Syntaxin-1 and Insulinoma-Associated Protein 1 Expression in Breast Neoplasms with Neuroendocrine Features

Introduction: A subset of breast neoplasia is characterized by features of neuroendocrine differentiation. Positivity for Neuroendocrine markers by immunohistochemistry is required for the diagnosis. Sensitivity and specificity of currently used markers are limited; based on the definitions of WHO Classification of Tumours, 5th edition, about 50% of breast tumors with features of neuroendocrine differentiation express chromogranin-A and 16% express synaptophysin. We assessed the applicability of two novel markers, syntaxin-1 and insulinoma-associated protein 1 (INSM1) in breast carcinomas.Methods: Hypercellular (Type B) mucinous carcinomas, solid papillary carcinomas, invasive carcinomas of no special type with neuroendocrine features and ductal carcinomas in situ of neuroendocrine subtype were included in our study. The immunohistochemical panel included chromogranin A, synaptophysin, CD56, syntaxin-1 and INSM1. The specificity of syntaxin-1 and INSM1 was determined using samples negative for chromogranin A, synaptophysin and CD56.Results: The sensitivity of syntaxin-1 was 84.7% (50/59), with diffuse positivity in more than 60% of the cases. Syntaxin-1 also had an excellent specificity (98.1%). Depending on the definition for positivity, the sensitivity of INSM1 was 89.8% (53/59) or 86.4% (51/59), its specificity being 57.4% or 88.9%. The sensitivities of chromogranin A, synaptophysin and CD56 were 98.3, 74.6 and 22.4%, respectively.Discussion: Syntaxin-1 and INSM1 are sensitive and specific markers of breast tumors with neuroendocrine features, outperforming chromogranin A and CD56. We recommend syntaxin-1 and INSM1 to be included in the routine neuroendocrine immunohistochemical panel.

Serous Borderline Ovarian Tumor Diagnosis, Management and Fertility Preservation in Young Women

Borderline ovarian tumors (BOT) represent about 10 to 20 percent of all epithelial tumors of the ovary. They constitute intermediate lesions between benign ovarian cysts and invasive carcinomas. They often occur in young women of reproductive age, and, albeit with a favorable prognosis, it may recur on the ipsilateral or contralateral ovary. Controversies surround the diagnostic criteria used for their assessment, and the optimal management to minimize their risk of recurrence and/or transformation into malignant carcinoma. Fertility preservation (FP) is considered a priority in the management of these patients, and studies aim at finding the safest and most effective way to help women with BOT history conceive with minimal risk. We present the experience of a single institution in managing three cases of serous BOT in young nulliparous women, followed by a thorough review of the existing literature, highlighting controversies and exploring the possible FP techniques for these women.

The peri- and intratumoral immune cell infiltrate and PD-L1 status in invasive squamous cell carcinomas of the penis

Introduction Penile carcinomas are rare tumors throughout Europe. Therefore, little attention is drawn to this disease. That makes it important to study tumor-associated key metrics and relate these to known data on penile neoplasias. Materials and methods A cohort of 60 well-defined penile invasive carcinomas with known human papillomavirus (HPV) infection status was investigated. Data on tumor type, grading and staging were recorded. Additionally, data on the peri- and intratumoral immune cell infiltrate in a semiquanititave manner applying an HE stain were assessed. Results Our study showed a significant correlation of immune cell infiltrate and pT stage with overall survival. Therefore, in a subset of tumors, PD-L1 staining was applied. For tumor proportion score (TPS), 26 of 30 samples (87%) were scored >0%. For the immune cell score (IC), 28 of 30 samples (93%) were defined as >0% and for CPS, 29 of 30 samples (97%) scored >0. PD-L1 expression was not associated with overall survival. Conclusion PD-L1 is expressed in penile carcinomas, providing a rationale for targeted therapy with checkpoint inhibitors. We were able to show that immune reaction appears to be prognostically relevant. These data enhance the need for further studies on the immune cell infiltrate in penile neoplasias and show that PD-L1 expression is existent in our cohort, which may be a potential target for checkpoint inhibitor therapy.

