Progress in triple negative breast carcinoma pathophysiology: Potential therapeutic targets

Triple-negative breast carcinoma (TNBC) is a subtype of breast carcinoma defined by negativity for estrogen receptor (ER) or progesterone receptor (PR) by immunohistochemical analysis and negativity for human epidermal growth factor receptor (Her2) by immunohistochemistry or in situ hybridization. TNBC is clinically marked by its high aggressiveness, particularly poor outcomes including a low survival rate, and the lack of specific and effective treatments. Therefore, new potential targets for the treatment of TNBC must be identified. This review summarizes recent evidence supporting novel targets and possible therapeutic regimens in the treatment of TNBC.     

An associated classification of triple negative breast cancer: the risk of relapse and the response to chemotherapy

Background: Triple negative breast cancer (TNBC) is heterogeneous and considered as an aggressive tumor. This study was to evaluate the associated classification and its correlations with prognosis and the response to chemotherapy in Chinese women. Methods: Four hundred and twenty-eight cases of invasive TNBC were involved in this study. The expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and cytokeratin 5/6 (CK5/6), Ki67 and p53 were analyzed by immunohistochemistry and compared with patient outcome, and its implications and chemotherapy response were evaluated in four subgroups: typical medullary carcinoma (TMC), atypical medullary carcinoma (AMC), non-specific invasive ductal carcinoma (IDC) and other types. Results: The factors of tumor grade, tumor stage, lymph node status, EGFR/CK5/6 status and p53 labeling index were different among the groups. TMC tumors had the lowest rate of relapse (5.8%), while AMC, IDC and other types were associated with an increased risk of relapse (19.1%, 26.7% and 38.2% respectively). Many factors were risk predictors of relapse for TNBC and IDC, while only positive lymph node was for AMC. For MC tumors, adjunctive chemotherapy decreased the risk of relapse in lymph node positive subgroup (36.8% and 66.7%), while not significant in lymph node negative one (8.1% and 10.0%). Conclusion: The classification based on histologic and IHC findings may be a significant improvement in predicting outcome in TNBC. The different chemotherapy response in subgroups may contribute to guiding the treatment of TNBC.     

Micropapillary carcinoma of the urinary bladder: report of a case and review of its cytologic features

Micropapillary carcinoma (MPC) is an aggressive variant of urothelial carcinoma. MPC has a propensity to invade lymphovascular spaces and detrusor muscle early in the disease that often leads to upstaging and/or lymph node metastasis in many cases at cystectomy. Its association with the usual high-grade urothelial carcinoma provides an easy recognition of malignancy in cytology specimens without attempt at separating or identifying the MPC component. This may be related to our limited familiarity of its cytologic features with only 4 cases described in the literature. We report another case of MPC and highlight its features in cytologic preparations including the presence of singly scattered tumor cells with high nuclear to cytoplasmic ratio and pleomorphic nuclei, clustered cells devoid of fibrovascular core (micropapillae), 3-dimensional cell aggregates, cytoplasmic vacuoles, and micropapillae exhibiting some features of low-grade urothelial neoplasm. Appreciation of these features may help facilitate its early diagnosis and hopefully a better outcome for these aggressive tumors.     

The low nuclear grade breast neoplasia family

Breast cancer is a heterogeneous disease with varied morphological and molecular features and clinical behaviour. Recently a group of invasive tumours and precursor lesions was reported to exhibit strikingly similar low-grade nuclear features, immunophenotypic and molecular profiles and coexist at frequencies that could not be justified by chance alone. These lesions are grouped together into a single class termed low-grade breast neoplasia family (LGBNF) to differentiate them from high-grade neoplasms, which are thought to develop through different evolutionary pathways. Precursor lesions in this family include columnar cell lesions (CCLs), flat epithelial atypia (FEA), atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), lobular carcinoma in-situ (LCIS) and low-grade DCIS. Invasive LGBNF tumours include invasive tubular and cribriform carcinomas, invasive lobular carcinoma, low-grade invasive mucinous and low-grade ductal no special type (NST) carcinomas. These lesions are characterized by strong uniform expression of hormone receptors, lack of HER2 expression and HER2 gene amplification, and exhibit a unique pattern of genetic aberrations mainly deletions of 16q and gains of 1q. In this review, we present the concept of LGBNF with emphasis on their characteristic phenotypic, genotypic and molecular profiles and their impact on BC management strategies and discuss a hypothetical model of breast cancer evolution and progression.     

