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On fine-needle aspiration (FNA), fibroadenomas have a characteristic cytological appearance, although occasional cases are misinterpreted as carcinomas and vice versa. In a review of 521 breast aspirates correlated with the subsequent histology, six of 87 fibroadenomas (7%) were malignant or suspicious of malignancy on FNA (false positives). Following cytological review, four were still suspicious of malignancy because of cellular dyscohesion and prominent nucleoli, while two were fibroadenomas. On FNA, four of 145 carcinomas (3%) were diagnosed as fibroadenomas (false negatives). On review, three were malignant or suspicious of malignancy, while one was consistent with a fibroadenoma. Three false negative diagnoses were due to underappreciation of single malignant cells present between epithelial groupings typical of a fibroadenoma, while one was due to undersampling of the carcinoma. Cytologically, some fibroadenomas are sufficiently atypical that histological confirmation is necessary to exclude a malignancy. Misinterpreting carcinomas as fibroadenomas could be avoided by careful study of the morphology of isolated cells.

The human gene sequences encoding the translation-associated functions of alpha-subunit of elongation factor 1 (EF-1 alpha) and the ubiquitin carboxyl extension protein (HUBCEP80) have been isolated by differential cDNA screening, and found to have significantly higher levels of expression in fibroadenomas (benign) compared with carcinomas (malignant) of the breast. These data parallel our previous findings that the acidic ribosomal phosphoprotein P2 also has higher expression levels in the benign breast tumours (Sharp et al., 1990). In situ hybridisation has shown these genes to be expressed predominantly in the epithelium of breast tumours.

The fine needle aspiration cytology of the breast is the only way for the morphological examination of suspicious palpable lesions without surgical procedure. The cytological examination is able to produce clinical relevant results on the basis of typical microscopical pictures especially in breast carcinoma, fibroadenoma, and cysts. However it must be taken into account that not all breast tumors can be detected by fine needle aspiration cytology. Therefore negative and doubtful results have to be interpreted in connection with clinical and mammographic findings. An essential condition for good results is an effective punction technique to obtain representative probes of cell material. In case punction and cytological examination are not performed by the same investigator there is the risk that an inadequate punction technique is not noticed and leads to unsatisfactory cytological results. In connection with clinical and mammographic examinations the fine needle aspiration cytology can be used as alternative diagnostic way and replace the conventional breast tumor diagnostic procedure by surgical biopsy and frozen section, if the necessary requirements are fulfilled. This includes a high standard of clinical, mammographic and cytological examinations and a critical summarizing interpretation of the examination results.

We report herein a case of a 31 year old housewife who underwent an excisional biopsy for a well-circumscribed lump in her breast. The lump contained 2 histological patterns, namely, fibroadenoma and tubular adenoma. These patterns had no transitional zone, were distinct and changed abruptly. This case was histologically diagnosed as "a fibroadenoma in tubular adenoma of the breast, benign", with no other such case ever having been reported in Japan. The histological findings of this case, convinced us that tubular adenoma is closely related to fibroadenoma.

This study on the different types of epithelial hyperplasia in fibrocystic disease was inspired by the observation of myoepithelial (basocellular) hyperplasia identified by strong expression of S100 protein and a weak reaction with antibodies against cytokeratin (KL1) in cells forming solid and acinar buds. The cells do not contain immunohistochemically detectable actin or desmin. Glandular transformation and proliferation give rise to basocellular circumductal adenosis. Normal breast tissue, 51 cases of fibrocystic disease with mild, florid and atypical hyperplasias, 7 fibroadenomas and 20 cases of carcinoma in situ were studied and a semiquantitative analysis revealed basal buds and adenosis in less than 40% of cases of mild hyperplasia and up to 73% in florid hyperplasia. Epitheliosis is characterized by a heterogeneous cell pattern with cells positive for S100 protein in 30-60%, but in small ducts up to 100% with an immediate connection to the basal cell layer were positive. Carcinoma in situ contained very rare tumour cells positive for S100 protein. The cells expressing S100 protein in terminal ducts, in adenosis and epitheliosis showed only some of the characteristics of myoepithelial cells, since they lack immunoreactivity with antibodies against actin. These basal clear cells are interpreted as transitional or indeterminate cells with features of myoepithelial precursor cells, but with the ability to develop basocellular nodular and glandular hyperplasia in the ductulo-lobular units in cases of adenosis and juvenile fibroadenoma.

A case of concurrent carcinoma of the breast with a fibroadenoma in a 59-year-old woman is described. The diagnosis was made on fine needle aspiration cytology. Despite the rarity of such a lesion, it is felt that a cytological diagnosis of this lesion from a fine needle aspirate specimen is possible.

