Pleomorphic lobular carcinoma of the breast: clinicopathologic features of 12 cases

Pleomorphic lobular carcinoma (PLC) of the breast was recently identified as a histologic variant of infiltrating lobular carcinoma (ILC) with a poor prognosis. Twelve cases identified from a large series of breast carcinomas were studied retrospectively. Of 11 cases with adequate follow up, 9 were fatal. This was significantly worse than either infiltrating ductal carcinoma (IDC) or classical ILC (P < or = .002), even when stratified by axillary lymph node status. Among the fatal cases, the median survival time was 2.1 years, significantly shorter than that for classical lobular, but not ductal, carcinoma A distinctive pattern of in situ carcinoma, which has been described as PLC in situ, was identified in 7 of the 12 patients. This in situ component was composed of tumor cells with nuclear atypia, cytologically similar to the invasive tumor. Most PLCs lacked estrogen and progesterone receptors and stained with BRST-2, an antibody to gross cystic disease fluid protein-15, suggesting the presence of apocrine differentiation. In summary, PLC has many of the histologic features of ILC but has anaplastic nuclei, abundant cytoplasm, and apocrine differentiation. PLC is often aneuploid, usually lacks steroid receptors, and has a significantly poorer prognosis than does classical ILC.     

Multiplex inheritance of component phenotypes in a murine model of lupus

Histopathological identification of invasive breast carcinoma in its earliest phases is fraught with pitfalls. Preinvasive malignant lesions complicated by radial scar, sclerosing adenosis, and lobular cancerization, among other lesions, may simulate invasive carcinoma. Fibrosis, inflammatory reaction, and other stromal changes around in situ carcinoma may mask microinvasive foci on routine stains. Conventional immunohistochemistry to demonstrate basement membrane or myoepithelial cell layer may not, by itself, be unequivocally diagnostic of invasion. We performed a novel double immunoenzyme labeling technique using an avidin-biotin complex peroxidase-diaminobenzidine system for smooth-muscle actin followed by an alkaline phosphatase anti-alkaline phosphatase-new fuchsin system for cytokeratin antigen on formalin-fixed, paraffin-embedded histology sections to evaluate 32 such problematic cases. The initial histologic impression with hematoxylin and eosin staining alone was as follows-first group: microinvasive carcinoma-10; second group: carcinoma in situ--"stromal invasion cannot be ruled out"--15; third group: frankly infiltrating carcinoma of various grades and morphologic types-6. The last group served as positive control for invasion. One fibroadenoma with fine-needle-aspiration-induced artifact simulating stromal invasion was also included. The double immunoenzyme labeling technique imparted a dark brown color to the myoepithelial cells and a vivid red color to the epithelial cells, making individual or loosely cohesive groups of malignant epithelial cells infiltrating the stroma easily detectable, whereas their in situ counterparts were contained within dark brown myoepithelial boundaries. The TNM 1997 definition of pT1mic, i.e., extension of malignant cells in the stroma with no focus measuring >0.1 cm, was followed to classify microinvasion. In the first group, microinvasion was confirmed in six cases but was not demonstrable in four. In the second group, definite invasion was identified in five cases, ruled out in nine, and in one case the suspicion of early invasion could not be entirely ruled out even after double immunoenzyme labeling. Thus, it was possible to render a definite opinion regarding presence or absence of invasion in 24 of 25 (96%) cases diagnosed as or suspected to be microinvasive. The precise and simultaneous elucidation of topography between malignant cells and myoepithelial cells on a single permanent section makes this technique a useful diagnostic tool in the evaluation of those cases of breast carcinoma that exhibit equivocal invasion.     

