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Percutaneous core biopsy (CB) has been introduced to increase the ability of accurately diagnosing breast malignancies without the need of resorting to surgery. Compared to conventional automated 14 gauge needle core biopsy (NCB), vacuum-assisted needle core biopsy (VANCB) allows obtaining larger specimens and has recognized advantages particularly when the radiological pattern is represented by microcalcifications. Regardless of technical improvements, a small percentage of percutaneous CBs performed to detect breast lesions are still classified, according to European and UK guidelines, in the borderline B3 category, including a group of heterogeneous lesions with uncertain malignant potential. We aimed to assess the prevalence and positive predictive values (PPV) on surgical excision (SE) of B3 category (overall and by sub-categories) in a large series of non-palpable breast lesions assessed through VANCB, also comparison with published data on CB. Overall, 26,165 consecutive stereotactic VANCB were identified in 22 Italian centres: 3107 (11.9%) were classified as B3, of which 1644 (54.2%) proceeded to SE to establish a definitive histological diagnosis of breast pathology. Due to a high proportion of microcalcifications as main radiological pattern, the overall PPV was 21.2% (range 10.6%-27.3% for different B3 subtypes), somewhat lower than the average value (24.5%) from published studies (range 9.9%-35.1%). Our study, to date the largest series of B3 with definitive histological assessment on SE, suggests that B3 lesions should be referred for SE even if VANCB is more accurate than NCB in the diagnostic process of non-palpable, sonographically invisible breast lesions.

The coexistence of multiple and synchronous primary neoplasms in the same organ (including kidney) has only rarely been described in the literature. We herein present a case of collecting duct carcinoma (CDC) combined with papillary renal carcinoma (RCC) having a 57-month disease-free survival CDC is a rather rare and aggressive neoplasm of the kidney. Sharing probably the same embryological origin, synchronous or metachronous association with in situ orpapillary transitional cell carcinoma (TCC) may be found; association with RCC has been only once reported in the literature. The high incidence of c-erbB-2 oncogene amplification in CDC further characterizes this tumor as a separate entity from renal cell carcinoma, and shows some genetic characteristics in common with TCC. The histological diagnosis of Bellini CDC can be confirmed by the positive immunohistochemical staining with a collecting duct marker and distal tubule marker and negative staining with a proximal tubule marker.

Secondary tumour to the kidney is quite frequent. Even if, theoretically, all solid tumours may give rise to renal metastasis, secondary lesions to the kidney occur more commonly in patients with lung and breast cancer, melanoma and lymphoma. Only 15 cases of renal metastasis arising from a follicular thyroid carcinoma have been reported in the literature. Rarely, metastases to the kidney present as primary renal tumours and may be treated surgically for that mistaken diagnosis. Nevertheless, in patients with solitary late distant metastasis of thyroid cancer, complete surgical resection may be proposed, followed by 131I ablation in order to offer a better chance of prolonged survival. We describe a case of a renal mass undergoing radical surgery and revealing itself as a solitary metastasis from follicular carcinoma of the thyroid, appearing 10 years after total thyroidectomy and 131I ablation therapy.

Spermatic cord liposarcoma is a rare pathology (1-4); currently about one hundred cases are documented. The therapy of choice is surgery, followed sometimes by radiotherapy. We herein describe our experience of 4 cases between 1995 and 2000, with median follow-up of 34 months (mean 48 months, range 28-95 months), in order to stress the role of orchifuniculectomy, even when mass-ablation first procedure may seem radical.

Thyroglobulin is considered a reliable marker of recurrent disease in patients with well-differentiated thyroid carcinoma. However, some patients present recurrence with no increase in serum thyroglobulin. In the attempt to identify patients who might present recurrence with no such sign of the disease, thyroglobulin levels have been determined pre-operatively in 185 consecutive patients scheduled for primary treatment for well-differentiated thyroid carcinoma from June 1997 to May 2002 at the Head and Neck Division of the European Institute of Oncology. In 22 patients (11.9% of total), serum thyroglobulin was undetectable. In none of these 22 cases was thyroglobulin detected during follow-up, either during thyroxin suppressive therapy or during withdrawal for radioiodine scan. One of these low-thyroglobulin patients developed recurrent disease involving cervical lymph nodes, with positive radioiodine scan: thyroglobulin remained undetectable. On the contrary, in the patients with high or normal thyroglobulin presenting recurrence, the recurrence was indicated, in all cases, by increased thyroglobulin levels. From these findings it may be concluded that pre-operative assessment of serum thyroglobulin may identify patients who might present recurrence without increased thyroglobulin, and in whom standard follow-up by monitoring thyroglobulin serum levels is inadequate.

