Service screening mammography reduces breast cancer mortality among elderly women in Turku.

OBJECTIVES: The aim of this study was to assess the effects of service screening mammography on breast carcinoma incidence and refined mortality among women aged 55-69 at entry in three cities employing different screening policies. METHODS: Since 1987, the city of Turku, Finland, has provided service screening mammography for women aged 55-69 at entry (in 1987), and Tampere provided screening for women aged 55-59 at entry, whereas Helsinki did not screen any of these age groups. The incidence of breast carcinoma during the screening period 1987-97 in women born in 1918-32 (1918-22, 1923-27, 1928-32) was compared with incidence during the pre-screening period 1976-86 in women born in 1907-21 (1907-11, 1912-16, 1917-21) in each city. The follow-up for mortality was four years longer. RESULTS: Breast carcinoma incidence was 31-38% higher in the screening period in all three cities irrespective of screening. In breast carcinoma mortality, no significant changes were seen in Helsinki or Tampere. In Turku, a 36% mortality reduction (relative risk [RR] 0.64; 95% confidence interval [CI] 0.47-0.88; P=0.007) in the whole study population and a 47% reduction in women aged 65-69 at entry (RR 0.53; 95% CI 0.28-0.99; P=0.047) were seen. CONCLUSIONS: The incidence of breast carcinoma increased in all study cities irrespective of screening. The comprehensive screening programme in Turku including women aged 55-69 at entry was associated with a significant reduction in breast carcinoma mortality. The pronounced decrease in mortality in the oldest age group (65-69 years at entry) also indicated that women of this age group greatly benefit from mammography screening.

A missense mutation in the BRCA2 gene in three siblings with ovarian cancer.

Inherited susceptibility to ovarian cancer has been associated with germline defects at several loci. The major known ovarian cancer susceptibility gene is BRCA1 on chromosome 17q, which confers a risk of approximately 60% by the age of 70 years. Truncating mutations in BRCA2 on chromosome 13q also predispose to ovarian cancer, although they confer a lower risk than mutations in BRCA1. We have studied the molecular basis of ovarian cancer predisposition in a Finnish family with three affected sisters. Analysis of polymorphic markers provided evidence against linkage to BRCA1, but the sibship was consistent with linkage to BRCA2. Conformation-sensitive gel electrophoresis was used to screen the entire coding sequence of BRCA2. A G to A transition at nucleotide 8702 was observed, which is predicted to convert glycine 2901 to aspartate in the encoded protein. This sequence variant was not detected in 220 cancer-free Finnish control individuals, or in several hundred cancer families of many nationalities previously screened for BRCA2 mutations. Taken together with the fact that this amino acid residue and the surrounding region of BRCA2 is identical in mouse and chicken, the data suggest that this alteration is a disease-causing BRCA2 missense mutation. Previously published data indicate that the risks of breast and ovarian cancer conferred by BRCA2-truncating mutations varies with the position of the mutation in the gene. The missense mutation reported here suggests that the BRCA2 domain including and surrounding glycine 2901 may be more important in preventing neoplastic transformation in ovarian epithelium than in breast epithelium.

Assessment of cervical lymph node status in head and neck cancer patients: palpation, computed tomography and low field magnetic resonance imaging compared with ultrasound-guided fine-needle aspiration cytology.

OBJECTIVE: Since the assessment of lymph node metastases in head and neck cancer patients remains a major problem, the findings of different imaging methods and the role of these methods in the clinical management are compared. MATERIAL AND METHODS: Palpation, computed tomography (CT) and low field magnetic resonance imaging (MRI; 0.1 T) are evaluated and compared with ultrasound-guided fine-needle aspiration cytology (US-guided FNAC) prospectively in 105 consecutive patients with a primary cancer in the head and neck region. RESULTS: In the subgroup of 86 patients with palpable normal necks, CT showed lymph nodes fulfilling the radiologic criteria for malignancy in 27% (23/86), MRI in 17% (10/60) and US in 14% (12/86) of the patients US guided FNAC usually showed malignancy in necks containing lymph nodes with central necrosis on CT, but the enlarged lymph nodes that were also common on the contralateral side were often benign on cytology. In 5 patients, FNAC under US-guidance showed malignancy although none of them had lymph nodes fulfilling the radiologic criteria for malignancy. In the other subgroup of 19 patients with palpable metastatic necks, 2 patients had bilateral metastases detected by all imaging methods but not by palpation. CONCLUSION: CT is superior to low field MRI in depicting small pathologic lymph nodes. Unlike lymph node structure, lymph node size is not a highly reliable criterion for malignancy. The findings must be correlated in relation to the primary disease. Since FNAC under US-guidance offers additional information about enlarged lymph nodes and since it can show malignancy in small lymph nodes not found by other methods, it can be recommended for most head and neck cancer patients irrespective of the use of CT or MRI.

