Improving the TIR3B oncological stratification: try to bridge the gap through a comprehensive presurgical algorithm.

PURPOSE: Indeterminate cytology still puzzles clinicians, due to its wide range of oncological risks. According to the Italian SIAPEC-IAP classification, TIR3B cytology holds up to 30% of thyroid cancer, which justifies the surgical indication, even if more than half of cases do not result in a positive histology. The study aim is to identify potential clinical, ultrasound or cytological features able to improve the surgical indication. METHODS: Retrospective analysis. A consecutive series of TIR3B nodules referred to the Endocrine Unit of Careggi Hospital from 1st May 2014 to 31st December 2021 was considered for the exploratory analysis (Phase 1). Thereafter, a smaller confirmatory sample of consecutive TIR3B diagnosed and referred to surgery from 1st January 2022 to 31st June 2022 was considered to verify the algorithm (Phase 2). The main clinical, ultrasound and cytological features have been collected. A comprehensive stepwise logistic regression was applied to build a prediction algorithm. The histological results represented the final outcome. RESULTS: Of 599 TIR3B nodules referred to surgery, 451 cases were included in the exploratory analysis. A final score > 14.5 corresponded to an OR = 4.98 (95% CI 3.24-7.65, p < 0.0001) and showed a PPV and NPV of 57% and 79%, respectively. The Phase 2 analysis on a confirmatory sample of 58 TIR3B cytology confirmed that a threshold of 14.5 points has a comparable PPV and NPV of 53% and 80%, respectively. CONCLUSIONS: A predictive algorithm which considers the main clinical, US and cytological features can significantly improve the oncological stratification of TIR3B cytology.

Clinical impact of the new SIAPEC-IAP classification on the indeterminate category of thyroid nodules.

BACKGROUND: The increasing frequency in the diagnosis of thyroid nodules has raised a growing interest in the search for new diagnostic tools to better select patients deserving surgery. In 2014, the major Italian Societies involved in the field drafted a new cytological classification, to better stratify pre-surgical risk of thyroid cancer, especially for the indeterminate category, split into TIR3A and TIR3B subclasses, associated to different therapeutic decisions. MATERIALS AND METHODS: This retrospective cross-sectional survey analyzed thyroid fine-needle aspiration biopsy performed at our outpatient clinic before and after the introduction of the new SIAPEC-IAP consensus in May 2014. RESULTS: 8956 thyroid nodules were included in the analysis: 5692 were evaluated according to the old classification and 3264 according to the new one. The new criteria caused the overall prevalence of TIR3 to increase from 6.1 to 20.1%. Of those, 10.7 and 9.4% were included in the TIR3A and TIR3B subgroups, respectively. Each of the 213 TIR3B nodules underwent surgery and 86 (40.4%) were diagnosed as thyroid cancer, while among the 349 TIR3A nodules, only 15 of the 60 that underwent surgery were found to be thyroid cancer. CONCLUSIONS: This analysis shows that the new SIAPEC-IAC criteria significantly increased the proportion of the overall TIR3 diagnosis. The division of TIR3 nodules into two subgroups (A and B) allowed a better evaluation of the oncologic risk and a better selection of patients to be referred to surgery.

International multicenter tool to predict the risk of four or more tumor-positive axillary lymph nodes in breast cancer patients with sentinel node macrometastases.

Recently, many centers have omitted routine axillary lymph node dissection (ALND) after metastatic sentinel node biopsy in breast cancer due to a growing body of literature. However, existing guidelines of adjuvant treatment planning are strongly based on axillary nodal stage. In this study, we aim to develop a novel international multicenter predictive tool to estimate a patient-specific risk of having four or more tumor-positive axillary lymph nodes (ALN) in patients with macrometastatic sentinel node(s) (SN). A series of 675 patients with macrometastatic SN and completion ALND from five European centers were analyzed by logistic regression analysis. A multivariate predictive model was created and validated internally by 367 additional patients and then externally by 760 additional patients from eight different centers. All statistical tests were two-sided. Prevalence of four or more tumor-positive ALN in each center's series (P = 0.010), number of metastatic SNs (P < 0.0001), number of negative SNs (P = 0.003), histological size of the primary tumor (P = 0.020), and extra-capsular extension of SN metastasis (P < 0.0001) were included in the predictive model. The model's area under the receiver operating characteristics curve was 0.766 in the internal validation and 0.774 in external validation. Our novel international multicenter-based predictive tool reliably estimates the risk of four or more axillary metastases after identifying macrometastatic SN(s) in breast cancer. Our tool performs well in internal and external validation, but needs to be further validated in each center before application to clinical use.

