Microglandular adenosis of the breast: a deceptive and still mysterious benign lesion.

Microglandular adenosis (MA) of the breast, a benign glandular proliferation, was originally described approximately 35 years ago. The lesion is constituted by small glands, all of the same size. Glands are lined by one layer of cuboidal epithelial cells encircled by basal lamina without any evidence of interposed myoepithelial elements. Cells are positive for low-weight keratins and S-100 protein and negative for estrogen receptor, progesterone receptor, and HER-2. Since then, in the years that followed, several malignant lesions all showing microglandular architecture have been regarded either as a precursor or as an equivalent manifestation of MA. The latter has been associated with a large number of malignancies that include ductal carcinoma in situ, lobular carcinoma in situ, ademyoepithelioma, high-grade basal-like carcinoma, adenoid cystic carcinoma, matrix-producing carcinoma, invasive duct carcinoma not otherwise specified, and spindle cell carcinoma, not to mention acinic cell carcinoma. None of the above tumors were identical to MA. Differences mainly rested not only on the specific structure of the small glands but also on the cytological composition and immunohistochemical features of different lesions. Here, a review of the features of MA together with the differential diagnosis with lesions showing microglandular structure is discussed. MA shows similarities to a lesion named microglandular hamartoma/adenosis of the nasal cavity. The relation of the 2 similar lesions is discussed.

Solid Papillary Breast Carcinomas Resembling the Tall Cell Variant of Papillary Thyroid Neoplasms: A Unique Invasive Tumor With Indolent Behavior.

Thirteen cases of invasive solid papillary breast carcinomas resembling the tall cell variant of papillary thyroid neoplasms (BPTC) are reported here. Some cases had long-term follow-up. BPTC is a special type of primary breast neoplasm showing a triple-negative profile but low aggressive potential. Knowledge on BPTC is still scanty; therefore, the aim of the present paper was to report on the features of an additional 13 cases. All the patients were female individuals, and the mean age at presentation was 62.6 years; nodule sizes ranged from 0.6 to 2.5 cm (average, 1.6 cm). All the cases were characterized on histology by papillary, follicular as well as solid structures. The cells were columnar, eosinophilic mostly with granular cytoplasms, rich in mitochondria, with the features of oncocytes in no fewer than 7 cases. Estrogen and progesterone receptors as well as HER2 were consistently negative. The Ki67 proliferative index was low. Markers consistent with thyroid origin, such as TTF1 and thyroglobulin, were negative. Five cases stained for mammoglobin and GATA 3 were positive. All cases proved to be invasive and 2 cases each experienced metastases to 1 lymph node (axillary and intramammary). One case of the latter had a local recurrence. Nevertheless, all the patients are alive, free of disease 24 to 132 months after surgery, of which 8 are without further treatment The present series confirms that BPTC is a primary breast tumor of low malignant potential.

The morphological spectrum of salivary gland type tumours of the breast.

Salivary gland like tumours of the breast constitute a wide spectrum of entities each one showing peculiar features and clinical behaviour. They can be subdivided as follows: (1) tumours showing pure myoepithelial cell differentiation, such as pure benign and malignant myoepitheliomas; (2) tumours with mixed epithelial and myoepithelial cell differentiation, such as pleomorphic adenoma, adenomyoepithelioma and adenoid cystic carcinoma; and (3) tumours with pure epithelial cell differentiation, such as acinic cell carcinoma, oncocytic carcinoma, mucoepidermoid carcinoma and polymorphous adenocarcinoma. These tumours share similar features with the salivary gland counterparts, but different clinical behaviour. Most salivary gland type tumours of the breast are negative for oestrogen and progesterone receptor and lack HER2 gene amplification, therefore they are classified as 'triple negative' tumours. Nevertheless, some of the malignant entities (such as classical adenoid cystic carcinoma) exhibit good behaviour and do not need any treatment in addition to local control. The aim of the present paper is to review the morphological and prognostic features of salivary gland like tumours of the breast, in order to highlight the correct clinical management.

