinoma with the reverse expression pattern (P = .040 or P = .022). Multivariate analyses revealed that nuclear expression of lysyl oxidase L2 was an independent prognostic factor for esophageal squamous cell carcinoma. These results suggest that lysyl oxidase L2 exerts a critical effect on esophageal squamous cell carcinoma progression and can be a predictive marker of lymph node metastasis and outcome.

Clinicopathologic significance and function of S-phase kinase-associated protein 2 overexpression in hepatocellular carcinoma - Corrected Proof

2011-12-28

Summary: The F-box protein S-phase kinase-associated protein 2 is frequently overexpressed in human cancers. Herein, we aimed to investigate the expression pattern, clinical significance, and biological function of S-phase kinase-associated protein 2 in hepatocellular carcinoma. Analysis by reverse transcriptase polymerase chain reaction, Western blot, and immunohistochemistry revealed that S-phase kinase-associated protein 2 was aberrantly overexpressed in hepatocellular carcinomas relative to adjacent nontumor liver tissues. This overexpression was significantly associated with advanced tumor stage, increased histologic grade, vascular invasion, and intrahepatic metastasis, as well as worse overall survival and higher early recurrence rate. Knockdown of the endogenous S-phase kinase-associated protein 2 expression in 1 hepatocellular carcinoma cell line, Huh7, by RNA interference reduced cell proliferation, blocked the cell cycle at G1 phase, and increased apoptosis. S-phase kinase-associated protein 2 silencing resulted in a deregulation of multiple cell-cycle regulatory proteins in Huh7 cells, as detected by quantitative real-time polymerase chain reaction arrays. Furthermore, high S-phase kinase-associated protein 2 immunoreactivity was found to be significantly correlated with reduced expression of P27, P21, and cell-cycle checkpoint kinase 2, as well as with increased expression of transcription factors Dp-1, cyclin D2, and cyclin D1 in hepatocellular carcinoma tissues. These data demonstrate that S-phase kinase-associated protein 2 expression is closely linked to tumor progression and represents an independent predictor of poor prognosis in hepatocellular carcinoma. S-phase kinase-associated protein 2 is involved in hepatocellular carcinoma cell proliferation through regulating numerous genes involved in cell-cycle progression, thereby providing a potential therapeutic target for this malignancy.

Expression of therapeutic targets in Ewing sarcoma family tumors - Corrected Proof

Atif A. Ahmed, Ashley K. Sherman, Bruce R. Pawel — 2011-12-23

Summary: Ewing sarcoma family tumor is an aggressive malignant tumor of bone and soft tissue in children and adolescents. Despite advances in modern therapy, metastasis occurs in 20% to 25% of cases and results in mortality in 80% of patients. Intracellular molecules mammalian target of rapamycin, Akt, vascular endothelial growth factor, nuclear factor κB, and BRAF are important kinases and transcription factors that regulate the proliferation of tumor cells. We studied the expression of these proteins in 72 Ewing sarcoma family tumors. Patients' survival data were available in 55 cases. Formalin-fixed, paraffin-embedded tumor sections were stained with antibodies against phosphorylated mammalian target of rapamycin, Akt, BRAF, vascular endothelial growth factor, and nuclear factor κB proteins. Stained sections were analyzed for percentage and strength of staining, and a composite score (0-200) was subsequently generated. Although most tumors expressed mammalian target of rapamycin, Akt, nuclear factor κB, and vascular endothelial growth factor, only 37%, 86%, 55%, and 12%, respectively, showed high expression (staining score ≥100). There was no significant correlation between mammalian target of rapamycin and Akt expression and clinical outcome. High nuclear factor κB expression was significantly associated with tumors in pelvic locations. Decreased vascular endothelial growth factor expression (score <100) was significantly associated with better prognosis (P < .05). BRAF was not expressed in most cases and showed negative or weak staining (score <100) in 97% of cases. Thus, except for BRAF, Ewing sarcoma family tumors may be amenable to treatment that targets the expressed proteins. High Akt expression suggests potential universal response to Akt-targeted therapy. BRAF kinase inhibitors are unlikely to be effective in the treatment of Ewing sarcoma family tumors.

