Lennart Bondeson

Histopathological Variables and Dna Cytometry in Parathyroid Carcinoma

To undertake an evaluation of histopathological variables in parathyroid carcinoma, 95 cases with this diagnosis were collected from 37 hospitals. Two tumor categories emerged from a review of tissue sections and follow-up information: 56 cases demonstrating extraglandular invasiveness or tumor recurrence were classified as definitive carcinomas, whereas 39 tumors lacking these criteria were classified as equivocal cases. Several morphological variables other than invasiveness differed between the two groups: Fibrosis, necrosis, nuclear atypia (especially macronucleoli), and mitotic figures were significantly more frequent in the carcinoma group. These variables also showed a positive correlation with an aberrant DNA pattern demonstrated by image cytometry. The triad macronucleoli, more than five mitoses per 50 high-power fields, and necrosis were associated with an aggressive behavior in terms of recurrent disease. A minority of the carcinomas had a bland cytologic appearance and differed from benign lesions only by their invasiveness. Certain patterns of fibrosis and necrosis were common but neither pathognomonic nor constant features of malignancy. Mitotic activity constituted a prognostic risk factor but was of limited diagnostic significance. In half of the carcinomas, the frequency of mitoses did not exceed values recorded in benign parathyroid lesions.

Chromosome studies in thyroid neoplasia

Cytogenetic studies in thyroid neoplasia were performed by G‐banding of chromosome preparations obtained from the in vitro cultures of nine adenomas, one follicular carcinoma, five papillary carcinomas, and two medullary carcinomas. Complex structural chromosome aberrations were found in one adenoma. Two more adenomas, both composed of Hürthle cells, showed multiple numerical chromosome deviations with trisomy 4 and tetrasomy 7 in common. Six metastasizing carcinomas were characterized by normal stemlines, which indicates that malignancy in thyroid neoplasia cannot be excluded by cytogenetic techniques used currently. Comparisons between cytogenetic findings and cytophotometric DNA measurements in the material studied illustrate that euploid tumors represent a heterogenous group including cases with various gross structural chromosome aberrations of yet unknown clinical significance. Further studies of additional material with long‐term follow‐up are called for by our findings of structural and numerical chromosome aberrations in follicular neoplasms that are benign according to histologic criteria.

Oxyphil tumors of the thyroid: follow-up of 42 surgical cases.

Histopathologic and clinical follow-up data on 42 patients observed 2-20 years after operations for oxyphil neoplasms of the thyroid are presented. In eight patients histologic signs of malignancy were found but only two patients showed a clinically malignant course with development of distant metastases. The results do not indicate that oxyphil thyroid neoplasms are especially prone to assume a malignant course with the mode of treatment applied. Our policy is to remove any differentiated epithelial thyroid neoplasm with at least lobectomy. Total thyroidectomy is reserved for cases with capsular penetration, blood vessel invasion and/or metastases.

Serum levels of vitamin D, PTH and calcium and breast cancer risk-a prospective nested case-control study.

Previous studies indicate that calcium and its regulating hormones, i.e., parathyroid hormone (PTH) and vitamin D, might affect breast cancer risk. Evidence also suggests that this relationship could be influenced by menopausal status and BMI. We examined breast cancer risk related to prediagnostic serum levels of vitamin D (25OHD2 and 25OHD3), PTH and calcium using a nested case–control design within the Malmö Diet and Cancer Study. There were 764 incident breast cancer cases, and 764 controls were selected by incidence density matching, using age as the underlying time scale, matching on calendar time at inclusion, menopausal status and age at inclusion. Using logistic regression analysis, odds ratios (OR) with 95% confidence intervals were calculated for breast cancer risk in different quartiles of the analyzed factors. All analyses were adjusted for risk factors for breast cancer, and for levels of albumin, creatinine and phosphate. Analyses were repeated stratified for BMI and menopausal status, and for low vs. high levels of 25OHD3, PTH and calcium. There was a weak, nonsignificant inverse association between breast cancer risk and 25OHD3, and the OR for the 2nd, 3rd and 4th quartiles, as compared to the first, were 0.84 (0.60–1.15), 0.84 (0.60–1.17) and 0.93 (0.66–1.33). Serum calcium was positively associated with breast cancer in premenopausal women (OR for the 4th quartile = 3.10:1.33–7.22 and p for quartile trend = 0.04), and in women with BMI > 25 (OR for the 4th quartile = 1.94:1.12–3.37 and p for trend < 0.01). There was no association between baseline serum PTH and breast cancer risk.

