Bilateral Disease Common Among Slovenian CHEK2-Positive Breast Cancer Patients.

BACKGROUND: Currently, data on pathogenic variants in the CHEK2 gene and their impact on cancer risk are lacking. This study aimed to explore the characteristics of breast cancer (BC) patients from families with CHEK2 pathogenic variants in Slovenia. METHODS: In the years 2014 to 2019, CHEK2 pathogenic variants/likely pathogenic variants (PV/LPVs) were found in probands from 50 different families who underwent genetic counseling and testing using a multigene panel at the authors' institution. Altogether, the study enrolled 75 individuals from 50 CHEK2 families who were carriers of a CHEK2 PV/LPV. The clinical data on 41 BC patients with CHEK2 PV/LPV and other carriers of CHEK2 PV/LPV from Slovenia were collected and analyzed. RESULTS: Breast cancer was diagnosed in 41 of 75 CHEK2 PV/LPV carriers (40 females, 1 male). The mean age at BC diagnosis was 42.8 years (range, 21-63 years), and 27 (65.8%) of the 41 of patients with BC had a positive family history for BC. Contralateral BC (CBC) was observed in 8 (19.5%) of the 41 patients (mean age, 55.6 years). Of 12 patients with human epidermal growth factor receptor 2 (HER2)-positive tumor type, a c.444+1G > A PV/LPV was detected in 4 patients, c.349A > G in 3 patients, deletion of exons 9-10 in 3 patients, deletion of exon 8 in 1 patient, and c.1427C > T PV/LPV in 1 patient. CONCLUSION: Bilateral BC was diagnosed in as many as 19.5% of the Slovenian BC patients with CHEK2 PV/LPVs. Breast cancer associated with a germline CHEK2 PV/LPV occurs in younger patients compared with sporadic BC.

Reducing indications for radial scar surgical excision in Slovenian breast cancer screening program.

PURPOSE: Management of the radial scar (RS)/complex sclerosing lesion (CSL) diagnosed by core needle biopsy (CNB) in breast cancer screening population (BCSP) is controversial due to its intrinsic malignant potential. We aimed to determine (i) the rate of upgrade of the RS/CSL to malignant lesions and (ii) radiological characteristics and CNB histopathological findings of the lesions related to the upgrade of the RS/CSL to malignant lesions after surgical excision in our BCSP. PATIENTS AND METHODS: Database of Slovenian National Breast Cancer Screening Program was checked for terms RS/CSL in all patients who underwent CNB in the period 2008-2018. The ratios of upgrade from CNB RS/SCL to malignant lesions after surgical excision were calculated with specific interest to the radiological characteristics and the CNB patohistologically findings of the lesions. RESULTS: Of 162 patients with diagnosis of RS/CSL on the CNB, 121/156 (78%) cases underwent surgical excision. 6 of 121 (5%) cases were upgraded to a malignant diagnosis in surgical specimen, 3 cases of invasive carcinoma and 3 cases of DCIS, respectively. Five of the upgraded cases (5/6, 83.3%) showed atypical epithelial proliferative lesions (AEPL) on CNB. In one upgraded case without AEPL the lesion presented as 33 mm architectural distortion with microcalcifications on the mammogram. CONCLUSIONS: In BCSP setting RS/CSL without AEPL/papilloma and those measuring less than 2 cm in the largest diameter can be followed radiologically. Increasing the number of cores and adequate sampling of the periphery and the centre of the RS/CSL improves the pick-up rate of associated atypia/malignancy.

Cytology material is equivalent to tumor tissue in determining mutations of BRCA 1/2 genes in patients with tubo-ovarian high grade serous carcinoma.