Low-grade endometrioid carcinoma of the ovary associated with undifferentiated carcinoma: case report and review of the literature

The association of low-grade endometrioid carcinoma with undifferentiated carcinoma (UC) was first reported in endometrium carcinoma, termed with dedifferentiated carcinoma (DC). However, the coexistence of low-grade endometrioid carcinoma (LGEC) or serous carcinoma (LGSC) with UC has received minimal attention in ovary, and the behavior of this kind of neoplasm remains at further discussion. In this study, we reported a case of low-grade ovarian endometrioid carcinoma associated with UC and reviewed another four cases previously reported. We found a histological continuity between the LGEC and UC components in H&E section, which suggested a dedifferentiation from LGEC to UC components. In summary, this kind of pathological type has aggressive behavior and these patients have very poor prognosis regardless of the amount of undifferentiated carcinoma.     

Dedifferentiation in low-grade mucoepidermoid carcinoma of the parotid gland

Mucoepidermoid carcinoma (MEC), a common malignant salivary gland neoplasm, is generally divided into low-, intermediate-, and high-grade types according to the histologic features. To our knowledge, the present report describes the first case of dedifferentiation occurring in a low-grade MEC. A 55-year-old man presented with a biphasic neoplasm of the right parotid gland composed of low-grade MEC and dedifferentiated high-grade anaplastic undifferentiated carcinoma. Immunohistochemically, carcinoembryonic antigen expression was restricted to the low-grade MEC portion. The Ki-67-labeling index was higher in the dedifferentiated component than in the low-grade component. On image cytometric analysis, the low-grade MEC was diploid, whereas the dedifferentiated carcinoma was aneuploid. Although the patient was alive 10 years after the initial diagnosis, the tumor has recurred twice, at 3 months and 7 months after the initial resection. It is important to recognize that dedifferentiation can occur in a low-grade MEC, similar to other low-grade salivary gland carcinomas.     

Tubular carcinoma of the breast and associated intra-epithelial lesions: a comparative study with invasive low-grade ductal carcinomas

Ductal intra-epithelial lesions of the breast are associated with invasive neoplasms and comprise a large spectrum of histological patterns. We have examined 23 cases of pure tubular carcinomas (TCs) of the breast and 53 cases of invasive ductal low-grade carcinomas to determine the relationship and distribution of intra-epithelial lesions, mainly of ductal in situ carcinoma type, but including also lobular intra-epithelial neoplasia (LIN) in both entities. Eleven cases of TC showed flat epithelial atypia (FEA) (47.8%), and, in 14 and 6 cases, micropapillary and cribriform low-grade ductal carcinoma in situ (DCIS) were present (60.7 and 26.1%, respectively). On the opposite, in ductal grade I invasive carcinomas, the most frequent architectural pattern was low-grade DCIS growing in arcades in 26 cases (49%). While absent in TCs, low-grade DCIS of solid type was found in five (9.4%) cases of ductal invasive carcinomas, where FEA were present in seven (13.2%) cases. LIN lesions were present in four (17.4%) cases of TC, whereas they represented 7.5%, as reported by Carstens et al. (Am J Clin Pathol 58:231–238, 1972), of cases of low-grade carcinomas. These results suggest that invasive pure TC and low-grade ductal carcinomas of the breast are different lesions, and support the fact that TC, of low histopathological grade, is a particular distinct tumoural entity.     

A case of extensively spreading acinic cell carcinoma of the breast with microglandular features

Acinic cell carcinoma (ACC) is an exceptionally rare type of breast carcinoma with a low-grade morphology and a favorable prognosis. It is postulated to be a type of invasive carcinoma arising in microglandular adenosis (MGA). We report a case of extensively spreading ACC of the breast with MGA-like features. Macroscopically, yellowish nodules were widely distributed throughout the right breast, up to the axilla, without mass formation. Microscopically, the tumor consisted of two distinct carcinoma components: one was multiple nodular lesions showing invasive carcinoma with fused solid nests, and the other was a widely spreading lesion exhibiting MGA-like features with uniform small single glands. Immunohistochemically, both components were negative for ER, PR, and HER2, and expressed EMA, S100 and lysozyme. The distinct morphology and molecular expression indicated ACC. The single glands in the MGA-like area lacked myoepithelial cells but were linearly surrounded by type IV collagen, a basement membrane component. This case supports the hypothesis that ACC and MGA have the same lineage and indicates that ACC is not necessarily a low-grade malignancy and can be aggressive.     