A simple ultrasound score for the identification of candidates to fine needle aspiration of thyroid nodules.

BACKGROUND: Cytological examination of fine needle aspirates (FNA) is the standard procedure for discriminating potentially malignant thyroid nodules to be referred to surgery. In a fraction of cases, ultrasound (US) examination could provide information theoretically sufficient to avoid FNA, when typical US features suggesting malignancies are lacking. AIM: The aim of this study was to construct a simple US score predicting malignant nodules so as to reduce the number of unnecessary FNA. SUBJECTS AND METHODS: In a series of 1632 consecutive patients undergoing US-guided FNA (1812 nodules), echostructure, echogenicity, margins, halo, microcalcification, and vascularization were assessed. RESULTS: At multivariate analysis, the following parameters showed a strong predictive value for positive cytology (Thy 4 and Thy 5, suspicious and diagnostic for malignancy, respectively, according to the Thyroid British Association): solid echostructure, irregular margins and hypoechogenicity [adjusted odd ratio (OR) 5.13 (1.58-16.66), 3.03 (1.70-5.39), 2.05 (1.17-3.57), respectively]. A 10-point Thyroid Risk Ultrasound Score (TRUS) was constructed on the basis of the adjusted OR. A TRUS≥6 identified malignant nodules with sensitivity and specificity of 73% and 65%, respectively. Among the patients with follicular lesions (Thy 3) and final diagnosis of carcinoma, about 65% had a TRUS≥6.0. CONCLUSIONS: The sensitivity of TRUS, although higher than that of other scores, could still be insufficient for the identification of patients who could avoid FNA in routine clinical practice, whereas its predictive value for Thy 3 lesions deserves further investigations.

Follicular nodules (THY3) of the thyroid: we recommend surgery.

OBJECTIVE: To determine the need of total thyrodectomy for patients with follicular nodules of thyroid. SUBJECTS AND METHODS: From January 2005 through June 2008, 2249 consecutive patients (438 males, 1811 females; mean age 54 yr, range 9-87) with thyroid nodules were submitted to 2518 ultrasound-guided fine-needle aspiration (USgFNA) for cytological examination. USgFNA were performed by experienced surgeon (RP) and endocrinologist (RGG) under ultra- sonographyc guidance, using a 10-MHz linear transducer. Liquid-based cytology was used. RESULTS: All cytological samples were classified in 5 diagnostic classes (THY1, THY2, THY3, THY4, THY5) in agreement with the British Thyroid Association (BTA); 1.4% specimen were classified as THY5, 2.1% as THY4, 7.6% as THY3, 79.5% as THY2 and 9.4% as THY1. In 97% of THY5 patients, malignancy was found. Among THY4 patients, 95.5% were positive for thyroid tumor. Among THY3 patients, malignancy was found in 29.1%. THY3 patients with thyroid tumors were younger than those with benign lesions (46 ± 14.1 yr vs 50 ± 13.8 yr; p<0.05, t test). No statistical difference was found neither in malignancy frequency among men and women nor in mean size of nodules (24 ± 11.8 mm malignant vs 23 ± 9.4 mm benign). CONCLUSIONS: this study provides evidence that USgFNA offers a very sensitive and accurate method in reducing THY1 samples and in detecting malignancy (>95% both in THY5 and THY4, and >29% in THY3 lesions). Our proposal is to submit to total thyroidectomy all patients with THY5 and THY4 lesions and THY3 thyroid nodule >1 cm.

Impact of molecular subtypes classification concordance between preoperative core needle biopsy and surgical specimen on early breast cancer management: Single-institution experience and review of published literature.