AVAREG: a phase II, randomized, noncomparative study of fotemustine or bevacizumab for patients with recurrent glioblastoma.

BACKGROUND: Few prospective studies have assessed the role of bevacizumab and included a control arm with standard treatments for recurrent glioblastoma. We conducted a noncomparative phase II trial (AVAREG) to examine the efficacy of bevacizumab or fotemustine in this setting. METHODS: Eligible patients were randomized 2:1 to receive bevacizumab (10 mg/kg every 2 weeks) or fotemustine (75 mg/m(2) on days 1, 8, and 15, then 100 mg/m(2) every 3 weeks after a 35-day interval). The primary endpoint was 6-month overall survival (OS) rate (OS-6). No formal efficacy comparison was made between the treatment arms. RESULTS: Ninety-one patients were enrolled (bevacizumab n = 59; fotemustine n = 32). Median age was 57 years (range, 28-78 y), and patients had Eastern Cooperative Oncology Group performance status of 0 (n = 42), 1 (n = 35), or 2 (n = 14). OS-6 rate was 62.1% (95% confidence interval [CI], 48.4-74.5) with bevacizumab and 73.3% (95% CI, 54.1-87.7) with fotemustine. OS-6 rates were lower in bevacizumab-treated patients with MGMT promoter methylated tumors than in those with unmethylated tumors (50% and 85%, respectively), but higher in fotemustine-treated patients (87.5% and 50%, respectively). OS rates at 9 months were 37.9% (95% CI, 25.5-51.6) and 46.7% (95% CI, 28.3-65.7) with bevacizumab and fotemustine, respectively, and median OS was 7.3 months (95% CI, 5.8-9.2) and 8.7 months (95% CI, 6.3-15.4), respectively. Toxicity was as expected with the 2 agents. CONCLUSION: Single-agent bevacizumab may have a role in patients with recurrent glioblastoma.

Phyllodes tumours of the breast: a consensus review.

Phyllodes tumours constitute an uncommon but complex group of mammary fibroepithelial lesions. Accurate and reproducible grading of these tumours has long been challenging, owing to the need to assess multiple stratified histological parameters, which may be weighted differently by individual pathologists. Distinction of benign phyllodes tumours from cellular fibroadenomas is fraught with difficulty, due to overlapping microscopic features. Similarly, separation of the malignant phyllodes tumour from spindle cell metaplastic carcinoma and primary breast sarcoma can be problematic. Phyllodes tumours are treated by surgical excision. However, there is no consensus on the definition of an appropriate surgical margin to ensure completeness of excision and reduction of recurrence risk. Interpretive subjectivity, overlapping histological diagnostic criteria, suboptimal correlation between histological classification and clinical behaviour and the lack of robust molecular predictors of outcome make further investigation of the pathogenesis of these fascinating tumours a matter of active research. This review consolidates the current understanding of their pathobiology and clinical behaviour, and includes proposals for a rational approach to the classification and management of phyllodes tumours.

Breast lesions of uncertain malignant nature and limited metastatic potential: proposals to improve their recognition and clinical management.

Breast lesions comprise a family of heterogeneous entities with variable patterns of presentation, morphology and clinical behaviour. The majority of breast lesions are classified traditionally into benign and malignant conditions and their behaviour can, in the vast majority of cases, be predicted with a reasonable degree of accuracy. However, there remain lesions which show borderline features and lie in a grey zone between benign and malignant, as their behaviour cannot be predicted reliably. Defined pathological categorization of such lesions is challenging, and for some entities is recognized to be subjective and include a range of diagnoses, and forms of terminology, which may trigger over- or undertreatment. The rarity of these lesions makes the acquisition of clinical evidence problematic and limits the development of a sufficient evidence base to support informed decision-making by clinicians and patients. Emerging molecular evidence is providing a greater understanding of the biology of these lesions, but this may or may not be reflected in their clinical behaviour. Herein we discuss some breast lesions that are associated with uncertainty regarding classification and behaviour, and hence management. These include biologically invasive malignant lesions associated with uncertain metastatic potential, such as low-grade adenosquamous carcinoma, low-grade fibromatosis-like spindle cell carcinoma and encapsulated papillary carcinoma. Other lesions of uncertain malignant nature remain, such as mammary cylindroma, atypical microglandular adenosis, mammary pleomorphic adenoma and infiltrating epitheliosis. The concept of categories of (1) breast lesions of uncertain malignant nature and (2) breast lesions of limited metastatic potential are proposed with details of which histological entities could be included in each category, and their management implications are discussed.

