A multicenter study of interobserver variability in pathologic diagnosis of papillary breast lesions on core needle biopsy with WHO classification

Background@#Papillary breast lesions (PBLs) comprise diverse entities from benign and atypical lesions to malignant tumors. Although PBLs are characterized by a papillary growth pattern, it is challenging to achieve high diagnostic accuracy and reproducibility. Thus, we investigated the diagnostic reproducibility of PBLs in core needle biopsy (CNB) specimens with World Health Organization (WHO) classification. @*Methods@#Diagnostic reproducibility was assessed using interobserver variability (kappa value, κ) and agreement rate in the pathologic diagnosis of 60 PBL cases on CNB among 20 breast pathologists affiliated with 20 medical institutions in Korea. This analysis was performed using hematoxylin and eosin (H&E) staining and immunohistochemical (IHC) staining for cytokeratin 5 (CK5) and p63. The pathologic diagnosis of PBLs was based on WHO classification, which was used to establish simple classifications (4-tier, 3-tier, and 2-tier). @*Results@#On WHO classification, H&E staining exhibited ‘fair agreement’ (κ = 0.21) with a 47.0% agreement rate. Simple classifications presented improvement in interobserver variability and agreement rate. IHC staining increased the kappa value and agreement rate in all the classifications. Despite IHC staining, the encapsulated/solid papillary carcinoma (EPC/SPC) subgroup (κ = 0.16) exhibited lower agreement compared to the non-EPC/SPC subgroup (κ = 0.35) with WHO classification, which was similar to the results of any other classification systems. @*Conclusions@#Although the use of IHC staining for CK5 and p63 increased the diagnostic agreement of PBLs in CNB specimens, WHO classification exhibited a higher discordance rate compared to any other classifications. Therefore, this result warrants further intensive consensus studies to improve the diagnostic reproducibility of PBLs with WHO classification.

Lymphomatoid Granulomatosis Involving the Lung and Brain in a Child: A Case Report

Lymphomatoid granulomatosis (LG) is a rare B-cell type angiocentric lymphoproliferative disease that can progress to extranodal lymphoma with high mortality. It most commonly affects the lungs, although extrapulmonary systems, including the brain and skin, can also be involved. LG in pediatric patients has been very rarely reported in the literature with limited imaging features. Herein, we report a pediatric case of LG involving the lung and brain with characteristic imaging findings.

Clinicopathologic characteristics of HER2-positive pure mucinous carcinoma of the breast

Background@#Pure mucinous carcinoma (PMC) is a rare type of breast cancer, estimated to represent 2% of invasive breast cancer. PMC is typically positive for estrogen receptors (ER) and progesterone receptors (PR) and negative for human epidermal growth factor receptor 2 (HER2). The clinicopathologic characteristics of HER2-positive PMC have not been investigated. @*Methods@#Pathology archives were searched for PMC diagnosed from January 1999 to April 2018. Clinicopathologic data and microscopic findings were reviewed and compared between HER2-positive PMC and HER2-negative PMC. We also analyzed the differences in disease-free survival (DFS) and overall survival according to clinicopathologic parameters including HER2 status in overall PMC cases. @*Results@#There were 21 HER2-positive cases (4.8%) in 438 PMCs. The average tumor size of HER2-positive PMC was 32.21 mm (± 26.55). Lymph node metastasis was present in seven cases. Compared to HER2-negative PMC, HER2-positive PMC presented with a more advanced T category (p < .001), more frequent lymph node metastasis (p = .009), and a higher nuclear and histologic grade (p < .001). Microscopically, signet ring cells were frequently observed in HER2-positive PMC (p < .001), whereas a micropapillary pattern was more frequent in HER2-negative PMC (p = .012). HER2-positive PMC was more frequently negative for ER (33.3% vs. 1.2%) and PR (28.6% vs. 7.2%) than HER2-negative PMC and showed a high Ki-67 labeling index. During follow-up, distant metastasis and recurrence developed in three HER2-positive PMC patients. Multivariate analysis revealed that only HER2-positivity and lymph node status were significantly associated with DFS. @*Conclusions@#Our results suggest that HER2-positive PMC is a more aggressive subgroup of PMC. HER2 positivity should be considered for adequate management of PMC.

