Ductal carcinoma in situ-like structures in metastatic breast carcinoma

In this report, we present two cases of axillary lymph node metastatic breast carcinoma with features mimicking ductal carcinoma in situ (DCIS): one was of the comedo-like type and the other was suggestive of the micropapillary type. In the first case, the primary tumor presented DCIS of the comedo type; however, in the second case, the primary tumor consisted only of the invasive ductal component. Immunohistochemistry against smooth muscle actin, S100-protein, CK5/6, CD10, P63, and 34betaE12 did not identify myoepithelial cells either in DICS of the first primary tumor or in both metastases. These features probably do not represent the true DCISs, but only mimic them. This observation suggests that a proportion of "primary DCIS" may constitute an invasive pseudo-DCIS carcinoma, and immunohistochemical identification of myoepithelial cells may be helpful in such cases.     

Validation of immunolocalization of the urokinase receptor expression in ductal carcinoma in situ of the breast: comparison with detection by non-isotopic in-situ hybridization

AIMS: Ductal carcinoma in situ (DCIS) is a pre-invasive form of mammary carcinoma with no microscopic evidence of cancer cell invasion through the basement membrane. However, for initiation of invasion, tumour cells have to acquire and focus proteolytic activity on to the cell surface in order to infiltrate the surrounding extracellular matrix. The receptor (uPA-R or CD87) for the serine protease urokinase-type plasminogen activator (uPA) plays a central role in invasion and metastasis. This study was performed to determine and localize m-RNA and protein of uPA-R in ductal carcinoma in situ of the breast. METHODS AND RESULTS: We analysed uPA-R mRNA and protein expression by in-situ hybridization and immunohistochemistry, respectively, in 50 formalin-fixed, paraffin-embedded specimens of DCIS. Three different antibodies were used to stain cell-associated uPA-R; chicken polyclonal antibody (pAb) HU277 and monoclonal antibodies (mAb) IID7 and 3936. In all cases, myoepithelial and stromal cells reacted with either antibody. Especially, reaction of macrophage-like cells with mAb 3936 resulted in a well-marked and bright staining. Applying mAb IID7, in 46 of the 50 breast specimens tumour cells showed a positive immunoreaction. Likewise pAb HU277 stained tumour cells in 40 of the 50 cases, whereas mAb 3936 reacted with only 24 of the 50 tissue sections. Endothelial cells were marked by both mAb IID7 and pAb HU277 (46/50 and 35/50, respectively); mAb 3936 did not label at all. All of the cell types stained by mAb IID7 and pAb HU277 also displayed reactivity with uPA-R mRNA-specific antisense oligonucleotides in in-situ hybridization. CONCLUSIONS: Our results reveal the presence of the tumour invasion-related receptor for the protease uPA not only in invasive ductal breast carcinoma but also in different types of DCIS.     

Fine-needle aspiration biopsy of invasive micropapillary carcinoma of the breast: a report of five cases

Invasive micropapillary carcinoma of the breast is an uncommon variant of infiltrating ductal carcinoma. Observing its distinctive cytologic appearance and aggressive behavior is important for early diagnosis by fine-needle aspiration cytology (FNAC). There are only a few reported cases in the literature. Five women presented with breast masses. FNAC showed malignant epithelial tumors, and mastectomy materials showed invasive micropapillary carcinoma for all of them. Three patients had axillary lymph node metastases. Invasive micropapillary carcinoma, with its angulated papillary clusters lacking a fibrovascular core, and irregular crowded nuclei, has a distinctive cytologic appearance which correlates with its histological features. A differential diagnosis from other primary or metastatic papillary lesions of the breast may be possible using immunohistochemistry and some cytologic features. The limited experience with invasive micropapillary carcinoma should not discourage others from undertaking further studies.     

Myoepithelial carcinoma of the breast with distant metastasis and accompanied by adenomyoepitheliomas

A breast tumour in a 47-year-old female with axillary lymph node metastasis was interpreted as the rare malignant adenomyoepithelioma based on morphological and immunohistochemical studies. Multiple bone metastases developed and the patient died after 7 months. The malignant neoplasm consisted of cords and interlacing bundles of spindle cells with indistinct cell borders and clear cytoplasm. The cells stained positively for cytokeratin. S-100 protein, GFAP, and muscle-specific actin, and possessed basal lamina, pinocytic vesicles, tonofilaments, desmosomes, and intermediate filaments with dense bodies. In some areas, cells with microvillous projections enclosed small spaces. In the breast, foci of myoepithelioma with various morphological subtypes and infiltration coexisted, demonstrating the origin of the malignant tumour. The histogenesis of the myoepithelial tumours is discussed.     