BACKGROUND: High-grade serous ovarian cancer is a detrimental disease. Treatment options in patients with a recurrent disease are dependent on BRCA1/2 mutation status since only patients with known BRCA mutation are eligible for treatment with poly(ADP-ribose) polymerase inhibitors (PARPi). The aim of this study was to compare concordance of BRCA mutation analyses from cytological samples (CS) with BRCA mutation analyses from histological formalin fixed paraffin embedded (FFPE) samples. METHODS: Mutation analysis of BRCA1 and BRCA2 genes was performed in 44 women diagnosed with primary or recurrent high-grade ovarian cancer from three different samples: blood, cytological sample (ascites, pleural effusion and enlarged lymph nodes) and tumor tissue. Results from all three samples were compared. RESULTS: Among 44 patients, there were 15 germline mutations and two somatic mutations. A 100% concordance was found between cytological and histologic samples. CONCLUSION: There is a 100% concordance in BRCA mutation testing between cytological and histologic samples. BRCA mutation testing from CS could replace testing from FFPE tissue in clinical decision making in ovarian cancer patients. TRIAL REGISTRATION: The study was retrospectively registered at ISRCTN registry on 24/11/2015 - ISRCTN42408038 .

Pre-operative and intra-operative detection of axillary lymph node metastases in 108 patients with invasive lobular breast cancer undergoing mastectomy.

BACKGROUND: Despite the recent changes in the treatment of the axilla in selected breast cancer patient, positive sentinel lymph node (SLN) in patients undergoing mastectomy still necessitates axillary lymph node dissection (ALND). In invasive lobular carcinoma (ILC), pre-operative detection of the lymph node metastasis may be demanding due to its unique morphology. The aim of this study was to examine the benefit of preoperative axillary ultrasound (AUS), ultrasound-guided fine-needle aspiration biopsy (US-FNAB), and intra-operative imprint cytology (IIC), in order to avoid two-stage axillary surgery in patients with ILC undergoing mastectomy. METHODS: The object of this study were 102 patients (median age 52, range 34-73 years) with clinically non-suspicious axilla in whom 108 mastectomies were performed after a pre-operative AUS investigation. Whenever a metastasis was detected in a sentinel lymph node, ALND was done. Reports of the pre-operative AUS investigation, US-FNAB, and IIC were compared with definitive histopathological reports of surgical specimens. RESULTS: In 46 cases lymph node metastases were diagnosed. AUS suspicious lymph nodes were found in 29/108 cases and histopathology confirmed metastases in 22/30 cases. US-FNAB was performed in 29 cases with AUS suspicious lymph nodes. Cytology proved metastases in 11/29 cases. Histopathology confirmed metastases in 10/11 cases with only isolated tumor cells found in one case. IIC investigation was performed in 63 cases and in 10/27 cases metastases were confirmed by histopathology. Pre-operative AUS, US-FNAB, and/or IIC investigation enabled ALND during a single surgical procedure in 20/46 patients with metastases in lymph nodes. CONCLUSION: Pre-operative AUS, US-FNAB, and/or IIC are/is beneficial in patients with ILC planned for mastectomy in order to decrease the number of two stage axillary procedures.

Treatment and outcome of 32 patients with distant metastases of Hürthle cell thyroid carcinoma: a single-institution experience.

BACKGROUND: It is generally believed that patients with Hürthle cell thyroid carcinoma (HCTC) have a poor prognosis. Furthermore, distant metastases represent the most frequent cause of thyroid cancer-related death of patients with HCTC. The aim of this study was to report the treatment and outcomes of patients with distant metastases. METHODS: Altogether 108 patients were treated for HCTC from 1972 to 2011 in our tertiary center and 32 patients (19 females, 13 males; median age 64.5 years) had either initially proven metastatic disease (N = 12) or distant progression of HCTC after initial treatment (N = 20). Patients with metastases were followed for 1-226 (median 77) months. Data were collected on the patients' gender and age, extent of their disease, morphologic characteristics, therapy, outcome, and survival rate. Statistical correlation between possible prognostic factors and cause-specific survival from time of detection of metastases was analyzed by univariate analysis and log-rank test. RESULTS: The most common were lung metastases, followed by bone, mediastinum, kidney, and liver in 24, 8, 2, 1, and 1 case, respectively. Total thyroidectomy, lobectomy, subtotal thyroidectomy and neck dissection were performed in 19, 10, 3, and 7 patients, respectively. Radioiodine (RAI) ablation of thyroid remnant was performed in 30 patients, while 20 of them had RAI therapy (median 4 times). RAI uptake in metastases was present in 16 patients and ranged from 0.05 % to 12 %. Chemotherapy was used in 13 patients and external beam radiotherapy in 19 patients. Locoregional control of disease was achieved in 19/21 (90 %) cases who succumbed due to HCTC. Estimated 10-year disease-specific survival for all patients was 60 %. 10-year disease-specific survival for patients with pulmonary metastases and other sites metastases was 60 % and 62 %, respectively. 10-year disease-specific survival for patients with single organ and multiple organ metastases was 52 %, and 100 %, respectively. Estimated median disease-specific survival after the diagnosis of metastatic disease for all patients was 77 months. The median disease-specific survival after the diagnosis of metastatic disease for patients with pulmonary metastases and other sites metastases was 72 and 138 months, respectively. CONCLUSIONS: Ten-year disease-specific survival for all patients with metastatic Hürthle cell thyroid carcinoma, patients with pulmonary metastases and bone metastases was 60 %, 60 % and 68 %, respectively.

