Malignant salivary gland tumours in families with breast cancer susceptibility.

Salivary gland cancers (SGCs) are rare malignancies with highly heterogeneous histological features. Patients affected with SGCs are at increased risk of secondary malignancies, including breast cancer (BC). Previous studies enlightened a possible link between SGCs and hereditary predisposition to BC. Here, we searched for SGC-affected patients in 1796 high-risk BC families recruited at the Genetic Unit of the Istituto Nazionale dei Tumori of Milan, 516 of which carried pathogenic variants in BRCA1 and/or BRCA2, the main genetic risk factors for BC. We detected five families with an individual affected with SGC, including two male patients, one carrying a constitutional mutation in BRCA1 and the other in BRCA2. Loss of heterozygosity of BRCA wild-type alleles was assessed in the patients' tumour DNA. We conclude that our observations support the hypothesis that genetic factors associated with BC susceptibility might play a role also in at least a subset of SGCs.

Neoadjuvant Chemotherapy Exerts Selection Pressure Towards Luminal Phenotype Breast Cancer.

BACKGROUND: Breast cancer (BC) phenotype after neoadjuvant chemotherapy (NAC) has not been extensively described and few data exist on whether expression of the primary tumor hormone receptors, HER2 and Ki-67 changes as a result of chemotherapy. MATERIALS AND METHODS: We analyzed specimens from all BC patients treated with anthracycline/taxane-based NAC at our Institution between January 2010 and March 2015 (n = 325). The expression of estrogen receptor (ER), progesterone receptor (PR), HER2 and Ki-67 was determined in pre- and post-NAC specimens. McNemar's test was used to compare paired proportions. RESULTS: Among patients with residual disease after NAC, basal phenotype was luminal A, luminal B, HER2 positive and triple negative in 44, 111, 74 and 27 cases, respectively. PR-positive tumors decreased from 68.0% in the initial biopsy sample to 61.7% in the surgical specimen (p = 0.024). A Ki-67 of < 20% increased from 23.6% to 45% (p < 0.001). ER expression changed from positive to negative in 5% and from negative to positive in 16.7% of cases. Overall, 30% of cases underwent subtype changes, 79% of them towards luminal differentiation. CONCLUSIONS: The switch towards luminal phenotype suggests some kind of endocrine effect of NAC. Our findings raise renewed interest in combinatorial cytotoxic chemotherapy with concomitant or rather sequential endocrine therapy, either alone or with targeted agents.

Morcellator's Port-site Metastasis of a Uterine Smooth Muscle Tumor of Uncertain Malignant Potential After Minimally Invasive Myomectomy.

Since the safety warning from the US Food and Drug Administration on the use of power morcellators, minimally invasive procedures involving the removal of uterine myomas and large uteri are under scrutiny. Growing evidence suggests that morcellation of undiagnosed uterine malignancies is associated with worse survival outcomes of patients affected by uterine sarcoma. However, to date, only limited data regarding morcellation of low-grade uterine neoplasms are available. In the present article, we reported a case of a (morcellator) port-site implantation of a smooth muscle tumor that occurred 6 years after laparoscopic morcellation of a uterine smooth muscle tumor of uncertain potential. This case highlights the effects of intra-abdominal morcellation, even in low-grade uterine neoplasms. Caution should be used when determining techniques for tissue extraction; the potential adverse consequences of morcellation should be more fully explored.

Bulky mesonephric adenocarcinoma of the uterine cervix treated with neoadjuvant chemotherapy and radical surgery: report of the first case.

AIMS AND BACKGROUND: Malignant mesonephric adenocarcinoma of the uterine cervix is a rare occurrence with few cases described in the literature. Although surgery seems to be effective in the treatment of early-stage tumor, no cases describing outcomes of locally advanced stage are available. METHODS: We report the first case of a patient with International Federation of Obstetrics and Gynecologists stage IIB mesonephric adenocarcinoma undergoing neoadjuvant chemotherapy and radical surgery. CONCLUSIONS: Despite the inherent limitation of a single description of a case, our experience supports the utilization of neoadjuvant chemotherapy in patients with malignant mesonephric adenocarcinoma of the uterine cervix. Further prospective multi-institutional studies are needed.