Progranulin expression in breast cancer with different intrinsic subtypes

Progranulin is a newly discovered 88-kDa glycoprotein originally purified from the highly tumorigenic mouse teratoma-derived cell line PC. We found that high progranulin expression was associated with higher breast carcinoma angiogenesis, reflected by increased vascular endothelial growth factor expression and higher microvessel density. However, no immunohistochemical evidence currently exists to correlate progranulin expression with clinicopathological features in different intrinsic subtypes of breast carcinoma biopsies. The aim of this study was to investigate the progranulin expression profiles in the intrinsic subtypes of breast carcinomas and their relevance to histopathological and clinicopathological features. Tissue blocks containing 264 cases of breast carcinomas from 2006 to 2009 were classified as different intrinsic subtypes. Tissues of four intrinsic subtypes were immunostained for progranulin, vascular endothelial growth factor and CD105. Their relevance to histopathological and clinicopathological features was also analyzed. Twenty tissue samples from breast fibroadenomas were included in this study. Progranulin expression showed no significant differences in different intrinsic subtypes, although an increasing tendency could be found in the triple-negative breast cancer (TNBC) subgroup (χ(2)=5.00, df=3, p=0.17). However, differences were significant when pathologically node metastasis-positive (pN(+)) TNBC were excluded (χ(2)=17.84, df=3, p<0.01). Some clinicopathological parameters, including CK5/6 (χ(2)=0.08, df=3, p=0.78), E-cadherin (χ(2)=0.71, df=3, p=0.40) and P53 (χ(2)=0.05, df=3, p=0.83), displayed no correlation with activity of progranulin in pathologically node metastasis-negative (pN(-)) TNBC. It was noted that the EGFR expression level of the pN(-) TNBC subtype was significantly higher in cases with strong progranulin expression than in cases with weak progranulin expression (χ(2)=11.26, df=1, p<0.01). A significantly higher expression level of progranulin in pN(-) TNBC suggests that progranulin is a promising new target for pN(-) TNBC treatment. Strong expression of progranulin correlates with positive EGFR expression in the pN(-) TNBC subtype. The close relationship between EGFR and progranulin/VEGF/CD105 expression may partly play a role in high angiogenesis levels in the pN(-) TNBC subtype.     

Histological subtypes in triple negative breast cancer are associated with specific information on survival

Much research has focused on finding novel prognostic biomarkers for triple negative breast cancer (TNBC), whereas only scattered information about the relation between histopathological features and survival in TNBC is available. This study aims to explore the prognostic value of histological subtypes in TNBC.A multicenter retrospective TNBC cohort was established from five Dutch hospitals. All non-neoadjuvantly treated, stage I-III patients with estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 negative breast cancer diagnosed between 2006 and 2014 were included. Clinical and follow-up data (overall survival; OS, relapse free survival; RFS) were retrieved and a central histopathological review was performed.Of 597 patients included (median follow up 62.8 months, median age at diagnosis 56.0 years), 19.4% developed a recurrence. The most prevalent histological subtypes were carcinoma of no special type (NST) (88.4%), metaplastic carcinoma (4.4%) and lobular carcinoma (3.4%). Collectively, tumors of special type were associated with a worse RFS and OS compared to carcinoma NST (RFS HR 1.89; 95% CI 1.18–3.03; p = 0.008; OS HR 1.94; 95% CI 1.28–2.92; p = 0.002). Substantial differences in survival, however, were present between the different histological subtypes.In the presented TNBC cohort, special histological subtype was in general associated with less favorable survival. However, within the group of tumors of special type there were differences in survival between the different subtypes. Accurate histological examination can provide specific prognostic information that may potentially enable more personalized treatment and surveillance regimes for TNBC patients.     

