Pleomorphic/solid lobular carcinoma of male breast with PALB2 germline mutation: case report and literature review.

Male breast cancer (MBC) accounts for approximately 1% of all breast cancers and among these infiltrating lobular carcinomas (ILC) represents only 1-2% of all MBC cases. Pleomorphic invasive lobular carcinoma (PILC) is an aggressive variant of ILC with only eight cases reported until now in males. Up to 10% of MBC cases have a germline pathogenic variant in a predisposing gene such as BRCA1 and BRCA2 genes. Mutations in PALB2 (partner and localizer of BRCA2) have been reported in men with breast cancer, with a frequency that ranges from 0.8 to 6.4%, but it has never been reported in male ILC. Here, we report a rare and interesting case of an invasive pleomorphic/solid lobular carcinoma, which carries a pathogenic variant in PALB2 gene, and a family history of breast cancer without other well defined risk factors for developing this type of neoplasia. In addition, we review the current literature.

Clipping a Positive Lymph Node Improves Accuracy of Nodal Staging After Neoadjuvant Chemotherapy for Breast Cancer Patients, but Does It Drive Management Changes?

BACKGROUND: Sentinel lymph node (SLN) biopsy for cN+ breast cancer patients after neoadjuvant chemotherapy (NAC) is controversial because the false-negative rate (FNR) is high. Identification of three or more SLNs with a dual tracer improves these results, and inclusion of a clipped lymph node (CLN) (targeted axillary dissection [TAD]) may be even more effective. METHODS: A retrospective, single-institution analysis of consecutive cN+ patients undergoing NAC from 2019 to 2021 was performed. Patients routinely underwent placement of a clip in the positive lymph node before NAC, and TAD was performed after completion of therapy. RESULTS: The study analyzed 73 patients, and the identification rate for CLN was 98.6% (72/73). A complete response in the lymph nodes was achieved for 43 (59%) of the 73 patients. Overall, the CLN was not a SLN in 18 (25%) of 73 cases, and for women who had one or two and those who had three or more SLNs identified, this occurred in 11 (32%) and 7 (21%) of 34 cases, respectively. Failure of SLN or TAD to identify a positive residual lymph node status after NAC occurred in 10 (15%) of 69 and 2 (3%) of 73 cases, respectively (p = 0.01). In four cases, a SLN was not retrieved (5.5%), and two of these cases had a positive CLN. In three cases, the CLN was the only positive node and did not match with a SLN, directing lymphadenectomy and oncologic management change in two cases. Therefore, 7 (10%) of 73 cases had a change in surgical or oncologic management with TAD. CONCLUSIONS: For a conservative axillary treatment in this setting, TAD is an effective method. It is more accurate than SLN alone and allows management changes. Further studies are warranted.

Non-Small Cell Lung Cancer Testing on Reference Specimens: An Italian Multicenter Experience.

INTRODUCTION: Biomarker testing is mandatory for the clinical management of patients with advanced non-small cell lung cancer (NSCLC). Myriads of technical platforms are now available for biomarker analysis with differences in terms of multiplexing capability, analytical sensitivity, and turnaround time (TAT). We evaluated the technical performance of the diagnostic workflows of 24 representative Italian institutions performing molecular tests on a series of artificial reference specimens built to mimic routine diagnostic samples. METHODS: Sample sets of eight slides from cell blocks of artificial reference specimens harboring exon 19 EGFR (epidermal growth factor receptor) p.E746_AT50del, exon 2 KRAS (Kirsten rat sarcoma viral oncogene homologue) p.G12C, ROS1 (c-ros oncogene 1)-unknown gene fusion, and MET (MET proto-oncogene, receptor tyrosine kinase) Δ exon 14 skipping were distributed to each participating institution. Two independent cell block specimens were validated by the University of Naples Federico II before shipment. Methodological and molecular data from reference specimens were annotated. RESULTS: Overall, a median DNA concentration of 3.3 ng/µL (range 0.1-10.0 ng/µL) and 13.4 ng/µL (range 2.0-45.8 ng/µL) were obtained with automated and manual technical procedures, respectively. RNA concentrations of 5.7 ng/µL (range 0.2-11.9 ng/µL) and 9.3 ng/µL (range 0.5-18.0 ng/µL) were also detected. KRAS exon 2 p.G12C, EGFR exon 19 p.E736_A750del hotspot mutations, and ROS1 aberrant transcripts were identified in all tested cases, whereas 15 out of 16 (93.7%) centers detected MET exon 14 skipping mutation. CONCLUSIONS: Optimized technical workflows are crucial in the decision-making strategy of patients with NSCLC. Artificial reference specimens enable optimization of diagnostic workflows for predictive molecular analysis in routine clinical practice.

