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Fibroepithelial lesions of the breast (FELs) are a heterogeneous group of neoplasms exhibiting a histologic spectrum ranging from fibroadenomas (FAs) to malignant phyllodes tumors (PTs). Despite published histologic criteria for their classification, it is common for such lesions to exhibit overlapping features, leading to subjective interpretation and inter-observer disagreements in histologic diagnosis. Therefore, there is a need for a more objective diagnostic modality to aid in the accurate classification of these lesions and to guide appropriate clinical management. In this study, the expression of 750 tumor-related genes was measured in a cohort of 34 FELs (5 FAs, 9 cellular FAs, 9 benign PTs, 7 borderline PTs, and 4 malignant PTs). Differentially expressed gene analysis, gene set analysis, pathway analysis, and cell type analysis were performed. Genes involved in matrix remodeling and metastasis (e.g., MMP9, SPP1, COL11A1), angiogenesis (VEGFA, ITGAV, NFIL3, FDFR1, CCND2), hypoxia (ENO1, HK1, CYBB, HK2), metabolic stress (e.g., UBE2C, CDKN2A, FBP1), cell proliferation (e.g., CENPF, CCNB1), PI3K-Akt pathway (e.g., ITGB3, NRAS) were highly expressed in malignant PTs and less expressed in borderline PTs, benign PTs, cellular FAs, and FAs. The overall gene expression profiles of benign PTs, cellular FAs, and FAs were very similar. Although a slight difference was observed between borderline and benign PTs, a higher degree of difference was observed between borderline and malignant PTs. Additionally, the macrophage cell abundance scores and CCL5 were significantly higher in malignant PTs compared with all other groups. Our results suggest that the gene expression profiling-based approach could lead to further stratification of FELs and may provide clinically useful biological and pathophysiological information to improve the existing histologic diagnostic algorithm.

Background: Ki67 values >10% 2-4 weeks (wks) after starting neoadjuvant ET (NET) indicates persistent cell proliferation, resistance to ET, and is associated with increased risk of recurrence. The ACOSOG Z1031 trial suggested that these tumors are also relatively chemotherapy (chemo) resistant with a low pathologic complete response (pCR) rate to NCT. The ALTERNATE trial (NCT01953588) is a randomized study of neoadjuvant anastrozole (ANA), fulvestrant (FUL), or ANA + FUL in postmenopausal patients (pt) with newly diagnosed clinical stage II or III ER+ (Allred score 6-8)/HER2- BC. Ki67 >10% at wk 4 or 12 after starting NET triggered triage to NCT of physician choice or weekly paclitaxel. Pts who refused protocol-directed therapy, were not candidates for NCT, or decided to undergo immediate surgery are being followed per protocol. Here we report the rates of pCR and residual cancer burden (RCB) following NCT for pts triaged to NCT due to Ki67 >10% at wk 4 or 12. Results: Of the 1,299 eligible pts randomized to receive ANA, FUL, or ANA + FUL, 286 (22%) had Ki67 >10% at wk 4 or 12. 168 of these 286 pts (58.7%) chose to switch to NCT, 32 went to surgery (11.2%), and 86 discontinued further protocol-directed therapy (30.1%). Among the 168 pts who underwent NCT, the presenting clinical T stages were cT2 (n=113; 67.26%), cT3 (n=47; 27.98%) and cT4 (n=8; 4.76%) and N stages were cN0 (n=82; 48.8%), cN1 (n=75; 44.6%), cN2/3 (n=9; 5.4%) and cNx (n=2; 1.2%). Central ER testing was performed on pre-treatment biopsies and confirmed ER Allred score 6-8 in 155 of 168 (92.2%) pts, with the rest being ER Allred score 4-5 (n=5; 3%), ER- (Allred score 0) (n=2; 1.2%), or not tested (n=6; 3.6%). Most (n=139; 82.7%) were ER+/PR+, while 17.3% (n=29) were ER+/PR-, and tumor grades were G1 (n=10; 6%), G2 (n=99; 58.9%), G3 (n=54; 32.1%), not reported (n=5; 3%). Baseline Ki67 levels prior to NET were >10% in 94% (n=158), ≤10% in 3% (n=5), and not done in 3% (n=5). NCT regimens administered included doxorubicin/cyclophosphamide (AC) followed by paclitaxel (T) (n=60; 35.71%); weekly paclitaxel (n=56; 33.33%), docetaxel/cyclophosphamide (TC) (n=33; 19.65%), other doxorubicin and/or taxane containing regimen (n=17; 10.12%), and cyclophosphamide/methotrexate/fluorouracil (CMF) (n=2; 1.19%). 35 (20.8%) pts did not complete planned course of NCT due to toxicity (n=27) or refusal (n=8). 154 NCT pts underwent surgery (mastectomy in 40.3%, and breast conserving surgery in 59.7%). The path ypT stages were Tis/0 (n=10; 6.5%), T1 (n=62; 40.3%), T2 (n=61; 39.6%), and T3/4 (n=21; 13.6%), and the ypN stages were N0 (n=66; 42.9%), N1 (n=57; 37%), N2/3 (n=30; 19.5%), and Nx (n=1; 0.6%). Among the 168 pts who started on NCT (intent to treat population), there were 8 pCRs (no invasive disease in the breast or lymph nodes) (4.8%; 95% CI: 2.1% to 9.2%). Residual Cancer Burden (RCB) categories include RCB 0 (n=8; 4.8%), RCB 1 (n=15; 8.9%), RCB 2 (n=82; 48.8%), RCB 3 (n=42; 25.0%), and not determined (n=21; 12.5%). Correlations of baseline pt and tumor characteristics with pathology response to NCT will also be presented. Conclusion: In pts with NET-resistant ER+/HER2- BC, salvage NCT is not likely to induce a complete or near complete response. More effective treatments are needed for this high-risk ER+/HER2- pt population. Support: U10CA180821, U10CA180882, U24CA196171, UG1CA189856, U10CA180868 (NRG); NCI BIQSFP, BCRF, Genentech, AstraZeneca. https://acknowledgments.alliancefound.org. Clinical Trials.gov Identifier: NCT01953588 Citation Format: Cynthia X Ma, Vera Suman, A. Marilyn Leitch, Souzan Sanati, Kiran Vij, Gary W Unzeitig, Jeremy Hoog, Mark Watson, Olwen Hahn, Joseph Guenther, Abigail Caudle, Erika Crouch, Horacio Maluf, Amy Tiersten, Monica Mita, Wajeeha Razaq, Tina J Hieken, Yang Wang, Travis Dockter, Jo Anne Zujewski, Anna Weiss, Kelly Hunt, Clifford Hudis, Eric P Winer, Matthew J Ellis, Lisa A Carey, Ann H Partridge. Neoadjuvant chemotherapy (NCT) response in postmenopausal women with clinical stage II or III estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC) resistant to endocrine therapy (ET) in the ALTERNATE trial (Alliance A011106) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS4-05.

