Low Proliferation Index Research Articles

Landscape of HER2-low breast cancer: Insights from a six-year study on incidence and clinicopathological characteristics.

e13148 Background: Human epidermal growth factor receptor 2 (HER2)-low breast cancer has emerged as a subtype of breast cancer, defined by HER2 1+ or 2+ in immunohistochemistry (IHC) and the absence of the ERBB2 gene amplification on fluorescence in situ hybridization (FISH). Recent trials showed marked response of HER2 breast cancer to novel anti-HER2 antibody-drug conjugates, rising interest in the HER2-low subtype. To date, data on characteristics of HER2-low breast cancer subtype is limited. Herein, we describe the clinicopathological characteristics of HER2-low breast cancer subtype compared HER2-zero/negative breast cancer. Methods: Real-world data from the Anatomic Pathology Division of Hotel Dieu de France, spanning 2017-2022, was retrospectively collected. Patients with HER2-IHC 3+ and HER2-IHC 2+ with ISH-amplified (HER2-positive) were excluded to compare HER2-low to HER2-zero breast cancer subtypes. Patients were then categorized based on their hormone receptor (HR) status. Clinicopathological characteristics between the groups were compared using a Chi-Square and Mann–Whitney U tests. Results: Out of 1195 patients, we observed 341 (28.5%) HER2-low breast cancers cases. HER2-positive breast cancer cases (n=178; 14.9%) were subsequently excluded. There was no significant difference in age and sex between the HER2-low and the HER2-zero group (p=0.3 and 0.8, respectively). HER2-low breast cancer was associated with positive estrogen receptor (ER) status and positive progesterone receptor (PR) status (p<0.001 and p=0.01, respectively). Ductal adenocarcinomas were more frequently observed in the HER2-low group, whereas lobular and metaplastic adenocarcinomas were especially prevalent in the HER2-zero group (all p<0.001). When stratified by HR status, 87.4% of patients had HR-positive status and 12.6% were HR-negative. Furthermore, the occurrence rate of tumors with a low Ki-67 labeling index was comparable between the two groups (p=0.9). However, among the HR-negative group, HER2-low tumors tended to show lower proliferation index compared to HER2-zero tumors (p = 0.04; Table). Conclusions: In conclusion, this study showed that HER2-low is a distinct from HER2-zero and is frequently present among patients with breast cancer. Clinicopathological features such as histological type differ between HER2-zero and HER2-low breast cancer. Our findings suggest that, within HR-negative breast cancer, breast cancer with low HER2 expression exhibits a less aggressive profile when compared to HER2-zero tumors. [Table: see text]

Landscape of HER2-low breast cancer: Insights from a six-year study on prevalence and clinicopathological characteristics

Human epidermal growth factor receptor 2 (HER2)-low breast cancer has emerged as a subtype of breast cancer, defined by HER2 1+/2+ in immunohistochemistry (IHC) and absence of ERBB2 gene amplification on fluorescence in situ hybridization (FISH). Recent trials showed marked response of HER2-low breast cancer to novel anti-HER2 antibody-drug-conjugates. Data on characteristics of HER2-low breast cancer subtype is limited. Real-world data from the Anatomic Pathology Department of Hotel-Dieu de France, spanning 2017–2023, was retrospectively collected. HER2-positive patients were excluded to compare HER2-low to HER2-zero breast cancer subtypes. Clinicopathological characteristics between the groups were compared using a Chi-Squared test. Out of 1195 patients, we observed 341 (28.5 %) HER2-low breast cancers cases. HER2-positive breast cancer cases (n = 178; 14.9 %) were excluded. There was no significant difference in age and sex between HER2-low and HER2-zero group (p = 0.33 and 0.79, respectively). HER2-low breast cancer was associated with positive estrogen receptor status and positive progesterone receptor status (p < 0.001 and p = 0.01, respectively). Ductal adenocarcinomas were more commonly observed in HER2-low group (p < 0.001). When stratified by hormone (HR) status, 87.4 % of patients had HR-positive status and 12.6 % were HR-negative. Among the HR-negative group, HER2-low tumors tended to show lower proliferation index compared to HER2-zero tumors (25%vs.10 %, p = 0.04). This study showed that HER2-low is distinct from HER2-zero and is common among patients with breast cancer. Clinicopathological features such as histological type differ between HER2-zero and HER2-low breast cancer. Within HR-negative breast cancer, those with low HER2 expression exhibit a less aggressive profile compared to HER2-zero tumors.

Abstract PO1-18-10: ANNE: A phase II single-arm clinical trial to assess the feasibility and efficacy of neoadjuvant anastrozole in patients with luminal breast cancer and low proliferative index in TNM stages II and III