Added value of contrast-enhanced spectral mammogram in assessment of suspicious microcalcification and grading of DCIS

Background Breast microcalcifications are one of the most difficult mammographic findings to assess. The purpose of this study is to assess the ability of contrast-enhanced spectral mammography in the assessment of suspicious microcalcification and in predicting the grade of DCIS. Methods Three hundred and forty cases with suspicious microcalcification were reviewed in this study. We excluded 160 cases associated with masses. We enrolled 180 cases for analysis of suspicious microcalcification on mammograms with no underlying masses. We reviewed the microcalcification for their morphology, distribution, and associated pathological enhancement according to BI-RADS lexicon with pathology results reviewed and classified into benign and malignant which subdivided into low, intermediate, or high-grade DCIS or invasive carcinoma. Results Three hundred and forty cases with suspicious microcalcification were reviewed in this study. We excluded 160 cases associated with masses. Forty-five of 180 cases were benign, and 135/180 cases were malignant. Twenty-five of 135 cases were diagnosed as invasive breast carcinomas while 110/135 were ductal carcinoma in situ. From the latter, 110 patients with DCIS, 22/110 cases were low grade, 11/110 cases were intermediate grade, and 77/110 cases were high grade (44 with micro-invasion). A total of 25 invasive carcinomas showed pathological non-mass enhancement, 76/77 cases of high-grade DCIS, and 6/11 cases of intermediate-grade DCIS. No abnormal enhancement appeared with benign entities, low-grade DCIS, and 5/11 cases of intermediate DCIS. The diagnostic performance of CESM in anticipation of high grade in DCIS patients was sensitivity of 98%, specificity of 81.8%, and accuracy of 93.1%. CESM sensitivity, specificity, and accuracy in prediction of invasiveness or high-grade DCIS were 98.5%, 81.8%, and 87.5%, respectively. Conclusion CESM can provide a fundamental contribution in the evaluation of suspicious microcalcification as high-grade DCIS or invasive component can present by non-mass enhancement, but enhancement paucity is favorable to diagnose benign lesion or non-invasive/low-grade DCIS.

Epithelial Mesenchymal Transition and Immune Response in Metaplastic Breast Carcinoma

Metaplastic breast carcinoma (MBC) is a heterogeneous group of infrequent triple negative (TN) invasive carcinomas with poor prognosis. MBCs have a different clinical behavior from other types of triple negative breast cancer (TNBC), being more resistant to standard chemotherapy. MBCs are an example of tumors with activation of epithelial–mesenchymal transition (EMT). The mechanisms involved in EMT could be responsible for the increase in the infiltrative and metastatic capacity of MBCs and resistance to treatments. In addition, a relationship between EMT and the immune response has been seen in these tumors. In this sense, MBC differ from other TN tumors showing a lower number of tumor-infiltrating lymphocytes (TILS) and a higher percentage of tumor cells expressing programmed death-ligand 1 (PD-L1). A better understanding of the relationship between the immune system and EMT could provide new therapeutic approaches in MBC.

Prognostic Value Of Vascular Invasion In Breast Tumours In She-Dogs (Pilot Study)

Breast tumours are the most common neoplasm in intact she-dogs. However, breast tumours in she-dogs differ significantly in morphological features and biological behaviour, so the definition of prognostic factors is relevant. A study on tumour cell dissemination in breast tumours in she-dogs by migration of these cells into blood and lymphatic vessels depending on their histological characteristics and disease stage was conducted. The study of the problem was performed on the basis of the clinic of modern veterinary medicine “Best” in Zaporizhzhia. She-dogs with breast neoplasms of different ages and breeds were used as objects in the proven absence of signs of metastatic lesions of other organs and tissues, including lungs, abdominal organs and bones. The presence of cancer cells in the vessels was determined by the tumour clots formed by them, fixed to the endothelium. The study revealed the presence of angioinvasion regardless of the clinical stage of the tumour process. In this case, the dissemination of tumour cells by migration into lymphatic vessels was observed only in the second clinical stage of breast tumours. In patients with stage 1 breast cancer in the vast majority of cases (66.7% of patients) angioinvasion is registered in the micropapillary invasive carcinomas (ICD-O code 8507/2). Tumour cells in blood vessels were verified in simple cribriform carcinoma (ICD-O code 8201/3) in more than 80% of she-dogs with stage 3 breast cancer. In contrast to the above groups, in patients with stage 2 cancer, migration of tumour cells into both blood and lymphatic vessels was found. Most often the signs of angio- and lymphoinvasion were found in invasive carcinoma mixed type (ICD-O code 8562/3), tubulopapillary carcinoma (ICD-O code 8503/3), and tubular carcinoma (ICD-O code 8211/3) ‒ in 34.1% and 36.8%, 19.3% and 26.3%, 17.0% and 10.5% of cases, respectively. The obtained results allow predicting the probability of penetration of tumour cells into blood and lymphatic vessels with a high degree of reliability, which in the future can better predict the biological behaviour of breast tumours

Coexpression of EphA10 and Gli3 promotes breast cancer cell proliferation, invasion and migration