Human Epidermal Growth Factor Receptor 2-positive Mucinous Carcinoma with Signet Ring Cell Differentiation, Which Showed Complete Response after Neoadjuvant Chemotherapy / 한국유방암학회지

Mucinous carcinoma (MC) is a rare subtype of breast cancer, which is composed of tumor cells floating in the abundant extracellular mucin. This form of cancer is usually estrogen receptor/progesterone receptor positive and human epidermal growth factor receptor 2 (HER2) negative. Here, we present a case of HER2-positive MC with an unusual signet ring cell differentiation. It is very rare that a breast tumor consists entirely of signet ring cells. The tumor showed pathologic complete response (pCR) after neoadjuvant chemotherapy with trastuzumab and pertuzumab. pCR of HER2-positive MC has rarely been described in literature. It is important to consider the biological heterogeneity of MCs for effective management.

Additional lesions seen in magnetic resonance imaging of breast cancer patients: the role of second-look ultrasound and imaging-guided interventions

PURPOSE: The purpose of this study was to investigate the final outcomes of magnetic resonance imaging (MRI)-identified additional lesions (MRALs) in breast cancer patients and the role of second-look ultrasound (SLUS) and imaging-guided interventions. METHODS: We analyzed breast cancer patients with MRALs on preoperative MRI between January and June 2012. MRALs were defined as additional lesions suspected on MRI but not suspected on mammograms or ultrasound. The malignancy rate of MRALs, MRI-based Breast Imaging Reporting and Database System (BI-RADS) category, positional relationship with the index cancer, MRI-concordant lesion visibility on SLUS, performance of imaging-guided interventions, and total mastectomy (TM) rates were evaluated for the confirmed lesions. RESULTS: Among the 119 confirmed lesions, SLUS and imaging-guided interventions were performed in 94 (79.0%) and 82 cases (68.9%), respectively. The malignancy rate was 68.1% (81 of 119), and was significantly higher in BI-RADS 4C-5 lesions than in 4A-4B lesions (94.6% vs. 56.1%, P < 0.01) and in ipsilateral same-quadrant lesions than in contralateral lesions (84.2% vs. 33.3%, P < 0.01). The lesion visibility rate on SLUS was 90.4%. The malignancy rate was not significantly different according to lesion visibility on SLUS. The TM rate in the 98 cases with ipsilateral MRALs was 37.8%, while it was significantly lower in patients who underwent an imaging-guided intervention than in those who did not (27.9% vs. 54.1%, P=0.017). CONCLUSION: MRALs show a high probability of malignancy, especially if they are ipsilateral. SLUS and imaging-guided interventions can eliminate many unnecessary TMs.

TFE3-Expressing Perivascular Epithelioid Cell Tumor of the Breast

Perivascular epithelioid cell tumor (PEComa) is a very rare mesenchymal tumor with a distinctive morphology and immunophenotype. PEComas usually harbor TSC2 alterations, although TFE3 translocations, which occur in MiT family translocation renal cell carcinoma and alveolar soft part sarcoma, are also possible. We recently experienced a case of PEComa with TFE3 expression arising in the breast. An 18-year-old female patient presented with a right breast mass. Histologically, the tumor consisted of epithelioid cells with alveolar structure and showed a diffuse strong expression of HMB45 and TFE3. TSC2 was preserved. Melan A and smooth muscle actin were negative. To our knowledge, this is the first Korean case of PEComa of the breast that intriguingly presented with TFE3 expression.

