[Hannover and Ibsen: two Danish anatomists in the middle of the 19th century. Were they enemies?]. / Hannover og Ibsen - to danske anatomer i midten af 1800-tallet. Var de uvenner?

Adolph Hannover (1814-94), Danish anatomist and pathologist, introduced the microscopy to the medical research in Denmark. He published several papers on anatomy and pathology, among others Om Mikroskopets Bygning og dets Brug (1847) which was translated to several European languages, among others to English On the structure of the microscope and its use. As a jew he never succeeded in obtaining a post at the University of Copenhagen, Ib Pedersen Ibsen (1801-62) was educated at the Academia Chirurgorium Regia, the college of surgeons in Copenhagen, and he never became a scholarly anatomist, writing one paper only, published after his death. He was a competent anatomist and an appreciated teacher. The two anatomists competed for a post as lecturer in anatomy at the University of Copenhagen. Ibsen obtained the job after a public competition. The Museum of Medical History in Copenhagen is in possession of Ibsen's own copy of Hannover's dissertation on the cartilage, the muscles and the nerves of the external ear. In this copy Ibsen by hand has written some critical and unkind remarks against Hannover. Was this a sign of hostility? We conclude that they hardly were friends, but that the language between colleagues at the university could be rather harsh at that time.

Salivary gland carcinomas: prognostic significance of simple mucin-type carbohydrate antigens.

The prognosis of salivary gland carcinomas is difficult to assess. Simple mucin-type carbohydrates (T and sialosyl-T antigens, Tn and sialosyl-Tn antigens) have been shown to be of value in predicting prognosis for carcinomas in other locations. We studied the prognostic significance of the expression of these structures in a retrospective study of 133 patients with salivary gland carcinomas, using immunohistochemistry and a panel of well-defined monoclonal antibodies (MAbs) on formalin-fixed paraffin-embedded tissues. Sialosyl-Tn, T and sialosyl-T antigens were not correlated with prognosis. Univariate analyses showed no overall difference in survival or locoregional control between patients with Tn-positive and patients with Tn-negative tumours, but indicated that expression of the Tn antigen was associated with early locoregional recurrences and deaths. Tn was, however, not an independent prognostic factor by multivariate regression analysis.

Salivary gland carcinomas--prognostic factors.

A retrospective study of factors of prognostic significance for clinical course and survival was performed using uni- and multivariate analyses in 251 patients with primary salivary gland carcinoma admitted during the period 1958-1992. Univariate analyses indicated that site of primary tumour, histology, clinical stage, presence of node metastases at primary diagnosis, and status of surgical margins were important prognostic factors for cause-specific survival, locoregional control and distant metastases. Multivariate analyses confirmed that histology was important for both locoregional control and cause-specific survival, whereas primary site was only of importance for locoregional control. Presence of node metastases at diagnosis was more important for locoregional control than clinical stage, whereas clinical stage was the most important factor for cause-specific survival. Status of surgical margins was of major importance for both cause-specific survival and locoregional control. Radiotherapy in addition to surgery improved locoregional control only, whereas survival was not affected.

Observer variability in histological malignancy grading of adenoid cystic carcinomas.

The value of malignancy grading of adenoid cystic carcinomas (ACC) is controversial. Some studies have shown that tumours with a solid growth component have a rapid fatal course, compared to tumours without a solid growth component, in which recurrences develop even many years after initial treatment. Other studies have failed to correlate growth patterns with clinical course. No universally accepted grading system exists and no reproducibility studies of the existing grading systems have been performed. The aim of this study was to examine the reproducibility of grading based on semi-quantitative assessment of the solid growth pattern in ACC. Two different grading systems were assessed by 3 observers on a material of 59 ACC. Interobserver agreement was evaluated using the kappa statistic. The reproducibility of grading was poor, except for the category "solid component constituting 50% or more of the tumour" (kappa = 0.52). It is concluded that quantitative methods are necessary if grading is to be used in prognostic evaluation of ACC. The rarity of the tumours, however, combined with difficulties in diagnosis will impede such investigations unless multicentre studies are undertaken.

Clinical and histopathological prognostic factors in chondrosarcomas.