BACKGROUND: Core needle biopsy (CNB) plays a crucial role as diagnostic tool for breast cancer (BC). The characterization of biomarkers status before surgical treatment is crucial when primary systemic therapy is a therapeutic option. The aim of this analysis was to report concordance between preoperative CNB and surgical specimen (SS) in evaluating biomarkers and molecular subtypes. METHODS: Data have been collected from a cohort of 101 patients affected by early BC treated at Careggi Florence University Hospital, between January 2014 and March 2015. The conformity between molecular subtype classification was tested using kappa (κ) test. RESULTS: Mean age was 57.5 years (range 29-86). There was concordance between the estrogen receptor (ER) assessment on CNB and SS in 95 cases (94.1%). Concordance of the progesterone receptor (PgR) assessment was observed in 89 cases (88.1%). Concordance for detecting immunohistochemistry-assessed BC molecular subtypes was 87.1% (κ = 0.78). Concerning Ki-67 evaluation, we report a concordance rate of 88.1% (κ = 0.68). The evaluation of luminal A plus luminal B/HER negative subgroup showed a κ-value of 0.65. CONCLUSIONS: CNB showed good accuracy in evaluating hormonal receptors status, HER2, and BC molecular subtypes. Evaluation of Ki67 status was less accurate than other biomarkers; therefore, we recommend that it should be detected both on CNB and SS samples, especially in hormonal positive HER2 negative tumors, in order to avoid a misclassification of tumor subtypes that could lead to an omission of potential effective systemic therapy.

The value of cytokeratin immunohistochemistry in the evaluation of axillary sentinel lymph nodes in patients with lobular breast carcinoma.

BACKGROUND: Cytokeratin immunohistochemistry (IHC) reveals a higher rate of occult lymph node metastases among lobular carcinomas than among ductal breast cancers. IHC is widely used but is seldom recommended for the evaluation of sentinel lymph nodes in breast cancer patients. OBJECTIVE: To assess the value of cytokeratin IHC for the detection of metastases in sentinel lymph nodes of patients with invasive lobular carcinoma. METHODS: The value of IHC, the types of metastasis found by this method, and the involvement of non-sentinel lymph nodes were analysed in a multi-institutional cohort of 449 patients with lobular breast carcinoma, staged by sentinel lymph node biopsy and routine assessment of the sentinel lymph nodes by IHC when multilevel haematoxylin and eosin staining revealed no metastasis. RESULTS: 189 patients (42%) had some type of sentinel node involvement, the frequency of this increasing with increasing tumour size. IHC was needed for identification of 65 of these cases: 17 of 19 isolated tumour cells, 40 of 64 micrometastases, and 8 of 106 larger metastases were detected by this means. Non-sentinel-node involvement was noted in 66 of 161 cases undergoing axillary dissection. Although isolated tumour cells were not associated with further lymph node involvement, sentinel node positivity detected by IHC was associated with further nodal metastases in 12 of 50 cases (0.24), a proportion that is higher than previously reported for breast cancer in general. CONCLUSIONS: IHC is recommended for the evaluation of sentinel nodes from patients with lobular breast carcinoma, as the micrometastases or larger metastases demonstrated by this method are often associated with a further metastatic nodal load.

Accuracy and Reproducibility of HER2 Status in Breast Cancer Using Immunohistochemistry: A Quality Control Study in Tuscany Evaluating the Impact of Updated 2013 ASCO/CAP Recommendations.

The correct identification of HER2-positive cases is a key point to provide the most appropriate therapy to breast cancer (BC) patients. We aimed at investigating the reproducibility and accuracy of HER2 expression by immunohistochemistry (IHC) in a selected series of 35 invasive BC cases across the pathological anatomy laboratories in Tuscany, Italy. Unstained sections of each BC case were sent to 12 participating laboratories. Pathologists were required to score according to the Food and Drug Administration (FDA) four-tier scoring system (0, 1+, 2+, 3+). Sixteen and nineteen cases were HER2 non-amplified and amplified respectively on fluorescence in situ hybridization. Among 192 readings of the 16 HER2 non-amplified samples, 153 (79.7%) were coded as 0 or 1+, 39 (20.3%) were 2+, and none was 3+ (false positive rate 0%). Among 228 readings of the 19 HER2 amplified samples, 56 (24.6%) were scored 0 or 1+, 79 (34.6%) were 2+, and 93 (40.8%) were 3+. The average sensitivity was 75.4%, ranging between 47% and 100%, and the overall false negative rate was 24.6%. Participation of pathological anatomy laboratories performing HER2 testing by IHC in external quality assurance programs should be made mandatory, as the system is able to identify laboratories with suboptimal performance that may need technical advice. Updated 2013 ASCO/CAP recommendations should be adopted as the widening of IHC 2+ "equivocal" category would improve overall accuracy of HER2 testing, as more cases would be classified in this category and, consequently, tested with an in situ hybridisation method.

