Atypical Medullary Carcinoma Research Articles

Hormone Receptor Status May Impact the Survival Benefit Between Medullary Breast Carcinoma and Atypical Medullary Carcinoma of the Breast: A Population-Based Study.

BackgroundA rare subtype of breast cancer, atypical medullary carcinoma of the breast (AMCB), shows a highly adverse prognosis compared to medullary carcinoma of the breast (MBC). The current study aimed to establish a correlated nomogram for the identification of the prognostic factors of AMCB and MBC.MethodsKaplan–Meier and Cox regression analyses were applied to data acquired from the Surveillance, Epidemiology and End Results (SEER) database for 2004 to 2013 to analyse tumour characteristics and overall survival. Propensity score matching (PSM) analysis was performed to determine the overall survival (OS) among those with AMCB and MBC. A predictive nomogram was created, and the concordance index (C-index) was used to predict accuracy and discriminative ability.ResultsA total of 2,001 patients from the SEER database were diagnosed with MBC between 2004 and 2013, including 147 patients diagnosed with AMCB. The number of diagnoses gradually increased in both groups. Cox analysis of multivariate and Kaplan–Meier analysis showed that older age (HR = 3.005, 95% CI 1.906–4.739) and later stage were significantly associated with poor prognosis, while cancer-directed surgery was an independent protective factor (HR = 0.252, 95% CI 0.086–0.740). In the HR-negative stratification analysis, older age (HR = 2.476, 95% CI 1.398–4.385), later stage and histological type (HR=0.381, 95% CI 0.198-0.734) were found to be independent prognostic factors for low standard survival. The log-rank analysis demonstrated significantly worse prognostic factors for patients with AMCB than for those with MBC (P = 0.004). A nomogram (C-index for survival = 0.75; 95% CI 0.69–0.81) was established from four independent prognostic factors after complete identification.ConclusionsMBC is rare, and cancer-directed surgery, older age, and later stage are independently linked with prognosis. In the HR negative population, AMCB patients show a worse survival gain than those with MBC.

Atypical medullary carcinoma of the breast has similar prognostic factors and survival to typical medullary breast carcinoma: 3,976 cases from the National Cancer Data Base.

Medullary breast carcinoma (MBC) is a subtype with a more favorable prognosis. Tumors with some, but not all, characteristics of MBC are classified as atypical medullary carcinoma of the breast (AMCB). Patients with invasive MBC and AMCB reported to the National Cancer Data Base (NCDB) from 2004 to 2013 were compared for tumor characteristics and overall survival, using infiltrating ductal carcinoma (IDC) as a reference. Patients with MBC (n = 3,688), AMCB (n = 288), and IDC (n = 918,870) met inclusion criteria. Comparing MBC with AMCB, the mean age at diagnosis (52.9 vs. 53.9 years), mean tumor size (2.4 vs. 2.5 cm), lymph node positivity (22.8% vs. 22.4%), estrogen receptor (ER) positivity (22% vs. 25%), progesterone receptor (PR) positivity (14% vs. 15%), HER2 positivity (11% vs. 14%), rate of breast conserving surgery (67% vs. 68%), use of chemotherapy (76% vs. 75%), and use of hormonal therapy (19% vs. 18%), respectively, were not clinically or statistically different. Five-year (92% vs. 89%) and 10-year survival rates (85% vs. 87%) were not significantly different (P = 0.46). There does not appear to be any reason to differentiate between AMCB and MBC given the similarities in presentation, treatment and prognosis. J. Surg. Oncol. 2016;114:533-536. © 2016 Wiley Periodicals, Inc.

