Valeria Barresi

Colorectal carcinoma grading by quantifying poorly differentiated cell clusters is more reproducible and provides more robust prognostic information than conventional grading

The most widely used system to define the histological grade of colorectal carcinoma (CRC) is based on the degree of gland formation. This system suffers from significant interobserver variability which may limit its prognostic value and consequently better standardized criteria for the assessment of histological grading of CRC are needed. The present study aims to evaluate and to compare, in a cohort of postsurgical pTNM stage I CRC, conventional histological grading, and a novel grading system based on the number of poorly differentiated clusters of neoplastic cells, in terms of interobserver reproducibility, prognostic significance on progression-free survival, and association with other clinicopathological characteristics. Grading with both systems was performed by two pathologists independently and blinded to the clinicopathological data. Interobserver agreement was higher when grade was assessed by counting poorly differentiated clusters than by assessing the relative proportion of the glandular component. Contrary to conventional grading, the novel system provided significant prognostic information in terms of progression-free survival and was significantly associated with budding, invasive growth, lymphatic invasion, and occult nodal metastases of CRC. In conclusion, our findings suggest that a tumor grading system based on the number of poorly differentiated clusters is more reproducible and provides better prognostic stratification of pTNM stage I CRC patients than conventional grading.

Histologic grading based on counting poorly differentiated clusters in preoperative biopsy predicts nodal involvement and pTNM stage in colorectal cancer patients

Histologic grading is commonly assessed in colorectal cancer preoperative biopsies. Nevertheless, its clinical impact is limited by low interobserver reproducibility and poor concordance with grading found in the final resection specimen. In the present study, we aimed to investigate the reproducibility, accuracy, and predictive value on lymph node status or pTNM stage of a novel grading system based on the number of poorly differentiated clusters in colorectal cancer preoperative endoscopic biopsies. Grading based on counting poorly differentiated clusters was assessed in 163 colorectal cancer endoscopic biopsies and corresponding surgical specimens. With this system, 152 biopsies could be graded with good interobserver agreement (κ = 0.735). In comparison with the surgical specimens, 75% of colorectal cancers were correctly graded in the biopsy, and 81% of poorly differentiated colorectal cancers were identified at initial biopsy. High poorly differentiated clusters grade in the biopsy was significantly associated with nodal metastasis, high pTNM stage (P < .0001), or histologic features suggestive of more aggressive behavior (tumor budding, perineural invasion, vascular invasion, and infiltrating tumor border) in the surgical specimen. Furthermore, this system identified colorectal cancer with nodal involvement or high pTNM stage with a 78% positive predictive value and 71% and 69% negative predictive values, respectively. Our findings suggest that a grading system based on the quantification of poorly differentiated clusters is feasible in most colorectal cancer endoscopic biopsies. In view of its good reproducibility, accuracy, and predictive value on the anatomical extent of the disease, it may be taken into account for decision-making in colorectal cancer treatment.

Increased ratio of vascular endothelial growth factor to semaphorin3A is a negative prognostic factor in human meningiomas

Semaphorin3A (SEMA3A) is an anti‐angiogenic factor which is expressed in human meningiomas in association with low microvessel density (MVD). It competes with vascular endothelial growth factor (VEGF) for receptor neuropilin‐1 (NRP‐1). The ratio between VEGF and SEMA3A has been recently demonstrated to regulate neo‐angiogenesis, proliferation and progression of tumors. To clarify the involvement of these proteins in the above‐mentioned phenomena, we analyzed the immunohistochemical expression of SEMA3A, VEGF and NRP‐1 and their correlation with MVD in a series of 48 cases of meningioma with different histotype and histological grade. SEMA3A and VEGF expression was encountered in about half the cases, although at different levels. NRP‐1 staining was evidenced in the vessels within all but two tumors and in the neoplastic cells of 18/48 meningiomas. A negative significant correlation emerged between SEMA3A amount and MVD; on the other hand, high VEGF levels appeared to be significantly associated with high MVD. A high VEGF/SEMA3A was significantly associated with high histological grade, proliferation index and MVD as well as with a higher recurrence rate of the meningiomas. Present data suggest that the balance between the expression of the pro‐angiogenic factor VEGF and the anti‐angiogenic SEMA3A may be involved in the regulation of neo‐angiogenesis and proliferation in meningiomas, representing also a predictor of recurrences in these tumors. Further validation of our results may open the way for the use of drugs targeting not only VEGF, but also NRP‐1 and SEMA3A to prevent recurrences of meningiomas.