Purpose. In an attempt to identify clinical and histopathological factors of prognostic importance in chondrosarcomas, 115 cases of malignant and borderline chondromatous tumours were reviewed.Patients/methods. Histopathological features tested for prognostic information as well as reproducibility included cellularity, nuclear pleomorphism, multinucleated cells, mitotic activity and grade. Eleven patients had a biopsy only, and a short survival (median 2.0 years); these were excluded from further analysis. The remaining 104 patients who had received intended curative treatment had a median survival of 14.7 years.Results. In univariate analysis, tumour size, extra-compartmental growth, surgical margin and sex were significantly correlated to recurrence-free survival (RFS); sex was marginally significant while age, site and pathological parameters were not significant. Overall survival (OAS) was likewise found to be independent of pathological features as well as site, size and surgical margin; but age, sex and extra-compartmental growth were statistically significant. However, when the same parameters were entered into a stepwise Cox (multivariate) analysis, only surgical margin, cellularity and pleomorphism were significantly related to RFS; margin, grade, pleomorphism and age to OAS. Overall inter-observer agreement on grade was relatively low: 0.54, with a Kappa value of 0.32. It was not better for the other histological parameters, with the exception of the mitotic count. However, acceptable values were achieved when the material was divided into low-grade (grade I and below) vs high-grade (grade II and III) lesions: overall agreement 0.79, Kappa 0.56.Discussion. Although the grading of chondrosarcomas is in need of improvement, its replacement by semiquantitative evaluation of individual histopathological parameters as performed in this study offers no advantage. Among the clinical parameters, only the adequacy of the surgical treatment and the patient's age appear to be important.

Local recurrences in giant cell tumour of bone. Long-term follow up of 31 cases.

We studied the value of histopathological grading in determining the prognosis of giant cell tumour (osteoclastoma) and the rate of local and distant recurrences in a consecutive series of 31 patients. We found that grading had no prognostic value. Eighteen patients were treated by intralesional curettage and 13 by wide excision. Ten patients (56%), who were all treated by curettage, had local recurrences, but none of the tumours with wide excision recurred (p < 0.05). Five (16%) had local recurrences as well as distant metastases, usually to the lungs. The recurrences developed later than an average of 12 years after primary treatment in 3 patients. Wide excision and life-long follow up should be considered in the management of these tumours.

Medullary carcinoma of the breast. Prevalence and prognostic importance of classical risk factors in breast cancer.

In an earlier study of 235 breast cancers with medullary features, we concluded from a multivariate Cox regression analysis that only four histopathological features contained significantly positive prognostic information. In the present study, continuing our work on the same population base, we used these histological characteristics (predominantly syncytial growth pattern, no tubular component, diffuse stromal infiltration with mononuclear cells and sparse necrosis (< 25%), as diagnostic criteria for medullary carcinoma of the breast (MC). We found a significantly better prognosis for patients with MC than those with non-medullary carcinoma (NMC) or infiltrating ductal carcinoma (IDC). All tumours in the MC group were grade II or III (96% grade III). A significantly different distribution of general risk factors such as lymph node status, invasion, steroid receptor status, and menopausal status, was found between the group of MC and the control group of IDC grades II + III. Further, general risk factors, which are found to be of major prognostic importance in IDC, had little prognostic impact in MC. We found MC to be biologically unique, and patients with MC have a better than average prognosis compared to that of IDC. We propose a new histological definition of MC, but stress that prospective studies have to be performed.

DNA ploidy and S-phase fraction in medullary carcinoma of the breast--a flow cytometric analysis using archival material.

In a population of 110 primary breast cancers with medullary features, registered in the Danish Breast Cancer Cooperative Group (DBCG) from 1977-82, we have determined ploidy and S-phase fraction (SF) by flow cytometry (FCM) on paraffin embedded tumour tissue. The distribution of DNA ploidy is not different from the distribution described for breast cancers in general. No difference is found between the subgroups of medullary and non-medullary cancer when using a new simplified histopathological definition of medullary carcinoma of the breast, recently proposed by us. When using the definition proposed by Ridolfi et al. in 1977, we find significantly more tumours with aneuploidy and high SF in the groups of typical medullary carcinoma (TMC) and atypical medullary carcinoma (AMC) than in the small group of non-medullary carcinoma (NMC), which seems a paradox, as patients with NMC have the worst prognosis. However, the number of patients in the NMC group is very small, and the percentage of aneuploid tumours is very low. In 84 protocolled patients we found no statistically prognostic importance of ploidy or SF, either in the whole group assessed or when stratifying for the histopathological subgroups. However, a prognostic influence of SF can be traced for the non-medullary cancers, according to the new definition, but not for the medullary cancers of the breast. The result emphasizes the impression of MC as being biologically different from other histological types of breast cancer.

Medullary carcinoma of the breast, prognostic importance of characteristic histopathological features evaluated in a multivariate Cox analysis.

