Maria Rosaria Raspollini

Cancer-associated fibroblasts and M2-polarized macrophages synergize during prostate carcinoma progression

Inflammation is now acknowledged as an hallmark of cancer. Cancer-associated fibroblasts (CAFs) force a malignant cross talk with cancer cells, culminating in their epithelial–mesenchymal transition and achievement of stemness traits. Herein, we demonstrate that stromal tumor-associated cells cooperate to favor malignancy of prostate carcinoma (PCa). Indeed, prostate CAFs are active factors of monocyte recruitment toward tumor cells, mainly acting through stromal-derived growth factor-1 delivery and promote their trans-differentiation toward the M2 macrophage phenotype. The relationship between M2 macrophages and CAFs is reciprocal, as M2 macrophages are able to affect mesenchymal–mesenchymal transition of fibroblasts, leading to their enhanced reactivity. On the other side, PCa cells themselves participate in this cross talk through secretion of monocyte chemotactic protein-1, facilitating monocyte recruitment and again macrophage differentiation and M2 polarization. Finally, this complex interplay among cancer cells, CAFs and M2 macrophages, cooperates in increasing tumor cell motility, ultimately fostering cancer cells escaping from primary tumor and metastatic spread, as well as in activation of endothelial cells and their bone marrow-derived precursors to drive de novo angiogenesis. In keeping with our data obtained in vitro, the analysis of patients affected by prostate cancers at different clinical stages revealed a clear increase in the M2/M1 ratio in correlation with clinical values. These data, coupled with the role of CAFs in carcinoma malignancy to elicit expression of stem-like traits, should focus great interest for innovative strategies aimed at the co-targeting of inflammatory cells and fibroblasts to improve therapeutic efficacy.

The Role of M1 and M2 Macrophages in Prostate Cancer in relation to Extracapsular Tumor Extension and Biochemical Recurrence after Radical Prostatectomy

Introduction. The aim of our work was to investigate the causal connection between M1 and M2 macrophage phenotypes occurrence and prostate cancer, their correlation with tumor extension (ECE), and biochemical recurrence (BR). Patient and Methods. Clinical and pathological data were prospectively gathered from 93 patients treated with radical prostatectomy. Correlations of commonly used variables were evaluated with uni- and multivariate analysis. The relationship between M1 and M2 occurrence and BR was also assessed with Kaplan-Meier survival analysis. Results. Above all in 63.4% there was a M2 prevalence. M1 occurred more frequently in OC disease, while M2 was more represented in ECE. At univariate analysis biopsy and pathologic GS and M2 were statistically correlated with ECE. Only pathologic GS and M2 confirmed to be correlated with ECE. According to macrophage density BCR free survival curves presented a statistically significant difference. When we stratified our population for M1 and M2,we did not find any statistical difference among curves. At univariate analysis GS, pTNM, and positive margins resulted to be significant predictors of BCR, while M1 and M2 did not achieve the statistical significance. At multivariate analysis, only GS and pathologic stage were independent predictors of BR. Conclusion. In our study patients with higher density of M count were associated with poor prognosis; M2 phenotype was significantly associated with ECE.

c-Kit Expression in Patients with Uterine Leiomyosarcomas: A Potential Alternative Therapeutic Treatment

Purpose: Uterine leiomyosarcomas are rare tumors characterized by their resistance to chemotherapy and radiation treatment. Surgery is the primary method of treatment, but for patients with unresectable disease, alternate therapeutic options are clearly warranted. According to initial observations of c-KIT expression, correlation with a bad prognosis, and the successful therapeutic possibility of STI571 in gastrointestinal stromal tumors, the data have encouraged us to study c-KIT expression in these tumors. Experimental Design: We analyzed the expression of c-KIT and genetic assessment of exon 11 of c-kit gene in 32 uterine leiomyosarcomas. Results: In 17 cases (53.1%), we observed a c-KIT expression in tumor cells. Of the 17 patients with distinct c-KIT-positive immunoreactivity, eight had I or II stage disease and nine had III or IV stage disease. Molecular genetic analysis of exon 11, analyzed by direct DNA sequencing, was performed for all of the c-KIT-positive uterine leiomyosarcomas. No mutations were found. Conclusion: The conventional chemotherapy in leiomyosarcomas appears to be ineffective for patients with metastatic or unresectable disease, and the management of these patients poses a special problem. In these women, new therapeutic strategies are warranted. The treatment with STI571 in leiomyosarcoma patients might be hypothesized, because uterine leiomyosarcomas also express c-KIT.

Utility of CDX-2 in distinguishing between primary and secondary (intestinal) mucinous ovarian carcinoma: an immunohistochemical comparison of 43 cases.