Simultaneous loss of E-cadherin and catenins in invasive lobular breast cancer and lobular carcinoma in situ

Loss of expression of the intercellular adhesion molecule E-cadherin frequently occurs in invasive lobular breast carcinomas as a result of mutational inactivation. Expression patterns of E-cadherin and the molecules comprising the cytoplasmic complex of adherens junctions, alpha-, beta- and gamma-catenin, were studied in a series of 38 lobular breast carcinomas with known E-cadherin mutation status. The effect of loss of E-cadherin by mutational inactivation (or other mechanisms) on the expression of catenins was investigated. Complete loss of plasma membrane-associated E-cadherin expression was observed in 32 out of 38 invasive lobular carcinomas, for which in 21 cases a mutation was found in the extracellular domain of E-cadherin. In total, 15 frameshift mutations of small deletions or insertions, ranging from 1 to 41 bp, three non-sense mutations, and three splice mutations were identified. Mutations were scattered over the whole coding region and no hot spots could be detected. In all cases, simultaneous loss of E-cadherin and alpha- and beta-catenin expression was found; in 50 per cent of these cases, additional loss of gamma-catenin was observed. In six invasive lobular carcinomas, expression of both E-cadherin and catenins was retained. In none of these carcinomas was an E-cadherin mutation detected. Lobular carcinoma in situ adjacent to invasive lobular carcinoma showed simultaneous loss of E-cadherin and catenins in all the cases studied--remarkably, also, in four cases positive for E-cadherin and catenin expression in the invasive component. These results indicate that simultaneous loss of E-cadherin and alpha-, beta- and gamma-catenin may be an important step in the formation of lobular carcinoma in situ, as a precursor of invasive lobular breast cancer. Events additional to E-cadherin inactivation must be involved in the transition of lobular carcinoma in situ to invasive lobular carcinoma.     

Lobular carcinoma in situ of the breast: results of a radiosurgical conservative treatment

From 1980 to 1992, 17 women underwent lumpectomy (13) or quadrantectomy (4) and whole breast irradiation (median dose: 52 Gy) for pure lobular carcinoma in situ (LCIS). Three cases correspond to palpable lesions and 14 were discovered only by mammography. Twelve women also received tamoxifen at 20 mg/day for two years. With a median follow-up of 88 months, no local or regional recurrences have been recorded. The global rate of bilateral carcinoma was 17.6% (2 synchronous and one metachronous). In the literature, only eight other cases of LCIS were treated by lumpectomy and radiation therapy, but without details and data on long-term results. After biopsy alone for LCIS subsequent infiltrating carcinoma occurred in about 15% of the cases. Thus, the classical radiosurgical association should represent an interesting alternative both for biopsy alone and radical surgery until now only proposed to treat LCIS.     

Vimentin expression in different types of breast carcinoma immunohistochemical study

Vimentin was preferentially expressed in medullary and high grade ductal not otherwise specified (NOS) carcinomas. It was not expressed in lobular carcinoma whether of the classical or the variant types. In the present study, 58 cases of invasive breast carcinomas were tested for vimentin on formaldehyde fixed paraffin embedded sections. Vimentin was expressed in 14/ 44 (32%) of infiltrating duct carcinoma NOS. It was expressed in less than 10% of tumour cells in 5/44 (11.4%) and in > or = 10% of tumour cells in 4/7 (57%). However, none of the lobular carcinoma expressed vimentin. Vimentin was expressed in 9 of 18 (50%) of grade III infiltrating duct NOS carcinoma versus 5 of 21 (24%) of grade II and 0 of 5 (0%) of grade I carcinoma. It was preferentially expressed in tumour growing in broad anastomosing bands or sheets with numerous mitoses, high nuclear grade, scanty supportive stroma and extensive necrosis.     

Core needle biopsy of synchronous ipsilateral breast lesions: impact on treatment

OBJECTIVE: The purpose of this study was to evaluate the role of core biopsy in the diagnosis of multiple synchronous ipsilateral breast lesions and to determine the impact of this information on patients' management. MATERIALS AND METHODS: Of 371 patients who underwent core-needle breast biopsy under stereotaxic (n = 278) or sonographic (n = 93) guidance, 20 (5%) underwent core biopsy of two mammographically separate lesions in the ipsilateral breast on the same date. Fourteen of these 20 patients subsequently underwent surgery. We retrospectively reviewed the medical, radiographic, and histopathologic records in these 14 patients and in 91 patients with single mammographic lesions diagnosed as carcinoma by means of core biopsy during the same period. RESULTS: In 11 patients, core biopsy revealed two sites of carcinoma. Core biopsy findings in these 11 patients were two areas of infiltrating ductal carcinoma (n = 5), one infiltrating ductal carcinoma and one infiltrating lobular carcinoma (n = 2), one infiltrating ductal carcinoma and one ductal carcinoma in situ (n = 1), and two foci of ductal carcinoma in situ (n = 3). All 11 patients with two core biopsy-proven foci of carcinoma underwent mastectomy. Patients were significantly more likely to be treated with mastectomy if core biopsy revealed two rather than one site of carcinoma (100% versus 38%, p < .001). CONCLUSION: Core-needle biopsy is useful in diagnosing multiple synchronous ipsilateral breast lesions. By showing whether carcinoma is present in one or more sites in the breast, core biopsy can provide information of critical importance in making treatment decisions.     

