Guo, Ruifeng

ABSTRACT A previously healthy 29-year-old man presented with abdominal pain and was found to have a liver mass with periductal infiltration and a stricture of the common bile duct, concerning for cholangiocarcinoma. Hepatic function panel disclosed alanine transaminase 293 U/L, aspartate aminotransferase 122 U/L, γ-glutamyl transferase 2019 U/L, normal total bilirubin, carcinoembryonic antigen, and carbohydrate antigen 19-9. Biopsy established the diagnosis of diffuse large B-cell lymphoma, with no underlying hepatic disease. He was started on polatuzumab-rituximab-cyclophosphamide-doxorubicin-prednisone chemotherapy and achieved complete tumor response. This case highlights the importance of a thorough evaluation of liver tumors and the critical role of tissue diagnosis.

Abstract Introduction and rationale: There is a wide-spread urgent need for an objective reproducible diagnostic tool capable of precisely classifying atypical mammary lesions into cancer vs. benign. Current diagnostic methods in pathology rely on routine and highly subjective histomorphologic and immunophenotypic features. Some authors report a 35% error rate in pathologic interpretation of atypical lesions of the breast (Elmore, 2015). Diagnostic variability can drop to the flip-of-the-coin 50%, even amongst expert breast pathologists (Tozbekian, 2017; Samples, 2017) and is largely attributed to the lack of innovative tools to adequately distinguish biologic differences (Allison, 2016), resulting in diagnoses that are described as “murky” and “arbitrary” (Khoury, 2022). Genomic imprinting, a vital epigenetic regulatory mechanism, is critical in mammalian development and tumorigenesis (Barlow, 2014, Murrell, 2006). Typically, imprinted genes exhibit parent-specific allele silencing through differential methylation. However, in cancer, this regulation often breaks down, resulting in the aberrant activation of the typically silenced allele—a phenomenon known as loss of imprinting (LOI) (Jelinic, 2016). LOI is considered one of the earliest molecular changes in cancer development, occurs early in tumorigenesis, making it ideal for identifying precursor lesions. Objectives: We hypothesize loss of imprinting (LOI) can be developed as a diagnostic, predictive and prognostic novel epigenetic marker (Quantitative Chromogenic Imprinted Gene In-Situ Hybridization, QCIGISH) for breast precancerous lesions and cancer detection. Our objective is to initiate a proof of concept for atypical breast lesions with QCIGISH and develop a diagnostic model. Methods: We retrospectively identified benign, atypical, and carcinoma core needle specimens from year 2023 in the Department of Pathology at Mayo Clinic Florida. Inclusion criteria included female patients, ages 18-99, with archived breast material obtained through standard of care (n=20). All diagnoses were ascertained by a breast pathologist (MKK). Following a thorough literature review, we processed the material for in situ hybridization, and pretreated with RNA scope preparation procedure using probes targeting noncoding intronic regions of nascent RNAs (QCIGISH). Based on high Area Under the Receiver Operating Characteristics Curve (AUROC), 2 genes - HM13 and GRB10 were identified as the most promising candidates for classification with QCIGISH. Upon test completion, the detected gene-expression site appeared as a distinct red dot on the slide under the common bright-field microscope. Next, the gene expression signals were counted and further classified as bi-allelic (BAE), multi-allelic (MAE) and total expression (TE). Results: A decision tree model based on BAE, MAE, and TE metrics showed differential signal expression. High MAE was a strong predictor for malignancy. We achieved 100% sensitivity and specificity with the ground truth, thereby initiating proof of concept. Furthermore, one histomorphologically challenging atypical lesion, for which the positive LOI finding accurately classified as ductal carcinoma in situ (DCIS), was confirmed indeed DCIS by ground truth validation on the excision specimen. Conclusion: We have demonstrated a breakthrough molecular biomarker that is fully objective, reproducible, and practical. First of its kind, the innovative QCIGISH has superior performance than the current standard of care in breast cancer diagnostics allowing for single-cell resolution of epigenetic changes. Next, we seek to undergo full model validation. Citation Format: M. Abdollahi Neisani, R. Guo, T. Cheng, M. K. Komforti. Epigenetic Imprinting as a Novel Precision Biomarker for Early Breast Cancer and Precancer Diagnosis and Detection [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-07-09.