Primary and secondary mucinous tumors can involve the ovaries and have similar histologic appearances. The differential diagnosis is important for surgical and chemotherapeutic treatment and for the prognosis, but often it is extremely difficult. This article discusses an immunohistochemical panel that includes carcinoembryonic antigen (CEA), cytokeratin (CK) 7, CK20, CA125, CA19.9, and a new marker, CDX-2, for the distinction between primary ovarian mucinous carcinomas and metastatic (intestinal) ovarian tumors. Forty-three cases representing primary and secondary ovarian tumors were considered and consisted of 14 primary mucinous ovarian carcinomas (PMOCs) and 29 secondary (intestinal) ovarian tumors (SI-OTs). Fisher exact test was performed to evaluate the reliability of the respective antibodies to discriminate between PMOCs and SIOTs. CDX-2 was diffusely positive in all SIOTs and was expressed focally in 3 cases (21.42%) of PMOCs. CK7 was diffusely positive in 13 cases (44.82%) of SIOTs and in 13 cases (92.85%) of PMOCs. CK20 was diffusely positive in 17 cases (58.62%) of SIOTs and in 6 cases (42.85%) of PMOCs. CEA was diffusely positive in 28 cases (96.55%) of SIOTs and in 12 cases (85.71%) of PMOCs. CA19.9 was positive in all SIOTs and in 12 cases (85.71%) of PMOCs. CA125 was positive in 3 cases (10.34%) of SIOTs and in 4 cases (28.57%) of PMOCs. CK7 and especially CDX-2, a specific and sensitive marker, can aid pathologists in making a differential diagnosis (P = 0.003 and P < 0.0005, respectively), whereas CEA, CK20, CA125, and CA19.9 markers are not high enough to distinguish between primary and secondary mucinous ovarian tumors.

Correlation of Epidermal Growth Factor Receptor Expression with Tumor Microdensity Vessels and with Vascular Endothelial Growth Factor Expression in Ovarian Carcinoma

We analyzed in advanced ovarian serous G3 carcinoma the correlation between epidermal growth factor receptor (EGFR) overexpression and tumor angiogenesis and their relation with clinical outcome. Microvessel density (MVD) and vascular endothelial growth factor (VEGF) were statistically correlated with disease-free interval and death from disease both in univariate and multivariate analyses while EGFR expression was not correlated with clinical outcome. MVD was significantly associated with progression of disease during chemotherapy while VEGF and EGFR expression were not correlated with responsiveness to chemotherapy (Fisher’s exact test). VEGF expression was correlated with MVD (Fisher’s exact test). EGFR showed a trend to correlation with MVD. Further studies focusing on the use of angiogenesis inhibitors in addition to EGFR inhibitors on ovarian carcinoma cells may produce therapeutic strategies in the selection of tailored therapies in ovarian cancer patients.

Triage with human papillomavirus testing of women with cytologic abnormalities prompting referral for colposcopy assessment

The current study was conducted to evaluate the cost‐effectiveness of triaging for colposcopy using human papillomavirus (HPV) testing.

Primary cervical adenocarcinoma with intestinal differentiation and colonic carcinoma metastatic to cervix: an investigation using Cdx-2 and a limited immunohistochemical panel.

CONTEXT Cdx-2 is expressed in normal colonic epithelia and in most colorectal adenocarcinomas. No data exist on Cdx-2 expression in primary cervical adenocarcinoma with colonic differentiation. OBJECTIVE To ascertain the utility of Cdx-2 and a limited immunohistochemical panel in differentiating between primary cervical adenocarcinoma with intestinal differentiation and secondary (colonic) cervical adenocarcinoma, which call for different surgical and chemotherapeutic treatment protocols. DESIGN We examined cervical tract adenocarcinomas in women with previously negative medical histories for neoplastic disease and in women with colonic carcinoma. An immunohistochemical panel consisting of cytokeratin 7, cytokeratin 20, carcinoembryonic antigen, and a new marker, Cdx-2, was evaluated in all cases. The clinical data, the morphologic features, and the immunohistochemical staining patterns were compared. RESULTS Of the tumors diagnosed as metastatic intestinal adenocarcinoma of the cervix, based on clinical data and hematoxylin-eosin-stained sections, all were Cdx-2 positive, whereas Cdx-2 was not expressed in any of our cases of primary cervical adenocarcinoma with colonic differentiation. Carcinoembryonic antigen was expressed both in primary cervical tumor and in secondary (intestinal) cervical adenocarcinoma. Cytokeratin 20 was not expressed in our cases of cervical adenocarcinoma, and it was not expressed in 7.15% of cervical metastases from intestinal carcinoma. Immunostaining with cytokeratin 7 was positive in cervical adenocarcinoma, but was negative in secondary (intestinal) cervical adenocarcinoma. CONCLUSIONS Our immunohistochemical analysis shows that Cdx-2 has good specificity and would be a good marker to use in a limited panel of immunohistochemical markers, such as cytokeratin 7, cytokeratin 20, and carcinoembryonic antigen, to distinguish primary cervical adenocarcinoma from intestinal metastases to the cervix.