A unique four-hub protein cluster associates to glioblastoma progression.

Gliomas are the most frequent brain tumors. Among them, glioblastomas are malignant and largely resistant to available treatments. Histopathology is the gold standard for classification and grading of brain tumors. However, brain tumor heterogeneity is remarkable and histopathology procedures for glioma classification remain unsatisfactory for predicting disease course as well as response to treatment. Proteins that tightly associate with cancer differentiation and progression, can bear important prognostic information. Here, we describe the identification of protein clusters differentially expressed in high-grade versus low-grade gliomas. Tissue samples from 25 high-grade tumors, 10 low-grade tumors and 5 normal brain cortices were analyzed by 2D-PAGE and proteomic profiling by mass spectrometry. This led to identify 48 differentially expressed protein markers between tumors and normal samples. Protein clustering by multivariate analyses (PCA and PLS-DA) provided discrimination between pathological samples to an unprecedented extent, and revealed a unique network of deranged proteins. We discovered a novel glioblastoma control module centered on four major network hubs: Huntingtin, HNF4α, c-Myc and 14-3-3ζ. Immunohistochemistry, western blotting and unbiased proteome-wide meta-analysis revealed altered expression of this glioblastoma control module in human glioma samples as compared with normal controls. Moreover, the four-hub network was found to cross-talk with both p53 and EGFR pathways. In summary, the findings of this study indicate the existence of a unifying signaling module controlling glioblastoma pathogenesis and malignant progression, and suggest novel targets for development of diagnostic and therapeutic procedures.

Working formulation of neuroendocrine tumors of the skin and breast.

In the skin and breast, endocrine tumors are composed of a heterogeneous mixture of endocrine and exocrine cells. The definition of "pure" endocrine carcinomas is a matter for debate, and as a consequence, there is lack of uniform diagnostic criteria. There are no significant clinical differences in either overall or disease-free survival between matched neoplasms with endocrine and without endocrine differentiation nor between the degree of endocrine differentiation and tumor size, stage, or prevalence of vascular invasion for both sites (skin and breast). Here, endocrine tumors of the skin and breast are grouped respectively into three categories that include most of the neuroendocrine tumors of the skin and breast as seen in routine practice. It was felt that the number of different types of neuroendocrine tumors is so conspicuous that it is impossible to organize them in an orderly classification. It has been proposed therefore, for practical diagnostic routine purposes, to arrange these neoplasms into a working formulation. The latter includes heterogeneous lesions respectively of the skin and breast within the same group that have clinical features in common.

Lobular neoplasia of the breast revisited with emphasis on the role of E-cadherin immunohistochemistry.

Lobular neoplasia (LN) is a term that encompasses both lobular carcinoma in situ and atypical lobular hyperplasia. These lesions have been shown to constitute both risk indicators and nonobligate precursors of invasive breast cancer, they are relatively uncommon, and are most often identified in specimens taken for other reasons. Their incidence has increased in the last 2 decades, and novel variants, including a pleomorphic type, have been described. Loss of E-cadherin expression is recognized as a hallmark diagnostic feature of LN and invasive lobular carcinomas, and immunohistochemical (IHC) analysis using anti-E-cadherin antibodies has been proven to be a useful method to differentiate between lobular and ductal lesions. The frequent use of E-cadherin IHC analysis in routine diagnostic histopathology, however, has resulted in confusion with regard to the actual value of IHC with antibodies against E-cadherin and other proteins of the cadherin-catenin complex. This review provides an update on recent clinicopathologic and molecular data on LN and invasive lobular carcinoma and a discussion about the use and limitations of IHC with E-cadherin in diagnostic breast pathology.