Abstract Background: Neoadjuvant endocrine therapy (NET) is recommended for the treatment of invasive breast cancer (BC), particularly luminal subtypes, in locally advanced stages. Previous randomized studies have demonstrated the benefits of aromatase inhibitors (AIs) in this context. However, in clinical practice, NET is typically reserved for elderly or frail patients who may not tolerate neoadjuvant chemotherapy. Ideally, after identifying suitable candidates for NET, patients undergo tumor re-biopsy after 2 to 4 weeks of treatment, and only those with Ki67 ≤ 10% proceed with NET. Limitations of this strategy include the standardization of re-biopsy and the reliability of Ki67 immunohistochemical analysis, as treatment decisions are based on these results. Objective: To evaluate the feasibility and efficacy of NET in postmenopausal patients with stage II and III luminal BC and to identify predictive biomarkers of therapeutic response. The efficacy will be measured by the rate of patients with Ki67 ≤ 10% after 4 weeks and Preoperative Endocrine Prognostic Index (PEPI) score 0 on the surgical specimen. The feasibility of the study will be assessed by the acceptance rate of participating in the study (recruitment rate ≥ 50%) and the inclusion rate of &amp;gt;2 patients per month. Methods: This non-randomized phase II clinical trial includes postmenopausal women with invasive breast carcinoma, Scarf-Bloom-Richardson histological grades 1 or 2, Estrogen Receptor positive (Allred ≥ 6), progesterone receptor positive (any value), HER2 negative, Ki-67 antigen &amp;lt; 50% on immunohistochemistry, stages TNM II-III, with palpable tumor ≥ 2 cm, and ECOG 0-2. All eligible patients will receive anastrozole (1 mg/day) continuously until the day before the surgical procedure or exclusion from the study (in case of disease progression during endocrine therapy). After 2 to 4 weeks, a re-biopsy of the breast tumor will be performed. If Ki67 &amp;gt; 10%, endocrine therapy will be suspended, and the patient will be excluded from the study and redirected to neoadjuvant chemotherapy (routine care) or immediate surgery (as per attending clinical oncologist and surgeon). If Ki67 ≤ 10%, the patient will continue to receive NET. Extended NET will be administered for up to 10 months, with monthly physical examinations (using calipers) and bimonthly breast ultrasound. The presence of stable disease on ultrasound at 4, 6, and 8 months indicates scheduling surgery within 2 months thereafter, and disease progression at any time indicates surgery within one month. Patients will complete the EORTC QLQ-C30 and its supplemental module BR45 questionnaires every 2 months. Toxicity will be assessed using CTCAE version 4.0, and patients will respond to 11 specific items extracted from the Brazilian version of PRO-CTCAE. The radiological response will be evaluated by RECIST 1.1. Blood samples for molecular analyses will be collected at baseline and during re-biopsy. MicroRNA profiles will be evaluated using Nanostring, and extracellular vesicles will be examined using ATR-FTIR to identify predictive markers of therapeutic response (Ki67 &amp;lt; 10%) in re-biopsy. All cases will be evaluated using PAM50 at the initial biopsy and at surgery to determine the molecular phenotype (luminal A, B, or other) and molecular response (ROR score difference). Pathologic therapeutic response will be assessed using the PEPI score in all operated cases. The sample size was calculated to be 59 patients. The study was initiated in July 2022, and since then, a total of 26 patients have been enrolled. This study is registered with The Brazilian Registry of Clinical Trials (ReBEC): RBR-5pygzhj. Citation Format: Carlos Paiva, Izabella Oliveira, Vitor Guimarães, Alinne Faria, Domício Lacerda, Anapaula Uema, Nilton Onari, Bianca Paiva, Augusto Antoniazzi, Karina Oikawa, Maria Fernanda Machado, Matheus Godinho, Cristiano Souza, Chrissie Amirati, Gustavo Teixeira, Idam de Oliveira Jr, Márcia Marques, Yara Maia. ANNE: A phase II single-arm clinical trial to assess the feasibility and efficacy of neoadjuvant anastrozole in patients with luminal breast cancer and low proliferative index in TNM stages II and III [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-18-10.

Abstract PO3-24-02: Molecular characterization and therapeutic approach for VISTA+ triple-negative breast cancers

Abstract Introduction: Current FDA-approved immunotherapeutics for triple-negative breast cancer are only available for a subset of patients, highlighting the need to develop improved immune-targeting strategies. VISTA (V-domain Ig suppressor of T cell activation) is a single-pass transmembrane immune checkpoint receptor that is an emerging clinical target for cancer immunotherapy. It is expressed widely on lymphoid and myeloid cells in healthy individuals, is commonly expressed on cells of the tumor microenvironment and can be abnormally upregulated on tumor cells in a wide variety of tumors. Although VISTA confers quiescence to naïve T cells, molecular mechanisms responsible for this effect remain unclear. Also, the effects of VISTA expression on tumor cells remains poorly defined. Methods: Multi-omic profiling was performed in human breast cancer cells lines to determine immune regulatory genes controlled by growth factor stimulation. Human triple-negative breast cancer tumor specimens (N=248) were examined by immunohistochemistry for expression of VISTA, PDL1, PD1 and FoxP3. VISTA expression was engineered into human and mouse triple-negative breast cancer cell lines and growth metrics were characterized in vitro and in immunocompetent (syngeneic) and immunodeficient (xenograft) mouse tumor models. Membrane receptor trafficking and localization of EGFR was performed in human TNBC cells lines expressing VISTA and VISTA mutants. Proximity biotinylation identified protein partners that interacted with VISTA’s intracellular domain. Deletion mutagenesis was performed to identify motifs required for biochemical interactions between VISTA and clathrin adaptor proteins. Clathrin adapter localization was examined in WT and VISTA knock-out cell lines. Cytokine response, clathrin adaptor localization and tumor growth kinetics were measured in TNBC cell lines expressing VISTA or VISTA mutants. Results: A class of human triple-negative breast cancers were identified with high VISTA expression, low tumor infiltrating lymphocytes and low proliferative index (8-20% of all TNBCs). Tumor models demonstrated that enforced expression of VISTA in tumor cells caused growth suppression, even in the absence of an immune system. This effect was mapped to the cytoplasmic domain of VISTA, which lacks defined signaling domains. Through biochemical approaches, the clathrin-adaptor molecules NUMB and GULP1 were found in complex with a VISTA intracellular NPGF motif. This motif sequestered NUMB at early endosomes, resulting in diminished NUMB recycling for EGFR endocytosis, thereby causing growth suppression. VISTA impaired NUMB recycling by blocking Rab11 effector complex formation. VISTA NPGF mutations did not disrupt cytokine secretion in mixed lymphocyte assays. VISTA-targeted antibodies did not disrupt NUMB sequestration. VISTA+ tumors were selectively sensitive to VISTA-blocking antibodies. Conclusions: VISTA+ TNBC have distinct features including slower proliferative index and increased sensitivity to VISTA-blocking antibodies. This work identifies mechanisms by which VISTA enforces a quiescent cellular state by sequestering clathrin adapter proteins away from sites of endocytosis in cancer cells. This is the first description of intracellular molecular mechanisms controlled by VISTA’s intracellular tail. It may inform features of the VISTA-dependent immune checkpoint that could be exploited to improve anti-tumor immunity. Citation Format: Yan Zhao, Fatima Charles, Andrew Lipchik, Yan Peng, James Ford, Melinda Telli, Song Zhang, Allison Kurian, Michael Snyder, Joshua Gruber. Molecular characterization and therapeutic approach for VISTA+ triple-negative breast cancers [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-24-02.