In this paper the authors described those of the breast fine needle aspirates which were difficult for interpretation e.g. clear-cut differentiation between benign and malignant character of the lesion could not be made. There were 40 such cases (1.96%) out of 2332 breast tumors biopsied between 1987-1989. In the cases that proved to be malignant on histology the authors described cytological features which speak in favour of malignancy. In the group of smears which proved to be benign on histology the authors described the features that imitate atypia and should not be misdiagnosed as malignant. The described criteria may be of some help in cytological diagnosis of breast masses.

In a series of 1137 diagnostic breast biopsy specimens in a 2-year period, nearly half (n = 534) underwent specimen mammography. Calcifications were found in 48% of the specimen mammograms. In a quarter of the cases, calcification was a marker either for carcinoma or a significant precursor lesion. Moreover, in the majority of these malignancies, calcifications were markers of preinvasive carcinoma. In another quarter of cases, some form of proliferative ductal hyperplasia accounted for calcifications, and in the remainder, cysts and miscellaneous other conditions accounted for calcifications. The yield of malignancy was much lower in noncalcified specimens (12%). A nodular or asymmetric density proved to be a fibroadenoma in 30% of cases. However, the majority of cases had less well-defined changes, probably representing some form of lobular fibrosis. We found submission of a duplicate specimen mammogram with the breast biopsy specimen to pathology to be a significant adjunct to correlation. The abnormal area is marked on the mammogram by the radiologist for the pathologist. This is particularly helpful for localizing noncalcified stromal abnormalities. Calcifications are most easily and reliably isolated by serial slicing and performing another radiograph of the slices.

Epidermal growth factor receptor (EGF-R) was studied with monoclonal antibody 2E9 on 50 ovarian tumors of various histological types and 10 non-tumorous ovarian tissues by immunohistochemistry. Enhanced expression was observed in 26/50 (52%) of the tumors. Only 25 out of 46 epithelial tumors (54%) showed positivity in epithelial tumor cells. Staining was cytoplasmic in all cases. No correlation was established between EGF-R expression and the histological type of the epithelial tumor. Apart from EGF-R expression in tumor cells, low immunoreactivity was also observed in stromal and endothelial cells in both normal and tumorous ovarian tissues. Furthermore in 8/9 specimens containing necrotic areas, EGF-R was noticed in these areas as well. Both of the latter observations may have impact on the evaluation of the prognostic value of EGF-R activity in tumors, when based on EGF-R measurements using biochemical binding studies. We therefore recommend that EGF-R is measured with both methods in studies regarding its clinical value.

The measurement of nuclear area was carried out in 30 benign and 32 malignant breast lumps using Omnicon Alpha 500 Image Analyzer. The mean nuclear area of duct cells in malignant group was greater (157.6 +/- 58.64 sq.microns with a peak around 140 sq.microns) and more heterogenous within and amongst cases than observed in duct cells from most of the cases of fibroadenoma (85.05 ae 14.2 sq.microns with a peak around 80 sq.microns). Taking into consideration 110 sq.microns as a differentiating limit, a significant difference was observed between benign and malignant conditions (p). Similarly taking 118 sq.microns as differentiating limit duct cell carcinomas could be divided into two groups i.e. 9(28.1%) cases of small nuclear type with a range of 80-118 sq.microns and 23(71.9%) cases of large nuclear type with a range of 118-320 sq microns .6(18.8%) cases with small nuclei had an overlap with fibroadenoma. Although 13(72.2%) cases of large nuclear type carcinomas had lymph node metastasis as against 4(44.4%) in small nuclear group, the difference was not statistically significant.

Although most anatomical pathologists have encountered breast lesions with the composite histological features of fibroadenoma (FA) and fibrocystic change (FC), referred to as fibroadenomatosis or fibroadenomatoid mastopathy (FAM), little is known about its prevalence or clinico-pathological significance. In a retrospective histological review of 400 consecutive breast lesions, among both East and West Malaysians, coded either as FA or FC in the files of the Department of Pathology, University of Malaya, we found 45 (11.3%) cases of FAM. Typically, FAM lesions showed fibroadenomatoid foci in a background of fibrocystic change. The finding of FAM among lesions coded as FC was higher (18.5%) than among FA (4%). The mean age of patients with FAM (32.1 years) was similar to FC (35.1 years) but significantly older than that of FA (26.1 years). The notion that FA and FC are lesions at two ends of a spectrum of growth disorder of breast related to oestrogen-progesterone interplay, and that FAM occupies a position intermediate between the two, may explain its morphological and age patterns, but remains speculative. It is hoped that increasing awareness of this condition will lead to better understanding of breast pathophysiology. Nevertheless, until its biological nature, histogenesis and malignant potential are more clearly understood, defining FAM as a distinct form of breast disease may not be meaningful to patient management.

