Les difficultés du diagnostic : du carcinome basocellulaire aux tumeurs trichoblastiques: From basal cell carcinoma to trichoblastic tumors: a diagnostic challenge.

Basal cell carcinoma (BCC) is a very common tumor, of which the diagnosis is generally easy. Clinical prediction of histopathological subtype however is however often difficult, i.e. the majority of sclerosing BCCs believed to be morpheaform are in fact trabecular or nodular. There is a subgroup of aggressive BCCs, including trabecular (the most common), morpheaform (rare) and micronodular (very rare) subtypes. Differentiating trichoblastoma from BCC is not always easy, but there are distinctive histopathologic criteria and preferential expression of Berp4 in BCC and PHLDA1 in trichoblastoma that may be of help. The group of trichoblastic tumors comprises giant but benign trichoblastomas and trichoblastic carcinomas at the end of the spectrum (of low or high grade). In case of metastatic BCC, one must rule out trichoblastic carcinoma. Morphologic variants of BCC such as pigmented, clear cell, granular cell BCC or BCC with areas of keratinisation are not of poorer prognosis than the classic types. On the opposite, BCC with sebaceous differentiation (in fact sebaceomas) belong to the spectrum of tumors found in Muir-Torre and must be identified. Basosquamous BCCs should be treated like squamous cell carcinomas as they are more aggressive than the nodular subtype. Cet article fait partie du numéro supplément Prise en charge des carcinomes basocellulaires difficiles à traiter réalisé avec le soutien institutionnel de Sun Pharma.

Sumoylation pathway is required to maintain the basal breast cancer subtype.

The TFAP2C/AP-2γ transcription factor regulates luminal breast cancer genes, and loss of TFAP2C induces epithelial-mesenchymal transition. By contrast, the highly homologous family member, TFAP2A, lacks transcriptional activity at luminal gene promoters. A detailed structure-function analysis identified that sumoylation of TFAP2A blocks its ability to induce the expression of luminal genes. Disruption of the sumoylation pathway by knockdown of sumoylation enzymes, mutation of the SUMO-target lysine of TFAP2A, or treatment with sumoylation inhibitors induced a basal-to-luminal transition, which was dependent on TFAP2A. Sumoylation inhibitors cleared the CD44(+/hi)/CD24(-/low) cell population characterizing basal cancers and inhibited tumor outgrowth of basal cancer xenografts. These findings establish a critical role for sumoylation in regulating the transcriptional mechanisms that maintain the basal cancer phenotype.

Basal-like breast cancer: update on clinicopathologic, immunohistochemical, and molecular features.

CONTEXT: Basal-like breast carcinoma (BLBC) is a distinct molecular subtype of breast carcinoma identified through gene expression profiling studies. OBJECTIVE: To provide the clinical background, the histologic profile, and the immunohistochemical profile of these tumors and discuss the current knowledge of their molecular signature and their implications on targeted molecular therapy. DATA SOURCES: Data were obtained from review of the pertinent peer-reviewed literature. CONCLUSIONS: Basal-like breast carcinomas are aggressive tumors with poor prognosis. Lack of targeted therapy makes their treatment a challenging task. Traditional chemotherapy is still associated with a high risk of relapse and death in a high percentage of patients. Platinum-based chemotherapy has been considered as a candidate for the treatment of BLBCs owing to their BRCA1 phenotype. Approximately 22% of patients treated with single-agent cisplatin show pathologic complete response, which is a comparable rate to that seen with nonplatinum agents. Antiangiogenic agents have been promising, but their currently demonstrated limited response is considered disappointing. Additionally, epidermal growth factor receptor was not shown to be a helpful target for BLBC. A recent study has shown that BLBC appears to be especially sensitive to MEK inhibitors, making it a promising therapeutic possibility. The list of new targets is still evolving and the "magic" therapeutic target is yet to be discovered.

Metastatic breast cancer in a Nigerian tertiary hospital.