Mammography screening interval and the frequency of interval cancers in a population-based screening.

In a population-based mammography screening, 129,731 examinations were carried out among 36,000 women aged 40-74 in the city of Turku, Finland, in the period 1987-94. Women older than 50 were screened at 2-year intervals, and those younger than 50 at either 1-year or 3-year intervals, depending on their year of birth. Screen-detected breast cancers numbered 385 and, during the same time period, 154 women were diagnosed with breast cancer outside screening in the same age group in the same city, and 100 interval cancers were detected. Two hundred and fifty (67%) of the screen-detected cancers were of post-surgical stage I compared with 45 (45%) of the interval cancers and 52 (34%) of the cancers found outside screening (P<0.0001). However, among women aged 40-49 the frequency of stage I cancers did not differ significantly among screen-detected cancers, interval cancers and cancers found outside screening (50%, 42% and 44% respectively; P=0.73). Invasive interval cancers were more frequent among women aged 40-49 if screening was done at either 1-year (27%) or 3-year intervals (39%) than in older women screened at 2-year intervals (18%; P=0.08 and P=0.0009 respectively). Even if adjusted for the primary tumour size, screen-detected cancers had smaller S-phase fractions than interval cancers or control cancers (P=0.01), but no difference in the S-phase fraction size was found between cancers of women younger than 50 and those older than this (P=0.13). We conclude that more interval cancers were found among women younger than 50 than among those older than 50 and that this could not be explained by the rate of cancer cell proliferation.

Prediction of survival with fluorine-18-fluoro-deoxyglucose and PET in head and neck cancer.

UNLABELLED: The aim of this prospective study was to investigate if high uptake of 18F-fluoro-2-deoxy-D-glucose (FDG) is associated with aggressiveness in head and neck cancer and low probability of survival. METHODS: Thirty-seven patients with squamous-cell carcinoma of the head and neck underwent FDG-PET in the fasting state before cancer treatment. FDG uptake in primary tumor was quantitated as the standardized uptake value of FDG normalized to the predicted lean body mass (SUVlean, n = 37) and as the graphically determined metabolic rate for FDG (rMR[FDG], n = 34). Paraffin-embedded tumor samples were used for histologic evaluation, and expression of cytokeratin and Ki-67 antigen were assessed by immunohistochemistry. RESULTS: Interobserver agreement for the determination of quantitative uptake of FDG in tumors was excellent (r2 = 0.996, p < 0.00001), and all 37 primary tumors were visualized. A high uptake of FDG as assessed by SUVlean was associated with a higher than the median mitotic count (p = 0.01), absence of keratinization (p = 0.03), low or moderate histological grade of differentiation (p = 0.046) and advanced stage (p = 0.03), but not with Ki-67 expression (p = 0.11). The overall survival of patients with a SUVlean lower than or equal to the median value (9.0) was clearly better in univariate analysis than that of patients with a SUVlean higher than the median (3-yr survival 73% versus 22%, relative risk of death (RR) 4.2, 1.6-11.0). However, in a multivariate analysis the only independent predictors of survival were the mitotic count (RR 4.0, 1.4-11.7) and stage (3.8, 1.2-12.2). CONCLUSION: High uptake of FDG in untreated head and neck cancer is associated with advanced disease, and may portend poor survival. Aggressive treatment approaches should be considered for patients presenting with a tumor with high uptake of FDG.

PAP smear after radiation therapy for cervical carcinoma.