Maspin influences response to doxorubicin by changing the tumor microenvironment organization.

Altered degradation and deposition of extracellular matrix are hallmarks of tumor progression and response to therapy. From a microarray supervised analysis on a dataset of chemotherapy-treated breast carcinoma patients, maspin, a member of the serpin protease inhibitor family, has been the foremost variable identified in non-responsive versus responsive tumors. Accordingly, in a series of 52 human breast carcinomas, we detected high maspin expression in tumors that progressed under doxorubicin (DXR)-based chemotherapy. Our analysis of the role of maspin in response to chemotherapy in human MCF7 and MDAMB231 breast and SKOV3 ovarian carcinoma cells transfected to overexpress maspin and injected into mice showed that maspin overexpression led to DXR resistance through the maspin-induced collagen-enriched microenvironment and that an anti-maspin neutralizing monoclonal antibody reversed the collagen-dependent DXR resistance. Impaired diffusion and decreased DXR activity were also found in tumors derived from Matrigel-embedded cells, where abundant collagen fibers characterize the tumor matrix. Conversely, liposome-based DXR reached maspin-overexpressing tumor cells despite the abundant extracellular matrix and was more efficient in reducing tumor growth. Our results identify maspin-induced accumulation of collagen fibers as a cause of disease progression under DXR chemotherapy for breast cancer. Use of a more hydrophilic DXR formulation or of a maspin inhibitor in combination with chemotherapy holds the promise of more consistent responses to maspin-overexpressing tumors and dense-matrix tumors in general.

Neoplastic and stromal cells contribute to an extracellular matrix gene expression profile defining a breast cancer subtype likely to progress.

We recently showed that differential expression of extracellular matrix (ECM) genes delineates four subgroups of breast carcinomas (ECM1, -2, -3- and -4) with different clinical outcome. To further investigate the characteristics of ECM signature and its impact on tumor progression, we conducted unsupervised clustering analyses in 6 additional independent datasets of invasive breast tumors from different platforms for a total of 643 samples. Use of four different clustering algorithms identified ECM3 tumors as an independent group in all datasets tested. ECM3 showed a homogeneous gene pattern, consisting of 58 genes encoding 43 structural ECM proteins. From 26 to 41% of the cases were ECM3-enriched, and analysis of datasets relevant to gene expression in neoplastic or corresponding stromal cells showed that both stromal and breast carcinoma cells can coordinately express ECM3 genes. In in vitro experiments, ß-estradiol induced ECM3 gene production in ER-positive breast carcinoma cell lines, whereas TGFß induced upregulation of the genes leading to ECM3 gene classification, especially in ER-negative breast carcinoma cells and in fibroblasts. Multivariate analysis of distant metastasis-free survival in untreated breast tumor patients revealed a significant interaction between ECM3 and histological grade (p = 0.001). Cox models, estimated separately in grade I-II and grade III tumors, indicated a highly significant association between ECM3 and worse survival probability only in grade III tumors (HR = 3.0, 95% CI = 1.3-7.0, p = 0.0098). Gene Set Enrichment analysis of ECM3 compared to non-ECM3 tumors revealed significant enrichment of epithelial-mesenchymal transition (EMT) genes in both grade I-II and grade III subsets of ECM3 tumors. Thus, ECM3 is a robust cluster that identifies breast carcinomas with EMT features but with accelerated metastatic potential only in the undifferentiated (grade III) phenotype. These findings support the key relevance of neoplastic and stroma interaction in breast cancer progression.

Shed HER2 extracellular domain in HER2-mediated tumor growth and in trastuzumab susceptibility.