Carcinomas of the breast showing myoepithelial cell differentiation

 Myoepithelial cells are normally located between the epithelial cells and the basal lamina of secretory elements of exocrine glands. Their role in the histogenesis of breast tumours has been studied extensively, and a definite differentiation towards myoepithelial cells has been demonstrated in adenoid cystic carcinoma, adenomyoepithelioma, low-grade adenosquamous (syringomatous) carcinoma, pure malignant myoepithelioma and poorly differentiated myoepithelial-rich breast carcinoma. All these tumours are of low malignancy, with the exception of malignant myoepithelioma and poorly differentiated myoepithelial-rich carcinoma. When a low-grade tumour is associated with a spindle cell component, distant metastases must be expected. Pure malignant myoepithelioma shows morphological and clinical features similar to those of monophasic sarcomatoid carcinomas, and it is possible that this last tumour is linked histogenetically to sarcomatoid carcinomas. Received: 8 April 1997 / Accepted: 10 November 1997     

Mutational Analysis of KRAS, BRAF, and TP53 Genes of Ovarian Serous Carcinomas in Korean Women

Purpose

To assess the prevalence of KRAS, BRAF, and TP53 mutations in cases of low-grade and high-grade serous carcinomas and to evaluate the clinical outcomes of these morphologically distinct carcinomas.

Materials and Methods

Patients with primary invasive serous carcinomas were classified according to the universal grading system. Grade 2 serous tumors were excluded. A total of 100 patients were included for clinical evaluation. Thirty-seven patients, including 20 with low-grade and 17 with high-grade carcinomas, were selected for mutational analysis.

Results

The low-grade carcinoma group was characterized by young age and premenopausal period compared with the high-grade carcinoma group, but there were no statistically significant differences in stage, metastasis of lymph node and residual disease. There were no statistically significant differences in survival rates, however, the low-grade carcinoma group showed a trend for improved progression-free survival compared with the high-grade carcinoma group of early stage (p = 0.064). Mutations in KRAS and BRAF were found in 6 (30%) and 2 (10%) patients in the low-grade carcinoma group, respectively, however, they were not found in the high-grade carcinoma group. KRAS and BRAF mutations were mutually exclusive, and both mutations were observed in 40% (8/20). The frequency of TP53 mutations in low-grade and high-grade carcinoma groups were found in 20% (4/20) and 70.6% (12/17), respectively (p = 0.009).

Conclusion

Low-grade serous carcinoma shows mutation pattern different from that with high-grade carcinoma. As there were no significant differences in stage distribution and survival, especially in advanced stage, we suggest that more studies are needed to segregate these patients into distinct disease entities.     

Primary mucoepidermoid carcinoma of the thyroid: Diagnosis by fine-needle aspiration biopsy

Fine-needle aspiration biopsy (FNAB) has been recognized as a safe and reliable procedure in the evaluation of thyroid nodules. We herein report a case of a low-grade mucoepidermoid carcinoma of the thyroid that was diagnosed with this technique. Examination of an intra-operative FNAB showed cohesive clusters of polygonal squamoid cells with distinct cellular borders, uniform round nuclei, distinct nucleoli, and homogeneous amphophilic to cyanophilic cytoplasm. Focal keratin “pearl” formation was apparent, along with extracellular, lightly basophilic mucin deposits mantled by squamoid cells. These cytologic features are characteristic of low-grade mucoepidermoid carcinoma, as seen in other anatomic sites. This impression was confirmed by examination of paraffin sections. Previous reports have indicated that mucoepidermoid thyroid carcinoma is an indolent, locally recurring lesion. However, in spite of low-grade histology in our case, the neoplasm presented with distant metastases to bones, pleura, and lung.     