A total of 183 consecutive patients undergoing biopsies for unilateral microcalcifications concentrated in one or more segments of the breast in the absence of any palpable findings were analyzed to characterize their risk of cancer. Biopsy findings were benign in 86 patients (47%) and malignant in 97 (53%). Of the clinical and mammographic characteristics evaluated, an increasing number of linear microcalcifications, either without a dominant density (p = 0.014) or with a dominant density (p = 0.019) and the presence of heterogeneous microcalcifications (p = 0.055), were associated with a significantly increased risk of malignancy. Conversely a fibronodular parenchymal pattern (p = 0.008) was associated with a significantly decreased risk of malignancy. A high-risk group was identified, 95% (40/42) of whom had malignant biopsy findings, whose mammograms had more than 10 linear microcalcifications not associated with a dominant density (16/17) or at least one linear microcalcification associated with a dominant density (24/25). Conversely a low-risk group for cancer was identified, 88% (28/32) of whom had benign biopsy findings, whose mammograms had exclusively punctate microcalcifications within a fibronodular parenchymal milieu (26/30) or demonstrated some change in the configuration of the microcalcifications on the various mammographic views (10/10). For the remaining 109 patients there was an almost equal division between malignant and benign diagnoses (49% vs 51%).

Of 1,612 fine needle aspirates (FNA) of breast lesions performed over a seven-year period, 25 cases (1.5%) were identified as breast masses associated with pregnancy. Patients ranged in age from 16 to 46 years, with a mean of 27. Gestational age at the time of FNA ranged from three months to three months postpartum or following breast-feeding. Cytologic diagnoses of these pregnancy-associated breast masses were: galactocele (5 cases, 20%), lactating adenoma (9 cases, 36%), fibroadenoma with lactational change (7 cases, 28%), juvenile fibroadenoma with lactational change (1 case, 4%), atypical reactive duct cells with lactational change (1 case, 4%) and infiltrating duct carcinoma (2 cases, 8%). The degree of lactational change varied proportionately with gestational age. None of the 22 patients with benign cytologic diagnoses of galactocele, lactating adenoma or fibroadenoma subsequently developed carcinoma. The mean clinical follow-up for these 22 patients was 27 months. Three cases of fibroadenoma and the case of juvenile fibroadenoma were confirmed by surgical excision. Biopsy of the lesion cytologically diagnosed as atypical reactive duct cells with lactational change revealed infiltrating duct carcinoma (IDC). All three patients with IDC had involvement of multiple axillary lymph nodes, and 1 patient had widely metastatic disease. In two cases of IDC the background lactational breast epithelium exhibited marked cytologic atypia that closely resembled the IDC. Pregnancy-related cellular atypia potentially results in a false-positive diagnosis of breast carcinoma on FNA. FNA is useful in distinguishing benign breast masses of pregnancy from those with marked cytologic atypia requiring surgical biopsy and may minimize the delayed diagnosis of carcinoma associated with pregnancy.

Identification of key cytologic criteria for various lesions by means of stepwise logistic regression is common today and is often claimed to facilitate cytologic diagnosis. As can be expected, there usually is good agreement between the selected criteria and those given in the cytologic literature. In a study by Bottles et al based on 64 fibroadenomas, stroma, antler horn clusters and honeycomb sheets differentiated fibroadenoma from ductal carcinoma. We applied Bottles's criteria to our fibroadenoma material in order to test their value in clinical cytologic practice. In fine needle aspirates from histologically (cytologically) diagnosed fibroadenomas, stroma was found in 41 (57%), antler horn clusters in 59 (90%) and honeycomb sheets in 62 (81%), which reduced the clinical value of the criteria.

The entity of lobular carcinoma in situ within a fibroadenoma is being increasingly recognized. Clinical examination, mammography, and fine-needle aspiration are the cornerstones in managing breast masses. A patient is presented with three lumps in the left breast. Although the workup was completely negative, pathological examination revealed lobular carcinoma in situ within one of the fibroadenomas.

Ultrasound examinations of solid breast masses were reviewed retrospectively to determine whether quantitative data of their dimensions could distinguish benign from malignant tumors. Forty-nine fibroadenomas and 30 carcinomas with cytologic or histologic proof were identified. No significant difference was found between carcinomas and fibroadenomas when comparing the average ratio of length to anteroposterior (L/AP) diameter or the mean ratio of anteroposterior diameter to transverse diameter (AP/T). In this limited series, quantification of the degree of mass elongation along the natural breast tissue planes had low sensitivity in distinguishing malignant from benign tumors.

