TP53 and/or BRCA1 Mutations Based on CtDNA Analysis as Prognostic Biomarkers for Primary Triple-Negative Breast Cancer.

Precise biomarkers for predicting the therapeutic efficacy of molecularly targeted drugs are limited at the protein level; thus, it has been important to broadly scrutinize individual cancer driver gene mutations for effective cancer treatments. Multiplex cancer genome profiling can comprehensively identify gene mutations that are therapeutic targets using next-generation sequencing (NGS). In addition, circulating tumor DNA (ctDNA) is a DNA fragment released into the blood by tumor cell-derived cell death or apoptosis. Liquid biopsy with ctDNA is a novel clinical test for identifying genetic mutations in an entire population noninvasively, in real-time, and heterogeneously. Although there are several reports on ctDNA, fewer have evaluated ctDNA with NGS before an initial treatment for breast cancer patients. Therefore, we examined whether analyzing tumor-associated gene mutations in primary breast cancer based on ctDNA could serve as a biomarker for prognosis and optimal treatment selection. Ninety-five primary breast cancer patients treated at our department from January 2017 to October 2020 were included. Pretreatment plasma samples were subjected to NGS analysis of ctDNA, and correlations with patients' clinicopathological characteristics were evaluated. Fifty-nine (62.1%) patients were positive for ctDNA. ctDNA tended to be positive in hormone receptor-negative, and TP53 (34%), BRCA1 (20%), and BRCA2 (17%) gene mutations were more frequent. Regarding recurrence-free survival, the prognosis was poor in the TP53 and/or BRCA1 mutation-positive groups, especially in triple-negative breast cancer (TNBC) patients. In conclusion, the results of this study indicate that ctDNA with liquid biopsy could identify the poor prognosis group before treatment among TNBC patients and for those for whom optimal treatment selection is desirable; additionally, optimal treatment could be selected according to the ctDNA analysis results.

Beckwith-Wiedemann syndrome with juvenile fibrous nodules and lobular breast tumors: a case report and review of the literature.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is a genomic imprinting disorder caused by diverse genetic and/or epigenetic disorders of chromosome 11p15.5. BWS presents with a variety of clinical features, including overgrowth and an increased risk of embryonal tumors. Notably however, reports of patients with BWS and breast tumors are rare, and the association between these conditions is still unclear. Insulin-like growth factor-2 (IGF2) expression is known to be associated with the development of various cancers, including breast cancer, and patients with BWS with specific subtypes of molecular defects are known to show characteristic clinical features and IGF2 overexpression. CASE PRESENTATION: A 17-year-old girl who had been diagnosed with BWS based on an umbilical hernia, hyperinsulinemia, and left hemihypertrophy at birth, visited our department with a gradually swelling left breast. Her left breast was markedly larger than her right breast on visual examination. Imaging examinations showed two tumors measuring about 10 cm each in the left breast, and she was diagnosed with juvenile fibroadenoma following core needle biopsy. The two breast tumors were removed surgically and the patient remained alive with no recurrence. The final diagnosis was juvenile fibroadenoma without malignant findings. Immunohistochemical staining using IGF2 antibody revealed overexpression of IGF2 in the cytoplasm of ductal epithelial cells. Because of her clinical features and IGF2 overexpression, molecular defects of 11p15.5 including a possible genetic background of paternal uniparental disomy of chromosome 11 or hypermethylation of imprinting center 1 was suspected. CONCLUSIONS: In this case, overexpression of IGF2 suggested a possible relationship between BWS and breast tumors. Moreover, the characteristic clinical features and IGF2 staining predicted the subtype of 11p15.5 molecular defects in this patient.

Granzyme B Expression in the Tumor Microenvironment as a Prognostic Biomarker for Patients with Triple-Negative Breast Cancer.

Tumor-infiltrating lymphocytes in the tumor microenvironment are important in the treatment of triple-negative breast cancer (TNBC). Cytotoxic T cells produce cytokines and cytotoxic factors, such as perforin and granzyme, which induce apoptosis by damaging target cells. To identify biomarkers of these cells, we investigated granzyme B (GZMB) in the tumor microenvironment as a biomarker of treatment response and prognosis in 230 patients with primary TNBC who underwent surgery without preoperative chemotherapy between January 2004 and December 2014. Programmed cell death ligand 1 (PD-L1) positivity was defined as a composite positive score ≥10 based on the PD-L1 immunostaining of tumor cells and immune cells. GZMB-high was defined as positivity in ≥1% of tumor-infiltrating lymphocytes (TILs). Among the 230 TNBC patients, 117 (50.9%) had CD8-positive infiltrating tumors. In the PD-L1-positive group, a Kaplan-Meier analysis showed that GZMB-high TNBC patients had better recurrence-free survival (RFS) and overall survival (OS) than GZMB-low patients and that OS was significantly longer (RFS: p = 0.0220, OS: p = 0.0254). A multivariate analysis also showed significantly better OS in PD-L1- and GZMB-high patients (hazard ratio: 0.25 (95% IC: 0.07-0.88), p = 0.03). Our findings indicate that GZMB is a useful prognostic biomarker in PD-L1-positive TNBC patients.

Intracholecystic papillary neoplasm associated with invasive carcinoma of the remnant gallbladder after subtotal cholecystectomy: a case report.