Functional polymorphisms in antioxidant genes in Hurthle cell thyroid neoplasm - an association of GPX1 polymorphism and recurrent Hurthle cell thyroid carcinoma.

BACKGROUND: Hurthle cells of the thyroid gland are very rich in mitochondria and oxidative enzymes. As a high level oxidative metabolism may lead to higher level of oxidative stress and can be associated with an increased risk for cancer, we investigated whether common functional polymorphisms in antioxidant genes (SOD2, CAT, GPX, GSTP1, GSTM1 and GSTT1) are associated with the development or clinical course of Hurthle cell thyroid carcinoma (HCTC). METHODS: A retrospective study was performed in 139 patients treated by thyroid surgery for a Hurthle cell neoplasm. HCTC, Hurthle cell thyroid adenoma (HCTA) or Hurthle cell thyroid nodule (HCTN) were diagnosed by pathomorphology. DNA was extracted from cores of histologically confirmed normal tissue obtained from formalin-fixed paraffin-embedded specimens and genotyped for investigated polymorphisms. Logistic regression was used to compare genotype distributions between patient groups. RESULTS: HCTC, HCTA and HCTN were diagnosed in 53, 47 and 21 patients, respectively. Metastatic disease and recurrence of HCTC were diagnosed in 20 and 16 HCTC patients, respectively. Genotypes and allele frequencies of investigated polymorphisms did not deviate from Hardy-Weinberg equilibrium in patients with HCTC, HCTA and HCTN. Under the dominant genetic model we observed no differences in the genotype frequency distribution of the investigated polymorphisms when the HCTA and HCTN group was compared to the HCTC group for diagnosis of HCTC or for the presence of metastatic disease. However, GPX1 polymorphism was associated with the occurrence of recurrent disease (p = 0.040). CONCLUSIONS: GPX1 polymorphism may influence the risk for recurrent disease in HCTC.

Antioxidant defence-related genetic variants are not associated with higher risk of secondary thyroid cancer after treatment of malignancy in childhood or adolescence.

BACKGROUND: Thyroid cancer is one of the most common secondary cancers after treatment of malignancy in childhood or adolescence. Thyroid gland is very sensitive to the carcinogenic effect of ionizing radiation, especially in children. Imbalance between pro- and anti-oxidant factors may play a role in thyroid carcinogenesis. Our study aimed to assess the relationship between genetic variability of antioxidant defence-related genes and the risk of secondary thyroid cancer after treatment of malignancy in childhood or adolescence. PATIENTS AND METHODS: In a retrospective study, we compared patients with childhood or adolescence primary malignancy between 1960 and 2006 that developed a secondary thyroid cancer (cases) with patients (controls), with the same primary malignancy but did not develop any secondary cancer. They were matched for age, gender, primary diagnosis and treatment (especially radiotherapy) of primary malignancy. They were all genotyped for SOD2 p.Ala16Val, CAT c.-262C>T, GPX1 p.Pro200Leu, GSTP1 p.Ile105Val, GSTP1 p.Ala114Val and GSTM1 and GSTT1 deletions. The influence of polymorphisms on occurrence of secondary cancer was examined by McNemar test and Cox proportional hazards model. RESULTS: Between 1960 and 2006 a total of 2641 patients were diagnosed with primary malignancy before the age of 21 years in Slovenia. Among them 155 developed a secondary cancer, 28 of which were secondary thyroid cancers. No significant differences in the genotype frequency distribution were observed between cases and controls. Additionally we observed no significant influence of investigated polymorphisms on time to the development of secondary thyroid cancer. CONCLUSIONS: We observed no association of polymorphisms in antioxidant genes with the risk for secondary thyroid cancer after treatment of malignancy in childhood or adolescence. However, thyroid cancer is one of the most common secondary cancers in patients treated for malignancy in childhood or adolescence and the lifelong follow up of these patients is of utmost importance.