This study investigated the influences of EphA10 and Gli3 on breast cancer (BC) cell proliferation, invasion and migration. Immunohistochemistry was used to reveal the expressions of EphA10 and Gli3 in 18 intraductal carcinomas, 124 invasive carcinomas, 50 paracancerous tissues (2 cm away from the tumor, when possible or available), 50 lobular hyperplastic tissues and 30 normal breast tissues. qRT-PCR and Western blotting were applied to detect the expressions of EphA10 and Gli3 in invasive BC cells (MDA-MB-231, BT20 and Hs578T) and normal human mammary epithelial cells (MCF10A). MDA-MB-231 and BT20 cells were transfected with sh-EphA10, sh-Gli3 or sh-EphA10+sh-Gli3. CCK-8 was used to test the proliferation of transfected MDA-MB-231 and BT20 cells. Transwell and scratch assays were used for evaluation of invasion and migration of the transfected cells. EphA10 and Gli3 were highly expressed in invasive carcinomas and invasive BC cells. The expressions of EphA10 and Gli3 were associated with the clinicopathological characteristics and poor prognosis of patients with invasive BC. Knockdown of EphA10 or Gli3 suppressed activities of BC cells. Knockdown of both EphA10 and Gli3 was more effective than knockdown of Gli3 alone. Taken together, coexpression of EphA10 and Gli3 promotes BC cell proliferation, invasion and migration.

Colibactin-Producing Escherichia coli Induce the Formation of Invasive Carcinomas in a Chronic Inflammation-Associated Mouse Model

Background: Escherichia coli producing the genotoxin colibactin (CoPEC or colibactin-producing E. coli) abnormally colonize the colonic mucosa of colorectal cancer (CRC) patients. We previously showed that deficiency of autophagy in intestinal epithelial cells (IECs) enhances CoPEC-induced colorectal carcinogenesis in ApcMin/+ mice. Here, we tested if CoPEC trigger tumorigenesis in a mouse model lacking genetic susceptibility or the use of carcinogen. Methods: Mice with autophagy deficiency in IECs (Atg16l1∆IEC) or wild-type mice (Atg16l1flox/flox) were infected with the CoPEC 11G5 strain or the mutant 11G5∆clbQ incapable of producing colibactin and subjected to 12 cycles of DSS treatment to induce chronic colitis. Mouse colons were used for histological assessment, immunohistochemical and immunoblot analyses for DNA damage marker. Results: 11G5 or 11G5∆clbQ infection increased clinical and histological inflammation scores, and these were further enhanced by IEC-specific autophagy deficiency. 11G5 infection, but not 11G5∆clbQ infection, triggered the formation of invasive carcinomas, and this was further increased by autophagy deficiency. The increase in invasive carcinomas was correlated with enhanced DNA damage and independent of inflammation. Conclusions: CoPEC induce colorectal carcinogenesis in a CRC mouse model lacking genetic susceptibility and carcinogen. This work highlights the role of (i) CoPEC as a driver of CRC development, and (ii) autophagy in inhibiting the carcinogenic properties of CoPEC.

Multidimensional Diffusion Magnetic Resonance Imaging for Characterization of Tissue Microstructure in Breast Cancer Patients: A Prospective Pilot Study

Diffusion-weighted imaging is a non-invasive functional imaging modality for breast tumor characterization through apparent diffusion coefficients. Yet, it has so far been unable to intuitively inform on tissue microstructure. In this IRB-approved prospective study, we applied novel multidimensional diffusion (MDD) encoding across 16 patients with suspected breast cancer to evaluate its potential for tissue characterization in the clinical setting. Data acquired via custom MDD sequences was processed using an algorithm estimating non-parametric diffusion tensor distributions. The statistical descriptors of these distributions allow us to quantify tissue composition in terms of metrics informing on cell densities, shapes, and orientations. Additionally, signal fractions from specific cell types, such as elongated cells (bin1), isotropic cells (bin2), and free water (bin3), were teased apart. Histogram analysis in cancers and healthy breast tissue showed that cancers exhibited lower mean values of “size” (1.43 ± 0.54 × 10−3 mm2/s) and higher mean values of “shape” (0.47 ± 0.15) corresponding to bin1, while FGT (fibroglandular breast tissue) presented higher mean values of “size” (2.33 ± 0.22 × 10−3 mm2/s) and lower mean values of “shape” (0.27 ± 0.11) corresponding to bin3 (p < 0.001). Invasive carcinomas showed significant differences in mean signal fractions from bin1 (0.64 ± 0.13 vs. 0.4 ± 0.25) and bin3 (0.18 ± 0.08 vs. 0.42 ± 0.21) compared to ductal carcinomas in situ (DCIS) and invasive carcinomas with associated DCIS (p = 0.03). MDD enabled qualitative and quantitative evaluation of the composition of breast cancers and healthy glands.