Measurement of somatostatin receptor subtype 2 mRNA in breast cancer and corresponding normal tissue.

Somatostatin analogs are effective in inhibiting growth of human breast cancer cell lines. These antiproliferative effects are mediated by specific receptors located on cell membranes. The somatostatin receptor subtype 2 (sst2) is the principal mediator of somatostatin effects in normal and cancer cells, and its presence has already been demonstrated in breast cancer. The purpose of our study was to evaluate the clinical relevance of the expression of sst2 by quantifying its mRNA in a large group of infiltrating breast cancers and their corresponding normal tissues. The expression of sst2 mRNA was measured with quantitative real time RT-PCR in 169 breast cancers and in their corresponding unaffected tissues. We evaluated the association of sst2 expression with the commonest clinical-pathologic features of breast cancer. The correlation with a marker of cell proliferation (Ki-67) and with receptor concentration was also evaluated. In cancer tissues, we found that the absolute concentrations of sst2 mRNA were significantly higher in estrogen receptor (ER)-positive samples (P=0.002) as well as in lymph-node-negative cancers (P=0.04) (Student's t-test or one-way ANOVA). In addition, sst2 mRNA was significantly higher in breast cancers than in corresponding unaffected tissues (P=0.0002). However, when the clinical-pathologic parameters were considered, this gradient maintained its statistical significance only in tumors expressing positive prognostic markers, such as the presence of ER (P=0.0005) and progesterone receptors (PgR) (P=0005), and the lack of lymph-node involvement (P=0.0003). The same difference was also significant in postmenopausal women (P=0.001) and in T1 patients (P=0.001). In addition, sst2 mRNA expression was significantly higher (P=0.008) in low-proliferating breast cancers. Finally, we found that the quantitative expression of sst2 mRNA was directly related to the PgR concentration in breast cancer tissues (P<0.001). Our data seem to indicate that an upregulation of sst2 gene expression is a common feature of breast cancers which, on the basis of conventional predictive parameters, are expected to have a better prognosis. Featuring a possible role of somatostatin analogs in combined endocrine therapies for breast cancer, our results seem to confirm that the sst2 status of the tumor should be previously investigated.

Assessment of the early impact of the population-based breast cancer screening programme in Florence (Italy) using mortality and surrogate measures.

The aim of this study was to evaluate the effects by the end of 1999 of the Florence breast screening programme that started in 1990. Approximately 60000 women (aged 50-69 years) were enrolled from 1990 to 1993. Breast cancer cases diagnosed from 1990 to 1996 were partitioned by the method of detection, classified by their tumour size and nodal status and followed-up for mortality at on the 31 December 1999. Incidence-based mortality in the 50-74-year-old women and advanced carcinomas rates were assessed. Due to low compliance (approximately 60%) and the long enrollment phase, only approximately 35% of the total age-specific population person-years were screened. The number of invasive cases diagnosed was 1122, 17% higher than the 958 expected. After the prevalence screening, a reduction of approximately a quarter in advanced carcinomas was observed in the invited women (Odds Ratio (OR): 0.74; 95% Confidence Interval (CI): 0.55-0.98). In the period 1990-1999, 547 breast cancer deaths were observed: 78 (14%) occurred in women invited and half of these in never responders, 385 (70%) occurred in cases diagnosed before screening started. Disproportionate numbers of deaths occurred in women with advanced tumours. The 19% mortality reduction for the invited women was of borderline statistical significance (observed/expected (O/E) deaths: 0.81; 95% CI: 0.64-1.01); by a one-sided test the result would be unequivocally significant. The mortality reduction attributable to screening in the whole population over the 10-year period was 3.2%. The incidence-based mortality analysis confirmed the current follow-up time is too short for screening to have had a major effect on the breast cancer mortality trends. Screening performance might be improved by a higher level of compliance and shorter interval times, but the estimate of the mortality reduction for the invited and the lower rate of advanced carcinomas confirmed that the effect of the programme is in the expected direction.

