[Scope and limitations of diagnostics in breast disease--focussing on large core biopsy]. / Möglichkeiten und Grenzen der Mammadiagnostik unter besonderer Berücksichtigung der perkutanen Stanzbiopsie.

Percutaneous high speed large core biopsy (LCB) using a 14-gauge-needle, supported by sonographic procedures, is a safe and reliable method for the diagnosis of benign and malignant breast lesions in daily practice. All malignant diagnoses (B5)--comprising 44 % (267/604) of cases--were confirmed by subsequent surgical biopsy. This indicates a positive predictive value of 100 %. Evidence for uncertain dignity in LCB (categories B3 and B4) was found in 3 % of our cases (20/604), requiring open breast surgery for further clarification. This is strongly supported by the fact that 22 % of B3 and 82 % of B4 cases were identified as carcinomas in subsequent surgery. In 9 % of our cases (53/604), histology was only questionably representative (category B1) without cancer in the follow-up. In the B2-category--which comprised nearly 44 % of all cases (n = 263)--the positive predictive value ranged at 2 %. For clinical investigation, mammography, breast ultrasound and LCB the sensitivity were at 79 %, 92 %, 92 % and 98 %, respectively. The specificity of clinical findings, mammography, breast ultrasound and LCB ranged at 88 %, 67 %, 79 % and 99 %, respectively. The combination of the 3 methods: clinical findings, mammography and breast ultrasound (leading to a "total diagnostic score" provided a sensitivity and specificity of 97 % and 52 %. LCB revealed an excellent specificity of 99 %. Therefore, large core biopsy takes up a definite and reliable place in procedures of breast diagnostics, thereby preventing a high number of unnecessary open surgical interventions.

[Percutaneous large core breast biopsy]. / Perkutane Brustdrüsenstanzbiopsie : Evaluation in der ambulanten Diagnostik.

Percutaneous large core biopsy of the breast with a 14-gauge needle, supported by sonographic and mammographic procedures, shows a high degree of safety during the collection for benign and malignant lesions. All malignant diagnoses (B 5) with a portion of 44% (267/604) were confirmed surgically, whereby the typing with 79% and grading with 58% were congruent. In 3.3% (20/604), there was uncertainty (B 3 and B 4), with the necessity for further clarification by open biopsy. This was supported by the fact that in 10/16 operated cases carcinoma was found. In the B 2-category, with a portion of nearly 44% (264/604), four cases of cancer were verified--not due to a wrongly negative histology but to non-representative material. In 8.8% (53/604), a questionable representative histology (B 1) occurred, but no cancer was found after surgical intervention (n=7). The indication for surgery is not only the punch biopsy result, but additionally negative histology and suspect or malignant clinical findings.

Dynamic force spectroscopy to probe adhesion strength of living cells.

We studied the mechanical strength of the adhesion of living cells to model membranes. The latter contained a RGD lipopeptide which is a high affinity binding site for a cell adhesion molecule (integrin alpha(V)beta(3)). Cells adhered specifically to the vesicles. We used micropipette aspiration for breaking this adhesion with well defined forces. Systematic variation of the rate of force application revealed pronounced kinetic effects. The dependence of the detachment forces on the loading rate was well described by a power law (exponent approximately 0.4), in agreement with recent theoretical work.

[Current standards for the diagnosis of breast carcinoma in routine practice]. / Aktueller Standard der Diagnostik des Mammakarzinoms in der Praxis.

Every pathologist in active practice must be aware of and follow, set standards and recommendations for the diagnosis of breast carcinoma in order to ensure that the patient has the preconditions for an adequate therapy, regardless of the particular hospital setting. According to present-day knowledge, the standard obligatory examinations include conventional morphology (staging, typing and grading of the tumour) and the analysis of the steroid hormone receptor status (estrogen and progesterone). The immunohistochemical determination of tumour growth fraction with the Ki-67 antibody is economically justifiable, since it serves as an adjunct for histological/cytological tumour grading, a method that has a poor level of reproducibility. Since the introduction of herceptin immunotherapy, the determination HER-2/neu overexpression has gained a practical role and should now be included as an obligatory component of the diagnostic testing. Additional tumour markers are not components of routine diagnosis and these should be limited to clinical studies as long as their prognostic and therapeutic value have not been proven.

Frequent loss of heterozygosity at chromosome 13q12-13 with BRCA2 markers in sporadic male breast cancer.

