Wnt (canonical and non canonical) pathways in breast carcinoma with extensive vascular invasion and inflammatory breast carcinoma.

BACKGROUND: Breast carcinoma with extensive peritumoral vascular invasion (ePVI-BC) is a cancer with massive vascular invasion (>10) detected in more than one slide. This neoplasm shows clinic-pathological affinity with inflammatory breast carcinoma (IBC). In this paper we evaluate their biological relationship through the study of surrogate markers (ß-catenin and NFAT5) of Canonical (cWnt) and non-canonical (nWnt) Wnt pathways activation. METHODS: By immunoistochemistry, we investigate ß-catenin and NFAT5 in 39 IBC, 74 ePVI-BC and 84 control cases (CG-BC). RESULTS: cWnt was activated in 100 % of ePVI-BC, in 64 % of IBC and 10 % of CG-BC. nWnt was activated in 20 % of ePVI-BC, 50 % of IBC and 1% of CG-BC. The prognosis of carcinomas with nWnt activated was poor similar to IBC. The statistical analysis evidences as both the pathways are synergistic in malignant progression and survival time. ß-catenin show an important association with prognostic factors and NFAT5 shows a relevant prognostic role on OS (p = 1.5*10-6) and DFS (P = 1,2*10-4). nWnt is associated with a worse prognosis independently of cWnt. cWnt is associated with adverse prognosis (DFS p = 0.0469; OS p = 0.004891) but its prognostic role is indifferent in carcinoma with nWnt activated. CONCLUSIONS: Canonical Wnt pathway is involved in malignant progression with dominant role for vascular invasion whereas non canonical Wnt pathway plays an important role on survival time including the capacity to identify carcinomas with IBC-like prognosis. Furthermore ePVI may represent a "prodromal form of IBC" as demonstrated by its clinicopathological and biological similarity with IBC.

CROCC-mutated rhabdoid colorectal carcinoma showing in intercellular spaces lamellipodia and cellular projections revealed by electron microscopy.

BACKGROUND: Rhabdoid colorectal carcinoma (RC) is a rare lesion localized to the proximal colon of patients with a mean age at diagnosis of around 70 years. This tumor shows an aggressive behavior with an overall survival period shorter than 12 months. The diagnostic hallmark is the presence of rhabdoid cells. Alterations in chromatin remodeling (SMARCB1) and in the centrosome structure (CROCC) are reported in RC usually BRAFmut and MSI-H. RKO intestinal neoplastic cells culture (BRAFmut, SMARCB1wt, MSI-H) with CROCC knockdown exhibit rhabdoid features and develop prominent projections from the edge of the cell. METHODS: Here, we investigated two cases of CROCCmutSMARCB1wt RC by scanning and transmission electron microscopy (SEM, TEM). RESULTS: TEM confirmed the diagnostic presence of intermediate cytoplasmic filaments and nucleolar margination. SEM showed cellular protrusions (lamellipodia) in the intercellular spaces not evident at light microscopy. CONCLUSIONS: These protrusions CROCC-related might represent the pathogenetic mechanism underlying the rhabdoid aggressive behavior, independently of tumor staging. To our knowledge, the SEM technique was applied in the study of this neoplasm for the first time.

The importance of immunohistochemistry in the differential diagnosis of molar disease.

The differential diagnosis among complete moles, partial moles and hydatidiform abortions may be challenging during routine diagnostic activity. These entities share the histological aspect of enlarged villi, but here we summarize also some peculiar features of all of them. If histology does not clarify this distinction, the immunohistochemistry is the most important tool for pathologists to complete such diagnosis. The correct management of immunohistochemistry and of further possible analysis is also reviewed. Lastly, the most important antibodies, starting from p57, are presented.

Pathological complete response in a patient affected by multiple synchronous, breast and lung primary malignancies: a case report and review of the literature.