Instability at dinucleotide and trinucleotide repeats in breast cancer.

We analyzed 7 mono-, 6 di- and 2 trinucleotide repeat loci in a well characterized series of 69 breast cancer cases, treated in the period 1985-1986 and followed for 12 years. Tumor-associated allele contractions or expansions were observed only at di- and trinucleotide repeats, and were detected in 14/69 cases (20%), of which 7 (10%) showed instability at 2 or more loci (10%). No alterations were detected at mononucleotide repeats known to be unstable in gastrointestinal tumors with the microsatellite mutator phenotype. Disease-free survival at 5 years, overall survival at 12 years of follow-up, tumor stage, estrogen/progesteron receptor status, and expression of the Ki-67 proliferation marker were independent of microsatellite status.

Accuracy and reliability of frozen section diagnosis in a series of 672 nonpalpable breast lesions.

Frozen section (FS) diagnosis was routinely performed in a large series of nonpalpable breast lesions from 1977 through 1991. The original FS diagnoses of 672 patients were classified in four categories (1 = benign lesion, 2 = in situ carcinoma, 3 = invasive carcinoma, 4 = deferred diagnosis) and compared with the diagnoses obtained at review of the permanent paraffin sections to estimate the accuracy of FS. A review of the mammographic pattern of the lesion was also performed. Frozen section diagnostic conclusion was deferred to permanent paraffin sections in only 22 cases (3.3%). Benign or malignant (grouping in situ and invasive carcinomas) FS diagnoses were accurate in 623 of 650 cases (95.8%). Overall, the prevalence of malignant lesions was 44.8% with a benign/malignant ratio of 1.2. The diagnosis was modified on the basis of permanent sections in 27 cases (4.2%) with three false positives and 24 false negatives. Sensitivity and specificity of FS diagnoses were 91.7 and 99.2%, respectively. When the comparison between FS and histologic diagnoses was analyzed according to the mammographic pattern, sensitivity among patients with microcalcifications as the only alteration was lower (88.8%) than among patients with opacities (94.9%). On the basis of these results, FS is to be considered a feasible and reliable diagnostic procedure in nonpalpable breast lesions, particularly in cases excised because of a mammographic opacity that is identifiable on gross examination of the surgical specimen.

Lack of prognostic value of p53 protein expression in node-negative breast cancer.

AIMS AND BACKGROUND: The association of p53 protein accumulation and prognosis in node-negative breast cancer patients has been alternately demonstrated and denied in literature reports, and opinions on the use of p53 expression as an indicator of high risk of recurrence and as a guide for adjuvant therapy are controversial. STUDY DESIGN: The association of p53 protein accumulation with prognosis was retrospectively evaluated in a series of 221 node-negative breast cancer patients treated with surgery alone and followed up for a minimum of 10 years. p53 accumulation was determined by immunohistochemistry on archive material, and classified into four grades of increasing immunostaining. RESULTS: No association was observed between p53 and age or pT category, whereas a significant association with nuclear grade was found (P = 0.0014). Univariate and multivariate analysis of 10-yr disease-free and overall survival showed a significant and independent prognostic association for tumor size (pT category) and nuclear grading but not for p53 expression, whatever grade grouping was used. CONCLUSIONS: We did not find any evidence supporting the use of p53 immunostaining in current practice as an independent prognostic indicator or as a discriminant factor for adjuvant treatment of node-negative breast cancer patients.

[Surgical treatment of thyroid microcarcinoma]. / Trattamento chirurgico dei microcarcinomi tiroidei.

Thyroid microcarcinoma is nowaday defined as a tumor of one centimeter or less in the maximum diameter. It occurs in less than five per cent of all thyroid carcinomas. In personal experience four thyroid microcarcinomas have been found in specimens from 121 thyroidectomies and have been retrospectively reviewed clinical data and the long term follow-up of the patients. Total thyroidectomies nor prophylactic lymphadenectomies were never performed. All patients at present are well. Our purpose was to focus on the current surgical treatment of microcarcinoma. Many hypotheses are done to explain pathogenesis and fairly good prognosis of thyroid microcarcinomas, without univocal conclusions. Almost all authors agree that microcarcinoma of the thyroid gland is a low-aggressive tumor, with good biological behaviour, but the therapeutic strategies are not codified yet. Particularly, doubt still exists about the choice between total thyroidectomy and more conservative procedure, and lymphadenectomy, especially when tumor is found in specimens after surgery for benign disease. In conclusion, in our opinion conservative management is the best choice, provided that the patient is included in a correct long-term follow-up.