Abstract PO4-19-03: FES-PET/MRI for Tailored treatment of luminal A and lobular breast cancer: a prospective cohort study

Abstract Background: Breast cancer (BC) staging is essential to planning the most appropriate treatment pathway. Currently, BC management has become more tailored to the tumor’s and patient’s characteristics. However, BC imaging shows varying performance according to tumor subtypes. In particular, routine imaging may pose some challenges when evaluating luminal A BC (LumA) and lobular BC (Lob). LumA, due to low grade and proliferation index (&amp;lt; 20%) shows lower sensitivity on axillary US, reduced MRI enhancement, and low FDG-avidity on PET. Similarly, Lob, due to its peculiar single-cell growth pattern, exhibits inferior sensitivity on axillary MRI and FDG-avidity. LumA and Lob account for &amp;gt;50% of all BCs. Despite their favourable prognosis, metastases and recurrences still occur; this translates into a higher absolute number of events than in other subtypes. As a result, a concrete risk of disease underestimation and under-treatment exists. Two ongoing studies on FDG-PET/MRI imaging in our institution have already demonstrated that its sensitivity also decreases in LumA and Lob. Based on these premises, our hypothesis states that by combining the advantages of hybrid PET/MRI with the high accuracy of 16α -18F-fluoro-17-beta-estradiol(FES), a radiolabeled form of estrogen binding to functionally active ER, we could obtain a reliable, non-invasive, operator-independent, one-stage imaging method for staging LumA and ER-positive Lob. Trial design: This is a prospective cohort study where patients with LumA and ER-positive Lob will be enrolled in four cohorts undergoing: A) primary surgery; B) induction endocrine therapy; C) neoadjuvant chemotherapy, and D) systemic therapy for metastatic disease. FES PET/MRI examinations will be performed at baseline for local and systemic staging in all cohorts and a second exam after systemic therapy in cohorts C-D. Correlations between the FES PET/MRI parameters and pathology, gene expression, and FDG PET parameters, when available, will be investigated. Study aims will evaluate: 1) the performance of the FES PET/MRI in axillary staging compared with axillary surgery; 2) potential correlations between changes in FES uptake and changes in proliferation index after three weeks of endocrine therapy (ET); 3) the performance of the FES PET/MRI in systemic staging of patients undergoing systemic therapy in comparison with standard imaging; 4) biological determinants of tumor heterogeneity on pathological, imaging, and genomic levels. Statistics: The primary analysis in cohort A will test the sensitivity of the FES PET/MRI in detecting macrometastatic axillary nodes. Assuming that the probability that a patient has positive nodes is 33%, 119 patients (10% drop-out included) will provide 80% power to reject the null hypothesis about sensitivity at a 5% significance level if the true sensitivity is at least 50%. Results from the FES PET/MRI will be also compared with standard imaging in terms of sensitivity and number of lesions detected using the Mc-Nemar test for paired proportions and the Wilcoxon signed-rank test for paired data. The primary analysis in Cohort B will test the association between the FES-SUV change from pre-ET to post-ET and the Ki-67 change from core biopsy to post-ET in ER positive BC patients with a Ki-67 &amp;gt;10%. The association between these changes will be measured by the Pearson correlation index ρ. Α total of 52 patients (10% drop-out included) from Cohort B will provide 80% power to reject the null hypothesis about ρ at a 5% significance level if the true ρ is at least 0.4. No formal sample size was calculated for cohort C and D: results will be considered descriptive in nature, informing sample size considerations for future trials. We intent to recruit 20 and 30 patients, respectively. Accrual has not started yet. Project funded by AIRC (Associazione Italiana Ricerca sul Cancro) Next Gen Clinician Scientist ID 28378 Contact: Dr. Rosa Di Micco, dimicco.rosa@hsr.it Citation Format: Rosa Di Micco, Carla Canevari, Francesca Gallivanone, Nicole Rotmensz, Veronica Zuber, Sara Baleri, Giovanni Cisternino, Mario Rampa, Stefania Zambelli, Giulia Viale, Patrizia Zucchinelli, Manuela Morgante, Paola Scifo, Elena Venturini, Paola Magnani, Isabella Sassi, Vincenzo Bagnardi, Pietro Panizza, Giampaolo Bianchini, Arturo Chiti, Oreste Davide Gentilini. FES-PET/MRI for Tailored treatment of luminal A and lobular breast cancer: a prospective cohort study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-19-03.