Among 145 patients with the complex of myxomas, spotty pigmentation, endocrine overactivity, and psammomatous melanotic schwannomas, 31 (21%) had mammary lesions. The ages of these 26 females and five males ranged from 6 to 64 years (mean, 30 years). Five patients had breast symptoms. In 21 (81%) of the females, benign mesenchymal lesion(s) were detected pathologically. These were characterized by accumulations of large amounts of ground substance in the lobules that alterated the stroma to a very loose and myxoid tissue. The change involved single lobules (lobular myxoid change), small groups of lobules (nodular myxoid change), and large aggregates of lobules (myxoid fibroadenoma); the interlobular stroma was affected to a lesser degree. The lesions were multicentric and bilateral in eight patients (38%). Because the myxoid breast lesions were familial, were frequent findings in the complex, and were similar histologically to the cardiac and cutaneous myxomas in the complex, they undoubtedly are a component and a pathologic marker of the complex. They were the presenting feature of the complex in six patients (19%). Therefore, discovery of the myxoid breast lesions on pathologic examination should raise suspicion of the complex, and affected patients (and their primary relatives) should be evaluated accordingly.

One hundred two patients with mammographically suspicious, nonpalpable lesions underwent stereotactic breast biopsy with a biopsy gun and an automated 14-gauge cutting needle. After biopsy, a localization wire was placed and surgical biopsy performed. There was agreement of the histologic results from the gun biopsy and the surgical biopsy specimens in 98 cases (96%), including 22 of 23 carcinomas (96%) (kappa = 0.936). The gun biopsy yielded findings that led to the correct diagnosis in two cases involving lesions that were missed at surgical biopsy; two lesions found at surgery were missed at gun biopsy. The results of this study suggest that the use of 14-gauge needles improves agreement between surgical and needle core biopsy findings and that stereotactic biopsy with an automated needle and gun can be an acceptable alternative to surgical biopsy in women with mammographically suspicious breast lesions.

The activities and distribution of monoamine oxidase (MAO) and semicarbazide-sensitive amine oxidase (SSAO) in solid breast tumour induced in the rat by treatment with 7,12-dimethylbenz(alpha)anthracene (DMBA) were studied. The mammary tumours were classified according to anatomopathological criteria into: the benign fibroadenoma (FAD) and the malignant adenocarcinoma (ADC) and infiltrant adenocarcinoma (I-ADC). The proportions of total MAO (15%) and SSAO activities (85%) did not change with malignancy. However, an increasing degree of malignancy was associated with an increase in MAO-A activity and a decrease in MAO-B and SSAO activities. Kinetic constants were calculated for SSAO and for each MAO form separately, using specific substrates. The Km values did not change significantly with the degree of malignancy, but Vmax values for MAO-A increased whereas Vmax for SSAO and MAO-B diminished with malignancy. The dependence of SSAO activity on protein concentration indicated the presence of endogenous reversible inhibitory material in extracts from the more malign tumours. This inhibitor was associated with the microsomal fraction and was not removed by dialysis. It was also present in detergent-solubilized extracts, suggesting that the phenomenon might be due to an association of the enzyme itself producing an inactive species.

The clinical and pathologic findings of 17 hamartomas of the breast were studied. All neoplasms were evident as clinically and mammographically discrete masses. The pathologic findings were varied and included circumscribed fibrocystic disease, adenolipoma, fibroadenoma with fat and fibroadenoma with lobules. The heterologous elements identified were cartilage and smooth muscle. All lesions were treated by simple excision. In this study, four different microscopic patterns of hamartoma are described and the necessity for a close clinicopathologic correlation is pointed out in the diagnosis of this lesion.

Multiple, giant fibroadenomas are histologic and clinical variants of "juvenile" or "giant" fibroadenomas. These tumors are rare and occur mainly in adolescent and young adult black females. The individual lesions are well encapsulated with a histologic pattern primarily of the "juvenile" type, although cases of the "adult" type have been reported. A high incidence of recurrence is noted upon local excision, although this may decrease as the patient becomes older. Management options include local excision with reconstruction, reduction mammoplasty, and simple mastectomy with reconstruction. A case is described of this condition with review of the literature.