Invasive micropapillary carcinoma of the breast: high incidence of lymph node metastasis with extranodal extension and its immunohistochemical profile compared with invasive ductal carcinoma

AIMS: Invasive micropapillary carcinoma of the breast is an aggressive and distinctive variant of breast cancer. These tumours have a characteristic histological appearance and have been associated with a high incidence of axillary lymph node metastases and a poor clinical outcome. The aims of this study were to investigate the immunohistochemical profile of invasive micropapillary carcinoma of the breast, to compare it with invasive ductal carcinoma, and to identify the morphological parameters which predict its poor outcome. METHODS AND RESULTS: Fifty-three (2.6%) invasive micropapillary carcinomas of the breast from 2022 cases of infiltrating breast carcinomas were identified by retrospective review. The patient age at presentation ranged from 33 to 78 years (mean 52.5 years). The tumour size ranged from 5 to 70 mm (mean 27 mm). Eighty-two percent (43 of 53) were of high histological grade; 69% (33 of 48) of cases with axillary lymph node dissections had positive lymph nodes; and 75.5% (40 of 53) had lymphatic invasion: 46% (22 of 48) of cases had extranodal extension. Of lymph node-positive cases, 61% had four or more metastatic lymph nodes. Of tumours with tumour size >10 mm, 77% had positive lymph nodes. The percentages of cases positive for oestrogen receptor (ER) and progesterone receptor (PR) were 68% and 61%, respectively. These values were significantly higher than the values for invasive ductal carcinomas. p53 and c-erbB-2 were detected in 48% and 54% of cases, respectively. The mean value of Ki67 was 26%. Follow-up was available in 36 patients. Eight patients had local recurrences, nine patients had distant metastases, and 10 patients died of disease within a follow-up period of 9 years. CONCLUSION: Lymphotropism and an unfavourable prognosis are the hallmarks of this distinct entity. Prognostic markers such as ER, PR, p53, and c-erbB-2 failed to provide new criteria to allow discrimination of these tumours from other breast cancers.     

E-selectin and Sialyl Lewis X expression is associated with lymph node metastasis of invasive micropapillary carcinoma of the breast

To investigate the possible roles of E-selectin and its ligand, Sialyl Lewis X, in lymph node metastasis of invasive micropapillary carcinoma of the breast, 100 cases of invasive micropapillary carcinoma and 97 cases of invasive ductal carcinoma were analyzed immunohistochemically for the expression of E-selectin and Sialyl Lewis X, along with CD34, to measure the microvessel density of invasive micropapillary carcinoma. We found that the number of E-selectin-positive vessels was greater in invasive micropapillary carcinoma than in invasive ductal carcinoma, and it was significantly correlated with the histological grade, the number of positive lymph nodes, and the microvessel density of invasive micropapillary carcinoma. The Sialyl Lewis X expression of invasive micropapillary carcinoma was higher than that of invasive ductal carcinoma, which was also associated with lymph node metastasis. In invasive micropapillary carcinoma, the Sialyl Lewis X expression was predominantly in the stroma-facing surface of the cell clusters and the adjacent stroma, while in invasive ductal carcinoma it was largely intracytoplasmic or intercellular. These findings suggested that E-selectin and Sialyl Lewis X might play an important role in lymph node metastasis in invasive micropapillary carcinoma. The expression pattern of Sialyl Lewis X in invasive micropapillary carcinoma suggested that the reversal of cell polarity of invasive micropapillary carcinoma might be as an important factor for the morphogenesis and possibly the pathogenesis, especially their higher rates of lymph node metastasis.     

Increased expression of SDF-1/CXCR4 is associated with lymph node metastasis of invasive micropapillary carcinoma of the breast

Aims:  Stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 are implicated in tumour chemotaxis and metastasis. The aim was to examine their roles in the metastasis of invasive micropapillary carcinoma (IMPC) of the breast, a tumour with a high propensity for nodal spread.
Methods and results:  We compared the expression of SDF-1 and CXCR4 in 103 cases of breast cancer containing IMPC components with a control group of 96 cases of invasive ductal carcinoma (IDC), not otherwise specified type by immunohistochemistry and chemical in situ hybridization (CISH). The results showed that the predominant cytoplasmic expression of both SDF-1 and CXCR4 was greater in tumour cells of the IMPC components than in those of the non-IMPC components and the control IDC cases, and was correlated significantly with the number of positive lymph nodes ( P  < 0.05). SDF-1 expression on cell membranes was less frequently identified in IMPC than IDC ( P  = 0.021). Immunohistochemical detection of SDF-1 in endothelial cells of lymphatic vessels was more common in IMPC ( P   =  0.007) and correlated significantly with lymph node status ( P  = 0.002), although SDF-1 mRNA was rarely detected by CISH.
Conclusions:  This study suggests that up-regulation of cytoplasmic expression of SDF-1/CXCR4 might be one of the molecular mechanisms facilitating lymph node metastasis of IMPC.     