Abstract PO5-27-12: TALL CELL CARCINOMA WITH REVERSED POLARITY: A RARE SUBTYPE OF INVASIVE BREAST CARCINOMA WITH UNUSUAL ONCOGENIC DRIVER MUTATION R132C IN IDH1 GENE

Abstract Introduction: Tall cell carcinoma with reversed polarity (TCCRP) is a rare subtype of invasive breast carcinoma with a distinguishing morphogical feature, which is the predilection of nuclei to polarize to the apical pole of tall columnar epithelial cells. These tumours are most commonly associated with IDH2 p.Arg172 hotspot mutations. All reported cases of TCCRP affected women ranging from 39 to 89 years (mean age of 64 years). The tumours presented as a mammographic or palpable mass, only rarely associated with axillary lymph node metastases. TCCRP are usually associated with an indolent clinical course and a favourable prognosis. Morphologically, TCCRP is composed of circumscribed nests of epithelial cells often exhibiting delicate fibrovascular cores, conveying a solid papillary pattern. True papillae and cystic structures containing colloid-like material may be observed in some cases. The tumour cells are tall and columnar, with abundant eosinophilic cytoplasm, containing bland, round to ovoid nuclei disposed at the apical pole of the columnar epithelial cells. Mitotic figures are rare. Most TCCRPs exhibit a triple-negative phenotype and a low (&amp;lt; 20%) Ki-67 proliferation index. Molecular features of TCCRP comprise IDH2 p.Arg172 hotspot mutations, reported in about 84% of the cases studied, as well as PIK3CA missense mutations, identified in about 68% of these tumours. Only one case of TCCRP was associated with IDH1 gene mutations according to the literature. Case report: A 62 year old woman presented with a palpable mass and no axillary adenopathy was identified. Hematoxylin-eosin (HE) stain showed an invasive breast carcinoma, with epithelial tumour cells arranged in a solid and papillary pattern with thin fibrovascular cores. Neoplastic cells are tall and columnar, with abundant eosinophilic cytoplasm and round to ovoid nuclei, exhibiting no pleomorphism and disposed in the apical pole of the cells. Mitotic figures were not detected. Considering the highly suggestive morphology on HE stain, biopsy sample was sent for molecular analysis by next generation sequencing (NGS). Results and discussion: Molecular analysis by NGS using the TruSight Oncology 500 panel (Illumina) revealed the presence of the oncogenic mutations R132C and H1047R in IDH1 and PIK3CA genes, respectively. Contrary to what occurs in almost all cases of Tall cell carcinoma with reversed polarity (TCCRP), in which an oncogenic mutation is described in codon R172 of the IDH2 gene, in this case a mutation was observed in the IDH1 gene. Such a mutation has been described in only one case diagnosed with TCCRP according to the literature, this being the second reported case. Conclusion: This case report aims to warn of the possibility that other driver mutations may be associated with the diagnosis of TCCRP, such as IDH1 R132 and not just IDH2 R172, and that a comprehensive testing approach of the IDH1/2 genes might be more accurate in these cases. Citation Format: Karla Prigenzi, Luiz Gustavo Ferreira Cortes, Paulo Vidal Campregher, João Bosco de Oliveira Filho, Nestor Andrade Piva. TALL CELL CARCINOMA WITH REVERSED POLARITY: A RARE SUBTYPE OF INVASIVE BREAST CARCINOMA WITH UNUSUAL ONCOGENIC DRIVER MUTATION R132C IN IDH1 GENE [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-27-12.

SEOM-GEINO clinical guidelines for grade 2 gliomas (2023)

The 2021 World Health Organization (WHO) classification has updated the definition of grade 2 gliomas and the presence of isocitrate dehydrogenase (IDH) mutation has been deemed the cornerstone of diagnosis. Though slow-growing and having a low proliferative index, grade 2 gliomas are incurable by surgery and complementary treatments are vital to improving prognosis. This guideline provides recommendations on the multidisciplinary treatment of grade 2 astrocytomas and oligodendrogliomas based on the best evidence available.

ASSESSMENT OF THYROID FUNCTION AND ULTRASONOGRAPHIC FINDINGS IN PATIENTS WITH MUCOPOLYSACCHARIDOSIS

Objective: The thyroid gland, with its high vascularity and low proliferation index of thyrocytes, is highly susceptible to storage diseases, however it has not been evaluated adequately in patients with in mucopolysaccharidosis (MPS). Therefore, the aim of this study is to assess the function, morphology, B- mode, and Doppler ultrasonography features of the thyroid gland in pediatric and adolescent patients with MPS and to evaluate whether the thyroid gland is involved in this disease. Material and Methods: Thyroid hormone functions were measured in all patients, and B-mode ultrasound and color Doppler imaging were performed. Results: Eight boys and 17 girls with MPS were included in the study. Eight patients were diagnosed with MPS I, 2 with MPS II, 3 with MPS III, 3 with MPS IVA, and 9 with MPS VI. Nineteen patients were receiving enzyme replacement therapy, while three patients diagnosed with MPS III remained untreated due to the unavailability of treatment options. Thyroid hormone levels were within normal limits for all patients. B-Mode ultrasound imaging revealed slightly heterogeneous echo texture in only 2 (8%) patients, both with MPS VI. Except for one patient with MPS VI, all color Doppler assessments were within normal limits. Conclusion: The results of our study demonstrate that both thyroid function tests and thyroid gland morphology are normal in MPS through childhood and adolescence. Therefore, we believe that thyroid gland dysfunction does not play a crucial role in the development of symptoms such as growth retardation, dry skin, coarse facial features, and intellectual disability, which could potentially be attributed to thyroid dysfunction. Instead, we think that these findings are more likely attributed to the primary disease involvement process

Rhabdomyomatous Mesenchymal Hamartoma: Report of 4 Cases With Histochemical and Immunohistochemical Findings and Emphasis on Potential Pitfalls.