Semaphorin3A immunohistochemical expression in human meningiomas: correlation with the microvessel density

The immunoexpression of the antiangiogenic factor semaphorin3A (SEMA3A) was evaluated in a series of meningiomas. Then, its correlations with the microvessel density (MVD) of the tumors and with the clinicopathological parameters as well with the survival time or recurrence-free interval were investigated. A positive SEMA3A immunostaining was found in most of meningiomas and a significant association was found between a high expression of this protein and a low MVD of the tumors. Moreover, a low SEMA3A immunoexpression was significantly correlated with a higher recurrence rate of meningiomas. In conclusion, our findings suggest a role for SEMA3A as an antiangiogenic factor in meningiomas with its decrease being associated with the development of recurrences. The supplementation of SEMA3A might be used in novel therapeutic antiangiogenic strategies to prevent the recurrence of highly vascularized meningiomas.

Immunohistochemical assessment of lymphovascular invasion in stage I colorectal carcinoma: prognostic relevance and correlation with nodal micrometastases.

Several studies have suggested that the presence of occult nodal metastases (micrometastases) is related to adverse clinical course in stage I colorectal carcinoma. Herein we analyzed the correlation between nodal micrometastases and lymphovascular invasion (LVI) or lymphatic vessel density (LVD) in a series of stage I colorectal carcinomas; the cohort included cases characterized or not characterized by disease progression during the follow-up. In these cases, LVI and LVD were evidenced through the immunohistochemical detection of the specific marker for lymphatic vessels, D2-40. LVI was significantly more frequent in colorectal carcinomas characterized by the presence of micrometastases (P<0.0001), high peritumoral LVD (P<0.0001), and disease progression (P<0.0001). The analysis for progression risk indicated that nodal micrometastases and LVI were significant, negative, independent prognostic parameters associated with shorter disease-free survival of stage I colorectal cancer (P=0.0001; P=0.0242). In conclusion, in this study we demonstrated for the first time that LVI is significantly associated with nodal occult metastases in stage I colorectal carcinoma. In the light of its significant, independent, prognostic value in this neoplasia, the detection of LVI may represent a faster and cheaper tool compared with the time-consuming evaluation of micrometastases to select high-risk patients who may benefit from adjuvant systemic treatment. Furthermore, the assessment of LVI may be applied to establish the likelihood of nodal involvement from carcinomas treated with conservative local excision techniques, which provide no regional nodes for histologic examination.

Innovative Therapeutic Strategies in the Treatment of Brain Metastases

Brain metastases (BM) are the most common intracranial tumors and their incidence is increasing. Untreated brain metastases are associated with a poor prognosis and a poor performance status. Metastasis development involves the migration of a cancer cell from the bulk tumor into the surrounding tissue, extravasation from the blood into tissue elsewhere in the body, and formation of a secondary tumor. In the recent past, important results have been obtained in the management of patients affected by BM, using surgery, radiation therapy, or both. Conventional chemotherapies have generally produced disappointing results, possibly due to their limited ability to penetrate the blood–brain barrier. The advent of new technologies has led to the discovery of novel molecules and pathways that have better depicted the metastatic process. Targeted therapies such as bevacizumab, erlotinib, gefitinib, sunitinib and sorafenib, are all licensed and have demonstrated improved survival in patients with metastatic disease. In this review, we will report current data on targeted therapies. A brief review about brain metastatic process will be also presented.

HER2 status in unusual histological variants of gastric adenocarcinomas

Aim To investigate HER2 status in a cohort of 109 gastric adenocarcinomas also including unusual variants, such as 14 hepatoid (HAS) and 9 mitochondrion-rich (MRC), characterised by an opposing clinical behaviour. Methods and Results Using HercepTest (DAKO) and FISH test (pharmDx DAKO), HER2 overexpression/amplification was encountered in 23 of 109 (21.10%) of all gastric adenocarcinomas. A progressive increase in HER2 overexpression was observed moving from the poorly cohesive histotype to MRC, tubular adenocarcinomas and HAS. A statistically significant difference was found between poorly cohesive carcinomas and the others; a similar significant difference was encountered between HAS and all other variants of adenocarcinoma. HER2 overexpression was significantly associated with high grade, advanced stage, high Ki-67 labelling index value and death from gastric cancer. Multivariate analysis identified HER2 overexpression as an independent unfavourable prognostic variable for adenocarcinomas as a whole and also for the HAS variant. Conclusions Trastuzumab has been confirmed as an additional useful therapeutic standard option for patients with HER2-positive advanced gastric cancers, and also in aggressive variants of adenocarcinomas such as HAS.

Neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9) prognostic value in stage I colorectal carcinoma

The expression of neutrophil gelatinase-associated lipocalin (NGAL) has been suggested to behave like a negative prognostic marker in stage I colorectal carcinoma. In the aim of clarifying whether its association with adverse outcome may descend from NGALs ability to regulate matrix metallo-proteinase-9 (MMP-9), we analyzed the correlation, prognostic value, and association with neo-angiogenesis of NGAL and MMP-9 immunohistochemical expression in a series of stage I colorectal carcinomas. A variable NGAL immunoexpression was demonstrated in 17 of the 48 analyzed cases with a significantly higher frequency of positive cases among patients showing disease progression. NGAL expression was also positively correlated with VEGF expression detected in the same cases. MMP-9 immunostaining was present in the cytoplasm of the neoplastic cells in 30 cases; no significant correlations were evidenced with NGAL expression, as well as with the various clinico-pathological parameters or with progression of the colorectal carcinomas. By contrast, NGAL expression was confirmed as a significant independent negative prognostic marker related to a shorter disease-free survival in stage I colorectal carcinoma. Our preliminary results suggest that the association of NGAL with poor outcome might be independent from MMP-9 regulation, thus highlighting its prognostic value in this neoplasia. If our findings are confirmed in further analyses, NGAL assessment might be used in order to select those patients with a higher progression risk and to submit them to adjuvant therapies useful to prevent adverse outcome.

The expression of adiponectin receptors Adipo-R1 and Adipo-R2 is associated with an intestinal histotype and longer survival in gastric carcinoma

Background: Adiponectin (ApN) is a 30 kDa adipocytokine which mediates an antineoplastic effect after binding to its receptors, Adipo-R1 and Adipo-R2. The expression of these receptors has been documented in gastric cancer (GC) cell lines, but only a few data exist on their expression in GC neoplastic tissue. Aim: To investigate the expression of Adipo-R1 and Adipo-R2 in a series of surgically resected GCs and to assess its association with various tumour clinicopathological characteristics as well as with patient survival. Methods: Forty-nine surgically resected GCs were submitted to immunohistochemical assays for Adipo-R1, Adipo-R2 and ApN. Results: Adipo-R1 and Adipo-R2 immunoexpression was found in 22/49 GCs and in intestinal metaplasia areas near the tumours, whereas only slight immunoreactivity for these proteins was found in adjacent normal gastric epithelium. No ApN expression was encountered in any of the cases analysed. Adipo-R1/Adipo-R2 expression was significantly associated with an intestinal histotype of the tumours and with longer overall survival of the patients. Conclusions: Intestinal-type GCs often express Adipo-R1/R2 in association with a better prognosis. The presence of these receptors could be exploited for novel anticancer therapies based on ApN addition in GC.

Brachyury: A Diagnostic Marker for the Differential Diagnosis of Chordoma and Hemangioblastoma versus Neoplastic Histological Mimickers

Brachyury is a transcription factor which is required for posterior mesoderm formation and differentiation as well as for notochord development during embryogenesis. Due to its expression in the neoplastic cells of chordoma, a malignant tumour deriving from notochordal remnants, but not in tumors showing a similar histology, brachyury has been proposed as a diagnostic marker of this neoplasia. Though commonly considered a hallmark of chordoma, the expression of brachyury has been also documented in the stromal cells of hemangioblastoma (HBL), a slow growing tumor which may involve the central nervous system (CNS) and, rarely, the kidney. Herein we review the role of brachyury immunohistochemical detection in the identification and differential diagnosis of chordoma and HBL towards histological mimickers and suggest that brachyury is added to the panel of immunohistochemical markers for the recognition of HBL in routinary practice, principally in unusual sites.