Spindle cell carcinoma of the breast

A case of spindle cell carcinoma of the breast in association with myoepithelial cell hyperplasia is presented. Immunocytochemistry demonstrated labelling of tumour cells for cytokeratin, vimentin and S-100 protein. Electronmicroscopy showed desmosomes and bundles of tonofilaments as well as fine filaments in the cytoplasm. The findings in the present case point to the metaplastic spindle cell nature of squamous carcinoma of the breast. The possible role of myoepithelial cells in the origin of the spindle cell component is discussed.     

Invasive breast carcinoma with granulomatous response and deposition of unusual amyloid.

AIMS: To report an unusual case of invasive breast ductal carcinoma associated with non-caseating epithelioid granuloma and unusual deposition of amyloid. METHODS: Formalin fixed, paraffin wax embedded tissue from breast and lymph nodes were stained with a variety of methods. Representative tissue fragments were sampled and fixed in 2.5% buffered glutaraldehyde, postfixed in 1% osmium tetroxide, dehydrated and embedded in Araldite. Thin sections were viewed under a Phillips 400T transmission electron microscope. RESULTS: Multinucleated giant Langhans' cells were found in the granulomatas tissue in both breast carcinoma and metastatic axillary lymph node carcinoma. Electron microscopic examination showed "tubular" amyloid deposition intermingled with invasive carcinoma and granuloma. "Tubular amyloid" was characterised by a mesh of non-branching curving fibrils with hollow profiles. These tended to be located in the cell membranes. CONCLUSION: The presence of an epithelioid granulomatous reaction and deposition of "tubular" amyloid in an invasive breast carcinoma could be related to an abnormal immunological response.     

Metastatic potential of encapsulated (intracystic) papillary carcinoma of the breast: a report of 2 cases with axillary lymph node micrometastases

Intracystic papillary carcinoma of the breast has rarely been reported to be associated with metastases. Presented are 2 cases, both of which showed micrometastatic carcinoma in axillary lymph nodes; neither demonstrated stromal invasion. Nearly complete absence of a myoepithelial cell layer around the periphery of the lesions was noted. One case showed 3 separate foci of micrometastatic carcinoma in 1 of 3 sentinel lymph nodes; the second showed micrometastases in 2 of 11 axillary lymph nodes. The clinical significance of micrometastases in lymph nodes associated with intracystic papillary carcinoma is unknown. The term encapsulated papillary carcinoma has been proposed to name papillary carcinomas that are surrounded by a fibrous rim, but which show a scant or absent myoepithelial cell component. The current 2 cases offer evidence to support the use of this term for particularly large encysted lesions. Sentinel lymph node biopsy may be prudent in such cases.     

Metaplastic variant of invasive micropapillary breast carcinoma: a unique triple negative phenotype

Invasive micropapillary carcinomas (IMC) and metaplastic breast carcinoma (MBC) have different clinicopathologic features. This study reports an unusual case of multifocal grade III IMC associated with MBC component in a 35-year-old woman. MBC was vimentin positive, pancytokeratin negative, and showed focal p63 positivity. Immunostains for estrogen and progesterone receptor, and fluorescence in situ hybridization for Her2/neu amplification were negative. All the left axillary lymph nodes dissected were positive for metastatic carcinoma with ductal and IMC patterns, but without metaplastic component. Postmastectomy computed tomography and magnetic resonance imaging scans showed metastases to lungs, liver, brain, and vertebrae. The biologic behavior of tumor was in accordance with histology, so that the nodal and distant metastases were testament to the underlying inherently aggressive IMC, whereas large tumor size and triple negativity reflected the features of MBC. To the best of the authors' knowledge, this is the first report of a metaplastic variant of invasive micropapillary breast carcinoma with triple negative phenotype.     