BACKGROUND: Late presentation of breast carcinoma is common in resource-limited countries with attendant poor outcome. OBJECTIVE: To describe the pattern of clinical presentation and challenges of treating patients presenting with metastatic breast carcinoma in a Nigerian hospital. METHOD: Clinical records of all patients who presented with metastatic breast carcinoma between January 1991 and December 2005 at the Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria were reviewed. RESULTS: More than half of all histologically confirmed breast cancer patients seen within the study period presented with metastatic disease. Their ages ranged between 20-81 years with a mean age of 45.9 years. Only 3% (6 of 202) were males. Two-thirds had more than one secondary site on initial evaluation and the commonest sites were liver (63%), lung parenchyma (51%), pleura (26%) and contralateral breast in 25%. On immunohistochemistry, basal like tumours were found in 46.1%. Mastectomy was done in 37 patients with fungating breast masses while only one third of those referred to a nearby center for radiotherapy had it done. One year survival rate was 27%. CONCLUSION: Metastatic disease is common in Nigeria and treatment is limited due to resource limitations. Improved awareness of the disease is advocated to reduce late presentation.

Fibroepithelioma of Pinkus: variant of basal cell carcinoma or trichoblastoma? Case report.

INTRODUCTION: Fibroepithelioma of Pinkus (FeP) is a rare tumor that most often affects women aged between 40 and 60 years. Clinically FeP presents as a soft, usually solitary, polypoid or papillomatous well circumscribed tumor of skin color. It is typically located to the trunk and extremities. CASE REPORT: A 75 year old male presented to our Department complaining for the presence of a lesion of the dorsal region. His medical history was free except for several basal cell carcinoma (BCC) surgically excised. Clinical examination revealed a pigmented lesion in the back. The lesion was surgically excised and histopathology showed of a fibroepithelioma of Pinkus. DISCUSSION: Currently, FeP is considered a rare variant of basal cell carcinoma, with characteristic histopathological features, although this view is somewhat controversial as some authors considered FeP to be a variant of trichoblastoma. The pathogenesis of FeP is still under investigation. It is thought that a mutation in the tumor suppressor gene TP53 might predispose to the development of FeP. CONCLUSIONS: Our case is interesting for two reasons. First, in our case FeP is pigmented. Moreover we present a case of Fep in a patient with a history of BCC, a finding that supports the classification of fibroepithelioma of Pinkus as a variant of basal cell carcinoma.

Distinctive immunohistochemical profile of penile intraepithelial lesions: a study of 74 cases.

Several classification schemes for penile precancerous lesions have been proposed, but none of them seems to correlate with the current understanding of penile cancer pathogenesis. Recently, a system, which takes into account morphologic features and purported etiopathogenesis, was proposed, separating penile intraepithelial neoplasia (PeIN) in differentiated and warty/basaloid subtypes. This study was designed to seek an immunohistochemical profile that can be helpful in the classification and differential diagnosis of penile epithelial abnormalities and precancerous lesions using the aforementioned system. The immunohistochemical panel included stains for p16, p53, and Ki-67. For p16 immunostaining, only full-thickness positivity in all epithelial cells was considered as positive; for p53 and Ki-67 immunostaining, patchy or diffuse nuclear positivity above the basal layer was considered as positive. Seventy-four lesions in 59 patients were selected and classified as follows: differentiated PeIN, 34 cases; squamous hyperplasia (SH), 21 cases; basaloid PeIN, 15 cases; and warty PeIN, 4 cases. The mean age of patients was 64 years. Forty-two lesions (56.8%) were located in the glans and 32 (43.2%) in the foreskin. Overexpression of p16 was useful for distinguishing SH from warty/basaloid PeINs (0% vs. 94.7%, P<0.0001) but not SH from differentiated PeINs (0% vs. 5.9%, P=0.519). In addition, p16 allowed the distinction of differentiated and warty/basaloid PeINs (5.9% vs. 94.7%, P<0.0001). Immunohistochemistry results for p53 allowed the separation of SH and differentiated PeIN (9.5% vs. 44.1%, P=0.0078) and SH and warty/basaloid PeIN (9.5% vs. 55.6%, P=0.0042). Ki-67 immunostain was useful for distinguishing SH from differentiated PeIN (52.6% vs. 89.7%, P=0.0062) and SH from PeIN with warty and/or basaloid features (52.6% vs. 100%, P=0.0011). There seems to be a distinctive immunohistochemical profile for associated and precursor epithelial lesions of the penis. SH was p16 and p53 negative, with variable Ki-67 positivity. Differentiated PeIN was p16 negative and Ki-67 positive, with variable p53 positivity. Basaloid and warty PeINs were consistently p16 and Ki-67 positive, with variable p53 positivity. The use of a triple p16/p53/Ki-67 immunohistochemical panel was found to be helpful in the classification, differential diagnosis, and morphologic standardization of penile intraepithelial lesions.