Abstract: Melanoma exhibits a broad spectrum of histopathologic variations, including rare forms with neural differentiation. Neurotropism in melanoma encompasses both perineural invasion and neural-like transformation, but the prognostic implications of these features remain uncertain. Although (peri)neural invasion is well documented, true neural differentiation in melanomas is exceedingly rare. In this study, we describe an unusual case of primary cutaneous malignant melanoma exhibiting extensive Wagner–Meissner-like bodies, a feature more commonly associated with benign neural tumors and nevi. In this case, histopathology revealed a dual-component lesion with a neurotized and an epithelioid melanocytic component, both showing PRAME expression and p16 loss. Chromosomal microarray identified heterozygous loss of 9p22.1p13.1 (including CDKN2A / CDKN2B ), and loss of 10q22.2q26.3 (including PTEN ), supporting malignancy. These findings suggest that in this case, Wagner–Meissner-like bodies likely represent neurotization rather than a benign or collision lesion, highlighting the need for integrated histopathologic, immunohistochemical, and molecular analysis in challenging melanocytic neoplasms.

Neuroendocrine carcinomas of the breast are a rare subtype of invasive breast carcinomas, and those with morphologic and immunophenotypic features supporting Merkel cell carcinoma (MCC) are even more rare. Accurate diagnosis of these entities is important for clinical decision-making regarding the selection of optimal treatments. We report a patient withMCC in the deep breast parenchyma of a 52-year-old woman, without evidence of a cutaneous component. This tumor exhibited characteristic morphologic and immunophenotypic features of MCC, including sheets of high grade, hyperchromatic tumor cells, with perinuclear dot-like staining of keratin 20. To our knowledge, this is the sixth report of parenchymal breast MCC, and due to its rarity and aggressive course, we reviewed the literature, including prior experience on its diagnosis and management.

Abstract: Papillary eccrine adenoma/tubular apocrine adenoma (PEA/TAA) is a rare sweat gland neoplasm. Because PEA/TAA shares morphologic features with other sweat gland tumors, including digital papillary adenocarcinoma, histologic diagnosis may be challenging. We report a case of PEA/TAA presenting as a nodule on the left foot of a 43-year-old man. Histopathologic examination revealed a well-circumscribed dermal proliferation of variably sized glands composed of ductal cells with an outer layer of myoepithelial cells. By immunohistochemistry, the ductal tumor cells showed strong, diffuse expression of BRAF V600E, and the myoepithelial cells were positive for p63. This case illustrates the utility of immunohistochemistry in the diagnosis of this rare neoplasm. Particularly when PEA/TAA is located on an acral site, distinction from digital papillary adenocarcinoma is critical, because these tumors show significant differences in clinical behavior.

ABSTRACTVarious cutaneous adnexal neoplasms have been associated with gene fusions as the main driver of their histogenesis, most of which showed poroid or hidradenomatous differentiation or represented other tumors of sweat glands. Recently, we encountered two cases of primitive basaloid neoplasms of predominantly folliculogenic/pilosebaceous origin, both surprisingly harboring recurrent EWSR1 rearrangements. Both tumors presented in young patients of either sex (1 F; 17 years; 1 M; 37 years) and involved the dermis and subcutaneous tissue of the abdominal wall (case 1) and the buttock (case 2). Histologically, the tumors were composed of primitive, basaloid cells with areas of keratinization (case 1) or foci of sebaceous differentiation (case 2) and stained strongly with keratins, p40 (case 1) or p63 (case 2), while lacking significant CD99 expression in both cases. Case 1 harbored an EWSR1::FLI1 fusion while case 2 harbored an EWSR1::PBX3 fusion. Clinical follow‐up was available for case 2 and showed no evidence of disease at 15 months of follow‐up. Methylation profiling showed case 1 to cluster with cutaneous squamous cell carcinoma, while case 2 was independent but positioned close to salivary gland epithelial‐myoepithelial carcinoma. These findings expand on the histopathologic and molecular genetic features of basaloid tumors with apparent adnexal differentiation and raise awareness to carefully interpret and correlate molecular findings with morphology and immunophenotype to avoid misinterpretation as a mesenchymal neoplasm.