Specific Histological Types Research Articles

＜Editors' Choice＞ Stanniocalcin-1 mRNA expression in soft-tissue tumors.

ABSTRACTStanniocalcin-1 (STC1) is a glycoprotein that was originally identified as a calcium-regulating hormone in bony fish, and that has been shown to also critically mediate cell growth, proliferation and differentiation, etc. in humans. Increased STC1 expression levels have been previously detected in different human cancer samples, such as those isolated from lung, breast, ovary, colon, pancreas, and liver tumors; thus, the present study evaluated STC1 expression in various soft-tissue tumors. STC1 mRNA isolated from 16 cell lines and 186 clinical soft-tissue tumor specimens were analyzed via quantitative real-time PCR, and the calculated expression levels were normalized to those exhibited by STC1-expressing MDA-MB-231 cells. The results of these analyses did not reveal any specific histological tumor types that displayed significantly increased STC1 expression; however, they did not indicate that STC1 expression was significantly higher in malignant compared to benign soft-tissue tumors. Furthermore, in adipocytic tumors, STC1 expression in dedifferentiated liposarcomas was found to be highest and lowest in lipoma tissues, respectively, suggesting that adipocytic tumors may express increasely high levels of STC1 mRNA as they become histologically more advanced. STC1 expression correlates with the malignancy grade in soft-tissue tumors.

Adjuvant and neoadjuvant therapy for breast cancer.

Systemic therapies for operable breast cancer patients have improved outcomes and have thus become standard treatments. Recently, new molecular target drugs and regimens are being developed based on the predicted sensitivity for specific breast cancer histological types. Systemic therapy is selected according to recurrence risk, with the treatment for low-risk patients being de-escalated, while high-risk patients receive aggressive systemic treatment with an adequate dose and duration. Neoadjuvant systemic therapy has a different aim. The efficacy of systemic therapies, based on the sensitivities to drugs, is supported by improvements in the rate of breast-conserving therapy. The response to neoadjuvant systemic therapy is the most important factor for predicting outcomes and selecting the optimal adjuvant therapy. Novel biological markers unique to individual patients allow appropriate targeted therapy, which can achieve optimal efficacy.

Histological profile of patients served in a reference center in the city of São Paulo

Introduction: Breast cancer is the most common cancer in women worldwide. In Brazil, according to INCA, it had an incidence of 57,900 new cases in 2018, 16,340 cases in the state of São Paulo. The WHO classifies tumors according to morphological criteria, including non-special breast cancer (CMI-SOE), which is seen in 70% of cases, with more than 20 other special histological types, among which invasive lobular carcinoma (ILC) has a higher prevalence (10‒15%). Objective: To describe the histological profile of breast cancer patients at the Pérola Byington Hospital between the years 2009 to 2019. Method: Cross-sectional, descriptive study, obtained through a database review. It included patients with suspected invasive neoplasms seen at the service. Results: During the period, 10,539 patients with malignant lesions and ductal carcinoma in situ (DCIS) were treated, among those who had cancer, 91% were CMI-SOE, 5% lobular neoplasia, and 3.95% of the other special subtypes. The least frequent type was metaplastic, with only 20 cases in the period. In addition, 7.14% of the patients seen had DCIS. Conclusions: It is possible to observe the predominance of CMI-SOE in this series, as well as described in analyses carried out throughout the country and in the world, followed by lobular carcinoma and other special subtypes.

Triple negative breast cancer: special histological types and emerging therapeutic methods.

Triple negative breast cancer (TNBC) is a complex and malignant breast cancer subtype that lacks expression of the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), thereby making therapeutic targeting difficult. TNBC is generally considered to have high malignancy and poor prognosis. However, patients diagnosed with certain rare histomorphologic subtypes of TNBC have better prognosis than those diagnosed with typical triple negative breast cancer. In addition, with the discovery and development of novel treatment targets such as the androgen receptor (AR), PI3K/AKT/mTOR and AMPK signaling pathways, as well as emerging immunotherapies, the therapeutic options for TNBC are increasing. In this paper, we review the literature on various histological types of TNBC and focus on newly developed therapeutic strategies that target and potentially affect molecular pathways or emerging oncogenes, thus providing a basis for future tailored therapies focused on the mutational aspects of TNBC.

Histological and molecular classification of breast cancer: what do we know?