Molecular subtypes of breast cancer are associated with characteristic DNA methylation patterns.

INTRODUCTION: Five different molecular subtypes of breast cancer have been identified through gene expression profiling. Each subtype has a characteristic expression pattern suggested to partly depend on cellular origin. We aimed to investigate whether the molecular subtypes also display distinct methylation profiles. METHODS: We analysed methylation status of 807 cancer-related genes in 189 fresh frozen primary breast tumours and four normal breast tissue samples using an array-based methylation assay. RESULTS: Unsupervised analysis revealed three groups of breast cancer with characteristic methylation patterns. The three groups were associated with the luminal A, luminal B and basal-like molecular subtypes of breast cancer, respectively, whereas cancers of the HER2-enriched and normal-like subtypes were distributed among the three groups. The methylation frequencies were significantly different between subtypes, with luminal B and basal-like tumours being most and least frequently methylated, respectively. Moreover, targets of the polycomb repressor complex in breast cancer and embryonic stem cells were more methylated in luminal B tumours than in other tumours. BRCA2-mutated tumours had a particularly high degree of methylation. Finally, by utilizing gene expression data, we observed that a large fraction of genes reported as having subtype-specific expression patterns might be regulated through methylation. CONCLUSIONS: We have found that breast cancers of the basal-like, luminal A and luminal B molecular subtypes harbour specific methylation profiles. Our results suggest that methylation may play an important role in the development of breast cancers.

Genomic subtypes of breast cancer identified by array-comparative genomic hybridization display distinct molecular and clinical characteristics.

INTRODUCTION: Breast cancer is a profoundly heterogeneous disease with respect to biologic and clinical behavior. Gene-expression profiling has been used to dissect this complexity and to stratify tumors into intrinsic gene-expression subtypes, associated with distinct biology, patient outcome, and genomic alterations. Additionally, breast tumors occurring in individuals with germline BRCA1 or BRCA2 mutations typically fall into distinct subtypes. METHODS: We applied global DNA copy number and gene-expression profiling in 359 breast tumors. All tumors were classified according to intrinsic gene-expression subtypes and included cases from genetically predisposed women. The Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm was used to identify significant DNA copy-number aberrations and genomic subgroups of breast cancer. RESULTS: We identified 31 genomic regions that were highly amplified in > 1% of the 359 breast tumors. Several amplicons were found to co-occur, the 8p12 and 11q13.3 regions being the most frequent combination besides amplicons on the same chromosomal arm. Unsupervised hierarchical clustering with 133 significant GISTIC regions revealed six genomic subtypes, termed 17q12, basal-complex, luminal-simple, luminal-complex, amplifier, and mixed subtypes. Four of them had striking similarity to intrinsic gene-expression subtypes and showed associations to conventional tumor biomarkers and clinical outcome. However, luminal A-classified tumors were distributed in two main genomic subtypes, luminal-simple and luminal-complex, the former group having a better prognosis, whereas the latter group included also luminal B and the majority of BRCA2-mutated tumors. The basal-complex subtype displayed extensive genomic homogeneity and harbored the majority of BRCA1-mutated tumors. The 17q12 subtype comprised mostly HER2-amplified and HER2-enriched subtype tumors and had the worst prognosis. The amplifier and mixed subtypes contained tumors from all gene-expression subtypes, the former being enriched for 8p12-amplified cases, whereas the mixed subtype included many tumors with predominantly DNA copy-number losses and poor prognosis. CONCLUSIONS: Global DNA copy-number analysis integrated with gene-expression data can be used to dissect the complexity of breast cancer. This revealed six genomic subtypes with different clinical behavior and a striking concordance to the intrinsic subtypes. These genomic subtypes may prove useful for understanding the mechanisms of tumor development and for prognostic and treatment prediction purposes.

Morphological characteristics of basal-like subtype of breast carcinoma with special reference to cytopathological features.