The question of the serum HER2 extracellular domain (HER2/ECD) measurement for prediction of response to the anti-HER2 antibody Trastuzumab is still an open and current matter of clinical debate. To elucidate the involvement of shed HER2/ECD in HER2-driven tumor progression and in guiding therapy of individual patients, we examined biological effects exerted by elevated HER2/ECD in cancer growth and in response to Trastuzumab. To this purpose SKOV3 tumor cells were stably transfected to release a recombinant HER2/ECD molecule (rECD). Transfectants releasing high levels of 110-kDa rECD, identical in size to native HER2/ECD (nECD), grew significantly slower than did controls, which constitutively released only basal levels of nECD. While transmembrane HER2 and HER1 were expressed at equal levels by both controls and transfected cells, activation of these molecules and of downstream ERK2 and Akt was significantly reduced only in rECD transfectants. Surface plasmon resonance analysis revealed heterodimerization of the rECD with HER1, -2, and -3. In cell growth bioassays in vitro, shed HER2 significantly blocked HER2-driven tumor cell proliferation. In mice, high levels of circulating rECD significantly impaired HER2-driven SKOV3 tumor growth but not that of HER2-negative tumor cells. In vitro and in mice, Trastuzumab significantly inhibited tumor growth due to the rECD-facilitated accumulation of the antibody on tumor cells. Globally our findings sustain the biological relevance of elevated HER2/ECD levels in the outcome of HER2-disease and in the susceptibility to Trastuzumab-based therapy.

Hysteroscopy in endometrial cancer: new methods to evaluate transtubal leakage of saline distension medium.

OBJECTIVE: This study was undertaken to evaluate transtubal fluid leakage after low pressure office saline solution hysteroscopy. STUDY DESIGN: Forty stage I/II endometrial cancer patients were submitted to office hysteroscopy at the National Cancer Institute of Milan. Uterine cavity was distended by a 1000-mL saline solution bag, placed 50 cm above the patient's plane. After visualization of uterine cavity, a radiotracer (technetium Tc 99m) and patent blue dye were injected subendometrially. During the staging surgery peritoneal free fluid was analyzed to detect patent blue dye, technetium Tc 99m or free cancer cell by cytologic examination. RESULTS: Technetium Tc 99m and patent blue dye were detected on the peritoneal surface and in the peritoneal fluid in 2 patients. In 1 of these peritoneal cytology was negative for cancer cells. Peritoneal cytology was positive in 2 cases. CONCLUSION: The risk of transtubal fluid leakage during hysteroscopy is absent when performed with intrauterine pressure less than 40 mm Hg. Transtubal fluid leakage is not a synonym of cancer cell dissemination.

Incidental carcinomas in prophylactic specimens in BRCA1 and BRCA2 germ-line mutation carriers, with emphasis on fallopian tube lesions: report of 6 cases and review of the literature.

The identification of germ-line mutations in 2 genes (BRCA1 and BRCA2) responsible for the majority of hereditary ovarian cancers has led an increasing number of women carriers of these mutations to undergo prophylactic oophorectomy (PO) to reduce their risk of subsequent ovarian carcinoma. A large number of unexpected, clinically occult neoplasms are thus being discovered. Up to December 2004, the Medical Genetics Service of the National Cancer Institute in Milan, Italy, has tested 756 probands from breast and/or ovarian cancer families for BRCA1 and BRCA2 germ-line mutations. Molecular screening of family members led to the identification of 344 female carriers of BRCA1 (239) or BRCA2 (105) germ-line mutations. Of the 186 potentially eligible women (37 of whom had tested positive for BRCA1 and 13 for BRCA2 mutation), 50 (26.8%) chose to undergo PO. Six clinically occult primary gynecologic malignancies (2 stage IIIC serous carcinomas of the ovary, 3 in situ serous carcinomas of the fallopian tube, and 1 stage IIB invasive serous carcinoma of the fallopian tube) and 1 occult ovarian metastasis from breast carcinoma were identified in the PO specimens of 7 women (all BRCA1 mutated). Four of the patients with occult primary gynecologic cancers are alive without disease 129, 87, 38, and 7 months after PO, respectively. One of the 2 patients with primary ovarian cancer and the single patient with tubal invasive carcinoma are alive with recurrent disease 83 and 20 months after PO, respectively. In addition, one of the patients whose PO specimen did not show any malignancy presented with stage IIIC tubal carcinoma 77 months after PO. The relatively high number of tubal neoplasms found at PO in this group of patients underlines the linkage between mutation and the risk of developing tubal cancer, and stresses the need to include removal of the entire tubes at the time of PO and of thoroughly evaluating the specimens at the microscopic level. The upstaging of all 3 invasive carcinomas after staging surgery, and the late recurrence and persistence of 2 of them despite treatment indicate that small size of the tumors should not preclude therapy.