Spontaneous regression of breast cancer with axillary lymph node metastasis: a case report and review of literature

Spontaneous regression (SR) of cancer is a rare but well-documented biological phenomenon. However, the mechanism remains to be elucidated. We herein report a case of the SR of breast cancer at both the primary site and metastatic axillary lymph node with spontaneously-induced T cell-mediated immunological responses. A 52-year-old female with a lump in the left axilla was diagnosed to have a small breast carcinoma with a distinct axillary lymph node metastasis. During the preoperative systemic examination, she was diagnosed to have severe type 2 diabetes mellitus, was treated with insulin, and the hyperglycemia was normalized after one month. Surgery for left breast cancer was then performed. The postoperative histopathological examination revealed the SR of breast cancer at both the primary site and metastatic axillary lymph node. Immunohistochemical studies revealed that estrogen receptor positive, AE1/AE3-positive ductal carcinoma completely underwent necrosis associated with extensive infiltration of CD3-positive T cells in the tumor nodule in the lymph node. In addition, primary ductal carcinoma cells also underwent single cell necrosis with infiltration of T cells with lymph follicle-like organization of B cells in the mammary gland. The features were suggestive that the tumor eradication in the metastatic lymph node and regression of the primary ductal carcinoma could be due to host T cell response to the ductal carcinoma. As far as we know it is the first report that shows the spontaneous regression of breast cancer, probably due to the spontaneously-induced T cell response.     

Cylindroma (dermal analog tumor) of the breast: a comparison with cylindroma of the skin and adenoid cystic carcinoma of the breast

We compared 4 breast cylindromas with 50 dermal cylindromas and 8 adenoid cystic breast carcinomas. Except for a modest increase in the number of eccrine ducts and reactive Langerhans cells in dermal cylindromas, breast and dermal cylindromas showed identical histologic and immunohistochemical features. Both were characterized by epithelial islands containing central basaloid cells and peripheral myoepithelial cells surrounded by a thickened, continuous, periodic acid-Schiff-positive basement membrane that was immunoreactive for collagen IV. Clusters of sebaceous cells and a few eccrine ducts are described in breast cylindromas. Cytokeratin 7 labeled predominantly the central basaloid cells, and smooth muscle actin stained peripheral myoepithelial cells in breast and dermal cylindromas. Eccrine ducts were highlighted by epithelial membrane antigen and carcinoembryonic antigen. S-100 protein and CD1a showed a variable number of dendritic Langerhans cells. Cylindromas of the breast and skin did not express cytokeratin 20, gross cystic disease fluid protein 15, or estrogen or progesterone receptor. Breast cylindroma might be confused with the solid variant of adenoid cystic carcinoma, especially in needle core biopsy specimens, because they share nodular and trabecular patterns, basaloid cells, myoepithelial cells, eccrine ducts, and hyaline globules of basement membrane material. However, adenoid cystic carcinoma displays an infiltrative growth pattern, cytologic atypia, and mitotic figures and lacks the continuous, thickened basement membrane.     

Adenoid cystic carcinoma of the breast

The clinical, histologic, cytologic, and ultrastructural features of three adenoid cystic carcinomas of the breast are presented. All three neoplasms occurred in postmenopausal women. One patient was treated by wide re-excision of the biopsy site. Two were treated by modified radical mastectomy; no axillary lymph node metastases were found. None of the neoplasms has recurred. Neither estrogen nor progesterone receptors were detected in any of the neoplasms. The histopathologic criteria for the diagnosis of adenoid cystic carcinoma are described, and the differential diagnosis is discussed. Since the cytopathologic features of adenoid cystic carcinoma of the breast appear to be distinctive, the neoplasm can be diagnosed by fine-needle aspiration based upon the presence of the following features: 1) a cellular smear; 2) a uniform population of small, basaloid tumor cells; and 3) small globules of mucoid material surrounded by a rim of neoplastic cells. Ultrastructurally, the predominant cell type has the appearance of a modified myoepithelial cell, but true lumina lined by microvillous epithelial cells are also present. The ultrastructural findings are consistent with the proliferation of neoplastic cells that have the capacity to produce all of the epithelial elements of the breast, i.e., ductal, acinar, and myoepithelial, and so recapitulate the complete ductal or acinar unit.     

Cytohistologic features of invasive micropapillary carcinoma in a young female

Invasive micropapillary carcinoma (IMPC) is a recently reported variant of breast carcinoma in women. There has been only a single report describing the cytologic features of IMPC in the literature. We report on the cytohistologic features of IMPC with diffuse involvement of two quadrants of the breast and axillary lymph node metastases in a 32-yr-old female. The cytologic appearance of IMPC was characterized by high cellularity, marked cell discohesion, and epithelial cells forming aggregates, morules, and angular and papillary clusters without fibrovascular cores and showing high nuclear/cytoplasmic ratio, irregular nuclear contours, and finely stippled chromatin. Occasional psammoma bodies were noted. Histologic examination showed a pure IMPC composed of clusters, morules, and aggregates of malignant epithelial cells surrounded by distinctly clear spaces separated by thin fibrovascular septa. The tumor involved both inner quadrants and axillary lymph nodes. A primary tumor elsewhere, particularly in the ovaries, was excluded. The patient has been disease-free 38 mo after the initial diagnosis.     