Neoadjuvant chemotherapy in 13 patients with locally advanced poorly differentiated thyroid carcinoma based on Turin proposal - a single institution experience.

BACKGROUND: There is a paradigm that chemotherapy is ineffective in thyroid carcinoma. The aim of our study was to find out whether neoadjuvant chemotherapy before thyroid surgery had an effect on the size of primary tumour in patients with poorly differentiated thyroid carcinoma (PDTC) based on Turin proposal. PATIENTS AND METHODS: Altogether, 13 patients (8 women, 5 men; median age 61 years) with PDTC based on Turin proposal were treated with neoadjuvant chemotherapy between 1986 and 2005. Tumour diameter was from 4.5 to 18 cm (median 9 cm). Regional and distant metastases were detected in 6 and 9 patients, respectively. Eight patients had pT4 tumour. RESULTS: Altogether, 29 (range 1-5) cycles of chemotherapy were given. Tumour diameter decreased in all the patients and by more than 30% in 5 patients (= 38%). Two of these five patients had also preoperative external beam irradiation (EBRT). Total thyroidectomy, lobectomy and neck dissection were performed in 10, 3 and 5 cases, respectively. R0 and R1 resection was done in 5 and 8 cases, respectively. Eight patients had postoperative EBRT of the neck and upper mediastinum. The 5-year and 10-year cause-specific survival rates of patients were 66% and 20%, respectively. CONCLUSIONS: After neoadjuvant chemotherapy a partial tumour regression was observed in 38% of patients with PDTC based on Turin proposal.

Prognostic factors for disease-specific survival in 108 patients with Hürthle cell thyroid carcinoma: a single-institution experience.

BACKGROUND: Hürthle cell thyroid carcinoma (HCTC) is a rare disease. It is believed that it is more aggressive than follicular thyroid carcinoma. The aim of our study was to identify factors associated with disease-specific and disease-free survival. METHODS: Altogether, 108 patients with HCTC (26 male, 82 female; median age 62 years; range 19-87 years) treated at our Institute from 1972 to 2011 were included in the present retrospective study. Data on age, clinical and histopathological factors, tumor stage, recurrence, disease-free and disease-specific survival were collected. Univariate analysis was used to identify factors associated with disease-specific survival. Cox's multivariate regression model was used to identify independent prognostic factors for disease-specific survival. RESULTS: The follow-up period was 1 to 337 (median 105) months. Of 108 patients, 12 (11%) had distant and 8 (7%) had locoregional metastases before primary treatment. Recurrence was diagnosed in 26 cases (24%): locoregional, distant, and both locoregional and distant in 12, 11, and 3 cases, respectively. The 5-year, 10-year, and 20-year disease-specific survival were 96%, 88%, and 67%, respectively. Independent prognostic factors for disease-specific survival were: age of patients at diagnosis, distant metastases and residual tumor after surgery. CONCLUSION: Long disease-specific survival was found in patients with HCTC younger than 45 years of age without distant metastases and without residual tumor after surgery.

Long-term use of metformin and the molecular subtype in invasive breast carcinoma patients - a retrospective study of clinical and tumor characteristics.