Rhabdomyomatous mesenchymal hamartoma (RMH) typically presents as a congenital midline head and neck cutaneous polyp in infants. Perianal and mucocutaneous lesions have been reported, and recently, acquired adult-onset variants have been proposed. This makes the true prevalence, etiopathogenesis, and clinicopathologic distribution and classification of RMHs in children compared with those in adults uncertain. We performed a retrospective review to highlight the salient histopathologic, histochemical, and immunohistochemical features in RMHs and to emphasize their specific clinicopathologic criteria to avoid diagnostic pitfalls. We found 4 (0.3%) infants [2 female infants and 2 male infants, average age: 4 months] with mental, nasal, lingual, and perianal midline RMHs (average size: 1.0 cm) of 1303 patients with cutaneous polypoid lesions. Three were isolated, and 1 was associated with Goldenhar syndrome. The cutaneous polyps demonstrated intermixed skeletal muscle, adipose, and fibrocollagenous core stroma that extended into the dermis and around the dermal appendages. The lingual lesion demonstrated skeletal muscle and fibrocollagenous stroma with prominent nerve bundles and little adipose tissue. All showed interstitial loose mesenchyme. Masson trichome demarcated the triphasic stromal components. Alcian blue demonstrated the loose myxoid mesenchyme. Elastic van Gieson did not show elastic fibers. Desmin demonstrated the skeletal muscle bundles, S100 highlighted the adipose tissue lobules and the nerve bundles, and CD34 displayed the mesenchymal stroma. Ki67 showed a low proliferation index in the loose mesenchyme. Smooth muscle actin did not reveal smooth muscle bundles, but with CD31, they highlighted the thick blood vessels. CD117 revealed prominent mast cells. From our retrospective review series, 4 cases that originally diagnosed as RMHs were excluded. Likewise, we found some examples of the reported cases in the English literature that might have been mistaken for RMHs. This is because they did not fulfill the diagnostic clinicopathologic criteria. RMH constitutes a rare entity with specific clinicopathologic features. Most lesions are isolated. Some are associated with congenital anomalies and syndromes. Strict clinicopathologic diagnostic criteria should be applied to avoid mislabeling look-alike lesions for RMHs.

Clinicopathologic and Molecular Characterization of Xanthomatous Giant Cell Renal Cell Carcinomas: Further Support for a Close Morphologic Spectrum to Eosinophilic Solid and Cystic Renal Cell Carcinomas.

A recent study described a rare subtype of tuberous sclerosis complex ( TSC )-mutated renal cell carcinoma primarily characterized by Xanthomatous giant cell morphology. Only 2 cases in young individuals have been reported so far, making the correct diagnosis challenging from a pathological perspective. It remains unknown whether this tumor represents an independent subtype or belongs to other TSC -mutated tumors. We conducted a clinicopathologic evaluation and immunohistochemical profiling of 5 cases of Xanthomatous Giant Cell Renal Cell Carcinoma (XGC RCC) with confirmed TSC2 mutations through targeted DNA sequencing. In addition, we analyzed transcriptomic profiles using RNA-seq for the following samples: XGC RCC, Low-grade Oncocytic tumors (LOT), High-grade Oncocytic tumors/Eosinophilic Vacuolar Tumors (HOT/EVT), Eosinophilic Solid and Cystic Renal Cell Carcinomas (ESC RCC), Chromophobe cell Renal Cell Carcinomas (ChRCC), Renal Oncocytomas (RO), clear cell Renal Cell Carcinomas (ccRCC), and normal renal tissues. There were 2 female and 3 male patients, aged 22 to 58 years, who underwent radical nephrectomy for tumor removal. The tumor sizes ranged from 4.7 to 9.5cm in diameter. These tumors exhibited ill-defined boundaries, showed an expansive growth pattern, and featured distinctive tumor giant cells with abundant eosinophilic to Xanthomatous cytoplasm and prominent nucleoli. All tumors had low Ki-67 proliferation indices (<1%) and demonstrated immune reactivity for CD10, PAX8, CK20, CathepsinK, and GPNMB. Next-generation sequencing confirmed TSC2 mutations in all cases. RNA sequencing-based clustering indicated a close similarity between the tumor and ESC RCC. One patient (1/5) died of an accident 63 months later, while the remaining patients (4/5) were alive without tumor recurrences or metastases at the time of analysis, with a mean follow-up duration of 43.4 months. Our research supports the concept that Xanthomatous giant cell renal cell carcinoma (XGC RCC) shares clinicopathological and molecular characteristics with ESC RCC and shows a relatively positive prognosis, providing further support for a close morphologic spectrum between the two. We propose considering XGC RCC as a distinct subtype of ESC RCC.