[Thyroid cancer: anatomy and pathologic histology]. / Il cancro della tiroide: anatomia e istologia patologica.

Current pathological classifications of thyroid carcinoma only partially reflect the radical changes in our knowledge of these tumors, due to a large series of clinicopathological studies carried out over the past few years. Based on a critical review of this growing body of information concerning malignant thyroid neoplasms, a working formulation for clinical usage is proposed. This scheme has been adopted to classify 1339 consecutive cases of thyroid carcinoma observed at the Pathology Institute of the University of Florence between June 1966 and December 1993. The clinical implications of newer classification systems with regard to diagnosis, treatment and outcome of thyroid carcinoma are also discussed.

[Intraoperative histological study of nonpalpable lesions of the breast]. / L'esame istologico intra-operatorio nelle lesioni non palpabili della mammella.

The intraoperative frozen section technique has proven to be valid and accurate in the diagnosis of palpable breast lesions, while its use in non-palpable lesions of the breast has been recently discussed. In order to estimate the accuracy of frozen section technique in non-palpable breast lesions we reviewed our series of 672 cases of non-palpable lesions examined intraoperatively between January 1977 and December 1991. Frozen section diagnoses were compared with diagnoses obtained at review of the permanent paraffin sections. A review of the mammographic pattern of each lesion was also carried out. Frozen section diagnosis was replaced by permanent paraffin sections in 22 cases (3.3%). Benign or malignant (in situ and invasive carcinomas) frozen section diagnoses were accurate in 623 of 650 cases (95.8%). Frozen section diagnosis was modified on the basis of permanent sections in 27 cases (4.2%), with 3 false positives and 24 false negatives. Sensitivity and specificity of frozen section technique were 91.7% and 99.2%, respectively. Comparing frozen section and definitive diagnosis according to the mammographic pattern, sensitivity was lower in patients with microcalcifications as the only alteration (88.8%) compared with patients with opacities (94.9%). On the basis of our results the frozen section technique in non-palpable breast lesions is to be considered a valid and reliable diagnostic procedure, particularly in lesions detectable at mammography as an opacity and identifiable on gross examination of the surgical specimen.

Phyllodes tumours of the breast diagnosed as B3 category on image-guided 14-gauge core biopsy: analysis of 51 cases from a single institution and review of the literature.

AIMS: Image-guided 14-gauge (G) core biopsy (CB) has been shown to be an accurate method providing histological diagnosis of breast lesions. The purpose of this study was to evaluate the reliability of image-guided 14-G CB in the diagnosis of phyllodes tumours (PT) reported as B3 category and its accuracy in distinguishing this lesion from fibroadenomas (FA). MATERIALS AND METHODS: The records of 10 000 image-guided 14-G CB of the breast performed from January 2001 to August 2011 at the Diagnostic Senology Unit of Careggi University Hospital were reviewed; 2554 (25.5%) were fibroepithelial lesions: 56 of them (2%) were diagnosed as PT and reported as B3 category. The database of the Pathological Anatomy Unit of Careggi University Hospital was then searched to verify the histological diagnosis after surgical excision. Fifty-one cases of PT diagnosed as B3 category in 51 women were included in the present study. RESULTS: Of the 51 cases of PT diagnosed as B3 category on 14-G CB, 39 (76.5%) lesions were confirmed as PT on SE (30, 4 and 5 as benign, borderline and malignant PT respectively) with a PPV of 76.5%. Twelve lesions (23.5%) were diagnosed as FA after surgical excision. CONCLUSIONS: Our study shows that 14-G CB is a valuable tool, in a preoperative setting, in diagnosing PT.

Invasive breast cancer: a significant correlation between histological types and molecular subgroups.