BACKGROUND: Metformin may exhibit inhibitory effects on cancer cells by inhibiting mTOR signaling pathway. The aim of our retrospective study was to examine if patients with breast carcinoma (BC) and diabetes mellitus (DM) receiving metformin have a lower stage of carcinoma in comparison to patients not receiving metformin, and if the use of metformin correlates with the molecular subtype of BC. METHODS: A chart review of 253 patients with invasive BC and DM (128 on metformin and 125 not on metformin) was performed. Control group consisted of 320 consecutive patients with invasive BC without DM. BC subtypes were classified by immunohistochemical surrogates as luminal A (estrogen receptor [ER] + and/or progesterone receptor [PR]+, HER-2-), luminal B (ER + and/or PR+, HER-2+), HER-2 (ER-, PR-, HER-2+), triple-negative/basal (ER-, PR-, HER-2-). RESULTS: Patients on metformin had a lower proportion of T3 or T4 tumors than patients who were not receiving metformin (16% vs. 26%; p = 0.035). No statistical difference was found between the two study groups in N stage. Patients with DM on metformin, with DM not on metformin and the control group had different molecular subtypes of BC (p = 0.01): the luminal A subtype was found in 78%, 83% and 71%, the luminal B in 12.6%, 9% and 11%, HER-2 in 0.8%, 1.6% and 8%, and the triple-negative/basal-like subtype in 8.6%, 6.4% and 10%, respectively. CONCLUSION: Our data indicate that long-term use of metformin use correlates with molecular subtype of BC in diabetics on metformin in comparison to diabetics not on metformin and patients without DM. However, most likely, different distribution of the molecular subtypes of BC in these three groups of patients was caused by other risk factors for breast carcinoma, such as age of patients or obesity.

Association of androgen receptor and tumour-infiltrating lymphocytes with bone recurrence in triple-negative breast cancer.

Background: As compared to endocrine responsive breast cancer bone is less frequent site of distant recurrence in triple-negative breast cancer (TNBC). A biomarker which predicts bone recurrence would allow a more personalized treatment approach with adjuvant bisphosphonates in TNBC. Here we hypothesised that tumour expression of androgen receptor (AR) is associated with bone recurrence in TNBC. Materials and methods: Patients with operable TNBC who were treated at the Institute of Oncology Ljubljana between 2005 and 2015 and developed distant recurrence were included into our study. Nuclear expression of AR in the tissue of primary tumours was determined immunohistochemically by using the Androgen Receptor (SP107) Rabbit Monoclonal Antibody. We applied a logistic regression model to test the association between expression of AR and development of bone metastases. The model was adjusted for selected known prognostic factors and possible confounders in TNBC, including the level of the stromal tumour-infiltrating lymphocytes (sTILs). Results: At recurrence 45 (45 %) out of 100 patients presented with bone metastases. Additionally, seven (7 %) developed bone metastases metachronously. AR was expressed in primary tumours of 35 (35 %) women and 19 (54.3 %) developed bone recurrence. In 25 (25 %) patients sTILs were absent. Neither the proportion of AR positive cancer cells (OR = 1.00; 95 % CI 0.96-1.03; p = 1.00) nor the intensity of AR positive reaction (OR = 0.71; 95 % CI 0.02-21.4; p = 1.00) were significantly associated with bone recurrence. However, women with at least mild level of the sTILs were at significantly lower risk for bone recurrence as compared to those without any sTILs (OR = 0.01; 95 % CI < 0.01-0.08; p = 0.01). Conclusions: Expression of AR is not significantly associated with the development of bone metastases in TNBC. However, patients with absent sTILs in their primary tumours are highly susceptible for recurrence in the bone and might particularly benefit from adjuvant bisphosphonates.

Clinical and Analytical Validation of Two Methods for Ki-67 Scoring in Formalin Fixed and Paraffin Embedded Tissue Sections of Early Breast Cancer.

Proliferation determined by Ki-67 immunohistochemistry has been proposed as a useful prognostic and predictive marker in breast cancer. However, the clinical validity of Ki-67 is questionable. In this study, Ki-67 was retrospectively evaluated by three pathologists using two methods: a visual assessment of the entire slide and a quantitative assessment of the tumour margin in 411 early-stage breast cancer patients with a median follow-up of 26.8 years. We found excellent agreement between the three pathologists for both methods. The risk of recurrence for Ki-67 was time-dependent, as the high proliferation group (Ki-67 ≥ 30%) had a higher risk of recurrence initially, but after 4.5 years the risk was higher in the low proliferation group. In estrogen receptor (ER)-positive patients, the intermediate Ki-67 group initially followed the high Ki-67 group, but eventually followed the low Ki-67 group. ER-positive pN0-1 patients with intermediate Ki-67 treated with endocrine therapy alone had a similar outcome to patients treated with chemotherapy. A cut-off value of 20% appeared to be most appropriate for distinguishing between the high and low Ki-67 groups. To summarize, a simple visual whole slide Ki-67 assessment turned out to be a reliable method for clinical decision-making in early breast cancer patients. We confirmed Ki-67 as an important prognostic and predictive biomarker.