Expression profiling of invasive breast carcinomas by DNA microarray techniques has identified five distinct subtypes of tumors (luminal A, luminal B, normal breast-like, HER2 overexpression, and basal-like) that are associated with different clinical outcomes and with different chemotherapy. Basal-like carcinoma is associated with younger patient age, high histological grade, aggressive clinical course, development of distant metastasis, poor prognosis, and relatively high mortality rate. Basal-like carcinomas do not express estrogen receptor, progesterone receptor, or HER2 (triple-negative phenotype). Therefore, patients with basal-like carcinomas are not likely to benefit from endocrine therapies or trastuzumab, but are likely to benefit from systemic chemotherapy. Although genetic, morphological, and immunohistochemical features of basal-like carcinomas have been reported, there is no universal definition for those tumors. Furthermore, there are no specific morphological and immunohistochemical features that can identify those tumors in routine diagnostic materials. In the present paper, we present data of histological and cytological features of basal-like breast carcinoma, and discuss about its morphological spectrum.

Molecular subtyping of breast cancer: opportunities for new therapeutic approaches.

Evidence is accumulating that breast cancer is not one disease but many separate diseases. DNA microarray-based gene expression profiling has demonstrated subtypes with distinct phenotypic features and clinical responses. Prominent among the new subtypes is 'basal-like' breast cancer, one of the 'intrinsic' subtypes defined by negativity for the estrogen, progesterone, and HER2/neu receptors and positivity for cytokeratins-5/6. Focusing on basal-like breast cancer, we discuss how molecular technologies provide new chemotherapy targets, optimising treatment whilst sparing patients from unnecessary toxicity. Clinical trials are needed that incorporate long-term follow-up of patients with well-characterised tumour markers. Whilst the absence of an obvious dominant oncogene driving basal-like breast cancer and the lack of specific therapeutic agents are serious stumbling blocks, this review will highlight several promising therapeutic candidates currently under evaluation. Thus, new molecular technologies should provide a fundamental foundation for better understanding breast and other cancers which may be exploited to save lives. (Part of a Multi-author Review).

Identification of typical medullary breast carcinoma as a genomic sub-group of basal-like carcinomas, a heterogeneous new molecular entity.

INTRODUCTION: Typical medullary breast carcinoma (MBC) has recently been recognized to be part of the basal-like carcinoma spectrum, a feature in agreement with the high rate of TP53 mutations previously reported in MBCs. The present study was therefore designed to identify phenotypic and genetic alterations that distinguish MBCs from basal-like carcinomas (BLC). METHODS: Expression levels of estrogen receptor (ER), progesterone receptor (PR), ERBB2, TP53, cytokeratins (KRTs) 5/6, 14, 8/18, epidermal growth factor receptor and KIT, as well as TP53 gene sequence and high-density array comparative genomic hybridization (CGH) profiles, were assessed and compared in a series of 33 MBCs and 26 BLCs. RESULTS: All tumors were negative for ER, PR and ERBB2. KRTs 5/6 were more frequently expressed in MBCs (94%) than in BLCs (56%) (p = 0.0004). TP53 mutations were disclosed in 20/26 MBCs (77%) and 20/24 BLCs (83%). Array CGH analysis showed that a higher number of gains (95 regions) and losses (34 regions) was observed in MBCs than in BLCs (36 regions of gain; 13 regions of losses). In addition, gains of 1q and 8q, and losses of X were found to be common to the two groups, whereas gains of 10p (53% of the cases), 9p (30.8% of the cases) and 16q (25.8% of the cases), and losses of 4p (34.8% of the cases), and amplicons of 1q, 8p, 10p and 12p were the genetic alterations found to characterize MBC. CONCLUSION: Our study has revealed that MBCs are part of the basal-like group and share common genomic alterations with BLCs, the most frequent being 1q and 8q gains and X losses; however, MBCs are a distinct entity within the basal-like spectrum, characterized by a higher rate of KRT 5/6 expression, a higher rate of gains and losses than BLCs, recurrent 10p, 9p and 16q gains, 4p losses, and 1q, 8p, 10p and 12p amplicons. Our results thus contribute to a better understanding of the heterogeneity in basal-like breast tumors and provide potential diagnostic tools.

Metaplastic breast carcinomas are basal-like tumours.