NEMO expression in human hepatocellular carcinoma and its association with clinical outcome - Corrected Proof

2011-12-16

Summary: The nuclear factor κ-light-chain enhancer of activated B-cells (NF-κB) signaling pathway is regarded as an important factor in inflammation and carcinogenesis. Recently, a role in hepatocarcinogenesis has been attributed to the NF-κB regulatory subunit IKKγ (NEMO) using knockout mice. However, a detailed investigation of NEMO expression in human hepatocellular carcinomas (HCCs) has not yet been reported. We selected 85 HCC patients who had undergone curative liver resection and analyzed NEMO expression of the respective tumors by immunohistochemistry, Western blotting, and real-time PCR. NEMO expression was correlated with clinicopathological parameters, and the impact on 5-year disease-free survival and 5-year overall survival was calculated using multivariate Cox proportional models. In our study, complete loss of NEMO immunoreactivity was found in 34 (40%) of 85 HCCs compared with their adjacent nonneoplastic tissue (P < .05). NEMO messenger RNA (mRNA) expression was detected in all HCC cases; however, no correlation between NEMO immunoreactivity and mRNA level was found. Five-year overall survival rates for patients with low and high NEMO expression were 22% and 50%, respectively (P = .049). However, high tumor stage, but not level of NEMO expression, was confirmed as an independent poor prognostic factor for 5-year disease-free survival (hazards ratio [HR] = 2.1, 95% confidence interval [CI] = 1.3-3.6, P = .009) and 5-year overall survival (HR = 2.5, CI = 1.4-4.4, P = .002). In conclusion, a loss of NEMO immunoreactivity occurs in a substantial proportion of human HCCs. Although low NEMO expression is correlated with a poor 5-year overall survival in patients with HCC, NEMO cannot be regarded as an independent prognostic marker for predicting the clinical outcome of patients suffering from HCC.

Unusual thyroid carcinoma with excessive extracellular hyaline globules: a case of “hyalinizing papillary carcinoma” - Corrected Proof

2011-12-16

Summary: We present an unusual case of papillary thyroid carcinoma in a 47-year-old Japanese woman. The tumor, 0.8 cm in diameter, was located in the upper left lobe of the thyroid. Histologically, we observed a microfollicular-like and trabecular arrangement of the tumor cells with marked hyalinized stroma and hyaline globules. Immunohistochemically, tumor cells were positive for thyroglobulin and thyroid transcription factor 1. Hyaline stroma and globular bodies were immunopositive for laminin and type IV collagen. MIB-1 index was approximately 1% without membranous immunoreactivity. Under the electron microscope, hyaline stroma and globules showed electron-dense, complex meshwork structures composed of granular and fibrous elements similar to the structure of the lamina densa. Genetic analysis demonstrated a BRAFV600E mutation. Based on these findings, we diagnosed the present tumor as a rare morphological variation of papillary thyroid carcinoma with excessive hyaline globules consisting of basal membrane materials.

Expression of CXCR4 indicates poor prognosis in patients with clear cell carcinoma of the ovary - Corrected Proof