Pathological characteristics and prognostic effect of peritumoral capsule penetration in renal cell carcinoma after tumor enucleation

OBJECTIVE To evaluate the pathological characteristics of peritumoral capsule (PC) and the prognostic effect of capsule penetration on tumor recurrence in patients treated with tumor enucleation for clinically intracapsular renal cell carcinomas (RCCs). METHODS AND MATERIALS PC status was analyzed in 304 consecutive patients with single intracapsular RCC. Degree and side of capsule penetration if present were evaluated. Mean (median, range) follow-up was 49 months (46, 25-69). Local recurrence rate, progression-free survival (PFS), and cancer-specific survival were the main outcomes. Statistical analyses included the Kaplan-Meier method, log-rank test, and univariate and multivariate Cox regression models. RESULTS Overall, 51% of RCCs had intact PC and free from neoplastic invasion (PC-), 34.9% had capsular penetration on the parenchymal side (PCK), and 14.1% had tumor invasion on the perirenal fat tissue side (PCF). None of the patients had positive surgical margins. The 5-year PFS rates for tumors PC-, PCK, and PCF were 97.5%, 96.7%, and 77.1%, respectively (P<0.0001). The multivariate Cox model showed PCF to be the sole significant independent predictor of PFS, whereas patients who had PCK did not present a significant increased risk in developing recurrence. CONCLUSIONS Tumor enucleation is an oncologically safe nephron-sparing surgery technique. PCF is a significant and independent predictor of tumor recurrence in patients with clinically intracapsular RCCs scheduled for nephron-sparing surgery. PCK does not predict the risk of recurrence.

Plasmacytoid urothelial carcinoma of the urinary bladder: clinicopathologic, immunohistochemical, ultrastructural, and molecular analysis of a case series.

A plasmacytoid variant of urothelial carcinoma has been recently recognized in the World Health Organization classification system. This is characterized by a discohesive growth of plasmacytoid cells with eccentric nuclei, extending in the bladder wall and often in the perivesical adipose tissue. Herein, we report the clinicopathologic, immunohistochemical, ultrastructural, and molecular features of a series of plasmacytoid urothelial carcinoma of the urinary bladder. Four bladder carcinomas characterized by epithelial cells with morphologic appearance resembling plasma cells were evaluated at the immunohistochemical, electron microscopic, and molecular genetic levels. Tumor cells stained with cytokeratins, epithelial membrane antigen, GATA-3 (endothelial transcription factor 3), CD15, p53, and p16. In addition, malignant cells strongly stained with CD138 in all the cases, whereas leukocyte common antigen and multiple myeloma 1/interferon regulatory factor 4 were completely negative, nor immunoreactivity was seen for either κ or λ light chains. The electron microscopic examination showed the presence of divergent squamous and glandular differentiation. At variance with conventional urothelial carcinoma, the analysis of exons 4-9 of TP53 gene revealed no alteration in all the 4 tumors tested, and this can be of value in choosing additional chemotherapy after surgery. Plasmacytoid carcinoma of the bladder is a tumor entity, which can be characterized by specific immunohistochemical markers, including positivity for GATA-3, and presents phenotypic and genotypic peculiarities.

Simple enucleation versus standard partial nephrectomy for clinical T1 renal masses: Perioperative outcomes based on a matched-pair comparison of 396 patients (RECORd project)

OBJECTIVES To compare simple enucleation (SE) and standard partial nephrectomy (SPN) in terms of surgical results in a multicenter dataset (RECORd Project). MATERIALS AND METHODS patients treated with nephron sparing surgery (NSS) for clinical T1 renal tumors between January 2009 and January 2011 were evaluated. Overall, 198 patients who underwent SE were retrospectively matched to 198 patients who underwent SPN. The SPN and SE groups were compared regarding intraoperative, early post-operative and pathologic outcome variables. Multivariable analysis was applied to analyze predictors of positive surgical margin (PSM) status. RESULTS SE was associated with similar WIT (18 vs 17.8 min), lower intraoperative blood loss (177 vs 221 cc, p = 0.02) and shorter operative time (121 vs 147 min; p < 0.0001). Surgical approach (laparoscopic vs. open), tumor size and type of indication (elective/relative vs absolute) were associated with WIT >20 min. The incidence of PSM was significantly lower in patients treated with SE (1.4% vs 6.9%; p = 0.02). At multivariable analysis, PSM was related to the surgical technique, with a 4.7-fold increased risk of PSM for SPN compared to SE. The incidence of overall, medical and surgical complications was similar between SE and SPN. CONCLUSIONS Type of NSS technique (SE vs SPN) adopted has a negligible impact on WIT and postoperative morbidity but SE seems protective against PSM occurrence.