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Summary In this manuscript, we summarize the main features of angiomyolipoma highlighting the recognition of epithelioid angiomyolipoma and the discovery of immunohistochemical expression of HMB45 in a group of tumors that now are referred to as as PEComas. In this scenario, Dr. Rosai believed in our intuition, demonstrating his intellectual honesty and motivated us with his experience (“when a tumor seems malignant it is malignant”) and enthusiasm for the new entities (“in Verona, you use HMB45 instead of H&E”). He really pushed the improvement of the knowledge in this field.

Angiomyolipoma is the most common mesenchymal tumour of the kidney, even if for a long time it has been viewed as a hamartoma rather than a neoplasm. It belongs to a family of neoplasms, named PEComa, characterised by the constant presence of perivascular epithelioid cells that co-express smooth muscle and melanogenesis markers. Angiomyolipoma can occur in patients with tuberous sclerosis, a hereditary syndrome due to the alteration of TSC1 or TSC2 genes, or sporadically. Angiomyolipoma and its variants are indolent tumours; however, some epithelioid angiomyolipomas/pure epithelioid PEComas are aggressive, and criteria for malignancy have been proposed to identify those cases. Although typical angiomyolipoma is a straightforward diagnosis, pathologists should be aware of the wide morphological spectrum of its variants which could be tricky in routine clinical practice and could require immunohistochemical analysis for resolution. The differential diagnosis may range from an inflammatory process (for instance xanthogranulomatous pyelonephritis) to the most common renal cancers and sarcomas. The immunoexpression of melanogenesis markers (HMB45 and Melan-A) and cathepsin K is extremely helpful in the majority of cases. Recently, a subset of epithelioid angiomyolipoma/pure epithelioid PEComa harbouring TFE3 gene fusions has been described, raising questions about its relationship with the family of perivascular epithelioid cell tumour. The activation of the mTOR pathway due to genetic alterations of tuberous sclerosis complex in TSC1 or TSC2 genes in angiomyolipoma has also been reported as well as the subsequent therapeutic implications.

Invasive breast cancer is the most common malignancy in women. Its most common site of metastasis is represented by the lymph nodes of axilla, and the sentinel lymph node (SLN) is the first station of nodal metastasis. Axillary SLN biopsy accurately predicts axillary lymph node status and has been accepted as standard of care for nodal staging in breast cancer. To date, the morphologic aspects of SLN metastasis have not been considered by the oncologic staging system. Extranodal extension (ENE) of nodal metastasis, defined as extension of neoplastic cells through the nodal capsule into the peri-nodal adipose tissue, has recently emerged as an important prognostic factor in several types of malignancies. It has also been considered as a possible predictor of non-sentinel node tumor burden in SLN-positive breast cancer patients. We sought out to clarify the prognostic role of ENE in SLN-positive breast cancer patients in terms of overall and disease-free survival by conducting a systematic review and meta-analysis. Among 172 screened articles, 5 were eligible for the meta-analysis; they globally include 624 patients (163 ENE+ and 461 ENE−) with a median follow-up of 58 months. ENE was associated with a higher risk of both mortality (RR=2.51; 95% CI: 1.66–3.79, p&nbsp

Objectives: Extensive peritumoral neoplastic lymphovascular invasion (ePVI) is a marker of aggressiveness in invasive breast carcinoma (BC). Methods: We explored the impact of ePVI on different BC subtypes. In a total of 2,116 BCs, 91 ePVI-BCs, 70 inflammatory breast carcinomas (IBCs), and 114 casual BCs as a control group (CG-BC) were recruited. Results: Patients affected by ePVI-BC were younger, had larger tumors, higher histologic grade, elevated Ki-67 score, Her2/neu overexpressed, and more lymph node metastases compared with CG-BC (P < .001). Interestingly, only younger mean age at diagnosis differentiated patients with ePVI-BC from patients affected by IBC. ePVI-BC showed a clinical outcome intermediate between the prognoses of IBC and CG-BC. Conclusions: Results suggest that ePVI-BC and IBC may share some pathologic processes, providing a novel perspective on the heterogeneity of BC. Epidemiologic data and molecular studies on gene expression features are needed to rationally classify these tumors into their identified subtypes.

Background The aim of this analysis was to investigate the potential impact of Ki67 assay in a series of patients affected by early stage invasive lobular carcinoma (ILC) undergone surgery. Methods Clinical-pathological data were correlated with disease-free and overall survival (DFS/OS). The maximally selected Log-Rank statistics analysis was applied to the Ki67 continuous variable to estimate appropriate cut-offs. The Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was performed to assess the interaction between ‘pure’ or ‘mixed’ histology ILC and Ki67. Results At a median follow-up of 67 months, 10-years DFS and OS of 405 patients were 67.8 and 79.8 %, respectively. Standardized Log-Rank statistics identified 2 optimal cut-offs (6 and 21 %); 10-years DFS and OS were 75.1, 66.5, and 30.2 % (p = 0.01) and 84.3, 76.4 and 59 % (p = 0.003), for patients with a Ki67 21 %, respectively. Ki67 and lymph-node status were independent predictor for longer DFS and OS at the multivariate analysis, with radiotherapy (for DFS) and age (for OS). Ki67 highly replicated at the internal cross-validation analysis (DFS 85 %, OS 100 %). The STEPP analysis showed that DFS rate decreases as Ki67 increases and those patients with ‘pure’ ILC performed worse than ‘mixed’ histology. Conclusions Despite the retrospective and exploratory nature of the study, Ki67 was able to significantly discriminate the prognosis of patients with ILC, and the effect was more pronounced for patients with ‘pure’ ILC. Electronic supplementary material The online version of this article (doi:10.1186/s13046-016-0325-z) contains supplementary material, which is available to authorized users.

To evaluate the diagnostic accuracy and complication rate of percutaneous ultrasound-guided fine-needle aspiration (US-FNA) of solid pancreatic neoplasms through the analysis of 10-year experiences of two centres. Clinical, radiological and pathologic data of 2,024 patients with solid pancreatic masses who underwent US-FNAs were retrospectively evaluated. Indications for aspiration were: unresectable lesions before neo-adjuvant therapy; doubtful imaging findings; and suspicion of uncommon neoplasms with prognostic or therapeutic implications such as metastases or lymphoma. US-FNAs were performed using aspiration needles with a cytopathologist present in centre 1. In centre 2, cytologic samples were collected with Chiba needles and separately evaluated by a cytopathologist. US-FNA had a diagnostic sample rate of 92.2 % (centre 1: 95.9 %; centre 2: 87.2 %). US-FNA repetition after non-diagnostic samples provided a diagnosis in 86.3 % of cases. Sensitivity, specificity, positive and negative predictive values, and accuracy were 98.7 %, 100 %, 100 %, 75.5 %, and 98.7 %, respectively. The complication rate was 0.8 %. Percutaneous US-FNA is a sensitive, accurate and safe method for the invasive diagnosis of solid pancreatic neoplasms. The use of aspiration needles and the on-site presence of a cytopathologist may lead to a high rate of diagnostic samples, thus reducing the need for US-FNA repetition. • Percutaneous ultrasound-guided fine-needle aspiration of pancreatic neoplasms is sensitive and accurate. • The short-term complication rate of percutaneous ultrasound-guided fine-needle aspiration is low. • Technical aspects may influence the rate of diagnostic samples.