2011-12-14

Summary: Recent reports have shown that CXCR4 is expressed in various solid tumors and is involved in tumor development and metastasis. We examined the distribution and expression of this molecule in clear cell carcinoma of the ovary to elucidate its clinical significance. Paraffin sections from clear cell carcinoma of the ovary tissues (n = 42) were immunostained with CXCR4 antibody, and the staining intensities were evaluated. The clinicopathologic factors examined were age, FIGO (International Federation of Gynecology and Obstetrics) staging, preoperative value of cancer antigen 125 test, and residual tumor after cytoreductive surgery. Overall survival and progression-free survival were evaluated using the Kaplan-Meier method, and multivariate analysis was completed using Cox proportional hazards analysis. Of the 42 carcinomas, lower level CXCR4 immunoexpression was observed in 21 cases (50.0%) (CXCR4low group); and higher level immunoexpression, in 21 cases (50.0%) (CXCR4high group). Five-year overall survival was significantly poorer in the CXCR4high group than in the CXCR4low group (overall survival, CXCR4low group [90.2%], CXCR4high group [50.3%]; P = .0002). In addition, CXCR4high immunoexpression significantly predicted a poorer progression-free survival when compared with lower expression (5-year progression-free survival, CXCR4low group [90.5%], CXCR4high group [36.2%]; P < .0001). Furthermore, multivariate analyses including the age, preoperative cancer antigen 125 test value, FIGO stage, and CXCR4 expressions revealed that CXCR4high expression was an independent prognostic factor for poorer overall survival and progression-free survival of patients with clear cell carcinoma of the ovary (overall survival, P = .0011; progression-free survival, P = .0008, respectively). Our current study suggested that the assessment of CXCR4 immunoreactivity may be a useful prognostic indicator and that CXCR4 may play a critical role in the progression of clear cell carcinoma of the ovary.

Distribution and characterization of subtypes of penile intraepithelial neoplasia and their association with invasive carcinomas: a pathological study of 139 lesions in 121 patients - Corrected Proof

2011-12-14

Summary: We are presenting the morphological features of 121 cases of atypical penile intraepithelial lesions. The term penile intraepithelial neoplasia (PeIN) was used to encompass all of them, and lesions were classified into 2 major groups, differentiated and undifferentiated. The latter was further divided in warty, basaloid, and warty-basaloid subtypes. Ninety-five cases were associated with invasive squamous cell carcinomas. Differentiated lesions predominated (68%), followed by warty-basaloid (14%), basaloid (11%), and warty (7%) subtypes. Multifocality was found in 15% of the cases. Differentiated lesions were preferentially located in foreskin, whereas warty and/or basaloid subtypes were more prevalent in the glans. The former lesions were preferentially seen in association with keratinizing variants of squamous carcinoma, whereas the latter subtypes were found mostly in conjunction with invasive warty, basaloid, and warty-basaloid carcinomas. Lichen sclerosus was present in 51% of cases of differentiated lesions and absent in warty and/or basaloid subtypes. In summary, PeIN can be classified into 4 distinctive morphological subtypes. The proper pathological characterization of these lesions may provide important clues to the understanding of the pathogenesis and natural history of penile cancer.

Progression of morphological changes after transplantation of a liver with heterozygous α-1 antitrypsin deficiency - Corrected Proof

Sun-Mi Lee, K. Vincent Speeg, Marilyn S. Pollack, Francis E. Sharkey — 2011-12-12

Summary: Inadvertent transplantation of an α-1 antitrypsin–deficient liver into an adult man provided a unique opportunity to follow the natural history of morphological changes in serial liver biopsies. After doing well initially, the patient developed liver function test abnormalities 6 years posttransplant, but biopsies at that time and 2 years later revealed only chronic hepatitis with no specific features. It was only upon repeat biopsy 10 years posttransplant that characteristic cytoplasmic inclusions appeared. Genotypic and phenotypic testing of pretransplant and posttransplant specimens confirmed α-1 antitrypsin deficiency in the transplanted liver. Serologic tests for viral hepatitis and autoimmune disease were negative throughout the pretransplant and posttransplant period. The case suggests that patients with chronic hepatitis of unknown etiology should be tested for the possibility of α-1 antitrypsin deficiency and illustrates the prolonged course that may precede the development of typical cytoplasmic inclusions in the liver.