Complete response in the axilla and the non-triple negative subtype are favourable prognostic factors for survival outcomes in inflammatory breast cancer.

AIM: To assess real-world outcomes and prognostic factors of non-metastatic inflammatory breast cancer according to immunohistochemistry (IHC)-based subtype and treatment regimen. METHODS: An institutional retrospective analysis of patients treated with neoadjuvant systemic treatment (NAST) for stage III inflammatory breast cancer diagnosed between 2001 and 2018 was performed. The survival outcomes in relation to patient characteristics, tumour characteristics, treatment modality and response to NAST were analyzed. RESULTS: 225 patients fulfilled the inclusion criteria, 90% of patients were node-positive. IHC-based subtypes: 39.1% were HR+/HER2-, 19.1% HR+/HER2+, 23.1% HR-/HER2+ and 18.7% HR-/HER2-. Treatment was multimodal: NAST (100%), surgery (94.2%) and radiotherapy (94.2%). 53.3% of patients received adjuvant endocrine therapy, 34.3% (neo)adjuvant trastuzumab. Tri-modality therapy was applied in 89.3% of patients. Following NAST, a pathologic complete remission (pCR) in the breast was found in 16.9%, in the axilla in 29.7% and in both the breast and axilla in 10.3% of patients. The axillary pCR rate was significantly higher in HR- subtypes. Median overall survival (OS) was 8.9, 7.2, 5.8 and 2.3 years (p < 0.001) for HR+/HER2-, HR+/HER2+, HR-/HER2+ and HR-/HER2- subtype, respectively. On multivariate analysis, IHC-based subtype, age and axillary pCR were found as independent prognostic factors for RFS and OS. pCR rate and median OS improved over time, 5.8% vs 14.7% and 4.7 vs 10.0 years (2001-2009 vs. 2010-2018), respectively. CONCLUSIONS: Axillary pCR and the non-triple-negative IHC-based subtype are favourable prognostic factors for RFS and OS in inflammatory breast cancer. Introduction of taxanes and antiHER2 drugs contributed to improved pCR rate and OS.

The Possible Role of Anti- and Protumor-Infiltrating Lymphocytes in Pathologic Complete Response in Early Breast Cancer Patients Treated with Neoadjuvant Systemic Therapy.

The tumor microenvironment, composed of pro- and antitumor immune cells, affects cancer cell behavior. We aimed to evaluate whether tumor-infiltrating lymphocyte (TIL) density and TIL subtypes in core biopsies at the diagnosis of breast cancer patients could predict a pathologic complete response (pCR; ypT0/is ypN0) from neoadjuvant systemic therapy (NST). The TIL subtypes were determined based on the proportions of presumably antitumor (CD8+, CXCL13+) and protumor (PD-1+, FOXP3+) immune cells. A prospective, noninterventional study, including 171 participants undergoing NST, was performed. The median TIL density for the entire cohort was 10% (IQR: 3.5-23.8), and 59 (35%) patients achieved pCR. TIL density was positively associated with pCR (univariately and multivariably). In the multivariable logistic regression model, TIL density was an independent predictor of pCR (p = 0.012, OR 1.27; 95% CI 1.05-1.54) when controlled for age (p = 0.232), Ki-67 (p = 0.001), node-negative status (p = 0.024), and HER2+/triple negative vs. luminal B-like subtype (p < 0.001). In our sample, higher proportions of PD-1+ TILs and FOXP3+ TILs were associated with a higher probability of pCR but the association was not statistically significant and we could not make any conclusions on the direction of associations in the model with all four biomarkers. In the exploratory multivariable analysis, we showed that only higher CD8+ TILs were associated with pCR. In conclusion, TIL density and its subtypes are associated with pCR.

Preoperative serum thyroglobulin concentration is an independent predictive factor of malignancy in follicular neoplasms of the thyroid gland.