Molecular genetic analysis indicates that the BRCA2 gene plays an important role in familial male breast cancer. To determine a possible involvement of this tumor suppressor gene in sporadic male breast cancer, we examined 30 sporadic male breast carcinomas for loss of heterozygosity (LOH) at two loci on chromosome 13q12-13, a region that spans the BRCA2 locus. Sixteen of 24 (67%) informative cases showed LOH in at least one marker on chromosome 13q12-13. The affected cases included both invasive ductal carcinomas and other types of invasive breast carcinoma and were detected preferentially in patients who were 50 years or older, in patients with lymph node metastasis, and in progesterone receptor-negative cases. We report, for the first time, a high frequency of LOH at chromosome 13q12-13 in sporadic male breast cancer and its association with factors indicating a poor prognosis for this tumor (e.g., lymph node metastasis and negative progesterone receptor status). These findings suggest an important role for BRCA2 in the development and progression of sporadic male breast cancer.

[Breast carcinoma in the man. Current results from the viewpoint of clinic and pathology]. / Mammakarzinom des Manns. Aktuelle Ergebnisse aus Sicht der Klinik und Pathologie.

Breast cancer is the most frequent malignant tumor in women, whereas it is rare in men. In our own case series the ratio is 175:1. The present paper deals with an evaluation of clinical and morphological findings from a series of 54 de novo male breast cancers observed in our institution from 1978 to 1996 and a comparative discussion of 528 female breast cancers from the same geographic area. We should like to focus on the following observations: At the time of histopathological diagnosis, male patients with breast cancer were on average 67 (34-87) years old and thus 5 years older than women. Below the age of 40, breast cancer is very rare in men. The lag time between first symptoms and surgery was on average 42 weeks, i.e. twice as long as in women. In the vast majority of cases palpation of a retromamillary nodule was the leading diagnostic symptom. Mamillary secretion appeared to be an early symptom with favorable relation to prognosis by tumor size whereas diffuse breast swelling was an unfavorable late symptom. Bilateral carcinoma and double cancer (breast and prostatic cancer) was observed in one case each. Three patients (3/51 = 6%) had a positive family history (breast cancer in 1st and 2nd degree relatives). The average invasive tumor size was nearly identical with 23 mm (s11.02) in men and 25 mm (s13.48) in women. Men presented more frequently with regional lymph node metastases (53% versus 45%), which tended to develop earlier. pT4 cancers were twice as frequent in men compared to women. In situ cancers were found in 2% (1/54) in men and 4% in women. Similar to females, male breast cancers are predominantly of ductal histological type (NOS-cancers), classical lobular carcinoma with LCIS-components were not observed; special forms (tubular, papillary, mucinous) are slightly more common in men. When reviewing our series, need for revision of the origin of tumor was not found in any of the cases. Metastases of prostatic cancer were never misinterpreted as primary breast cancer. In case of isolated NSE-reaction, cancers with carinoid differentiation pattern are to be found in nearly every second tumor. However, when multiple markers were used (chromogranin A or synaptophysin) only 10% displayed such pattern, which corresponded to a positive hormone receptor status in each case. Quantitative (enzyme immunoassay) and semiquantitative (immunohistochemistry) analysis of steroid hormone receptor status was positive in 86% of 35 cases in men and in 75% in women. In contrast to female breast cancer, hormone status proved to be independent of age in males. The average levels of estrogen and progesterone were higher in men. Overlapping results were found only when cases were compared with postmenopausal women. The Nottingham prognostic index, a product of primary tumor size, axillary lymph node status and grading allows an approximative estimate of the course of the disease; its predictive value is higher than that of isolated tumor markers.

[Breast carcinoma and breast saving therapy--a critical comment from the viewpoint of the pathologist]. / Mammakarzinom und brusterhaltende Therapie (BET)--Eine kritische Stellungnahme aus der Sicht des Pathologen.

The pathologist's contribution to decision-making for or against breast conserving treatment is based on his examination of the specimen from primary tumour surgery. First-line criteria for the assessment of the specimen are completeness, contour and versus plurifocal/multicentric spread), intracanalicular tumour components, lymphangiosis and haemangiosis. Second-line criteria are the histological and cytological grade of malignancy, preconditions for breast conserving treatment are favorable in consolidated in situ carcinomas up to 25 mm in diameter and in unifocal invasive carcinomas up to stage pT2 with low grade malignancy and without additional intraductal spread or angiosis. Breast conserving treatment is not indicated for multifocal or pT4 carcinomas and for carcinomas with extensive intraductal components or angiosis. When considering an unselected group of breast cancer patients, the pathological anatomic preconditions for breast conserving treatment will be very favourable in one-quarter of the cases. This approach will be feasible with limitations only in another one-fourth of the cases, whereas in about 50% of the patients, breast conserving treatment is dubious or should be rejected.

[The histology of mastopathy and cumulative ipsilateral breast cancer sequence]. / Die Histologie der Mastopathie und die kumulative ipsilaterale Mammakarzinomsequenz.