MEDULLARY CARCINOMA OF THE BREAST: ROENTGENOLOGIC AND ULTRASOUND SEMIOTICS

Breast cancer (BC) is the most common female cancer type and the leading cause of female cancer mortality in Russia and in majority countries of the world. Along with the most common type of BC – ductal carcinoma, there are a lot of histological types, distinguished by structure features, which lead to a variable clinical and instrumental semiotics. Thes e histological types of BC in the group marked out special types of BC, including medullary carcinoma. The concept of medullary cancer includes typical medullary BC, atypical medullary BC and invasive ductal BC with evidence of medullary morphology. Base d on the current literature data, the authors discuss the main epidemiological, clinical and morphological diagnostic features of medullary BC. The authors pay special influence pathological picture, forming the characteristic diagnostic features of medullary cancer detected using X-ray mammography and ultrasound of the breast – the basic techniques of BC and other breast diseases detection. I n 2003–2013 diagnosed 19 medullary BC cases in women aged 18–56 years, with 18 of them were recorded in patients aged 34–56 years. The authors describe in detail the features of clinical, mammographic and ultrasound semiotics of medullary BC. Article is focused on the main X-ray and ultrasound characteristics, such as mass shape and margin features, as well as its internal structure, and also the results of power Doppler. One of the main features of this article is description of ultrasound elastography pattern of medullary BC, which could be find in only a small number of scientific articles. T ypica l medullary BC, atypical medullary cancer and ductal carcinoma with medullary signs have different prognosis. This problem leads to necessity find reliable distinguishing features in mammograpic and ultrasound semiotics. It is seems important to reveal sites with indistinct margin. We have found the indistinct margin detection is not statistically significant for the differential diagnosis of typical forms of medullary BC from atypical forms and invasive ductal BC with evidence of medullary structure. Th e authors conclude that the mammographic and ultrasound semiotics of medullary BC makes accurate differential diagnosis with benign breast pathology by X-ray mammography as well as breast ultrasound impossible. There are no statistically significant differences in the results of the mammography and breast ultrasound in different histological types of medullary BC. So these diagnostic features are not reliable for the differential diagnosis. However, the application of a comprehensive usage of mammography and breast ultrasound using modern technology of ultrasound diagnosis allows to suspect BC.

CD8+ lymphocytes and apoptosis in typical and atypical medullary carcinomas of the breast

Medullary breast carcinoma (MBC) is a form of ductal invasive carcinoma (DIC) characterized by an abundant infiltration of the tumour by lymphocytes. MBC has been classified histologically into typical medullary carcinoma (TMC) and atypical medullary carcinoma (AMC), with TMC having a better prognosis than AMC and other DIC. The distribution of CD8+ lymphocytes within tumour nests and lymphocyte tracts, and apoptosis in lymphocytes and tumour cells within tumour nests, were studied in archived formalin fixed and paraffin embedded tissues of TMC and AMC. CD8+ lymphocytes tend to accumulate along the margins of lymphocyte tracts that adjoin tumour nests. There were significantly more CD8+ lymphocytes within tumour nests of TMC than AMC. TMC also tended to have more CD8+ lymphocytes within lymphocyte tracts than AMC. Apoptosis of lymphocytes in contact with tumour cells and of tumour cells in contact with lymphocytes was observed in both AMC and TMC within tumour nests but differences in the proportions of apoptotic tumour cells and lymphocytes between the two tumour types could not be established. The findings are consistent with CD8+ cytotoxic lymphocyte-mediated immunity contributing to the more favourable prognosis for TMC compared to AMC.

First description of an acinic cell carcinoma of the breast in a BRCA1 mutation carrier: a case report

BackgroundAcinic cell carcinoma (ACC) is a rare malignant epithelial neoplasm characterized by the presence of malignant tubular acinar exocrine gland structures. Diagnosis is generally made in salivary glands and in the pancreas. ACC of the breast has been reported in few cases only. Carriers of inherited mutations in the BRCA1 gene are prone to the development of breast cancer, mainly invasive ductal or medullary type carcinomas. We describe for the first time a BRCA1 mutation carrier with a diagnosis of ACC of the breast.Case presentationThe patient developed an invasive ductal carcinoma (IDC) at the age of 40 years and an ACC in the contralateral breast at 44 years. Immunohistochemical examination of the ACC revealed a triple negative status (i.e., negativity for estrogen receptor, progesterone receptor and HER2 protein) and positivity for p53. Using a combination of loss of heterozygosity (LOH) and sequencing analyses, the loss of the wild-type BRCA1 allele was detected in both the ACC and the IDC. In addition, two different somatic TP53 mutations, one in the ACC only and another one in the IDC only, were observed.ConclusionBoth the immunohistochemical and molecular features observed in the ACC are typical of BRCA1-associated breast cancers and suggest an involvement of the patient’s germline mutation in the disease. The occurrence of rare histological types of breast cancers, including malignant phyllodes tumor, atypical medullary carcinoma and metaplastic carcinoma, in BRCA1 mutation carriers has been already reported. Our findings further broaden the spectrum of BRCA1-associated breast malignancies.

