Atypical Epithelial Hyperplasia Research Articles

Differential requirement for focal adhesion kinase signaling in cancer progression in the transgenic adenocarcinoma of mouse prostate model

Increasing evidence indicates that adhesion signaling plays an important role in the tumor microenvironment, contributing to cancer progression, invasion, and metastasis. Focal adhesion kinase (FAK) is a nonreceptor protein tyrosine kinase that regulates adhesion-dependent cell signaling and has been implicated in mediating steps in cancer progression and metastasis in many human cancers, including prostate. We have investigated the role of FAK in the appearance of adenocarcinoma (atypical epithelial hyperplasia of T antigen) and neuroendocrine carcinomas in the transgenic adenocarcinoma of mouse prostate (TRAMP) model using either Cre-mediated recombination to genetically ablate FAK expression or pharmacologic inhibition of FAK activity with the small-molecule inhibitor, PF-562,271. We provide evidence that loss of FAK or its inhibition with PF-562,271 does not alter the progression to adenocarcinoma. However, continued FAK expression (and activity) is essential for the androgen-independent formation of neuroendocrine carcinoma. These data indicate that integrin signaling through FAK is an important component of cancer progression in the TRAMP model and suggest that treatment modalities targeting FAK may be an appropriate strategy for patients with castrate-resistant cancer.

Morphological transition of proliferative inflammatory atrophy to high‐grade intraepithelial neoplasia and cancer in human prostate

Inflammation has been implicated as a potential etiological agent in human prostate cancer (PCa). Proliferative inflammatory atrophy (PIA) in prostate consists of areas of glandular atrophy associated with chronic inflammation and epithelial cell proliferation. It has been suggested that PIA is a candidate precursor of prostate malignancy. We aimed to explore the morphological transition between PIA and co-existing high-grade prostate intraepithelial neoplasia (HGPIN) and/or PCa. Serial slides of 50 whole-mounted radical prostatectomies were studied with H&E staining and immunostaining of cytokeratin 5 (CK5), glutathione S-transferase pi (GSTP1), hepatocyte growth factor receptor (c-MET), CCAAT/enhancer binding protein beta (C/EBPbeta), and Ki-67. Utilizing immunohistochemical stains to examine HGPIN, PIA-merging HGPIN, and PIA-merging PCa lesions, respectively. A total of 1,188 HGPIN lesions were identified, of which 17% (198) were in the morphological process of merging with PIA. Thirty-six PIA-merging PCa lesions were also detected. The atrophic epithelial cells in such merging lesions had increased Ki-67 index and an intermediate phenotype: increased expression for CK5, GSTP1, c-MET, and C/EBPbeta. In addition, clusters of atypical epithelial cell hyperplasia, that is, with nuclear enlargement, hyperchromasia, and prominent nucleoli, were found in 16 PIA lesions. Such clusters of atypical cells that meet the criteria for HGPIN still expressed CK5 and were adjacent to focal chronic inflammation. Direct morphological transition between PIA and HGPIN and/or PCa was present. The atrophic cells in these merging lesions had an intermediate phenotype. Clusters of atypical epithelial cell hyperplasia might represent the earliest transition from PIA to HGPIN. Prostate 69: 1378-1386, 2009. (c) 2009 Wiley-Liss, Inc.

Update on atypical epithelial hyperplasia and ductal carcinoma in situ

Atypical ductal hyperplasia (ADH) as an indicator of increased risk for developing breast cancer is well established. Refinement in its molecular characterisation, especially as it relates to risk, continues to be challenging, largely because of its small and very focal nature. Also a challenge is appropriate management of ADH when present on core biopsy. Additional support for ductal carcinoma in situ (DCIS) as a precursor to invasive cancer, as well as recent molecular characterisation of DCIS are presented. The importance of margin assessment in cases of DCIS and the limited role for sentinel lymph node biopsy in this setting are reviewed.