Surgical treatment of elastofibroma dorsi. Personal experience and a review of the literature.

AIM: To report our experience in treating elastofibroma, an uncommon lesion, usually arising into subscapular area; it has been included between soft tissue tumors and is characterized by progressive growth and benign behavior METHODS: Patients with an histologically proved elastofibroma, operated at our ward unit over a 3-year period, entered this study. Early results of surgical treatment have been analyzed and compared to those of Literature, focusing on selection criteria, hospital morbidity and relative risk factors RESULTS: Fourteen surgical procedures have been performed on 11 patients; EF presented as bilateral on 3 patients (27.3%) and these patients were treated with sequential 2-stages excision. All patients received complete surgical resection according to marginal excision technique; mean operative time was 75.8 ± 21.4 min. (range 55-135) while mean size of resected EF was 8.57 ± 2.2 cm. (range 5-12). Three patients developed significative postoperative seroma (21.4%), while neither hemorrhages nor recurrences have been observed. Increased B.M.I. was the only factor significantly related to hospital morbidity at univariate analysis (p = 0.0339) CONCLUSIONS: Patients carring elastofibroma larger than 5 cm. and symptomatic should undergo surgical treatment; marginal excision represents the standard technique; we recommend the use of ultrasound energy device for tissue dissection: its current use seems to prevent postoperative bleeding. Development of postoperative seroma seems related to increased patient's B.M.I. and to larger size of EF, rather than to different methods of dissection. KEY WORDS: Chest wall tumors, Elastofibroma dorsi, Elastin, Marginal resection, Soft-tissue tumors.

CD73 expression and pathologic response to neoadjuvant chemotherapy in triple negative breast cancer.

The immune system plays a key role in tumor surveillance and escape. Recently, CD73 has been proposed as a prognostic biomarker associated with disease-free survival and overall survival in triple negative breast cancer (TNBC). In this study, we investigated the role of both CD73 expression and stromal tumor-infiltrating lymphocytes (TILs) in predicting the pathologic response of TNBC to neoadjuvant chemotherapy (NACT). We retrospectively analyzed CD73 immunohistochemical expression and stromal TILs on 61 consecutive biopsies from patients who received standard NACT. Twenty-three patients (38%) achieved pathologic complete response (pCR). TILs were present in the majority of biopsies (93%) with percentages ranging from 2 to 80%. High TILs (≥ 50%) were found in 30% of cases, and in this group, pCR was achieved in 76.5% of cases. Levels of TILs were associated with a better pathologic response only at univariate analysis (p = 0.037). The median value of CD73 expression on tumor cells was 40%. In 32 (52.5%) basal biopsies, CD73 expression was below or equal to median value ("low CD73"). A pCR was obtained in 53% of cases with "low CD73" and in 21% with high CD73, and this was statistically different both at univariate (p = 0.011) and multivariate (p = 0.014) analysis.Our results suggest that CD73 expression better predicts the response to NACT than TILs in TNBC. Characterization of both TILs and microenvironment could be a promising approach to personalize treatment.

Breast cancer subtypes affect the nodal response after neoadjuvant chemotherapy in locally advanced breast cancer: Are we ready to endorse axillary conservation?