In a retrolective and follow-up study the ipsilateral cumulative risk of breast carcinoma after histological benign diseases in women under 66 years of age (n = 1397) is investigated. The subtypes are mastopathy I (= changes without proliferative lesions), mastopathy II (= proliferative lesions without atypia), and mastopathy III (id sunt atypical ductal and lobular hyperplasias). The cumulative risk with mastopathy I and II over a 15 year time period corresponds with the ordinary age related risk, the cumulative risk with mastopathy III is four times higher (p = 0.001). There is no difference between atypical ductal and lobular hyperplasia (p = 0.7). Women in reproductive age have a higher risk (p = 0.03), which exists even after a carcinoma-free survival of more than 10 years. The mastopathy is more a stigma for a higher breast cancer risk than a direct precancerous lesion.

[The pathology of mastopathy and breast cancer]. / Pathologie der Mastopathie und des Mammakarzinoms.

Radiologists and pathologists play the most important role in the diagnosis of breast diseases. The combination of mammographic and cytological investigations can lead to the determination of which lesions require an operation and which do not. Fibroadenomas, mastopathies and carcinomas are the most common histological diagnoses. It is necessary to decide which type of mastopathy (atypical intraductal or intralobular hyperplasia) might involve a higher risk of carcinoma. When classifying carcinomas, the pathologist must give details about prognostic factors such as staging (pTN status), histological typing, grading, and hormone receptors (oestrogen and gestagen).

Three cases of malignant neoplasm, pneumonitis, and pancytopenia during treatment with low-dose methotrexate.

A 77-year-old man with chronic obstructive pulmonary disease was treated with low-dose methotrexate (7.5-15 mg per week). After 15 months a diagnosis of urothelial carcinoma of the bladder was made; after a further 6 months pneumonitis and pancytopenia developed. The patient died due to massive pulmonary hemorrhage. A malignant teratoma was diagnosed in a 65-year-old asthmatic man 16 months after initiation of methotrexate therapy (15 mg per week). The patient died 4 months later due to fulminant progression of the neoplasm. A third malignant neoplasm (dermal squamous cell carcinoma) was seen in a 64-year-old woman with rheumatoid arthritis after 13 months treatment with 7.5 mg methotrexate per week. These three cases, while obviously not proving a causal relationship between long-term treatment with low-dose methotrexate and development of malignant neoplasm, do call for stringent treatment criteria, close surveillance, and prospective studies.

[Mastopathy. Histological forms and long-term observations]. / Mastopathie. Histologische Formen und Langzeitbeobachtung.

Long-time observation of women with bioptically secured mastopathy has provided evidence to the effect that, in the context of statistical mean values, aggravated carcinoma risk needed to be expected only along with the presence of atypical epithelial proliferation. The risk to women with atypical Grade III mastopathy (atypical ductal and lobular hyperplasia) was found to be at least four times as high as that to women with simple Grade I mastopathy or to patients without any previous mastopathy record. Grade III mastopathy is identical with atypical hyperplasia of mammary gland parenchyma (according to nomenclature recommendations by the Consensus Meeting of the American Cancer Society, 1985). No hard evidence has, as yet, been produced as to whether atypical hyperplasia is a precancerous lesion or simply a marker for breast cancer. Women thus affected anyway should be kept under long-time monitoring as a high-risk group.

[Pathology of premalignant and malignant diseases of the female breast]. / Pathologie der prämalignen und malignen Erkrankungen der weiblichen Brust.

There are three frequent, basic diagnoses of breast lesions: fibroadenomas, fibrocystic diseases and carcinomas. The atypical fibroadenoma, the phyllodes tumour, the atypical ductal and/or lobular hyperplasia and the atypical papilloma are important because they may be a premalignant condition. For therapy it is important to know that the non-invasive carcinomas are often plurifocal, multicentric and bilateral. Women with manifest invasive breast cancer have a very high risk of contralateral cancer, but generally the cancer on the opposite side is microfocal.

Sarcoidosis and immunocytoma.

The current literature contains reports of sarcoidosis with polyclonal increases in immunoglobulins. There are also reports of lymphoma in patients with pre-existing sarcoidosis. This is believed to be the first report of a patient in whom a monoclonal IgM kappa paraproteinemia developed after the diagnosis of sarcoidosis. This paraproteinemia was linked with a histologically proved non-Hodgkin's lymphoma. The possible relationships between the two disease entities are discussed.

[Long-term study of women with biopsy-proven mastopathy]. / Langzeitbeobachtung von Frauen mit bioptisch gesicherter Mastopathie.

Out of a total of 1306 women (average age 42 years) with a biopsy proven mastopathy, manifest ipsilateral carcinoma occurred in 13 during the following 6 years. Thus the incidence of carcinoma differed little from the expected number of new cases in women of a comparable age. However, subdivision of breast lesions into simple (n = 1052) and proliferative (n = 254) forms showed that the carcinoma risk is double in proliferative mastopathy and fourfold higher when mastopathy with atypical epithelial proliferation is considered. An association with contraceptive hormones was not seen.