Tall cell carcinoma of the breast with reversed polarity - a report of three cases with a review of the literature.

Tall cell carcinoma with reverse polarity (TCCRP) is a rare special type of breast epithelial neoplasm presented by columnar cells with opposite nuclear polarity, solid and solid-papillary architecture, and frequent IDH2 gene alterations. Hereby, the authors present three cases of TCCRP in women aged 56, 66 and 67 years with maximum tumour sizes of 29 mm, 10 mm and 8 mm. Tumours showed histomorphological characteristics of TCCRP supported by immunohistochemical profile of tumour cells, in which positive expression of CK7, CK5/6, GCDFP15, mammaglobin, GATA3 and calretinin and negativity of CK14, p63, TTF1, thyroglobulin and neuroendocrine markers were demonstrated. Two tumours were triple negative, and in one tumour, only weak focal ER expression was noted along with PR and HER2 negativity. Pathogenic somatic variants in mutational hotspot region p.R172 in IDH2 gene were detected using NGS technology in all three tumours. Moreover, in two of these tumours, the most common pathogenic variants p.E545A and p.H1047R of PIK3CA were identified. TCCRP represents a rare breast neoplasm of low malignant potential, the incidence of which will probably increase due to the more clearly defined histomorphological, immunohistochemical and molecular-genetic characteristics, which were all responsible for including this entity into the 5th edition of WHO classification breast tumours.

Partial loss of heterozygosity events at the mutated gene in tumors from MLH1/MSH2 large genomic rearrangement carriers.

BACKGROUND: Depending on the population studied, large genomic rearrangements (LGRs) of the mismatch repair (MMR) genes constitute various proportions of the germline mutations that predispose to hereditary non-polyposis colorectal cancer (HNPCC). It has been reported that loss of heterozygosity (LOH) at the LGR region occurs through a gene conversion mechanism in tumors from MLH1/MSH2 deletion carriers; however, the converted tracts were delineated only by extragenic microsatellite markers. We sought to determine the frequency of LGRs in Slovak HNPCC patients and to study LOH in tumors from LGR carriers at the LGR region, as well as at other heterozygous markers within the gene to more precisely define conversion tracts. METHODS: The main MMR genes responsible for HNPCC, MLH1, MSH2, MSH6, and PMS2, were analyzed by MLPA (multiplex ligation-dependent probe amplification) in a total of 37 unrelated HNPCC-suspected patients whose MLH1/MSH2 genes gave negative results in previous sequencing experiments. An LOH study was performed on six tumors from LGR carriers by combining MLPA to assess LOH at LGR regions and sequencing to examine LOH at 28 SNP markers from the MLH1 and MSH2 genes. RESULTS: We found six rearrangements in the MSH2 gene (five deletions and dup5-6), and one aberration in the MLH1 gene (del5-6). The MSH2 deletions were of three types (del1, del1-3, del1-7). We detected LOH at the LGR region in the single MLH1 case, which was determined in a previous study to be LOH-negative in the intragenic D3S1611 marker. Three tumors displayed LOH of at least one SNP marker, including two cases that were LOH-negative at the LGR region. CONCLUSION: LGRs accounted for 25% of germline MMR mutations identified in 28 Slovakian HNPCC families. A high frequency of LGRs among the MSH2 mutations provides a rationale for a MLPA screening of the Slovakian HNPCC families prior scanning by DNA sequencing. LOH at part of the informative loci confined to the MLH1 or MSH2 gene (heterozygous LGR region, SNP, or microsatellite) is a novel finding and can be regarded as a partial LOH. The conversion begins within the gene, and the details of conversion tracts are discussed for each case.