Stereotactic vacuum-assisted breast biopsy in 268 nonpalpable lesions

We evaluated the reliability of stereotactic vacuum-assisted breast biopsies (VAB) from our personal experience. Between January 2003 and December 2005, 268 patients underwent VAB with an 11-gauge probe at our institution. Inclusion criteria were nonpalpable lesions, undetectable by ultrasound and suspected at mammography (microcalcifications, circumscribed mass, architectural distortion), for which cytology and/or core biopsy could not provide a definite diagnosis. Lesion mammographic patterns were microcalcifications in 186 cases (77.5%), mostly localised clusters (130/186: 70%); circumscribed mass with or without microcalcifications in 36 cases (15%) and architectural distortion with or without microcalcifications in 18 cases (7.5%). On the basis of the Breast Imaging Reporting and Data System (BI-RADS) classification, 16 cases (7%) were graded as highly suspicious for malignancy (BI-RADS 5), 81 (34%) as suspicious for malignancy (BI-RADS 4b), 97 (40%) as indeterminate (BI-RADS 4a) and 46 (19%) as probably benign (BI-RADS 3). Lesion size was <or=10 mm in 161 cases (67%) and >20 mm in only 38 cases (16%), 30 of which appeared as microcalcifications. In 28/268 lesions (10.5%) the biopsy could not be performed (nonidentification of the lesion; inaccessibility due to location or breast size). In 12/240 (5%) biopsies, the sample was not representative. Pathology revealed 100/240 (42%) malignant or borderline lesions and 140/240 (58%) benign lesions. Among the malignant lesions, 16/100 (16%) were invasive carcinoma [infiltrating ductal carcinoma (IDC) or infiltrating lobular carcinoma (ILC)], 13/100 (13%) were microinvasive (T1mic), 35/100 (35%) were ductal carcinoma in situ (DCIS), 9/100 (9%) were lobular carcinoma in situ (CLIS). Among the borderline lesions, 27/100 (27%) were atypical epithelial hyperplasia [atypical ductal hyperplasia (ADH) or atypical lobular hyperplasia (ALH)]. In 9/100 surgically treated lesions (9%), there was discordance between the microhistological findings of VAB and the pathological results of the surgical procedure: 8/9 were underestimated by VAB (four ADH vs. DCIS, three DCIS vs. IDC, one ADH vs. IDC), and 1/9 was overestimated (T1mic vs. DCIS). Complications following VAB occurred in 9/240 patients (3.7%). In our experience, VAB showed fair reliability in the diagnosis of nonpalpable breast lesions despite a portion of failed (10.5%), nonsignificant (5%) procedures and underestimated lesions (9%).

The Clinical Significance of Lobular Neoplasia on Breast Core Biopsy

A core biopsy diagnosis of atypical ductal epithelial hyperplasia is upstaged on follow-up excisional biopsy (FUEB) to in situ or invasive carcinoma in about 20% of cases, thus prompting a FUEB. In contrast, upstaging information for a core biopsy diagnosis of pure lobular neoplasia (LN), without mass lesions or other risk-associated lesions is less clear. In this retrospective study, we report the largest consecutive series of patients who had a breast core biopsy diagnosis of LN and a FUEB. Core needle breast biopsies with a diagnosis of LN were retrieved from our files for the period 1999 to 2005, yielding 110 patients. One hundred and one patients had a follow-up surgical excision. Cases of LN with coexisting high-risk lesions (n=9, 10%) were excluded from the study. Patients with associated mass lesions all had benign findings (n=15, 16%) and had no impact on the study results. The remaining 77 core biopsies had no masses or risk lesions and were mammographically Breast Imaging Reporting and Data System 4 (BIRADS) for microcalcifications. Overall, 8/77 (10%) of patients with a radiographic BIRADS 4 image with calcifications and a core biopsy diagnosis of LN on core biopsy were upstaged on FUEB to ductal carcinoma in situ or invasive carcinoma. The numbers upstaged from core biopsies were as follows: atypical lobular hyperplasia (ALH) 4/52 (8%), mixed ALH/lobular carcinoma in situ (LCIS) 1/9 (10%), and pure LCIS 3/16 (19%). A core biopsy of LCIS with neoplastic epithelial calcifications was nearly 3 times more likely to be upstaged on FUEB compared with ALH. We conclude that a finding of LN on breast core biopsy in a patient with a BIRADS 4 image and calcifications is associated with a risk of 8% to 19% of upstaging to a treatable disease on FUEB.

Risk of neoplastic transformation in asymptomatic radial scar. Analysis of 117 cases

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.

Are the criteria of Tabar and Dean still relevant to radial scar?