INTRODUCTION: The special types of breast cancer seem to have not only distinct morphological features but also distinct biological features. MATERIALS AND METHODS: Women diagnosed with a first primary invasive breast cancer in the 2004-2005 period were identified through Tuscan Cancer Registry. Information on age, tumor size, lymph node status, histological type and grade, hormonal receptors, HER2 immunohistochemical expression were collected. Five subtypes were defined: luminal A, luminal B HER2+, luminal B HER2-, triple negative, and HER2 positive. The association between the histological type and molecular subgroups was assessed by a Fisher's exact test, and a multinomial logistic regression model was used. RESULTS: Out of 1,487 patients, 34 % were luminal A subtype, 25 % luminal B HER2-, 11 % luminal B HER2+, 19 % triple negative, and 10.2 % HER2+; 58.5 % of cancers were ductal NOS types. With luminal A as reference, histological types distribution was significantly different between the subgroups. Mucinous, tubular, and cribriform histotypes were found among luminal A cancers more than in other subgroups; all medullary carcinomas were triple negative cancers. Pathological stage at diagnosis was more advanced, and histological grade was lower among subgroups other than luminal A. CONCLUSIONS: Significant association between breast cancer histotypes and molecular subgroups was found.

Biological characteristics of interval cancers: a role for biomarkers in the breast cancer screening.

INTRODUCTION: In a population-based screening program, a percentage of tumors remain undetected; these tumors comprise a heterogeneous group, and they are more likely to have adverse prognostic features. The aim of this study was to identify differences in biological characteristics of screen-detected versus interval breast cancers in a population-based screening program according to molecular subtypes. MATERIALS AND METHODS: We analyzed the population-based data from a long-running screening program in the area of Florence. Data on screening history and on age, T and N status, grade, histotype, hormonal status and Ki-67 and HER2 expression were retrieved. Subtypes of breast cancer were defined on the expression of ER, PR, Ki-67 and HER2: luminal A if ER/PR+, HER2- and Ki67 <14 %, luminal B (HER2 negative) if ER/PR+, HER2- and Ki67 ≥14 %, luminal B (HER2 positive) if ER/PR+ and HER2+, triple negative if ER/PR-and HER2-, HER2 positive if ER/PR- and HER2+. Association between molecular subtypes and mode of detection will be evaluated by a logistic regression model adjusted for the potential confounding variables. RESULTS: Information about biomarkers was known for 277 cases, 211 screening-detected and 66 interval cancers. Among interval cases, the triple-negative cancers were more represented than luminal A (OR = 3.52; CI, 1.112-11.13; p = 0.0319), while the proportion of HER2+ was quite similar (OR = 1.57; p = 0.4709). CONCLUSION: Although made on a small number of cases, our results suggest a difference in distribution of molecular subtypes according to mode detection, confirming the results of earlier studies.

Circulating BRAFV600E in the diagnosis and follow-up of differentiated papillary thyroid carcinoma.

CONTEXT: Cell-free nucleic acids circulating in plasma are considered a promising noninvasive tool for cancer monitoring. BRAF(V600E) mutation in cell-free DNA (cfDNA) could represent an appropriate marker for papillary thyroid carcinoma (PTC). OBJECTIVE: Our aim is to investigate the role of BRAF(V600E)-mutated allele in cfDNA as a marker for the diagnosis and follow-up of PTC. STUDY DESIGN: BRAF(V600E) allele was detected and quantified by an allele-specific real-time quantitative PCR assay in plasma from 103 patients affected by nodular goiter. As control populations, we enrolled 49 healthy subjects and 16 patients with non-nodular thyroid diseases. RESULTS: The percentage of circulating BRAF(V600E) was significantly different between patients and controls and throughout different cytological categories of ultrasound-assisted fine-needle aspiration. Patients with a histopathological diagnosis of PTC showed a higher percentage of circulating BRAF(V600E) (P = .035) compared to those with benign histology. In 19 patients, a second blood draw, taken 3-6 months after surgery, showed a lower percentage of BRAF(V600E) in cfDNA than the presurgical sample (P < .001). The diagnostic performance of circulating BRAF(V600E) was assessed by receiver operating characteristic curve analysis resulting in an area under the curve of 0.797. A cutoff value was chosen corresponding to maximum specificity (65%) and sensitivity (80%). On this basis, we evaluated the predictive value of BRAF(V600E) in Thy 3 patients with a resulting positive predictive value of 33% and a negative predictive value of 80%. CONCLUSIONS: The results of the present study provide encouraging data supporting the possibility to take advantage of circulating BRAF(V600E) in the management of PTC.