PIK3CA Mutations and Neoadjuvant Therapy Outcome in Patients with Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: A Sequential Analysis / 한국유방암학회지

PURPOSE: PIK3CA mutation is considered to be a possible cause for resistance to neoadjuvant chemotherapy (NAC) in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. We investigated the association between PIK3CA mutations and the outcome of NAC in HER2-positive breast cancers. METHODS: A total of 100 HER2-positive breast cancer patients who had undergone NAC and surgery between 2004 and 2016 were examined. Mutation status was sequentially assessed in pre-NAC, post-NAC, and recurrent specimens taken from these patients. RESULTS: PIK3CA mutations were identified in the sequential specimens of 17 patients (17.0%). These 17 patients experienced shorter disease-free survival (DFS) than the rest of the patients (58.3 months vs. 119.3 months, p=0.020); however, there was no significant difference in pathologic complete response (pCR) and overall survival (OS) (pCR, 17.6% vs. 33.7%, p=0.191; OS, 84.5 months vs. 118.0 months, p=0.984). While there was no difference in pCR between the wild-type and mutant PIK3CA groups in pre-NAC specimens (25.0% vs. 31.8%, p=0.199), PIK3CA mutations correlated with lower pCR in post-NAC specimens (0.0% vs. 24.3%, p < 0.001). Multivariate analysis revealed significantly worse DFS in the mutant PIK3CA group than in the wild-type group (hazard ratio, 3.540; 95% confidence interval, 1.001–12.589; p=0.050). Moreover, the DFS curves of the change of PIK3CA mutation status in sequential specimens were significantly different (p=0.016). CONCLUSION: PIK3CA mutation in HER2-positive breast cancer was correlated with a lower pCR rate and shorter DFS. These results suggest that PIK3CA mutation is a prognostic marker for NAC in HER2-positive breast cancer, especially in post-NAC specimens.

The Prognostic Impact of Synchronous Ipsilateral Multiple Breast Cancer: Survival Outcomes according to the Eighth American Joint Committee on Cancer Staging and Molecular Subtype

BACKGROUND: In the current American Joint Committee on Cancer staging system of breast cancer, only tumor size determines T-category regardless of whether the tumor is single or multiple. This study evaluated if tumor multiplicity has prognostic value and can be used to subclassify breast cancer. METHODS: We included 5,758 patients with invasive breast cancer who underwent surgery at Samsung Medical Center, Seoul, Korea, from 1995 to 2012. RESULTS: Patients were divided into two groups according to multiplicity (single, n = 4,744; multiple, n = 1,014). Statistically significant differences in lymph node involvement and lymphatic invasion were found between the two groups (p < .001). Patients with multiple masses tended to have luminal A molecular subtype (p < .001). On Kaplan-Meier survival analysis, patients with multiple masses had significantly poorer disease-free survival (DFS) (p = .016). The prognostic significance of multiplicity was seen in patients with anatomic staging group I and prognostic staging group IA (p = .019 and p = .032, respectively). When targeting patients with T1-2 N0 M0, hormone receptor–positive, and human epidermal growth factor receptor 2 (HER2)–negative cancer, Kaplan-Meier survival analysis also revealed significantly reduced DFS with multiple cancer (p = .031). The multivariate analysis indicated that multiplicity was independently correlated with worse DFS (hazard ratio, 1.23; 95% confidence interval, 1.03 to 1.47; p = .025). The results of this study indicate that tumor multiplicity is frequently found in luminal A subtype, is associated with frequent lymph node metastasis, and is correlated with worse DFS. CONCLUSIONS: Tumor multiplicity has prognostic value and could be used to subclassify invasive breast cancer at early stages. Adjuvant chemotherapy would be necessary for multiple masses of T1–2 N0 M0, hormone-receptor-positive, and HER2-negative cancer.

Secretory Carcinoma Arising in a Fibroadenoma: A Brief Case Report

No abstract available.

NanoString nCounter® Approach in Breast Cancer: A Comparative Analysis with Quantitative Real-Time Polymerase Chain Reaction, In Situ Hybridization, and Immunohistochemistry / 한국유방암학회지

PURPOSE: Accurate testing for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) is essential for breast cancer treatment. At present, immunohistochemistry (IHC)/florescence in situ hybridization (FISH) are widely accepted as the standard testing methods. To investigate the value of NanoString nCounter®, we performed its comparative analysis with IHC/FISH and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) for the assessment of ER, PR, and HER2. METHODS: Data on IHC/FISH results for ER, PR, and HER2 in 240 patients from a single tertiary hospital in Korea were collected and compared with NanoString nCounter® and qRT-PCR results at a single institution. RESULTS: Expression levels for each gene using NanoString nCounter® showed good correlation with the corresponding data for protein expression by IHC (p<0.001) and gene amplification status for HER2 (p<0.001). Comparisons between gene expression and IHC data showed good overall agreement with a high area under the curve (AUC) for ESR1/ER (AUC=0.939), PgR/PR (AUC=0.796), and HER2/HER2 (AUC=0.989) (p<0.001). CONCLUSION: The quantification of ER, PgR, and HER2 mRNA expression with NanoString nCounter® may be a viable alternative to conventional IHC/FISH methods.