In this study of 136 breast cancers with medullary features (MC), registered in the Danish Breast Cancer Cooperative Group (DBCG) from 1982 to 1987, we confirmed the prognostic importance of a new definition of medullary carcinoma of the breast (MC newdef) which was recently proposed by us, deduced from a previous study of a corresponding tumour material (DBCG 77-82). However, the individual histological criteria did not have the same prognostic importance as in our previous study, although prognostic trends were the same. To further improve and validate the diagnostic criteria, we combined the two populations and performed a multivariate Cox regression analysis. In the final Cox model, four histological parameters retained positive prognostic importance: (1) predominantly syncytial growth pattern, (2) no tubular component, (3) diffuse stromal infiltration with mononuclear cells and (4) sparse necrosis. We propose that these criteria are emphasized in the histological diagnosis of medullary carcinoma of the breast.

Vimentin expression in 98 breast cancers with medullary features and its prognostic significance.

The expression of vimentin, as assessed by immunohistochemistry, has been evaluated in 69 medullary carcinomas of the breast: 28 typical medullary carcinomas (TMC), 41 atypical medullary carcinomas (AMC), and 29 invasive ductal carcinomas with subtle medullary features that, however, did not fulfill the strict criteria of TMC or AMC. Immunoreactivity of at least 10% of the component cells was found in 14 of the medullary carcinomas (5 out of 28 TMC, 9 out of 41 AMC whereas only 1 of the invasive ductal carcinomas was vimentin-positive. The patients were followed for 8-13 years. No difference in recurrence-free survival or overall survival could be documented between vimentin-positive and vimentin-negative carcinomas with medullary features. No biological significance could be established for vimentin labelling in these lesions.

Sarcomatoid tumours of the breast in Denmark from 1977 to 1987. A clinicopathological and immunohistochemical study of 100 cases.

One hundred sarcomatoid breast tumours, which had been diagnosed and registered in Denmark from January 1977 to January 1987, were subclassified using a combination of conventional morphological evaluation and immunohistochemistry, and the diagnosis was in each case related to clinical follow-up of 5-14 years or until death of the patient. Conventional histological examination resulted in 36 benign, 19 borderline and 18 malignant phyllodes tumours, 1 angiosarcoma and 26 non-specified sarcomatous tumours, 6 with small carcinoma-like foci. Immunohistochemical staining revealed that 23 of the non-phylloid sarcomatous tumours showed a tumour cell reaction for epithelial markers, predominantly cytokeratin and, therefore, the tumours were interpreted as metaplastic carcinomas. Clinical follow-up showed for phyllodes tumours and for the three cytokeratin-negative sarcomatous tumours local recurrence rates of 21 and 33%, respectively, whereas metastases only occurred from the angiosarcoma and from one borderline phyllodes tumour with five recurrences (5%). In contrast, metaplastic carcinomas gave rise to distant metastases in 50% of cases but no local recurrences. Axillary lymph nodes had been examined in 28 cases, 13 from metaplastic carcinomas. Only two of these showed metastatic spread, both with a pattern similar to the primary tumour. The differences in survival between patients with metaplastic carcinoma and patients with a borderline/malignant phyllodes tumour or a cytokeratin-negative sarcomatous tumour has in this study proven to be highly significant (P < 0.0001), and we find it of importance to use immunohistochemistry in the subclassification of sarcomatous breast tumours for appropriate surgery, reliable prognostic outlook and optimal postoperative therapy.

Grading of soft tissue sarcomas: experience of the EORTC Soft Tissue and Bone Sarcoma Group.

A practical grading system for soft tissue sarcomas was developed, based on 282 eligible patients entered in an EORTC adjuvant clinical trial. The primary tumours in this trial had to be adequately treated. Histopathological parameters, which appeared significant in two preceding studies, were tested. These parameters were differentiation of the tumour, presence and amount of necrosis, the presence and amount of myxoid areas and the number of mitoses. In addition, the size of the tumour was also analysed. The quantitative data (mitotic count and size of the tumour) were not a priori grouped, but were divided into categories based on the results of the statistical analysis. Based on a multivariate analysis only mitotic count, the presence or absence of necrosis and the size of the tumour were significantly correlated with the duration of survival or the time to distant metastases. Of these parameters, the mitotic count was the most important.

Histopathological grade and response to chemotherapy in advanced soft tissue sarcomas.