This study was undertaken to determine the expression of p53 gene in cytologic specimens from benign and malignant breast lesions. To detect p53 an immunocytochemical assay with p53 (pAb421) monoclonal antibody was used. Abnormalities in p53 expression were found in 19 out of 40 Fine Needle Aspiration (FNA) smears with infiltrating ductal breast carcinomas. Benign epithelial breast cells obtained from fibroadenomas, fibrocystic disease and smears from nipple discharge reacted negatively for p53 in 38 out of 39 cases. Moderate positive reaction, confined to a few clusters of epithelial cells, was observed in one smear of fibroadenoma with cellularity. The results recorded in this study show that no significant association was found between p53 staining and stage of disease, tumor size or nodal status and that the immunocytochemical assay represents a simple method for the detection of p53 associated proteins in breast lesions.

Diethylstilbestrol (DES) has been associated with vaginal neoplasia and malformations in humans. We have studied a test population of 504 female Wistar rats given diethylstilbestrol at from 0.0 to 0.5 mg/kg maternal body weight on days 18, 19, and 20 of gestation. Animals were euthanized in extremis, or at 2 years of age. The incidence of vaginal epithelial tumors was dose related. The types of epithelial tumors of the vagina were adenocarcinoma, squamous cell carcinoma, and mixed carcinoma, containing discrete adenomatous and squamous components. The incidence of vaginal epithelial tumors was determined to be dose related: rats exposed to 0 mg DES/kg maternal weight had an incidence of 0.6% (1 of 167 rats); 0.1 mg/kg, 4.1%; and 0.5 mg/kg, 4.3% (6 of 140); 25 mg/kg, 1.6% (1 of 63); and 50 mg/kg, 11.5% (3 of 26). Tumors of other reproductive tissues (mammary gland, ovary, oviduct, cervix, or uterus) demonstrated no discernible DES dose-response relationship. There was no oncogenic effect of postnatal administration of oral contraceptives (0 oral contraceptives, 31.25 micrograms/kg diet ethynylestradiol, and 31.25 micrograms/kg diet norethindrone or 104 micrograms/kg diet ethynylestradiol and 31.25 micrograms/kg diet norethindrone). Thus, vaginal tumors can be induced in a dose-related manner in the rat following in utero DES exposure. Oral contraceptive treatment did not increase the risk of neoplasia.

Is it conservative or radical management to excise all fibroadenomas of the breast, especially in women less than 30 years old? Once a definite diagnosis is established by physical examination, fine-needle aspiration cytologic testing, and mammography, is it prudent to monitor women with small fibroadenomas (less than 4 cm in diameter)? We reviewed 498 cases of biopsy-proved fibroadenomas and 17 cases of phyllodes tumors (by biopsy) seen at Los Angeles County/University of Southern California Medical Center from 1986 to 1989. Analysis of patient age and measured tumor size in 203 fibroadenomas and 10 phyllodes tumor specimens revealed similar ranges for both tumors. The mean values were 28.5 years and 2.3 cm for fibroadenomas and 44 years and 3.8 cm for phyllodes tumors. No cases of coincident carcinoma within a fibroadenoma or of metastatic malignant phyllodes tumors were present in this review. As an alternative to excising all breast tumors, cytologically diagnosed fibroadenomas can be monitored, because they have no intrinsic premalignant potential and tend to regress with time. All breast tumors that rapidly increase in size should probably be excised at any age.

The authors report the clinicopathologic features of 105 carcinomas arising within fibroadenomas (FAs) of the breast. The mean age of the patients was 44 years. The presentation and gross characteristics of these tumors rarely differed from those of uncomplicated FAs. Carcinoma in situ (CIS) was the predominant type of malignancy (95%) found to arise in FAs, and lobular and ductal types occurred with equal frequency. Nine of ten FAs harboring an invasive carcinoma also contained CIS supporting the origin of the infiltrative component in the FAs. CIS within FAs was associated with in situ malignancy in surrounding breast tissue in 21% of cases. Age, fibroadenoma size, and type and extent of CIS were similar in patients with disease limited to the FA and in those with associated malignant disease in the remainder of the breast. Axillary nodal metastases were not detected. Sixty-three patients were observed for a mean period of 8.4 years. Only one of 26 patients with CIS within an FA who was treated conservatively developed an ipsilateral carcinoma. None of the 26 developed contralateral carcinoma; however, 3 of 23 with similar lesions, who were treated by mastectomy, did so. The contralateral carcinomas were invasive in two patients, one of whom died with distant metastases. Seven patients with FAs harboring lobular CIS underwent bilateral mastectomy. Their postoperative course was uneventful. None of seven patients with invasive carcinoma arising in an FA, two of whom were treated conservatively, succumbed to disease. However, one developed contralateral carcinoma. The authors recommend breast-conserving therapy for CIS arising in an FA.

