Human Pathology

Masthead

2010-08-01

Editorial Board

2010-08-01

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2010-08-01

In This Issue

2010-08-01

EGFR fluorescence in situ hybridization-positive lung adenocarcinoma: incidence of coexisting KRAS and BRAF mutations

Simion Chiosea, Yongli Shuai, Kathleen Cieply, Marina N. Nikiforova, Sanja Dacic — 2010-04-09

Summary: Despite growing evidence that epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation analysis is the most reliable predictor of the lung carcinoma response to EGFR-targeted therapies, there is still discussion about the role of EGFR fluorescence in situ hybridization (FISH). Studies focusing on EGFR FISH as a predictor of response to EGFR-targeted therapies mostly focused on the relationship between EGFR FISH and EGFR mutations. The incidence of KRAS and V-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations in EGFR-amplified or EGFR FISH-positive lung adenocarcinomas remains unknown. The aim of this study was to prospectively characterize the incidence of KRAS and BRAF mutations in EGFR FISH-positive surgically treated lung adenocarcinomas. Of 386 primary lung adenocarcinomas, 77 (20%) were EGFR FISH positive by University of Colorado criteria. The incidence of KRAS mutations in EGFR FISH-positive lung adenocarcinomas was 23% and was not significantly different from the incidence of KRAS mutations in EGFR FISH-negative subsets of adenocarcinoma (32%). A higher mean ratio between EGFR and chromosome 7 enumeration probe (EGFR/CEP7) was observed in EGFR-mutated tumors when compared to cases with KRAS mutation (13 versus 4.5, respectively). Our results showed significant number of EGFR FISH positive/amplified lung adenocarcinomas harboring KRAS mutation. It appears that an increase in EGFR/CEP7 ratio to cutoff point of 4.5 may distinguish between coexisting EGFR (FISH ratio of >5) or KRAS (FISH ratio of 2 to 5) mutations. Observations presented here indicate that the patient selection for EGFR-targeted therapies should include EGFR and KRAS mutational analysis, probably complemented by EGFR FISH studies.

Solitary cell infiltration is a novel indicator of poor prognosis and epithelial-mesenchymal transition in pancreatic cancer

2010-04-23

Summary: Pancreatic cancer is one of the most aggressive and lethal human malignancies in the Western world. A wide variety of intratumor glandular differentiation, including solitary infiltrating cancer cells, is a prominent microscopic finding in pancreatic cancer. We reviewed 114 resected cases of pancreatic ductal adenocarcinoma to investigate the prognostic impact of the degree of solitary cell infiltration, defined by the number of solitary infiltrating cancer cells. The clinicopathologic correlation of solitary cell infiltration was further evaluated. Seventy-six (67%) cases showed 7 or more solitary infiltrating cancer cells in 10 high-power fields and were labeled as having a high degree of solitary cell infiltration. A high degree of solitary cell infiltration correlated significantly with poor overall survival, the grade, lymphatic invasion, and lymph node metastasis. Multivariate analysis revealed that the degree of solitary cell infiltration, the grade, and the margin status were independent prognostic factors. Grade 1 and 2 tumors with a high degree of solitary cell infiltration, compared with low infiltration, correlated significantly with poor overall survival. Grade 3 tumors showed a worse overall survival than grade 1 and 2 tumors with either a high or a low degree of solitary cell infiltration. Immunohistochemical analysis showed that a high degree of solitary cell infiltration correlated with reduced E-cadherin and increased vimentin expression. In conclusion, solitary cell infiltration is a significant prognostic indicator and serves as a morphological clue to epithelial-mesenchymal transition in pancreatic cancer.

DNA methyltransferases 1, 3a, and 3b overexpression and clinical significance in gastroenteropancreatic neuroendocrine tumors

2010-04-09

Summary: The alteration of DNA methylation is one of the most common epigenetic changes in human cancers. Three genes, namely, DNA methyltransferase 1, 3a, and 3b, which code for DNA methyltransferases that affect promoter methylation status, are thought to play an important role in the development of cancers and may be good anticancer therapy targets. The methylation of tumor suppressor genes has been reported in gastroenteropancreatic neuroendocrine tumors; however, there have been no studies about DNA methyltransferase protein expression and its clinical significance in gastroenteropancreatic neuroendocrine tumors. In this study, the expression of DNA methyltransferase 1, 3a, and 3b was studied in 63 gastroenteropancreatic neuroendocrine tumors by immunohistochemistry. The expression of DNA methyltransferase 1, 3a, and 3b was frequently detected in gastroenteropancreatic neuroendocrine tumors (87%, 81%, and 75%, respectively). The DNA methyltransferase 3a expression level was significantly higher in poorly differentiated neuroendocrine carcinomas than in well-differentiated neuroendocrine tumors or well-differentiated neuroendocrine carcinomas (P < .01 and P < .05, respectively). The expression of DNA methyltransferase 1, 3a, and 3b showed significantly higher levels in stage IV tumors than in stage I or II tumors. In addition, the expression levels of DNA methyltransferase 1, 3a, and 3b were positively correlated with the MIB-1 labeling index in gastroenteropancreatic neuroendocrine tumors (R = 0.293, P = .019; R = 0.457, P = .001; and R = 0.249, P = .049; respectively). In addition, the expression levels and positive immunostaining frequencies of DNA methyltransferase 3a and 3b were significantly lower in midgut neuroendocrine tumors than in foregut or hindgut neuroendocrine tumors. Our findings suggest that the overexpression of DNA methyltransferase 1, 3a, and 3b is related to tumorigenesis and the progression of gastroenteropancreatic neuroendocrine tumors.