A pathological complete response in a patient affected by multiple synchronous, breast and lung primary malignancies is reported. A 63-year-old woman presented with an invasive ductal carcinoma of the breast and a lung adenocarcinoma. After multidisciplinary discussion, the patient underwent pulmonary left lower lobectomy followed by radio-chemotherapy with cisplatin and vinorelbine and started hormone therapy with letrozole. Ten months later, a left mastectomy with axillary lymph nodes dissection was performed. Histologically, a pathological complete response (pCR) was documented. With a review of the Literature, we discuss the issue of multiple primary malignancies, with its diagnostic and therapeutic implications. In cases of multiple synchronous malignancies it has been highlighted the importance of the choice of the best therapeutic approach for both the malignancies, reducing collateral individual effects.

Lung metastasis from TTF-1 positive sigmoid adenocarcinoma. pitfalls and management.

The lung is a frequent site of metastatic involvement, and in many cases the differential diagnosis between a metastasis and a primary carcinoma is a substantial question. TTF-1 is considered as a reliable marker for differential diagnosis in distinguishing primary lung carcinoma and metastasis, especially when dealing with an adenocarcinoma or a large-cell carcinoma. It was generally thought that adenocarcinomas arising in the gastrointestinal tract do not express TTF-1. Recently, it has been reported that a small percentage (1.8%-5.8%) of intestinal adenocarcinoma TTF-1 positive show differences in sensitivity/specificity depending on the antibody clones. We report a case of lung localization of a TTF-1 positive adenocarcinoma in a patient with a history of colon adenocarcinoma. Based on the current results and previous reports, we propose the following criteria for diagnosing lung metastasis from TTF-1 positive intestinal adenocarcinoma. 1) Clinical features and anamnestic history are diagnostic milestones, and provide very important information as a prognostic parameter of primary carcinoma and the time interval between the two localizations (primary and metastasis). 2) The histologic features are compatible with an enteric differentiation. 3) TTF-1 must be tested in the primary carcinoma. 4) In lung lesions, in association with TTF-1, it could be useful to test other immunohistochemical markers such as CDX-2 and NapsinA. 5) Testing other immunohistochemical or molecular markers in either lesion is not very useful. Heterogeneity between primary and metastatic lesions has been reported in the literature. Application of the above-mentioned criteria would simplify diagnosis of lung metastases from TTF-1 positive intestinal adenocarcinoma.

Perfusion CT can predict tumoral grading of pancreatic adenocarcinoma.

OBJECTIVES: To describe perfusion CT features of locally advanced pancreatic ductal adenocarcinoma and to evaluate correlation with tumor grading. METHODS: Thirty-two patients with locally advanced pancreatic adenocarcinoma were included in this study. Lesions were evaluated by P-CT and biopsy after patient's informed consent. P-CT parameters have been assessed on a large single and on 6 small intratumoral ROIs. Values obtained have been compared and related to the tumor grading using Mann-Whitney U test. Sensibility, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy in predicting tumor grading have been calculated for cut-off values chosen by using ROC curves. RESULTS: Out of 32 lesions, 12 were classified as low grade and 20 as high grade. A statistically significant difference between high and low grade neoplasms were demonstrated for PEI and BV parameters. PEI and BV cut-off values were respectively 17.8 HU and 14.8 ml/100g. PEI identified high grade neoplasms with a 65% sensitivity, 92% specificity, 93% PPV, 61% NPV and 75% accuracy. BV identified high grade neoplasms with a 80% sensitivity, 75% specificity, 84% PPV, 69% NPV, 78% accuracy. Considering both PEI and BV, P-CT identified high grade lesions with a 60% sensitivity, 100% specificity, 100% PPV, 60% NPV and 75% accuracy. CONCLUSIONS: PEI and BV perfusion CT parameters proved their efficiency in identifying high grade pancreatic adenocarcinoma.

Inflammatory breast carcinoma and locally advanced breast carcinoma: characterisation with MR imaging.