In the last few years, ultrasound-guided vacuum-assisted breast biopsy (US-VABB) has replaced surgical biopsy due to higher diagnostic accuracy and lower patient discomfort, and, at present, an even greater possibility is represented by the new wireless ultrasound-guided VAB device (Wi-UVAB). The purpose of our study is to determine the diagnostic accuracy of this new device in a sizeable representative number of patients. From January 2014 to June 2018, 168 biopsies were performed in our institution using the new Wi-UVAB device. We analyzed sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of biopsies obtained with the new device using surgical results as reference point, following patients for at least one year. In our cohort, we obtained a complete sensitivity of 97.5%, an absolute sensitivity of 94.3%, a complete specificity of 98%, and an absolute specificity of 98%. The positive predictive value of the procedure was 97.5% while the negative predictive value was 98%. The diagnostic accuracy was 98%. The Wi-UVAB is a safe procedure with high diagnostic accuracy, comparable to that of the traditional vacuum-assisted breast biopsy and even higher than that of core needle biopsy (CNB). Moreover, the Wi-UVAB is easy to use and shows low costs as core needle biopsy (CNB).

Myoid gonadal stromal tumor represents a rare testicular neoplasm displaying smooth muscular and gonadal stromal differentiation. This entity has very few cases reported in the literature that describe heterogeneous clinical and pathological characteristics. Bayesian statistics provides a useful framework to combine information from diverse sources. We here presented a case series-the largest so far reported-of myoid gonadal stromal tumor (4 cases) with extensive morphologic, immunohistochemical, and molecular characterization, performed a systematic review of the literature (that identified 9 papers), and used a Bayesian data analysis to understand the characteristics of this disease. Our study collectively described 16 cases. This neoplasm is mainly found in adults (mean age about 40 years) and often has a size of about 3 cm. By morphology, the tumor can infiltrate testicular tubules and is composed of spindle cells; few mitoses can be seen (usually 2/10 HPF). Neoplastic cells are diffusely positive with α-smooth muscle actin with a tram-track staining pattern. S100 protein, FOXL2, and SF1 are also characteristically positive. Moreover, this neoplasm can display epithelial differentiation, in about half of the cases. In conclusion, we foresee the use of this statistical approach in pathology: our analysis allowed a more precise description of this rare entity.

Objectives: To develop a novel nomogram to identify candidates for active surveillance (AS) that combines clinical, biopsy and multiparametric magnetic resonance imaging (mpMRI) findings; and to compare its predictive accuracy to, respectively: (i) Prostate Cancer Research International: Active Surveillance (PRIAS) criteria, (ii) Johns Hopkins (JH) criteria, (iii) European Association of Urology (EAU) low-risk classification, and (iv) EAU low-risk or low-volume with International Society of Urological Pathology (ISUP) Grade Group (GG) 2 classification. Patients and Methods: We selected 1837 patients with ISUP GG1 or GG2 prostate cancer (PCa), treated with radical prostatectomy (RP) between 2012 and 2018. The outcome of interest was the presence of unfavourable disease (i.e., clinically significant PCa [csPCa]) at RP, defined as: ISUP GG (Formula presented.) 3 and/or pathological T stage (pT) ≥3a and/or pathological N stage (pN) 1. First, logistic regression models including PRIAS, JH, EAU low-risk, and EAU low-risk or low-volume ISUP GG2 binary classifications (not eligible vs eligible) were used. Second, a multivariable logistic regression model including age, prostate-specific antigen density (PSA-D), ISUP GG, and the percentage of positive cores (Model 1) was fitted. Third, Prostate Imaging-Reporting and Data System (PI-RADS) score (Model 2), extracapsular extension (ECE) score (Model 3) and PI-RADS + ECE score (Model 4) were added to Model 1. Only variables associated with higher csPCa rates in Model 4 were retained in the final simplified Model 5. The area under the receiver operating characteristic curve (AUC), calibration plots and decision curve analyses were used. Results: Of the 1837 patients, 775 (42.2%) had csPCa at RP. Overall, 837 (47.5%), 986 (53.7%), 348 (18.9%), and 209 (11.4%) patients were eligible for AS according to, respectively, the EAU low-risk, EAU low-risk or low-volume ISUP GG2, PRIAS, and JH criteria. The proportion of csPCa amongst the EAU low-risk, EAU low-risk or low-volume ISUP GG2, PRIAS and JH candidates was, respectively 28.5%, 29.3%, 25.6% and 17.2%. Model 4 and Model 5 (in which only PSA-D, ISUP GG, PI-RADS and ECE score were retained) had a greater AUC (0.84), compared to the four proposed AS criteria (all P&nbsp