Brunello E, Brunelli M, Manfrin E, Nottegar A, Bersani S, Vergine M, Molino A, Fiorio E, Chilosi M, Gobbo S, Martignoni G & Bonetti F (2012) Histopathology 60, 482–488 Classical lobular breast carcinoma consistently lacks topoisomerase-IIα gene amplification: implications for the tailored use of anthracycline-based chemotherapies [Correction added after online publication, 17 January 2012: Title amended to match main article title.] Aims: There is consistent lack of data focusing the topoisomerase-IIα gene status in lobular breast carcinoma, a subtype that usually shows poor responsiveness to chemotherapies including those using anthracycline drugs. Methods and results: Forty-six infiltrative lobular carcinomas, 13 with matched metastases, were used. Topoisomerase-IIα gene amplification was evaluated by chromogenic in situ hybridization (CISH) and fluorescence in situ hybridization (FISH). We also assessed Her2/neu status by CISH, FISH and silver in situ hybridization (SISH). HER2 immunoexpression was assessed by the HercepTest. Forty-four of 46 (95%) cases revealed no topoisomerase-IIα amplification, whereas two of 46 (5%) cases were amplified by all three techniques. Eleven of the 13 metastatic sites showed no amplification either in the primary or in the metastases (85%); the remaining two were amplified (15%). Her2/neu was not amplified in 44 of 46 (95%) cases nor was it amplified in 11 of 13 (95%) metastatic tissues. The two cases showing Her2/neu and topoisomerase-IIα amplification scored 3+; the remaining non-amplified cases scored 0 or 1+ in 40 and 2+ in four cases. Conclusions: In the era of personalized and tailored therapies, we suggest that patients affected by the classical lobular subtype of breast carcinoma constantly lack the ad hoc predictive rationale for receiving common chemotherapy that includes anthracyclines.

Epithelioid angiomyolipomas (perivascular epithelioid cell tumors) of the kidney are defined as potentially malignant mesenchymal lesions that are closely related to classic angiomyolipoma. Although approximately 120 cases are published, mostly as case reports with variably used diagnostic criteria, the pathologic prognostic predictors of outcome are unknown. We analyzed the clinicopathologic parameters in a large series of 41 cases of pure epithelioid angiomyolipomas of the kidney, which we designate as pure (monotypic) epithelioid PEComas to contrast them from classic angiomyolipomas that are regarded by some as PEComas. We use the terminology "pure" to separate these cases from those that may have variable epithelioid components. The mean age of the patients was 40.7 years (range, 14 to 68 y). The male-to-female ratio was 1:1. Seventy-nine percent of patients were symptomatic at presentation with metastatic disease at onset in 12 cases. Follow-up and/or disease progression information were available for 33 of 41 cases (mean, 44.5 mo and median, 24.5 mo; range, 4 to 240); 9 patients had a history of associated tuberous sclerosis. Recurrence and metastasis were seen in 17% and 49% of patients; 33% of patients died of disease. Lymph node involvement was seen in 24% of patients; the liver (63%), lung (25%), and mesentery (18.8%) were the most common metastatic sites. Clinicopathologic parameters associated with disease progression (recurrence, metastasis, or death due to disease) in univariate analysis included associated tuberous sclerosis complex or concurrent angiomyolipoma (any metastasis, P=0.046), necrosis (metastasis at diagnosis, P=0.012), tumor size >7 cm (progression, P=0.021), extrarenal extension and/or renal vein involvement (progression, P=0.023), and carcinoma-like growth pattern (progression, P=0.040) (the 5 adverse prognostic parameters for pure epithelioid PEComas). Tumors with

We evaluated intratumoral heterogeneity of 30 ductal breast carcinomas with HER2/neu amplification, scored by the American Society of Clinical Oncology/ College of American Pathologists (ASCO/CAP) criteria, and 3+ immunoexpression. High-grade (ratio ≥4.0) vs low-grade amplification (ratio >2.2 to On whole tissue sections, 20 tumors (67%) showed high-grade and 10 (33%) showed low-grade HER2/ neu amplification. Of 20 tumors with high-grade amplification, 14 (70%) showed no intratumoral genotypic heterogeneity; 6 (30%) showed at least 1 core with low-grade amplification. Of 10 cases with low-grade amplification, 6 (60%) showed no intratumoral heterogeneity; 4 (40%) showed chromosome 17 polysomy without gene amplification in 2 of 3 cores per case. Of 30 cases with gene amplification, 4 (13%) showed a “not-amplified pattern” in other parts of the tumor. The routine assessment of HER2/neu amplification using the ASCO/CAP criteria on whole tissue sections is not significantly confounded by intratumoral heterogeneity in breast cancer with high-grade amplification; however, genetic heterogeneity exists in a subset of breast carcinomas with low-grade amplification. The clinical relevance and impact on treatment outcome of intratumoral heterogeneity in breast cancer with low-grade HER2/neu amplification or chromosome 17 polysomy need further investigation.

Pre-operative diagnostic procedures are adopted in the investigation ofsuspicious or equivocal screen-detected breast lesions to avoidunnecessary open biopsy. The high-quality performance of a nono-perative procedure provides the best benign-to-malignant ratio inopen biopsy. The quality assurance system is an integrated part ofbreast screening programs

S100A1 is a calcium-binding protein, which has been recently found in renal cell neoplasms. We evaluated the diagnostic utility of immunohistochemical detection of S100A1 in 164 renal cell neoplasms. Forty-one clear cell, 32 papillary, and 51 chromophobe renal cell carcinomas, and 40 oncocytomas, 164 samples of normal renal parenchyma adjacent to the tumors and 13 fetal kidneys were analyzed. The levels of S100A1 mRNA detected by quantitative RT-PCR analysis of frozen tissues from seven clear cell, five papillary, and six chromophobe renal cell carcinomas, four oncocytomas, and nine samples of normal renal tissues adjacent to neoplasms were compared with the immunohistochemical detection of protein expression. Clear cell and papillary renal cell carcinomas showed positive reactions for S100A1 in 30 out of 41 tumors (73%) and in 30 out of 32 (94%) tumors, respectively. Thirty-seven renal oncocytomas out of 40 (93%) were positive for S100A1, whereas 48 of 51 (94%) chromophobe renal cell carcinomas were negative. S100A1 protein was detected in all samples of unaffected and fetal kidneys. S100A1 mRNA was detected by RT-PCR in all normal kidneys and renal cell neoplasms, although at very different levels. Statistical analyses comparing the different expression of S100A1 in clear cell and chromophobe renal cell carcinomas observed by immunohistochemical and RT-PCR methods showed significant values (P

Perivascular epithelioid cell tumors (PEComas) are mesenchymal tumors composed of histologically, immunohistochemically, ultrastructurally, and genetically distinctive cells. PEComas have been described in different organs and are considered ubiquitous tumors. In this review we discuss recent informations related to PEComas in the genitourinary tract.