Evaluation of the detection of melanin by the Fontana-Masson silver stain in tissue with a wide range of organisms including Cryptococcus - Corrected Proof

2011-12-12

Summary: It is not uncommon for surgical pathologists to encounter yeast and yeast-like organisms in tissue sections, and correct identification is imperative for guiding therapy. The Fontana-Masson silver stain for detecting melanin has been accepted as a relatively specific stain for diagnosing cryptococcosis in tissue based on few studies with limited numbers of organisms. This study was designed to test the value of the Fontana-Masson silver by investigating a large collection of tissues with infections that may mimic cryptococcosis. Cases of cryptococcosis and other infections that can morphologically mimic it were identified in the pathology archives of The Johns Hopkins Hospital and The Armed Forces Institute of Pathology. Overall, Fontana-Masson silver was positive in 25 (56%) of 45 cases, including infections caused by Cryptococcus neoformans (9/9), Coccidioides immitis (7/7), Blastomyces dermatitidis (4/10), Paracoccidioides brasiliensis (2/2), Lacazia loboi (1/1), and Rhinosporidium seeberi (1/1). The percentage of organisms staining varied widely, from less than 1% to 100%. Fontana-Masson silver was negative in all infections caused by Histoplasma capsulatum (n = 10), Histoplasma duboisii (n = 1), Sporothrix schenckii (n = 1), and the alga genus Prototheca (n = 2). Fontana-Masson silver was 100% sensitive for cryptococcosis. The specificity was low, however, with 5 of 9 noncryptococcal species being positive in some cases. These results need to be confirmed and extended to other isolates and species but it is clear that many organisms in the morphological differential diagnosis of cryptococcosis can be Fontana-Masson silver stain positive. Accordingly, results of the Fontana-Masson silver stain, especially a positive, should be interpreted cautiously and only in the context of the organism's morphological features and host factors.

MAPK7 and MAP2K4 as prognostic markers in osteosarcoma - Corrected Proof

2011-12-12

Summary: Osteosarcoma is a class of cancer originating from the bone, affecting mainly children and young adults. Cytogenetic studies showed the presence of rearrangements and recurrent gains in specific chromosomal regions, indicating the possible involvement of genes located in these regions during the pathogenesis of osteosarcoma. These studies investigated expression of 10 genes located in the chromosomal region involved in abnormalities in osteosarcoma, 1p36, 17p, and chromosome 19. The purpose of this study was to investigate the expression profile of genes located in regions involved in chromosomal rearrangements in osteosarcoma. We used quantitative real-time polymerase chain reaction to investigate the expression of 10 genes located in 1p36.3 (MTHFR, ERRFI1, FGR, E2F2), 17p (MAPK7, MAP2K4), and chromosome 19 (BBC3, FOSB, JUND, and RRAS), in 70 samples taken from 30 patients (30 prechemotherapy, 30 postchemotherapy, and 10 metastases specimens) and 10 healthy bones as a control sample. The most interesting results showed a strong association between the expression levels of MAPK7 and MAP2K4 genes and clinical parameters of osteosarcoma. Overexpression of these genes was significantly associated to a poor response to treatment (P = .0001 and P = .0049, respectively), tumor progression, and worse overall survival (P = .0052 and P = .0085, respectively), suggesting that MAPK7 and MAP2K4 could play an important role in osteosarcoma tumorigenesis. Thus, these genes could be good markers in assessing response to treatment and development of osteosarcoma.

c-kit gene mutation and CD117 expression in human anorectal melanomas - Corrected Proof

2011-12-12

Summary: c-kit and BRAF mutations play an important role during the pathogenesis of melanoma. The subtypes of melanomas arising from different parts of the body have variable c-kit or BRAF mutation frequencies. Few studies in the literature have examined c-kit and BRAF mutation status in melanomas that occur in the anus and rectum. In this study, we analyzed 40 cases of anorectal melanoma for c-kit and BRAF mutations by DNA sequencing using paraffin-embedded tissues. c-kit Mutations were detected in exons 9, 11, 13, and 17. CD117 expression in tumor cells was analyzed by immunohistochemistry. Our study showed that a c-kit mutation was found in 7 of the 40 cases of anorectal melanoma. CD117 expression was detected in 16 of the 40 cases, and 3 of these 16 cases also had c-kit mutations. Mutations in BRAF were also identified in 2 patients. These results indicate that a subset of anorectal melanomas have activating c-kit mutations, which suggests that kinase inhibitors such as imatinib may be used to treat this subset of melanoma patients. In addition, our results show that c-kit mutations do not correlate with CD117 expression.