We evaluated the impact of breast cancer subtypes on pathologic complete response (pCR) in 181 patients with positive nodes undergoing neoadjuvant chemotherapy (NAC). After NAC, patients underwent surgery, with sentinel lymph node biopsy (SLNB) or axillary dissection (ALND). In 28.2% of cases a pCR was achieved, with the highest rate in Her2+ and triple negative tumors. Overall, nodal pCR was more frequent than breast pCR (P = 0.003) with higher percentages in Her2+ and LLB-Her2+ (P < 0.05). In the Her2+ group, nodal pCR was observed only with breast pCR. Thus, in Her2+ tumors, breast pCR predicts node pCR, supporting the use of SLNB in this subgroup to stage the axilla avoiding ALND.

Pleomorphic lobular carcinoma: is it more similar to a classic lobular cancer or to a high-grade ductal cancer?

BACKGROUND: Pleomorphic invasive lobular carcinoma (P-ILC) is an uncommon variety of invasive lobular carcinoma with aggressive clinical features. Little is described in the literature regarding this topic. MATERIALS AND METHODS: We reviewed our experiences from 2010 to 2015 and compared 40 patients with P-ILC, 126 patients with classic-ILC (C-ILC) and 574 cases of high-grade invasive ductal carcinoma (HG-IDC). We studied the histologic and immunohistochemical features, clinical presentation and surgical treatment. RESULTS: P-ILC is diagnosed at the same age and tumor diameter as those of the other two histologic types. It is associated more frequently with multiple lymph node metastases and high proliferative index, and HER2/neu is amplified in 10% of cases. In spite of sharing some histologic characteristics with C-ILC (same growth pattern, loss of E-cadherin expression, same genetic pathway), its clinical and pathologic features define an autonomous entity. Its surgical treatment is similar to those of C-ILC and HG-IDC. CONCLUSION: This is the first review comparing these three pathologic entities. Our findings may be useful in understanding this variety of invasive lobular carcinoma, and further studies are certainly needed in this field.

PD-L1 Expression in TNBC: A Predictive Biomarker of Response to Neoadjuvant Chemotherapy?

Triple negative breast cancer (TNBC) has an aggressive clinical behaviour, with a poorer prognosis compared to other subtypes. Recently, tumor-infiltrating lymphocytes (TILs) have been proposed as a predictive biomarker for a better clinical outcome and pathological response (pR) after neoadjuvant chemotherapy (NACT) in TNBC. These data confirm the role of the immune system in the neoplastic progression and in the response to therapy. We performed a retrospective analysis of 54 pre-NACT biopsies of TNBC and compared both the percentage of stromal TILs and the degree of PD-L1 expression with the extent of pR to standard NACT. A pathological complete response (pCR) was achieved in 35% of cases. Univariate analysis showed (i) a significant association between PD-L1 expression in ≥25% of neoplastic cells and the achievement of a pCR (p = 0.024); (ii) a significantly higher frequency of pCR in cases showing ≥50% stromal TILs (p < 0.001). However in the multivariate analysis only PD-L1 expression on tumor cells remained significantly associated with pCR (OR = 1,13; 95% CI 1,01-1,27), suggesting that the expression of this biomarker could be associated with a subpopulation of TNBC more likely to respond to chemotherapy. These data need to be confirmed by larger studies.

A Clinico-pathologic Study of Oxidized Cellulose as Topical Hemostatic Agent in Neurosurgery.

Hemostasis is extremely important in neurosurgical procedures to prevent major postoperative bleedings and their catastrophic consequences. Emoxicel TAF Retilight (Bioster, a.s., Czech Republic) is a sterile, resorbable, hemostatic reticulum, mainly used to stop capillary and venous bleeding. The textile form of the hemostatic material allows, in several cases, perfect adjustment to the varied shape of the surgical cavities and of the epidural space to which it adheres when wet. Hemostatic effect is rapid, and complete hemostasis can be achieved in several minutes after application. This topical hemostatic agent is biocompatible, biodegradable, and highly resorbable. It has a hemostatic and antimicrobic effect. The main aim of this study was to verify the efficacy, broadness of use, and safety of this topical hemostatic in neurosurgical procedures. A total of 43 cases were included, 18 cranial and 25 spinal, and in only one case a postoperative epidural bleeding was reported. A histopathologic study of the hemostatic was performed. No allergic reactions were reported. Emoxicel was useful not only in stopping minor bleeding, but also for bleeding prevention in the postoperative period.