BACKGROUND: A distinction between a benign follicular neoplasm (FN) and a malignant FN based entirely on cytologic examination of fine-needle aspiration biopsy is not possible. The aim of this retrospective study was to find predictive factors of carcinoma in patients with FN. METHODS: A chart review of 388 patients (314 females, 74 males; mean age 50 years, range 9-81 years) with FN, who were surgically treated between 1988 and 2009, was performed. Predictive factors for malignancy were identified by the chi-squared test and multivariate logistic regression. RESULTS: The histopathological diagnoses were carcinoma, adenoma, and benign goiter in 127 (33%), 126 (32%), and 135 (35%) patients, respectively. The independent predictors of malignancy as shown by multivariate logistic regression were age of patients (OR 1.88, P = 0.008), solitary tumor (OR 1.72, P = 0.037), and Tg concentration (OR 2.36, P = 0.001). Carcinoma was more common in patients younger than 45 years, with solitary tumor and with preoperative serum Tg concentration more than 400 ng/ml. CONCLUSIONS: The independent predictors of malignancy in FN were age of patients, solitary tumor, and preoperative Tg concentration. The determination of Tg concentration may be useful in the patients with FN in order to decrease the number of completion thyroidectomies.

Lobular breast carcinoma metastasis to a superficial plexiform schwannoma as the first evidence of an occult breast cancer.

Tumor to tumor metastasis is a rare phenomenon, in which one, benign or malignant, tumor is involved by metastatic deposits from another. Most documented tumor to tumor metastases have been located intracranially, in which, in the majority of cases, either a breast or a lung carcinoma metastasized to a meningioma. Only 7 cases of metastases to schwannoma have so far been reported in the English literature, in 6 cases to an intracranial acoustic schwannoma and in a single case to a subcutaneous schwannoma. We present a case of dermal/subcutaneous plexiform schwannoma containing metastatic deposits of an occult lobular breast carcinoma, creating a unique schwannoma with epithelioid cells. Differential diagnosis of schwannoma with epithelioid cells includes malignant transformation of schwannoma and metastasis of a carcinoma or melanoma to schwannoma, epithelioid schwannoma, and schwannoma with glandular or pseudo glandular elements.

The role of molecular diagnostics in aneurysmal and simple bone cysts - a prospective analysis of 19 lesions.

Aneurysmal (ABC) and simple bone cysts (SBC) have been traditionally distinguished by radiological and histopathological features. However, there is some radiological and histopathological overlap between ABC and SBC. ABC is characterised by USP6 fusions while, recently, NFATC2 fusions have been found in a large proportion of SBC. Identifying these fusions may assist in confirming the diagnosis of either ABC or SBC. To elaborate the potential benefit of molecular testing, we report a prospective series of 19 consecutive bone cysts with comprehensive radiological, histopathological and molecular diagnostics. Integrating radiological, histopathological and molecular findings, 11 cysts were diagnosed as SBC and 8 as ABC. Radiologically, 6 of 11 SBC and 6 of 8 ABC were diagnosed as ABC. Fibrin-like collagen deposits were identified in 8 of 11 (73%) SBC and 3 of 8 (38%) ABC. Nodular fasciitis-like areas were identified in 6 of 8 (75%) ABC and in 7 of 11 (64%) SBC. A USP6 fusion was identified in all 8 ABC, including a novel RBM5-USP6 fusion. An NFATC2 fusion was found in 7 of 11 SBC (FUS-NFATC2 fusion in 5 and EWSR1-NFATC2 in 2 cases). There is radiological and histopathological overlap between SBC and ABC in a significant proportion of cases. A diagnosis of ABC is frequently suggested radiologically in SBC, and fibrin-like deposits, thought to be specific for SBC, may be found in some ABC. Molecular testing may significantly improve diagnostic accuracy in bone cysts.

Quality assured implementation of the Slovenian breast cancer screening programme.