Background Inflammatory breast cancer (IBC) is the most rare and aggressive variant of breast cancer (BC); however, only a limited number of specific gene signatures with low generalization abilities are available and few reliable biomarkers are helpful to improve IBC classification into a molecularly distinct phenotype. We applied a network-based strategy to gain insight into master regulators (MRs) linked to IBC pathogenesis. Methods In-silico modeling and Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe) on IBC/non-IBC (nIBC) gene expression data (n = 197) was employed to identify novel master regulators connected to the IBC phenotype. Pathway enrichment analysis was used to characterize predicted targets of candidate genes. The expression pattern of the most significant MRs was then evaluated by immunohistochemistry (IHC) in two independent cohorts of IBCs (n = 39) and nIBCs (n = 82) and normal breast tissues (n = 15) spotted on tissue microarrays. The staining pattern of non-neoplastic mammary epithelial cells was used as a normal control. Results Using in-silico modeling of network-based strategy, we identified three top enriched MRs (NFAT5, CTNNB1 or β-catenin, and MGA) strongly linked to the IBC phenotype. By IHC assays, we found that IBC patients displayed a higher number of NFAT5-positive cases than nIBC (69.2% vs. 19.5%; p-value = 2.79 10-7). Accordingly, the majority of NFAT5-positive IBC samples revealed an aberrant nuclear expression in comparison with nIBC samples (70% vs. 12.5%; p-value = 0.000797). NFAT5 nuclear accumulation occurs regardless of WNT/β-catenin activated signaling in a substantial portion of IBCs, suggesting that NFAT5 pathway activation may have a relevant role in IBC pathogenesis. Accordingly, cytoplasmic NFAT5 and membranous β-catenin expression were preferentially linked to nIBC, accounting for the better prognosis of this phenotype. Conclusions We provide evidence that NFAT-signaling pathway activation could help to identify aggressive forms of BC and potentially be a guide to assignment of phenotype-specific therapeutic agents. The NFAT5 transcription factor might be developed into routine clinical practice as a putative biomarker of IBC phenotype. Electronic supplementary material The online version of this article (doi:10.1186/s12967-015-0492-2) contains supplementary material, which is available to authorized users.

PEComas are mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular epithelioid cells that are characterized by the coexpression of muscle and melanogenetic markers. This group of lesions includes angiomyolipoma, clear cell "sugar" tumor of the lung and extrapulmonary sites, lymphangioleiomyomatosis, clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres, and rare clear cell tumors of other anatomical sites. In the genitourinary tract, PEComas have been described in the kidney, bladder, prostate, testis, and urethra. Although most PEComas behave as benign tumors, some are potentially malignant, and criteria for malignancy have been suggested for both and renal and extrarenal lesions. Recently, the expression of cathepsin K has been demonstrated in a large number of PEComas and has been proposed as a relatively specific marker to distinguish these proliferations from the majority of human cancers. In addition, a distinctive subset of PEComas harboring TFE3 gene fusions has been reported, giving rise to a possible relationship between them and MiTF/TFE family translocation renal cell carcinomas. The genetic alterations of tuberous sclerosis complex that promote activation of the mTOR pathway have been identified in PEComas. Therapy with mTORC1 inhibitors has been shown to be effective in some cases.

Meeting abstracts Inflammatory Breast Cancer (IBC) is the most aggressive and highly metastatic form of breast cancer [[1][1]–[3][2]]. In a recent study [[4][3]], we analysed breast cancer with peritumoral neoplastic lymphovascular invasion (ePVI) in comparison with inflammatory breast cancer

The most common renal lesions of tuberous sclerosis complex, an autosomal-dominant syndrome resulting from losses of TSC1 (9q34) or TSC2 (16p13.3), are renal cysts and angiomyolipomas. Epithelial neoplasms are less common. The TSC2 gene lies adjacent to PKD1, the major gene responsible for autosomal-dominant polycystic kidney disease. Recently, a deletion mutation disrupting both TSC2 and PKD1 has been described in young children with tuberous sclerosis complex with severe renal cystic disease. This disease has been termed the TSC2/PKD1 contiguous gene syndrome. We describe the lesions in the resected kidneys of two adults with TSC2/PDK1 contiguous gene syndrome, at the time of the nephrectomies: a 31-year-old man and his 44-year-old mother. The four kidneys were enlarged reniform masses composed of cysts lined by flattened, cuboidal, or, infrequently, large deeply eosinophilic epithelial cells. The kidneys also contained numerous classic angiomyolipomas and rare intraglomerular microlesions. In the son the largest tumor was a monotypic epithelioid angiomyolipoma. In the wall of his left renal pelvis there was a plaque-shaped, HMB-45-positive localized lesion of lymphangioleiomyomatosis. This is the first description of the renal lesions in adults with genetically confirmed TSC2/PDK1 contiguous gene syndrome. The pathologic findings highlight the importance of thorough sampling for histology in polycystic kidney diseases and indicate that the observation of an angiomyolipoma in biopsy material from patients with enlarged cystic kidneys should suggest the diagnosis of TSC2/PKD1 contiguous gene syndrome, even in cases without ultrasonographic and macroscopic evidence of angiomyolipoma.

Extensive peritumoral neoplastic lymphovascular invasion (ePVI) is a marker of aggressiveness in invasive breast carcinoma (BC).We explored the impact of ePVI on different BC subtypes. In a total of 2,116 BCs, 91 ePVI-BCs, 70 inflammatory breast carcinomas (IBCs), and 114 casual BCs as a control group (CG-BC) were recruited.Patients affected by ePVI-BC were younger, had larger tumors, higher histologic grade, elevated Ki-67 score, Her2/neu overexpressed, and more lymph node metastases compared with CG-BC (P.001). Interestingly, only younger mean age at diagnosis differentiated patients with ePVI-BC from patients affected by IBC. ePVI-BC showed a clinical outcome intermediate between the prognoses of IBC and CG-BC.Results suggest that ePVI-BC and IBC may share some pathologic processes, providing a novel perspective on the heterogeneity of BC. Epidemiologic data and molecular studies on gene expression features are needed to rationally classify these tumors into their identified subtypes.

The perivascular epithelioid cell has been proposed to be the unifying proliferating cell type in a number of lesions such as angiomyolipoma, lymphangiomyomatosis, clear cell "sugar" tumor and renal capsuloma. With the exception of rare examples of angiomyolipoma, they are non-metastasizing. We report four examples of a new member of this family of perivascular epithelioid cell neoplasms that occur in abdominopelvic location and show metastatic properties. The patients, all women, were aged 19 to 41 years (mean, 32), and presented with a tumor mass involving the serosa of the ileum, uterus or pelvic cavity. Morphologically, the tumors were composed of sheets of large polygonal cells with glycogen-rich clear or eosinophilic cytoplasm and moderately pleomorphic nuclei, traversed by a delicate vasculature, mimicking clear cell carcinoma. There were areas of coagulative necrosis and occasional mitotic figures. Intracytoplasmic brown pigment was present in two cases. Spindly cells, smooth muscle and fat were absent. Lymphovascular invasion was present in all, lymph node metastasis was documented in two and metastasis to the ovary was present in one case. Two patients developed widespread metastatic disease after 10 and 28 months from diagnosis. One patient showed the clinical signs of tuberous sclerosis. In spite of the epithelial-like appearance, the tumor cells were negative for epithelial markers but were strongly positive with the melanogenesis-related marker HMB45. Another melanogenesis marker (MART-1) was positive in two cases. Other markers including S-100 protein, vimentin, muscle-specific actin, desmin and chromogranin A were negative. Thus, these tumors are not readily classifiable in the existing schema of known entities, and show overlapping morpho-phenotypic features of clear cell "sugar" tumor of the lung and epithelioid angiomyolipoma. We consider them as sarcomas composed of a pure population of uncommitted perivascular epithelioid cell, that lack modulation toward smooth muscle or adipose cells.

