Neuroendocrine proliferations of the stomach: a pragmatic approach for the perplexed pathologist.

The classifications of neuroendocrine proliferations that lead from enterochromaffin-like cell hyperplasia to neuroendocrine tumors in the stomach are complicated and relatively inaccessible to nonspecialists. Consequently, these lesions tend to remain widely underdiagnosed until they progress to easily recognizable neuroendocrine tumors. This review provides simple, yet rigorous guidelines on how to recognize, classify, and diagnose the neuroendocrine proliferations found in the stomach, emphasizing the most common background in which they arise, atrophic gastritis. After a succinct outline of the types and distribution of the neuroendocrine cells in the normal gastric mucosa we discuss the most common situations in which the pathologist needs to think about gastric neuroendocrine cells. In general practice gastric biopsy specimens are often numerically and topographically inadequate for the evaluation of atrophic gastritis; therefore, we have included an algorithm to address specifically the steps that should be taken when confronted with suboptimal sampling. Finally, we illustrate the suggested diagnostic process with 4 cases that are fairly representative of the type of situations encountered in everyday practice. The pathologist who follows our simple steps will be better aware of this neglected area of gastric pathology and will learn to suspect, recognize, and accurately diagnose the most common abnormalities of the neuroendocrine system in the stomach.

ADAMTS4 (aggrecanase-1) cleaves human brain versican V2 at Glu405-Gln406 to generate glial hyaluronate binding protein.

Human brain tissue from cerebellum and hippocampus was obtained between 2 h and 24 h post mortem and, after extraction in the presence of proteinase inhibitors, proteoglycans were purified by anion-exchange chromatography. The versican component was characterized by Western analysis with antibodies to the N-terminal peptide (LF99), the N-terminal globular domain (12C5) and the two GAG (glycosaminoglycan) attachment regions (anti-GAG-alpha and anti-GAG-beta). The results indicated that versican V2 is the major variant in all brain samples, and that it exists as the full-length form and also as at least six C-terminally truncated forms. The major immunoreactive species present is a 64 kDa product, which we identified by biochemical and immunological analysis as the brain protein previously termed GHAP (glial hyaluronate binding protein) [Perides, Lane, Andrews, Dahl and Bignami (1989) J. Biol. Chem. 264, 5981-5987]. Immunological analysis of purified human GHAP using a new anti-neoepitope antiserum (JSCNIV) showed that its C-terminal sequence is NIVSFE(405), and digestion of human cerebellum proteoglycans with ADAMTS4 (aggrecanase-1, where ADAMTS, a disintegrin and metalloproteinase with thrombospondin-1-like motifs) indicated that GHAP is a product of cleavage of versican V0 or V2 at the Glu(405)-Gln(406) bond. Since human cerebellum extracts contained multiple forms of ADAMTS4 protein on Western analysis, these data suggest that one or more members of the 'aggrecanase' group of the ADAMTS family (ADAMTS 1, 4, 5 and 9) are responsible for turnover of versican V2 in the adult human brain.

Modulatory effect of neoadjuvant chemotherapy on biomarkers expression; assessment by digital image analysis and relationship to residual cancer burden in patients with invasive breast cancer.

The use of digital imaging techniques for biomarker assessment has gained recognition as a valid tool for clinical use. In this study, we used image analysis for evaluation of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER2), Ki-67 index, and p53 in 172 patients with invasive breast cancer treated with neoadjuvant chemotherapy and compared it with an untreated group (100 cases). We also examined the relationship between biomarker expression and the extent of residual disease using the Web-based MD Anderson residual cancer burden (RCB) calculator. Residual disease was classified as RCB 0/I, II, and III corresponding to complete/near-complete response, moderate, and extensive residual disease, respectively. Overall change in ER, PR, and HER2 status in the treated group was seen in 9.02% (P = .0148), 18.4% (P = .011), and 12.0% (P = .0042), respectively. Change in HER2 status, positive to negative and negative to positive, occurred in 27.2% and 7.0%, respectively. The group with RCB 0/I was frequently younger (P = .0057) and showed higher ER(-) status (P = .0316), lower ER scores (P = .0103), higher Ki-67 index (P = .0008), and p53 (P = .0055) compared with those with RCB II and III. Pathologic tumor stage (P = .0072), lumpectomy versus mastectomy (P = .0048), and p53 expression (P = .0190) were independent predictors of recurrence-free survival. The RCB categories (P = .0003) and tumor grade (P = .0049) were independent predictors of overall survival. This is the first study to conduct a comprehensive analysis of biomarkers in neoadjuvant chemotherapy-treated patients versus an untreated group using the digital image analysis method. We have demonstrated for the first time the relationship between RCB, tumor biomarkers expression, and clinical outcome.

Expression of cell cycle-related molecular markers in patients treated with radical cystectomy for squamous cell carcinoma of the bladder.

We evaluated the association of p53, p21, p27, cyclin E, and Ki-67 expression with pathologic features and clinical outcomes of patients with squamous cell carcinoma (SCC) of the urinary bladder. Immunohistochemical staining was performed on radical cystectomy specimens with pure SCC from 1997 to 2003. Bright field microscopy imaging coupled with advanced color detection software was used. The relationship between these markers and pathologic parameters as well as clinical outcome was assessed. The study included 152 patients (80.9% with bilharziasis), 99 males and 53 females, with a median age of 51 years (range, 36-74 years). The presenting stage was T2 or higher, and the presenting grade was grade II or lower in 93.4% of patients. Altered cyclin E expression was associated with stages (P = .02), altered p21 with grades (P = .02), and altered p27 with lymphovascular invasion (P = .01). In multivariable analyses, altered p53 expression was the only marker associated with an increased risk of disease recurrence (hazards ratio, 1.77; 95% confidence interval, 1.03-3.38, P = .04; and hazards ratio, 2.28; 95% confidence interval, 1.01-5.70, P = .05) and bladder cancer-specific mortality (hazards ratio, 1.76; 95% confidence interval, 1.06-2.99, P = .05, and hazards ratio, 2.64; 95% confidence interval, 1.05-5.54, P = .05) in all patients and in patients with T1-3N0 tumors, respectively. In conclusion, cell cycle-related molecular markers are commonly altered in SCC of the urinary bladder. Only p53 had a prognostic role in patients treated with radical cystectomy for SCC. Our findings support the need for further evaluation of molecular markers and their signaling pathways in SCC.