Nucleophosmin, p53, and Ki-67 expression patterns on an oral squamous cell carcinoma tissue microarray

2010-03-25

Summary: Oral cancer is the eighth most prevalent cancer worldwide. It causes significant mortality and morbidity rates, which have motivated the search for prognostic factors to better tailor the individual management of oral squamous cell carcinoma patients. Nucleophosmin is a multifunctional protein that is involved in many cellular activities, such as, regulation of the tumor suppressor genes TP53 and p14ARF and is associated with proliferative and growth suppressive roles in the cell. Nucleophosmin is overexpressed in many solid tumors in human, including tumors of the colon, liver, stomach, ovary, and prostate. In this study, we analyzed the expression of nucleophosmin, Ki-67, and p53 by immunohistochemistry in oral squamous cell carcinomas. Less than 10% of nuclear staining was observed in 90.3%, 50.6%, and 65.3% of the cases for nucleophosmin, p53, and Ki-67, respectively. Expression of p53 was not significantly associated with any of the clinicopathologic parameters analyzed. Increased expression of Ki-67 was associated with the presence of lymph node metastasis (P < .0001), advanced stages of disease (P = .0030), tumors occurring in the floor of mouth (P = .0018), and moderately/well-differentiated tumors (P = .0287). Local recurrence was associated with higher expression of nucleophosmin (P = .0233), and disease-free survival rate was significantly better in patients with low expression of nucleophosmin. Multivariate analysis suggested that expression of nucleophosmin could be an independent prognostic factor for oral squamous cell carcinoma patients.

Adenocarcinoma of the small intestine: a multi-institutional study of 197 surgically resected cases

2010-03-24

Summary: Small intestinal adenocarcinoma is a rare malignant neoplasm, and its clinicopathologic characteristics have not been well elucidated. A total of 197 small intestinal adenocarcinoma cases were collected from 22 institutions in South Korea and were evaluated for clinicopathologic factors that affect the prognosis of small intestinal adenocarcinoma patients using univariate and multivariate analyses. The mean patient age was 59 years, and the male-to-female ratio was 1.7:1. Tumors were located in the duodenum of 108 cases (55%), the jejunum in 59 (30%), and the ileum in 30 (15%). Predisposing conditions were observed in 23 cases (12%), including 17 cases with sporadic adenomas, 3 with Peutz-Jeghers syndrome, 2 with Meckel diverticulum, and 1 with Crohn disease. Synchronous or metachronous malignant tumors were identified in 31 cases (16%), including 13 colorectal and 10 stomach cancers. About 90% of tumors were classified as either pT3 (63 cases) or pT4 (112 cases). The median survival time for all small intestinal adenocarcinoma patients was 39.7 months. Compared with small intestinal adenocarcinomas without accompanying sporadic adenomas, small intestinal adenocarcinomas with accompanying adenomas were more well differentiated (P < .0001), with a more polypoid growth pattern (P < .0001), a lower pT classification (P < .0001), less perineural invasion (P = .01), and less lymphatic invasion (P = .03). Small intestinal adenocarcinoma patients with associated sporadic adenomas (77%) had a significantly better 5-year survival rate than those without sporadic adenomas (38%, P = .02). By univariate analysis, small intestinal adenocarcinoma patients had significantly different survival based on pT classification (P = .003), lymph node metastasis (P < .0001), distal location (jejunal and ileal carcinomas) (P = .003), retroperitoneal tumor seeding (P < .0001), vascular invasion (P = .007), lymphatic invasion (P = .001), peritumoral dysplasia (P = .004), and radiation therapy (P = .006). By multivariate analysis, lymph node metastasis (P = .01) and distal location (P = .003) were independent predictors of a worse prognosis. In conclusion, (1) small intestinal adenocarcinomas are diagnosed at an advanced disease stage; therefore, the development of strategies for detection at an earlier stage is needed. (2) Small intestinal adenocarcinoma patients with an adenomatous component had a better survival than those without an adenomatous component. (3) Lymph node metastasis and distal location (jejunum and ileum) of tumor are the most important independent prognostic factors.

