Invasive papillary and pseudopapillary (micropapillary) carcinoma of breast

Classical invasive papillary carcinoma of the breast, is rare. In their pure form, they constitute 1.5% of all invasive breast carcinomas. Only one study clearly distinguishes them from intra-ductal papillary carcinomas; in this study they display a low metastatic potential and a relatively good prognosis. Lately, a new type of papillary carcinoma has been described which is characterized by inversion of the tumor cell polarity and papillations devoid of fibrovascular cores. Described by several authors by the term "micropapillary" carcinoma, the originally suggested term "pseudo-papillary" seems to be more appropriate; moreover, this designation would more clearly distinguish them from papillary carcinomas from which they clearly differ by their behavior. Furthermore, the pseudo-papillary carcinomas present an important lymphotropism, the effect of which on their clinical course is not yet clear. Further studies are necessary to determine whether these tumors, more frequent than classical papillary carcinomas, should be considered as a distinct clinical entity.     

Stromal fragments in invasive carcinoma. Source of diagnostic difficulty in aspiration cytology

OBJECTIVE: To analyze three cases of stromal fragments in invasive carcinoma that created diagnostic difficulty in aspiration cytology. STUDY DESIGN: A retrospective review of fine needle aspiration cytology (FNAC) smears of a breast tumor, scalp tumor and neck mass. Cytomorphologic features of all the smears were reviewed after histology became available. RESULTS: FNAC smears revealed a biphasic pattern: a carcinomatous component and a stromal component that was either discrete or in close apposition to the carcinoma. The cytopathologist had suggested the diagnosis of a biphasic tumor in each case--phyllodes, malignant skin adnexal and salivary gland tumor. Histopathology revealed an invasive carcinoma with altered stroma in the first two cases and metastatic lymph node with perinodal soft tissue extension in the third case. CONCLUSION: Stromal changes in response to infiltrating carcinoma are well documented in surgical pathology. However, these may also be encountered in FNAC smears. The above cases stress the importance of recognizing stromal fragments in aspiration cytology in order to avoid diagnostic errors.     

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.     

Drug resistance to 5-aza-2''-deoxycytidine, 2'',2''-difluorodeoxycytidine, and cytosine arabinoside conferred by retroviral-mediated transfer of human cytidine deaminase cDNA into murine cells

Squamous metaplasia can be demonstrated in about 4% of all invasive carcinomas of the breast. Primary squamous cell carcinomas of the breast are rare, since they occur in less than 1% of all primary invasive breast carcinomas. In order to classify a breast tumor as a primary squamous cell carcinoma one must exclude an epidermal origin, especially from the nipple region and the possibility of metastatic infiltration of the breast by a squamous cell carcinoma from a different location. Causative and formal pathogenesis of primary squamous cell carcinoma of the breast is not clear. A pluripotent embryonal stem cell origin is discussed, considering the phylogenetic descent of the mammary gland from skin appendages. Squamous metaplasia is also suggested to be a precursor of squamous cell carcinoma. Here endocrine stimulation and chronic inflammation may both play an inductive role. The number of published cases of squamous cell carcinomas developing years and decades after implantation of silicon prostheses has increased in recent years. These tumors probably develop on top of squamous metaplasia induced by the inflammatory pseudocapsule. Estimating the prognosis and therapeutic management in patients with squamous cell carcinoma of the breast should follow the same guidelines as for other squamous cell cancers.     

Solitary breast metastasis as first manifestation of ovarian carcinoid tumor

Carcinoid tumor metastatic to the breast is very uncommon. The rarity of this finding may be the reason for its common misinterpretation as primary breast carcinoma. A patient with primary ovarian carcinoid that presented initially with a solitary breast mass is reported. A review of the literature discloses only 12 reported cases of carcinoid tumor metastatic to the breast, with none of the primaries found to be the ovary.     

