Ji Shin Lee

Background: This study aimed to determine the prevalence of human epidermal growth factor receptor 2 (HER2)–ultralow breast cancer among cases initially classified as HER2 immunohistochemistry (IHC) 0 and assess interobserver variability in interpreting low-level HER2 expression. Methods: In this multicenter retrospective study, all invasive breast cancer cases diagnosed between January and December 2022 across 10 Korean institutions were retrieved. Institutional pathologists reexamined HER2 IHC slides originally reported as IHC 0 according to the 2018 American Society of Clinical Oncology/College of American Pathologists guidelines and reclassified them as HER2-null (0), HER2-ultralow (0+), or HER2-low (1+). Slides from 10% of HER2-null and HER2-ultralow cases were digitized for central review and independently assessed by two pathologists, with discrepancies resolved by consensus. Results: Among 8,026 cases, 2,836 cases (35.5%) were initially reported as IHC 0. Upon re-review, 1,673 (59.0%), 1,139 (40.2%), and 24 (0.8%) cases were reclassified as HER2-null, HER2-ultralow, and HER2-low, respectively. The prevalence of HER2-ultralow breast cancer varied considerably across institutions (23.7%–78.1%). Central review of 268 digitized cases showed concordance in 193 cases (72.0%). Among the 75 discordant cases, 54 tumors (72.0%) were upgraded from HER2-null to HER2-ultralow, and 18 (24.0%) tumors were upgraded from HER2-ultralow to HER2-low. Furthermore, two tumors (2.7%) were downgraded from HER2-ultralow to HER2-null. Conclusions: Approximately 40% of cases initially categorized as IHC 0 were reclassified as HER2-ultralow. The substantial inter-institutional variability observed in interpreting low-level HER2 expression highlights the need for standardized training and quality assurance to ensure accurate identification of patients eligible for HER2-targeted antibody–drug conjugates.

Background/Objectives: Elevated expression of human epididymis protein 4 (HE4) has been observed in breast cancer and is associated with cancer progression; however, its role in ductal carcinoma in situ (DCIS) remains unclear. This study aimed to evaluate HE4 levels in serum and tissue from patients with DCIS and their correlation with clinicopathological features. Methods: Preoperative serum HE4 levels were measured in 59 DCIS patients. HE4 mRNA and protein expression in DCIS and adjacent normal tissues were assessed using RNAscope in situ hybridization and immunohistochemistry, respectively. An additional independent tissue microarray of 41 DCIS cases was also analyzed for HE4 expression in tumor tissue only. Furthermore, the BreastMark database was applied to assess the prognostic significance of HE4 expression in a larger cohort of breast cancer. Results: Serum HE4 levels (mean ± SD: 39.4 ± 11.9 pmol/L) were within the normal range and showed no significant correlation with clinicopathological parameters except menopausal status. HE4 expression was significantly higher in DCIS tissues compared to adjacent normal tissues, with a positive correlation between mRNA and protein levels (r = 0.771, p < 0.001). High HE4 mRNA and protein expression was associated with ER positivity, HER2 negativity, low stromal tumor-infiltrating lymphocyte density, and HR+/HER2− subtypes, but was not predictive of DCIS recurrence. In breast cancer patients, high HE4 expression was significantly correlated with improved survival outcomes. Conclusions: Although serum HE4 is not elevated in DCIS, high HE4 expression in tissue is associated with favorable clinicopathological features. These findings highlight the need for further investigation into the potential prognostic role of HE4.