Counting myenteric ganglion cells in histologic sections: an empirical approach

Maya Swaminathan, Raj P. Kapur — 2010-03-26

Summary: An abnormal density of myenteric neurons is a putative cause of intestinal pseudo-obstruction. Quantification of myenteric ganglion cells may be necessary to establish hyper- or hypoganglionosis, but published norms are very discordant. We investigated how observer bias and tissue sampling affect the accuracy and reproducibility of myenteric neuron counts obtained from histologic sections immunostained for HuC/D, a neuronal cell body-specific antigen. Despite a collective effort to standardize neuronal identification criteria, significant discrepancies were found between the counts obtained by different observers. In contrast, counts by a single observer, over a period of several months, revealed excellent reproducibility. To investigate effects of tissue sampling on the accuracy of ganglion cell density estimates, one observer counted immunoreactive neurons in 22 full-circumference rectal sections from the same paraffin block. The mean number of neurons per circumference from all 22 sections was considered a target, against which estimates from smaller samples were compared. To ensure an accurate estimate of the circumferential density (within 10% of the target value), counts had to be averaged from at least 5 sections of nearly the full circumference. Examinations of fewer sections or less than two thirds of the circumference were prone to errors. Application of these principles to sections from the transitional zone in Hirschsprung disease validated the approach and discriminated relatively subtle changes in neuronal density. We conclude that neuronal counts are best performed by individuals using their own normative data for reference and that biopsies of small portions of the circumference may not resolve potentially significant hypo- or hyperganglionosis.

Exploring the peritoneal surface malignancy phenotype—a pilot immunohistochemical study of human pseudomyxoma peritonei and derived animal models

2010-03-25

Summary: Peritoneal surface malignancies are characterized by the propensity for tumor growth on peritoneal surfaces without development of extraperitoneal metastases, but the molecular basis for this phenomenon is incompletely understood. Five human tumors and corresponding orthotopic animal models of human pseudomyxoma peritonei and peritoneal mucinous carcinomatosis from colorectal carcinoma were extensively characterized by immunohistochemical analysis of molecular markers of tissue differentiation (carcinoembryonal antigen, CK20, CK7, and vimentin), proliferation and metastasis (Ki-67, vascular endothelial growth factor, and S100A4), mucins (MUC1, MUC2, MUC4, MUC5AC), and adhesion molecules (E-cadherin, N-cadherin, P-cadherin, claudin 1, claudin 3, and claudin 4). Macro- and microscopic growth patterns of implanted human tissues were preserved through passages in the animals, as were with few exception immunohistochemical staining profiles, supporting the relevance of the models as tools for studying the human disease. Tissue differentiation marker expression was in accordance with previously published results and high Ki-67 score confirmed high proliferative capacity, whereas absence of metastatic capacity was supported by low expression levels of the studied metastasis markers. These mucinous tumors expressed high levels of MUC2 and MUC4, whereas MUC1 was not expressed and MUC5AC expression was variable. Similarly, specific adhesion molecules from the cadherin and claudin families were shown to be of relevance in the investigated samples. The results indicate that mucinous peritoneal surface malignancies of intestinal origin are characterized by the presence of specific molecular markers and represent a step toward understanding the complexity of this intriguing phenotypic entity.

Evaluation of cell cycle protein expression in gastric cancer: cyclin B1 expression and its prognostic implication

2010-03-24

Summary: The cell cycle progression is regulated by interactions of specific cyclin-dependent kinases at the G1-S and G2-M checkpoints. In addition, the cell cycle dysregulation plays a major role in carcinogenesis of human cancers. To investigate the role of cell cycle regulators in the pathogenesis and progression of human gastric cancer, the expression of cyclin D1, A, B1, p16INK4a, p21CPI1, p27KIP1, p53, and pRb was investigated in 482 gastric carcinomas using immunohistochemistry in terms of histologic type, tumor invasion, size, location, and metastatic behavior. The cyclin D1, A, and B1 expression (>10%) was observed in 49%, 69%, and 49% of the cases, respectively. Negative cases for p16INK4a, p21CPI1, and p27KIP1 were detected in 90%, 86%, and 50.5%. There were 30% and 68% of the gastric tumors positive for p53 and pRb, respectively. Diffuse carcinomas frequently were positive for cyclin B1 and pRb, and negative for p21. A relationship between p53 expression and intestinal type carcinomas was found. In addition, the expression of cyclin B1 was associated with regional lymph node metastasis and poor prognosis. No relationship was noticed between any other cell cycle proteins expression and age, sex, tumor size, tumor location, and lymph node involvement. These findings have shown alterations in several cell cycle regulators, and it was suggested that cyclin B1 expression is closely associated with poor behavior in gastric cancer.