Fatal neuroendocrine differentiation (NED) of castration-resistant prostate cancer is a recurrent mechanism of resistance to androgen deprivation therapies (ADT) and antiandrogen receptor pathway inhibitors (ARPI) in patients. The design of effective therapies for neuroendocrine prostate cancer (NEPC) is complicated by limited knowledge of the molecular mechanisms governing NED. The paucity of acquired genomic alterations and the deregulation of epigenetic and transcription factors suggest a potential contribution from the microenvironment. In this context, whether ADT/ARPI induces stromal cells to release NED-promoting molecules and the underlying molecular networks are unestablished. Here, we utilized transgenic and transplantable mouse models and coculture experiments to unveil a novel tumor-stroma cross-talk that is able to induce NED under the pressure of androgen deprivation. Castration induced upregulation of GRP78 in tumor cells, which triggers miR29-b–mediated downregulation of the matricellular protein SPARC in the nearby stroma. SPARC downregulation enabled stromal cells to release IL6, a known inducer of NED. A drug that targets GRP78 blocked NED in castrated mice. A public, human NEPC gene expression dataset showed that Hspa5 (encoding for GRP78) positively correlates with hallmarks of NED. Finally, prostate cancer specimens from patients developing local NED after ADT showed GRP78 upregulation in tumor cells and SPARC downregulation in the stroma. These results point to GRP78 as a potential therapeutic target and to SPARC downregulation in stromal cells as a potential early biomarker of tumors undergoing NED. Significance: Tumor–stroma cross-talk promotes neuroendocrine differentiation in prostate cancer in response to hormone therapy via a GRP78/SPARC/IL6 axis, providing potential therapeutic targets and biomarkers for neuroendocrine prostate cancer.

No abstract available

Purpose The authors assessed the adequacy and sensitivity of CT-guided bone biopsy in 308 procedures performed in 286 cancer patients with suspected bone metastases. Materials and methods An electronic search of our CT-guided bone biopsy database was retrospectively performed to evaluate the adequacy of samples and, in the event of negative samples, whether the patients had radiological progression at the site of biopsy (false negative). Adequacy and false-negative rate were compared with radiological features, biopsy location, specimen length and complications to assess any statistically relevant association with a multivariate logistic regression model. Results A total of 290/308 (94.1 %) samples were adequate. Forty-five patients had normal bone marrow and were followed-up, with evidence of progression at the site of biopsy in 10 cases (false-negative cases); overall sensitivity was 96.7 %. Specimen length was significantly correlated to the probability of an adequate biopsy (p = 0.035) and inversely correlated to the probability to obtain a false-negative result (p = 0.02). We encountered 11/308 (3.5 %) minor complications and no major complications. Conclusion CT-guided biopsy of bone lesions in cancer patients allows for a final diagnosis in 94 % of cases. A specimen longer than 1 cm may lead to a significant result in terms of adequacy and sensitivity. Negative biopsies with positive positron emission tomography or magnetic resonance imaging and specimen shorter than 1 cm should be repeated to avoid a false-negative result. © 2014 Italian Society of Medical Radiology.

Most patients who initially respond to treatment with the multi-tyrosine kinase inhibitor sunitinib eventually relapse. Therefore, developing a deeper understanding of the contribution of sunitinib's numerous targets to the clinical response or to resistance is crucial. Here, we have shown that cancer cells respond to clinically relevant doses of sunitinib by enhancing the stability of the antiapoptotic protein MCL-1 and inducing mTORC1 signaling, thus evoking little cytotoxicity. Inhibition of MCL-1 or mTORC1 signaling sensitized cells to clinically relevant doses of sunitinib in vitro and was synergistic with sunitinib in impairing tumor growth in vivo, indicating that these responses are triggered as prosurvival mechanisms that enable cells to tolerate the cytotoxic effects of sunitinib. Furthermore, higher doses of sunitinib were cytotoxic, triggered a decline in MCL-1 levels, and inhibited mTORC1 signaling. Mechanistically, we determined that sunitinib modulates MCL-1 stability by affecting its proteasomal degradation. Dual modulation of MCL-1 stability at different dose ranges of sunitinib was due to differential effects on ERK and GSK3β activity, and the latter also accounted for dual modulation of mTORC1 activity. Finally, comparison of patient samples prior to and following sunitinib treatment suggested that increases in MCL-1 levels and mTORC1 activity correlate with resistance to sunitinib in patients.