Oncocytic glioblastoma: a glioblastoma showing oncocytic changes and increased mitochondrial DNA copy number.

Ten cases of glioblastomas showing oncocytic changes are described. The tumors showed mononuclear to multinuclear cells and abundant, granular, eosinophilic cytoplasm. The cytoplasm of these same cells was filled by strongly immunoreactive mitochondria. At ultrastructure, numerous mitochondria, some of which were large, were evidenced in the cytoplasm of neoplastic cells. Finally, 9 of 10 of these cases had a significantly high mitochondrial DNA content compared with control tissue (P < .01). It seems that, for these tumors, the designation of oncocytic glioblastoma is appropriate. To the best of our knowledge, oncocytic changes have not been previously reported in such neoplasms. Oncocytic glioblastomas have to be added to the long list of various tumors that can manifest "unexpected" oncocytic changes in different organs. Albeit failing to show statistical significance (log-rank test, P = .597; Wilcoxon test, P = .233), we observed a trend for longer median survival in oncocytic glioblastomas, when compared with "ordinary" glioblastomas (median survival of 16 versus 8.7 months). Thus, it seems that the definition of neoplasms showing oncocytic changes, currently based on classic morphological parameters (ie, histology, ultrastructure, and immunohistochemistry), can be expanded by including the quantitative assessment of mitochondrial DNA content.

Atypical epithelioid cell myofibroblastoma of the breast with multinodular growth pattern: a potential pitfall of malignancy.

Myofibroblastoma (MFB) of the breast is the prototypical benign spindle cell tumor arising from the mammary stroma. Over the last two decades, several morphological variants of this tumor have been recognized. Epithelioid cell MFB is composed predominantly of neoplastic elements with epithelioid morphology. It represents a potential diagnostic pitfall of malignancy, especially when evaluating small biopsies. We report a unique case of a mammary epithelioid cell MFB composed of large mono- to multi-nucleated cells showing mild to moderate nuclear pleomorphism, predominantly arranged in a multinodular growth pattern. This tumor needs to be distinguished from invasive apocrine, oncocytic, pleomorphic lobular carcinoma, as well as metastases. Immunohistochemistry revealed the fibroblastic/myofibroblatic (positivity for vimentin, desmin, CD34 and focally for α-smooth muscle actin) nature of proliferating cells, and therefore was crucial for a correct diagnosis.

Palisaded myofibroblastoma of the breast: a tumor closely mimicking schwannoma: Report of 2 cases.

Myofibroblastoma is a relatively rare, benign mesenchymal tumor that typically occurs in the breast parenchyma. Unlike mammary-type myofibroblastoma, myofibroblastoma that primarily arises in the lymph nodes exhibits nuclear palisading, and the term palisaded myofibroblastoma has been proposed, accordingly. We report 2 unusual cases of myofibroblastoma of the male breast, which showed a predominant (>90% of the entire tumor) nuclear palisading and Verocay-like bodies. The present cases represent a hitherto unreported variant of mammary-type myofibroblastoma closely mimicking schwannoma. The diagnosis of myofibroblastoma was supported by immunohistochemical analyses showing a diffuse staining for desmin and CD34. In addition, the diagnosis of myofibroblastoma was confirmed in 1 case cytogenetically by the demonstration of the monoallelic loss of the FOXO1/13q14 locus by fluorescence in situ hybridization. Pathologists should be aware of this unusual variant of mammary myofibroblastoma to assure a correct diagnosis.

Genetic clonal mapping of in situ and invasive ductal carcinoma indicates the field cancerization phenomenon in the breast.