Breast cancer is the neoplasm most diagnosed malignancy and the leading cause of mortality among women on a global scale. A profound increase in the understanding and clinical management of breast cancer has occurred over the past two decades, which has led to significant progress in prevention, early detection, and personalized breast cancer therapy. However, the biggest obstacle still faced in clinical practice is the complete understanding of intertumoral and intratumoral heterogeneity, in addition to the mechanisms of multiple drug resistance in the systemic treatment of the disease. In view of this, many studies focus on analyzing morphological and, mainly, molecular patterns of breast cancer, with the purpose of grouping these tumors into classes or entities to assist in clinical management, in the elaboration of epidemiological and functional studies, and in the performance of clinical trials. The most common special histological types of breast cancer include: medullary carcinoma, metaplastic carcinoma, apocrine carcinoma, mucinous carcinoma, cribriform carcinoma, tubular carcinoma, neuroendocrine carcinoma, classic lobular carcinoma, and pleomorphic lobular carcinoma, in addition to the non-specific type of invasive ductal carcinoma, which constitutes the majority of newly diagnosed cases. As to their molecular aspect, intrinsic subtypes were identified based on global studies of gene expression profiles. Today, four molecular subgroups are widely reproduced and well established in the clinical routine, namely: Luminal A, Luminal B, HER2 +, and Triple Negative. Thus, the present article aims to briefly address the histological and molecular classification of breast cancer.

RARE Malignant Breast Pathologies with Benign Imaging Features : About Three Clinical Cases and Literature Review

Deceptive cancers mimic benign breast tumors and are primarily represented by the group of round-shaped cancers with well-circumscribed contours. These account for about 10 to 20% of breast cancers. They most often correspond to grade III invasive carcinomas without specific features, particularly triple-negative cancers. Other etiologies of round-shaped carcinomas correspond to specific histological types including colloid (or mucinous) carcinoma, and medullary carcinoma (especially frequent in patients mutated for BRCA1). It is crucial to recognize their presentation in conventional imaging, mammography, and ultrasound, and to consider them in the presence of morphological criteria of benign appearance (cystic component in ultrasound) combined with subtle non-typical benignity criteria such as the presence of microcalcifications in mammography, microlobulated contours, a complex cystic component in ultrasound, or intratumoral vascularization in Doppler mode. In case of doubt, it is imperative to indicate a micro-biopsy for histological analysis.

Matrix-producing Carcinoma as an Aggressive Triple-negative Breast Cancer: Clinicopathological Features and Response to Neoadjuvant Chemotherapy.

Breast matrix-producing carcinomas (MPCs) are rare, and usually triple-negative (TNBC; i.e. oestrogen receptor-, progesterone receptor-, and human epidermal growth factor receptor 2-negative). This study evaluated the clinical features, immunohistochemical profiles, and pathological response to neoadjuvant chemotherapy (NAC) of patients with MPCs. Five MPCs were identified among 247 patients with TNBC receiving anthracycline- and taxane-based NAC. Pathological response was assessed using surgical specimens. All tumours were histological grade 3 according to pre-treatment core biopsies. Mean Ki-67 and p53 positivity were 65% and 90%, respectively. All tumours were TNBC, and epidermal growth factor receptor-, cytokeratin 5/6-, and vimentin-positive. Grade 3 (pathological complete response) was achieved in 0% (0/5) and 32% (77/242) of those with MPCs and with TNBCs of no specific histological type, respectively, and grade 1a (poor response) in 80% (4/5) and 13% (31/242), respectively. MPCs are basal-type TNBCs expressing epithelial-mesenchymal transition markers, with a poor response to standard NAC. Further studies are needed to improve the treatment of this rare but aggressive tumour.