Background. In patients with metastatic breast cancer, the evaluation of the biological characteristics of metastatic bone deposits may be a valuable adjunct in clinical practice. We assessed the discordance in expression levels for estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) between primary tumor and bone metastases and its clinical impact on patient management. Material and methods. We retrospectively reviewed 363 CT-guided bone biopsies performed from January 1997 to December 2009. The proportions of ER, PgR and HER2 positive tumors at primary diagnosis and bone metastases, determined by IHC and/or FISH, were compared using McNemar's test. The impact of the biopsy reassessment on treatment choice was evaluated with Fisher's exact test. Results. We selected 109 metastatic breast cancer patients with histologically confirmed bone metastases. Among 107 assessable patients the overall discordance rate was detected in 22 (20.5%) and in 47 (43.9%) patients for ER and PgR, respectively, and in six of 86 assessable patients (6.9%) for HER2 status. The indication to change endocrine therapy occurred in 62% and 30% of patients with ER discordance and ER concordance, respectively (p = 0.01). The indication to change targeted therapy occurred in 67% and 8% of patients with HER2 discordance and HER2 concordance, respectively (p = 0.002). Conclusions. We confirm that biopsy of metastases, including bone metastases, for reassessment of biology should be considered, since it is likely to impact on treatment choice.

INTRODUCTION: Diagnosis of breast ductal intraepithelial neoplasia (DIN) has increased over the last decades, but proper postsurgical treatment remains controversial. We analyzed risk factors and treatment outcome in a large series of women treated at one institution. METHODS: Women undergoing surgery for DIN at the European Institute of Oncology between 1996 and 2005, with follow-up until December 2006, were included. RESULTS: We evaluated the postsurgical treatment outcome of 974 and 293 patients who underwent breast-conserving surgery (BCS) or mastectomy, respectively. The 5-year cumulative incidence of breast cancer (BC) events was 11.8%, with a significant trend according to age (from 43% in women 65 years). Among the 727 BCS patients with DIN2-DIN3 histology, 414 (57%) received radiotherapy (RT), and they were both younger and with worse prognostic factors than the 313 patients who did not receive it. In these groups, the adjusted hazard ratio (HR) for RT versus non-RT was 0.40 (95% confidence interval [CI], 0.26-0.63). Among the 691 BCS patients with estrogen receptor (ER)(+) disease, 329 (48%) received low-dose tamoxifen (either 5 mg/day or 20 mg once a week) and they were younger than the 362 who did not receive it. In these groups, the adjusted HR for tamoxifen versus no tamoxifen was 0.68 (95% CI, 0.43-1.07), and the HR was 0.55 (95% CI, 0.32-0.97) after excluding human epidermal growth factor receptor (HER)2/neu-overexpressing DIN. CONCLUSIONS: BC events were more frequent in young patients. RT was associated with a lower incidence of BC events. Low-dose tamoxifen was associated with a lower incidence of BC events in patients with ER(+) disease when HER-2 was not overexpressed. Further prospective studies should confirm our observations.

Background:: Medullary carcinoma (MC) of the breast is associated with favorable prognosis compared with other histological types, despite high nuclear grade, fast proliferation and lack of steroid hormone receptor expression. We retrospectively evaluated the clinical relevance of selected immunohistochemical features of tumors in three cohorts of patients with typical medullary (MC), ‘atypical’ medullary (AMC) or ductal (DC) breast carcinoma. Patients and methods:: Evaluation was performed on node-negative tumor specimens from 40 patients who had either MC (12 patients), AMC (nine patients) or DC (19 patients), treated in a single institution. All had no hormonal receptor, Ki-67 ≥30%, G3, expansive pattern of growth and peritumoral lymphocytic infiltration. In addition, p27, p21 and HER2/neu overexpression, p53, cyclin E and E-cadherin expression, presence of apoptotic cells, stromal tenascin (TN), and type of immune cell infiltration (CD3- and CD68-positive cells) were assessed. Results:: No difference in expression of HER2/neu, p21, p27, p53, number of apoptotic cells and CD68-positive cells was detected. Lower levels of stromal TN expression were found in MC compared with DC (P = 0.0007), but differences between MC and AMC were not significant (P = 0.27). A higher proportion of intratumoral CD3-positive cells was seen in MC than in AMC (P = 0.046). No differences were seen between MC and DC (P = 0.73). With a median follow-up of 67 months, three patients with DC had relapsed in distant sites, while one patient with AMC had a second primary. Two patients with MC had reappearance of DC in the breast. Conclusions:: The three distinct disease types, selected by having similar high proliferation, had similar expression of cell cycle regulators. The lower expression of TN and massive infiltration of T lymphocytes might both indicate a special interaction between tumor cells and microenvironment, important features for conferring improved prognosis through negligible invasive and metastatic potential to MC. In our series, however, patients with a previous MC are not free from the risk of developing a subsequent DC. Finally, defining AMC as a distinct entity from DC is not justified.