The presence of somatostatin receptors was investigated in 57 primary human ovarian tumors using in vitro receptor autoradiography with three different somatostatin radioligands, 125I-[Tyr11]-somatostatin-14, 125I-[Leu8, D-Trp22, Tyr25]-somatostatin-28, or 125I-[Tyr3]-SMS 201-995. Three cases, all belonging to epithelial tumors, were receptor positive; specifically 1 of 42 adenocarcinomas, 1 of 3 borderline malignancies, and 1 of 2 cystadenomas. Four other epithelial tumors (3 fibroadenomas, 1 Brenner tumor), 4 sex cord-stromal tumors (2 fibrothecomas, 2 granulosa cell tumors), and 2 germ cell tumors (1 dysgerminoma, 1 teratoma) were receptor negative. In the positive cases, the somatostatin receptors were localized on epithelial cells exclusively, were of high affinity (KD = 4.6 nmol/l [nanomolar]), and specific for somatostatin analogs. These receptors bound somatostatin-14 and somatostatin-28 radioligands with a higher affinity than the octapeptide [Tyr3]-SMS 201-995. Healthy ovarian tissue had no somatostatin receptors. A subpopulation of relatively well-differentiated ovarian tumors, therefore, was identified pathobiochemically on the basis of its somatostatin receptor content. This small group of somatostatin receptor-positive tumors may be a target for in vivo diagnostic imaging with somatostatin ligands.

A cytogenetic study on 25 breast fibroadenomas from 17 women is reported. Seven tumors in five patients showed clonal structural chromosome changes. In three patients the breaks involved chromosome 12, occurring in two tumors in band 12p12 and in band 12q15 in all three tumors of one patient. The finding of an identical aberration, t(11;12)(q21;q15), in three adenomas from the same patient strongly suggests a clonal origin of multiple fibroadenomas of the breast.

Results of measurements of ultrasound speed and absorption coefficients in the range 3 to 8 MHz in breast tissues at 37 C are reported and analyzed in attempts to identify a set of ultrasound parameters capable of discriminating normal, benign, and malignant tissues. We analyzed 118 tissue regions, comprising 47 normal, 55 benign, and 16 malignant by straight-line fitting of frequency dependence of attenuation. Data for ten additional regions, for a total of 128, became available and were added to the cohort when we subsequently fitted quadratic curves. Sound speed consistently emerged as the variable with greatest discriminating power, particularly for separating normal from benign and malignant tissue. Great difficulty was encountered in discriminating benign from malignant, even when the jackknife technique was used. More success was found with classification and regression trees (CART), although results were sensitive to assigned misclassification costs. Best results from straight-line fits were obtained when discriminating malignant from combined normal/benign data after randomly assigning 75 percent of the data to the learning set and 25 percent to the test set. Then, 23 out of 25 normal/benign and 4 out of 4 malignant cases in the test set were correctly classified. With quadratic fitting, best results were obtained in the three-class case--the false positive rate for malignancy was reduced to zero in the learning (0/31) and test (0/10) sets. Nevertheless, the false negative rate increased to 13 out of 31 (42 percent) in the learning set, while attaining zero (0/4) in the test set.

In the Nottingham Breast Clinic 5000 new cases are seen annually; 3000 are sent because the general practitioner believes that he/she has found a lump. It is the diagnosis and management of this common problem that is considered in this chapter. The traditional management of the palpable breast lump included excision to establish accurate diagnosis; indeed up until 20 years ago even simple cysts were excised. Now most surgeons accept that a woman with no residual palpable abnormality after aspiration of blood-free fluid from a cyst requires no further treatment. Most solid breast lumps are benign on histological examination; their routine removal a mistake in judgement. The challenge in the management of a palpable lesion is to correctly diagnose all the cancers without having to remove those which are benign, unless the patient wishes.

Terminology in benign breast conditions has been confused by multiplicity of terms which do not relate accurately to clinical or histological patterns. Further confusion arises because terminology is not based on sound concepts of pathogenesis. The ANDI classification has been put forward as a nomenclature based on pathogenesis to replace the division of benign breast disorders into 'normal' and 'disease'. It recognizes that a spectrum exists for most conditions which extends from normal, through mild abnormality--'aberrations'--to disease. This classification allows precise definition of an individual patient problem in terms of pathogenesis, histology and clinical implications. It has proved helpful in deciding rational clinical management and in teaching the significance of benign breast disorders.

Approximately 25% of all 'discrete' breast lesions are fibroadenomas or breast cysts and they more commonly cause a breast lump than breast cancer. Despite their frequency, their natural history and relationship to subsequent breast cancer have not been clearly defined, although it would appear that palpable breast cysts, but not fibroadenomas, are associated with some increased risk of breast cancer. The diagnosis of these two entities is now possible by fine needle aspiration and excision of these lesions is only indicated in certain circumstances.

