Purpose: Early breast cancer presents with a remarkable heterogeneity of outcomes.Undetected, microscopic lymph node tumor deposits may account for a significant fraction of this prognostic diversity. Thus, we systematically evaluated the presence of lymph node tumor cell deposits V0.2 mm in diameter [pN 0(i+) , nanometastases] and analyzed their prognostic effect. Experimental Design: Single-institution, consecutive patients with 8 years of median follow-up (n = 702) were studied. To maximize chances of detecting micrometastases and nanometastases, whole-axilla dissections were analyzed. pN 0 cases (n = 377) were systematically reevaluated by lymph node (n = 6676) step-sectioning and anticytokeratin immunohistochemical analysis. The risk of first adverse events and of distant relapse of bona fide pN 0 patients was compared with that of pN 0(i+) , pN 1mi , and pN 1 cases. Results: Minimal lymph node deposits were revealed in 13% of pN 0 patients.The hazard ratio for all adverse events of pN 0(i+) versus pN 0(iÀ) was 2.51 (P = 0.00019). Hazards of pN 1mi and pN 0(i+) cases were not significantly different. A multivariate Cox model showed a hazard ratio of 2.16 for grouped pN 0(i+) /pN 1mi versus pN 0(iÀ) (P = 0.0005). Crude cumulative incidence curves for metastatic relapse were also significantly different (Gray's test m 2 = 5.54, P = 0.019). Conclusion: Nanometastases are a strong risk factor for disease-free survival and for metastatic relapse. These findings support the inclusion of procedures for nanometastasis detection in tumor-node-metastasis staging.The tumor-node-metastasis (TNM) staging system for breast cancer (1) has proven invaluable in categorizing the extent of neoplastic disease, and as a basis to estimate prognosis and to direct treatment (2). However, this has not lead to the definition of tightly homogeneous prognostic classes, as considerable heterogeneity of outcomes can be observed among disease cases currently categorized as similar. This is particularly evident in the case of small breast tumors (2). We argued that a diverse extent of lymph node dissemination at early stages of disease may account for diverse disease recurrence dynamics. The principle that the macroscopic burden of metastatic cells (e.g., number of invaded lymph nodes) dictates different risks of disease recurrence has been recognized (1,3). This principle might be equally important at the low end of the spectrum, i.e., in the case of microscopic tumor cell deposits (1, 4).Serial sectioning coupled to immunohistochemical analysis has considerably improved the detection of small tumor cell clusters in lymph nodes (5 -10). Occult metastases can indeed be identified in up to 30% of cases previously classified as pN 0 (7 -9), in 14% to 20% of the cases by single lymph node sections (9, 10). Studies based on these procedures have shown that axillary lymph node microinvasion is a prognostic factor for breast cancer patients, and is associated with poorer diseasefree and overall survival (7, 8, 11 -13). As a consequenc...

Rhabdoid colon tumors (RCTs) are rare lesions whose existence as an independent distinct entity remains controversial. To date, 6 RCTs have been reported. This study reports a novel case associated with polyposis coli in a 73-year-old woman. Histologically, the neoplasia was heterogeneous consisting of an adenocarcinoma associated with rhabdoid features. In rhabdoid component, an intense expression of MSH2 was noted but MLH1 was negative. A BRAF V600E mutation and no KRAS mutations were identified. The promoter regions of subset of genes highly specific to characterize the CIMP status (NEUROG1, IGF2, RUNX3, SOCS1, including MLH1) were hypermethylated, suggesting the presence of CIMP+ and MSI high tumor. In conclusion, all RCTs have similar clinical features. The presence of polyposis and adenocarcinoma component as well as the expression of mesenchymal marker suggests a sarcomatous dedifferentiation. It is argued that RCT could be a very aggressive entity of colon, which could benefit from new biological colonic treatments.

BackgroundRhabdoid colorectal tumor (RCT) is a rare, highly aggressive neoplasm recurrent in elderly patients, commonly at the caecum. The molecular mechanisms underlying RCT pathogenesis remain poorly elucidated. The differential diagnosis is with the malignant rhabdoid tumors of infancy characterized by genetic inactivation of SMARCB1 (INI1) or deletions of chromosome 22q12 locus.Materials and methodsTo shed light on RCT pathogenesis, we investigated genetic and epigenetic alterations in two cases of pure and composite RCT and compared them with the profiles of matched adenomas and normal mucosa. Immunohistochemical analysis, FISH, methylation specific PCR and DNA sequencing analysis were performed on paraffin-embedded tissues.ResultsLoss of epithelial markers, (CK20, CDX2 and E-cadherin) and intense vimentin expression was observed in RCTs but neither in the normal mucosa or adenomas. INI1 expression was detected in normal mucosa, adenomas and retained in pure RCT, while it was undetected in composite RCT. Rearrangement of the 22q12 locus was found only in pure RCT. The APC/β-catenin pathway was not altered, while MLH1 immunostaining was negative in RCTs and positive in adenomas and normal mucosa. These expression profiles were associated with V600E BRAF mutation, a progressive accumulation of promoter methylation at specific CIMP loci and additional genes from the normal mucosa to tubular adenoma and RCT.ConclusionsRight-sided RCT could be characterized by epigenetic events and molecular features likely similar to those occurring in the serrated pathway and associated with epithelial-mesenchymal transition. These extremely rare tumors may benefit from the use of new biological molecules specific for colorectal carcinoma.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1641385210804556

BackgroundINI1 (Integrase interactor 1), also known as SMARCB1, is the most studied subunit of chromatin remodelling complexes. Its role in colorectal tumorigenesis is not known.MethodsWe examined SMARCB1/INI1 protein expression in 134 cases of colorectal cancer (CRC) and 60 matched normal mucosa by using tissue microarrays and western blot and categorized the results according to mismatch repair status (MMR), CpG island methylator phenotype, biomarkers of tumor differentiation CDX2, CK20, vimentin and p53. We validated results in two independent data sets and in cultured CRC cell lines.ResultsHerein, we show that negative SMARCB1/INI1 expression (11% of CRCs) associates with loss of CDX2, poor differentiation, liver metastasis and shorter patients’ survival regardless of the MMR status or tumor stage. Unexpectedly, even CRCs displaying diffuse nuclear INI1 staining (33%) show an adverse prognosis and vimentin over-expression, in comparison with the low expressing group (56%). The negative association of SMARCB1/INI1-lack of expression with a metastatic behavior is enhanced by the TP53 status. By interrogating global gene expression from two independent cohorts of 226 and 146 patients, we confirm the prognostic results and identify a gene signature characterized by SMARCB1/INI1 deregulation. Notably, the top genes of the signature (BCR, COMT, MIF) map on the long arm of chromosome 22 and are closely associated with SMARCB1/INI1.ConclusionOur findings suggest that SMARCB1/INI1-dysregulation and genetic hot-spots on the long arm of chromosome 22 might play an important role in the CRC metastatic behavior and be clinically relevant as novel biomarkers.

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