Background/Objectives: Elevated human epididymis protein 4 (HE4) expression has been observed in breast cancer and is linked to cancer progression; however, its role in ductal carcinoma in situ (DCIS) remains unclear. This study evaluated HE4 levels in DCIS serum and tissue and their correlation with clinicopathological features. Methods: Preoperative serum HE4 levels were measured in 59 DCIS patients. HE4 mRNA and protein expression were assessed in DCIS and adjacent normal tissues via RNAscope in situ hybridization and immunohistochemistry. An independent tissue microarray of 41 DCIS cases was also analyzed, and the BreastMark database was applied to explore the prognostic relevance of HE4. Results: Serum HE4 levels (mean ± SD: 39.4 ± 11.9 pmol/L) were within the normal range and did not significantly correlate to clinicopathological parameters except menopause status. HE4 expression was significantly higher in DCIS tissues than in adjacent normal tissues, with mRNA and protein levels positively correlated (r = 0.771, p < 0.001). High HE4 mRNA and protein expression was associated with ER positivity, HER2 negativity, low stromal tumor-infiltrating lymphocyte density, and HR+/HER2- subtypes but did not predict DCIS recurrence. High HE4 expression in breast cancer patients correlated with better survival outcomes. Conclusions: While serum HE4 is not elevated in DCIS, high HE4 expression in tissues is linked to favorable clinicopathological characteristics; thus, further research is warranted on its potential prognostic role.

While some forms of invasive or in situ carcinoma of the breast may be partly composed of signet-ring cells, signet-ring cells rarely become a prominent feature of pleomorphic lobular carcinoma in situ (LCIS). We report a rare example of pleomorphic LCIS composed predominantly of signet-ring cells with a papillary pattern mimicking ductal carcinoma in situ (DCIS). A 58-year-old woman presented with a mass in the left breast detected by ultrasonography. Fourteen years previously, the patient underwent right breast-conserving surgery for invasive breast carcinoma of no special type. Ultrasonography revealed an irregular parallel, angular hypoechoic mass measuring 1.5 cm in the left breast. An ultrasound-guided core needle core biopsy was conducted. Microscopically, the lesion was composed of epithelial cells supported by a fibrovascular stroma. The majority (> 70%) of the lesional cells between the fibrovascular stalks showed signet-ring cell features. Some of the nuclei of the signet-ring cells showed intermediate-grade atypia. A mucicarmine stain showed intracytoplasmic mucin in the signet-ring cells. Immunohistochemistry for E-cadherin was negative in the tumor cells. After surgical excision, the final diagnosis was a pleomorphic LCIS. To our knowledge, there have been no previous reports of pleomorphic LCIS consisting primarily of signet-ring cells with a papillary pattern.

This study assessed pretreatment breast MRI coupled with machine learning for predicting early clinical responses to neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC), focusing on identifying non-responders. A retrospective analysis of 135 TNBC patients (107 responders, 28 non-responders) treated with NAC from January 2015 to October 2022 was conducted. Non-responders were defined according to RECIST guidelines. Data included clinicopathologic factors and clinical MRI findings, with radiomics features from contrast-enhanced T1-weighted images, to train a stacking ensemble of 13 machine learning models. For subgroup analysis, propensity score matching was conducted to adjust for clinical disparities in NAC response. The efficacy of the models was evaluated using the area under the receiver-operating-characteristic curve (AUROC) before and after matching. The model combining clinicopathologic factors and clinical MRI findings achieved an AUROC of 0.752 (95% CI 0.644–0.860) for predicting non-responders, while radiomics-based models showed 0.749 (95% CI 0.614–0.884). An integrated model of radiomics, clinicopathologic factors, and clinical MRI findings reached an AUROC of 0.802 (95% CI 0.699–0.905). After propensity score matching, the hierarchical order of key radiomics features remained consistent. Our study demonstrated the potential of using machine learning models based on pretreatment MRI to non-invasively predict TNBC non-responders to NAC.

There are markers of metabolic coupling in breast cancer. Loss of caveolin‑1 (Cav‑1) and upregulation of monocarboxylate transporters (MCTs), especially MCT1 and MCT4, serve an important role in metabolic coupling necessary for release and uptake of metabolites. However, the occurrence of these phenomena in phyllodes tumors (PTs) of the breast is unclear. A total of 101 PTs (60 benign, 26 borderline and 15 malignant) and nine breast tissue samples with no pathological lesions were analyzed. Immunohistochemical staining for Cav‑1, MCT1 and MCT4 was performed using tissue microarray and their expression in both stromal and epithelial components was assessed. Cav‑1 expression in PTs demonstrated a significant decrease in the stromal component compared with that in the normal breast tissues (P<0.001). MCT1 expression in both epithelial and stromal components was significantly increased in PTs, compared with that in normal breast tissues (both P<0.001). Stromal MCT1 and MCT4 expression were different depending on tumor grade of PTs, and stromal MCT1 expression significantly increased with increasing tumor grade (P<0.001). Although not statistically significant, stromal Cav‑1 expression notably decreased with increases in PT grade. High stromal MCT1 expression was significantly associated with lower disease‑free survival rate in comparison with low stromal MCT1 expression (P<0.05). These results suggested that changes in protein expression of Cav‑1, MCT1 and MCT4 may be associated with tumorigenesis and progression of PTs of the breast.