Stromal expression of actin is a marker of aggressiveness in basal cell carcinoma

Patrick A. Adegboyega, Sarah Rodriguez, Jerry McLarty — 2010-04-09

Summary: Basal cell carcinoma is a very common malignant skin tumor that rarely metastasizes but is often locally aggressive. In a number of studies conducted by different investigators, Bcl2, β-catenin, cyclin D1, hMSH2, and α-smooth muscle actin have been reported to have potential for predicting basal cell carcinoma aggressiveness. However, these reports were inconclusive and sometimes contradictory. We therefore studied the expression and topographic locations (tumor versus stroma) of all these gene products in a group of clinically proven aggressive basal cell carcinomas (n = 30) and randomly selected control cases of nonaggressive basal cell carcinomas (n = 33). The results were subjected to statistical analysis with Mann-Whitney test and logistic regression. The accuracy of the resulting significant discriminating criteria was further tested using the omnibus tests of model coefficients. With multivariate analysis, differential expression of Bcl-2, β-catenin, and cyclin D1 was not significantly different between aggressive and nonaggressive tumors. hMSH2 expression was up-regulated in the aggressive tumors (P = .005). α-Smooth muscle actin was expressed by tumor cells in both study groups, but stromal expression of α-smooth muscle actin was restricted to the aggressive tumors and highly predictive of aggressive behavior (P < .001; accuracy, 87%). Logistic regression combining the expression of α-smooth muscle actin and hMSH2 yielded a predictive model with 97% accuracy (P < .001). These data show conclusively that aggressive basal cell carcinomas express α-smooth muscle actin in the stroma, whereas nonaggressive basal cell carcinomas express α-smooth muscle actin in the tumor cells, and that stromal expression of α-smooth muscle actin is an accurate, reliable, and easy to use marker of aggressiveness in basal cell carcinomas and can be used in clinical practice for surgical therapeutic decisions.

Death after endoscopic retrograde cholangiopancreatography: findings at autopsy

Sarah E. Kerr, Michel Kahaleh, Robin D. LeGallo, Edward B. Stelow — 2010-04-09

Summary: More than half a million endoscopic retrograde cholangiopancreatography (ERCP) procedures are performed annually in the United States. The risk of severe complications after ERCP is less than 1%; however, autopsy pathologists see a select group of patients having fatality. Thirty-five autopsies were performed after ERCP over a 13-year period. Fourteen of these 35 patients died of ERCP complications. The remaining patients formed the control group. Fatal complications of ERCP included acute pancreatitis (7), sepsis (5), gastrointestinal/biliary perforation (3), bleeding (2), myocardial infarction (2), and cardiac arrhythmia (1). Cancer (14) and chronic pancreatitis (4) were the most reported causes of death in the control group. Median times to death after ERCP in ERCP-related deaths versus controls were 9.5 and 40 days, respectively. The most common indications for the procedure in ERCP-related deaths were suspected choledocholithiasis and jaundice/biliary obstruction; in controls, jaundice/biliary obstruction and chronic pancreatitis were more common. Patients having fatal ERCP complications had more cannulations reported as “difficult” (69% versus 20%; P = .003). The Klöppel chronic pancreatitis score was lower (mean, 2.6 versus 6.6; P = .03), and the percentage of nonfibrotic pancreatic parenchyma was higher (mean, 85% versus 56%; P = .02) in ERCP-related death group versus controls. Although patients rarely die after ERCP, our findings suggest that healthy acinar tissue is a risk factor for ERCP-related death, especially in the setting of difficult cannulation.

The distribution of PAX-2 immunoreactivity in the prostate gland, seminal vesicle, and ejaculatory duct: comparison with prostatic adenocarcinoma and discussion of prostatic zonal embryogenesis