Huge mesenchymal hamartoma in a young adult: a case report

Abstract Mesenchymal hamartoma of the liver (MHL) is rare. Less than 50 adult cases have been described. Due to their potential degeneration or recurrence, a complete surgical resection must be performed. We describe a case of a 26-year-old with a palpable solid lesion, which displaced abdominal organs. Percutaneous needle biopsies suggested the diagnosis of MHL. A right hemi-hepatectomy without segment 1 was performed; the post-operative course was uneventful. The mesenchymal component of the tumour was reactive to desmin and smooth muscle actin. Low proliferation index was confirmed (MIB1). Genetic counselling: the sequencing analysis of DICER1 and CDKN1C gene was negative, DNA methylation analysis on the chromosome 11p15 region was normal. After 42 months, there was no recurrence. In conclusion, clinicians should consider MHL in the differential diagnosis. The dimension and the need of radicality impose major liver resections or liver transplantations, which should be performed in referral centres.

Patients with recurrent vulvovaginal candidiasis exhibit a decrease in both the fungicidal activity of neutrophils and the proliferation of peripheral blood mononuclear cells.

Recurrent vulvovaginal candidiasis (RVVC) is an important and underestimated fungal infection. We aimed to determine the fungicidal and proliferative capacities of neutrophils and peripheral blood mononuclear cells (PBMCs), respectively and the clinical and microbiological characteristics of a cohort of Colombian patients diagnosed with RVVC. A cross-sectional study was conducted. A total of 66 women were included (40 diagnosed with RVVC and 26 healthy women [HW]). Demographic and clinical data were recorded. Vaginal fluid samples were obtained for isolation, identification and antifungal susceptibility testing of Candida species using selective culture media and the Vitek 2.0® system. Blood samples were also obtained to evaluate cell subpopulations; furthermore, neutrophils and PBMCs were isolated to determine their fungicidal and proliferative capacities, respectively. The median age was 29 (IQR: 34-23) for RVVC and 24 (IQR: 30-23) for HW. Only two species of the genus Candida were identified: Candida albicans (92.5%) and Candida lusitaniae (7.5%). Resistance to fluconazole, voriconazole, flucytosine and amphotericin B was observed on six C. albicans isolates and one C. lusitaniae isolate. Only the family history of vulvovaginal candidiasis was associated with RVVC occurrence. The RVVC group exhibited a significantly higher number of neutrophils but with lower fungicidal activity in comparison to HW; likewise, PBMCs from RVVC patients presented a lower proliferation index when stimulated with C. albicans. Contrary to what has been reported worldwide, in Colombian patients with RVVC, C. albicans was the main isolated species without increased antifungal resistance. The diminished fungicidal and proliferative capacities of neutrophils and PBMCs, respectively, could suggest a possible alteration in the innate and adaptive immune responses.

Ependymomas of the spinal region in adults: Clinical and pathological features and MYCN expression levels in spinal ependymomas and myxopapillary ependymomas

BackgroundEpendymomas (EPNs) of the spinal region are a heterogeneous group of tumors that account for 17.6 % in adults. Four types have been recognized: subependymoma, spinal ependymoma (Sp-EPN), myxopapillary ependymoma (MPE), and Sp-EPN-MYCN amplified, each with distinct histopathological and molecular features. MethodsThis study investigated the clinical and pathological characteristics and MYCN expression levels of 35 Sp-EPN and MPE cases diagnosed at a tertiary university hospital over a decade-long period. ResultsTwenty-five cases were Sp-EPN and 10 cases were MPE, and were graded as WHO grade 2, except for 1 Sp-EPN case with grade 3 features. The most common symptoms were lower back pain and difficulty in walking. Radiology showed different tumor sizes and locations along the spinal cord, with MPEs exclusively in the lumbosacral region. Surgery was the main treatment, and gross total resection was achieved in all cases except for one. Immunohistochemistry showed low Ki-67 proliferation indices in all cases, and no MYCN expression. During follow-up, 3 (8.6 %) cases recurred and/or metastasized and 5 cases (14.3 %) died. No significant difference was found in disease-free survival or overall survival between Sp-EPN and MPE cases. However, 3 cases with grade 2 histology demonstrated recurrence and/or metastasis, despite the lack of MYCN expression. ConclusionOur results underscore the multifactorial nature of tumor aggressiveness in EPNs of the spinal region. This study enhances our knowledge of the clinical and pathological features of Sp-EPNs and MPEs and highlights the need for better diagnostic and prognostic markers in these rare tumors.

A radiologic-pathologic study of the histopathologic variants of ameloblastomas and their proliferation indices

Objectives: This study aimed to analyze the clinicoradiologic features and Ki-67 proliferation indices between the histopathologic variants of ameloblastomas (ABs) for possible associations. Study design: The diagnosis and histopathologic variant were confirmed for all cases by experienced Oral and Maxillofacial Pathologists. Immunohistochemistry for Ki-67 was performed on the most representative formalin-fixed paraffin-embedded tissue block. Demographic, clinical data and radiologic features were analyzed from patient records and available radiographic examinations. The investigators were blinded to the histopathologic variant and proliferation index when the clinicoradiologic features were assessed. Results: The current study included 116 cases of AB in the final sample. The indolent behavior of the unicystic variant was supported by their low proliferation index and slow growth paired with low frequencies of cortical destruction, loss of teeth, root resorption, and encroachment on anatomical structures. In contrast, the comparatively high proliferation index of the plexiform variant correlated with their fast growth and pain. Furthermore, high radiologic frequencies of cortical destruction, loss of teeth, and encroachment of surrounding anatomical structures supported their more aggressive clinical course. Conclusion: Statistically significant differences were noted between certain variants and Ki-67, location, borders, locularity, and cortical destruction, providing better insight into their biological behavior.