Histologic and immunohistochemical analysis of early submucosal invasive carcinoma of the colon and rectum

To investigate the development and progression of colorectal carcinoma, submucosal invasive carcinoma (SMC) with residual intramucosal neoplasm was studied histopathologically. Intramucosal neoplasm was confirmed by immunohistochemical staining against anti-alpha-smooth muscle actin antibody. Submucosal invasive carcinoma was classified into polypoid growth-type carcinoma (PGC) and non-polypoid growth-type carcinoma (NPGC), depending on the presence of intramucosal tumor proliferation. Tumors were > 15 mm in size in 78.2% of the PGC lesions studied, but the degree of submucosal invasion was minimal (invasion of the upper 500 microm of the submucosal layer) in 52.9% of the PGC lesions. Conversely, 64.4% of NPGC lesions were 15 mm in size and the degree of submucosal invasion was moderate or severe (involving the middle and deeper layer of the submucosa) for 72.9% of NPGC. In other words, lesions of NPGC were significantly smaller in size but showed deeper infiltration than PGC lesions. Furthermore, PGC was derived from intramucosal polypoid carcinoma (including carcinoma with adenoma) and was morphologically identical to polyp cancer as reported previously. However, NPGC was derived from the flat and/or depressed type of intramucosal carcinoma classified not as polyp type, but as the superficial type. Typical NPGC was, therefore, also of the superficial type. In addition, approximately 25% of PGC lesions were identified as having an adenoma-carcinoma sequence. There was no coexistence with adenoma in the NPGC lesions, suggesting de novo development. When the degree of histologic atypia in the two types of intramucosal carcinoma was compared, 74.7% of PGC lesions showed low-grade carcinoma, regardless of tumor size, while 62.7% of NPGC lesions showed high-grade carcinoma in the intramucosal lesion. Approximately 25% of carcinomas with low-grade atypia were positive for p53 (as were the high-grade lesions), but it was not expressed in the adenoma. Therefore, tumor development and the degree of invasion differed significantly between the two types of carcinoma.     

Oncocytic neuroendocrine tumors of the lung: histopathologic spectrum and immunohistochemical analysis of 15 cases

Oncocytic neuroendocrine tumor of the lung is rare. To reveal the clinicopathologic features of oncocytic neuroendocrine tumor, we reviewed surgical resections from 80 patients diagnosed with carcinoid tumors and 35 high-grade neuroendocrine carcinomas. We discovered 7 cases from the 80 carcinoid tumors and added 8 patients from personal consultation files. There were no statistically significant differences among the clinical features (such as age, location, and survival). Although most oncocytic neuroendocrine tumors were low-grade neuroendocrine carcinomas, we found that they could be of any grade. Tumor cells showed an ample amount of granular oncocytic cytoplasm and had a round-to-oval nucleus with coarse chromatin. Two cases mainly consisted of small-sized to medium-sized cells resembling plasma cells. This tumorous area intermingled with the conventional oncocytic area. Other histologic features were a large conspicuous nucleolus in 9 cases and the presence of giant cells in 8 cases. In the 80 carcinoid cases, bone formation (P = .034), the presence of giant cells (P?=?.021), and tumor cells with a conspicuous nucleolus (P = .021) were more frequently observed. Immunohistochemical analysis revealed that oncocytic cells were positive for antimitochondria antibody. In conclusion, most of the tumors were low-grade neuroendocrine carcinomas, but we found that oncocytic neuroendocrine tumor can display features of high-grade neuroendocrine carcinoma. The oncocytic change was induced by accumulation of mitochondria. Although this variant does not differ in clinical features of nononcocytic neuroendocrine tumors, histologic features of the oncocytic neuroendocrine tumor can be a potential cause of diagnostic error.     

Poorly differentiated myoepithelial cell rich carcinoma of the breast

Three unusual cases of invasive breast carcinoma are reported, each comprising a dual malignant cellular proliferation consisting of ‘ordinary’ epithelial cells as well as myoepithelial cells haphazardly intermingled. The cases displayed features which did not match any of the four main types of invasive malignant breast tumours containing myoepithelial elements, i.e. adenomyoepithelioma, adenoid cystic carcinoma, pure myoepithelioma and low-grade adenosquamous carcinoma. The designation of ‘poorly differentiated myoepithelial cell rich carcinoma’ (PDMC) is proposed for these tumours.     