2010-04-23

Summary: PAX-2 is a homeogene strongly expressed during development of the genitourinary tract, including the kidney and both wolffian- and müllerian-derived tissues. Expression of PAX-2 by immunohistochemistry has been studied mainly in renal epithelial neoplasms with little attention to the lower male genitourinary tract. We studied PAX-2 expression in epithelium of normal seminal vesicle, normal ejaculatory duct, normal prostatic secretory epithelium, and prostatic adenocarcinoma to define its immunoreactivity pattern throughout the prostate gland and to evaluate its potential diagnostic role in the discrimination of seminal vesicle/ejaculatory duct epithelium from prostatic adenocarcinoma. In addition, given that PAX-2 is highly expressed in tissues of wolffian duct embryologic origin, we also sought to confirm the divergent embryogenesis of the central zone, seminal vesicle, and ejaculatory duct from other regions of the prostate. Prostatectomy specimens from 12 patients were reviewed to identify blocks containing seminal vesicle, ejaculatory duct, periurethral glands, benign prostatic glands, and prostatic acinar adenocarcinoma. A total of 35 blocks from the 12 patients were evaluated. In addition, 2 tissue microarrays representing 15 additional seminal vesicles and 45 prostatic adenocarcinomas, 7 whole sections from prostatic adenocarcinomas of the central zone, and 5 core needle biopsies of seminal vesicle were also evaluated with anti–PAX-2 antibody. In the 12 radical prostatectomy whole sections, nuclear reactivity for PAX-2 was identified in 12 (100%) of 12 of the seminal vesicle epithelium, 9 (90%) of 10 of the ejaculatory duct epithelium, 0 of 12 of the prostatic adenocarcinoma, and 0 of 6 of the high-grade prostatic intraepithelial neoplasia. All 20 total additional seminal vesicles were positive for PAX-2 in the tissue microarray and biopsies; and all 52 additional prostatic adenocarcinomas were negative, including 7 of central zone origin. The staining intensity and percentage of immunoreactive cells in seminal vesicle were both 3+ in all cases. Although the ejaculatory ducts also showed diffuse staining, their staining intensity was less (2+) than that in the seminal vesicles, particularly in the ejaculatory ducts in the periurethral area (1-2+intensity). The smaller glands surrounding the main seminal vesicle duct also showed less intense staining than the luminal cells of the main duct. Of the 19 total cases with evaluable central zone glands, 2 (10.5%) had focal nuclear reactivity in normal, benign prostatic secretory cells. All other benign prostatic secretory epithelia from the peripheral and transition zones were negative for PAX-2. In conclusion, nuclear PAX-2 immunoreactivity is typical in epithelium of the seminal vesicle and ejaculatory duct; but the intensity of staining is less in the ejaculatory duct. No reactivity for PAX-2 was seen in prostatic adenocarcinoma or high-grade prostatic intraepithelial neoplasia. PAX-2 has diagnostic utility as a positive immunohistochemical marker of seminal vesicle and ejaculatory duct epithelium. In addition, these data add further support to the proposed embryogenesis of the prostatic central zone, seminal vesicle, and ejaculatory ducts from the wolffian system.

Bone marrow involvement in patients with posttransplant lymphoproliferative disorders: incidence and prognostic factors

2010-04-09

Summary: Posttransplant lymphoproliferative disorders are classified as monomorphic, polymorphic, early lesions, or Hodgkin lymphoma type. Staging bone marrow examination is recommended in posttransplant lymphoproliferative disorder patients; however, information regarding bone marrow involvement in these disorders, especially as related to the posttransplant lymphoproliferative disorder subtype, is scarce. We reviewed the clinicopathologic features of 72 posttransplant lymphoproliferative disorder cases to determine the frequency of bone marrow involvement by various subtypes of posttransplant lymphoproliferative disorder, the clinical features of patients with and without bone marrow involvement, and their outcome. We also compared the incidence of bone marrow involvement of monomorphic posttransplant lymphoproliferative disorder (diffuse large B-cell lymphoma) with de novo diffuse large B-cell lymphoma (in both immunocompetent and HIV+ patients), and assessed the utility of various hematologic and serologic parameters as predictors of bone marrow involvement. Bone marrow involvement was seen in 23.5% of monomorphic posttransplant lymphoproliferative disorders and 15.7% of polymorphic posttransplant lymphoproliferative disorders, and the detection of bone marrow involvement on staging bone marrow biopsy upstaged 42% of monomorphic posttransplant lymphoproliferative disorders and 100% of polymorphic posttransplant lymphoproliferative disorders. Although bone marrow involvement appeared independent of patient age, organ transplanted, Epstein-Barr virus status, interval from transplantation to posttransplant lymphoproliferative disorder, or involvement of the grafted organ, it was significantly more frequent in cases without extranodal involvement; and it was associated with a significantly shorter survival. The incidence of bone marrow involvement in monomorphic posttransplant lymphoproliferative disorder (diffuse large B-cell lymphoma) was similar to that in HIV-associated diffuse large B-cell lymphoma, but higher than that in immunocompetent diffuse large B-cell lymphoma cases. No individual hematologic and serologic parameter was predictive of bone marrow involvement; however, the combination of elevated lactate dehydrogenase (>225 U/L) and decreased hemoglobin (<10 g/DL) can be used as a sensitive screening tool in determining which patients should proceed to bone marrow staging biopsy.