Background It is well known that mammographic screening reduces breast cancer mortality. One possible explanation for this effect is that screening makes it possible to detect smaller breast cancers with fewer involved nodes, but another hypothesis is that some screening-detected tumors are in a pathologically and biologically different phase of evolution from those that are detected clinically. The aim of the present study was to compare the biological, pathological and clinical characteristics of symptomatic vs. asymptomatic breast cancers. Patients and methods: The study considers a series of 1916 consecutive patients who underwent surgery for stage I and II infiltrating breast cancer at Verona hospitals after having undergone ultrasound and mammography (at least one of which was positive). They were divided into two groups on the basis of why they decided to undergo the imaging examinations: group A refers to the 1247 patients with a palpable lump, and group B to the 616 who were asymptomatic. Results The patients in group A were older, and had larger tumors and a higher percentage of positive nodes than those in group B; they also had significantly higher grade tumors, higher Ki-67 levels, and a higher percentage of ER and PgR negative and c-erbB-2 positive tumors (all of the P-values were significant). A logistic regression analysis adjusted for tumor diameter and age showed a reduction in the significance of each of the considered variables, but all of them remained significantly associated with the modality of diagnosis except ER, PgR and c-erbB-2. Conclusions Our results suggest that asymptomatic tumors are biologically different from their clinically presenting counterparts, thus confirming the hypothesis that progression towards greater malignancy may occur during the natural history of breast cancer.

Over the last few years, estrogen receptor determination by means of immunohistochemistry has been extensively used. The aim of this study was to compare this technique with estrogen receptor determination by means of dextran-coated charcoal, and to evaluate whether one of the two methods is more predictive of prognosis. Estrogen receptors were determined by means of both the dextran-coated charcoal method and immunohistochemistry in 405 patients with primary breast cancer; age, pathological tumor size, nodal status, and progesteron receptors by dextran-coated charcoal method were also recorded. The disease-free and overall survival probabilities were estimated using the product-limit method; Cox's proportional hazard model was used to evaluate the prognostic role of estrogen receptors as determined by the two methods. There appears to be a close association between estrogen receptor determination by the two methods (81.5% of concordant results) and their prognostic role was similar, even when the patients were divided into different groups (on the basis of their estrogen receptor status) and adjustments for the effect of other prognostic variables were taken into account. Our study shows that the two methods can be used indifferently to evaluate estrogen receptor status as a prognostic factor in breast cancer patients.

Purpose: Triple (ER-, PR-, HER2-) negative breast carcinoma lack targeted therapies, making this group of tumors difficult to treat. By definition, the lack of HER2 expression means a case scoring 0 or 1+ after immunophenotypical analysis and makes the patients avoiding therapeutical chances with anti-HER2 inhibitors. We sought to recruit from a group of triple negative breast carcinoma, patients eligible for effective personalized targeted therapy with anti-HER therapies on the basis of their HER2 gene status. Methods: 135 patients diagnosed with IHC triple negative breast carcinoma were studied. Whole tissue sections were used for in situ hybridization analysis. Results: 8/100 (8 %) of ductal-type triple negative breast carcinoma presented Her-2/neu gene amplification versus 2/35 (5.7 %) non-ductal triple negative breast carcinoma. Three cases showed a ratio 2.5. One case showed Her-2/neu heterogeneous gene amplification, ratio 2.3. The other six showed from 7 to 8 absolute Her-2/neu gene copy number. Two cases staged pT1c, and eight cases staged pT2. Eight cases graded G3 and two cases G2. Conclusion: (1) Eight percentage of ductal and 5.7 % non-ductal-type triple negative breast carcinoma present Her-2/neu gene amplification, (2) the standard diagnostic flowchart “do not FISH in 0–1+ (HER2-) breast carcinoma” should be replaced by “do FISH in triple (ER-, PR-, HER2-) negative breast carcinoma,” to avoid loss of therapeutical chances in a cohort of such a patients, (3) we demonstrated the identification of a small but significant subset of patients targetable with anti-HER2 inhibitors, giving patients affected by (ex)triple negative breast carcinoma new personalized therapeutical chances.

Background: The classification of renal cell neoplasms includes different subtypes of tumors characterized by different outcome. Some overlapping morphological features and the increasing recognition of new entities are making the traditional histologic distinction of renal cell neoplasms difficult and more tools improving the specificity of the correct identification are needed. Among molecular analyses, immunohistochemistry and fluorescence in situ hybridization have become the most helpful procedures, solving many issues in the differential diagnosis of the renal cell neoplasms. Objective: The aim of this review is to merge the large amount of recent knowledge regarding molecular markers of renal cell neoplasms into a helpful diagnostic algorithm. Conclusion: It is proposed that immunoreactions for CD10, Alpha-methylacyl-CoA racemase, cytokeratin 7, parvalbumin and S100A1, and the cytogenetical analysis of chromosomes 3p, 1, 2, 6, 7, 10, 17 and Y can now offer the most specific tools for the classifica...

To evaluate increment cancer detection rate generated by ultrasound (US).US only detected cancers were assessed for 22,131 self-referring asymptomatic women with negative mammography and subgroups by age, previous cancer, breast density. Invasive assessment and surgical biopsy rate were evaluated.The overall US detection was 1.85 per thousand (41/22,131). In the subgroups it was: 1.95 per thousand (22/11,274) in women50 years vs 1.75 per thousand (19/10,857) in women ≥ 50 years (p = 0.42), 5.49 per thousand (12/2183) in women with previous cancer vs 1.45 per thousand (29/19,948) in women without cancer history (p = 0.0004), 2.21 per thousand (22/9960) in dense breasts (p = 0.17) vs 1.56 per thousand (19/12,171) in fatty breasts. The US generated invasive assessment was 1.9% (422/22,131). The benign to malignant open surgical biopsy ratio was 0.17 (7/41).Adding US to negative mammography allowed for substantial incremental cancer detection rate (1.85 per thousand), particularly at age50 years, in women with previous breast cancer and in dense breasts.

544Background: In clinical practice, the prognostic potential (and best cut-off) of Ki67 for pure ILC is usually borrowed from the ductal histotype, though a formal validation has not yet been full...

The perivascular epithelioid cell (PEC) is a unique cell type coexpressing contractile proteins (mainly α-smooth muscle actin), melanocytic markers, including microphthalmia-associated transcription factor (MITF), and estrogen and progesterone receptors. It is constantly present in a group of tumors called PEComas. Renal PEComas include the common angiomyolipoma as well as less common lesions such as microscopic angiomyolipoma, intraglomerular lesions, angiomyolipoma with epithelial cysts, epithelioid angiomyolipoma, oncocytoma-like angiomyolipoma and lymphangioleiomyomatosis of the renal sinus. It has been demonstrated that most of these lesions are determined by mutations affecting genes of the tuberous sclerosis complex, tuberous sclerosis 1 (TSC1) and tuberous sclerosis 2 (TSC2), with eventual deregulation of the RHEB/MTOR/RPS6KB2 pathway, and it has been observed that some PEComas regressed during sirolimus therapy, an MTOR inhibitor. Recently, overexpression of MITF has been related to the expression of the papain-like cysteine protease cathepsin K in osteoclasts where it has inhibited MTOR. The aim of this study is to evaluate cathepsin K immunohistochemically in the entire spectrum of PEComa lesions in the kidney. The study population consisted of 84 renal PEComa lesions, including 5 composed predominantly of fat (lipoma-like angiomyolipoma), 15 almost exclusively composed of spindle-shaped smooth muscle cells (leiomyoma-like angiomyolipoma) and 31 common angiomyolipomas composed of a mixture of fat, spindle and epithelioid smooth muscle cells, and abnormal thick-walled blood vessels, 15 microscopic angiomyolipomas, 5 intraglomerular lesions, 2 oncocytoma-like angiomyolipomas, 8 epithelioid angiomyolipomas, 2 angiomyolipomas with epithelial cysts and 1 example of lymphangioleiomyomatosis of the renal sinus. In all of the renal PEComas, cathepsin K was found to be constantly and strongly expressed and seems to be a more powerful marker than other commonly used markers for their identification, especially to confirm the diagnosis on needle biopsies.