Exploring Collagen Parameters in Pure Special Types of Invasive Breast Cancer

One of the promising tools to evaluate collagen in the extracellular matrix is the second-harmonic generation microscopy (SHG). This approach may shed light on the biological behavior of cancers and their taxonomy, but has not yet been applied to characterize collagen fibers in cases diagnosed as invasive breast carcinoma (BC) of histological special types (IBC-ST). Tissue sections from 99 patients with IBC-ST and 21 of invasive breast carcinoma of no special type (IBC-NST) were submitted to evaluation of collagen parameters by SHG. Tissue microarray was performed to evaluate immunohistochemical-based molecular subtype. In intratumoral areas, fSHG and bSHG (forward-SHG and backward-SHG) collagen parameters achieved their lowest values in mucinous, papillary and medullary carcinomas, whereas the highest values were found in classic invasive lobular and tubular carcinomas. Unsupervised hierarchical cluster analysis and minimal spanning tree using intratumoral collagen parameters allowed the identification of three main groups of breast cancer: group A (classic invasive lobular and tubular carcinomas); group B (IBC-NST, metaplastic, invasive apocrine and micropapillary carcinomas); and group C (medullary, mucinous and papillary carcinomas). Our findings provide further characterization of the tumor microenvironment of IBC-ST. This understanding may add information to build more consistent tumor categorization and to refine prognostication.

Molecular screening program to select molecular-based recommended therapies for metastatic cancer patients: analysis from the ProfiLER trial.

Antitumor activity of molecular-targeted agents is guided by the presence of documented genomic alteration in specific histological subtypes. We aim to explore the feasibility, efficacy and therapeutic impact of molecular profiling in routine setting. This multicentric prospective study enrolled adult or pediatric patients with solid or hematological advanced cancer previously treated in advanced/metastatic setting and noneligible to curative treatment. Each molecular profile was established on tumor, relapse or biopsies, and reviewed by a molecular tumor board (MTB) to identify molecular-based recommended therapies (MBRT). The main outcome was to assess the incidence rate of genomic mutations in routine setting, across specific histological types. Secondary objectives included a description of patients with actionable alterations and for whom MBRT was initiated, and overall response rate. Four centers included 2579 patients from February 2013 to February 2017, and the MTB reviewed the molecular profiles achieved for 1980 (76.8%) patients. The most frequently altered genes were CDKN2A (N = 181, 7%), KRAS (N = 177, 7%), PIK3CA (N = 185, 7%), and CCND1 (N = 104, 4%). An MBRT was recommended for 699/2579 patients (27%), and only 163/2579 patients (6%) received at least one MBRT. Out of the 182 lines of MBRT initiated, 23 (13%) partial responses were observed. However, only 0.9% of the whole cohort experienced an objective response. An MBRT was provided for 27% of patients in our study, but only 6% of patients actually received matched therapy with an overall response rate of 0.9%. Molecular screening should not be used at present to guide decision-making in routine clinical practice outside of clinical trials.This trial is registered with ClinicalTrials.gov, number NCT01774409.

Abstract P2-08-10: Similarities between low hormone receptor positive and hormone receptor negative breast cancer: An analysis of 4366 patients from multicenter clinical trials

Abstract Background: Currently, patients with breast cancer (BC) with hormone receptor (HR) immunohistochemical expression between 1-9% are eligible to receive endocrine therapy. However, recent data suggest that these tumors express a basal-like molecular phenotype associated with triple negative BC (TNBC) rather than luminal phenotype associated with HR positive BC. Here, we aimed to determine the differences between strong HR positive, low HR positive and negative HR BC, in regard to responsiveness to neoadjuvant chemotherapy (NACT) and disease free survival (DFS) in large cohorts from GBG clinical trials. Methods: In this retrospective analysis of data from women with BC treated in the neoadjuvant GeparQuinto (n=2572), GeparSixto (n=588) and GeparSepto (n=1206) clinical trials, we compared patients with three HR phenotypes: low positive (ER and/or PR= 1-9%), strong positive (ER or PR= 10-100%), and negative (ER and PR= <1%), regarding pathological complete response (pCR, ypT0 ypN0) and DFS. A logistic regression model for endpoint pCR was performed on pooled data from all trials. Cox regression was used to model DFS for patients participating in GeparQuinto and GeparSixto trial, including 71 with low HR positive phenotype. The models were adjusted by age, tumor and nodal status, grading, Her2 status, histological type, stromal and tumor infiltrating lymphocytes and clinical trial. The survival model was additionally adjusted by pCR after NACT. Results: Patients median age was 49 years, the majority had clinical tumor stage 2 (54.1%), negative nodal status (54.7%), and Her2 negative tumors (72.4%). 85.1% of women had BC classified as no special histological type. The pCR rate across the studies was 26.2%. 145 (3.4%) patients had low HR positive, 2417 (57.3%) strong HR positive and 1658 (39.3%) HR negative tumors. After NACT, 16.3% of patients with strong HR positive BC achieved a pCR, while among those with HR negative and low HR positive tumors, pCR rates were 40.2% and 37.9%, respectively (p<0.001). In the adjusted logistic regression model, there was no statistically significant difference between low HR positive and HR negative tumors (OR: 1.34, 95%-CI: (0.84-2.13), p=0.222). But strong HR positive tumors had a significantly lower chance of achieving a pCR compared to low HR positives (OR 0.48, 95%-CI: 0.30-0.76, p=0.002). Patients with strong HR positive BC had a better DFS than patients with low HR positive tumors (hazard ratio 0.35, 95%-CI: 0.18-0.70, p=0.003). DFS was not significantly different between patients with HR negative and low HR positive tumors (hazard ratio 0.74, 95%-CI: 0.38-1.43, p=0.370). Conclusions: Similarly to patients with negative HR tumors, patients with low HR positive tumors have a better responsiveness to NACT and worse survival rates, compared to patients with strongly HR positive BC. We suggest that studies on treatment options for basal-like/TNBC, should also consider including patients with low HR positive tumors. Citation Format: Villegas SL, Lederer B, Untch M, Holms F, Ulmer H-U, Diebold K, Fasching PA, Weber K, Schmitt WD, Tesch H, Rezai M, Marmé F, Sinn B, Hackmann J, Schneeweiss A, Tannapfel A, Nekljudova V, Denkert C, Loibl S. Similarities between low hormone receptor positive and hormone receptor negative breast cancer: An analysis of 4366 patients from multicenter clinical trials [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-10.