Vaginal PAP smear is frequently used for the follow-up of cervical carcinoma after primary therapy. Irradiation induced atypia can interfere with cytological analysis and thus detection of a local recurrence, or simulate malignant atypia and cause unnecessary suspicion of recurrence. In this retrospective study we evaluated the reliability of cytological analysis and the reported frequency of irradiation induced atypia after radiotherapy. Eighty-nine patients treated for cervical carcinoma at Turku University Central Hospital during the years 1970-88 were included in the study. During the median follow-up of 34 months a total of 697 PAP smears were taken with a median of 7.8 samples per patient. During the follow-up 44 (50%) patients had a recurrent disease, which was local in 17 (39%) cases. Nine out of 12 PAP smears taken 0-60 days before detection of a local recurrence showed class III-V cellular atypia. However, three PAP smears showed class I-II, and were therefore false negative. The rate of false positive samples was only 3%. In 567 PAP smears irradiation induced atypia was indicated as present/not present (+/-) and it was positive in 89 (16%) samples. The detection rate was considerably higher (75%) in class II samples than in rest of the material. Irradiation induced atypia was detected in 28% of the PAP smears taken during the first four months after radiotherapy and the rate decreased thereafter. Cytological analysis of vaginal PAP smear was a reliable indicator of recurrence in most cases and is a valuable tool for the detection of local recurrence of cervical carcinoma after primary radiotherapy.

Palpation, ultrasound, and ultrasound-guided fine-needle aspiration cytology in the assessment of cervical lymph node status in head and neck cancer patients.

BACKGROUND: Lymph node status of the neck is the most important prognostic factor in head and neck cancer patients. Assessment of the lymph nodes status is still often based on palpation only, although the low accuracy of palpation is known. METHODS: Altogether 105 consecutive head and neck cancer patients were examined using ultrasound (US) and ultrasound-guided fine-needle aspiration cytology (FNAC) to evaluate the additional information obtained by these methods. RESULTS: Of the 86 patients with palpable normal necks, FNAC taken under US-guidance showed malignancy in 13. The US size criteria for malignancy were fulfilled in 7 of these patients, whereas the lymph nodes were of normal size in 6 of them. In the whole patient material, US-guided FNAC showed bilateral metastasis in 3 patients although only unilateral or no metastasis was found by palpation. CONCLUSION: US combined with US-guided FNAC can be recommended as a method for evaluating for regional metastases in head and neck cancer patients, both for those with and those without palpable metastasis.

Fine-needle aspiration biopsy in the diagnosis of parotid gland lesions: evaluation of 438 biopsies.

The usefulness of fine-needle aspiration biopsy (FNAB) in the diagnosis and treatment of salivary gland lesions is still controversial. The 438 FNABs taken at the Turku University Central Hospital between 1984-1991 were reviewed. Of these FNABs, 218 had been confirmed histologically. Within this subset, 136 FNABs were taken from benign neoplasms, and of these, 103 were correct (sensitivity 76%, specificity 83%). Only 26 of the 47 FNABs from malignant lesions were cytologically considered to be malignant (sensitivity 55%) and 11 samples raised a false suspicion of malignancy (specificity 92%). Out of 35 FNABs from non-neoplastic lesions, 27 were correct (sensitivity 77%, specificity 80%). There were 175 patients (217 FNABs), who had not been operated on: the follow-up of these patients showed that false malignant and false benign findings were rare. FNAB was safe and no serious complications occurred. However, there was a delay in the treatment of six patients probably because of the physicians' limited understanding of the diagnostic role of FNAB. FNAB offers valuable information about the type of parotid lesion, but the clinician must know how to interpret the cytologic statement, and the decision to use operative and other treatment should not be based solely on the result of FNAB. Diagn Cytopathol 1996; 15:185-190.

Increased glucose metabolism in untreated non-Hodgkin's lymphoma: a study with positron emission tomography and fluorine-18-fluorodeoxyglucose.