PURPOSE: This study was done to identify the typical magnetic resonance (MR) imaging findings of inflammatory breast carcinoma (IBC) in comparison with noninflammatory locally advanced breast carcinoma (LABC). MATERIALS AND METHODS: MR images of 30 patients with IBC (T4d) were compared with those of a cohort of 30 patients with LABC (T3/T4a-c). The age distribution was approximately equal in the two groups. MR images were assessed for the following features: skin thickening (>4 mm), skin oedema, architectural distortion, enhancement pattern (mass-like/non-mass-like), time-signal intensity curve (continuous-persistent type/wash-out type), skin enhancement. Fisher's exact text was used to compare MR imaging appearances of IBC and LABC (significant p value <0.05). RESULTS: Skin involvement and enhancement pattern differed between groups: skin thickening was present in 16/30 IBC (53%) vs 8/30 LABC cases (27%, p=0.06), skin oedema was present in 26/30 IBC (87%) vs 8/30 LABC (27%, p < 0.0001), and skin enhancement in 10/30 IBC (33%) vs 2/30 LABC (7%, p=0.02); non-mass-like enhancement was present in 22/30 IBC (73%) vs 12/30 LABC (40%, p=0.02). CONCLUSIONS: IBC is a distinct clinical and pathological entity resulting in typical MR imaging features. Skin changes (thickening, oedema, enhancement) related to neoplastic involvement of the dermal lymphatics are suggestive of IBC and should prompt a skin biopsy to confirm or rule out the diagnosis.

Intra-operative frozen section technique for breast cancer: end of an era.

Data on 2436 primary breast carcinomas diagnosed between 1992 and 2006 were collected to evaluate the rate of frozen section procedures performed over time. Frozen section procedures performed to evaluate resection margins for conservative surgery or sentinel node status were excluded. Over time, there was a decrease in the use of frozen sections indistinctly extended to all pT cancer categories. The rate of cancers diagnosed with frozen sections was 51.2% in 1999, and 0% in 2005-2006. In the same period, the adoption of cytology and core biopsy for breast cancer diagnosis increased from 40% in 1992 to more than 90% since 1999. In an audited diagnostic activity on breast pathology, the routine use of frozen sections on primary lesions was considered inappropriate, particularly in assessment of clinically non-palpable lesions, and should be limited to cases with inadequate pre-surgical sampling.

B3 breast lesions determined by vacuum-assisted biopsy: how to reduce the frequency of benign excision biopsies.

PURPOSE: 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. MATERIALS AND METHODS: 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<0.05. RESULTS: The majority of cases were depicted as isolated microcalcifications (82.3%), were smaller than 10 mm (80.4%), had a low level of radiological suspicion (64.7%) and had 11 or more cores sampled (94.1%). Atypia at VAB was reported in 60 of 102 cases (58.8%). Carcinoma was found at excision in 5/60 (8%) B3 lesions with atypia and in no B3 lesions without atypia (p=0.146). Cancer at surgery was more frequent among cases of isolated microcalcifications (p=0.645), cases with high radiological suspicion (p=0.040) and those with a smaller number of cores sampled (borderline significant p=0.064). CONCLUSIONS: On the basis of our experience, the presence or absence of atypia in our series proved to be the reliable criterion to prompt or avoid surgery in cases with a VAB finding of B3 lesion. This criterion may therefore be adopted in practice to more accurately select patients for surgery.

Fischer's score criteria correlating with histopathological prognostic factors in invasive breast cancer.

PURPOSE: This study aimed to evaluate whether the Fischer score criteria on contrast-enhanced magnetic resonance (CE-MR) imaging could correlate with histopathological prognostic factors in invasive breast cancer. MATERIALS AND METHODS: Seventy-two women with histologically proven invasive breast cancer underwent preoperative CE-MR imaging. Images were assessed for the following parameters, according to the scoring system described by Fischer in 1999: tumour shape, margins, internal enhancement, signal intensity increase, signal intensity course and overall Fischer score. Evaluated histopathological prognostic factors included histological type, associated extensive intraductal component, diameter, lymph node metastasis, tumour grade, and oestrogen receptor (ER), progesterone receptor (PgR), Ki67 proliferation, oncogene c-erbB-2 (HER2/neu) expression. Fisher's exact test was used to correlate the CE-MR imaging parameters and histopathological findings (with significance set a p < 0.05). RESULTS: Fischer's score was 0-4 in 14/72 (19%) cases, >4 in 58/72 (81%) and 3 in 5/72 (7%; false negative), with a sensitivity of 93%. A significant correlation (p=0.02) was found between stellate-dendritic shape and the presence of an associated extensive intraductal component (EIC), which was found in 78% of stellate tumours vs. 49% of round-oval tumours. A significant correlation (p=0.039) was found between Ki67 expression and signal intensity course (Ki67 overexpression was present in 81% of tumours with washout course vs. 21% with plateau course). CONCLUSIONS: The CE-MR imaging findings that correlate with prognostic factors are shape and signal intensity curve. Fischer's multifactorial analysis was helpful in the interpretation of CE-MR images, showing a sensitivity of 93% for invasive breast cancer.