Abstract B13: High-risk patients found affected with breast cancer during a multimodality screening program: Triple negative versus non-triple negative breast cancers

Abstract Rationale and purpose: Triple negative breast cancers (TNBCs), characterized by lack of hormone receptors' expression in absence of HER2 amplification, partially overlap with the basal-like subtype, with frequent occurrence in BRCA1 mutation carriers (BRCA1+). TNBCs are often associated with earlier onset, interval cancer diagnosis, larger size and aggressive clinical course with peak risk of recurrence at 1-3 years and increased mortality rate in the first 5 years. Thus, when screening women at high risk of breast cancer, special attention should be paid to patient outcome for TNBCs in comparison with non-TNBCs. Our aim was to compare TNBCs and non-TNBCs diagnosed during a prospective, non-randomized, multimodality screening study – including clinical breast examination (CBE), mammography, ultrasound (US) and magnetic resonance imaging (MRI) – on women at familial/genetic high risk of breast cancer conducted in 18 centres from June 2000 to March 2008 (ISS-HIBCRIT-1; Sardanelli F et al, Invest Radiol 2011). Methods: Comparisons were performed using Mann-Whitney U, Fisher exact and χ2 tests. Results: Among the 44 patients diagnosed with invasive cancers, 14 (31%) were TNBCs and 30 (69%) non-TNBCs, the former being 13 invasive ductal (IDC) and 1 atypical medullary carcinoma, the latter also including 15/30 lobular subtypes and/or DCIS component (p=0.005). Of the 14 TNBCs, 10 (71%) were found in BRCA1+, 2 (14%) in BRCA2+ and 2 (14%) in BRCA-untested women with strong family history of breast/ovarian cancer; the same data for 30 non-TNBCs were 9 (30%), 6 (20%) and 15 (50%) respectively (p=0.028). We had only three interval cancers, all TNBCs. The median age at diagnosis was 49 years (range 36-62) for TNBCs and 53 years (range 35-72) for non-TNBCs (p=n.s). TNBCs presented a higher rate (11/14, 79%) of pathological grade 3 IDCs compared with non-TNBCs (8/30, 27%) (p=0.002). The mean tumor size was 1.6 cm for TNBCs and 1.2 cm for non-TNBCs (p=n.s). Nodal status was negative in 12/14 (86%) TNBCs and in only 16/30 (53%) non-TNBCs (p=0.038). MRI similarly outperformed CBE, mammography and US in both TNBCs and non-TNBCs. Clinical course and survival could be monitored for 40/44 patients (91%), 13 TNBCs and 27 non-TNBCs, with a follow-up of 5.8 and 6.3 years (p=n.s) respectively. The rate of disease-free patients for over 5 years was 8/13 (62%; mean disease-free interval 7.0 years, range 5.0-8.0) for TNBCs and 17/27 (63%; mean 7.2 years, range 5.2-9.9) for non-TNBCs. Death due to BC occurred for 2/13 TNBC (15%, at 3.5 and 4.2 years) and 3/27 non-TNBC patients (11%; at 2.0, 4.9 and 5.7 years). The rate of locoregional relapse was 1/13 (8%, at 4.4 years) and 5/27 (19%; mean time of 5.0 years, range 2.4-7.0) respectively. Distant recurrence was reported for only 2 non-TNBC patients. Conclusion: TNBCs showed stronger association with BRCA1+ status, lower rate of lobular subtypes or DCIS component, and less frequent nodal involvement. Despite a more frequent pathological grade 3 and the tendency to be diagnosed as interval cancers, under the current treatment protocols TNBCs showed relapse and BC-related death rates and over-5-year disease-free intervals similar to those of non-TNBCs. These data provide outcome evidence supporting the value of entering women at high risk of TNBC (in particular BRCA1+) in intensive screening programs including MRI. Citation Format: Franca Podo, Filippo Santoro, Siranoush Manoukian, Clelia de Giacomi, Laura Cortesi, Lorenzo Preda, Stefano Corcione, Francesco Sardanelli. High-risk patients found affected with breast cancer during a multimodality screening program: Triple negative versus non-triple negative breast cancers. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B13.