Abstract B027: Molecular characterization and therapeutic approaches for VISTA+ triple-negative breast cancers

Abstract Introduction: VISTA (V-domain Ig suppressor of T cell activation) is a single-pass transmembrane immune checkpoint receptor that is an emerging clinical target for cancer immunotherapy. Although VISTA confers quiescence to naïve T cells, molecular mechanisms responsible for this effect remain unclear. Also, the effects of VISTA expression on tumor cells remains poorly defined. Methods: Multi-omic profiling was performed in human breast cancer cells lines to determine immune regulatory genes. Human triple-negative breast cancers (N=248) were examined by immunohistochemistry for expression of VISTA, PDL1, PD1 and FoxP3. VISTA expression was engineered into human and mouse triple-negative breast cancer cell lines and growth was characterized in vitro and in mouse models. Membrane receptor trafficking and localization of EGFR and clathrin adapters was performed in cells expressing VISTA, VISTA mutants and VISTA knockouts. Proximity biotinylation identified protein partners that interacted with VISTA’s intracellular domain. Deletion mutagenesis was performed to identify functional VISTA cytoplasmic motifs. Cytokine response and tumor growth kinetics were measured in TNBC mouse models expressing VISTA or VISTA mutants. Results: A class of human triple-negative breast cancers were identified with high VISTA expression, low tumor infiltrating lymphocytes and low proliferative index (8-20% of all TNBCs). Tumor models demonstrated that enforced expression of VISTA in tumor cells caused growth suppression, even in the absence of an immune system. This effect was mapped to the cytoplasmic domain of VISTA, which lacks defined signaling domains. Through biochemical approaches, the clathrin-adaptor molecules NUMB and GULP1 were found in complex with a VISTA intracellular NPGF motif. This motif sequestered NUMB at early endosomes, resulting in diminished NUMB recycling for EGFR endocytosis, thereby causing growth suppression. VISTA impaired NUMB recycling by blocking Rab11 effector complex formation. VISTA NPGF mutations did not disrupt cytokine secretion in mixed lymphocyte assays. VISTA-targeted antibodies did not disrupt NUMB sequestration. VISTA+ tumors were selectively sensitive to VISTA-blocking antibodies. Conclusions: VISTA+ TNBC have distinct features including slower proliferative index and increased sensitivity to VISTA-blocking antibodies. This work identifies mechanisms by which VISTA enforces a quiescent cellular state by sequestering clathrin adapter proteins away from sites of endocytosis in cancer cells. This is the first description of intracellular molecular mechanisms controlled by VISTA’s intracellular tail. It may inform features of the VISTA-dependent immune checkpoint that could be exploited to improve anti-tumor immunity. Integration of these findings with ongoing VISTA clinical trials will be discussed. Citation Format: Joshua Gruber, Yan Zhao, Fatima Charles, Priyanka Reddy, Kristina Paul, Virginia Ezenwa, Marisa Juntilla, Idit Sagiv-Barfi, Yan Peng, Song Zhang, Allison Kurian, Michael Snyder. Molecular characterization and therapeutic approaches for VISTA+ triple-negative breast cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B027.

Primary Well-Differentiated Neuroendocrine Tumor/Carcinoid of the Prostate: Case Report and Review of Literature.

Primary well-differentiated neuroendocrine tumor (WDNT)/carcinoid of the genitourinary tract is rare. Many WDNT reported in the prostate gland have been seen in close association with conventional prostatic adenocarcinoma and/or label for prostate-specific immunohistochemical markers and are best considered prostatic adenocarcinomas with "carcinoid-like" features. We present a case of primary WDNT/carcinoid incidentally detected in a 67-year-old man who underwent radical prostatectomy for Grade group 2 prostatic adenocarcinoma. Morphologically, the neuroendocrine (NE) lesion appeared distinct from the prostatic adenocarcinoma, labeled for NE markers, was negative for prostatic markers (NKX3.1, PSA, and ERG), and showed an overall low Ki-67 proliferation index (<1%). Follow-up was uneventful with no evidence of residual disease or metastasis.

Nuclear size and pleiomorphism of breast cancer cells at high and low Ki-67 proliferation index

Background: Breast cancer cells are characterized by enlargement of nuclei and variation of nuclear size. The more anaplastic of cell nuclei reflect more aggressive and malignant cells that affect increase proliferation rate. The aim of this study is to reveal whether there was any difference of anaplastic characteristic of breast cancer cells in high and low degree of proliferation rate. Material and Methods: Twenty-three cases of breast cancer were collected from archive of Pathology Department composed of high and low Ki-67 proliferations index. Anaplastic characteristics of cancer cells were obtained by measuring the area and pleomorphism of breast cancer cells in cytologic specimen from aspiration biopsy material. Result and Discussion: There were no differences between breast cancer cells’ size between high and low Ki-67 proliferation index while there was a difference pleomorphism between high and low Ki67. Conclusion: The degree of anaplasia in breast cancer cells has a relationship with cancer cells proliferation. Further research should be made to reveal the mechanism of this phenomenon.

