Prognostic value of p21(WAF1) and p53 expression in breast carcinoma: an immunohistochemical study in 261 patients with long-term follow-up.

p21 protein (p21) inhibitor of cyclin-dependent kinases is a critical downstream effector in the p53-specific pathway of growth control and can also be induced by p53-independent pathways in relation to terminal differentiation. We investigated p21 immunoreactivity in 261 breast carcinomas (141 node negative and 120 node positive) with long-term follow-up (median, 73 months; range, 37-119). p21 was seen in 214 (82%) infiltrating tumors, staining was nuclear and heterogeneous, and the p21 labeling index ranged from 0 to 90%. Sixty-eight (32%) patients showed p21 overexpression (>10% of reactive tumor cells). p21 overexpression was associated with large tumor size, positive nodal status, high histological grade, and high mitotic count and was related to short disease-free survival (DFS) in the whole series of patients (P = 0.04), in the node-negative subgroup (P = 0.004), and in the group of patients who did not undergo systemic adjuvant therapy (P = 0.003). In patients treated with systemic adjuvant therapy, bivariate analysis of the combined p21 and p53 phenotypes showed that p21+/p53+ tumors were associated with long DFS and overall survival (OS), whereas p21-/p53+ tumors had the worst prognosis. In treated patients, multivariate analysis showed that the p21-/53+ phenotype was independently associated with short DFS and OS. Our present data support the hypothesis that p21/p53 heterogeneous expression may be of clinical relevance for the therapeutic response to chemotherapy/hormonotherapy. The p21-/p53+ phenotype could correspond to a situation where p53 overexpression really reflects complete abrogation of p53 function. These cases with disrupted p53 function should have impaired the G1 checkpoint and may not be able to activate the apoptotic cascade in response to DNA-damaging drugs.

Bcl-2 and p53 expression in node-negative breast carcinoma: a study with long-term follow-up.

Bcl-2 and p53 gene products (Bcl-2, p53) are important regulators of apoptosis and cell proliferation, and their immunohistochemical expression may help to identify high-risk breast cancer patients. The authors evaluated p53 and Bcl-2 immunoreactivity in 178 node-negative breast cancers (NNBC) with long-term follow-up (median, 60 months). Bcl-2 was seen in 111 (62%) cases, and was significantly associated with small tumor size, nonductal morphology, low tumor grade, estrogen-receptor (ER) positivity, and p53 negativity. p53 overexpression (ie, > 15% reactive nuclei) was observed in 31 (17%) cases, and was associated with lower age, large tumor size, ductal morphology, high tumor grade, negative ER status, and lack of Bcl-2 immunoreactivity. In univariate analysis, the variables associated with short relapse-free survival (RFS) were large tumor size (P = .002), high histological grade (P = .01), high mitotic count (P = .03), and high Nottingham prognostic index (NPI) (P = .0002). In multivariate analysis (final model), only the NPI was of independent prognostic value concerning RFS.

Pre-operative prediction of invasive vs intraductal breast cancer type: multivariate analysis of the accuracy of clinical and imaging findings.

Two consecutive series of 107 invasive carcinomas and 108 carcinomas in situ of the breast were considered retrospectively. The main symptomatic, clinical and cytological features were retrieved from clinical records, whereas the features at mammography and/or ultrasonography were reclassified at a blinded review by an expert radiologist. The power of predicting invasion on the basis of these features was then evaluated. The accuracy of such a prediction was compared to that of a mathematical model using the same diagnostic features by multivariate logistic regression analysis. Neither approach reached a satisfactory accuracy, but the radiologist's judgment (sensitivity 97.1%, specificity 81.9%, positive predictive value 98.4%, negative predictive value 71.6%, overall accuracy 95.8%) was slightly superior to the mathematical model (sensitivity 93.2%, specificity 87.9% positive predictive value 98.8%, negative predictive value 53.7%, overall accuracy 92.8%). Although some presentations are significantly associated with invasive or in situ status, diagnostic features alone are not sufficiently accurate to bypass histological confirmation, although they might give useful clinical indications.

