Geographical distribution of Slovenian BRCA1/2 families according to family origin: implications for genetic screening.

Knowledge of the geographical distribution of highly recurrent mutations may be useful for efficient screening in cancer families. Since the cloning of the BRCA1/2 genes, it is known that the wide spectrum of deleterious mutations shows high ethnic and geographic heterogeneity. In this study, we have tested probands from 582 breast/ovarian cancer families and positioned all 156 BRCA1/2 families on the map according to the family origin. We observed that high-risk families with the same recurrent mutation present a typical geographical distribution and that different recurrent mutations may show different distribution patterns. We then evaluated the genetic screening implications of this heterogeneous prevalence of the most recurrent mutations found [300T>G(c.181T>G), 1806C>T(c.1687C>T), 969ins7(c.844_850dupTCATTAC), 5382insC(c.5266dupC), 235G>A(c.116G>A) in BRCA1 and IVS16-2A>G(c.7806-2A>G) in BRCA2]. On the basis of these results, specific testing procedures for new incident cases may be offered according to their family origins and, according to the information regarding clusters revealed in this study, the individuals (especially those at low risk), originating from regions with clusters, might be screened preferentially for cluster mutations and analysis may be simplified according to the family origin.

Aggressiveness of therapy and prognosis of patients with Hürthle cell papillary thyroid carcinoma.

Hürthle cell papillary thyroid carcinoma (HCPTC) has been studied separately from other types of thyroid carcinoma in relatively few studies. The aim of our study was to determine the factors associated with the survival of patients with HCPTC in Slovenia, an iodine-deficient region. A total of 1552 patients with thyroid carcinoma were seen at our institute during the period of 1976-2003; of them, 42 patients (33 females, 9 males; age 10-85 years, median 56.5 years) had histopathologically verified HCPTC. The data on the patients' gender, age, disease history, extent of disease, morphologic characteristics, therapy, locoregional control, disease-free interval, and survival were collected. The statistical correlation between possible prognostic factors and the disease-free interval and survival was analyzed by chi2 test and log rank analysis. The tumor diameter ranged from 1 to 9 cm (median, 3 cm). Extrathyroid tumor growth was found in 19 patients, lymph node metastases in 13 patients, and distant metastases in 2 patients. Primary treatment consisted of total or near-total thyroidectomy (39 patients), lobectomy (2 patients), radioiodine ablation of the thyroid remnant (37 patients), external irradiation (14 patients), and chemotherapy (3 patients). Locoregional recurrence was diagnosed in four patients, and dissemination in 1 patient during the follow-up period of 0.75-20 years (median, 5.5 years). Three patients died of thyroid carcinoma during the follow-up period. The 5-year and 10-year survivals were 94% and 87%, respectively. The 5-year and 10-year disease-free intervals were 93% and 81%, respectively. The factors correlated with the survival were: age, extrathyroid tumor growth, primary tumor stage, and regional and distant metastases. Although extrathyroidal tumor growth was found in 45% of the patients with HCPTC, our patients had a favorable prognosis. Long-term survival and locoregional control of disease are likely after the radical tumor resection, radioiodine ablation of the thyroid remnant, and external irradiation.

Radioguided occult lesion localization (ROLL) of the nonpalpable breast lesions.

Standard localization techniques of the nonpalpable breast lesions (guide wire, carbon, skin marking) have several disadvantages. Radioguided occult lesion localization (ROLL) was recently proposed as a better alternative resulting in wider surgical margins and lower average specimen weight. The aim of our study was to compare ROLL to our previously published series of the standard guidewire localization, performed at the Institute of Oncology Ljubljana. ROLL was performed in 110 nonpalpable breast lesions. Human serum albumin macroaggregats, marked with 1.8-5.5 MBq 99mTc was injected in the nonpalpable lesion. During surgery the radioactive breast tissue was excised using hand held gamma probe. Nonpalpable breast lesions were excised in all 110 patients. The definitive histology revealed 32 invasive carcinomas, 19 DCIS, 5 LCIS in and 54 benign breast lesions. Mean specimen weight was 40 g which is less in comparison to 53 g of the guidewire series (p=0.002). Surgical margins were clear in 36/51 (70%) invasive breast cancer or DCIS patients and close or involved in 15/51 (30%) patients. Compared to the guidewire series, where 41/92 (44%) margins were clear and 51/92 (56%) were close or involved, the difference was statistically significant (p=0.005). ROLL proved to be superior to guidewire localization in our series, allowing excision of the nonpalpable breast lesion with wider surgical margins despite lower average specimen weight.