Loss of caveolin-1 (Cav-1) and upregulation of monocarboxylate transporters (MCTs, especially MCT1 and MCT4) in respectively tumor-associated stromal cells and malignant epithelial cells of invasive carcinoma have been found to play an important role in the metabolic coupling. However, this phenomenon has only been scarcely described in pure ductal carcinoma in situ (DCIS) of the breast. mRNA and protein expression levels of Cav-1, MCT1, and MCT4 in nine pairs of DCIS tissues and matched normal tissues were examined by quantitative real-time polymerase chain reaction, RNAscope in situ hybridization, and immunohistochemistry. Immunohistochemical staining of Cav-1, MCT1, and MCT4 in 79 DCIS samples was also done using tissue microarray. Cav-1 mRNA expression was significantly lower in DCIS tissues than in their corresponding normal tissues. In contrast, MCT1 and MCT4 mRNA expression levels were higher in DCIS tissues than in corresponding normal tissues. Low stromal Cav-1 expression was significantly associated with high nuclear grade. High epithelial MCT4 expression was associated with larger tumor size and human epidermal growth factor 2 positivity. At a mean follow-up of 10 years, patients with high epithelial MCT1/high epithelial MCT4 expression showed shorter disease-free survival than those with other expressions. No significant association was observed between stromal Cav-1 expression and epithelial MCT 1 or MCT4 expression. Changes in Cav-1, MCT1, and MCT4 are associated with carcinogenesis of DCIS. A high epithelial MCT1/high epithelial MCT4 expression might be associated with a more aggressive phenotype.

Lee HJ, et al. Korean J Radiol. 2023 Jun;24(6):498-511. https://doi.org/10.3348/kjr.2022.0731

Background: Prostate-specific membrane antigen (PSMA) overexpression has been observed in the endothelial neovasculature of several solid malignancies. This study aimed to identify PSMA expression in the primary tumor of classical papillary thyroid carcinoma (PTC) and assess the correlation between the degree of PSMA expression and recurrence. Methods: We reviewed the electronic medical records of patients who underwent total thyroidectomy and central neck dissection, with or without lateral neck dissection, for classical PTC between 2009 and 2014 at our institution. Recurrence was defined as a structural disease based on histological confirmation on follow-up. Fifty-one patients with the recurrent structural disease were matched, using a propensity score matching method, to patients with no disease evidence during follow-up. Clinicopathological and follow-up data were collected for 102 patients. The monoclonal mouse anti-human PSMA/FOLH1/NAALADase I antibody was used for staining the primary tumor. The score of PSMA expression was classified as negative (< 5% positivity), weak (5–10 % positivity), moderate (11–49% positivity), and strong (more than 50% positivity). Clinicopathological factors were compared between patients with low and high PSMA expression. Moreover, whether the degree of PSMA expression and clinicopathological factors could predict recurrence was investigated. Cox proportional hazard regression models were used to evaluate the risk of recurrence. Results: There was no significant difference in clinicopathological factors between low (negative or weak) and high (moderate or strong) PSMA expression. Gross extrathyroidal extension (ETE), absence of chronic lymphocytic thyroiditis, and high PSMA expression were all associated with lower recurrence-free survival (RFS) rate in a univariate analysis. In multivariate analysis, gross ETE (hazard ratio [HR], 2.279; 95% confidence interval [CI], 1.257−4.132; p = 0.007) and high PSMA expression (HR, 1.895; 95% CI, 1.073−3.348; p = 0.028) were associated with poor RFS. Conclusions: High PSMA expression in the primary tumor was a significant factor in predicting recurrence in classic PTC. PSMA could be a potential biomarker for personalized management for PTC.