Reiko Yoshida

Clinicopathological significance of invasive micropapillary carcinoma component in invasive breast carcinoma

Invasive micropapillary carcinoma (IMP) of the breast is a rare variant of invasive breast carcinoma and most cases of IMP are associated with nodal metastasis and lymphatic invasion. Lesions composed of an IMP component alone are rare and almost always coexist with other pathological components. However, few reports have documented IMP along with its proportion and the coexistent pathological type. We analyzed the total 486 breast cancer lesions operated in our hospital in 1998. We classified the lesions into five groups by the proportion of the IMP component in each lesion. Then we evaluated the incidence of nodal metastasis and lymphatic invasion in each group. The incidence of the invasive carcinoma containing any IMP components was 8.4%. The incidence of nodal metastasis and lymphatic invasion in lesions with an IMP component were significantly higher than that in those with no IMP. No correlation was seen between the incidence of nodal metastasis and the coexistent pathological type, shape of tumor clusters, nuclear grade and the expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 and gross cystic disease fluid protein‐15 in IMP components. The presence of IMP components was a significant predictive factor for nodal metastasis, even if it is detected in only a small proportion of the tumor.

The Costello syndrome: Are nasal papillomata essential?

SummaryTwo patients with the Costello syndrome are presented. One was a 7-year-old girl with a history of infantile hypotonia and feeding difficulties. The other was a 3 5/12-year-old boy with a history of neonatal sepsis and respiratory problems. Both had relative macrocephaly at birth, curly hair, large ear lobes, epicanthic folds, a low nasal bridge, thick lips, a short and wide nose, a short neck, a barrel chest, redundant skin, tight Achilles tendons, and pes equinovarus. Nasal papillomata, as described in Costellos two patients, were absent in both patients. Borochowitz et al. (1992) described five patients with what we interpreted as the Costello syndrome but without nasal papillomata. In view of these findings, nasal papillomata are not likely to be essential in the diagnosis of the Costello syndrome.

Mutation status of RAD51C, PALB2 and BRIP1 in 100 Japanese familial breast cancer cases without BRCA1 and BRCA2 mutations

In addition to BRCA1 and BRCA2, RAD51C, PALB2 and BRIP1 are known as breast cancer susceptibility genes. However, the mutation status of these genes in Japanese familial breast cancer cases has not yet been evaluated. To this end, we analyzed the exon sequence and genomic rearrangement of RAD51C, PALB2 and BRIP1 in 100 Japanese patients diagnosed with familial breast and ovarian cancer and without BRCA1 and BRCA2 mutations. We detected a large deletion from exons 6 to 9 in RAD51C, 4 novel BRIP1 missense variants containing 3 novel non‐synonymous variants, c.89A>C, c.736A>G and c.2131A>G, and a splice donor site variant c.918+2T>C. No deleterious variant of PALB2 was detected. The results of pedigree analysis showed that the proband with a large deletion on RAD51C had a family history of both breast and ovarian cancer, and the families of probands with novel BRIP1 missense variants included a male patient with breast cancer or many patients with breast cancer within the second‐degree relatives. We showed that the mutation frequency of RAD51C in Japanese familial breast cancer cases was similar to that in Western countries and that the prevalence of deleterious mutation of PALB2 was possibly lower. Furthermore, our results suggested that BRIP1 mutation frequency in Japan might differ from that in Western countries.

High rate of occult cancer found in prophylactic mastectomy specimens despite thorough presurgical assessment with MRI and ultrasound: findings from the Hereditary Breast and Ovarian Cancer Registration 2016 in Japan