Role of imprint cytology in the intraoperative evaluation of sentinel lymph nodes for malignant melanoma.

Controversy exists over the utility of different methods for intra-operative sentinel lymph node (SLN) evaluation in patients with malignant melanoma (MM). The aim of this study was to evaluate the role of intra-operative imprint cytology (IC) in patients with MM. 215 SLNs from 99 patients with MM were examined by IC and results compared with the results of permanent sections. 24 patients had MM deposits in their SLNs and this was confirmed by histological examination. Intraoperative IC was positive in 11 of these patients (46% sensitivity). In addition, there were three false-positive IC diagnoses (79% positive predictive value); one of these was due to contamination during the sectioning of the SLN. The specificity and the negative predictive values of the IC were 96 and 85%, respectively. IC is a valuable method of intra-operative SLN evaluation which can spare approximately half of the patients with clinically occult regional metastases from a second surgical procedure. However, special care must be taken to avoid false-positive results due to contamination.

Breast biopsy with wire localization: factors influencing complete excision of nonpalpable carcinoma.

Our aim was to find out the factors influencing the complete excision of nonpalpable carcinoma. During a 2-year period, 215 patients (median age 55 years) underwent biopsy after wire localization of 222 nonpalpable breast lesions. Mammographic, surgical and pathological factors were correlated with the outcome of surgery using contingence tables in SPSS statistical software. A total of 96 carcinomas were diagnosed: 38 in situ and 58 invasive carcinomas. Surgical margins were clear in 43, close in 20 and involved in 33 cases. Factors correlated with clear surgical margins are mammographically spicular lesion, cytologically proven carcinoma, excision of more than 50 g of tissue, carcinoma smaller than 10 mm, invasive carcinoma without in situ component, and unicentric ductal carcinoma in situ ( p<0.05). Complete excision of multifocal in situ carcinoma or invasive carcinoma with extensive in situ component, which are diagnosed on mammogram as suspicious microcalcifications, remains a puzzling surgical task.

Effect of primary treatment on survival in anaplastic thyroid carcinoma.

AIMS: Anaplastic thyroid carcinoma (ATC) is a fatal disease despite combined treatment consisting of chemotherapy, radiotherapy and surgery. The optimal sequence of treatment modalities is not known. The purpose of our retrospective non-randomized study was to find out whether timing of the treatment modality had any influence on survival, and to find out if primary surgery prolongs survival in comparison to primary chemotherapy and/or radiotherapy. METHODS: From our database of 162 patients with ATC treated at the Institute of Oncology Ljubljana from 1972-98, 79 patients (26 men, 53 women; age: 40-86 years, mean age 65 years) were included in this retrospective study. The 83 patients with distant metastases on admission, with the survival shorter than one month or patients without any treatment were excluded. The 79 patients were classified into (1) primary surgery group (n=26) and (2) primary chemotherapy and/or radiotherapy group (n=53), including the 12 patients in whom surgery was performed after chemotherapy and/or radiotherapy. The survival of both groups was compared by log-rank test and group characteristics by ANOVA and(2 test using SPSS program. RESULTS: In comparison to the primary surgery group, the patients from the primary chemotherapy and/or radiotherapy group were older and had faster growing, and larger tumours, which were not confined to the thyroid, and more frequently had regional metastases. There was no difference in the survival of the two groups (P=0.17). Survival for longer than one year was observed in 25% of patients with primary surgery and in 21% of patients with primary chemotherapy and/or radiotherapy. The best results (50% survival at one year) were obtained in patients in whom the tumour was surgically removed after primary chemotherapy and radiotherapy. CONCLUSION: This study suggests that the timing of the treatment modalities has an impact on survival and that treatment should start with chemotherapy and/or radiotherapy, with surgery to follow if possible.)

Prognostic factors in follicular carcinoma of the thyroid--a multivariate survival analysis.