Early invasive colorectal carcinomas metastatic to the lymph node with attention to their nonpolypoid development

Clinicopathologic study of six cases of early invasive colorectal carcinoma metastatic to lymph node was performed in order to elucidate possible characteristics relating to the risk of metastasis, with particular attention to the growth pattern of the primary tumor. All of the cases had at least one of the well-known risk factors for lymph node metastasis, including moderately or poorly differentiated histologic characteristics, considerable degree of submucosal invasion, and lymphatic invasion. An interesting finding of the present study was the identification of a nonpolypoid growth pattern with no concomitant adenomatous tissue, which seemed to be different from that of "malignant polyps" of previously reported cases showing adenoma-carcinoma sequence. This unique growth feature was found in all of the cases. Therefore, in addition to the accepted risk factors, nonpolypoid growth pattern and absence of adenomatous component may be risk factors predictive of nodal metastasis in patients with early invasive colorectal carcinoma.     

Breast metastasis of cervical carcinoma diagnosed by fine needle aspiration cytology. A case report

BACKGROUND: Metastatic disease of the breast is often an unexpected diagnosis in a female presenting with a breast mass. The most common metastatic cancer to involve the breast is melanoma. Among gynecologic tumors, the most common primary is ovarian carcinoma. Carcinoma of the cervix metastasizing to the breast is extremely rare. CASE: A 45-year-old female developed multiple bilateral breast masses during a course of radiotherapy for carcinoma of the cervix. Cytologic smears of the breast masses revealed adenocarcinomatous cells as well as keratinizing and nonkeratinizing malignant squamous cells, consistent with a histopathologic diagnosis of metastasizing adenosquamous carcinoma of the breast from primary cervical cancer. CONCLUSION: Fine needle aspiration cytology diagnosis of malignancy metastatic to the breast is important to differentiate it from a second primary tumor and avoid an unnecessary mastectomy.     

Carcinoid tumor metastatic to the breast

Breast metastases from nonmammary malignant neoplasms are uncommon, accounting for approximately 2% of breast tumors. There are 13 cases reported in the literature of carcinoid tumor metastatic to the breast, and more than half of these cases were misdiagnosed pathologically and treated as primary breast carcinoma, even in cases with a medical record of carcinoid tumor. We describe a patient with a history of asthma and diarrhea who presented to the University of Arkansas for Medical Sciences, Little Rock, with an exacerbation of the asthma. The results of routine physical examination revealed a mass in the left breast. A diagnosis of carcinoid tumor metastatic to the breast was made after a partial mastectomy was performed. The differential diagnosis between primary carcinoid tumor of the breast and carcinoid tumor metastatic to the breast is often controversial in surgical pathology. Diagnoses need to be made correlating clinical and histological examination in difficult cases in which there is not a diagnosis of carcinoid tumor elsewhere. Accurate diagnosis of breast metastases is important to avoid unnecessary treatment.     

Evidence for the multifocal origin of bilateral and advanced human serous borderline ovarian tumors

Borderline ovarian tumors (BOTs), or ovarian tumors of low malignant potential, represent a distinct category of epithelial ovarian neoplasms that have a clinically more favorable outcome than invasive epithelial ovarian cancer. Histologically, BOTs and invasive ovarian carcinomas both show cellular proliferation and pleomorphism, but unlike invasive ovarian carcinomas, BOTs lack stromal invasion. Although serous BOTs are frequently confined to a single ovary at the time of diagnosis, bilateral or extra-ovarian spread occurs in 30-40% of cases. The purpose of this study is to determine whether bilateral or extraovarian serous borderline lesions are metastatic sites from the original tumor, or represent separate primary tumors. DNA specimens from multiple tumor sites and normal tissue controls were obtained in eight women with bilateral or extra-ovarian serous borderline tumors. The pattern of loss of heterozygosity at the androgen receptor locus on the X chromosome was evaluated in the multiple tumor sites. In addition, the pattern of X-chromosome inactivation was determined using HpaII restriction endonuclease digestion, followed by PCR amplification of the androgen receptor locus. Multifocality was determined when alternate patterns of X-chromosome inactivation occurred. In two of the eight patients, the left and right ovarian tumor sites had different androgen receptor alleles inactivated, indicating that the bilateral tumors derived independently. In a third patient, the X inactivation pattern in the left ovarian tumor differed from the two peritoneal implants, suggesting that the implants were separate primary tumors, and not metastatic, from the left ovarian tumor. The remaining five patients had the same pattern of loss of heterozygosity and X inactivation in the tumor sites studied. These results suggest that bilateral and advanced stage serous BOTs may be multifocal in origin. This result is in contrast to invasive epithelial ovarian cancer, which has been shown to be unifocal in origin.     