Preoperative diagnosis of renal angiomyolipoma: fine needle aspiration cytology and immunocytochemical characterization.

A preoperative diagnosis of renal angiomyolipoma (AML) is of great importance for a correct management of these patients with this tumor. In fact when the lesion is small and asymptomatic a conservative approach may be considered. We have evaluated the radiographic and fine needle aspiration cytology (FNAB) findings in 8 cases of AML. In 3 cases both radiology and cytology were suggestive of carcinoma and thus the patients underwent surgery. In one case both techniques suggested AML but surgery was performed because the lesion was large and symptomatic. In 4 cases where both radiology and cytology suggested AML no surgery was performed. Follow-up data are consistent with the benign nature of the lesions. The immunocytochemical analysis of the FNAB with a panel of antibodies including keratin, vimentin, actin and HMB-45 was indicative of AML in 7 of 8 cases, including 2 of the 3 cases misdiagnosed as carcinomas. The presence of HMB-45-positive perivascular epithelioid cells in the FNABs was the most significant finding. It is concluded that immunocytochemical analysis of FNAB with this monoclonal antibody panel can increase the accuracy of preoperative diagnosis of AML, and allow consideration of a conservative approach in selected cases.

Melanocyte-marker-HMB-45 is regularly expressed in angiomyolipoma of the kidney.

HMB-45 (melanocytic cell-specific monoclonal antibody) immunoreactivity was investigated in 10 cases of angiomyolipoma (AML) (1 with massive regional lymph node involvement) of the kidney and detected in all of them. No HMB-45 immunoreactivity was found in other tumors of the region which can occasionally be confused with AML, such as renal cell carcinoma, Wilms' tumor, and retroperitoneal sarcoma (leiomyosarcoma and liposarcoma). These findings indicate that HMB-45 is not a melanocyte-restricted marker and suggest that its expression might be useful in distinguishing AML from other tumors of the kidney and retroperitoneum.

Time trends of benign/malignant breast biopsy ratios a multicenter Italian study.

AIMS AND BACKGROUND: Although they have been decreasing over time due to improved specificity of diagnostic assessment, benign biopsies of the breast are still common. Benign biopsies should be regarded as negative events, due to their economical and psychological cost and their possible negative impact on cosmesis and on further diagnostic evaluation. METHODS: Retrospective data on benign/malignant breast biopsies ratio (B/M) were collected in 9 Italian centers for a period of 10-15 years. The time trend of B/M and its association to age or to single centers was evaluated. RESULTS: Overall 31,001 cases were considered. A strong association of B/M to age was evident (average B/M values were 5.0, 1.3, 0.6, and 0.2 for women aged < 40, 40-49, 50-59, and > 59 years). A significant trend of decreasing B/M over time was observed only for one center. Age standardized B/M was significantly different (P < 0.000001) between centers, ranging between 0.34 and 1.69. Multivariate analysis confirmed an independent significant association of age and center to B/M. CONCLUSIONS: Marked differences in B/M are evident between centers, which cannot be explained by the confounding effect of age or by any apparent difference in the diagnostic protocol. The observed differences are likely ascribed to individual variations in diagnostic aggressivity. A progressive increase of the predictive value of calls for surgical biopsy may be achieved over time and centers with a high B/M should make every effort to optimize their performance. Acceptable (< 40 = 5, 40-49 = 1.5, 50-59 = 0.75, > 59 = 0.3) and desirable (2.5, 0.75, 0.35, 0.15) age specific reference standards for B/M are proposed.

Preoperative diagnostic accuracy of fine-needle aspiration in the management of breast lesions: comparison of specificity and sensitivity with clinical examination, mammography, echography, and thermography in 249 patients.