Glucose metabolism has been shown to be increased in neoplastic tissue. It has been suggested that high activity of glucose metabolism is associated with a high grade of malignancy of human cancer. We studied in vivo glucose metabolism in 22 patients with untreated non-Hodgkin's lymphoma with fluorine-18-fluorodeoxyglucose (FDG) and positron emission tomography (PET). FDG uptake in lymphoma deposits was measured blinded to clinical data, and compared with histologic classification and proliferative activity. Tracer uptake was measured by using two indices of FDG accumulation: the standardized uptake value (SUV) and the regional metabolic rate (rMR) for the tracer. The median SUV of the lymphomas was 8.5 (range, 3.5 to 31.0), and the median rMR 22.7 mumol/100 g/min (range, 9.0 to 124.3 mumol/100 g/min). A high FDG uptake in tumors was associated with high histologic degree of malignancy as defined by the Working Formulation (P = .005 for the SUV, and P = .04 for the rMR) or by the Kiel classification (P = .003 for the SUV, and P = .02 for the rMR). A high FDG accumulation was also associated with a high S-phase fraction (r = .786 for the SUV, P = .0002; and r = .774 for the rMR, P = .02). We conclude that in untreated non-Hodgkin's lymphomas high FDG uptake is associated with high histologic grade of malignancy and a high proliferation rate. This minimally invasive method may find application in assessing lymphoma lesions in patients who are poor candidates for surgery, and it may provide further information in cases where the grade of aggressiveness of lymphoma is not settled based on clinical or histologic data.

p53 protein detected by immunohistochemistry as a prognostic factor in patients with epithelial ovarian carcinoma.

BACKGROUND: The clinical significance of p53 suppressor gene nucleoprotein immunostaining in ovarian epithelial cancer has not been determined. METHODS: p53 protein expression was studied by immunohistochemistry from paraffin embedded tissue in a series of 136 patients with malignant ovarian epithelial tumors. The median follow-up time of the patients still alive was 10 years. RESULTS: Sixty (44%) carcinomas stained clearly positive for p53 protein. Positive staining for p53 protein was associated with the serous histologic type (P = 0.0006), a higher than the median S-phase fraction size determined by DNA flow cytometry (P = 0.02), and poor histologic grade of differentiation (P = 0.04), but not with the International Federation of Gynecology and Obstetrics (FIGO) stage, age at diagnosis, or DNA ploidy. Cancers with positive staining had only 17% 5-year and 9% 15-year survival rates compared with 42% 5-year and 36% 15-year survival rates corrected for intercurrent deaths among the rest of patients (P = 0.002). In a multivariate analysis, positive p53 staining was associated with poor survival (relative risk of death, 1.8, 95% confidence interval [CI], 1.2-2.9) together with less than radical surgery (nonradical vs. radical: RR, 5.5; 95% CI, 2.2-13.6), and advanced FIGO stage (RR, 1.4; 95% CI, 1.0-2.0). CONCLUSION: Although p53 protein immunostaining is associated with several other prognostic factors in epithelial ovarian cancer, it may also have independent prognostic value in this disease.

Fine-needle aspiration cytology of submandibular gland lesions.

The usefulness of fine-needle aspiration cytology (FNAC) in the diagnosis and treatment of submandibular gland lesions is not well known. The 210 FNACs taken from submandibular gland lesions at Turku University Central Hospital between 1984 and 1991 were reviewed. Of these FNACs, 78 samples from primary lesions were confirmed histologically. Within this subset 10 FNACs were taken from benign neoplasms, all of which were correctly classified (sensitivity 100 per cent; specificity 88 per cent). Only four of the 14 FNACs from malignant lesions were cytologically considered malignant (sensitivity 29 per cent). On the other hand, four FNACs raised a false suspicion of malignancy (specificity 6 per cent). Out of 54 FNACs from non-neoplastic lesions 43 were correct (sensitivity 80 per cent; specificity 63 per cent). There were 104 patients (123 FNACs), who had not been operated on: the follow-up of these patients shows that in this subset of FNACs there were no false malignant but probably one false benign finding (1 per cent). We conclude that FNAC can offer valuable information about the type of the submandibular gland lesion, but the decision of operative and other treatment should not be based solely on the result of FNAC.

The subrenal capsule assay in selecting chemotherapy for ovarian cancer: a prospective randomized trial.