BACKGROUND: Intracholecystic papillary neoplasm (ICPN) of the gallbladder is a rare tumor and a relatively new concept. Therefore, the natural history and imaging characteristics of ICPN have not yet been fully documented. Moreover, cases who underwent curative resection for remnant gallbladder cancer, including ICPN with associated invasive carcinoma, have been rarely reported. We report a resected case of ICPN of the remnant gallbladder with associated invasive carcinoma for which we could observe a temporal change in imaging findings until malignant transformation. CASE PRESENTATION: A 79-year-old female patient with a surgical history of subtotal cholecystectomy for acute cholecystitis was an ambulatory patient of our institution because of postoperative surveillance for colon cancer. Ultrasonography and computed tomography incidentally detected a small nodule in the cystic remnant gallbladder. The nodule had increased in size 3 months later; thus, additional investigations were performed. Magnetic resonance imaging revealed a 10-mm enhanced nodule without evidence of extraluminal invasion. Diffusion-weighted magnetic resonance imaging revealed restricted diffusion of the lesion, and positron emission tomography revealed marked accumulation in the lesion. The lesion was diagnosed as suspicious for a malignant remnant gallbladder tumor. Therefore, remnant cholecystectomy with gallbladder bed resection was performed. Because preoperative endoscopic retrograde cholangiography revealed a relatively long intact cystic duct, extrahepatic bile duct resection was planned to be omitted. Intraoperatively, the hepatic and duodenal side bile duct where the cystic duct diverged was taped. Using these tapes, which permitted pulling the bile duct, the cystic duct located behind the bile duct could be safely exposed. The lesion was pathologically diagnosed as biliary morphologic ICPN with associated invasive carcinoma. CONCLUSIONS: Because remnant cholecystectomy is an uncommon procedure and technically difficult, accurate preoperative investigation and surgical planning are important to prevent bile duct injury and omit extrahepatic bile duct resection. In the present case, intracystic change could be detected incidentally at an early stage because of previous remnant gallbladder producing (reconstituting) subtotal cholecystectomy and surveillance for other disease. This case suggests the existence of ICPN that can progress to invasive carcinoma during a short period.

Granulocyte-colony stimulating factor-producing malignant phyllodes tumor of the breast: a rare case.

BACKGROUND: Granulocyte-colony stimulating factor (G-CSF)-producing tumors can cause leukocytosis despite an absence of infection. G-CSF-producing tumors have been reported in various organs such as the lung, esophagus, and stomach but rarely in the breast. We report a case of G-CSF-producing malignant phyllodes tumor of the breast. CASE PRESENTATION: An 84-year-old woman visited our hospital complaining of a lump in her left breast without fever and pain. Laboratory tests revealed elevated white blood cell (WBC) count and G-CSF levels. A malignant tumor of the breast was diagnosed by core needle biopsy. We performed a total mastectomy and sentinel lymph node biopsy. The tumor was identified as a G-CSF-producing malignant phyllodes tumor. Within 7 days after surgery, the patient's WBC count and G-CSF level had decreased to normal levels. She is alive without recurrence 13 months after surgery. CONCLUSIONS: We encountered a rare case of G-CSF-producing malignant phyllodes tumor of the breast. PET-CT revealed diffuse accumulation of FDG in the bone. Phyllodes tumors need to be differentiated from bone metastasis, lymphoma, and leukemia. We must be careful to not mistake this type of tumor for bone marrow metastasis.

A rare case of symptomatic grossly-visible biliary intraepithelial neoplasia mimicking cholangiocarcinoma.

BACKGROUND: Biliary intraepithelial neoplasia (BilIN) is often distinguished by what it is not: the precancerous lesions are not mass-forming, are not the cause of bile duct obstruction, and are small enough (less than 5 mm long) to evade detection by the naked eye. Here, we describe an atypical case of BilIN resembling cholangiocarcinoma (CC) that was large enough to be identified by diagnostic imaging and presented with obstructive jaundice caused by a hematoma in the common bile duct (CBD). CASE PRESENTATION: A 64-year-old man presented to our hospital with upper abdominal pain and anorexia. Initial laboratory examinations revealed increased total bilirubin and a computed tomography (CT) scan revealed a dilated CBD. Gastroenterologists performed an endoscopic sphincterotomy (EST), which revealed that the cause of obstructive jaundice was a hematoma in the CBD. Enhanced CT scan and magnetic resonance cholangiopancreatography (MRCP) performed after the hematoma was drained showed improved dilation of the CBD and an enhanced wall thickness of bile duct measuring 25 × 10 mm at the union of the cystic and common hepatic ducts. A cholangioscope detected an elevated tumor covered by sludge in the CBD, and we performed an extrahepatic bile duct resection and cholecystectomy. The postoperative course was uneventful and the pathological examination of the resected tumor revealed that although the ulcerated lesion had inflammatory granulation tissue, it did not contain the components of invasive carcinoma. Many consecutive intraepithelial micropapillary lesions spread around the ulcerated lesion, and the epithelial cells showed an increased nucleus-to-cytoplasm ratio, nuclear hyperchromasia, and architectural atypia. The pathological diagnosis was BilIN-1 to -2. Immunohistochemical staining showed that S100P was slightly expressed and MUC5AC was positive, while MUC1 was negative and p53 was not overexpressed. CONCLUSION: We experienced an atypical case of BilIN mimicking CC that presented with obstructive jaundice caused by a hematoma in the CBD. Our case suggested that the occurrence of BilIN can be triggered by factors other than inflammation, and can grow to a size large enough to be detected by image analyses.