In a retrospective analysis, we evaluated the possible significance of histopathological grade with regard to response to chemotherapy in advanced soft tissue sarcomas. In three EORTC protocols, the same dose-schedule was used for patients randomised to treatment with doxorubicin as a single agent (75 mg/m2 every third week). The submitted pathological slides from 94 of these patients were reviewed and graded. The following parameters were subjectively graded (+/++/+ + +): nuclear pleomorphism, necrosis, cellularity and vascularity. Mitoses were counted in 20 high-power fields, and a final grade assigned as I, II, IIIA or IIIB. The results were tested both with regard to response (complete response + partial response vs. no change + progressive disease) and survival. However, no statistically significant correlations or trends could be demonstrated. Thus, tumour grade, although a prognostic factor by itself, does not seem to be able to predict response to chemotherapy in the advanced stage.

Malignant epithelial tumors in the minor salivary glands, the submandibular gland, and the sublingual gland. Prognostic factors and treatment results.

Ninety-five malignant tumors in the submandibular gland, the sublingual gland, and the minor salivary glands seen in a 25-year period were reviewed. The patients were retrospectively staged using the Union Internationale Contre le Cancer (UICC) classification. The most frequent tumor was adenoid cystic carcinoma, followed by adenocarcinoma. The submandibular gland was the most frequent location. Five-year and 10-year crude survival rates were 62% and 43%, respectively. Clinical stage was the most important prognostic factor. Survival was not correlated with location of tumor, although recurrence and metastases occurred more frequently in patients with cancer of the submandibular gland. Histologically, the 5-year and 10-year survival was significantly better for patients with adenoid cystic carcinoma compared with the other types; however, although still significant, this difference diminished at 10 years, confirming the need for a long observation time for patients with this tumor.

Medullary carcinoma of the breast, proposal for a new simplified histopathological definition. Based on prognostic observations and observations on inter- and intraobserver variability of 11 histopathological characteristics in 131 breast carcinomas with medullary features.

In a previous study of 131 breast carcinomas with medullary features, we evaluated the diagnostic inter- and intraobserver variation and its prognostic implications using the criteria of typical (TMC) and atypical (AMC) medullary carcinoma of the breast put forward by Ridolfi et al. (1977). We found a considerable interobserver variation as well as intraobserver variation, with significant implication on prognosis, and concluded that the histopathological definition of MC must be sharpened and simplified in order to increase the diagnostic reproducibility. In the present study of the same population of 131 patients with breast carcinomas with medullary features we have examined inter- and intraobserver variation concerning 11 histopathological characteristics. Furthermore, we have analysed the prognostic importance of these 11 histopathological features, and the prognostic implications of the observed inter- and intraobserver variation. Based on the observations, we have eliminated criteria with poor inter-/intraobserver agreement as well as those implying no or minimal impact on the prognosis. We propose a new simplified histopathological definition of medullary carcinoma of the breast (MC), retaining reproducible, prognostically significant criteria (syncytial growth pattern and diffuse, moderate or marked mononuclear infiltration). The prognosis of MC, based on this definition, is significantly better than those of infiltrating ductal carcinomas grade II + III.

Immunohistochemical staining for chondroitin sulphate and keratan sulphate. An evaluation of two monoclonal antibodies.

Immunohistochemical staining with commercially available antibodies against chondroitin sulphate (clone CS-56) and keratan sulphate (clone 1/20/5-D-4) was compared with two conventional histochemical methods for the demonstration of glycosaminoglycans, namely Alcian Blue with varying pH and critical electrolyte concentrations, and a modified PAS stain. The antibodies were tested on sections from both frozen and fixed, paraffin embedded human material from umbilical cord, skin, and bronchus. The results showed immunostaining to function equally well on frozen and routine sections, and to be superior to Alcian Blue and PAS with regard to morphological detail. Thus, reactivity with anti-chondroitin sulphate was demonstrated in vessel walls, in small nerves, in the basal membrane zone of the skin, in perichondrium, and in and around chondrocytes. Reactivity with anti-keratan sulphate occurred in chondroid matrix and in perichondrial tissue; however, some cells of the bronchial epithelium and mucous glands also exhibited positivity.

The prognostic importance of syncytial growth pattern in medullary carcinoma of the breast.

The histopathological criteria for medullary carcinoma of the breast (MC) used by most pathologists today were delineated by Ridolfi et al. in 1977. The prime criterion is: "A predominantly syncytial growth pattern", predominantly being defined as including 75% or more of the tumour. However, no indication has been given as to why this limit was set at 75%. The present study analyzes the prognostic importance of the extent of syncytial growth in a population of 102 breast cancers with medullary features. Generally, we find a positive prognostic influence of an extensive syncytial growth. The prognostic importance of setting the limit for predominantly syncytial growth at 90% and at 75%, respectively, is evaluated. This comparative study provides no basis for changing the definition of predominantly syncytial growth pattern.