Aims and background The role of distribution by stage at diagnosis in breast cancer has been considered in many studies, with particular regard to evaluation of prognosis, impact of screening programs and quality of care. Nevertheless, international comparisons of descriptive data can be hampered by lack of homogeneity in staging methods. The TNM is presently the most common staging system used all over the world, although some criticism have been raised recently against its pragmatic value. The present study reports a population-based survey of pathologic TNM distribution in incident cases of female breast cancer in the Verona province, a geographical area of northern Italy covered by cancer registration. Methods All histologically proven incident cases of breast cancer were identified in the study period 1988-1990 and classified as for tumor size and nodal involvement according to the pathological TNM criteria. The type of surgical treatment was also registered for all cases diagnosed in 1990. Results one thousand two hundreds and fifty-four invasive and in situ breast cancers were observed and pT1 cases accounted for 44.4%. Nodal involvement was present in 41.5% of invasive cancers. A surgical treatment was performed in 1213 patients (96.7%). Axillary dissection was reported in 1080 cases, 820 of them (76.6%) having 10 or more lymph nodes examined. Radical mastectomy accounted for 74% of the 458 breast cancers diagnosed in 1990 and 31.6% of the eligible cases were conservatively treated. Conclusions Cancer registries should be encouraged to report data on stage distribution in breast cancer (and in other malignancies). This practice could improve international comparisons and give an essential contribution to studies on survival, screening programs and quality of care.

Nosological classification of sinus histiocytosis with massive lymphadenopathy (SHML; Rosai-Dorfman disease) is difficult, and the normal cellular counterpart of Rosai-Dorfman (RD) cells is uncharacterised. The peculiar S-100+ phenotype of RD cells suggests a relationship with the dendritic cell family. Recent investigations have revealed cathepsin E to be selectively concentrated in antigen-presenting cells, whereas cathepsin D was found to be expressed in cells of macrophage lineage. Cathepsin D and E distribution was investigated by immunohistochemistry in a series of SHML biopsies and in two types of dendritic cell proliferative lesions: dermatopathic lymphadenitis (DL) and Langerhans' cell histiocytosis (LCH). In SHML biopsies, RD cells and monocyte-related elements of the sinuses and pulp coexpressed cathepsin D and E. LCH cells also stained for both these aspartic proteinases. Conversely, in DL cathepsin E and D were localised to separate cells that resembled Langerhans' cells (LC) or macrophages, respectively, in morphology and distribution. Our data outline the peculiar immunophenotype of RD and LCH cells and suggest that caution should be exercised in the identification of their normal cellular counterpart. The common expression of cathepsin D and E and of S-100 protein suggests some phenotypic overlap between SHML and LCH cells, despite their striking morphological divergence.

SummaryWe report a comparative study of 3 clear cell tumors of the lung (CCTL) and 3 angiomyolipomas (AML) of the kidney. Morphological analysis shows that the cells of CCTL are identical to the perivascular epithelioid component of AML.Phenotypically they both consistently expressed melanoma-associated antigens recognized by Moabs HMB45 and HMSA-1, while they were negative for HMSA-5. A minority of cells also expressed S-100 protein, vimentin and actin. In addition, one case of CCTL showed mature adipose tissue entrapped in the proliferation, thus suggesting an intermediate form between CCTL and AML.Based on morphological and phenotypical similarities, it is suggested that CCTL and AML belong to the same family of lesions, characterized by the presence of a peculiar muscle cell, expressing different melanoma-associated antigens.

We report the clinical, pathologic, and immunohistochemical features of an unusual tumor of the kidney composed of densely eosinophilic, polygonal epithelioid cells. The patients were a 56-year-old woman and a 35-year-old man. The renal tumors were discovered during follow-up for breast carcinoma and evaluation for abdominal pain, respectively. The tumors closely resembled oncocytoma in routine sections, but were negative for epithelial markers and positive for HMB-45, a pattern of reactions characteristic of angiomyolipoma. In the woman, a single additional microscopic angiomyolipoma was present in the renal parenchyma at a distance from the main tumor. Both patients are alive without recurrence 7 and 10 years after surgery, respectively. Based on clinical, morphologic, and immunophenotypic features, we conclude that these tumors are oncocytoma-like angiomyolipomas.

Cathepsin K is a protease whose expression is driven by microphthalmia transcription factor (MITF) in osteoclasts. TFE3 and TFEB are members of the same transcription factor subfamily as MITF and all three have overlapping transcriptional targets. We have shown that all t(6;11) renal cell carcinomas, which harbor an Alpha-TFEB gene fusion, as well as a subset of the Xp11 translocation renal carcinomas, which harbor various TFE3 gene fusions, express cathepsin K, while no other common renal carcinoma does. We have hypothesized that overexpression of TFEB or certain TFE3 fusion proteins function like MITF in these neoplasms, and thus activate cathepsin K expression. However, the expression of cathepsin K in specific genetic subtypes of Xp11 translocation carcinomas, as well as alveolar soft part sarcoma, which harbors the same ASPSCR1-TFE3 gene fusion as some Xp11 translocation carcinomas, has not been addressed. We performed immunohistochemistry for cathepsin K on 14 genetically confirmed t(X;1)(p11;q21) carcinomas, harboring the PRCC-TFE3 gene fusion; eight genetically confirmed t(X;17)(p11;q25) carcinomas, harboring the ASPSCR1-TFE3 gene fusion; and 18 alveolar soft part sarcomas (12 genetically confirmed), harboring the identical ASPSCR1-TFE3 gene fusion. All 18 alveolar soft part sarcomas expressed cathepsin K. In contrast, all eight ASPSCR1-TFE3 carcinomas were completely negative for cathepsin K. However, 12 of 14 PRCC-TFE3 carcinomas expressed cathepsin K. Expression of cathepsin K distinguishes alveolar soft part sarcoma from the ASPSCR1-TFE3 carcinoma, harboring the same gene fusion. The latter can be useful diagnostically, especially when alveolar soft part sarcoma presents in an unusual site (such as bone) or with clear cell morphology, which raises the differential diagnosis of metastatic ASPSCR1-TFE3 renal cell carcinoma. The difference in expression of cathepsin K between the PRCC-TFE3 and ASPSCR1-TFE3 carcinomas, together with the observed clinical differences between these subtypes of Xp11 translocation carcinomas, suggests the possibility of functional differences between these two related fusion proteins.