Invasive micropapillary urothelial carcinoma of the bladder

Antonio Lopez-Beltran, Rodolfo Montironi, Ana Blanca, Liang Cheng — 2010-04-09

Summary: In this report, we present the clinicopathologic features of 13 cases of the invasive micropapillary variant of urothelial carcinoma. This is a rare and aggressive variant of bladder cancer recognized by the current World Health Organization classification of urologic tumors. The micropapillary component varied from 50% to 100% of the tumor specimen; in 10 cases, the micropapillary component composed greater than 70% of the tumor, with 5 cases showing pure micropapillary carcinoma. The architectural pattern of the tumor varied from solid expansile nests with slender papillae within tissue retraction spaces to pseudoglandular growth with prominent ring-like structures (2 cases, 15%) and invasive micropapillary carcinoma with squamous differentiation (2 cases, 15%); a streaking solid architectural pattern of micropapillary carcinoma was additionally present in 2 cases (15%). At histology, the individual tumor cells had abundant eosinophilic cytoplasm and nuclei with prominent nucleoli and irregular distribution of chromatin, and frequent mitotic figures. Most neoplastic cells had nuclei of low to intermediate nuclear grade with occasional nuclear pleomorphism. Eight mixed cases had concurrent conventional high-grade urothelial carcinoma with squamous or glandular differentiation in 3 and 1 case(s), respectively. All patients had advanced-stage cancer (>pT2), and 8 (62%) had lymph node metastasis. Immunohistochemical staining demonstrated that both micropapillary and associated conventional urothelial carcinomas were positive for MUC1 and 2, cytokeratin 7, PTEN, p53, and Ki-67. Her2Neu, uroplakin, cytokeratin 20, 34βE12, CA125, and p16 were positive in 4, 10, 8, 7, 3, and 3 cases, respectively. MUC5A, MUC6, and CDX2 were negative in all micropapillary cases. Follow-up information was available in all cases (range, 2-21 months; mean, 10 months). Eleven of patients died of disease from 2 to 14 months, and 2 patients were alive with disease at 14 and 21 months. Univariate statistical analysis showed survival differences between invasive micropapillary and conventional urothelial carcinomas (P < .0001). In summary, invasive micropapillary variant of urothelial carcinoma is an aggressive variant associated with poor prognosis that presents at an advanced clinical stage. The immunophenotype of invasive micropapillary carcinoma supports urothelial origin; the immunoreactivity to Her2Neu and PTEN might be relevant in terms of future targeting therapy. The morphologic diversity of micropapillary carcinoma may represent a diagnostic pitfall in limited samples, where its distinction from conventional urothelial carcinoma is critical for its clinical management.

CD147 expression in pituitary adenomas and its significance for clinical outcome

2010-04-09

Summary: CD147, a transmembrane glycoprotein member of the immunoglobulin superfamily of receptors, is involved in invasion and angiogenesis of some types of tumors; but its roles and clinicopathologic significance in pituitary adenomas are not clear. Using immunohistochemistry and quantitative reverse transcriptase polymerase chain reaction, we measured the expression of CD147, matrix metalloproteinase–2, and Ki-67 in 74 pituitary adenomas and evaluated the associations of CD147 with matrix metalloproteinase–2, Ki-67 labeling index, clinicopathologic characteristics, and prognosis. The CD147 protein was expressed in 35 (87.5%) of 40 invasive and in 16 (47.1%) of 34 noninvasive pituitary adenomas; and matrix metalloproteinase–2, in 32 (80.0%) and in 14 (41.2%) of 34, respectively. The Ki-67 labeling index was 3.93% ± 2.48% for invasive samples and 1.32% ± 1.04% for noninvasive ones. In addition, the expression of CD147 was positively correlated with matrix metalloproteinase–2, Ki-67 labeling index, or both in invasive pituitary adenomas (P< .01 and P< .01, respectively). All of the 4 recurrent adenomas were concurrently positive for CD147 and matrix metalloproteinase–2, and the Ki-67 labeling indexes of all were greater than 3%. Thus, CD147 may play a pivotal role in the development and progression of invasive pituitary adenomas and also be a useful prognostic biomarker.