Two hundred and forty-nine women suffering from breast problems underwent a complete series of tests including clinical examination, mammography, echography, thermography, and fine-needle aspiration (FNA). Ninety-four of these patients were shown to be positive or to have suspected malignancy. Accordingly, they underwent surgical excision followed by histologic examination, while the remaining patients were re-examined after 12 to 18 mo in order to exclude false negatives. The analysis of specificity and sensitivity of every single procedure showed that FNA describes the best degree of sensitivity and specificity but no procedure allows, by itself, the detection of all carcinomas. When considered in combination, clinical examination, mammography, and fine-needle aspiration have a sensitivity of 100% and a specificity of 49%, and are the best diagnostic tests for a correct assessment of mammary lesions. Thermography and echography showed a low degree of sensitivity and should not be included in the routine diagnostic procedure of breast lesions.

Cytologic features of 22 radial scar/complex sclerosing lesions of the breast, three of which associated with carcinoma: clinical, mammographic, and histologic correlation.

Radial scar/complex sclerosing lesion (RS/CSL) of the breast has become more frequently detected with the increasing performance of mammography as a screening test. The clinical, mammographic, and cytologic features of 22 cases of histologically proved breast RS/CSL, 3 of which associated with carcinoma arising at the periphery of the lesion, were reviewed. Clinical examination and mammography did not show specific features in differentiating RS/CSL from carcinoma of the breast. Cytology of RS/CSL without associated malignant changes was dominated by bland epithelial clusters and bipolar naked nuclei. Apocrine cells, papillary clusters, foam cells, and fibrillary elastoid material were also frequently seen. At the cytologic review, only one case of RS with apocrine adenosis, showing atypical cells, was diagnosed as suspicious. Two of the three cases of CSL with associated carcinoma in situ were cytologically characterized by the presence of single atypical cells. In the third case, characterized by a small tubular carcinoma near to CSL, fine-needle aspiration cytology revealed few tubular clusters without myoepithelial cells. Although cytology of RS/CSL without associated carcinoma does not seem characteristic, in most cases a diagnosis of benignancy can be performed correctly. The application of fine-needle aspiration cytology to mammographic lesions with features suggesting RS/CSL may permit a better planning of these lesions.

Renal collecting duct carcinoma. Report of a case with urinary cytologic findings.

A case of collecting duct carcinoma of the kidney is presented with histologic and cytologic findings. Cytologic examination of voided urine showed glandlike clusters of large cells with granular cytoplasm and prominent nucleoli, along with normal transitional cells. Macroscopically the kidney had a pelvic tumor mass that, on microscopic examination, was consistent with renal collecting duct carcinoma. Urinary cytology is useful as a diagnostic procedure even in cases of rare entities, such as collecting duct carcinoma.

Fine needle aspiration of myofibroblastoma of the breast. Case report.

The cytologic and histologic findings of myofibroblastoma of a man's breast are reported. Cytologic specimens showed many scarcely cohesive clusters of bipolar or stellate cells. The cytoplasm was moderately eosinophilic and had clearly-defined edges. The nucleus was characterized by round or coffee-bean shape, regular chromatin and small nucleolus. Atypical features were absent. Immunocytochemical tests confirmed the mesenchymal nature of the lesion showing negativity for CAM 5.2 and positivity for vimentin. We stress the value of fine-needle aspiration biopsy in association with clinical- examination, mammography and/or echography in establishing the preoperative diagnosis of this benign tumor.

Small urothelial carcinoma: diagnosis and treatment by cold forceps biopsy.

From 1987 to 1988 we used cold biopsy forceps to remove completely 92 urothelial neoplasms ranging from 0.3 to 3 mm. Rigid biopsy forceps were used. The urologist usually treats these bladder neoplasms by diathermy coagulation, which obviously makes histological study impossible. On the other hand, due to the small size of these lesions even removal with the cutting loop inevitably causes deep regressive modifications that prevent accurate morphological evaluation. Histological examination of the neoplasms removed revealed the presence of low to medium grade (stage Ta, grades 1 to 2) noninfiltrating papillary carcinoma in 75 cases, high grade (stage Ta, grade 3) noninfiltrating papillary carcinoma in 9 and medium to high grade (stage T1, grades 2 to 3) infiltrating papillary carcinoma in 8, 1 of which had areas of squamous cell carcinoma. This method enabled us to study the morphology of the urothelial lesions in the initial phase. In our study population the number of high grade lesions and/or lesions with early signs of infiltration (17 of 92) appears to be noteworthy despite the small size of the tumors.