In order to find out whether the response rate and survival in epithelial ovarian cancer can be improved by aid of sensitivity testing with the subrenal capsule assay (SRCA), 196 patients with FIGO Stage II-IV epithelial ovarian cancer were randomized to be treated with either cyclophosphamide-doxorubicin-cisplatin (CAP) or SRCA-guided chemotherapy. The drug combinations tested with the SRCA were (1) cyclophosphamide-doxorubicin-carboplatin (CACAR), (2) CAP, (3) carboquone-methotrexate-tegafur (CQ-MTX-TEG), (4) cisplatin-etoposide-hexamethyl-melamine (P-VP-HXM), and (5) bleomycin-epirubicin-cisplatin (BEP). A total of 132 patients (CAP, 69; SRCA, 63) were eligible for efficacy analysis based on relaparotomy findings. The overall response rate was 59% in the CAP arm and 62% in the SRCA arm. In the SRCA arm, 16 patients were treated with CACAR, 24 with CAP, 10 with CQ-MTX-TEG, 11 with P-VP-HXM, and 2 with BEP. The response rate to CACAR was 63% and to SRCA-CAP was 75%. The number of complete responses was higher when CAP was given as guided by the assay than when given at random (14/24 vs 23/69; P = 0.03, Pearson chi 2). Survival curves as estimated by Kaplan-Meier method gave a median survival of 24 (SE = 4) months to the SRCA arm and 28 (SE = 5) for the CAP arm (P = 0.7; log-rank test). Because no survival benefit was achieved, the SRCA obviously needs further development before it can be routinely recommended in the choice of first-line chemotherapy for patients with ovarian cancer.

Detection of malignancy in endometrium by brush sampling in 1042 symptomatic patients.

Endometrial brush samples were taken from 1042 symptomatic hospital patients using Uterobrush(R), and the results were compared either to the histology of the endometrium obtained with dilatation and curettage (n = 313) or the patients' follow-up (n = 729). Only one cancer (100%) among patients 51 years of age (n = 365), 11 (91.7%) were detected by Papanicolaou classes III-V. One cancer was missed, whereas no false positive results were found. The diagnostic accuracy in this group of patients varied from 92.3% to 97.8%, depending on the group (true positive vs true negative) to which the Papanicolaou class III was placed. We conclude that endometrial cytology obtained by brushing is useful for symptomatic patients of all age groups and gives an indication for further examination. If cytology is normal and bleeding continues in postmenopausal patients, curettage is indicated.

The role of cul-de-sac aspiration cytology in the follow-up of ovarian cancer.

The methods most often used for follow-up of ovarian cancer are physical examination, CA-125 measurement and ultrasonography or computed tomography. In the present study the role of cul-de-sac aspiration cytology as a supplementary method was evaluated. We analyzed the records of 110 stage I-IV ovarian cancer patients who had undergone cul-de-sac aspiration as a part of their follow-up schedule after the primary treatment. During the median follow-up of 5 years altogether 577 cul-de-sac aspirations were performed with a median interval of 9 months. Only in 2 cases the obtained sample was insufficient for evaluation. Twenty patients had cul-de-sac cytology > or = class III at some point during the follow-up. In 12 cases the preceding or subsequent CA-125 values taken within 3 months were < 35 U/l. In 7 cases CA-125 values increased later, but in 5 cases the tumour marker values remained within normal range during the entire follow-up. Nine out of these 12 patients had a clinical recurrence later on, but 3 patients had no evidence of the disease. Twenty-seven recurrences were detected during the follow-up. Cul-de-sac aspiration cytology was the first or the only indication of recurrence in 9 cases (33%) and is a useful supplementary method in the follow-up of ovarian cancer.

Aneuploidy in salivary gland adenomas.

The occurrence of abnormal nuclear DNA content in major salivary gland adenomas is not well known and its correlation with tumor recurrence has not been documented previously. From 1987 to 1991, 119 consecutive major salivary gland adenomas were operated on at Turku University Central Hospital. These tumors were analyzed by flow cytometry and 100 (84%) were found to be diploid, 12 (10%) near-diploid and 7 (6%) aneuploid with DNA indexes > 1.15. The mean proliferation rate measured as a percentage of cells in the S-phase fraction was 2.5 +/- 1.6%. The histological slides were then blindly reclassified according to current World Health Organization classification. As a result histological classification was changed in 3 tumors: malignant cells were found in 2 aneuploid tumors and 1 diploid neoplasm. Preoperative cytological fine-needle aspiration biopsy had been considered as possibly malignant in 2 of these cases. Among all case material 10 specimens were recurrent tumors; although the tendency to recur depended on the extent and adequacy of the surgery performed, multiple recurrences were associated with non-diploid tumors.

p53 protein, PCNA staining, and DNA content in follicular neoplasms of the thyroid gland.