Evaluation of Pathologic Complete Response in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy: Experience in a Single Institution over a 10-Year Period

BACKGROUND: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) has been associated with favorable clinical outcome in breast cancer patients. However, the possibility that the prognostic significance of pCR differs among various definitions has not been established. METHODS: We retrospectively evaluated the pathologic response after NAC in 353 breast cancer patients and compared the prognoses after applying the following different definitions of pCR: ypT0/is, ypT0, ypT0/is ypN0, and ypT0 ypN0. RESULTS: pCR was significantly associated with improved distant disease-free survival (DDFS) regardless of the definition (ypT0/is, p = .002; ypT0, p = .008; ypT0/is ypN0, p < .001; ypT0 ypN0, p = .003). Presence of tumor deposits of any size in the lymph nodes (LNs; ypN ≥ 0(i+)) was associated with worse DDFS (ypT0 ypN0 vs ypT0 ypN ≥ 0(i+), p = .036 and ypT0/is ypN0 vs ypT0/is ypN ≥ 0(i+), p = .015), and presence of isolated tumor cells was associated with decreased overall survival (OS; ypT0/is ypN0 vs ypT0/is ypN0(i+), p = .013). Residual ductal carcinoma in situ regardless of LN status showed no significant difference in DDFS or OS (DDFS: ypT0 vs ypTis, p = .373 and ypT0 ypN0 vs ypTis ypN0, p = .462; OS: ypT0 vs ypTis, p = .441 and ypT0 ypN0 vs ypTis ypN0, p = .758). In subsequent analysis using ypT0/is ypN0, pCR was associated with improved DDFS and OS in triple-negative tumors (p < .001 and p = .003, respectively). CONCLUSIONS: Based on our study results, the prognosis and rate of pCR differ according to the definition of pCR and ypT0/is ypN0 might be considered a more preferable definition of pCR.

Association between Mutation and Expression of TP53 as a Potential Prognostic Marker of Triple-Negative Breast Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: TP53, the most frequently mutated gene in breast cancer, is more frequently altered in HER2-enriched and basal-like breast cancer. However, no studies have clarified the role of TP53 status as a prognostic and predictive marker of triple-negative breast cancer (TNBC). MATERIALS AND METHODS: We performed p53 immunohistochemistry (IHC), nCounter mRNA expression assay, and DNA sequencing to determine the relationship between TP53 alteration and clinical outcomes of TNBC patients. RESULTS: Seventy-seven of 174 TNBC patients were found to harbor a TP53 mutation. Patients with missense mutations showed high protein expression in contrast to patients with deletion mutations (positivity of IHC: wild type vs. missense vs. deletion mutation, 53.6% vs. 89.8% vs. 25.0%, respectively; p < 0.001). TP53 mRNA expression was influenced by mutation status (mRNA expression [median]: wild type vs. missense vs. deletion mutation, 207.36± 132.73 vs. 339.61±143.21 vs. 99.53±99.57, respectively; p < 0.001). According to survival analysis, neither class of mutation nor protein or mRNA expression status had any impact on patient prognosis. In subgroup analysis, low mRNA expression was associated with poor prognosis in patients with a TP53 missense mutation (5-year distant recurrence-free survival [5Y DRFS]: low vs. high, 50.0% vs. 87.8%; p=0.009), while high mRNA expression with a TP53 deletion mutation indicated poor prognosis (5Y DRFS: low vs. high, 91.7% vs. 75.0%; p=0.316). CONCLUSION: Association between TP53 mutation and expression indicates a potential prognostic marker of TNBC; hence both DNA sequencing and mRNA expression analysis may be required to predict the prognosis of TNBC patients.