A study of high-nuclear-grade breast cancer in Thailand: subclassification and correlation with prognostic factors and immunohistochemical study

To classify high-nuclear-grade breast cancer (BC) into typical medullary carcinoma (TMC), atypical medullary carcinoma (AMC), and non-medullary carcinoma (NMC), and luminal A, luminal B, and HER2, and to correlate these tumors with other prognostic factors. A retrospective study reviewing high-nuclear-grade BCs. The patients' age, histologic types, various histologic features, axillary lymph node (ALN) status, and results of immunohistochemical (IHC) study were recorded and analyzed. One-hundred and eighty-one cases of high-nuclear-grade BCs were reviewed and categorized into IDC, NOS (140, 77.3%), TMC (1, 0.6%), AMC (21, 11.6%), and others (19, 10.5%). The median age was younger in AMC than in NMC patients. NMC patients had a higher incidence of LVI and ALN metastasis with involvement of more than four lymph nodes (p = 0.006) whereas AMC patients had a higher mitotic index. Forty-six (35.9%) cases were triple-negative (TN), including 1 (100%), 7 (53.9%) and 38 (33.3%) cases of TMC, AMC, and NMC, respectively. AMC had a significantly lower number of node metastases (p = 0.006) than NMC; whereas TN had higher MI (p = 0.001) than non-TN. The non-TN group was subclassified into luminal A, luminal B, and HER2. Of these, TN and luminal B occurred at younger age (p = 0.01) whereas TN and luminal A had a higher mitotic count. TN had lower incidence of LNM including higher number of LNM. Overall, AMC-TN group showed a basal-like prognostic factor expression. NMC may be separated into TN and non-TN, with possibly different behavior. These sub-groupings should continue to be used. Interestingly, luminal A in our study tended to correlate with poor prognostic factors, thus, luminal A with high nuclear grade may not be representative of the usual luminal group profiles.

Atypical medullary carcinoma of the breast.

A 57-year-old woman was seen in our department for pain in the left breast, which had been noticed two months earlier. Her family history and past medical history were unremarkable. On arrival, a movable tumor 2 cm in diameter was palpated in the upper-outer-quadrant of the left breast. The ipsilateral axillary lymph nodes were not palpable. Blood chemistry results, including tumor markers, were normal. Mammography revealed a mass that had ill-defined borders and a higher central density with some spiculations in the left breast. The diagnosis was category 5 (Fig. 1). The tumor was seen by breast ultrasonography (Aplio, Toshiba, Tokyo, Japan) as a low echoic mass, 28 9 27 mm, with ill-defined borders, irregular margins, and internal heterogeneity. The anterior border was disrupted by tumor invasion (Fig. 2). Power Doppler US showed rich blood flow in the tumor (Fig. 3). Contrast-enhanced magnetic resonance imaging (MRI) showed the tumor as highly enhanced with irregular margins (Fig. 4). The time–intensity curve was an early peak and plateau pattern, suggesting malignancy. Pathological findings from a core needle biopsy revealed an infiltrating ductal carcinoma of the breast. Estrogen receptor (ER) and progesterone receptor (PgR) were positive, and the HER-2 score was 2?. No metastases were seen in the brain, lungs, liver, bones, abdominal cavity lymph nodes, infraclavicular lymph nodes, and axillary lymph nodes by computed tomography (CT) and bone scintigram. With a diagnosis of left breast cancer (T2N0M0 = Stage IIA), left quadrantectomy and biopsy of sentinel lymph nodes were performed. According to the intra-operative rapid pathological diagnosis, the sentinel lymph nodes were negative for metastasis. However, an intraductal carcinoma was noted at the resection margin on the papillary side of the resected breast tissue. Therefore, a pectoral muscle-sparing mastectomy was performed. The final pathological diagnosis was atypical medullary carcinoma (Fig. 5).

Clinicopathological characteristics of triple-negative breast cancers

Triple-negative breast cancer (TNBC) is defined as a group of breast carcinomas that are negative for expression of hormone receptors and HER2. Although patients with TNBC tend to have a poor prognosis, only chemotherapy is expected to be effective because no therapeutic targets have yet been established. DNA microarray analyses have proved that TNBCs are composed of the basal-like subtype and normal breast (or unclassified) subtype, the former being correlated with an aggressive clinical course. Histological types of TNBCs are reported to be common with those of basal-like subtype, comprising high-grade invasive ductal carcinoma, no special type [solid-tubular carcinoma (or atypical medullary carcinoma), invasive ductal carcinoma with a large central acellular zone], typical medullary carcinoma, and metaplastic carcinomas. The basal-like subtype is characterized by the expression of myoepithelial/basal markers and molecular changes including TP53 gene mutations, BRCA1 inactivation, and many chromosomal alterations. New target molecules for the treatment of TNBCs are under extensive investigation, and their clinical application is awaited.

