Pathology parameters and adjuvant tamoxifen response in a randomised premenopausal breast cancer trial.

BACKGROUND: Subgroups of breast cancer that have an impaired response to endocrine treatment, despite hormone receptor positivity, are still poorly defined. Breast cancer can be subdivided according to standard pathological parameters including histological type, grade, and assessment of proliferation. These parameters are the net result of combinations of genetic alterations effecting tumour behaviour and could potentially reflect subtypes that respond differently to endocrine treatment. AIMS: To investigate the usefulness of these parameters as predictors of the response to tamoxifen in premenopausal women with breast cancer. MATERIALS/METHODS: Clinically established pathological parameters were assessed and related to the tamoxifen response in 500 available tumour specimens from 564 premenopausal patients with breast cancer randomised to either two years of tamoxifen or no treatment with 14 years of follow up. Proliferation was further evaluated by immunohistochemical Ki-67 expression. RESULTS: Oestrogen receptor positive ductal carcinomas responded as expected to tamoxifen, whereas the difference in recurrence free survival between control and tamoxifen treated patients was less apparent in the relatively few lobular carcinomas. For histological grade, there was no obvious difference in treatment response between the groups. The relation between proliferation and tamoxifen response seemed to be more complex, with a clear response in tumours with high and low proliferation, whereas tumours with intermediate proliferation defined by Ki-67 responded more poorly. CONCLUSIONS: Clinically established pathology parameters seem to mirror the endocrine treatment response and could potentially be valuable in future treatment decisions for patients with breast cancer.

Cell biological factors in ductal carcinoma in situ (DCIS) of the breast-relationship to ipsilateral local recurrence and histopathological characteristics.

All cases of ductal carcinoma in situ (DCIS) diagnosed from 1987 to 1991 in the Southern Health Care Region of Sweden, and operated upon with breast conserving treatment (BCT) with (n=66) or without (n=121) postoperative radiation (RT) were clinically followed, morphologically re-evaluated and analysed for cell biological factors (immunohistochemical assays or DNA flow cytometry). Median age at diagnosis was 58 years (range 29--83 years) and median follow-up was 62 months. Oestrogen (ER)- and progesterone receptor (PR)-negativity, c-erbB-2 overexpression, low bcl-2 expression, p53 accumulation, DNA non-diploidy and high Ki67, were strongly associated with high grade DCIS, and comedo-type necrosis. In contrast, significant associations to growth pattern (not diffuse versus diffuse) were seen only for c-erbB-2 and PgR. There was also a strong relationship between the cell biological factors, and a summary cell biological index based on principal component analysis was introduced (CBI-7). In the group that had not received postoperative RT, 31 ipsilateral local recurrences occurred (13 invasive, 18 DCIS). Ipsilateral recurrence-free interval (IL-RFI) was in univariate analyses significantly, or almost significantly, shorter for patients showing p53 accumulation, high Ki67 or low bcl-2, compared with patients with normal p53, low Ki67 and high bcl-2. The prognostic importance of the remaining cell biological factors was less pronounced. On the other hand, the index CBI-7, was a strong predictor for recurrence.

Melanotic neuroectodermal tumour as a predominant component of an immature testicular teratoma. Case report with immunohistochemical investigations.

A case of melanotic neuroectodermal tumour (MNT), or so-called retinal anlage tumour, as a predominant component of an immature testicular teratoma is presented. The patient was a 17-year-old man who furthermore had a mature mediastinal teratoma. The MNT was composed mainly of two cell types: small immature neuroblast-like cells and large columnar or cuboidal epithelial-like cells with or without melanin granules. The tumour cells were arranged in solid formations, nests, cords, alveolar and pseudoglandular structures with cleft-like or glomeruloid-like spaces. Myogenic differentiation was found in minor foci. Immunohistochemistry showed both neuroepithelial and mesenchymal features with positive staining reaction for neuron-specific enolase (NSE), S-100 protein (S-100), melanoma antigen (HMB45), cytokeratin and vimentin. Vimentin, desmin and actin were present in the myoid cells. To the best of our knowledge this is the first reported case of MNT originating in the testis. As this tumour component occurred in an immature teratoma, neuroectodermal differentiation of germ cell origin is considered most likely.

Ipsilateral local recurrence in relation to therapy and morphological characteristics in patients with ductal carcinoma in situ of the breast.