Mammography as a priority method of diagnosis of breast nodules in young women is of low efficacy as a result of a dense background of the breast as distinct from echography permitting the detection of abnormal lesion against this background. Altogether 126 patients with clinical manifestations of breast nodules were investigated. Apparatus methods used for investigation of 38 of them, revealed but manifestations of fibrocystic mastopathy. Assessment of the efficacy of x-ray and ultrasound diagnostic methods was performed in 88 patients with breast nodules (the patients varied in age from 14 to 40). Radiodiagnostic accuracy in benign tumors was 54.1% that in malignant tumors--78.1%. Ultrasound investigation proved to be the most informative method for diagnosis of breast nodules in young women, and the use of a proposed algorithm would permit optimization of the diagnostic process.

Mucinous epithelium is the most uncommon type identified in ovarian adenofibromas. Because of the rarity of mucinous adenofibromas and the presence of cytologic atypia in some, these neoplasms may be mistaken for low-grade metastatic adenocarcinoma. The clinicopathologic features of 10 mucinous adenofibromas are reviewed. They occurred in women 24 to 76 (mean, 51) years of age, were unilateral, and ranged in diameter from 1 to 25 cm. Seven tumors were classified as benign, containing glands lined by a single layer of mucin-containing columnar cells. Three tumors that contained crowded glands lined by mucin-containing cells with mild to moderate nuclear atypia, nuclear stratification of up to three cells in thickness, and focal tufting were classified as benign with epithelial atypia. Most women had a hysterectomy and bilateral salpingo-oophorectomy. Follow-up information was available on six women, who were alive and well from 6 to 126 (mean 41) months after diagnosis. The identification of mucinous glands in typical fibromatous stroma should allow the distinction of these benign neoplasms from metastatic carcinomas.

Human skin mast cells (HSMC) in situ were examined by electron microscopy of surgical biopsy specimens obtained from a wide variety of circumstances. From these studies, it is apparent that the general ultrastructural morphology of normal HSMC is similar to that of human mast cells from other sites, except that the most prevalent granule pattern is that of crystal granules. Scroll granules, particle granules, and mixed granules can also occur in HSMC. Cytoplasmic lipid bodies occur in HSMC extremely rarely, unlike mast cells from lung and gut. Circumstances in which piecemeal degranulation (PMD) of HSMC occurs, such as bullous pemphigoid, examined at high magnifications, revealed typical, focal geographic losses from cytoplasmic granules, often leaving completely empty granule containers in the cytoplasm. Crystal portions of mixed granules were uniquely susceptible to granule losses typified by PMD. Cytoplasmic smooth vesicles were prominent in PMD. These structures were either empty or contained granule-like dense materials and were free in the cytoplasm or attached to granules. HSMC present in wound healing revealed recovery from PMD losses. Typically these granules contained numerous irregular foci of markedly dense new granule products within empty or partially empty granule containers. The morphology of PMD and recovery of HSMC in vivo is contrasted with the morphology of anaphylactic degranulation (AND) and recovery of human mast cells ex vivo.

Malignant transformation of murine and human cells is commonly associated with increased--GlcNAc beta 1-6Man alpha 1-6Man beta--branching in asparagine-linked oligosaccharides. Somatic mutations and drugs which block expression of the beta 1-6 branched oligosaccharides are potent inhibitors of tumor cell invasion and metastasis in animal models. This suggests that the oligosaccharides are required for metastasis to occur and therefore their increased presence in primary tumors may be diagnostic of metastatic disease. Although antibodies to the beta 1-6 branched portion of the oligosaccharides are not available, a plant lectin leukoagglutinin (L-PHA) has been shown to bind specifically to this structure. L-PHA lectin histochemistry was performed on paraffin sections of human breast and colon tissues. All breast carcinomas and epithelial hyperplasia with atypia showed significantly increased L-PHA staining compared to fibroadenomas and hyperplasia without atypia. In histological sections of colon, adenomas showed a small but significant increase in L-PHA staining compared to normal colonic epithelium, while carcinomas showed greatly increased reactivity. In addition, Dukes stage C tumors showed higher levels of L-PHA staining than stage A tumors. These results demonstrate that L-PHA-reactive beta 1-6 branched N-linked oligosaccharides are consistently increased in neoplasias of human breast and colon and that the level of L-PHA staining correlates with the pathological staging of the diseases.

Morphology of mammary fibroadenoma (FA) is well studied while this is not the case for its morphogenesis and prognosis. The role of a stromal component in the development of FA is outlined. Immune response in FA is mainly directed to the fibroblasts. Further studies of mammary FA will allow one to reveal the biological properties of this tumour and to evaluate adequately its prognosis as in 0.5-2% of cases it undergoes malignant transformation.