Cytologic Detection of Demodex folliculorum in Cases with Persisting Skin Disorders

To analyze fine needle aspiration cytology (FNAC) material from 20 cases of histologically verified medullary carcinoma (MC) of the breast and correlate the cytomorphologic features with histologic appearance to improve the diagnostic sensitivity and specificity of FNAC.We reviewed the cytologic features of 20 cases of MC of the breast in the archives of Ege University Hospital between 1994 and 2006.Twenty patients with an aspirate and confirmed diagnosis of MC were identified. Patient age was 30-74 years (mean, 48). The initial cytologic diagnoses were positive for cancer in 17 cases, atypical/suspicious for cancer in 2 cases and negative for cancer in 1 case. The cytologic picture was characterized by cellular smears composed of highly atypical epithelial tumor cells in loosely cohesive sheets and lying singly, admixed with polymorphous lymphocytes, plasma cells and neutrophils. Tumor cells had predominantly abundant finely granular, eosinophilic cytoplasm and moderate to marked nuclear pleomorphism with prominent nudcleoli. Histologic examination confirmed that 11 cases were atypical MC and 9 were pure MC.Breast MC is a rare, distinct category that appears to have rather characteristic cellular features. Familiarity with the cell components is a prerequisite in cytologic accuracy.

The prognostic significance of inflammation and medullary histological type in invasive carcinoma of the breast

The new gene expression molecular taxonomy of breast cancer places medullary carcinoma in the basal group. The basal group is considered to have a poor prognosis, but medullary carcinoma is considered to have a better prognosis than other grade 3 carcinomas. The prognostic significance of tumour associated inflammation, an important feature of medullary carcinomas, remains controversial. The aim of this study was to assess the prognostic importance of medullary histological type and inflammation in breast cancer. One thousand five hundred and ninety-seven patients who received no systemic adjuvant treatment and who had a median follow up of 9.5 years were studied. Results: Prominent inflammation was associated with high histological grade and with better survival [relative risk (RR) 0.57, 95% confidence intervals (CI) 0.44–0.74] on multivariate analysis. Typical and atypical medullary carcinomas ( n = 132) did not have significantly different survival and were grouped together. Medullary carcinoma did not have significantly different prognosis than grade 3 ductal carcinoma with prominent inflammation, but both had a better prognosis than grade 3 ductal carcinoma without prominent inflammation ( P < 0.0001 and P = 0.03). These differences were independent of other prognostic factors. These results question the current separation of typical and atypical medullary carcinoma. Prominent inflammation is associated with a better prognosis, and may explain the better prognosis in medullary carcinoma compared with grade 3 ductal carcinoma without prominent inflammation. The good prognosis of medullary carcinoma emphasises the heterogeneity of basal-like breast carcinomas. Further studies are needed to investigate the difference in survival between medullary carcinoma and other forms of basal carcinomas and the role of inflammation in any such differences in behaviour.

Clinical Analysis of Medullary Carcinoma of the Breast

Purpose: Medullary carcinoma of the breast is a variant of breast cancer characterized by the histologic appearance of poorly differentiated cells surrounded by a prominent lymphoid stroma. Medullary carcinoma has been reported to carry a prognosis better than other invasive breast carcinomas, but it is frequently overdiagnosed due to the difficulty in diagnosis. The aim of this study was to assess the clinical manifestations and outcome of medullary carcinoma of the breast. Methods: We reviewed the data of 91 patients diagnosed with medullary carcinoma and 3,743 patients with invasive ductal carcinoma, not otherwise specified (NOS) from January 1980 to December 2005 at Yonsei University Severance Hospital. The clinicopathologic features, disease free survival (DFS) and overall survival (OS) for patients with medullary carcinoma were compared with those of the NOS patients. Results: With reviewing the pathologic slides, 69 (75.8%) patients had findings compatible with typical medullary carcinoma (TMC) and the remaining 22 (24.2%) patients were reclassified as atypical medullary carcinoma (AMC). Early stage cancer was more frequent at medullary carcinoma and lymph node positive cancer was less frequent at medullary carcinoma. The expression of ER/PR was positive in either the TMC (18.9%/16.2%) and AMC (15.0%/20.0%) as compared to the NOS (63.2%/57.2%), and the difference was significant (p<0.001). In contrast, the HER-2/neu expression rate was significantly higher in the TMC (47.4%) and AMC (45.5%) than in the NOS (28.3%, p=0.001). The 10year disease free survival and 10-year overall survival of the atypical medullary carcinoma patients (67.8%, 77.8%) were in fact similar to the NOS carcinoma patients (68.3%, 74.7%). There was significant difference in 10-year disease free survival and 10-year overall survival between the TMC (77.8%, 86.0%) and NOS carcinoma (68.3%, 74.7%) patients (p=0.002, p=0.006). Conclusion: The clinical outcome of typical medullary carcinoma is favorable in spite of its aggressive pathologic features and it differs from atypical medullary carcinoma. For precise prediction of prognosis of medullary cancer, we should apply strict criteria for the diagnosis of subtype with medullary features.