Abstract P3-06-07: Recurrent but not pathognomonic fusion genes in mucinous carcinomas of the breast

Abstract Introduction: Mucinous carcinoma of the breast (MCB) is a rare histologic subtype of estrogen receptor (ER)-positive invasive carcinoma, and is characterized by tumor cells floating in pools of mucin. Despite their characteristic histology, MCBs are heterogeneous at the genetic level and no driver genetic alterations have been identified. Notably, MCBs lack the common genetic alterations found in ER-positive invasive ductal carcinomas (i.e. 16q losses, 1q gains and PIK3CA mutations). Fusion genes have been reported in breast cancer, including highly recurrent or pathognomonic fusions genes, such as the ETV6-NTRK3 and MYB/MYBL1 rearrangements in secretory carcinoma and adenoid cystic carcinoma, respectively. In this study we sought to define whether MCBs would be underpinned by a pathognomonic fusion gene. Materials and methods: Seven pure mucinous A (hypocellular), seven pure mucinous B (hypercellular), and the mucinous component of a mixed MCB were microdissected, and subjected to RNA extraction followed by RNA-sequencing for fusion gene discovery. Read pairs supporting chimeric transcripts were identified using INTEGRATE, FusionCatcher and STARfusion. The Bayesian driver probability of the candidate fusion genes was annotated using OncoFuse. In-frame fusion gene candidates with a high driver probability were validated using orthogonal methods (RT-PCR and Sanger sequencing). Results: Our analysis identified fusion genes in 47% (7/15) of the MCBs analyzed (29% (2/7) of type A MCBs, 57% (4/7) type B MCBs and in the mucinous component of one mixed MCB). The OAZ1-CSNK1G2 and RFC4-LPP fusion genes were identified in 20% (3/15) and 13% (2/15) of the cases, respectively. The OAZ1-CSNK1G2 chimeric transcript results in the truncation of the kinase domain of CSNK1G2, which represses ER transactivation. The RFC4-LPP chimeric transcript leads to the fusion of exons 1-3 of RFC4 and exons 5-11 of LPP, where the LIM domains of LPP are conserved. LPP is a known partner of fusion genes identified in mesenchymal tumors and reported to mediate TGF-β induced breast oncogenesis via its LIM domain. Additional validated, potentially pathogenic fusion genes identified in MCBs involved kinases, phosphatases or regulators of tyrosine kinase receptor signaling, such as IRAK3-PPM1H (n=1), GIGYF2–GFRA3 (n=1) and PHF20-FAM217B (n=1). Conclusions: MCBs harbor fusion genes in almost half of the cases with two fusions being recurrent, involving primarily genes encoding kinases, phosphatases or receptor tyrosine kinase signaling regulators. Nevertheless, due to the lack of recurrence of a specific fusion gene, this special histologic type of breast cancer is unlikely to be underpinned by a highly recurrent/ pathognomonic pathogenic fusion gene. Citation Format: Pareja F, Gularte-Merida R, Da Cruz Paula A, Brown D, Geyer FC, Piscuoglio S, Marchio C, Vincent-Salomon A, Brogi E, Weigelt B, Reis-Filho JS. Recurrent but not pathognomonic fusion genes in mucinous carcinomas of the breast [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-07.