Real-time reading in mammography breast screening.

PURPOSE: This study was undertaken to assess the role of real-time reading in the mammography screening programme carried out at the Hospital of Marzana, Verona, Italy. MATERIALS AND METHODS: During the 5-year period 1999-2004, 54,472 women attended the screening programme (32,291 first calls: unadjusted uptake 41.4%, adjusted uptake 50.3%; 21,551 2- year routine recalls: unadjusted uptake 86.4%, adjusted uptake 89.9%). Further diagnostic investigations [(FDI), imaging and cytohistological] were performed immediately after real-time reading of the screening mammograms (FDI rate among first calls 10.9%; FDI rate among 2-year recalls 5.4%). Overall, cytohistological FDI were requested in 27% of imaging FDI, with a clear prevalence of cytological [fine-needle aspiration cytology (FNAC) 87%] over histological procedures [core needle biopsy (CNB) 11%; vacuum aspiration biopsy (VAB) 2%]. RESULTS: Imaging FDI proved to be conclusive in 73%. Cytohistological FDI led to the use of surgical biopsy (SB) in 39.5% (ratio between benign and malignant SB: 0.19/first calls, 0.14/2-year recalls). There were a total of 427 screen-detected breast cancers (BC), with a very good breast cancer detection rate (BCDR/first calls 9.7 per thousand; BCDR/2-year recalls 5.1 per thousand). In the 427 screen-detected BC, the incidence of pTis, pT1a,b cancers was 59.6% (diagnostic anticipation); the incidence of pN0 cancers was 61.2%; the incidence of conservative surgical procedures was 78.6%. In interval cancers, the false negative rate was 8.3% only, whereas the proportional incidence was very low indeed (14% first year; 38% second year). CONCLUSIONS: The high sensitivity exhibited by the Marzana mammography screening programme suggests that the value of real-time reading should be validated by other programmes adopting a similar approach.

Ultrasonography of the pancreas. 5. Interventional procedures.

Interventional ultrasonography (US) is often used for the diagnosis and therapy of pancreatic pathologies, and its diffusion has definitely modified the diagnostic and therapeutic management of some diseases. US is particularly suitable for targeting percutaneous pancreatic interventional procedures and important technical features contribute to this result. First of all, US is dynamic, and thus the ongoing procedure can be continually monitored. Then, the high spatial resolution achieved by US imaging in recent years, its speed and availability and the low-cost of the technique, together with the technical features, have led to an ever-increasing use of US in pancreatic interventional procedures. This article will review the application of US as guide of diagnostic and interventional procedures in the different pancreatic pathologies.

Abdominopelvic sarcoma of perivascular epithelioid cells. Report of four cases in young women, one with tuberous sclerosis.

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.

Detection of bladder cancer by semi-automated microsatellite analysis of urine sediment.

Patients with transitional-cell carcinoma (TCC) require careful follow-up due to the high risk of recurrence. Cystoscopy and biopsy are reliable but invasive, while urine cytology is plagued by low sensitivity. It has recently been shown that allelic abnormalities detected by microsatellite analysis of DNA extracted from urine can be used to diagnose TCC with high reliability. As this analysis by classic techniques is unfeasible in a clinical setting, we performed a pilot study to determine the possibility of applying quick DNA extraction methods with laser detection and computer-based analysis of 15 fluorescently labeled PCR amplified microsatellites to detect molecular anomalies in urine sediment in 25 TCC follow-up patients. Of the eighteen cases with recurrent TCC, 14 (78%) were positive by the molecular test whereas only eight (44%) were detected by cytology. Of the seven patients with negative cystoscopy, one resulted positive by the molecular test and had recurrent TCC six-months later. Thus, this microsatellite analysis correctly predicted the clinical diagnosis in 84% (21/25) of cases, compared to 60% by cytology. The application of these semi-automated procedures allows the analysis of 18 samples with 15 markers in one day, encouraging a more expedient introduction into routine clinical use.