Loss of PTEN/MMAC1 activity is a rare and late event in the pathogenesis of nephroblastomas

2010-04-09

Summary: Recent genetic investigations of nephroblastomas point to an activation of the Wnt pathway. Data indicate however that activation might be partly due to cross talk of different signaling pathways including the tumor suppressor gene PTEN (phosphatase and tensin homolog on chromosome 10). Therefore, we examined expression and chromosomal aberrations of PTEN in nephroblastomas of different subtypes and the corresponding nephrogenic rests. Loss of heterozygosity was analyzed by high-resolution melting analysis of 4 different single nucleotide polymorphisms. Results were confirmed by sequence analysis of the polymerase chain reaction products. In addition, an intragenic insertion-deletion polymorphism of the PTEN gene was investigated. Protein expression was assessed by immunohistochemistry. Twenty-two nephroblastomas and their corresponding nephrogenic rests were included in the study. In the high-resolution melting analysis, 15 samples were homozygous, 6 were heterozygous, and for 1 sample results could not be obtained for technical reasons. None of the samples showed loss of heterozygosity. Nineteen of the tumors and corresponding nephrogenic rests were also examined immunohistochemically. All tumors showed cytoplasmic positivity, with the exception of 1 tumor that showed complete loss of staining. In 1 tumor, the epithelial component showed distinct cytoplasmic staining, whereas the immature muscle and hyaline cartilage were negative. All nephrogenic rests exhibited positive cytoplasmic staining of all components. Our results establish that inactivation of PTEN is a rare and late event in the pathogenesis of nephroblastomas.

A comparison of the fibrotic potential of nonalcoholic fatty liver disease and chronic hepatitis C

2010-04-23

Summary: In nonalcoholic fatty liver disease the amount of fibrosis for individual histologic stages is unknown. To better understand the fibrotic potential of nonalcoholic fatty liver disease, we compared the amount of fibrosis in nonalcoholic fatty liver disease versus chronic hepatitis C virus patients. The area of fibrosis for equivalent fibrosis stages was measured by micromorphometry in 70 nonalcoholic fatty liver disease and 70 matched, untreated, chronic hepatitis C virus controls. The area of fibrosis correlated with Brunt stage (r = 0.71; P < .001) in nonalcoholic fatty liver disease and METAVIR stage (r = 0.58; P < .001) in chronic hepatitis C virus. Mean area of fibrosis was similar in nonalcoholic fatty liver disease and chronic hepatitis C virus patients (7.77% versus 7.70%). Although chronic hepatitis C virus patients displayed higher area of fibrosis in early disease (no or mild fibrosis), nonalcoholic fatty liver disease and chronic hepatitis C virus patients had similar area of fibrosis in more advanced disease (7.83% versus 8.06%, respectively; P = .86 for bridging fibrosis; and 16.62% versus 12.98%, respectively; P = .29 for cirrhosis). The area of fibrosis was similar in Brunt stage 3 nonalcoholic fatty liver disease and METAVIR stage 2 chronic hepatitis C virus, the usual threshold for initiating therapy. The area of steatosis declined with increasing fibrosis stages confirming the early loss of liver fat with progressive fibrosis in nonalcoholic fatty liver disease. Fibrosis is as abundant in nonalcoholic fatty liver disease as in chronic hepatitis C virus, especially in the advanced stages of the disease. The fibrotic potential of nonalcoholic fatty liver disease is as severe as that of chronic hepatitis C virus.

Prognostic value of the X-linked inhibitor of apoptosis protein for invasive ductal breast cancer with triple-negative phenotype

Jinjing Wang, Yixin Liu, Ru Ji, Qiang Gu, Xiulan Zhao, Yanrong Liu, Baocun Sun — 2010-04-12

Summary: Molecular classification has raised new hopes of improving our understanding of breast cancer. Discovery of novel tumor markers that allow the identification of patients at higher risk for invasive ductal breast cancer with triple-negative phenotype remains a research and clinical priority. To evaluate the prognostic value of the X-linked inhibitor of apoptosis protein for invasive ductal breast cancer with triple-negative phenotype by correlating the expression of X-linked inhibitor of apoptosis protein with clinicopathologic parameters, thus determining its role in predicting tumor outcomes, 200 cases of patients with invasive ductal breast cancer, including their complete information, were obtained. Tissue microarrays were constructed; and immunohistochemical staining was performed to detect the expression of the estrogen receptor, progesterone receptor, HER2/neu, Ki-67, and X-linked inhibitor of apoptosis protein. We identified 42 cases of invasive ductal breast cancer with triple-negative phenotype. Of these, X-linked inhibitor of apoptosis protein expression was detected in 32 patients (80%). Significant correlations were found between X-linked inhibitor of apoptosis protein expression and primary tumor size (P = .027), and between X-linked inhibitor of apoptosis protein expression and Ki-67 index (P = .038). Kaplan-Meier survival analysis revealed a pattern of X-linked inhibitor of apoptosis protein expression with impaired overall and disease-free survival in patients with the disease. Most importantly, multivariate analysis also showed statistically significant worse outcomes for patients with tumors exhibiting X-linked inhibitor of apoptosis protein expression of at least 50% compared with those with X-linked inhibitor of apoptosis protein expression less than 50%. In conclusion, our results suggest that X-linked inhibitor of apoptosis protein is a novel biomarker and viable prognostic factor for invasive ductal breast cancer with triple-negative phenotype. Furthermore, the expression of X-linked inhibitor of apoptosis protein is significantly correlated with a more aggressive tumor phenotype and decreased overall and disease-free survival.