Smoking associated with hormone receptor negative breast cancer

Women who smoke have less favourable prognosis following breast‐cancer diagnosis. Some studies suggest that this is due to a more advanced stage at diagnosis, on average. Our present aim was to assess whether smoking is associated with other prognostic markers as well, e.g., hormone receptor status, histopathology and tumour differentiation. The evaluation was based on 268 incident cases in a cohort of 10,902 women (35% smokers) followed for an average of 12.4 years. An immunohistochemical method on recuts of tumour tissue was used to assess hormone receptor status. One pathologist classified all tumours according to the WHO system, Nottingham grade and Nottingham Prognostic Index. The relative risk (RR) of oestrogen receptor‐negative tumours was, for current smokers, 2.21 [95% confidence interval (CI) 1.23–3.96] and, for ex‐smokers, 2.67 (95% CI 1.41–5.06) compared to never‐smokers. Ex‐smokers had an increased risk of progesterone receptor‐negative tumours (RR = 1.61, 95% CI 1.07–2.41), but there were no other significant associations between smoking habits and oestrogen receptor‐positive or progesterone receptor‐positive or ‐negative tumours. The incidence of Nottingham grade III tumours was higher in ex‐smokers than in never‐smokers (RR = 2.03, 95% CI 1.17–3.54). In terms of histopathological type or Nottingham Prognostic Index, there were no significant differences between smoking groups. We conclude that smoking is associated with an increased occurrence of hormone receptor‐negative tumours.

Frequent rearrangements of chromosomes 1, 7, and 8 in primary liver cancer

Fifteen primary liver carcinomas (PLCs), including 12 hepatocellular carcinomas and three cholangiocellular carcinomas, were investigated cytogenetically after short‐term culture. Ten tumors displayed clonal chromosomal abnormalities, whereas only normal karyotypes were detected in four cases, and one sample failed to grow in vitro. Structural rearrangements most often involved chromosomes 1, 7, and 8 and chromosome bands 1p36, 1q25, 3q10, 5q13, 6p10, 7p15, 7q22, 7q32, 8q10, 8q13, 14q10, and 17p11. Frequent genomic imbalances included gains of 1q, 3q, 6p, 7p, and 8q and losses of 1p, 8p, 10q, 14p, 17p, and 19p. A compilation of findings for all 19 cytogenetically abnormal PLCs reported to date, including the present cases, reveals that structural aberrations particularly affect 1p11, 1p22, 1p32, 1p34, 1p36, 1q25, 7p15, 7q22, 8q10, 8q13, 14q10, 16q24, and 17p11, and that the abnormalities frequently result in overrepresentation of 1q, 3q, 6p, 7p10–14, 8q, and 17q and underrepresentation of 1p34–36, 6q27, 7q32–qter, 8p, 13p, 14p, 16q24, and 17p. These genomic regions are likely to harbor genes of importance in hepatocarcinogenesis, and the present cytogenetic mapping may hence be of value for further molecular genetic investigations of PLC. Genes Chromosomes Cancer 23:26–35, 1998.

Increased incidence of small and well-differentiated breast tumours in post-menopausal women following hormone-replacement therapy

Exposure to hormone‐replacement therapy (HRT) has consistently been associated with an increased incidence of breast cancer, particularly of small tumours. Other tumour characteristics in relation to HRT have received less scientific attention. Our aim in this population‐based prospective cohort study was to assess whether HRT is associated with an increased incidence of breast‐cancer subgroups defined in terms of stage, type (according to the WHO system), Nottingham grade and the Nottingham Prognostic Index (NPI). Evaluation was based on a cohort of 5,865 post‐menopausal women followed for an average of 9.8 years. Twenty percent of women reported current use of HRT at the time of the baseline interview. Record linkage with the Swedish Cancer Registry and local clinical registries identified 141 incident invasive breast‐cancer cases. All tumours were reclassified by 1 pathologist. The incidence of breast cancer in HRT users was 377/105 and in non‐users 221/105 person‐years [relative risk (RR) = 1.72, 95% confidence interval (CI) 1.17–2.52]. This risk remained statistically significant after adjustment for established risk factors in a Cox proportional hazards analysis (RR = 1.66, 95% CI 1.12–2.45). Among HRT users, there was over‐representation of cases with stage I tumours (adjusted RR = 2.33, 95% CI 1.44–3.76), of lobular carcinomas (RR = 4.38, 95% CI 1.60–12.0) and of tubular tumours (RR = 4.81, 95% CI 1.37–16.8). Nottingham grade I/II carcinomas (RR = 2.02, 95% CI 1.29–3.16) and cases with NPI ≤ 3.4 (RR = 2.29, 95% CI 1.41–3.72) were similarly over‐represented among HRT users. Incidence of breast cancer was increased in post‐menopausal women who used HRT at baseline. Among HRT users, there was over‐representation of tumours that, with regard to stage, type and grade, are associated with a favourable prognosis.