Renal angiomyolipoma with epithelioid sarcomatous transformation and metastases: demonstration of the same genetic defects in the primary and metastatic lesions.

Angiomyolipoma (AML) is a benign neoplasm that occurs either sporadically or in patients with tuberous sclerosis complex (TSC) and shows frequent allelic losses at chromosome arm 16p. It has been suggested recently that the melanogenesis marker-positive perivascular epithelioid cell (PEC) has been found consistently in AML. The authors report a 50-year-old woman without evidence of TSC affected by classic renal AML containing an area composed of atypical epithelioid cells with the same morphoimmunophenotypic characters of PEC. After 7 years from surgical removal of the lesion, the patient developed a local recurrence and successive lung and abdominal metastases that showed morphologic and immunohistochemical features overlapping those of the epithelioid area of the previously removed AML. Genetic analysis showed that the classic AML and its epithelioid area as well as the pulmonary and abdominal metastases shared the same allelic loss on chromosome arm 16p. Based on these findings, the authors view this case as evidence of a malignant transformation of a classic AML with morphologic, immunophenotypic, and genetic demonstration of its clonal origin.

bcl-2 but not p53 expression is associated with resistance to chemotherapy in advanced breast cancer.

Programmed cell death is an important determinant of the response to chemotherapy. Among the factors controlling this process, a significant role is played by bcl-2 and p53, the expression of which, together with estrogen receptor content and tumor proliferative activity, was investigated by means of immunohistochemistry in 55 advanced breast cancer patients (median age, 60 years; range, 25-71 years). Analysis of bcl-2 expression identified two groups of patients with a significant difference in response rate. A total of 17 patients (31%) responded to chemotherapy (5 had a complete response and 12 had a partial response): 14 of 32 (44%) bcl-2-negative patients (< 40% stained cells) and only 3 of 23 (13%) bcl-2-positive patients (> or = 40% of stained cells; P = 0.019 by Fisher's exact test). The two groups were well balanced in terms of age, performance status, disease-free survival, menopausal status, and type of chemotherapy. bcl-2-negative tumors showed a tendency toward a higher p53 expression and proliferation rate, whereas an excess of bone as the dominant disease site was evident among the bcl-2-positive ones. However, the only variable to result significantly different between the two groups was estrogen receptor expression (P = 0.004). A multivariate logistic regression model showed that bcl-2 maintained its power of discriminating two groups with a different probability of responding to chemotherapy, although the greatest contribution was given by dominant disease site and type of chemotherapy. In conclusion, the results of this study suggest a possible role for bcl-2 in predicting resistance to chemotherapy.

Apparent renal cell carcinomas in tuberous sclerosis are heterogeneous: the identification of malignant epithelioid angiomyolipoma.

Renal epithelial tumors (carcinoma and oncocytoma) have been reported with higher a frequency than expected in patients with the tuberous sclerosis complex. However, the recent identification of a monotypic, epithelioid variant of angiomyolipoma, closely simulating renal cell carcinoma, has cast doubt on the real frequency of carcinoma. Immunohistochemical analysis with a panel of antibodies, including melanogenesis marker HMB45, can discriminate between carcinoma and carcinoma-like angiomyolipoma. We studied five tumors previously reported as carcinoma and found that only one of them showed an immunohistochemical phenotype indicative of an epithelial tumor (Ker+, HMB45-). Three tumors exhibited a phenotype compatible with the monotypic epithelioid variant of angiomyolipoma (HMB45+, Ker-), and two of the three patients died of metastatic disease. The last patient had unusual clinical features, and the tumor was positive both for HMB45 and keratin. It is concluded that (1) renal cell carcinoma is less common in tuberous sclerosis complex than previously believed, (2) some cases called renal cell carcinoma probably represent a monotypic, epithelioid variant of angiomyolipoma, and (3) epithelioid angiomyolipoma is a potentially malignant tumor with invasion and metastases. These findings indicate that all reported renal carcinomas in tuberous sclerosis complex, therefore, must be reevaluated.