AIMS: Recently, an immunohistochemical panel comprising antibodies against HER2, oestrogen receptor (ER), epidermal growth factor receptor (EGFR) and cytokeratin (CK) 5/6 was reported to identify basal-like breast carcinomas, as defined by cDNA microarrays. Our aim was to analyse a series of metaplastic breast carcinomas (MBCs) using this panel plus two other basal markers (CK14 and p63) and progesterone receptor (PR), to define how frequently MBCs show a basal-like immunophenotype. METHODS AND RESULTS: Sixty-five cases were retrieved from the pathology archives of the authors' institutions and reviewed by three of the authors. Immunohistochemistry with antibodies for HER2, ER, EGFR, CK5/6, CK14 and p63 was performed according to standard methods. All but six cases (91%) showed the typical immunoprofile of basal-like tumours (ER- and HER2-, EGFR+ and/or CK5/6+). When CK14 and p63 were added to the panel, two additional cases could be classified as basal-like. The majority of MBCs lacked PR, except 4/19 (21%) carcinomas with squamous metaplasia. CONCLUSIONS: Our results demonstrate that MBCs show a basal-like phenotype, regardless of the type of metaplastic elements. Moreover, as these neoplasms frequently overexpress EGFR (57%), patients with MBC may benefit from treatment with anti-EGFR drugs.

Specific morphological features predictive for the basal phenotype in grade 3 invasive ductal carcinoma of breast.

AIMS: Cytokeratin (CK) 14, a myoepithelial marker, is also expressed in a proportion of breast carcinomas. There is evidence that these tumours show a differing metastatic pattern and clinical outcome from other invasive ductal carcinomas (IDCs) and may need different management. Currently, they are not identified in routine practice and no morphological guidelines exist to aid their identification. The aim of this study was to analyse the histological features of CK14+ IDC. METHODS AND RESULTS: A detailed histological review of 453 grade 3 IDCs revealed 88 (19.4%) that expressed CK14. Assessment was made independently by two pathologists using a standardized 'tick-box' proforma covering grade, architectural and cytological features. The results were analysed using logistic regression to identify features that predicted for basal phenotype. Concordance between the two pathologists was fair to good for most parameters (kappa 0.4-0.6). On multiple logistic regression, the basal phenotype was highly significantly associated with the presence of a central scar (P = 0.005), tumour necrosis (P < 0.0001), presence of spindle cells (P = 0.006) or squamous metaplasia (P < 0.0001), high total mitotic count (> 40 per 10 high-power field) (P = 0.0002) and high nuclear-cytoplasmic ratio (P = 0.0002). CONCLUSIONS: Specific morphological features are strongly associated with basal-like breast carcinoma. These could be used in routine diagnostic practice to identify this important subset of tumours.

Winer's dilated pore: the infundibuloma.

This article summarizes Louis H. Winer's description of the dilated pore and some of the pertinent literature about the dilated pore. To better understand the discussion that follows, there is a brief review of the histology of the follicular infundibulum and isthmus, then a discussion of the architectural and cytologic differentiation of proliferations that reputedly differentiate toward the infundibulum. These other proliferations with their original photomicrographs are discussed rather extensively to support the argument that they do not differentiate either architecturally or cellularly toward the infundibulum. I then present evidence that contradicts those authors who claim that Winer's dilated pore is only a cyst and conclude that it is a neoplasm sui generis and the only neoplasm of the skin that differentiates architecturally and cytologically towards the infundibulum (the infundibuloma).

The trichofolliculoma undergoes changes corresponding to the regressing normal hair follicle in its cycle.

The trichofolliculoma is a follicularly differentiated hamartoma, usually described as showing many vellus follicles, spreading from a central infundibular cyst. In spite of the well known regressive changes of normal hair follicles during catagen and telogen, the possibility of corresponding changes in the trichofolliculoma has not yet been discussed in the literature. By examining a total of 31 cases of trichofolliculoma it is demonstrated that this hamartoma undergoes an evolutionary process with great morphological changes, which can be attributed to the anagen, catagen, and telogen phase of the follicular cycle.

Classification and differential diagnosis of clear and basal cell tumors of the salivary glands.

Several cell types of the salivary glands and their neoplasms may have a clear cytoplasm. Classification of their cytological features is made possible with special stainings, immunohistochemistry, and electron microscopy. Clear cell tumors of the salivary glands are usually formed by one distinctive cytological type. A new but distinct and very rare salivary gland neoplasm is the hyalinizing clear cell carcinoma, which should be differentiated from other clear cell salivary tumors. Salivary gland tumors with predominance of a basal cell component are basal cell adenoma, basal cell adenocarcinoma, and the solid type of adenoid cystic carcinoma. The differential diagnosis of clear cell and basal cell tumors is of great importance for the prognosis and treatment of these tumors.