AI improves accuracy, agreement and efficiency of pathologists for Ki67 assessments in breast cancer

The Ki-67 proliferation index (PI) guides treatment decisions in breast cancer but suffers from poor inter-rater reproducibility. Although AI tools have been designed for Ki-67 assessment, their impact on pathologists' work remains understudied. 90 international pathologists were recruited to assess the Ki-67 PI of ten breast cancer tissue microarrays with and without AI. Accuracy, agreement, and turnaround time with and without AI were compared. Pathologists’ perspectives on AI were collected. Using AI led to a significant decrease in PI error (2.1% with AI vs. 5.9% without AI, p < 0.001), better inter-rater agreement (ICC: 0.70 vs. 0.92; Krippendorff’s α: 0.63 vs. 0.89; Fleiss’ Kappa: 0.40 vs. 0.86), and an 11.9% overall median reduction in turnaround time. Most pathologists (84%) found the AI reliable. For Ki-67 assessments, 76% of respondents believed AI enhances accuracy, 82% said it improves consistency, and 83% trust it will improve efficiency. This study highlights AI's potential to standardize Ki-67 scoring, especially between 5 and 30% PI—a range with low PI agreement. This could pave the way for a universally accepted PI score to guide treatment decisions, emphasizing the promising role of AI integration into pathologist workflows.

Cutaneous melanocytic tumor with CRTC1::TRIM11 fusion: a case report

BackgroundCutaneous Melanocytic Tumor with CRTC1::TRIM11 Fusion (CMTCT) represents a novel and rare entity in the realm of dermatological oncology, characterized by distinct melanocytic differentiation. This particular tumor type has yet to be officially recognized by the World Health Organization (WHO). CMTCT is generally perceived as a tumor with a relatively indolent nature; however, it is not devoid of metastatic potential. Therefore, ensuring complete surgical excision of the tumor, coupled with rigorous long-term follow-up, is paramount for patient management. In this context, we report the case of an 18-year-old female patient who presented with a dull red nodule on her left leg. Initial surgical intervention led to a pathological diagnosis of CMTCT, but it was determined that the tumor had not been fully excised. Consequently, a second surgical procedure was undertaken to achieve complete removal of the tumor. During a follow-up period of six months post-surgery, the patient showed no signs of local recurrence or metastasis, indicating a successful outcome.Case presentationAn 18-year-old female patient noticed a dull red nodule on her left leg three years ago, which exhibited slow growth over time. She underwent a subcutaneous tumor resection. Histological examination under high-power magnification revealed that the neoplasm consisted of epithelioid cells arranged in nests, fascicles, bundles, or sheets. The tumor cells had round or ovoid nuclei with prominent nucleoli and visible mitotic figures. Notably, areas resembling nevus cell clusters were observed. Immunohistochemical analysis confirmed melanocytic differentiation. Next-generation sequencing (NGS) identified a CRTC1::TRIM11 fusion, and fluorescence in situ hybridization (FISH) for CRTC1 confirmed rearrangement. Consequently, a diagnosis of cutaneous melanocytic tumor with CRTC1::TRIM11 fusion was established.ConclusionsCMTCT is a rare tumor characterized by melanocytic differentiation. In this case, the tumor predominantly comprised epithelioid cells with localized nevus cell clusters. The expression of melanocyte markers could easily lead to a misdiagnosis as cutaneous melanoma. However, several distinguishing features were noted: the tumor was not connected to the epidermis, exhibited low cellular heterogeneity and proliferation index, and showed minimal cellular atypia. Additionally, tests for EWSR1 rearrangement (FISH) and BRAF V600E mutation (PCR-ARMS) were negative.This case underscores the importance of a comprehensive diagnostic approach when clinical, microscopic, immunohistochemical, and molecular findings do not align. The presence of nevus cell clusters morphology in the tumor cells enhances our understanding of this disease’s histological spectrum and aids in avoiding misdiagnosis or missed diagnosis.

A Research Protocol for a Phase II Single-Arm Clinical Trial Assessing the Feasibility and Efficacy of Neoadjuvant Anastrozole in Patients With Luminal Breast Cancer and Low Proliferative Index: The ANNE Trial.

Neoadjuvant endocrine therapy (NET) is recommended for the treatment of invasive breast cancer (BC), particularly luminal subtypes, in locally advanced stages. Previous randomized studies have demonstrated the benefits of aromatase inhibitors in this context. However, NET is typically reserved for elderly or frail patients who may not tolerate neoadjuvant chemotherapy. Identifying non-responsive patients early and extending treatment for responsive ones would be ideal, yet optimal strategies are awaited. This non-randomized phase 2 clinical trial aims to assess NET feasibility and efficacy in postmenopausal stage II and III luminal BC patients, identifying predictive therapeutic response biomarkers. Efficacy will be gauged by patients with Ki67 ≤ 10% after 4 weeks and Preoperative Endocrine Prognostic Index (PEPI) scores 0 post-surgery. Study feasibility will be determined by participation acceptance rate (recruitment rate ≥50%) and inclusion rate (>2 patients/month). Postmenopausal women with luminal, HER2-tumors in stages II and III undergo neoadjuvant anastrozole treatment, evaluating continuing NET or receiving chemotherapy through early Ki67 analysis after 2 to 4 weeks. The study assesses NET extension for up to 10 months, using serial follow-ups with standardized breast ultrasound and clinical criteria-based NET suspension. Clinical and pathological responses will be measured overall and in the luminal tumor A subgroup. Toxicity, health-related quality of life, and circulating biomarkers predicting early NET response will also be evaluated.