The aim of this study was to identify parameters allowing differentiation among the diverse group of B3 lesion at stereotactic vacuum-assisted biopsy (VAB) to identify patients with a low risk of cancer and who can therefore be referred for follow-up rather than surgery and thus reduce the number of unnecessary surgical procedures. Among 608 VAB procedures performed for nonpalpable ultrasound (US)-occult mammographic abnormality, 102 cases of B3 were included in this study. Mammographic lesion type, lesion size, Breast Imaging Reporting and Data System (BIRADS) category, number of specimens per lesion and presence of atypia were retrospectively analysed. Results were compared with histological findings at surgery (53 cases) or mammographic findings during follow-up (49 cases). Statistical analysis was performed with univariate analysis (chi-square test), and statistical significance was set at p

The microphthalmia transcription factor/transcription factor E (TFE)-family translocation renal cell carcinomas bear specific translocations that result in overexpression of TFE3 or TFEB. TFE3 fusion gene product overexpression occurs as consequence of different translocations involving chromosome Xp11.2, whereas TFEB overexpression is the result of the specific translocation t(6; 11)(p21;q12), which fuses the Alpha gene to TFEB. Both TFE3 and TFEB are closely related members of the microphthalmia transcription factor/TFE-family, which also includes TFEC and microphthalmia transcription factor. These transcription factors have overlapping transcriptional targets. Overexpression of microphthalmia transcription factor has been shown to mediate the expression of cathepsin-K in osteoclasts. We hypothesize that the overexpression of the related TFE3 fusion proteins and TFEB in translocation renal cell carcinomas may have the same effect. We studied cathepsin-K in 17 cytogenetically confirmed microphthalmia transcription factor/TFE-family translocation renal cell carcinomas. Seven cases showed a t(6; 11)(p21; q12), ten cases showed translocations involving Xp11.2; five cases t(X; 1)(p11;q21) resulting in a PRCC-TFE3 gene fusion; three cases t(X; 1)(p11;p34) resulting in a PSF-TFE3 gene fusion, one t(X; 17)(p11;q25) resulting in an ASPL-TFE3 gene fusion, and one t(X; 3)(p11;q23) with an unknown TFE3 gene fusion. As control we analyzed cathepsin-K in 210 clear cell, 40 papillary, 25 chromophobe renal cell carcinomas and 30 oncocytomas. All seven TFEB translocation renal cell carcinomas were labeled for cathepsin-K. Among the cytogenetically confirmed TFE3 translocation renal cell carcinomas, 6 out of 10 were positive. None of the other renal neoplasms expressed cathepsin-K. We conclude the following: (1) cathepsin-K is consistently and strongly expressed in TFEB translocation renal cell carcinomas and in 6 of 10 TFE3 translocation renal cell carcinomas. (2) Cathepsin-K immunolabeling in both TFE3 and TFEB translocation renal cell carcinomas distinguishes these neoplasms from the more common adult renal cell carcinomas, and may be a specific marker of these neoplasms. (3) These results further support the concept that the overexpression of TFE3 or TFEB in these neoplasms activates the expression of genes normally regulated by microphthalmia transcription factor in other cell types. Modern Pathology (2009) 22, 1016-1022; doi: 10.1038/modpathol.2009.58; published online 24 April 2009 ZR 0 ZS 0 Z8 4 ZB 41

BACKGROUND: Cytology and core-needle biopsies are not always sufficient to exclude malignancy in benign breast lesions (BBL) that are at risk of developing cancer, and open biopsy often is mandatory. In screening programs, open biopsies performed for lesions that are at risk of developing malignancy are considered benign. The authors of this report evaluated the impact of the screen-detected BBL at risk of developing cancer that were counted in the quota of benign breast open biopsies in the Breast Cancer Screening Program of Verona. METHODS: Benign open biopsies were subdivided into 4 groups according to their risk of developing cancer: Histo1, normal histology; Histo2, ‘pure’ BBL (fibroadenoma, fibrocystic disease, mastitis, adenosis); Histo3, BBL with a low risk of developing cancer (radial scar, papilloma, papillomatosis, phyllodes tumor, mucocele-like lesion); and Histo4, BBL with a high risk of developing cancer (atypical columnar cell hyperplasia, atypical ductal hyperplasia, atypical lobular hyperplasia). RESULTS: Of 510 open biopsies, 83 biopsies were benign, and the ratio of benign to malignant biopsies was 1:5. Histo1 was observed in 4.8% of all benign open biopsies, Histo2 was observed in 37.4%, Histo3 was observed in 31.3%, and Histo4 was observed 26.5%. CONCLUSIONS: BBL at risk of developing cancer may be numerous in screening programs. It is inappropriate to include BBL at risk of developing cancer in the overall benign open biopsy rate. The authors propose separating pure BBL from lesions at higher risk of developing cancer. To date, there is no evidence to support the premise that detecting high-risk proliferative lesions leads to benefits in terms of reduced mortality; however, these lesions need to be counted separately for future evaluations. Cancer 2009. © 2008 American Cancer Society.

We evaluated intratumoral heterogeneity of 30 ductal breast carcinomas with HER2/neu amplification, scored by the American Society of Clinical Oncology/ College of American Pathologists (ASCO/CAP) criteria, and 3+ immunoexpression. High-grade (ratioor =4.0) vs low-grade amplification (ratio2.2 to4.0) and chromosome 17 polysomy were also evaluated. On whole tissue sections, 20 tumors (67%) showed high-grade and 10 (33%) showed low-grade HER2/ neu amplification. Of 20 tumors with high-grade amplification, 14 (70%) showed no intratumoral genotypic heterogeneity; 6 (30%) showed at least 1 core with low-grade amplification. Of 10 cases with low-grade amplification, 6 (60%) showed no intratumoral heterogeneity; 4 (40%) showed chromosome 17 polysomy without gene amplification in 2 of 3 cores per case. Of 30 cases with gene amplification, 4 (13%) showed a "not-amplified pattern" in other parts of the tumor. The routine assessment of HER2/neu amplification using the ASCO/CAP criteria on whole tissue sections is not significantly confounded by intratumoral heterogeneity in breast cancer with high-grade amplification; however, genetic heterogeneity exists in a subset of breast carcinomas with low-grade amplification. The clinical relevance and impact on treatment outcome of intratumoral heterogeneity in breast cancer with low-grade HER2/neu amplification or chromosome 17 polysomy need further investigation.

Lymphangioleiomyomatosis is a rare and progressive lung cystic disease, caused by the infiltration of lung parenchyma by mesenchymal cells characterized by co-expression of contractile proteins and melanocytic markers. The pathogenesis of lymphangioleiomyomatosis is determined by mutations affecting tuberous sclerosis complex (TSC) genes, with eventual deregulation of the Rheb/mTOR/p70S6K pathway, and the potential therapeutic activity of mTOR inhibitors is currently under investigation. To better understand the molecular mechanisms involved in the pathogenesis of lymphangioleiomyomatosis, we investigated the expression of cathepsin-k (a papain-like cysteine protease with high matrix-degrading activity). The rationale of this choice was based on the recent demonstration that mTOR inhibitors can regulate major functional activities of osteoclasts, including the expression of cathepsin-k. The immunohistochemical study included 12 cases of lymphangioleiomyomatosis. Twelve angiomyolipomas and several lung diseases (sarcoidosis, organizing pneumonia, usual interstitial pneumonia, emphysema) were investigated as controls. In all lymphangioleiomyomatosis cases, strong cathepsin-k immunoreactivity was demonstrated, restricted to lymphangioleiomyomatosis cells. Similar expression levels were observed in renal angiomyolipomas. These observations extend the knowledge regarding the immunophenotypic profile of lymphangioleiomyomatosis cells, and provide a useful new marker for diagnosis in difficult cases (eg, in small transbronchial biopsies). The strong expression of such a potent papain-like cysteine protease in lymphangioleiomyomatosis cells can significantly contribute to the progressive remodelling of lung parenchyma observed in this deadly disease, with eventual formation of lung cysts. It is possible to speculate that mTOR inhibitors may exert part of their action by limiting the destructive remodelling of lung structure.