EGFR, HER2, survivin, and loss of pSTAT3 characterize high-grade malignancy in salivary gland cancer with impact on prognosis - Corrected Proof

2011-12-12

Summary: Increased gene copy number (high polysomy or amplification) of EGFR and HER2 has evolved as a predictor for response to targeted therapy. STAT3 and the apoptosis inhibitor survivin represent distinct oncogenes in various human neoplasms. The purpose of this study was to evaluate protein and gene status of these biomarkers by immunohistochemistry and dual color fluorescence in situ hybridization on tissue microarrays of 286 salivary gland carcinomas in the context of clinical and histopathologic characteristics. Diverse tumor types showed overexpression and increased gene copy number of EGFR and HER2. Amplification of HER2 was found in 35.5% of salivary duct carcinomas. Protein overexpression was strongly associated with high gene copy number for both EGFR and HER2 (P < .001). Overexpression and increased gene copy number of EGFR and HER2 were correlated to high-grade malignancy (P < .001) and unfavorable prognosis (P < .001). Strong nuclear staining of survivin was found in 18.9% of tumors and was associated with high-grade malignancy (P < .001), overexpression, and high gene copy number of EGFR and HER2 (P ≤ .05) as well as unfavorable prognosis (P < .001). Overexpression of nuclear pSTAT3 was found in 28.3% of tumors and correlated with well tumor differentiation (P < .001) and favorable prognosis (P = .001). Loss or weak expression of pSTAT3 was inversely associated with overexpression of survivin (P < .001) as well as overexpression and high gene copy number of EGFR and HER2 (P < .05). Overall, overexpression and increased gene copy number of EGFR and HER2 characterize high-grade malignancy with unfavorable prognosis in salivary gland cancer. Nuclear survivin typifies aggressive tumors with worse prognosis, whereas nuclear pSTAT3 might play a role as a tumor suppressor in absence of EGFR, HER2, and survivin.

Androgen receptor expression is usually maintained in initial surgically resected breast cancer metastases but is often lost in end-stage metastases found at autopsy - Corrected Proof

2011-12-12

Summary: Androgen receptor (AR) is expressed in approximately 70% of primary breast carcinomas (PBCs) and is a promising therapeutic target for metastatic breast carcinoma (MBC). Here, we examine AR expression in a population of initial surgically resected metastases and a separate cohort of end-stage metastases harvested at autopsy compared with their matched PBCs. Tissue microarrays of matched PBC and MBC were labeled by immunohistochemistry for AR, estrogen receptor (ER), progesterone receptor (PR), and Her2 and classified into the following previously described categories: luminal (ER/PR+/Her2−), triple negative (ER/PR/Her2−), Her2 (ER/PR−/Her2+), and luminal loss (ER/PR loss from primary to metastasis). In the cohort of surgically resected metastases (n = 16), AR was expressed in 12 of 16 PBC and maintained in 11 of 12 corresponding MBCs. Of these, 36% showed stronger AR labeling in the metastases and none showed a decrease. In the cohort of metastases harvested at autopsy (n = 16), AR was expressed in 11 of 16 primary carcinomas and maintained in only 5 of 11 corresponding metastases. Of these, none showed increased AR and 80% showed decreased AR labeling. AR expression is overwhelmingly concordant between matched PBC and MBC at initial presentation. These findings validate AR as a therapeutic target in MBC and suggest that AR may need to be reevaluated in metastases even if the primary is negative. However, similar to ER/PR, AR expression is often decreased with a trend toward complete loss in end-stage metastases, suggesting a shift of AR expression between initial and end-stage metastases. This suggests an opportunity for targeted antiandrogen therapy at an earlier stage of disease progression.