Nearly 80% of well-differentiated in situ duct carcinomas (g1 DCIS) have been shown to be multicentric (multilobar) lesions, while most in situ poorly differentiated duct carcinomas (g3 DCIS) were unifocal (unilobar) lesions. Here we present a clonality study of 15 cases of DCIS, all showing multiple foci. Twelve of these cases were associated with an invasive duct carcinoma. Fifteen cases of female breast cancer patients all showing multiple DCIS foci (5 g1 DCIS, 5 g2 DCIS, 5 g3 DCIS) were randomly selected and histologically studied using large histological sections. Care was taken to laser-microdissect DCIS foci that were most distantly located from one another in the same large section, and pertinent cells were genetically studied. Invasive duct carcinoma and ipsilateral lymph node metastases and/or contralateral lesions, whenever present, were additionally microdissected. DNA of neoplastic cells was purified, and the mtDNA D-loop region was sequenced. Genetic distance of different foci from the same case was visualized by phylogenetic analyses using the neighbor-joining method. Patients ranged in age from 36 to 87 years (mean 65.1). All 9 cases of widely spread DCIS were not clonal. Four of 6 cases that showed multiple adjacent foci were clonally related on mtDNA analysis. In the present series, 11/15 DCIS appeared as multiple synchronous primary breast tumors, genetically not related to one another. The present data enhance the view that breast can also show the field cancerization phenomenon, paralleling what has already been proposed in other organs.

The value of large sections in surgical pathology.

Large format sections (LS) first have been introduced in breast pathology more than a century ago. Since then, they constituted for longtime a research tool to better understand breast microanatomy and the relationship between radiological images and pathological features. Similarly LS have been used to study neoplastic, inflammatory, and degenerative diseases affecting various organs, as brain, lung, gastrointentinal tract, bone, urinary tract, prostate, and placenta. Currently LS are mostly applied to diagnostic routine to better stage tumours such as prostate and breast carcinomas or to correlate radiologic imaging to gross specimens. The purpose of the present paper is to review the historical background and the basis of the applications of LS in surgical pathology, with special emphasis on breast tumours.

Synovial sarcoma involving the median nerve: a case report.

Synovial sarcoma may arise from different and unusual sites. Here a case of biphasic synovial sarcoma arising or invading the radial nerve in a 59-year-old female classically showing chromosomal reciprocal translocation (X; 18) is reported. The differential diagnosis from similar tumors is discussed.

Thyroid-like metastases to the scalp from a papillary renal cell carcinoma: a case report.

The skin can host metastatic tumors originating from different organs. We report a case of metastatic renal cell carcinoma to the scalp in a 73-year-old man with features very similar to those of thyroid papillary carcinoma. The histogenesis in relation to its structure is discussed.

Genomic profiling of mitochondrion-rich breast carcinoma: chromosomal changes may be relevant for mitochondria accumulation and tumour biology.

Oncocytic carcinomas are composed of mitochondrion-rich cells. Though recognised by the WHO classification as a histological special type of breast cancer, their status as a discrete pathological entity remains a matter of contention. Given that oncocytic tumours of other anatomical sites display distinct clinico-pathological and molecular features, we sought to define the molecular genetic features of mitochondrion-rich breast tumours and to compare them with a series of histological grade- and oestrogen receptor status-matched invasive ductal carcinomas of no special type. Seventeen mitochondrion-rich breast carcinomas, including nine bona fide oncocytic carcinomas, were profiled with antibodies against oestrogen, progesterone and androgen receptors, HER2, Ki67, GCDFP-15, chromogranin, epithelial membrane antigen, cytokeratin 7, cytokeratin 14, CD68 and mitochondria antigen. These tumours were microdissected and DNA extracted from samples with >70% of tumour cells. Fourteen cases yielded DNA of sufficient quality/quantity and were subjected to high-resolution microarray comparative genomic hybridisation analysis. The genomic profiles were compared to those of 28 grade- and oestrogen receptor status-matched invasive ductal carcinomas of no special type. Oncocytic and other mitochondrion-rich tumours did not differ significantly between themselves. As a group, mitochondrion-rich carcinomas were immunophenotypically heterogenous. Recurrent copy number changes were similar to those described in unselected breast cancers. However, unsupervised and supervised analysis identified a subset of mitochondrion-rich cancers, which often displayed gains of 11q13.1-q13.2 and 19p13. Changes in the latter two chromosomal regions have been shown to be associated with oncocytic tumours of the kidney and thyroid, respectively, and host several nuclear genes with specific mitochondrial function. Our results indicate that in a way akin to oncocytic tumours of other anatomical sites, at least a subset of mitochondrion-rich breast carcinomas may be underpinned by a distinct pattern of chromosomal changes potentially relevant for mitochondria accumulation and constitute a discrete molecular entity.