Abstract P3-06-08: Mucinous and neuroendocrine breast cancers: A spectrum of genetically-related lesions distinct from common forms of estrogen receptor-positive breast cancers

Abstract Introduction: Mucinous (MBCs) and neuroendocrine breast carcinomas (NBCs) are special histologic types of estrogen receptor (ER)-positive breast cancers. Together, MBCs and NBCs account for approximately 5% of invasive breast cancers. NBCs are defined by the expression of neuroendocrine markers (i. e., chromogranin and/ or synaptophysin), whereas MBCs consist of nests of cancer cells floating in pools of extracellular mucin and can be either hypocellular/type A (MBC-A) or hypercellular/type B (MBC-B). MBC-B may display neuroendocrine differentiation. We compared the repertoire of somatic genetic alterations in MBCs-A and MBCs-B, and in NBCs, and evaluated whether they differ from ER-positive/ HER2-negative invasive ductal carcinomas of no special type (IDC-NSTs). Materials and methods: Reanalysis of the targeted capture or whole exome sequencing data of 22 MBCs (12 MBCs-A and 10 MBCs-B), and of 15 NBCs was performed. The BAM files were retrieved and somatic mutations were detected with MuTect, indels with Strelka, Varscan2, Scalpel and Lancet, and copy number alterations using FACETS. The mutational repertoire of MBCs-A and MCBs-B was compared to that of NBCs, and of ER-positive/ HER2-negative IDC-NSTs from The Cancer Genome Atlas (TCGA) breast cancer study (n=310). Results: The most frequently mutated genes in MBCs-A were SF3B1 and FRG1B (17%, each); in MBCs-B were GATA3 and KMT2C (30%, each), and in NBCs were FOXA1 and TBX3 (20%, each) and KMT2C (20%). No significant differences were observed in single gene comparisons between MBCs-A, MBCs-B and NBCs (Fisher's exact tests, p>0.05). When compared with ER-positive/HER2-negative IDC-NSTs from TCGA, NBCs harbored a higher frequency of mutations targeting FOXA1 (20% vs 2.9%, Fisher's exact test, p<0.05) and TBX3 (20% vs 2.9%, Fisher's exact test, p<0.05), and a lower frequency of TP53 mutations (0% vs 23.9%; Fisher's exact test, p<0.05). We observed a lower frequency of PIK3CA mutations in both MBCs-A (8.3% vs 40%, Fisher's exact test, p<0.05) and MBCs-B (0% vs 40%; Fisher's exact test, p<0.01) compared to ER-positive/HER2-negative IDC-NSTs. Although not statistically significant, PIK3CA mutations were numerically less frequent in NBCs than in ER+/HER2- IDC-NSTs (13.3% vs 40%; Fisher's exact test, p>0.05). Concurrent 1q gains and 16q losses, the hallmark copy number alterations of ER-positive/HER2-negative breast cancer were found in 47% of the ER-positive/HER2-negative IDC-NSTs from TCGA, but only present in 20% of NBCs and in none of the MBCs-A or MBCs-B. Conclusion: Type A MBCs, type B MBCs and NBCs harbor similar patterns of genetic alterations, including a low frequency of PIK3CA mutations and of concurrent 1q gains/ 16q deletions. Taken together, our data suggest that both MBCs and the vast majority of NBCs constitute a spectrum of histologically and genomically related subtypes, distinct from ER-positive/HER2-negative IDC-NSTs. Citation Format: Pareja F, Da Cruz Paula A, Selenica P, Lee JY, Marchio C, Brown D, Geyer FC, Brogi E, Vincent-Salomon A, Weigelt B, Reis-Filho JS. Mucinous and neuroendocrine breast cancers: A spectrum of genetically-related lesions distinct from common forms of estrogen receptor-positive breast cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-08.