Unusual sonographic findings in a case of atypical medullary inflammatory carcinoma of the breast

We report the case of a 35-year-old woman who complained of a rapid enlargement of a pre-existing breast mass and yellowish nipple discharge. Clinical examination revealed a firm mass measuring 15 x 10 cm and "peau d'orange" phenomenon. Sonography revealed a well-defined mass with heterogeneous echotexture and hyperechoic trabecular structures that delineated hypoechoic areas, resulting in a honeycomb pattern. The patient underwent a surgical exploration and a biopsy of the mass and of the skin. The histopathologic examination revealed an atypical medullary carcinoma with high mitotic activity.

Mismatch Repair Genes hMLH1 and hMSH2 May Not Play an Essential Role in Breast Carcinogenesis

Breast carcinoma is one of the most common malignancies in women, and its carcinogenesis is still unknown. The role of microsatellite instability (MSI) in breast carcinogenesis has been inconsistent in the literature. Here we studied the expression of 2 mismatch repair genes, hMLH1 and hMSH2, in 211 cases of intraductal (DCIS; 90 cases) and invasive ductal carcinoma (121 cases) of the breast by immunohistochemical analysis; and evaluated its relationship with cytokeratin (CK) subtypes, along with expression of ER-alpha (138 cases positive, 73 cases negative); PR (118 cases positive, 93 cases negative), and HER-2/neu (47 cases positive, 164 cases negative); and clinical features such as patient age (157 cases>50 years, 54 cases<50 years), tumor size (31 cases of IDC>2 cm, 90 cases of IDC<2 cm), tumor grade (87 cases high nuclear grade, 124 case non-high grade), and lymph node metastasis (38 cases of IDC positive, 74 cases of IDC negative, 9 cases of IDC with no available data on lymph node status). For CK subtypes, 167 cases were classified as luminal subtype (expressing CK8 and/or CK18, negative for CK5/6, CK14, and CK17) and 44 cases were classified as nonluminal (most of them belonged to basal/stem subtype, expressing CK5/6, and/or CK14, and/or CK17). No typical or atypical medullary carcinoma was included in this study. Our results showed that no loss of nuclear expression of either hMLH1 or hMSH2 was identified in any of the 211 cases of DCIS or IDC regardless of the various pathological and clinical factors, suggesting that hMLH1 or hMSH2 may not play an essential role in the majority of cases of the breast carcinoma.

A Locally Advanced Breast Cancer with Difficult Differential Diagnosis of Carcinosarcoma and Atypical Medullary Carcinoma, which had Poor Response to Adriamycin- and Taxane-based Neoadjuvant Chemotherapy: A Case Report

Atypical medullary carcinomas and carcinosarcoma have unique histopathological features. Here we present a case with a breast malignancy that had pathological characteristics of both. A 54-year old patient with a malignant breast mass received 6 cycles of adriamycin-based chemotherapy, followed by 3 cycles of paclitaxel monotherapy, and had a poor clinical response to treatment. A modified radical mastectomy was performed. The pathological diagnosis was complicated by an inability to distinguish between atypical medullary carcinoma and carcinosarcoma. The findings included a tumor that was well-circumscribed, high grade and a syncytial growth pattern as well as biphasic sarcomatous and carcinomatous characteristics. In conclusion, atypical medullary carcinoma and carcinosarcoma of the breast have entirely different prognoses and should be managed differently. Both should be treated by surgical resection, and additional therapy should be considered based on the cancer with the poorer prognosis.