Granular cell tumor of the neurohypophysis: a single-institution experience.

Granular cell tumor (GCT) is a rare neoplasm occurring in the sellar and suprasellar spaces. It is a primary tumor of the neurohypophysis, presumably arising from the pituicytes, a distinctive glial cell of the neurohypophysis. GCTs in most reported cases show biologically benign behavior with slow growth. Only 70 cases of hypophyseal GCTs have been reported in the literature. We report a case of GCT in the neurohypophysis of a 46-year-old woman and discuss the histological and clinical features of this neoplasm together with the treatment modalities, reviewing the pertinent literature.

Bizzarre parosteal osteochondromatous proliferation: case report.

Nora's tumor, also known as bizzarre parosteal osteochondromatous proliferation (POPB), is an exophytic outgrowth arising from the cortical surface of the bone that consists of a mixture of bone, cartilage and fibrous tissue. It is a benign lesion with atipical microscopic features and a tendency to recur. It must be distinguishable from parosteal osteogenic sarcoma, parosteal chondrosarcoma, osteochondroma, florid reactive periostitis, turret exostosis, subungueal exostosis, myositis ossificans. The treatment is surgical, but a high rate of local relapse is described. The diagnosis is histological. We report a case of a patient with POPB involving the foot, underwent surgical excision and with no evidence of recurrence at one year.

Intraductal proliferative lesions of the breast-terminology and biology matter: premalignant lesions or preinvasive cancer?

Morphological criteria for the diagnosis of intraductal proliferative lesions of the breast have been an object of research and much controversy, and its terminology is rather confusing. Knowledge of the molecular aspects of this disease probably necessitates further research to clarify if these entities can be identified as breast cancer precursors or as a malignant preinvasive disease. These issues are of great interest not only for their biological implications, but also to the clinician who must understand the disease and direct therapies. Molecular studies have shown that epitheliosis (usual ductal hyperplasia) is not monoclonal, while malignant lesions (atypical ductal hyperplasia, flat epithelial atypia, low-grade and high-grade intraductal carcinoma) constantly show these characteristics. These malignant lesions, classified with a DIN grading system (ductal intraepithelial neoplasia), are not obligate precursors of invasive ductal carcinoma and do not represent different evolving grades in a linear model of cancerogenesis. Breast cancerogenesis probably has different pathways with different morphologic precursors.

Cross-platform Comparison of Two Pancreatic Cancer Phenotypes.

Model-based approaches for combining gene expression data from multiple high throughput platforms can be sensitive to technological artifacts when the number of samples in each platform is small. This paper proposes simple tools for quantifying concordance in a small study of pancreatic cancer cells lines with an emphasis on visualizations that uncover intra- and inter-platform variation. Using this approach, we identify several transcripts from the integrative analysis whose over-or under-expression in pancreatic cancer cell lines was validated by qPCR.

Gene expression profiles associated with advanced pancreatic cancer.

Few studies have addressed the expression profiles associated with progression of pancreatic cancer to advanced disease. Towards this end, we performed expression profiling of a series of normal pancreas, pancreatitis and cancer tissues representing early stage resected pancreatic cancers (stages pT2/T3), late stage unresectable cancers (stage pT4) and matched metastases to a variety of organ sites. Microarray data was analyzed using linear modeling of microarray data (LIMMA), and differentially expressed genes were subjected to Gene Set Enrichment Analysis (GSEA). While robust differences were found in primary cancers as compared to normal pancreatic tissues, no differences were found between primary cancers and metastases, whether using matched or unmatched samples. When resected pancreatic cancers were specifically compared to advanced pancreatic cancers, significant differences in gene expression were found associated with growth at the primary site. These differentially expressed genes were most prominent in gene classes that related to MAPK and Wnt pathway, metabolism, immune regulation, cell-cell and cell-matrix interactions within the infiltrating carcinoma. One candidate upregulated gene (MXI1) was validated as having increased expression in advanced stage (T4) carcinomas by real-time PCR (p<0.05) and immunolabeling (p<0.003). We conclude that in addition to the robust changes in expression that accompany pancreatic carcinogenesis additional specific changes occur in association with growth at the primary site. By contrast, metastatic spread is not accompanied by reproducible changes in gene expression. These findings add to our understanding of pancreatic cancer and offer new topics for investigation into the aggressive nature of this deadly tumor type.