BACKGROUND: Fine-needle aspiration cytology (FNAC) was adopted as the first-line method to assess breast lesions in the Verona Breast Cancer Screening Program. The radiological and pathological factors relating to the success of FNAC in breast cancer series were evaluated. METHODS: Between July 1999 and June 2004, 418 breast cancers were submitted to FNAC in the Verona Breast Cancer Screening Program. The results of FNAC diagnoses were compared with final histology. The FNAC sensitivity rate, underestimation of malignancy rate, and inadequacy rate were correlated with histotype, size, grading, and radiologic imaging. RESULTS: Of the 418 cancers, 95 were in situ, and 323 were invasive. The sensitivity rate was higher in invasive cancers (P < .001), and the underestimation of malignancy rate was greater in in situ cancers (P = .002). Lobular type cancers had a lower sensitivity rate in invasive and in situ cancers. The sensitivity rate was 100% in medullary, mucinous, and papillary cancers, and no case had inadequate sampling. The underestimation of malignancy rate was higher in tubular carcinoma (18.2%); lobular carcinoma showed a higher inadequacy rate (10.4%). The sensitivity rate was lower and the underestimation of malignancy rate was higher in low-grade carcinomas and in lesions

Summary A case of chondroblastoma of the temporal bone in a 53-year-old male patient is presented. The diagnostic and therapeutic processes are discussed.

Six cases of mediastinal large B-cell lymphoma (MLCL) with sclerosis were analyzed for the presence and patterns of c-myc and bcl-2 loci rearrangements, and for the presence of Epstein-Barr virus DNA sequences by Southern blot hybridization, c-myc gene alterations were found in three of six cases. Two cases showed the presence of mutations or small rearrangements at the 3′ end of the first exon. The c-myc gene abnormalities found in these two cases are similar to those observed in the translocation 8;14 of the endemic Burkitt's lymphomas or in its variants t(2;8) and t(8;22). A third case showed a major rearrangement of c-myc gene, with truncation within its first intron, similar to those observed in sporadic Burkitt's and in acquired immunodeficiency- associated lymphomas. None of the cases displayed bcl-2 gene rearrangements or contained viral sequences. Our data suggest a possible role for a translocation-mediated c-myc activation in the pathogenesis of MLCL. Conversely, bcl-2 gene and Epstein-Barr virus do not appear to be involved in the pathogenesis of these peculiar lymphomas. The association between c-myc structural modifications and MLCL also seems to be of relevance in light of the peculiar tendency of this tumor to involve unusual extranodal site (eg, kidney), reminiscent of the spreading attitude of Burkitt's limphomas.

Three different methods, morphologic, immunocytochemic, and fluorescence activated cell sorter (FC) analysis, were compared with respect to their efficiency in detecting breast cancer cells in bone marrow. In the first series of experiments, the three techniques were compared using bone marrow cells artificially mixed with a known amount of breast cancer cells, whereas in a second series bone marrow from breast cancer patients with bone metastases were used. The following results were obtained: When mixtures of the first series were analyzed, FC analysis detected from 1% to 10% of breast cancer cells in bone marrow (0.2% was a border line value), the morphologic method detected from 0.05% to 10%, and the immunocytochemic method, which was clearly superior, detected breast cancer cells in all mixtures (from 0.00025% to 10%). It was noted that, with both the morphologic and immunocytochemic methods, the percentage of breast cancer cells detected was 2 to 360 times higher than the percentage of added cells, and enrichment was inversely proportional to the percentage of added cells. This result could be a result of different separation of cells during centrifugation due to the different density of breast cancer cells. The superiority of the immunocytochemic method was confirmed in the second series of experiments.

Background Obesity in postmenopausal women is associated with increased breast cancer risk, development of more aggressive tumors and resistance to certain anti-breast cancer treatments. Some of these effects might be mediated by obesity hormone leptin, acting independently or modulating other signaling pathways. Here we focused on the link between leptin and HER2. We tested if HER2 and the leptin receptor (ObR) can be coexpressed in breast cancer cell models, whether these two receptors can physically interact, and whether leptin can transactivate HER2. Next, we studied if leptin/ObR can coexist with HER2 in breast cancer tissues, and if presence of these two systems correlates with specific clinicopathological features. Methods Expression of ObR, HER2, phospo-HER2 was assessed by immonoblotting. Physical interactions between ObR and HER2 were probed by immunoprecipitation and fluorescent immunostaining. Expression of leptin and ObR in breast cancer tissues was detected by immunohistochemistry (IHC). Associations among markers studied by IHC were evaluated using Fisher's exact test for count data. Results HER2 and ObR were coexpressed in all studied breast cancer cell lines. In MCF-7 cells, HER2 physically interacted with ObR and leptin treatment increased HER2 phosphorylation on Tyr 1248. In 59 breast cancers, the presence of leptin was correlated with ObR (the overall association was about 93%). This result was confirmed both in HER2-positive and in HER2-negative subgroups. The expression of leptin or ObR was numerically more frequent in larger (> 10 mm) tumors. Conclusion Coexpression of HER2 and the leptin/ObR system might contribute to enhanced HER2 activity and reduced sensitivity to anti-HER2 treatments.

Dirofilariasis is a zoonotic infection, which is occasionally seen in humans and rarely found as a subcutaneous orbital swelling. The authors report a case of a 62-year-old woman presented with a 3-month history of a right periorbital subcutaneous nodule. Treatment with antibiotics and corticosteroids was not satisfactory. Magnetic resonance imaging analysis showed a nodule with a central colliquative area. The lesion displaced the eyeball superiorly but did not affect the intraorbital muscles. The patient was subjected to excisional biopsy and the nodule measured 15 mm. Histological findings showed microabscess reaction with heterogeneous lymphoid infiltration. Additional consecutive sections finally showed Dirofilaria repens, curled up in spirals with external cuticular ridges in an environment characterized by epithelioid cells. The lesion did not recur for 5 months. Periorbital swelling can be rarely caused by Dirofilaria repens; therefore, this diagnosis should be considered in all cases of subcutaneous inflammatory or tumor-like lesion of unknown etiology.