Tubulolobular invasive breast cancer: a variant of lobular invasive cancer

Attention is directed to an apparently unique form of invasive breast cancer designated as tubulolobular invasive cancer. These neoplasms exhibit small tubules as well as cords of neoplastic cells in a lobular configuration reminiscent of lobular invasive carcinoma. The clinical and pathologic characteristics encountered in 24 examples were statistically compared with those of infiltrating ductal carcinomas without special specific features, pure tubular, and pure lobular invasive cancer. The results of these analyses as well as the morphologic characteristics of these lesions prompt the conclusion that this lesion represents a tubular variant of lobular invasive carcinoma. Short term treatment failure rates in patients with tubulolobular invasive carcinoma are intermediate between those of pure tubular cancer and lobular invasive carcinoma.     

E-cadherin inactivation in lobular carcinoma in situ of the breast: an early event in tumorigenesis

In breast cancer, inactivating point mutations in the E-cadherin gene are frequently found in invasive lobular carcinoma (ILC) but never in invasive ductal carcinoma (IDC). Lobular carcinoma in situ (LCIS) adjacent to ILC has previously been shown to lack E-cadherin expression, but whether LCIS without adjacent invasive carcinoma also lacks E-cadherin expression and whether the gene mutations present in ILC are already present in LCIS is not known. We report here that E-cadherin expression is absent in six cases of LCIS and present in 150 cases of ductal carcinoma in situ (DCIS), both without an adjacent invasive component. Furthermore, using mutation analysis, we could demonstrate the presence of the same truncating mutations and loss of heterozygosity (LOH) of the wild-type E-cadherin in the LCIS component and in the adjacent ILC. Our results indicate that E-cadherin is a very early target gene in lobular breast carcinogenesis and plays a tumour-suppressive role, additional to the previously suggested invasion-suppressive role.     

Metastatic gastric cancer arising from breast carcinoma: endoscopic ultrasonographic aspects

Linitis plastica of the stomach was diagnosed in four patients. Endoscopic ultrasonography (EUS) was performed in four cases; they were monitored by EUS and had their treatment adapted accordingly. According to the present study, the typical criteria of gastric linitis at EUS are: (a) rigidity of the gastric wall; (b) a wall thickness exceeding 6 mm; (c) a second enlarged layer marginally more echogenic than the fourth hypoechogenic layer (muscularis propria); (d) a third hyperechogenic enlarged layer; and (e) a poor demarcation between layers. Gastric linitis appears more likely to be specific metastasis from lobular breast carcinoma. In most of the follow-up cases, EUS showed correlation with a subsequent decrease of the CA15.3 level. At present, EUS seems to be the most effective and least invasive examination for clinical diagnosis and treatment surveillance of secondary gastric linitis arising from infiltrating lobular carcinoma (ILC) of the breast.     

Breast cancer screening: first round in the population-based program in Valencia, Spain. Collaborative Group of Readers of the Breast Cancer Screening Program of the Valencia Community

PURPOSE: To analyze the results of round 1 of the population-based Valencia Breast Cancer Screening Program. MATERIALS AND METHODS: In this program, 78,224 (72.98%) of the 107,178 women invited (aged 45-65 years) underwent screening. Complementary views were obtained in 5,771 women (7.38%). Among the total population studied, 3,502 (4.48%) underwent short-term mammographic follow-up studies; 3,898 (4.98%) underwent additional studies and treatment at hospitals. Five hundred eighty-seven women (0.75%) underwent biopsy. RESULTS: Cancer was detected in 334 patients (4.27 cancers per 1,000 women [3.24 per 1,000 women aged 45-49 years, 6.30 per 1,000 women aged 60-65 years]; six patients with lobular carcinoma in situ excluded). The estimated sensitivity was 89%; specificity, 99%. The positive predictive value of mammography was 8.56%; of mammography with additional examinations, 26.82%; and of biopsy, 56.89%. Forty-one patients (12.28%) had ductal carcinoma in situ; 284 (85.03%) had infiltrating carcinoma. In 73 (25.70%) of the 284 patients, infiltrating carcinomas were smaller than 1 cm. Two hundred twenty-five patients (76.27%) had no lymph node involvement. One hundred seventy-nine (61.09%) had stage 0 or 1 cancer. CONCLUSION: Results are consistent with other published results; differences are due to methods and patient population characteristics.     