Spatiotemporal Analysis of Lung Cancer Histological Types in Kentucky, 1995-2014.

Recent metabolic and genetic research has demonstrated that risk for specific histological types of lung cancer varies in relation to cigarette smoking and obesity. This study investigated the spatial and temporal distribution of lung cancer histological types in Kentucky, a largely rural state with high rates of smoking and obesity, to discern population-level trends that might reflect variation in these and other risk factors. The Kentucky Cancer Registry provided residential geographic coordinates for lung cancer cases diagnosed from 1995 through 2014. We used multinomial and discrete Poisson spatiotemporal scan statistics, adjusted for age, gender, and race, to characterize risk for specific histological types—small cell, adenocarcinoma, squamous cell, and other types—throughout Kentucky and compared to maps of risk factors. Toward the end of the study period, adenocarcinoma was more common among all population subgroups in north-central Kentucky, where smoking and obesity are less prevalent. During the same time frame, squamous cell, small cell, and other types were more common in rural Appalachia, where smoking and obesity are more prevalent, and in some high poverty urban areas. Spatial and temporal patterns in the distribution of histological types of lung cancer are likely related to regional variation in multiple risk factors. High smoking and obesity rates in the Appalachian region, and likely in high poverty urban areas, appeared to coincide with high rates of squamous cell and small cell lung cancer. In north-central Kentucky, environmental exposures might have resulted in higher risk for adenocarcinoma specifically.

Clinicopathological differences in signet ring cell adenocarcinoma between early and advanced gastric cancer.

Signet ring cell adenocarcinoma is a histological classification based on the WHO classification. The presence of this specific histological type is associated with a worse pathological appearance. The prognosis of signet ring cell adenocarcinoma in gastric cancer patients after curative surgery is still under debate. From January 1988 to December 2012, a total of 2971 patients, including 819 early and 2152 advanced gastric cancer patients underwent curative resection for gastric cancer. Among them, there were 185 cases of signet ring cell adenocarcinoma in early gastric cancer patients, while there were 570 cases in advanced gastric cancer patients. The overall incidence of signet ring cell adenocarcinoma was 25.4%. Our results showed that the 5-year overall survival rates of early gastric cancer patients with signet ring cell adenocarcinoma and non-signet ring cell adenocarcinoma were 90.7 and 83.2%, respectively (P = 0.001). The 5-year disease-free survival rates of early gastric cancer patients with signet ring cell adenocarcinoma and non-signet ring cell adenocarcinoma were 87.4 and 81.6%, respectively (P = 0.003). The 5-year overall survival rates of advanced gastric cancer patients with signet ring cell adenocarcinoma and non-signet ring cell adenocarcinoma were 32.1 and 37.9%, respectively (P = 0.041). The 5-year disease-free survival rates of advanced gastric cancer patients with signet ring cell adenocarcinoma and non-signet ring cell adenocarcinoma were 28.6 and 35.2%, respectively (P = 0.037). Signet ring cell adenocarcinoma was an independent predictor for overall survival in advanced gastric cancer (P = 0.017). The clinical features and prognosis of signet ring cell adenocarcinoma are different between early and advanced gastric cancer. Signet ring cell adenocarcinoma is a poor prognostic factor in advanced gastric cancer after curative resection.

Rare variant of metaplastic carcinoma of the breast: a case report and review of the\xa0literature

BackgroundMetaplastic carcinoma encompasses a group of neoplasms characterized by differentiation of the neoplastic epithelium into squamous cells and/or mesenchymal-looking elements. Spindle cell carcinoma is a rare variant of this special histological type. Its prognosis remains poor, with a high rate of local recurrence and distant metastasis. To date, only a small number of cases have been described. There is no clear agreement on this histological subtype.Case presentationWe report a case of a 53-year-old Moroccan woman who consulted our institution following palpation of a nodule of the left breast. Mammography in combination with breast ultrasonography revealed a lesion classified as Breast Imaging Reporting and Data System 4 with microcalcification. The patient was diagnosed with spindle cell carcinoma of the breast. The diagnosis was based primarily on histological and immunohistochemical studies of the breast biopsy and secondarily on the surgical specimen. No local or distant metastasis was found. The treatment used was total surgical excision followed by radiotherapy.ConclusionsWe describe the features (epidemiological, clinical, histological, immunohistochemical, and therapeutic outcomes) of our patient’s case and compare them with literature data.