Sir, We read with great interest the paper by Farshid et al (2008) recently published in the Br J Cancer. The authors address a complex problem that is the daily experience of professionals involved in breast cancer screening programmes worldwide. In fact, although radiologically suspicious lesions have well-recognised guidelines intended to determine the nature of the lesion, there is no definitive agreement as to how a discrete mass of indeterminate/equivocal significance (3B) should be approached. In particular it is not very clear whether these benign-looking lesions should be followed up with mammography or whether they warrant a more ‘aggressive' approach, using fine needle aspiration cytology or core biopsy, to define more precisely their nature. Using a stepwise approach to the use of FNAB and core biopsy in 1183 screen-detected category 3B lesions, Farshid et al (2008) have shown that 8.3% of these were, in fact, malignant. We would like to add our experience with 3B-circumscribed masses observed in the Verona Breast Cancer Screening Program. In Verona, the breast cancer screening programme is designed in a way similar to that reported by Farshid et al (2008), as it is based on an integrated radio-pathologic programme with on-site pathologists who perform real-time immediate assessments of FNAC samples and discuss these results with the radiologists. A stepwise approach is similarly employed with FNAC as the first-line diagnostic modality and core biopsy as the second-line modality. In the screening at Verona, the global FNAC accuracy in defining breast lesions (PPV of 99.3%, NPV of 98.6%) (Manfrin et al, 2008) reflects Farshid et al (2008) data, confirming FNAC as a reliable first diagnostic tool for the assessment of breast lesions. From 1999 to 2004, we have observed and cyto-histologically characterised 388 circumscribed 3B lesions, and the pathological analysis (387 FNAC and 23 core biopsies) has shown that 19 (4.89%) were, in fact, carcinomas (nine invasive ductal carcinomas of no special type, five mucinous carcinomas, one medullary carcinoma, one invasive papillary carcinoma, one invasive lobular carcinoma and two in situ carcinomas, one ductal type and one lobular type). No highly aggressive tumours were observed in our series. Thus, our findings confirm the experience reported by Farshid et al (2008) that cyto-histological assessment of circumscribed 3B lesions increases the number of cancers detected. But is this useful? In fact, there is no definite proof that the detection of more tumours, obtained with the assessment of circumscribed 3B lesions, will ameliorate the final results of the screening, namely the reduction of mortality. Although a longer follow-up is needed to clearly define the impact on mortality, we might consider that the tumours observed in Farshid et al (2008), and in our experience alike, are mostly of low-grade aggressiveness. Thus, a significant impact on the reduction of mortality seems unlikely. On the other hand, if all 3B lesions are assessed, an increase of the rate of recalls for assessment is inevitably derived. Not surprisingly, in the general report of activity of the Verona Breast Cancer Screening (Mariotto et al, 2007), we observed a high rate of assessments for breast lesions, 10.9% in the first round and 5.4% in subsequent rounds, not acceptable according to the European Guidelines, and a cancer detection rate of 9.7‰ in first round and 5.1‰ in subsequent rounds, which is within the desirable standards according to the European Guidelines (Commission of the European Communities, 2006). Thus, if the reduction of mortality is the sole and only goal of the screening, the assessment of 3B lesions should be discouraged. On the other hand, if we consider other factors, the balance between pros and cons becomes more difficult. As so well posed by Farshid et al (2008), ‘many clinicians are uncomfortable with the watchful waiting approach', as ‘delay in the diagnosis of malignancy is one of the chief factors in medico-legal disputes concerning breast disease'. We would like to add another aspect we have observed in our daily practice, namely a sort of ‘pressure' from the women attending the screening programme to obtain the same diagnostic quality of a breast clinic. Obviously, many other factors should also be considered, including the cost/benefit ratio, psychological impact, and so on. The paper of Farshid et al (2008) addresses this problem in a clear and documented manner and is likely to spark a fruitful debate about the best way to approach 3B lesions.

We evaluated HER-2/neu status in 100 consecutive ductal breast carcinomas by using the Food and Drug Administration (FDA) and American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) scoring systems. With the FDA system, scores were 3+ in 23.0%, 2+ in 25.0%, and 0 or 1+ in 52.0% of cases. With the ASCO/CAP system, scores were 3+ in 16.0%, 2+ in 34.0%, and 0 or 1+ in 50.0%. With the FDA and ASCO/CAP systems, respectively, 3+ cases (n = 23 and 16, respectively) showed high-grade, granular HER-2/ neu amplification in 15 (65%) and 14 (88%); low-grade, borderline amplification in 7 (30%) and 1 (6%); and chromosome 17 polysomy without amplification in 1 (4%) and 1 (6%). Concordance between schemes was higher for cases with high-grade, granular HER-2/ neu amplification (concordance coefficient, 0.74). Cases with low-grade, borderline HER-2/ neu amplification showed poor concordance (concordance coefficient, 0.20). The FDA and ASCO/CAP schemes for HER-2/neu evaluation select patients differently for trastuzumab therapy. Major discordance is present for low-grade, borderline HER-2/ neu amplification. FDA low-grade, borderline tumors would be reclassified as without HER-2/ neu amplification or as polysomic. The ASCO/CAP scheme has a great concordance coefficient between strong 3+ immunohistochemical cases and cases with high-grade, granular HER-2/ neu amplification.

Radial scar (RS) is a benign breast lesion but a variable percentage of cases are associated with atypical epithelial proliferations and cancer. Previous studies have shown that patient age and the size of RS are correlated to a potential neoplastic transformation. We collected 117 asymptomatic patients with suspected RS following a mammogram, histologically confirmed. The clinical, pathological and immunophenotypical analysis is reported. The cases are subdivided into three different groups: (1) RS “Pure”, without epithelial atypia; (2) RS associated with epithelial atypical hyperplasia; (3) RS with cancer. “Pure” RS was detected in 55 patients (47%); the mean age was 48.1 years and the mean size 0.94 cm. RS associated with atypical epithelial hyperplasia was identified in 25 cases (21%) with a mean age of 53.1 years and a mean size of 0.98 cm. Carcinoma in RS was observed in 37 cases (32%); the mean age was 55.5 years and the mean size was 1.16 cm. The mean age was statistically significant (P = 0.004) in separating RS with cancer from the two other RS groups. The size of RS was not sufficiently statistically significant (P = 0.2) to differentiate the risk. Atypical lesions and cancers showed a morphology and marker of low-grade aggressiveness. RS seems to represent a natural model of carcinogenesis starting from a proliferative lesion in patients of less than 50 years of age and developing into an atypical and later into a carcinomatous lesion. The fact that most carcinomas arising in RS are low grade also favors this hypothesis. All RS should be excised.

Loss of chromosome 9p has been implicated in the progression of renal cell carcinoma. We evaluated the clinical utility of fluorescence in situ hybridization analysis of loss of chromosome 9p in 73 patients with clear cell renal cell carcinomas with varied stage, size, grade, necrosis (SSIGN) scores. Loss of chromosome 9p was observed in 13 tumors (18%). The 5-year cancer-specific survival of patients without loss of chromosome 9p was 88% and was 43% in those with loss of chromosome 9p (P

The perivascular epithelioid cell (PEC) is a cell type constantly present in a group of tumors called PEComas. PEC expresses myogenic and melanocytic markers, such as HMB45 and actin. Recently, recurrent chromosomal alterations have been demonstrated in PEC. At present, PEComa is a widely accepted entity. In the past 10 years, the use of this term has allowed to report and describe numerous cases permitting to start highlighting the biology of this group of lesions. PEComas are related to the genetic alterations of tuberous sclerosis complex (TSC), an autosomal dominant genetic disease due to losses of TSC1 (9q34) or TSC2 (16p13.3) genes which seem to have a role in the regulation of the Rheb/mTOR/p70S6K pathway. There are some open questions about PEComas regarding its histogenesis, the definition of epithelioid angiomyolipoma and the identification of the histological criteria of malignancy. An innovative therapeutic trial using rapamycin is under way for tumors occurring in TSC such as renal angiomyolipoma and lymphangioleiomyomatosis. Its success could provide the rationale for the use of the same drug in other lesions composed of PECs, especially in the malignant ones.

The hallmark of chromophobe renal cell carcinoma is multiple chromosomal losses from among chromosomes 1, 2, 6, 10 and 17. Chromophobe renal cell carcinoma with distant metastases or sarcomatoid transformation are uncommon and little is known about their chromosomal abnormalities. We collected six sarcomatoid chromophobe renal cell carcinomas and three primary chromophobe renal cell carcinomas with distant metastases. A cytogenetic analysis by fluorescent in situ hybridization on paraffin-embedded tissue was performed using centromeric probes for chromosomes 1, 2, 6, 10 and 17. We found more than one signal in four of six (66%) sarcomatoid chromophobe renal cell carcinomas, in both sarcomatoid and adjacent epithelial components. Both primary chromophobe renal cell carcinomas and matched metastases showed single signals for all chromosomes studied in two cases and no abnormalities in the remaining case. We concluded that: (1) both epithelial and sarcomatoid components of sarcomatoid chromophobe renal cell carcinoma show different genetic abnormalities from those characteristic of chromophobe renal cell carcinoma; (2) sarcomatoid chromophobe renal cell carcinomas frequently have multiple gains (polysomy) of chromosomes 1, 2, 6, 10 and 17; (3) distant metastases show the same genetic patterns, usually chromosomal losses (monosomy), found in the primary tumors.