AIMS: Multivariate studies of the diagnosis, treatment and prognosis of patients with follicular carcinoma of the thyroid gland are relatively scarce. The aim of our multivariate analysis was to study the factors associated with survival of patients with follicular carcinoma in Slovenia, in an iodine-deficient region. METHODS: This retrospective study was carried out in a group of 154 patients (113 women, 41 men; median age 61 years) with follicular carcinoma of the thyroid treated at the Institute of Oncology in Ljubljana between 1972-1992. Data on patient gender, age, disease history, extent of disease, morphological characteristics, mode of therapy and survival were collected. Statistical correlations between possible prognostic factors and survival were analysed by univariate and Cox's multivariate analysis. RESULTS AND CONCLUSIONS: The 10-year survival of the 154 patients was 60%. Multivariate analysis showed that tumour differentiation, primary tumour size, vascular invasion, distant metastases, regional lymph-node metastases, histological tumour type and age were independent prognostic factors for survival. The best prognosis was found in patients with well-differentiated T1 or T2 tumours, without extensive vascular invasion, without distant or regional metastases and aged under 46 years. Patients with Hürthle-cell type carcinomas had better prognosis than those with the follicular type. The worst prognosis was found in patients with poorly differentiated T4 tumours, with extensive vascular invasion, with distant or regional metastases and aged over 60 years.

Anaplastic thyroid carcinoma in fine needle aspirates.

OBJECTIVE: To analyze the diagnostic problems with fine needle aspiration biopsy in anaplastic thyroid carcinoma (ATC) and to describe the cytomorphologic characteristics in 113 cases. STUDY DESIGN: A retrospective analysis of 113 fine needle aspirates and 67 surgical specimens from 113 patients with ATC admitted to the Institute of Oncology, Ljubljana, in 1972-1992. RESULTS: In a series of 113 fine needle aspirates of ATC, 3 (2.7%) were inadequate, 3 (2.7%) suboptimal and 107 (94.7%) diagnostic of malignancy. On reexamination, 96/107 (89.7%) were diagnosed as ATC, 6 (5.6%) as differentiated thyroid carcinoma, and 5 (4.6%) as a malignant tumor not otherwise specified. As to the predominant cell population, fine needle aspirates showed three different cell patterns: (1) pleomorphic cell (43 cases), (2) round cell (33 cases), and (3) spindle cell pattern (7 cases). In the present retrospective analysis we identified three main reasons for inadequate or nonrepresentative fine needle aspiration biopsy sampling: (1) tumor regressive changes (necrosis, hemorrhage, leukocytic infiltration), (2) extensive tumor fibrosis, and (3) distinct differentiated and anaplastic patterns in the same tumor. CONCLUSIONS: The major diagnostic problem with fine needle aspiration biopsy (FNAB) of ATC is related to sample quality. Cytomorphologic features of ATC are highly specific and easy to recognize. Due to the simple technique and high diagnostic accuracy, FNAB is the method of choice in patients with ATC.

Results of combined modality treatment in poorly differentiated and anaplastic thyroid carcinoma.

From 1973-1989 34 patients with poorly differentiated primarily inoperable and 89 with anaplastic giant-cell thyroid tumours entered a study on individualized multimodal treatment. The aim of the study was to find an effective, non-aggressive chemotherapy (ChT) and explore the possibility of individualized combined treatment. Infusions of low doses of vinblastine or cisplatinum or adriamycin or novantrone were used for perturbation of cellular kinetics in the tumours. Sequential fine-needle aspiration biopsies of tumours were performed for monitoring the drug-induced changes in tumour cells and for cytomorphological studies and DNA measurements, on the basis of which ChT was individualized. During the period of accumulation of cells in the S or G2 + M phases, drugs particularly effective in the respective phases were used. The same principle was used in planning a combination of ChT and irradiation. In the group of poorly differentiated carcinomas only 5/34 patients had MR to ChT. In 17/34 patients after ChT the tumour was removed surgically, 19/34 have NED 11+ to 72+ months after treatment. The results in 89 patients with anaplastic carcinoma are worse: 13/89 patients died before or at the beginning of treatment, of 77 treated patients only 10 could be operated on, 7 survived for more than one year (13+ to 72+ months). Only 1/77 patients survived for more than 5 years. A combination of DNA measurements and cytomorphological studies is a useful method for the understanding of tumour behaviour under treatment.