Sociosomatics and illness in chronic fatigue syndrome

Angiogenesis is essential for tumour growth and important in tumour metastasis and prognosis. Vascular endothelial growth factor (VEGF) stimulates endothelial proliferation in vitro and angiogenesis in vivo. VEGF expression has been correlated with high vascularity in tumours, including carcinoma of the breast. This study investigated VEGF expression and vascularity of invasive lobular (n = 10) and invasive ductal carcinoma (n = 28), and pure ductal carcinoma in situ of the breast (n = 33). VEGF protein expression was studied with immunohistochemistry and VEGF mRNA with in situ hybridization. Vascular density was assessed on sections stained for von Willebrand factor. There was more expression of both VEGF protein (P = 0.006) and mRNA (P = 0.002) in invasive ductal than in invasive lobular carcinoma. VEGF protein (rs = 0.32, P = 0.047) and mRNA (rs = 0.56, P = 0.04) correlated with vascular density in invasive ductal carcinoma. In invasive lobular carcinoma, vascular density did not correlate with VEGF mRNA (rs = 0.15, P = 0.35) and was inversely related to VEGF protein (rs = -0.57, P = 0.04). There were no significant differences in vascular density between the two types of invasive carcinoma, suggesting that VEGF is important in angiogenesis in invasive ductal carcinoma, but that other angiogenic factors are important in invasive lobular carcinoma. Although VEGF protein was frequently expressed in ductal carcinoma in situ, no relationship was found between VEGF and the two patterns of angiogenesis previously described.     

Morphogenesis of dysplasia and lobular cancer of the breast

During the recent ten-year period lobular cancer of the mammary gland arrests special interest. It is characterized by a specific clinical course, frequent bilateral involvement of the glands, multicentric and manifest invasive growth without any noticeable signs of destruction of the pre-existing glandular tissue. This cancer is preceded by carcinoma in situ. In the paper, the necessity is substantiated to differentiate this kind of cancer as a special nosological unit, its peculiar structure being described. Besides the classical form of the growth from small homologous cells like chains, also there was found a special form of the growth as alveolar structures consisting of light pagetoid cells. The initial stages of lobular cancer growth are described both against the background of carcinoma in situ and avoiding it from dysplasia. Attention is given to a tendency of this cancer to mucicarminophilia, a frequent association with mucous cancer, the data speaking in favour of its myoepithelial origin are reported. It is emphasized that carcinoma in situ may give rise both to lobular (myoepithelial origin) and other forms of cancer.     

Comparative genomic hybridization analysis of lobular carcinoma in situ and atypical lobular hyperplasia and potential roles for gains and losses of genetic material in breast neoplasia

Lobular carcinoma in situ (LCIS) and atypical lobular hyperplasia (ALH) of the breast are cytologically similar breast lesions that reportedly carry different relative risks of subsequent development of invasive carcinoma. They are frequently multifocal and bilateral. We have identified the chromosomal copy number changes in 31 LCIS and 14 ALH lesions from 28 cases and also the 7 invasive carcinomas that subsequently developed in 6 of these cases. This was achieved by comparative genomic hybridization analysis of microdissected formalin-fixed, paraffin-embedded material. There was no significant difference between the aberrations found in the unilateral versus the bilateral cases of LCIS. Loss of material from 16p, 16q, 17p, and 22q and also gain of material from 6q were found at a similar high frequency in LCIS and ALH. Loss of these genomic regions may indicate the locations of genes that predispose to the development of the lesions, and the results are consistent with LCIS and ALH representing the same genetic stage of development. Comparison of the comparative genomic hybridization results from LCIS/ALH with those from ductal carcinoma in situ and invasive cancer showed some similarities at the chromosomal level, but it also showed significant differences, including gain of 1q and 8q and evidence for genomic amplification, which were not found in LCIS/ALH. A genetic model is postulated for the possible relationships between noninvasive lobular lesions and invasive breast carcinoma, delineating potential roles for specific chromosome copy number changes.     