Extracutaneous Merkel cell carcinomas harbor polyomavirus DNA.

Merkel cell carcinoma is a neuroendocrine tumor, with characteristic morphological and immunohistochemical features. Originally reported as primary carcinoma of skin, it has been described in numerous other sites such as lymph nodes, oral cavity, breast, vaginal walls, and salivary glands. Recent studies have revealed in cutaneous Merkel cell carcinomas a clonally integrated polyomavirus, named Merkel cell polyomavirus. The aim of the present study was to verify the presence of Merkel cell polyomavirus in 5 cases of primary Merkel cell carcinomas of lymph nodes and 1 case of parotid gland to investigate similarities or differences among Merkel cell carcinomas from various sites. Cases studied were 5 primary Merkel cell carcinomas in lymph nodes, 1 in the parotid gland, and 12 in the skin. Twelve cases of primary and metastatic small cell carcinoma of the lung were also investigated. Immunohistochemistry for keratin 20, chromogranin, synaptophysin, and thyroid transcription factor 1 was performed in all cases. Viral DNA was studied using polymerase chain reaction assay and the products evaluated in agarose gel and sequenced. Cytokeratin 20 and Merkel cell polyomavirus were detected in all cases of primary Merkel cell carcinoma irrespective of their site of origin. On the contrary, all cases of pulmonary small cell carcinoma were negative for both Merkel cell polyomavirus and cytokeratin 20. It appears that cutaneous and extracutaneous Merkel cell carcinomas share similar histologic, immunohistochemical, and molecular features. This is further evidence that Merkel cell carcinomas are a multiorgan carcinoma and that Merkel cell polyomavirus might play a role in the pathogenesis of this neoplasm.

Expression of p63 is the sole independent marker of aggressiveness in localised (stage I-II) Merkel cell carcinomas.

Merkel cell carcinoma of the skin is a malignant neuroendocrine tumour, whose prognostic criteria are a matter of dispute. Specifically, no predictor is presently available in stage I-II tumours. We collected clinical and follow-up data from 70 Merkel cell carcinomas of the skin. The same cases were studied for p63 expression by immunohistochemistry, by reverse-transcription PCR (RT-PCR) and TP63 gene status by FISH and for presence of Merkel cell polyomavirus by PCR. Stage emerged as a significant prognostic parameter (P=0.008). p63 expression, detected in 61% (43/70) of cases by immunohistochemistry, was associated with both decreased overall survival (P<0.0001) and disease-free survival (P<0.0001). Variable expression patterns of the different p63 isoforms were found only in cases immunoreactive for p63. In these latter lesions, at least one of the N-terminal p63 isoforms was detected and TAp63α was the most frequently expressed isoform. TP63 gene amplification was observed by FISH in only one case. Presence of Merkel cell polyomavirus DNA sequences was detected in 86% (60/70) of Merkel cell carcinomas and did not emerge as a significant prognostic parameter. Merkel cell carcinoma cases at low stage (stage I-II) represented over half (40/70 cases, 57%) of cases, and the clinical course was uneventful in 25 of 40 cases while 15 cases died of tumour (10/40 cases) within 34 months or were alive with disease (5/40 cases) within 20 months. Interestingly, a very strict correlation was found between evolution and p63 expression (P<0.0001). The present data indicate that p63 expression is associated with a worse prognosis in patients with Merkel cell carcinoma, and in localised tumours it represents the single independent predictor of clinical evolution.