Simultaneous Bilateral Breast Carcinomas: A Category with Frequent Coexpression of HER-2 and ER-α, High Ki-67 and bcl-2, and Low p53

The aim of this study was to evaluate clinicopathological characteristics and immunophenotypes of simultaneous bilateral adenocarcinomas of the breast and their axillary metastases. Immunohistochemical analysis and in situ hybridization were performed using formalin-fixed/paraffin-embedded tissues. In total, 15 primary and 9 metastatic tumors from 8 patients were evaluated. The expression of estrogen receptor-alpha (ER-alpha), progesterone receptor (PR), Ki 67, p53, bcl-2, and bax were evaluated by immunohistochemistry. Her2 gene amplification was evaluated by chromogenic in situ hybridization (CISH). Four patients were younger that 40 years of age (mean 47 years). Six patients had pleomorphic lobular carcinoma in 1 breast. Four of these had invasive ductal carcinoma in the contralateral breast. One patient had atypical medullary carcinoma in both breasts and 1 patient had atypical medullary carcinoma in 1 breast and pleomorphic lobular carcinoma in the other. The phenotype of the primary tumors and corresponding metastatic tumors was similar for the expression of ER-alpha (p=0.001), PR (p=0.03), and HER-2 (p=0.018). While strong coexpression of HER-2 and ER-alpha is exceptional in hereditary breast carcinoma and sporadic breast carcinoma, 6/8 (75%) patients in this study had tumors with strong coexpression of HER-2 and ER-alpha. P53 protein expression was found in only 2/15 (13%) primary tumors, which is in contrast to BRCA1-related hereditary bilateral breast carcinomas, which often express p53 protein. Most of the patients presented with axillary metastases and had very aggressive course. Characteristically, the tumors showed high levels of expression of ER-alpha and Her2 amplification, were bcl-2 positive, and had high Ki-67 fraction. However, in patients with atypical medullary carcinoma there was no expression of ER-alpha or amplification of Her-2.

Frequent KIT and epidermal growth factor receptor overexpressions in undifferentiated‐type breast carcinomas with ‘stem‐cell‐like’ features

It was hypothesized that four histopathological types or subtypes of breast carcinoma were undifferentiated types characterized by bidirectional differentiation toward both luminal epithelial and myoepithelial cells and had characteristic molecular changes: invasive ductal carcinoma (IDC) with a large central acellular zone, atypical medullary carcinoma (a subgroup in Grade 3 solid-tubular carcinoma), matrix-producing carcinoma, and spindle-cell carcinoma (or carcinoma with spindle-cell metaplasia). In 32 cases of the undifferentiated type and 37 cases of the relatively differentiated types, we immunohistochemically examined the expressions of myoepithelial markers and KIT, epidermal growth factor receptor (EGFR), and c-erbB-2 oncoproteins. Vimentin, S-100, and alpha-smooth muscle actin were positive in 28 (88%), 22 (69%), and 15 (47%) of the undifferentiated types, but were positive in seven (19%), one (3%), and one (3%) of relatively differentiated types (P < 0.0001). KIT and EGFR overexpressions were detected more frequently in the undifferentiated types (34 and 88%, respectively) than in relatively differentiated types (3 and 3%, respectively) (P < 0.0001, for both). In 11 (85%) of 13 cases with KIT overexpression, EGFR overexpression concurred. c-erbB-2 overexpression was almost equally detected in both the undifferentiated and relatively differentiated types, and did not correlate with KIT or EGFR overexpression. Phosphotyrosine was detected in 16 (67%) of 24 cases with KIT, EGFR, and/or c-erbB-2 overexpression but only in six (18%) of 34 cases without KIT, EGFR, or c-erbB-2 overexpression (P = 0.0002). The undifferentiated-type breast carcinomas appeared to show mammary epithelial stem cell-like features, and they could be identified by KIT and/or EGFR overexpressions.