METHOD AND RESULTS: A standardized histopathological protocol has been designed, in which different histological characteristics of ductal carcinoma in situ (DCIS) are reported: nuclear grade (ng), growth pattern according to Andersen et al., necrosis, size of the lesion, resection margins and focality. Using this protocol a re-evaluation of a population-based consecutive series of 306 cases of DCIS has been done as well as a thorough clinical follow-up. After a median follow-up of 63 months, 13% have developed ipsilateral local recurrences, invasive and/or in situ. Ipsilateral local recurrence-free survival (IL-RFS) was significantly better for patients operated with mastectomy (ME) or breast conserving therapy (BCT) with radiotherapy (RT) than for patients operated with BCT without RT (5-year IL-RFS 96% vs 94% vs 79%, P<0.001). In the subgroup of BCT without RT there were significant differences in IL-RFS between histopathological subgroups: ng 1 + 2 (non-high grade) vs ng 3 (high grade; P=0.014), non-high-grade without comedo-type necrosis vs non-high-grade with comedo-type necrosis vs high-grade (the Van Nuys classification system; P=0.025). Growth pattern (not diffuse vs diffuse) and margins (free vs involved or not evaluated) showed a tendency (P=0.07 and 0.05, respectively) to be associated to IL-RFS. In contrast, no significant differences in IL-RFS were found in subgroups based on mode of detection, focality or size. Ninety-four per cent of the local recurrences after BCT appeared at the previous operation site. CONCLUSIONS: In the BCT without RT group, combinations of either non-high grade and not a diffuse growth pattern or non-high grade and free margins identified groups (constituting approximately 30% of the patients) were at low risk of developing ipsilateral recurrences (6-10%), compared to a 31-37% recurrence risk in the remaining groups during the observed follow-up time. The beneficial effect of post-operative RT for these low-risk groups can be questioned, and should be studied further.

Tissue response to silicone tubes used to repair human median and ulnar nerves.

Silicone tubes of appropriate sizes were used to enclose the injured zone of transsected ulnar and median nerves in the human forearm as an alternative to conventional microsurgical repair of the nerve trunk. A gap measuring 3-5 mm was left intentionally between the nerve ends inside the tube. The clinical early results from a prospective randomised study that compared these two principles have recently been presented. Seven patients (five men and two women), aged 15-49 years (median 20) were reexplored 12-44 months (median 22) after the initial procedure because of local discomfort from the tube in four patients. There was a new nerve structure bridging the former gap and in most cases it was impossible to distinguish the site of the injury. In all cases there was a thin capsule around the silicone tube that microscopically consisted of connective tissue with thin walls and no signs of inflammation, granuloma or macrophages (n = 4), while in two cases a mild foreign body reaction was seen at a single site (n = 1) or at patchy areas (n = 1). These results indicate that after more than one year there is a limited tissue reaction around silicone tubes used to repair median and ulnar nerves in humans.

[Gelatinous bone marrow transformation]. / Gelatinøs knoglemarvstransformation.

A case of gelatinous degeneration of the bone-marrow in a man aged 29 years is presented. The condition had developed on account of a combination of prolonged inadequate calorie and protein intake and physically demanding sport (triathlon). This has not been described previously. Accumulation of a gelatinous substance in the bone-marrow was found. Histochemical investigation demonstrated that this consisted of acid-mucopolysaccharides.

Malignant rhabdoid tumour of the kidney in an adult: a case report with immunohistochemical and ultrastructural investigation.

Rhabdoid tumours (RT) are highly aggressive neoplasms most often occurring in kidneys of children. Few cases of extrarenal RT have been reported among adults. This paper describes the first case of a RT in the kidney of an adult.

Oestrogen receptors alpha and beta show different associations to clinicopathological parameters and their co-expression might predict a better response to endocrine treatment in breast cancer.

AIMS: The majority of all breast cancers are hormone responsive, traditionally defined by the expression of oestrogen receptor (ER) alpha and/or progesterone receptors. In contrast to ERalpha, the clinical significance of the relatively recently identified ERbeta is still unclear. This study aimed to define the relationship between ERbeta and clinicopathological parameters in a mixed cohort of breast cancer and, furthermore, to investigate the impact of ERbeta expression on disease outcome. METHODS: The immunohistochemical expression of ERalpha and ERbeta was analysed in tissue microarrays containing a total number of 512 tumours with all incident breast cancers diagnosed at the Malmö University Hospital between 1988 and 1992. RESULTS: 78% of the tumours were ERalpha positive and 50% were ERbeta positive. ERbeta correlated positively with ERalpha (p = 0.001). In contrast to ERalpha, ERbeta was not associated with any important clinicopathological variables. Furthermore, no overall prognostic significance could be demonstrated for ERbeta. In the ERalpha-positive subgroup, however, a low expression of ERbeta correlated with a decreased disease-free survival in patients receiving endocrine treatment (p = 0.003). CONCLUSIONS: Although interrelated, ERalpha and ERbeta seem to be differentially associated to clinicopathological parameters, and this would support the fact that they might have different functions in vivo. Furthermore, ERbeta might be a predictive marker of response to endocrine therapy, although this needs to be confirmed in additional studies, preferably randomised trials.

The muscularis mucosae of the human urinary bladder. Implications for tumor staging on biopsies.