EWSR1-ATF1 chimeric transcript in a myoepithelial tumor of soft tissue: a case report - Corrected Proof

2011-12-09

Summary: Soft tissue myoepithelial tumors, a recently defined entity, include benign and malignant lesions showing a considerable morphological and immunohistochemical heterogeneity. EWSR1 rearrangements are well recognized in this tumor type, and some of the partner genes have been identified. Herein we describe a soft tissue myoepithelioma arising in the pelvis with an EWSR1-ATF1 fusion, therefore extending the spectrum of partner genes of EWSR1. In addition, this case indicates that there are overlapping genetic features of myoepithelial tumors, clear cell sarcoma, angiomatoid fibrous histiocytoma, and hyalinizing clear-cell carcinoma of the salivary gland.

Gastric schwannoma: a clinicopathologic study of 51 cases and critical review of the literature - Corrected Proof

Lysandra Voltaggio, Rebecca Murray, Jerzy Lasota, Markku Miettinen — 2011-12-02

Summary: Schwannoma is a rare gastrointestinal mesenchymal tumor, as the vast majority of gastric mesenchymal tumors are gastrointestinal stromal tumors. In this study, we analyzed clinicopathologically 51 gastric schwannomas. These tumors predominantly occurred in older adults with a marked female predominance (40 women and 11 men; median and mean ages, 60 and 58 years). They variably presented with gastric discomfort, bleeding, or rarely gastric outlet obstruction; and many were incidental findings during other medical procedures. The tumors ranged from 1 to 10.5 cm (median, 4.5 cm). The typical histologic features included spindle cells usually with microtrabecular architecture and focal nuclear atypia, and peritumoral lymphoid cuff, whereas features of soft tissue schwannomas, such as encapsulation, nuclear palisading, vascular hyalinization, and dilatation, were absent or infrequent. Median mitotic count was 2/50 high-power fields, with the highest count being 13/50 high-power fields. No malignant variants were recognized, and long-term follow-up did not reveal recurrences or metastases. Immunohistochemically, all examined tumors were S100 protein positive and most were also GFAP positive, whereas CD34 and NF68 were encountered rarely and all tumors were negative for HMB45, KIT, DOG1/Ano 1, smooth muscle actin, desmin, and synaptophysin. None of the 9 tumors studied contained gastrointestinal stromal tumor–specific KIT or PDGFRA mutations. Fluorescence in situ hybridization studies revealed multiple signals with BCR probe (chromosome 22) and centromeric probes for chromosomes 2 and 18 suggesting polyploidy. These findings indicate that gastric schwannoma is a distinctive form of peripheral nerve sheath tumor that in many ways differs from soft tissue schwannoma. It should be distinguished from gastrointestinal stromal tumor and other mesenchymal tumors of the gastrointestinal tract, such as the S100 protein–positive gastrointestinal clear cell sarcoma and metastatic melanoma.

Relationship between alpha-methylacyl–coenzyme A racemase expression and mucin phenotype in gastric cancer - Corrected Proof

Yujiro Nozawa, Ken Nishikura, Yoichi Ajioka, Yutaka Aoyagi — 2011-11-14

Summary: Alpha-methylacyl–coenzyme A racemase controls β-oxidation of branched-chain fatty acid and their derivatives. Many investigators have described alpha-methylacyl–coenzyme A racemase expression in various neoplasias and their precursor lesions. Although there have been a few reports regarding alpha-methylacyl–coenzyme A racemase expression in gastric neoplasia, these reports did not discuss the relationship between alpha-methylacyl–coenzyme A racemase expression and mucin phenotype. This study analyzed alpha-methylacyl–coenzyme A racemase expression of gastric carcinomas with regard to mucin phenotype. Alpha-methylacyl–coenzyme A racemase expression was evaluated in 85 cases of gastric biopsies including gastric epithelial neoplasia and nonneoplasia and in 108 cases of surgically resected early gastric cancer. In biopsy cases, alpha-methylacyl–coenzyme A racemase was more highly expressed in neoplasia (69.7%, 23/33) than in nonneoplasia (0%, 0/42) (P = .001). Alpha-methylacyl–coenzyme A racemase was overexpressed in 20.0% (2/10) of cases that were indefinite for neoplasia, and the 2 positive cases were ultimately diagnosed as adenocarcinoma. In resected cases of early gastric adenocarcinoma, alpha-methylacyl–coenzyme A racemase expression significantly correlated with mucin phenotype (P = .003), but not with tumor progression, histologic classification, or clinicopathologic features. Alpha-methylacyl–coenzyme A racemase expression was significantly higher in intestinal-phenotype carcinoma (90.2%, 37/40) than in gastric-phenotype carcinoma (56.3%, 18/31) (P = .006) and also correlated with an increase in CDX2 expression (P = .018) and a decrease in MUC5AC expression (P = .048). This tendency was observed in all histologic types. Our results indicate that alpha-methylacyl–coenzyme A racemase is a useful marker for distinguishing gastric neoplasia from nonneoplasia even at an early stage. Alpha-methylacyl–coenzyme A racemase expression is associated with mucin phenotypes of gastric neoplasia, particularly with the expression of CDX2 and MUC5AC.