SETTING: The organised, population-based breast cancer screening programme in Slovenia began providing biennial mammography screening for women aged 50-69 in 2008. The programme has taken a comprehensive approach to quality assurance as recommended by the European guidelines for quality assurance in breast cancer screening and diagnosis (4th edition), including centralized assessment, training and supervision, and proactive monitoring of performance indicators. This report describes the progress of implementation and rollout from 2003 through 2019. METHODS: The screening protocol and key quality assurance procedures initiated during the planning from 2003 and rollout from 2008 of the screening programme, including training of the professional staff, are described. The organisational structure, gradual geographical rollout, and coverage by invitation and examination are presented. RESULTS: The nationwide programme was up and running in all screening regions by the end of 2017, at which time the nationwide coverage by invitation and examination had reached 70% and 50%, respectively. Nationwide rollout of the population-based programme was complete by the end of 2019. By this time, coverage by invitation and examination had reached 98% and 76%, respectively. The participation rates consistently exceeded 70% from 2014 to 2019. CONCLUSIONS: The successful implementation of the screening programme can be attributed to an independent central management, external guidance, and strict adherence to quality assurance procedures, all of which contributed to increasing governmental and popular support. The benefits of quality assurance have influenced all aspects of breast care and have provided a successful model for multidisciplinary management of other diseases.

Dietary iodine intake, therapy with radioiodine, and anaplastic thyroid carcinoma.

Background Anaplastic thyroid cancer (ATC) is one of the most aggressive tumors. The aim of the study was to determine the correlation between a higher dietary intake of iodine, frequency of ATC and the characteristics of ATC, and to find out how often patients with ATC had a history of radioiodine (RAI) therapy. Patients and methods This retrospective study included 220 patients (152 females, 68 males; mean age 68 years) with ATC who were treated in our country from 1972 to 2017. The salt was iodinated with 10 mg of potassium iodide/ kg before 1999, and with 25 mg of potassium iodide/kg thereafter. The patients were assorted into 15-year periods: 1972-1986, 1987-2001, and 2002-2017. Results The incidence of ATC decreased after a higher iodination of salt (p = 0.04). Patients are nowadays older (p = 0.013) and have less frequent lymph node metastases (p = 0.012). The frequency of distant metastases did not change over time. The median survival of patients in the first, second, and third periods was 3, 4, and 3 months, respectively (p < 0.05). The history of RAI therapy was present in 7.7% of patients. Conclusions The number of patients with a history of RAI therapy did not change statistically over time. The incidence of ATC in Slovenia decreased probably because of higher salt iodination.

Significance of nuclear factor - kappa beta activation on prostate needle biopsy samples in the evaluation of Gleason score 6 prostatic carcinoma indolence.

Background The goal of our study was to find out whether the immunohistochemical expression of nuclear factor-kappa beta (NF-κB) p65 in biopsy samples with Gleason score 3 + 3 = 6 (GS 6) can be a negative predictive factor for Prostate cancer (PCa) indolence. Patients and methods Study was conducted on a retrospective cohort of 123 PCa patients with initial total PSA ≤ 10 ng/ml, number of needle biopsy specimens ≥ 8, GS 6 on biopsy and T1/T2 estimated clinical stage who underwent laparoscopic radical prostatectomy and whose archived formalin-fixed and paraffin-embedded (FFPE) prostate needle biopsy specimens were used for additional immunohistochemistry staining for detection of NF-κB p65. Both cytoplasmic and nuclear NF-κB p65 expression in biopsy cores with PCa were correlated with postoperative pathological stage, positive surgical margins, GS and biochemical progression of disease. Results After follow-up of 66 months, biochemical progression (PSA ≥ 0.2 ng/ml) occurred in 6 (5.1%) patients, 3 (50%) with GS 6 and 3 (50%) with GS 7 after radical prostatectomy. Both cytoplasmic and nuclear NF-κB p65 expressions were not significantly associated with pathological stage, positive surgical margin and postoperative GS. Patients with positive cytoplasmic NF-kB reaction had significantly more frequent biochemical progression than those with negative cytoplasmic NF-kB reaction with PSA 0.2 ng/ml as cutoff point (p = 0.015) and a trend towards more biochemical progression with PSA ≥ 0.05 ng/ml as cutoff point (p = 0.068). Conclusions Cytoplasmic expression of NF-κB is associated with more biochemical progression and might be an independent prognostic factor for recurrence-free survival (RFS), but further studies including larger patient cohorts are needed to confirm these initial results.