The human urinary bladder wall is traditionally described as being without a muscularis mucosae. A consecutive one year material of 772 bladder biopsies from 171 patients were examined for the proposed presence of lamina muscularis mucosae (MM). MM was observed in 15% of the biopsies and in 35% of the patients and graded into three patterns according to its continuity. Biopsies with transitional cell carcinomas were reviewed in order to find out whether MM-positive biopsies had been staged correctly. The data are discussed in relation to earlier studies on the subject.

Aggressive fibromatosis.

Fifteen patients with aggressive fibromatosis are presented. The patients ranged in age from one to 64 years, an average of 26 years, and the median time of follow-up study after treatment was ten years (a range of 2.5 to 22.0). Within this period, 60 per cent (nine of 15) of the tumors recurred. In a survey of the literature, when simple excision was compared with wide extirpation, the latter was found significantly superior (p less than 0.01) in terms of limiting a recurrence of the tumor. The results of a pathoanatomic study found that the number of mast cells and the size of the primary tumor could not prognosticate the clinical course. It was concluded that aggressive fibromatosis should be evaluated and treated like a low malignant soft tissue tumor.

Aggressive fibromatosis. Report of two cases with rare clinicopathological manifestations.

Two cases of aggressive fibromatosis are described, one with tricentric origin and with the first tumor originating in the hand, the other with malignant transformation into a myxoid fibrosarcoma, grade III. The primary treatment of aggressive fibromatosis should be wide excision, and the follow-up should be long, taking into account the possibility of multicentricity and the risk of malignant transformation.

Inverted papilloma of the upper urinary tract.

Four cases of inverted papilloma in the upper urinary tract are reported-three were located in the ureter and one in the renal pelvis. Clinical and pathological findings are described. In two cases the patients had a history of transitional cell carcinoma; while in one case, inverted papilloma was found in the same lesion as transitional cell carcinoma. The question of malignant transformation of inverted papilloma is discussed. It is concluded that inverted papilloma is a benign tumor with a very low frequency of recurrence, but regular follow-up is advised.

Herpes gestationis.

A case of clinically typical herpes gestationis is presented. The diagnosis was confirmed by light microscopy and immunofluorescence studies. The symptoms subsided at delivery, but recurred during subsequent oral contraceptive medication. The newborn infant was affected temporarily. The treatment, the fetal risk and the implications of the diagnosis on future pregnancies and contraceptive therapy are discussed.

Tissue microarray analyses of G1/S-regulatory proteins in ductal carcinoma in situ of the breast indicate that low cyclin D1 is associated with local recurrence.

Ductal carcinoma in situ (DCIS) of the breast constitutes about 10% of all diagnosed breast cancers and, despite surgical removal, it may recur, either as DCIS or invasive breast cancer. Nuclear grade and growth pattern according to Andersen et al as well as surgical margins are factors that have been used to predict local recurrence, but ideally a set of tumour-specific factors should be identified and used as prognostic markers. Many cell cycle regulatory gene products have been shown to be involved in the formation of tumours and are either oncogenes or suppressor genes and involved in key processes in the transformation. We therefore characterised the cell cycle regulators cyclin E, cyclin D1, p27 and p16 in a material of DCIS cases arranged in a tissue microarray. With a manual tissue arrayer, 52% of the initial 177 DCIS samples were successfully targeted allowing immunohistochemical analyses of all four proteins in 92 cases of DCIS. As also observed in invasive breast cancer, there was a trend indicating that DCIS cases with high cyclin D1 were cyclin E low and oestrogen receptor-positive, whereas cyclin E high DCIS cases were cyclin D1 low and oestrogen receptor-negative. For the 64 patients that did not receive postoperative radiotherapy, there were 16 local recurrences (eight DCIS and eight invasive breast cancer) during a mean follow-up time of 63 months. Cyclin E, p27 or p16 were not associated with local recurrence, but interestingly cyclin D1 was significantly and inversely associated with local recurrence, both using univariate and multivariate analyses. In summary, using a tissue array approach we have shown that cyclin D1, besides growth pattern, is a prognostic marker for local recurrence in DCIS.

Histologic grading in breast cancer--reproducibility between seven pathologic departments. South Sweden Breast Cancer Group.

Histologic grade, including tubular formations, nuclear grade, and mitotic activity, is a well-documented prognostic factor in breast cancer. In comparison with other prognostic parameters, the evaluation of histologic grade is cheap and can be performed, in principle, in all cases of breast cancer. One possible disadvantage is that the evaluation may vary between different pathological departments. The aim of the present work was therefore to study the reproducibility of the histologic grading system by distributing haematoxylin-erythrosin-stained slides from 93 invasive breast cancers to the seven pathology departments within the southern healthcare region of Sweden. The evaluation was performed blindly and without any knowledge of other clinical parameters. In 31% of the cases the same histologic grade was obtained for all departments. The overall mean kappa was 0.54, indicating a moderate reproducibility. Of the three factors included in histologic grade, the agreement was best for tubular formations and poorest for nuclear grade and mitotic activity. The overall moderate reproducibility should be considered when the clinical usefulness of histologic grading is compared with other prognostic instruments.