Atypical epithelial proliferation in fallopian tubes in prophylactic salpingo-oophorectomy specimens from BRCA1 and BRCA2 germline mutation carriers.

Although growing numbers of tubal carcinomas in carriers of BRCA1 and BRCA2 germline mutations have been reported, very little is known about the nature and frequency of their possible precursor lesions. The aim of this study is to investigate the occurrence of atypical proliferative tubal lesions in grossly normal fallopian tubes from 26 women with BRCA1 and BRCA2 germline mutations who underwent prophylactic salpingo-oophorectomy and whose ovaries were histologically negative for carcinoma. Fallopian tubes from 49 women who had undergone hysterectomy with salpingo-oophorectomy for uterine leiomyoma served as controls. In the 22 BRCA1-mutated women, there were two in situ carcinomas and two atypical hyperplasias of the tubal epithelium. The tubes of the BRCA2-mutated women and of the 49 control women did not show any atypical proliferation. The frequency of proliferative lesions of the tubal epithelium, including in situ carcinoma, appears to be increased in BRCA1 mutation carriers. Removal and thorough examination of the fallopian tubes at the time of surgical prophylaxis for ovarian cancer is therefore recommended.

Microinvasive squamous cell cervical carcinoma.

Several histologic tumor-related features are the key factors for further treatment planning in microinvasive cervical cancer (MIC) after conization. To better define the indications for conservative treatment of MIC we conducted a literature review for prognostic factors for MIC and we carried out a prospective observational study evaluating most important pathologic factors and the relationships between tumor and edges of the cone and incidence of recurrences. In our experience seven recurrences were observed. Two distinct groups of patients were identified with a clearance lower or higher of 10 and 8 mm for apical and lateral margin respectively. Depth of infiltration and even lymph-vascular involvement have been confirmed as the most important histologic parameters to be evaluated. Apical and lateral clearance of the tumor are significantly correlated with the recurrence rate. If an adequate lateral border of healthy tissue is present on the specimen, conization may be considered as definitive treatment of MIC.

Nerve-sparing radical hysterectomy: a pilot study.

Nerve-sparing radical hysterectomy has increasingly been used for cervical cancer, with less morbidity. We aimed with this study: i) to describe an alternative technique of nerve-sparing radical Piver III hysterectomy, using the CUSA, in which attention was given to the uterosacral ligament and cardinal ligament; ii) to evaluate the feasibility of this new nerve-sparing technique; iii) to describe the surgical anatomy of the autonomic nervous system; iv) to assess the early incidence of bladder dysfunction. Twelve consecutive patients with local-regional advanced cervical cancer were enrolled in the study on nerve-sparing radical hysterectomy with extended pelvic lymphadenectomy. The mean age was 44 years (range, 30-59), mean body mass index was 24 kg/m2 (range, 18-30), mean operating time was 217 mins (range, 195-240), and mean blood loss was 437 cc (range, 200-750). The average hospitalization time was 9 days (range, 5-15 days). Two patients presented pathologically positive parametrium. Two of 12 (17%) patients were discharged with self-catheterism. In the first outpatient follow-up, 1 patient had recovered spontaneous voiding. The nerve-sparing technique with CUSA can be an option to reduce radical hysterectomy-related morbidity. The technique proved to be feasible, with promising results in terms of preventing bladder dysfunction. An elevated body mass index and large tumors can impair the performance of the technique. Further studies clarifying neuroanatomy and neurophysiology of autonomic nervous structures, as well as a prospective controlled trial on nerve-sparing radical hysterectomy should be carried out to confirm our data.

Minimally Invasive Follicular Carcinoma.

The criteria for the diagnosis of follicular carcinoma of the thyroid and in particular of the "minimally invasive" variant are discussed. The introduction of a new terminology reflecting the indolent behavior of most of the thyroid neoplasms morphologically resembling follicular adenomas, and currently diagnosed as carcinomas on the sole basis of capsular invasion, is recommended.