CD5 positive breast carcinoma in a patient with untreated chronic lymphocytic leukaemia: molecular studies of chromosome 13q

A 67 year old woman presented with a right breast lump which proved to be a grade 2 invasive ductal carcinoma with axillary lymph node metastasis. She had a five year history of CD5 positive chronic lymphocytic leukaemia, which never required treatment. Immunoperoxidase stains for CD5, using the monoclonal antibody NCL-CD-54C7, showed that there was extensive infiltration of axillary lymph nodes with CD5 positive B lymphocytes. Strong staining for CD5 was also seen in the carcinoma cells within the breast and lymph node metastases. It has recently been suggested that there is a tumour suppresser locus in chronic lymphocytic leukaemia at 13q12.3 near or at the BRCA2 locus. Deletion of regions on chromosome 13q containing the BRCA2 and RB1 genes has also been reported in sporadic breast cancers. These observations suggest that there may be a link between these two diseases acting through chromosome 13, but amplification of several microsatellite repeat markers failed to show any loss of heterozygosity or repeat instability at either these or several other loci on chromosome 13. Examination of additional such cases is needed to perform a more comprehensive study of the significance of positive CD5 staining of breast carcinoma.     

A comparison of the patterns of laminin expression in fibroadenoma, fibrocystic diseases, pre-invasive and invasive ductal breast carcinoma

The basement membrane (BM), of which laminin is a major glycoprotein component, is an important barrier to tumour cells which must be breeched before metastatic spread can occur. We have compared the pattern of laminin expression in a range of benign and malignant breast lesions to better understand the process of tumour progression. A total of 162 cases of breast samples, comprising 18 fibroadenomas, 22 cases of fibrocystic disease, 96 cases of invasive ductal carcinoma and 26 carcinomas with intraductal components, were evaluated for laminin expression by a standard immunoperoxidase method on formalin-fixed, paraffin-embedded histological sections, using a commercial antibody against human laminin. The pattern of laminin expression was charted as follows: Type I, > 70% of BM complete/continuous; Type II, > 70% of BM moderately disrupted; Type III, > 70% of BM completely disrupted. The Type I pattern was observed in all cases of fibroadenoma and fibrocystic diseases, and in 77% of intraductal carcinoma components. Various patterns of BM disruption were observed in invasive ductal carcinoma. Severity of BM disruption correlated with histological grade of the carcinomas (P < 0.001). Small-sized tumours, those without lymphatic invasion and lymph node-negative tumours showed more complete patterns of laminin expression. The current study suggests that tumour cells with high histological grade possess an enhanced capacity to disrupt the basement membrane, an important step in the metastatic process. The detection of BM disruption by immunohistochemical staining for laminin is technically easy and may be usefully applied for the differentiation of in situ and microinvasive carcinoma.     

CD44 expression and axillary lymph node metastasis in infiltrating ductal carcinoma of the breast

Metastasising ability connotes one of the most important life-threatening properties of malignant neoplasms. Recent studies indicate that CD44 proteins, multifunctional cell adhesion molecules which contribute to "homing" of lymphocytes to lymph nodes as well as cell-cell and cell-matrix interactions, are potential markers of tumour progression. However, whether CD44 expression by human tumours contribute to increased metastatic risk remains controversial. In an attempt to clarify its role in breast cancer, we have investigated the correlation between CD44 expression by breast carcinoma and the presence of axillary lymph node metastases. CD44 expression was detected using a standard immunoperoxidase method on formalin-fixed, paraffin-embedded, primary infiltrating ductal breast carcinoma tissues taken from 60 female patients who underwent mastectomy with axillary node clearance. Tumours were graded according to the modified Bloom and Richardson criteria. 62% of patients had histologically-proven lymph node metastasis. 40% of primary cancers exhibited cytoplasmic membrane immunopositivity for CD44. 46% of primary tumours which have metastasied to axillary lymph nodes were CD44 positive whereas 30% of tumours which have not metastasised expressed CD44. CD44 positivity was expressed by 20% of grade 1, 31% grade 2 and 58% grade 3 tumours. Our results suggest that CD44 may have a role in the progression of breast cancer and emphasise the need to investigate its interaction with other mechanisms of cancer advancement.