The cytopathology of ductal carcinoma in situ of the breast. A detailed analysis of fine needle aspiration cytology of 58 cases compared with 101 invasive ductal carcinomas.

Bonzanini M., Gilioli E., Brancato B., Cristofori A., Bricolo D., Natale N., Valentini A., and Dalla Palma P. (2001)Cytopathology 12, 107-119. The cytopathology of ductal carcinoma in situ of the breast. A detailed analysis of fine needle aspiration cytology of 58 cases compared with 101 invasive ductal carcinomas. The existence of cytological findings that discriminate ductal carcinoma in situ (DCIS) of the breast from invasive ductal carcinoma (IDC) has not been unanimously accepted and the role of fine needle aspiration cytology (FNAC) remains controversial. We report the cytological findings of a large series of FNAC from histologically proven DCIS compared with those of ductal carcinomas having a different extent of the invasive component. The association of high cohesiveness of atypical cells and absence of tubular aggregates showed good sensitivity (SE) and specificity (SP) for the diagnosis of DCIS vs IDC. The simultaneous presence of necrotic background, atypical cells with abundant eosinophilic cytoplasm and a low percentage of single malignant cells resulted in low sensitivity but high specificity and positive predictive value (PPV) for differential cytological diagnosis of DCIS vs IDC.

Fine-needle aspiration cytology of the breast: a preliminary report on telepathology through Internet multimedia electronic mail.

Telepathology is a field of telemedicine that enables the exchange of histologic and cytologic images for consultations among pathologists of two or more remote institutions, through a suitable communication channel. The Internet can connect several scientific and medical institutions because of the existence of a set of standard protocols that allow different computers to communicate; multimedia electronic mail is one such protocol, which allows asynchronous transmission of multimedia documents, i.e., including text, images, movies, and sounds. The aim of the present article is to test a novel approach in which Internet multimedia electronic mail is used as a communication medium to obtain an asynchronous telepathology tool for remote consultation. To assess the diagnostic validity of the method, 48 cases of fine-needle aspiration cytology of breast lesions were sent from Udine to Trento, Italy. Comparisons between local and remote diagnoses, and cytologic diagnoses versus subsequent histologic reports demonstrated that Internet multimedia electronic mail is suitable for remote consultation. Internet multimedia electronic mail thus presents an additional diagnostic tool that is easy to use, available on a wide range of computers, and inexpensive, because its cost is independent of distance.

Tissue carcinoembryonic antigen and oestrogen receptor status in breast carcinoma: an immunohistochemical study of clinical outcome in a series of 252 patients with long-term follow-up.

Carcinoembryonic antigen (CEA) is a well-known tumour marker whose immunohistochemical expression could be prognostically relevant in breast carcinomas. We evaluated CEA immunohistochemical expression, using the specific T84.66 monoclonal antibody, in a series of 252 consecutive cases of infiltrating breast carcinomas (104 N0, 148 N1/2) with median follow-up of 84 months. Oestrogen receptor (ER) status has been evaluated with the immunohistochemical method (ER1D5 antibody, 10% cut-off value): 121 cases were ER negative, 128 cases were ER positive and in three cases ER status was unknown. CEA staining was cytoplasmic; staining intensity and percentage of reacting cells were combined to obtain a final score (CEA score). The difference between the distribution of CEA score within the modalities of the other variables was not statistically significant. Univariate survival analysis has been performed on the series of node-negative and node-positive patients. In the latter subgroup, this has been performed separately for patients treated with systemic adjuvant hormonal therapy or chemotherapy. A multivariate analysis was only performed for node-positive patients treated with adjuvant therapy. CEA immunoreactivity was not prognostically relevant in any subset of analysed patients. The most important prognostic markers were nodal status and tumour size.