Human bone cells stimulate the growth of human breast carcinoma cells

Human breast cancer cells were cultured together with their metastatic target, bone tissue, to analyze possible growth promotion effects. The coculture of human osteosarcoma cells (TE-85) with human mammary carcinoma cells (ZR-75.1) resulted in up to 8.4-fold stimulation of proliferation of the breast tumor cells. Cell contact of the two cultures was permitted through the channels of Nuclepore filters. However, physical contact turned out not to be necessary, since the proliferative stimulus was also mediated by a bone-derived diffusible factor. Conditioned medium (CM), collected from human primary bone cultures, enhanced the rate of proliferation of several breast tissue cell lines (ZR-75.1, BT-20, HBL-100), while some lines were not affected by osteoblast CM. Breast tissue lines responding to bone CM express low to intermediate levels of the c-erbB-2 gene, in contrast to nonstimulated lines, which overexpress the gene. Recent observations of metastatic spread in breast cancer patients suggest a distinctive pattern of secondary tumor distribution in association with c-erbB-2 protein expression. Bone tissue seems to be a preferential target for metastases of c-erbB-2-negative breast tumors.     

Vascularity of proliferative breast disease and carcinoma in situ correlates with histological features

The level of vascularity within an invasive breast carcinoma is a predictor of metastatic potential and survival. However, little is known about the vascular potential and prognostic value of angiogenesis in preinvasive breast pathology. Women with proliferative breast disease or carcinoma in situ are at increased risk of developing invasive breast cancer. This relative risk increases in correlation with defined histopathological features. We asked whether these early proliferative lesions and carcinoma in situ were capable of inducing a vascular supply. Vascularity in preinvasive archival paraffin-embedded breast tissue from 90 patients was quantified by immunohistochemical identification of vessels using anti-von Willebrand factor. Vascular scores were analyzed with respect to histopathological diagnosis, age at diagnosis, and presence of coincident invasive disease. These data indicate that: (a) the vascularity of histopathologically normal epithelium is greater in breasts containing invasive disease than in breasts lacking invasive disease; (b) simple proliferative breast disease induces a vascular supply greater than that of normal breast epithelium; and (c) vascularity increases in proportion to epithelial lesion progression and relative risk of invasion. These studies indicate that the vascularity of preinvasive breast pathology may be a clinically useful predictor of invasive breast cancer.     

Collagen gene expression in the neomatrix of carcinoma of the breast

Excessive deposition of extracellular matrix or neomatrix is a characteristic of desmoplastic invasive breast carcinomas. Type I and III collagens are abundant neomatrix components. Archival breast tissue sections were studied using 35S-labeled cDNA probes for alpha 1(I) and alpha 1(III) procollagen and in situ hybridization. Among the 33 invasive breast cancers, hybridization was seen forming a gradient-like pattern in fibroblasts closest to tumor cells. In the 10 ductal carcinomas in situ studied, a ring-like pattern of hybridization was seen in proximity to the basement membrane zone. Adjacent normal and benign tissues did not demonstrate the patterns of hybridization described in malignant tissues. Gene expression for neomatrix interstitial collagens occurs before there is evidence of invasion in carcinoma of the breast.     

Orangutan alpha-satellite monomers are closely related to the human consensus sequence

The extensive intraductal component (EIC) of primary breast carcinoma is a special spread pattern observed in the breast. Extensive intraductal component may extend diffusely over the entire breast. Therefore, EIC is considered to be an important risk factor for local recurrence in breast-conserving therapy. However, the pathogenesis of EIC remains uncertain. Whether or not the estrogen receptor (ER) has an influence on its biologic behavior has not been fully studied. A consecutive series of 142 breast carcinomas submitted to the pathology department were examined on step gross sections of 5.0 mm thick. Extensive intraductal component was determined and divided into three types. Estrogen receptor was examined using both immunohistochemistry (ER-IHC) and enzyme immunoassay (ER-EIA). Extensive intraductal component was found in 78 of 138 (56.52%) invasive carcinomas including invasive ductal carcinoma with a predominant intraductal component. Estrogen receptor-IHC positivity was 42.96% (61/142) in the invasive breast carcinoma. Estrogen receptor positivity showed no significant difference between EIC-positive and -negative cases, as well as between EIC and invasive main tumor in the EIC-positive cases. But within the EIC-positive group, ER positivity was found to be higher in the peripheral type of EIC-II and EIC-III than in the central type of EIC-I (P < 0.05). Although ER may not play an essential role in the pathogenesis of EIC, it has shown some significance in the development of peripheral type EIC because of its higher presence in the peripheral type of EIC-II and EIC-III than in the central type of EIC-I.     