Combined use of SOX10 and GATA3 in mammary carcinoma

The complementary coverage of different subsets of breast cancer by GATA3 and SOX10 makes their use in combination appealing for routine clinical use, but study of these markers has been largely limited to cases with high or absent ER expression. Here we report SOX10 and GATA3 immunostaining in parallel using a tissue microarray containing 246 invasive breast carcinoma cases with a range of ER expression. GATA3 and SOX10 were positive in 93 % (229/246) and 15 % (38/246) of cases overall and in 63 % (24/38) and 74 % (28/38) of triple negative breast carcinomas (TNBC), respectively; SOX10 was positive in 15 of the 17 cases that lacked GATA3 expression (88 %). SOX10 was also positive in 3 % (6/196) of ER + cases, including 50 % of cases with low ER (3/6), 20 % with intermediate ER (3/15), and 0 % with high ER (n = 175), so that ER-low cases more strongly resembled TNBC than those with high ER expression. GATA3 expression was lower in cases that co-expressed SOX10 in comparison to those that were positive for GATA3 alone. Less than 1 % (2/246) of cases were negative for both GATA3 and SOX10. Therefore, SOX10 is a useful adjunct to GATA3 in the detection of TNBC and cases with low ER expression and/or reduced GATA3 intensity relative to that typical of breast cancers with higher ER expression. Moreover, given such high sensitivity, metastatic tumors lacking either GATA3 or SOX10 are unlikely to be of breast origin. Additional study is necessary to determine the extent to which SOX10 may also improve specificity and to characterize its biologic significance in breast cancers with low ER expression.     

Polymorphous sweat gland carcinoma

We describe nine cases of a distinctive cutaneous neoplasm showing features of eccrine adnexal differentiation that were characterized by their variegated histological appearance and low-grade malignant behaviour. The term polymorphous sweat gland carcinoma is proposed to designate these lesions. The tumours presented as large, longstanding, slow growing, dermal nodules showing a marked predilection for the extremities. Six patients were women. The patients were aged 42–70 years (mean, 59.8 years). Histologically, the lesions were characterized by a highly cellular proliferation displaying a variety of growth patterns, including solid, trabecular, tubular, pseudopapillary and cylindromatous, with prominent stromal changes including haemorrhage, hyalinization and cystic change, and displaying moderate cytological atypia and mitoses. Focal areas showing features associated with eccrine differentiation (i.e. tubular structures, small glandular lumina) could be identified in all cases. Clinical follow-up in six cases showed that two of the lesions recurred locally over a period of 3–6 years, and one tumour metastasized to regional lymph nodes 3 years after excision. Polymorphous sweat gland carcinoma should be considered in the differential diagnosis of neoplastic epithelial dermal proliferations; complete but conservative surgical excision appears to be the treatment of choice for these lesions.     

Polymorphous low-grade adenocarcinoma of the salivary glands

Six cases of polymorphous low-grade adenocarcinoma (terminal duct adenocarcinoma) of the minor salivary glands are presented. In all but one there was a history of a painless intra-oral mass of fairly long duration. The histopathological appearances were characterized by cytological uniformity in a variety of morphological patterns, including tubular, solid, fascicular and cribriform areas. At a cellular level, the tumours possessed regular, often vesicular nuclei and generally eosinophilic cytoplasm. Five of the patients are still alive, although one had recurrent disease 16 years after her original operation; none died of their tumour. These findings are compared with those of six salivary adenoid cystic carcinomas, a neoplasm with many similar histological features, but with a much worse prognosis. The microscopic differences were mainly cytological and, to a lesser extent, morphological. The immunohistochemical reactions of the two tumours were not sufficiently dissimilar to be of practical value. Polymorphous low-grade adenocarcinoma has only rarely been reported in Britain, but we believe it deserves wider recognition as a distinct clinicopathological entity and, in particular, separation from adenoid cystic carcinoma.     

Poorly differentiated myoepithelial cell rich carcinoma of the breast

Three unusual cases of invasive breast carcinoma are reported, each comprising a dual malignant cellular proliferation consisting of 'ordinary' epithelial cells as well as myoepithelial cells haphazardly intermingled. The cases displayed features which did not match any of the four main types of invasive malignant breast tumours containing myoepithelial elements, i.e. adenomyoepithelioma, adenoid cystic carcinoma, pure myoepithelioma and low-grade adenosquamous carcinoma. The designation of 'poorly differentiated myoepithelial cell rich carcinoma' (PDMC) is proposed for these tumours.