A 76-year-old man with multiple erythematous lesions on his palms and soles which appeared following bullous pemphigoid (BP) is the subject of this case report. The lesions were not raised above the normal skin level, and there were no nodules on the erythematous lesions. The lesions had the histologic appearance of eccrine syringofibroadenoma. This condition is considered to be not a true tumor but a hyperplasia of eccrine sweat ducts following recurrent subepidermal blister formation in BP.

The carcinogenicity of ochratoxin A, a naturally occurring mycotoxin of the fungal genera Aspergillus and Penicillium, was evaluated in three strains of mice and in one strain of rats. The kidney, and in particular the tubular epithelial cells, was the major target organ for ochratoxin A-induced lesions. In male ddY and DDD mice, atypical hyperplasia, cystadenomas and carcinomas of the renal tubular cells were induced, as were neoplastic nodules and hepatocyte tumours of the liver. In B6C3F1 mice, tubular-cell adenomas and carcinomas of the kidneys were induced in male mice, and the incidences of hepatocellular adenomas and carcinomas were increased in male and female mice. In male and female F344 rats, ochratoxin A induced nonneoplastic (degeneration, karyomegaly, proliferation, cytoplasmic alteration, hyperplasia) and neoplastic effects (adenomas, and carcinomas with metastases) in the kidneys; the incidence of fibroadenomas of the mammary glands was also increased in female rats. Other studies on ochratoxin A were considered inadequate for evaluating the presence or absence of a carcinogenic effect; however, these are mentioned and referenced below. The collective experimental findings, together with accumulating evidence in humans, forecast further toxic and carcinogenic effects in humans exposed to ochratoxin A, mainly via foodstuffs.

Flow cytometric analysis of DNA ploidy level in fresh tissue samples of human breast tumors has been carried out extensively. Recently, investigations regarding the prognostic value of nuclear DNA content have been facilitated by using nuclei isolated from paraffin-embedded tissues. The aim of our study was to monitor the possible differences between the analysis in fresh and fixed paraffin-embedded tissues in the same tumor and to investigate the possible prognostic implications obtained with this new approach. Nuclei suspensions were obtained, according to the method proposed by Hedley et al. with minor modifications, from 45 carcinomas and 5 fibroadenomas. Flow cytometric analysis revealed diploidy in 57% of carcinomas, while the remaining 43% showed cytometric aneuploidy. Corresponding results were observed between fresh and paraffin-embedded tissue in 26/35 cases. Moreover, a fairly good correlation between the DNA indices of fresh and paraffin-embedded carcinoma samples was observed. Furthermore, the frequency of recurrence was higher in the aneuploid group. Finally, 4 fibroadenomas were diploid and one was aneuploid. Our results confirm that this approach permits retrospective studies to evaluate the potential prognostic significance of nuclear DNA content monitored by flow cytometry.

A case of carcinoma of the breast concurrent with a fibroadenoma in a 49-yr-old female is described in which the diagnosis was made on fine-needle aspiration cytology. Reports of such an occurrence are few, and to our knowledge none has previously documented the cytologic findings in detail.

Immunostaining for glial fibrillary acidic protein (GFAP) identifies a minor subpopulation of immunoreactive myoepithelial cells in the normal resting human breast. The GFAP-immunoreactive cells also express a panel of myoepithelial cell markers, including cytokeratin 14 (CK 14), vimentin, smooth-muscle-specific actin isoforms, nerve growth factor receptor (NGFR) and common acute lymphoblastic leukaemia antigen (CALLA). The percentage of GFAP-immunoreactive myoepithelial cells is greatly increased in various neoplastic and non-neoplastic diseases of the breast, being highest in adenomyoepitheliomas. Furthermore, in all the instances of fibroadenoma, phyllodes tumour, epitheliosis and gynaecomastia, a variable number of epithelial cells also acquires immunoreactivity for GFAP, vimentin, CK 14, NGFR and, to a lesser extent, for CALLA. Conversely, GFAP immunoreactivity has never been encountered in the malignant cells of the different types of breast carcinoma. These findings suggest that the expression of GFAP might be a (possibly transient) feature of proliferating epithelial and myoepithelial cells in breast diseases other than carcinomas.

The extracranial spread of primary intercranial tumours is infrequent, occurring most commonly with medulloblastoma. The spread of one malignant tumour to a second tumour, benign or malignant, is also very rare. This case appears to be unique, in that a primary malignant cerebral tumour metastasized to a benign extracranial tumour.