Genotator: a workbench for sequence annotation

The clinical, pathological, and immunohistochemical features of six cases of metastatic neuroendocrine and carcinoid tumors to the thyroid simulating medullary thyroid carcinoma (MTC) are described. The patients were women between the ages of 24 and 70 years who, without symptoms or significant past medical histories, presented with either a single mass or multiple thyroid nodules. The primary source of the tumor was only discovered on follow-up. Two of the neoplasms were classical carcinoid tumors, one was a carcinoid predominantly composed of large cells, another showed a prominent oval to spindle cell component, and the two remaining cases were atypical carcinoid/high-grade neuroendocrine carcinomas. The immunohistochemical profile was inconsistent with MTC in that all tumors were negative for calcitonin and only two were focally positive for carcinoembryonic antigen (CEA). A variable pattern of staining for other neuroendocrine and epithelial markers was obtained in each case. Despite the morphologic and immunohistochemical similarities with MTC, the diagnosis of a metastatic neuroendocrine tumor to the thyroid should be favored in the presence of a predominantly interstitial pattern of spread; occurrence of multiple tumor foci; folliculotropism; rosette formations with lumen and cuticular borders; and lack of immunoreactivity for calcitonin and CEA. The differential diagnosis between MTC and metastatic neuroendocrine carcinoma to the thyroid is of importance because of the vast differences in treatment and prognosis.     

maspin suppresses the invasive phenotype of human breast carcinoma

The recently discovered tumor suppressor gene maspin has been shown to inhibit tumor cell motility, invasion, and metastasis in breast cancer by our laboratories. Nonetheless, the exploitation of maspin as a potential diagnostic and/or therapeutic tool has remained limited due to the lack of knowledge concerning its molecular and biological mechanism(s) of action. The work reported here demonstrates that recombinant maspin (rMaspin) has the ability to induce higher cell surface levels of alpha5- and alpha3-containing integrins and reduced levels of alpha2-, alpha4-, alpha6-, alpha(v)-, and some beta1-containing integrins in the metastatic human breast carcinoma cell line MDA-MB-435 concomitant with its ability to inhibit the invasive process in vitro. Furthermore, treatment of MDA-MB-435 cells with rMaspin results in the selective adhesion of the cell to a fibronectin matrix and conversion from a fibroblastic to a more epithelial-like phenotype. In addition, the ability of rMaspin to inhibit the invasive process can be abrogated with a blocking antibody to the alpha5beta1 integrin, which diminishes the ability of the cells to invade through a fibronectin matrix-containing barrier in vitro. Taken together, these data address the hypothesis that rMaspin reduces the invasive phenotype of MDA-MB-435 cells by altering their integrin profile, particularly alpha5, which in turn converts these cells to a more benign epithelial phenotype, with less invasive ability. These data provide new insights into the biological significance of this tumor suppressor gene found in normal mammary epithelium and may form the basis of novel therapeutic strategies in the management of breast carcinoma.     

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.     