Prospectively measured triiodothyronine levels are positively associated with breast cancer risk in postmenopausal women

IntroductionThe potential association between hypo- and hyperthyroid disorders and breast cancer has been investigated in a large number of studies during the last decades without conclusive results. This prospective cohort study investigated prediagnostic levels of thyrotropin (TSH) and triiodothyronine (T3) in relation to breast cancer incidence in pre- and postmenopausal women.MethodsIn the Malmö Preventive Project, 2,696 women had T3 and/or TSH levels measured at baseline. During a mean follow-up of 19.3 years, 173 incident breast cancer cases were retrieved using record linkage with The Swedish Cancer Registry. Quartile cut-points for T3 and TSH were based on the distribution among all women in the study cohort. A Coxs proportional hazards analysis was used to estimate relative risks (RR), with a confidence interval (CI) of 95%. Trends over quartiles of T3 and TSH were calculated considering a P-value < 0.05 as statistically significant. All analyses were repeated for pre- and peri/postmenopausal women separately.ResultsOverall there was a statistically significant association between T3 and breast cancer risk, the adjusted RR in the fourth quartile, as compared to the first, was 1.87 (1.12 to 3.14). In postmenopausal women the RRs for the second, third and fourth quartiles, as compared to the first, were 3.26 (0.96 to 11.1), 5.53 (1.65 to 18.6) and 6.87 (2.09 to 22.6), (P-trend: < 0.001). There were no such associations in pre-menopausal women, and no statistically significant interaction between T3 and menopausal status. Also, no statistically significant association was seen between serum TSH and breast cancer.ConclusionsThis is the first prospective study on T3 levels in relation to breast cancer risk. T3 levels in postmenopausal women were positively associated with the risk of breast cancer in a dose-response manner.

Fat staining in parathyroid disease—Diagnostic value and impact on surgical strategy: Clinicopathologic analysis of 191 cases

The study comprised 191 cases of surgically treated hyperparathyroidism, with all principal types of parathyroid disease represented. At least two complete glands stained with a modified isopropanol oil red O method for fat, in addition to sections stained with hematoxylin-eosin, were available in each case. On the basis of the morphologic evaluation and the clinical follow-up data, it is concluded that access to two complete glands and the use of fat staining allow highly reliable intraoperative distinction between adenoma and hyperplasia. Of 105 patients followed up for at least one year (mean, 20 months) in whom adenomas were diagnosed, a single possible error was identified. In each of 68 cases classified as hyperplasia on the basis of two abnormal glands, every additional complete gland available (total, 182 glands) was at least partially abnormal, with distinct signs of hyperactivity, irrespective of size. The rate of equivocal findings for cases in which two glands were available (probably adenoma but hyperplasia not excluded) was 8 per cent in 165 cases of primary hyperparathyroidism. These results justify limitation of surgery to one side of the neck in patients in whom adenoma is diagnosed on the basis of a complete, functionally normal (inactive) gland in addition to the presumed adenoma. Thus, the methods described provide a basis for optimal utilization of imaging techniques that allow preoperative localization of parathyroid adenomas.

Surgical strategy in hyperparathyroidism due to solitary adenoma.

Based on the postulate that parathyroid adenoma is practically always a solitary lesion, unilateral parathyroidectomy including the homolateral normal parathyroid was applied as a principle in the treatment of this form of primary hyperparathyroidism. The exploration was confined to the adenoma side if this was the first to be explored. Intraoperative oil-red-O staining of frozen sections was used to exclude the possibility of a multiglandular involvement. This principle was applied in a consecutive series of 102 patients operated for hyperparathyroidism from 1977 to 1981 and diagnosed as parathyroid adenoma. In 43 patients where the abnormal gland was found on the side explored first, unilateral parathyroidectomy was performed on that side, avoiding exploration of the contralateral side. In 45 patients where normal glands were found on the side first explored, unilateral parathyroidectomy was performed on the contralateral side. In 14 patients other types of operations were performed as the above-mentioned principle could not be achieved. At follow-up 1 to 5 years after surgery, no cases of hypocalcemia were recorded. The results of the different operations were compared as to early and late hypocalcemia. Early hypercalcemia was more pronounced after a bilateral exploration. Two of the patients who had an atypical operation had a permanent need for vitamin D in order to maintain an adequate serum calcium level. Surgical principles for various possible exploratory findings are outlined. These are based upon the idea of performing a unilateral parathyroidectomy whenever intraoperative oil-red-O staining excludes multiglandular involvement as a cause for the hyperparathyroidism.