Evaluation of GATA-4 and GATA-5 methylation profiles in human pancreatic cancers indicate promoter methylation patterns distinct from other human tumor types.

The GATA-4 and GATA-5 transcription factors are increasingly recognized as playing a role in carcinogenesis of human tumors derived of endodermal and mesodermal origin. The pancreas is derived from endodermal tissues suggesting GATA-4 and GATA-5 gene methylation may play a critical role in the biology of human pancreatic cancer as well. We investigated GATA-4 and -5 by methylation-specific PCR (MSP) in normal and neoplastic pancreatic tissues, including isogenic xenografts or cultured cell lines derived from the coexistent primary cancer and/or metastases in patients with pancreatic carcinoma. The relationship of promoter methylation was correlated with mRNA expression for each gene, and methylation patterns were correlated with known clinicopathologic features of patients. GATA-4 demonstrated a significantly lower methylation frequency than GATA-5 in low passage pancreatic cancer xenografts or cell lines (1/34 versus 21/34, p < 0.001). GATA-4 and -5 were also evaluated in microdissected samples of normal duct epithelium and cancer from pancreas cancer tissues which confirmed infrequent GATA-4 methylation in pancreatic cancers as well as in normal duct epithelium. GATA-4 was frequently overexpressed at the mRNA level with 27 of 30 (90%) pancreatic cancers showing >5.0-fold overexpression compared to normal duct epithelial cells. By contrast, high frequency methylation of GATA-5 was confirmed in pancreatic cancers tissues, but was rarely methylated in normal duct epithelium, indicating hypermethylation of this gene during pancreatic cancer development. GATA-5 mRNA expression did not correlate with its promoter hypermethylation, and treatment with the demethylating agent 5-aza-2'-deoxycytidine only partially restored mRNA expression suggesting additional regulatory mechanisms of GATA-5 expression. The presence of GATA-5 methylation showed a trend towards worse long-term survival (14.0 +/- 9.2 months versus 19.5 +/- 3.9 months, p = 0.06). While hypermethylation of GATA-5 seems to be a universal feature among human tumors, infrequent methylation of GATA-4, and its corresponding overexpression, appears unique to pancreatic cancer from other tumor types reported thus far.

Blue rubber bleb nevus syndrome and pulmonary hypertension: an unusual association.

INTRODUCTION: Blue rubber bleb nevus syndrome (BRBNS) is a rare congenital systemic angiodysplasia with multiple vascular malformations in the skin, gastrointestinal tract and, less often, in other internal organs and the brain. CASE REPORT: A 36-year-old man with past history of BRBNS was admitted to our hospital for progressive dyspnea and fatigue. Primary pulmonary hypertension (PPH) was diagnosed. He then developed acute abdominal pain and dyspnea, dying in a few hours due to sudden cardiac arrest. Postmortem examination demonstrated angiomatous lesions located in the skin, small bowel, heart, lungs, liver and thyroid. The lesions were slightly raised, soft and compressible and microscopically consisted of dilated vascular channels lined by a flattened endothelium. The vascular wall was formed by several layers of smooth muscle cells, intermixed with abundant aggregates of elastic lamellae and thin collagen fibers. Luminal thrombi were a frequent finding. In the small bowel, we identified the presence of an abnormally large artery directly opening into a thin-walled venous channel. The most striking finding in the lungs was the presence of thrombi of varying age in the lumen of segmental and elastic arteries, as well as muscular arteries and arterioles. Severe medial hypertrophy of muscular arteries and muscolarization of arterioles were also present. Intimal proliferative lesions and plexiform lesions were never observed. CONCLUSION: The pulmonary findings are consistent with recurrent thromboembolic events from shunts in the visceral lesions. To our knowledge, this is the first report of BRBNS with visceral arterovenous (AV) fistulae complicated by thromboembolic pulmonary hypertension (PH).