Minimal-change nephrotic syndrome preceding Hodgkin lymphoma by 5 years with expression of tumor necrosis factor α in Hodgkin-Reed-Sternberg cells

2010-08-01

Summary: A 76-year-old man developed minimal-change nephrotic syndrome (NS). After treatment with prednisolone failed to induce sustained remission, cyclosporin was added. The NS improved, and prednisolone and cyclosporin doses were gradually decreased. However, he had repeated relapses of the syndrome, and at each relapse, the drug doses were increased. After 5 years, the patient developed left inguinal lymphadenopathy. The histological diagnosis was mixed cellularity classical Hodgkin lymphoma. He received 6 courses of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), and mixed cellularity classical Hodgkin lymphoma and NS both showed complete response. Although the association between Hodgkin lymphoma and minimal-change NS is well known, the pathogenesis is unknown. To the best of our knowledge, this is the first case report of minimal-change NS associated with Hodgkin lymphoma in which Hodgkin-Reed-Sternberg cells were immunostained for tumor necrosis factor-α (TNF-α) clearly demonstrating that Hodgkin–Reed–Sternberg produced TNF-α and in which the plasma level of TNF-α normalized after improvement of Hodgkin lymphoma by chemotherapy. The production of TNF-α by Hodgkin–Reed–Sternberg cells might play a key role as a potential mediator of minimal-change NS.

Hereditary diffuse gastric cancer due to a previously undescribed CDH1 splice site mutation

2010-08-01

Summary: Our patient was a 52-year-old man who was diagnosed with signet ring cell gastric adenocarcinoma. An extensive family history of gastric cancer raised suspicion for hereditary diffuse gastric cancer. Sequencing of the patient's CDH1 gene revealed a novel point mutation in a strictly conserved splice site within intron 6, c.833-2 A > G. This mutation was predicted to result in loss of function due to defective RNA splicing. To characterize the pathogenic mechanism of this mutation, we amplified the patient's CDH1 gene products by reverse transcriptase polymerase chain reaction. Primers flanking the region of the mutation detected 3 distinct transcripts. In addition to the wild-type product, a larger product consistent with activation of a cryptic splice site within intron 6 and a smaller product shown to result from exon 7 skipping were detected. In summary, we have identified a novel CDH1 mutation in a large hereditary diffuse gastric cancer kindred and identified its pathogenic mechanism.

Human Pathology

Masthead

Editorial Board

Information for Authors

Table of Contents

In This Issue

EGFR fluorescence in situ hybridization-positive lung adenocarcinoma: incidence of coexisting KRAS and BRAF mutations

Solitary cell infiltration is a novel indicator of poor prognosis and epithelial-mesenchymal transition in pancreatic cancer

DNA methyltransferases 1, 3a, and 3b overexpression and clinical significance in gastroenteropancreatic neuroendocrine tumors

Nucleophosmin, p53, and Ki-67 expression patterns on an oral squamous cell carcinoma tissue microarray

Adenocarcinoma of the small intestine: a multi-institutional study of 197 surgically resected cases

Counting myenteric ganglion cells in histologic sections: an empirical approach

Exploring the peritoneal surface malignancy phenotype—a pilot immunohistochemical study of human pseudomyxoma peritonei and derived animal models

Evaluation of cell cycle protein expression in gastric cancer: cyclin B1 expression and its prognostic implication

Stromal expression of actin is a marker of aggressiveness in basal cell carcinoma

Death after endoscopic retrograde cholangiopancreatography: findings at autopsy

The distribution of PAX-2 immunoreactivity in the prostate gland, seminal vesicle, and ejaculatory duct: comparison with prostatic adenocarcinoma and discussion of prostatic zonal embryogenesis

Bone marrow involvement in patients with posttransplant lymphoproliferative disorders: incidence and prognostic factors

Invasive micropapillary urothelial carcinoma of the bladder

CD147 expression in pituitary adenomas and its significance for clinical outcome

Loss of PTEN/MMAC1 activity is a rare and late event in the pathogenesis of nephroblastomas

A comparison of the fibrotic potential of nonalcoholic fatty liver disease and chronic hepatitis C

Prognostic value of the X-linked inhibitor of apoptosis protein for invasive ductal breast cancer with triple-negative phenotype

Minimal-change nephrotic syndrome preceding Hodgkin lymphoma by 5 years with expression of tumor necrosis factor α in Hodgkin-Reed-Sternberg cells

Hereditary diffuse gastric cancer due to a previously undescribed CDH1 splice site mutation