Forty-nine follicular adenomas and 11 follicular carcinomas of the thyroid were investigated by immunohistochemistry for the expression of p53 protein and proliferating cell nuclear antigen (PCNA). The DNA ploidy and the S-phase fraction (SPF) of the neoplasms were analysed by flow cytometry. Twelve adenomas (24 per cent) and six carcinomas (55 per cent) were DNA non-diploid (P = 0.07). The carcinomas had a higher proliferation rate than the adenomas when assessed either by SPF size (median 9.9 per cent vs. 2.9 per cent, P = 0.0003) or by PCNA staining intensity (P < 0.0001). Some scattered nuclei in two (4 per cent) adenomas and in three (27 per cent) carcinomas stained positively for p53 (P = 0.04). The two adenomas with positive staining for p53 were subserially sectioned, but no signs of invasion were found; both patients are alive and well 6 and 7 years after surgery. One of the two adenomas showing positive p53 nuclear staining was DNA aneuploid, and both were positive in PCNA staining, but their SPFs were low (2.1 and 3.3 per cent). We conclude that p53 protein expression is not confined to follicular carcinomas; scattered p53-positive cells may also be present in histologically and clinically benign follicular adenomas. Because both follicular adenomas and carcinomas may be DNA aneuploid and their SPF and PCNA staining distributions overlap, the distinction between follicular adenoma and carcinoma should still be based on histological criteria.

Immunohistochemical detection of p53 protein in borderline and malignant serous ovarian tumors.

The p53 suppressor gene protein expression was studied with immunoperoxidase staining in 61 serous tumors of the ovary. Twenty four (53%) of the 45 histologically malignant tumors were positive for p53, whereas neither the six benign nor the 10 tumors of borderline malignancy showed positive staining, except for one borderline tumor with atypia and increased mitotic activity. Therefore, p53 immunostaining may have diagnostic value in discriminating between borderline and malignant serous ovarian tumors. Malignant ovarian tumors with negative staining for p53 were associated with a 67% 3-year crude survival rate as compared with only an 18% 3-year survival rate if p53 staining was positive (p = 0.002). In a multivariate analysis, the p53 staining was the most important prognostic factor, with a relative risk of 4.2 (95% confidence interval, 1.8-9.9) followed by the FIGO stage (2.1, 1.3-3.5). We conclude that immunohistochemical p53 suppressor gene protein expression analysis has both diagnostic and prognostic value.

Brenner and transitional cell tumours of the ovary. Report of three cases.

Three rare epithelial ovarian tumours, one malignant Brenner tumour, one transitional cell carcinoma and one Brenner tumour of borderline malignancy, are presented with special emphasis on the diagnostic, prognostic and therapeutic modalities. Because the prognosis of transitional cell carcinoma of the ovary is worse, as in our case, than that of the malignant Brenner tumour, this classification is justified.

Basal cell adenocarcinoma of the parotid gland: a case report and review of the literature.

Basal cell adenocarcinoma is a rare salivary gland tumour. A DNA diploid parotid gland basal cell adenocarcinoma, with a low mitotic rate, in a 78-year-old female patient is described. Total removal of the affected salivary gland without sacrificing the facial nerve gave a good therapeutic result.

Glycoprotein CD44 expression and its association with survival in breast cancer.

To investigate the clinical significance of CD44 expression (lymphocyte-homing receptor) in adenocarcinoma, deparaffinized sections from 198 female breast carcinomas were stained with Hermes-3 MoAb for CD44 glycoprotein. In 16% of the cancers most (> or = 90%) of the cancer cells stained positively for CD44, whereas the rest of the cancers were either heterogenous (46%) or negative (38%) in CD44 staining. Cancers with > 50% CD44 positive cells were more often poorly differentiated (grade 3) than those with < or = 50% positive cells (38 vs. 19%, P = 0.006), they had higher mitotic counts (P = 0.04), and were more often estrogen receptor negative (52 vs. 31%, P = 0.01). Among ductal not otherwise specified cancers and node-positive cancers strong CD44 expression was associated with poor outcome (P = 0.05 and 0.02, respectively). However, CD44 expression was not an independent prognostic factor in these subgroups in a multivariate analysis. Unlike in lymphomas the unfavorable prognosis associated with CD44 expression may not be explained by the greater metastatic potential of CD44-positive cells, because the difference in mortality between the groups appeared to diminish with time, and CD44 positivity was associated with aggressive histological features.