Radiologic Findings of Primary Mucinous Cystadenocarcinoma of the Breast: A Report of Two Cases and a Literature Review / 한국유방암학회지

Primary mucinous cystadenocarcinoma (MCA) of the breast is a rare but pathologically distinct breast tumor. There have been some case reports on primary MCA of the breast; however, they have all focused on pathologic findings. Here, we report the radiologic findings of two cases of MCA along with a review of the literature. Breast MCA shows a circumscribed mass with some calcifications on mammography, an intracystic solid mass without increased vascularity or a vascular stalk on ultrasound, and a heterogeneously enhancing mass within a rim-enhancing cyst with intermediate signal intensity on T2-weighted magnetic resonance imaging. These radiologic findings and the presence of mucin in the percutaneous biopsy specimen should suggest the possibility of MCA in the differential diagnosis of a breast tumor.

Chest Wall Lipogranuloma after Hydrogel Implant Rupture: Case Report

We present a 53-year-old woman with a large chest wall mass in the interpectoral space, which was eventually confirmed as a lipogranuloma resulting from hydrogel implant rupture. Ultrasonography (US) showed reduced implant volume with surrounding peri-implant fluid collection, suggesting the possibility of implant rupture. A heterogeneously hypoechoic mass was found between the pectoralis major and minor muscles adjacent to the ruptured implant. On magnetic resonance imaging (MRI), there was a large mass in the left interpectoral space of the upper inner chest wall. The mass showed slightly high signal intensity (SI) on pre-contrast T1-weighted image (WI) with mixed iso and high SI on T2-WI. The signal of the mass was suppressed using the water suppression technique but not with the fat suppression technique on T2-WI. The mass showed diffuse enhancement upon contrast enhancement. The enhancing kinetics showed persistent enhancement pattern. US-guided core needle biopsy revealed a lipogranuloma and removal confirmed a ruptured PIP hydrogel implant.

Breast Metastases from Extramammary Malignancies: Typical and Atypical Ultrasound Features

Breast metastases from extramammary malignancies are uncommon. The most common sources are lymphomas/leukemias and melanomas. Some of the less common sources include carcinomas of the lung, ovary, and stomach, and infrequently, carcinoid tumors, hypernephromas, carcinomas of the liver, tonsil, pleura, pancreas, cervix, perineum, endometrium and bladder. Breast metastases from extramammary malignancies have both hematogenous and lymphatic routes. According to their routes, there are common radiological features of metastatic diseases of the breast, but the features are not specific for metastases. Typical ultrasound (US) features of hematogenous metastases include single or multiple, round to oval shaped, well-circumscribed hypoechoic masses without spiculations, calcifications, or architectural distortion; these masses are commonly located superficially in subcutaneous tissue or immediately adjacent to the breast parenchyma that is relatively rich in blood supply. Typical US features of lymphatic breast metastases include diffusely and heterogeneously increased echogenicities in subcutaneous fat and glandular tissue and a thick trabecular pattern with secondary skin thickening, lymphedema, and lymph node enlargement. However, lesions show variable US features in some cases, and differentiation of these lesions from primary breast cancer or from benign lesions is difficult. In this review, we demonstrate various US appearances of breast metastases from extramammary malignancies as typical and atypical features, based on the results of US and other imaging studies performed at our institution. Awareness of the typical and atypical imaging features of these lesions may be helpful to diagnose metastatic lesions of the breast.