Small cell carcinoma of the male breast: report of a case

An uncommon type of breast carconoma in a male studied by light and electron microscopy, is reported. Light microscopy reveals histologic characteristics and a pattern similar to infiltrating lobular carcinoma in the female breast. The ultrastructural study, because of close similarities in cellular characteristics with previously published reports, gives firm support to the light microscope findings.     

Pseudoangiosarcomatous carcinoma of the genitourinary tract

Two cases of pseudoangiosarcomatous carcinoma of the genitourinary tract, arising in the vulva in one and the bladder in the other, are presented. In case 1, an 84 year old woman, the vulvectomy specimen contained an irregular ulcerated tumour, infiltrating the left labia and extending into the clitoris. In case 2, a 59 year old woman, the excised bladder showed diffuse thickening of its wall by infiltrating haemorrhagic tumour. Both tumours showed focal keratinisation. This, in association with the presence of atypical squamous epithelium, immunohistochemistry and ultrastructural analysis, led to a diagnosis of pseudosarcomatous carcinoma in both cases. Pseudoangiosarcomatous carcinoma should be considered in the differential diagnosis of malignant angiomatoid tumours, particularly those that arise at sites, like the genitourinary tract, where angiosarcoma is rare.     

Surgical therapy strategies in carcinoma in situ of the breast

The surgical treatment of carcinoma in situ of the breast depends on the histological type. After detecting a lobular carcinoma in situ (CLIS) either an intensive (aftercare) follow-up is recommended or a bilateral mastectomy. The choice for one of these two very different forms of therapy can be done only after intensive psychological dialog with patient. The reason for the different forms of further treatment is the multicentric and often bilateral occurrence of CLIS and the potential risk of developing an invasive cancer. The therapy of the ductal carcinoma in situ (DCIS), which often spread out in a segment of one breast, is the total excision of the lesion with clear margins. The Van Nuys Prognostic Index depending on the histological results (tumor-diameter, thickness of clear margins, pathocytologic classification) indicates further treatment such as radiotherapy or mastectomy to lower the chance of local recurrence.     

Occurrence of asthma and chronic bronchitis among female hairdressers. A questionnaire study

AIMS: We examined the relationship between apoptosis and three different major stages of human breast carcinoma: intraductal carcinoma (DCIS), infiltrating duct carcinoma (IDC) and metastatic carcinoma in lymph nodes. We also determined the correlation between apoptosis and oestrogen receptor (ER), progesterone receptor (PR) and p53. METHODS AND RESULTS: The study investigates the extent of apoptosis in 63 breast carcinomas by in-situ end-labelling, in formalin-fixed, paraffin-processed tissue sections. The 63 breast carcinomas, included 22 DCISs, 26 IDCs, three infiltrating lobular carcinomas (ILC) and 12 metastatic lymph nodes. The apoptotic labelling index was higher in DCIS than IDC and metastatic carcinoma (P < 0.001, P < 0.007, respectively). By immunohistochemistry, we also analysed p53, ER and PR. Apoptosis correlated significantly with p53 (r = 0.748, P = 0.0004) in IDC. Also, ER correlated significantly with PR (r = 0.629, P = 0.00001). No apparent correlation was found between the apoptosis and ER or PR. CONCLUSION: Our data suggest that not only does apoptosis differ between intraductal carcinoma and infiltrating carcinoma but also it might be regulated by altered p53 expression.     