Relationship between the expression of various markers and prognostic factors in breast cancer

The immunohistochemical detection of six markers of breast cancer has been compared in the present study with known prognostic factors of the disease to establish locally a standard panel of markers for the management of breast cancer. Sections of tissue of 114 consecutive breast cancer cases were studied immunohistochemically, using antibodies against oestrogen receptor (ER), progesterone receptor (PR), androgen receptor, c-erbB2, cathepsin D, and cyclin D. Marker labelling was graded as recommended in the literature. Using the chi(2)-test, relationships were determined between marker labelling and histological type of cancer, tumour grade, tumour size, axillary lymph node status and age of patient. A p value below 0.05 was considered significant. A positive relationship was found between ER and PR and lower grades of cancer, and a negative relationship was found with medullary and atypical medullary carcinoma. The four other markers showed no relationship with grade or type of cancer. All markers showed no significant relationship with size of tumour, presence of axillary node metastasis or age of patient. There was positive correlation between c-erbB2 and cathepsin D. Our study confirms the association between ER and PR and histological type and grade of breast cancer, both known parameters of good prognosis. We found no consistent relationship between the other four markers and prognostic factors studied, other than the suggestion that c-erbB2 and cathepsin D may be useful markers for poor prognosis and can be usefully applied locally, especially in the light of the current availability of trastuzumab (Herceptin) for management of c-erbB2-positive cases. We found no relationship between the markers and tumour size, axillary lymph node status or age.

Estrogen receptor-negative breast carcinomas: a review of morphology and immunophenotypical analysis

Estrogen receptor (ER)-negative breast cancers are a group of tumors with poor prognosis and fewer cancer prevention and treatment strategies compared to ER-positive tumors. The aim of this study was to assess the morphological characteristics and immunohistochemical profile of ER-negative tumors and thus to understand the biological behavior and unique nature. In total, 291 consecutive ER-negative cases available from our primary breast cancer series were examined. Hematoxylin- and eosin-stained sections of all the cases were studied for several morphological parameters and their immunophenotype profile. These findings were correlated with patient and tumor characteristics and survival data. ER-negative tumors constituted 30% of the primary operable breast cancer series. The majority of tumors were grade 3 (94%) and the commonest histological types were ductal/no specific type (85%), and atypical medullary carcinoma (8%). High-grade comedo-type necrosis, lymphoid stroma, central necrosis/fibrosis and pushing margins were the most common morphological features. The presence of a pushing margin showed a significant relation to androgen receptor negativity, absence of epidermal growth factor receptor expression and negative lymph nodes. Lymphoid stroma and comedo-necrosis correlated with higher tumor grade. ER-negative breast cancers are a distinct group of tumors with several common morphological features. Grade 3 histology, pushing margin, lymphoid stroma, comedo-type necrosis and central fibrosis/necrosis are the dominant morphological findings. The presence of a pushing margin appears to have a significant correlation with negative lymph node status. ER-negative tumors show a higher expression of p53, CerbB2 and epidermal growth factor receptor compared to ER-positive breast cancer. These unique features support the concept that ER-negative tumors are a morphologically and phenotypically distinct entity and provide a rationale for the study and use of newer promising agents in the treatment of ER-negative breast cancer.

The pathology of hereditary breast cancer.

Several studies have demonstrated that familial breast cancers associated with BRCA1 or BRCA2 germline mutations differ in their morphological and immunohistochemical characteristics. Cancers associated with BRCA1 are poorly differentiated infiltrating ductal carcinomas (IDCs) with higher mitotic counts and pleomorphism and less tubule formation than sporadic tumours. In addition, more cases with the morphological features of typical or atypical medullary carcinoma are seen in these patients. Breast carcinomas from BRCA2 mutation carriers tend to be of higher grade than sporadic age-matched controls. Regarding immunophenotypic features. BRCA1 tumours have been found to be more frequently oestrogen receptor- (ER) and progesterone receptor-(PR) negative, and p53-positive than age-matched controls, whereas these differences are not usually found in BRCA2-associated tumours. A higher frequency and unusual location of p53 mutations have been described in BRCA1/2 carcinomas. Furthermore, BRCA1- and BRCA2-associated breast carcinomas show a low frequency of HER-2 expression. Recent studies have shown that most BRCA1 carcinomas belong to the basal cell phenotype, a subtype of high grade, highly proliferating ER/HER2-negative breast carcinoma characterized by the expression of basal or myoepithelial markers, such as basal keratins, P-cadherin, EGFR, etc. This phenotype occurs with a higher incidence in BRCA1 tumours than in sporadic carcinomas and is rarely found in BRCA2 carcinomas. Hereditary carcinomas not attributable to BRCA1/2 mutations have phenotypic similarities with BRCA2 tumours, but tend to be of lesser grade and lower proliferation index. The pathological features of hereditary breast cancer can drive specific treatment and influence the process of mutation screening.