Positive Expression of Insulin-Like Growth Factor-1 Receptor Is Associated with a Positive Hormone Receptor Status and a Favorable Prognosis in Breast Cancer / 한국유방암학회지

PURPOSE: Insulin-like growth factor 1 receptor (IGF-1R) is commonly expressed in primary breast cancers. Understanding the role of IGF-1R signaling in the different subtypes of breast cancer is important because each subtype has a different outcome and requires different treatment modalities. However, the precise biological significance of IGF-1R expression in cancer cells is still unclear. In this study, we examined the expression of IGF-1R in the different molecular subtypes of breast cancer. The effects of IGF-1R expression on the survival rates and outcomes of breast cancer were also examined. METHODS: IGF-1R expression was evaluated immunohistochemically in tissue microarray blocks constructed from 1,198 invasive breast cancer samples collected from six medical institutions. IGF-1R expression was interpreted according to the human epidermal growth factor receptor 2 (HER2)/neu immunohistochemistry scoring system. Scores of 2+ and 3+ were considered positive. RESULTS: Positive IGF-1R expression was observed in 65.4% of invasive breast cancer samples. IGF-1R expression was detected in all cancer subtypes (luminal A, 84.4%; luminal B, 75.9%; HER2, 21.2%; triple-negative, 46.6%) and was found to be associated with a positive hormone receptor status and the absence of HER2 amplification (p<0.001). Positive IGF-1R expression was significantly associated with high survival rates (p=0.014). However, a multivariate analysis revealed that the expression levels of IGF-1R did not achieve statistical significance. In the triple-negative cancer subtype, IGF-1R expression was found to be associated with a lower disease-free survival rate (p=0.031). CONCLUSION: Positive IGF-1R expression is associated with a favorable prognosis in breast cancer. IGF-1R is frequently expressed in the luminal A/B subtypes of breast cancer, and its expression is related to the hormone receptor status.

Polyostotic Fibrous Dysplasia Mimicking Multiple Bone Metastases in a Patient with Ductal Carcinoma In Situ / 한국유방암학회지

Whole-body bone scans and whole body 18F-fluorodeoxyglucose positron emission tomographic/computed tomographic scans are sensitive for detecting bone metastasis in patients with breast cancer. However, it is often difficult to discriminate between bone metastasis and other nonmalignant bone lesions. Polyostotic fibrous dysplasia is a rare disorder characterized by the osteoid medullary cavity filling with fibrous tissue causing bony expansion. We report the case of a 42-year-old female patient with ductal carcinoma in situ, which appeared to have multiple bone metastases on initial work-up images. Subsequently, the bone metastases were identified as polyostotic fibrous dysplasia. The patient underwent modified radical mastectomy and subsequently visited for a second opinion regarding the bony metastases. She underwent right ilium computed tomography-guided biopsy. Pathology was consistent with fibrous dysplasia. This patient received only adjuvant tamoxifen, and 1.5 years later, there was no evidence of recurrence.

Aggressive clinical course of extramammary Paget disease after radiotherapy

Extramammary Paget disease (EMPD) is a rare disease, especially in Asian populations. Surgical resection is considered the primary treatment option. Recently, radiotherapy has been suggested as an EMPD treatment, either as an alternative to surgical resection or in combination with surgical resection. This report reviewed a patient with EMPD who was treated with wide excision of the EMPD site followed by radiotherapy for remaining gross lymph node metastases. The aim of this report was to determine the optimal treatment for advanced EMPD.

Parenchymal Cavernous Hemangioma of the Breast showing Atypical Imaging Features: A Case Report

Vascular tumors of the breast are uncommon and most are angiosarcomas. Breast hemangioma, a rare benign vascular tumor, is usually found as a superficially located mass. We present an unusual case of breast hemangioma located in parenchyma with atypical imaging features.

Congenital Peribronchial Myofibroblastic Tumor: A Case Study and Literature Review

Congenital peribronchial myofibroblastic tumor (CPMT) is a benign pulmonary spindle cell neoplasm of intrauterine and perinatal period, which is thought to arise from primitive peribronchial mesenchyme. We present a case detected incidentally in a one-month-old infant. The solid and partially necrotic tumor involved the right middle and lower lobes of the lung with extension to the diaphragm. Histologically, the tumor was composed of fasciculated monotonous spindle cells, proliferating peribronchiolar cartilage and round cells with rich vasculature, and high mitotic activity was identified in the round cell area. Immunohistochemical and electron microscopic studies showed that the spindle cells were myofibroblastic in phenotype. Although the tumor showed several malignant pathological features, recurrence was not observed in the two-year follow-up period, consistent with the benign clinical behavior of CPMT.