PurposeProphylactic surgery is a preemptive strategy for hereditary breast and ovarian cancer (HBOC). Prophylactic mastectomy (PM) reduces breast cancer risk by > 90%. The aim of our study is to analyze the information of the Japanese pedigrees and to utilize the results for clinical practice.MethodsWe statistically analyzed records of HBOC registrees who had undergone BRCA1/2 genetic testing at seven medical institutions up until 2016. In the cases of PM, we examined breasts with the use of mammography (MMG), ultrasound (US), and magnetic resonance imaging (MRI) before surgery. After PM, the specimens were divided about 1 cm serially and examined in their entirety.ResultsOf 1527 registrees who underwent BRCA testing, 1125 (73.7%) were negative for BRCA1/2 mutation, 297 (19.5%) were positive for BRCA1/2 mutation (BRCA1/2MUT+), and 105 (6.9%) had uncertain results. To decide whether to undergo total mastectomy vs. breast-conserving surgery (BCS), 370 registrees underwent presurgical genetic testing. During the follow-up period, four new-onset breast cancers were found among the 55 non-affected BRCA carriers. Among the 73 BRCA1/2MUT+ carriers who underwent BCS, 3 were found to have ipsilateral breast cancer. Of 189 BRCA1/2MUT+ carriers with unilateral breast cancer, 8 were found to have contralateral breast cancer. Of 53 PM specimens, 6 (11.3%) were found to have occult breast cancer despite using MMG, US, and MRI.ConclusionsOur report showed a relatively higher incidence rate of occult cancer at 11.3% in PM specimens despite thorough pre-operative radiological evaluations, which included a breast MRI. Considering the occult cancer rates and the various pathological methods of our study and published studies, we propose the necessity of a histopathological protocol.

Peking University - Juntendo University Joint Symposium on Cancer Research and Treatment: Clinical Practice for Hereditary Breast and Ovarian Cancer (HBOC) in Japan

Hereditary breast and ovarian cancer (HBOC) patients with BRCA1/2 mutation are estimated to be approximately 1,560,000 in Japan. But general doctors and medical staff do not fully recognize the significance of medical intervention for HBOC in Japan in spite of the large number of potential patients. Thus, investigation into the actual conditions of HBOC has not been established. So, we have tried to establish a registration system to clarify the clinical and genetic characteristics of HBOC in Japan. Risk reducing salpingo-oophorectomy (RRSO) has been performed as a clinical examination in our hospital. Average age at the time of RRSO was 49 years. And many of them have a family history of ovarian cancer, with a frequency of 63.3%. Pathological examination revealed a p53 signature in one case out of 30 cases, but no occult cancers were observed at my institute. Genetic test for BRCA1/2 could also be used worldwide for companion diagnosis for the PARP2 inhibitor. Appropriate recognition for HBOC by general medical staff and cooperation with other departments will be required.

Evaluation of the BRCA1 and BRCA2 mutation prediction models in Japanese patients with breast cancer.

46 Background: The breast cancer genetic risk models for predicting BRCA1/2 mutation are widely used before genetic testing. BRCAPRO and Myriad II are common in Europe and America, and KOHBRA BRCA risk calculator (KOHCal) is utilized in the Asian model. However, it is unknown whether these mutation prediction models are useful in Japanese. In this study, we evaluated the accuracy of BRCAPRO, Myriad II and KOHCal in Japanese patients with breast cancer. METHODS We compared sensitivity and specificity with the 10% cut off value in 131 patients with breast cancer who underwent comprehensive BRCA1/2 genetic testing at Showa University Hospital between 2011 to 2014. All patients met the genetic testing criteria of NCCN Guidelines (Genetic/Familial High-Risk Assessment: Breast and Ovarian ver.1 2014) and were received counseling before genetic testing. We assessed validity of each model by constructing receiver operating characteristic (ROC) curves, and evaluating the area under each ROC curve (AUC). The carrier probabilities of BRCA1/2 with Myriad II were calculated using BRCA risk calculator from the Myriad company1), with BRCAPRO using the CancerGene software program (version 6.0) from the University of Texas South-western Medical Cernter2), and with KOHCal using KOHBRA BRCA risk calculator from the KOHBRA Study website (www.kohbra.kr)3). RESULTS DNA analysis identified 31 deleterious mutations (23.7%) and 10 unclassified variants (7.6%). The sensitivity of KOHcal (87.1%) was higher than BRCAPRO 67.7%) and Myriad II (72.2%) . BRCAPRO (AUC=0.882) had higher diagnostic accuracy than KOHCal (AUC=0.810) and Myriad II (AUC=0.763). KOHCal might be most suitable model to pick up patients for further genetic testing because its sensitivity was higher than Myriad II and BRCAPRO, although it had lower specificity than the other. CONCLUSION Our results suggest that BRCAPRO and KOHCal are useful in Japanese patients with breast cancer for decision making for further genetic testing for BRCA1/2 mutations.