The impact of the preoperative waiting period on the survival in patients with clinical stage II / III gastric cancer.

27 Background: Although prolonged preoperative waiting period (PWP) for gastric cancer (GC) may influence the prognosis, the relationship between PWP and survival outcome has not been elucidated. The aim of this study is to identify the impact of PWP on survival in patients with clinical stage (cStage) II / III GC. Methods: A total of 483 patients who underwent surgery for cStage II / III GC according to Japanese classification of GC, 14th edition, between January 2002 and December 2012 were included. The patients who underwent endoscopic submucosal dissection or neoadjuvant chemotherapy, or who had multiple cancer, special histological types of tumor, or urgent symptoms were excluded. We defined PWP as the period from the date of endoscopy for initial diagnose to that of surgery. Patients were divided into two groups according to PWP; short waiting period group (SWPG, PWP ≤ 60 days, n = 357) and long waiting period group (LWPG, PWP > 60 days, n = 126). Survival outcomes were compared between the groups and multivariate analysis for overall survival (OS) was conducted to identify independent prognostic factors. Results: The median PWP was 49 (21-323) days. In LWPG, patients were significantly older (P = 0.001) and had more comorbidities (P = 0.042) than those in SWPG. Preoperative lymph node status was significantly lower in LWPG (P = 0.031), although there were no differences in tumor depth and cStage between the groups. There was no difference in OS between the groups (5-year OS, SWPG: 61.0%, LWPG: 63.2%, P = 0.612). Multivariate analysis for OS identified age, BMI, histological type, and cStage as independent prognostic factors. Conclusions: Preoperative waiting period appears to have no influence on survival in patients with cStage II / III GC.

Association of Polymorphic Variants of <i>VEGF</i> and <i>KDR</i> Genes with Development and Metastasing of Non-Small Cell Lung Cancer

Vascular endothelial growth factor (VEGF) is one of the most important and specific factors affecting angiogenesis in tumor development. VEGFR2 is a receptor encoded by the KDR gene. VEGF and VEGFR2 transmit a signal to intracellular tyrosine kinase cascades. Polymorphic variants of the VEGF and KDR genes significantly influence the expression levels of the endothelial growth factor and its receptor, which leads to a change in the activation of angiogenesis in oncopathological processes. In this study, the relationship between the polymorphic variants rs2010963, rs699947 and rs3025039 of the VEGF gene and rs1870377 and rs2071559 of the KDR gene was analyzed with the development of a specific histological type of non-small cell lung cancer and its clinical and morphological characteristics. It was established that the development of squamous cell carcinoma is associated with -634CC genotype of the VEGF gene and the genotypes containing -2578A allele of the VEGF gene reduce the likelihood of this cancer type development. The development of adenocarcinoma is associated with +936CC VEGF/1719TT KDR and +936CT VEGF/1719TT KDR combinations. In women with non-small cell lung cancer, -634GC genotype of the VEGF gene is associated with a greater degree of the primary lesion spread. Genotype -2578СС of the VEGF gene is associated with a higher degree of the primary tumor spread in the general group of patients and with regional metastases in women. Haplotypes -634G/-2578C/+936C are risky for the occurrence of metastases in regional lymph nodes in women.

Genomic and transcriptomic heterogeneity in metaplastic carcinomas of the breast

Metaplastic breast cancer (MBC) is a rare special histologic type of triple-negative breast cancer, characterized by the presence of neoplastic cells showing differentiation towards squamous epithelium and/or mesenchymal elements. Here we sought to define whether histologically distinct subgroups of MBCs would be underpinned by distinct genomic and/or transcriptomic alterations. Microarray-based copy number profiling identified limited but significant differences between the distinct MBC subtypes studied here, despite the limited sample size (n = 17). In particular, we found that, compared to MBCs with chondroid or squamous cell metaplasia, MBCs with spindle cell differentiation less frequently harbored gain of 7q11.22-23 encompassing CLDN3 and CLDN4, consistent with their lower expression of claudins and their association with the claudin-low molecular classification. Microarray-based and RNA-sequencing-based gene expression profiling revealed that MBCs with spindle cell differentiation differ from MBCs with chondroid or squamous cell metaplasia on the expression of epithelial-to-mesenchymal transition-related genes, including down-regulation of CDH1 and EPCAM. In addition, RNA-sequencing revealed that the histologic patterns observed in MBCs are unlikely to be underpinned by a highly recurrent expressed fusion gene or a pathognomonic expressed mutation in cancer genes. Loss of PTEN expression or mutations affecting PIK3CA or TSC2 observed in 8/17 MBCs support the contention that PI3K pathway activation plays a role in the development of MBCs. Our data demonstrate that despite harboring largely similar patterns of gene copy number alterations, MBCs with spindle cell, chondroid and squamous differentiation are distinct at the transcriptomic level but are unlikely to be defined by specific pathognomonic genetic alterations.