The structure of the keratan sulphate chains attached to fibromodulin from human articular cartilage

We have previously demonstrated that fibroblasts and invasive human breast carcinoma (HBC) cells specifically activate matrix metalloproteinase-2 (MMP-2) when cultured on 3-dimensional gels of type I collagen but not a range of other substrates. We show here the constitutive expression of membrane-type 1 (MT1)-MMP in both fibroblasts, and invasive HBC cell lines, that have fibroblastic attributes presumably acquired through an epithelial-to-mesenchymal transition (EMT). Treatment with collagen type I increased the steady-state MT1-MMP mRNA levels in these cells but did not induce either MT1-MMP expression or MMP-2 activation in noninvasive breast carcinoma cell lines, which retain epithelial features. Basal MT3-MMP mRNA expression had a pattern similar to that of MT1-MMP but was not up-regulated by collagen. MT4-MMP mRNA was seen in both invasive and noninvasive HBC cell lines and was also not collagen-regulated, and MT2-MMP mRNA was not detected in any of the HBC cell lines tested. These data support a role for MT1-MMP in the collagen-induced MMP-2-activation seen in these cells. In situ hybridization analysis of archival breast cancer specimens revealed a close parallel in expression of both collagen type I and MT1-MMP mRNA in peritumoral fibroblasts, which was correlated with aggressiveness of the lesion. Relatively high levels of expression of both mRNA species were seen in fibroblasts close to invasive tumor nests and, although only focally, in certain areas close to preinvasive tumors. These foci may represent hot spots for local degradation and invasive progression. Collectively, these results implicate MT1-MMP in collagen-stimulated MMP-2 activation and suggest that this mechanism may be employed in vivo by both tumor-associated fibroblasts and EMT-derived carcinoma cells to facilitate increased invasion and/or metastasis.     

Role of intermediate filaments in migration, invasion and metastasis

The expression of intermediate filament proteins is remarkably tissue-specific which suggests that the intermediate filament (IF) type(s) present in cells is somehow related to their biological function. However, in some cancers-particularly malignant melanoma and breast carcinoma, there is a strong indication that vimentin and keratin IFs are coexpressed, thus presenting as a dedifferentiated or interconverted (between epithelial and mesenchymal) phenotype. In this review, two in vitro models are presented which recapitulate the interconverted phenotype in human melanoma and breast carcinoma, and allow, for the first time, unique observations to be made with respect to the role of IFs in cancer progression. These studies have provided direct evidence linking overexpression of keratin IFs in human melanoma with increased migratory and invasive activity in vitro, which can be down-regulated by substituting dominant-negative keratin mutants. Overexpression of vimentin IFs in the breast carcinoma model leads to augmentation of motility and invasiveness in vitro, which can be transiently down-regulated by treatment with antisense oligonucleotides to vimentin. Additional experimental evidence suggests that the mechanism(s) responsible for the differential expression of metastatic properties associated with the interconverted phenotype rest(s) in the unique interaction, either direct or indirect, of IFs with specific integrins interacting with the extracellular matrix. In this review, we discuss the observations derived from the human melanoma and breast carcinoma models to address the hypothesis that the ability to coexpress vimentin and keratins confers a selective advantage to tumor cells in their interpretation of and response to signaling cues from the extracellular matrix. The ramifications of these observations are discussed with respect to the patholophysiology of the respective in situ tumors.     

Biomechanical analysis and clinical treatment of blunt renal trauma

Moesin, one of the ERM (ezrin; radixin; moesin) family members, is directly associated with the cytoplasmic domain of CD44, which is now thought to be related to the metastatic potential of tumor cells. Using immunohistochemistry we investigated the expression of moesin in normal epidermis and various kinds of epithelial skin tumors: squamous cell carcinoma, verrucous carcinoma, Bowen's disease, solar keratosis, keratoacanthoma, basal cell carcinoma, and extramammary Paget's disease. Normal skin showed positive epidermal staining for moesin with the exception of the stratum corneum. The expression of moesin varied with the type of skin tumor. In basal cell carcinoma, Bowen's disease, and extramammary Paget's disease, moesin expression was either faint or negative. In contrast to Bowen's disease, invasive squamous cell carcinoma showed more intense and heterogeneous staining of the cytoplasm and the cell membrane. Verrucous carcinoma was weakly positive, with a tendency for the moesin to be distributed in the cell membrane. The staining pattern of moesin varied among the different kinds of epithelial skin tumors, and its expression was generally similar to that of the standard form of CD44. These results suggest that moesin is closely inter-related with CD44 in epithelial skin cells as seen in other cellular systems, and that the variable pattern of moesin staining among the skin tumor cells could reflect expression disorders associated with the transformation.