With less than 50 reported cases, gastrointestinal neuroectodermal tumor (GNET) is a rare malignant neoplasm. Here we report an unusual case of GNET with indolent clinical behavior. The patient is a 59-year-old Caucasian man whose 2 cm sigmoid colon mass did not increase significantly in size during a 10-year surveillance colonoscopy. This mass was recently resected due to change in bowel habits. H&E sections revealed a polypoid, low-grade spindle cell neoplasm, arising from the submucosa and infiltrating the muscularis propria. Negative CD117 and DOG-1 stains excluded a diagnosis of gastrointestinal stromal tumor (GIST). The tumor cells were positive for vimentin, S-100, synaptophysin, and CD56. Pertinent negative stains included Melan-A, HMB-45, smooth muscle actin, CD34, and cytokeratin. Electronmicroscopy showed no obvious sign of differentiation. A presumptive diagnosis of GNET was made. FISH for rearrangement of the EWSR1 gene was, however, negative. There was no evidence ofmetastatic disease at the time of surgery. One year after surgical removal of this tumor, the patient is asymptomatic. We propose that a subset of GNET may follow an indolent clinical course.

Dr. Louis “Pepper” Dehner has been one of the most influential surgical pathologists of the last century. Authoring more than 450 publications, he is the premier modern pediatric pathologist. Perhaps, an area that he is less recognized and in which we would like to describe his contributions, is his role as a creator of the art of pediatric dermatopathology. Dr. Dehner has had at least 50 major publications describing, discovering, and orienting the discipline in the fields of fibrohistiocytic disorders of childhood, vascular tumors, and histiocytosis among many others. Dr. Dehner has clearly manifested that while many similarities between adult and pediatric surgical pathology exist, “children get different diseases.” It is because of his mindful analysis and translation of the clinico-pathologic and biologic correlative between specific entities and advances in the field he has made that we are honored to describe some of his contributions to this particular area.

We describe a case of adenomatous polyp of the colon that harbored small foci of signet ring cell carcinoma. The patient was a 64-year-old woman with end-stage renal disease and sepsis who underwent colonoscopy to evaluate the possibility of pseudomembranous colitis. A polyp was found incidentally in the right colon and a biopsy was performed. Histologic examination of the polyp revealed typical features of tubular adenoma without evidence of high-grade dysplasia. However, 2 small foci of signet ring cell carcinoma were identified that infiltrated the lamina propria. In contrast to adenomatous epithelium, the signet ring cells were immunohistochemically positive for cytokeratin 7 and negative for cytokeratin 20, suggesting a metastasis rather than a primary tumor. Multiple random biopsies from the right and left colon, as well as the ileum, exhibited no histologic evidence of malignancy. Subsequently, signet ring cell carcinoma with similar morphology and identical immunophenotype was detected in biopsies from the endometrium, an unusual location for primary signet ring cell carcinoma. Preliminary workup excluded the breast as a possible primary site, but further investigation was not possible because of the patient's death with no autopsy granted. To the best of our knowledge, this is the first reported case of metastatic signet ring cell carcinoma to an adenomatous polyp of the colon. This case illustrates the necessity of submitting all polyps entirely and the importance of examining them carefully.