Invasive lobular carcinoma of the breast: A special histological type compared with invasive ductal carcinoma.

The clinical outcomes and therapeutic strategies for infiltrating ductal carcinoma (IDC) and infiltrating lobular carcinoma (ILC) are not uniform. The primary objectives of this study were to identify the differences in the clinical characteristics and prognoses between ILC and IDC, and identify the high-risk population based on the hormone receptor status and metastasis sites. The Surveillance, Epidemiology, and End Results Program database was searched and patients diagnosed with ILC or IDC from 1990 to 2013 were identified. In total,796,335 patients were analyzed, including 85,048 withILC (10.7%) and 711,287 withIDC (89.3%). The ILC group was correlatedwith older age, larger tumor size, later stage, lower grade, metastasis disease(M1) disease, and greater counts ofpositive lymph nodesandestrogen-receptor-positive (ER)/progesterone receptor-positive (PR) positive nodes. The overall survival showed an early advantage for ILC but a worse outcome after 5 years. Regarding the disease-specific survival, the IDC cohort had advantages over the ILC group, both during the early years and long-term. In hormone status and metastasis site subgroup analyses, the ER+/PR+ subgroup had the best survival, while the ER+/PR- subgroup had the worst outcome, especially the ILC cohort. ILC and IDC had different metastasis patterns. The proportion of bone metastasis was higher in the ILC group (91.52%) than that in the IDC (76.04%), and the ILC group was more likely to have multiple metastasis sites. Survival analyses showed patients with ILC had a higher risk of liver metastasis (disease-specific survival[DSS]; P = 0.046), but had a better overall survival than the bone metastasis group (P<0.0001). We concluded that the long-term prognosis for ILC was poorer than that for IDC, and the ER+/PR- subgroup had the worst outcome. Therefore, the metastasis pattern and prognosis must be seriously evaluated, and a combination of endocrine therapy and chemotherapy should be considered.

Cyclin D1 overexpression correlates with poor tumor differentiation and prognosis in gastric cancer

Overexpression of cyclin D is associated with the molecular tumorigenesis of gastric cancer. The purpose of the present study was to investigate the expression of cyclin D in human gastric cancer and to determine the potential correlations between cyclin D expression and clinicopathological characteristics of specific histological types, as well as its prognostic significance. In the present study, the expression of the cyclin D1 (CCND1), cyclin D2 (CCND2) and cyclin D3 (CCND3) genes in gastric cancer patients was explored using the Oncomine database, and their correlation with overall survival (OS) and progression-free survival (PFS) was evaluated using Kaplan-Meier analysis. The prognostic significance of CCND1 protein expression was evaluated by western blot analysis of 32 matched specimens of gastric adenocarcinomas and normal tissues obtained from patients treated at the National Cheng Kung University Hospital (Tainan, Taiwan). Analysis of the Oncomine cancer microarray database revealed that CCND1 gene expression was significantly increased in gastric intestinal-type adenocarcinoma, while CCND2 was significantly increased in diffuse gastric adenocarcinoma, gastric intestinal-type adenocarcinoma and gastric mixed adenocarcinoma. Kaplan-Meier analysis indicated that overexpression of CCND1 was associated with reduced OS and PFS. In addition, overexpression of CCND1 and downregulation of CCND2 were significantly correlated with receptor tyrosine-protein kinase erb-2-negative tumors and poor differentiation. The ratio of relative CCND1 expression (expressed as the CCND1/β-actin ratio) in tumor tissues compared with that in normal tissues was correlated with poor differentiation (P=0.0018). In summary, CCND1 overexpression is associated with shorter survival in patients with gastric cancer and with poorly differentiated tumors.