E-cadherin nuclear staining is useful for the diagnosis of ovarian adult granulosa cell tumor - Corrected Proof

2011-11-14

Summary: We recently have demonstrated nuclear localization of E-cadherin in ovarian adult granulosa cell tumors (Histopathology 2011;58:423). The purpose of the present study is to investigate the diagnostic utility of E-cadherin nuclear staining for the differential diagnosis between ovarian adult granulosa cell tumor and its morphological mimics. Tissue samples taken from 81 ovarian tumors and 20 extraovarian tumors were immunohistochemically stained using monoclonal anti–E-cadherin antibody recognizing cytoplasmic domain (clone 36 supplied by BD Biosciences, San Jose, CA). The ovarian tumors consisted of 30 adult granulosa cell tumors, 3 Sertoli-stromal cell tumors, 14 fibrothecomas, 5 carcinoid tumors, 1 large cell neuroendocrine carcinoma, 18 endometrioid adenocarcinomas, and 10 poorly differentiated serous adenocarcinomas. Extraovarian tumors consisted of 16 uterine endometrial stromal neoplasms and 4 pulmonary small cell carcinomas. Only tumor cells with nuclear staining were considered positive in this study. Ninety percent of adult granulosa cell tumors, 67% of Sertoli-stromal cell tumors, 64% of fibrothecomas, 75% of endometrial stromal neoplasms, 75% of small cell carcinomas, and the one large cell neuroendocrine carcinoma showed E-cadherin nuclear expression, whereas all the ovarian carcinoid tumors, endometrioid adenocarcinomas, and poorly differentiated serous adenocarcinomas were negative. E-cadherin nuclear staining is useful in distinguishing between adult granulosa cell tumors and ovarian adenocarcinomas or carcinoid tumors. However, it is of limited use for distinguishing between adult granulosa cell tumors and endometrial stromal neoplasms or small cell carcinomas. E-cadherin should be included in the immunohistochemical panel for an accurate diagnosis of ovarian adult granulosa cell tumors.

Histologic abnormalities of placental tissues in Fabry disease: a case report and review of the literature - Corrected Proof

Beth L. Thurberg, Juan M. Politei — 2011-11-14

Summary: Fabry disease is an X-linked lysosomal storage disease caused by deficiency of α-galactosidase A, resulting in the accumulation of globotriaosylceramide. Many women experience symptoms, but the understanding of placental and fetal aspects of the disease is limited. We report the pregnancy outcome in and placental pathology of a 37-year-old woman with Fabry disease. She became pregnant 2 years after starting enzyme replacement therapy and continued therapy throughout her pregnancy. At 38 weeks' gestation, she gave birth to a healthy boy with the same maternal Fabry mutation. The present case describes more extensive placental involvement by Fabry disease than has been previously reported. Globotriaosylceramide deposits were found within multiple cell types of the placenta, cord, and membranes. Because of the small numbers of cases described in the literature for comparison, it remains unclear if placental tissues are also targeted by enzyme replacement therapy.