Mucinous lesions of the breast. A pathological continuum

Mucocele-like tumor and invasive mucinous carcinoma of the breast may represent the two ends of the pathological spectrum of mucinous lesions of the breast, respectively. Little data exists on mucinous lesions that may be considered intermediate between mucocele-like tumor and invasive mucinous carcinoma. We studied 23 consecutive cases of invasive mucinous carcinoma of the breast and observed the following associated intermediate mucinous lesions: mucin-filled ducts (MFD) with unremarkable epithelium in 15 cases (65%), MFD with typical ductal hyperplasia in 9 cases (39%), MFD with atypical ductal hyperplasia in 5 cases (22%), and MFD with intraductal carcinoma in 13 cases (57%; micropapillary or cribriform types). Eighteen cases (78%) contained MFD with one of these four lesions and five cases (22%) contained all four lesions. Twenty-three consecutive cases of infiltrating ductal carcinoma-not otherwise specified (IDC-NOS), 21 cases of intraductal carcinoma, and 50 consecutive cases of surgically-excised breast tissue with fibrocystic change (FC), were similarly reviewed. Only one case (4%) of IDC-NOS, 1 case of intraductal carcinoma, and two cases (4%) of FC, contained small foci of MFD with intraductal carcinoma, intraductal carcinoma, and unremarkable epithelium, respectively. Our findings suggest the presence of a spectrum of mucinous lesions of the breast which represents a pathological continuum.     

Effect of ethanol on myocardial infarct size in a canine model of coronary artery occlusion-reperfusion

INTRODUCTION: We investigated the effectiveness of Levovist (SHU508A, Schering AG, Berlin, Germany) in the characterization of breast lesions. MATERIAL AND METHODS: June, 1996, to May, 1997, we studied 29 solid lesions in 29 patients (aged 17 to 83 years); our patients were 28 women and 1 man. The 29 solid lesions were 20 carcinomas (15 infiltrating ductal carcinomas, 4 ductal carcinomas in situ, 1 lobular carcinoma in situ), 6 fibroadenomas, 1 suspected postoperative recurrence and 2 apparently benign lesions. We used parameters suitable for the study of slow flows. A single bolus of contrast agent (300 mg/mL) was administered at 1-2 mL/s. Before Levovist injection, we studied the lesion signal intensity and the number of vascular poles. After contrast administration we re-evaluated both these parameters and studied the changes or presence of vessels undetected on the previous images. We also investigated the beginning and duration of enhancement and the presence of vessels inside and outside the lesions. RESULTS: We observed no signal enhancement in 17% of cases, mild enhancement in 7% and strong enhancement in 76% of cases. We found 3 more vascular poles (17%) in 5 lesions and 4 more poles in 3 lesions (10%). Increased vascularization was seen inside the lesion in 17% of cases, inside and outside it in 41% and only outside in 35% of cases. Carcinomas showed a rapid and long-lasting enhancement, while fibroadenomas showed a later and weaker enhancement. CONCLUSIONS: Levovist can be useful in the differential diagnosis of benign from malignant lesions, of recurrences from postoperative fibrosis, as well as in the staging and follow-up of the patients treated with neoadjuvant chemotherapy.     

Coexpression of hepatocyte growth factor and receptor (Met) in human breast carcinoma

Expression of hepatocyte growth factor (HGF) and HGF receptor (HGFR, product of the met proto-oncogene) mRNA were examined by nonisotopic in situ hybridization in a spectrum of benign and malignant human breast tissues. mRNA for both HGFR and HGF was detected in benign ductal epithelium. Epithelial expression of HGF mRNA was particularly intense in regions of ductal epithelial hyperplasia. Positive expression of HGF (but not HGFR) mRNA was also found in adipocytes, endothelial cells, and to varying degrees in stromal fibroblasts. In 12 of 12 cases of ductal carcinoma in situ and infiltrating ductal carcinoma, carcinoma cells showed a heterogeneous pattern of expression for both HGFR and HGF mRNA. In infiltrating ductal carcinomas, intense expression of HGFR mRNA was not restricted to ductular structures but as also seen in non-duct-forming carcinoma cells. The same zones of the tumors (most commonly at the advancing margins) that expressed strongly HGFR mRNA often were also strongly positive for HGF mRNA, suggesting a possible autocrine effect. The expression pattern of HGFR protein in 25 cases including the same series of tissues used for in situ hybridization analysis was similar to that of HGFR mRNA, as determined by an immunoperoxidase technique. The finding that HGFR is expressed by both benign and malignant epithelium, and its not restricted to duct-forming structures, suggests that, although the potential for HGF/HGFR binding is maintained in malignancy, the response to ligand binding at the level of the receptor or the cellular response to receptor activation may change at some point during progression.