Objective Aschoff's center of proliferation (ACP), poses significant problems of differential diagnosis both in imagery and histology with infiltrating carcinoma. Up to now the criteria of Tabar and Dean (classical criteria) are considered as diagnostically relevant. Material A retrospective study of 113 cases, enabled us to study their clinical, radiological and histological aspects. Results The ACP is a subclinical and seldom palpable entity (12%). The radiological signs of ACP are quite variable. The classical criteria lack specificity and are observed only in 48% of our stellate images. Whereas the frequency of microcalcifications is high (58.5% of the cases), their presence and their type are not predictive of an associated malignancy. The echographic diagnosis of ACP could be made in 55% of the cases but the echographic semiology lacked specificity. We noticed an associated atypical epithelial hyperplasia in 28.5% of the cases, intraductal or lobular in situ carcinoma in 9% and/or a ductal invasive carcinoma in 2% of the cases. Neither tumor size, age of the patients, nor any radiological signs were predictive of such an association. Conclusions The classical criteria are not completely reliable and are observed only in half of our stellate images, whereas microcalcifications are often present but are not predictive of an associated malignancy.

Quand se méfier des résultats des micro et macrobiopsies guidées mammaires ?

The development of imaging-guided biopsy techniques has considerably improved the early diagnosis of breast cancers following initial detection by screening. Nevertheless, in a small percentage of cases, histopathologic findings are unsatisfactory owing to false negative errors attributable to operator inexperience or inadequate sample material (this is especially true for microcalcifications with 20% underestimation rates for atypical hyperplasia); repeat biopsy is warranted in such situations. When a discrepancy exists with imaging findings and for cases of atypical epithelial hyperplasia, surgical excision is imperative so as not to overlook or underestimate a malignant lesion. Controversy continues concerning the best approach for radial scars (sclerosing ductal lesions), papillary lesions, atypical lobular hyperplasia and lobular carcinoma in situ: determination of which benign anomalies can merely be followed-up remains a problem. Better awareness of the limitations of percutaneous tissue sampling procedures should lead to refinement of the indications for these techniques and improvement of patient selection and thereby reduce delays in accurate diagnosis.

Vacuum-assisted breast biopsies: Experience at the Antoine Lacassagne Cancer Center (Nice, France)

This article presents the results of the first 318 aspiration-guided breast macrobiopsies performed using a dedicated table at the Antoine Lacassagne Cancer Center (Nice, France) between January 2001 and November 2002. A total of 288 procedures (90%) was performed for microcalcifications whereas that of 30 (10%) was performed for isolated opacities. There were 170 American College of Radiology (ACR) Category 4 (53.45%), 35 ACR 5 (11%), 111 ACR 3 (34.9%), and 2 ACR 2 lesions. There were 233 benign lesions that included 19 cases of atypical epithelial hyperplasia. Of the 85 malignant lesions, 33 had an invasive component. Seven of the atypical epithelial hyperplasia cases and all of the malignant lesions were managed surgically. Atypical epithelial hyperplasia was underestimated in 28.57% of the cases; ductal carcinomas in situ, in 21.15%. The positive predictive value of ACR 4 for the diagnosis of malignancy was 24.7% (42/128 cases), versus that of 12.6% for ACR 3 (14/97 cases). Among the 233 benign lesions, 128 were classified as ACR 4 and 6 as ACR 5 (all of these procedures obviated surgery). The advantages, drawbacks, and limitations of the technique are analyzed and indications are discussed, particularly for ACR 3 lesions.

Cytomegalovirus-induced embryopathology: mouse submandibular salivary gland epithelial-mesenchymal ontogeny as a model

BackgroundHuman studies suggest, and mouse models clearly demonstrate, that cytomegalovirus (CMV) is dysmorphic to early organ and tissue development. CMV has a particular tropism for embryonic salivary gland and other head mesenchyme. CMV has evolved to co-opt cell signaling networks so to optimize replication and survival, to the detriment of infected tissues. It has been postulated that mesenchymal infection is the critical step in disrupting organogenesis. If so, organogenesis dependent on epithelial-mesenchymal interactions would be particularly vulnerable. In this study, we chose to model the vulnerability by investigating the cell and molecular pathogenesis of CMV infected mouse embryonic submandibular salivary glands (SMGs).ResultsWe infected E15 SMG explants with mouse CMV (mCMV). Active infection for up to 12 days in vitro results in a remarkable cell and molecular pathology characterized by atypical ductal epithelial hyperplasia, apparent epitheliomesenchymal transformation, oncocytic-like stromal metaplasia, β-catenin nuclear localization, and upregulation of Nfkb2, Relb, Il6, Stat3, and Cox2. Rescue with an antiviral nucleoside analogue indicates that mCMV replication is necessary to initiate and maintain SMG dysmorphogenesis.ConclusionmCMV infection of embryonic mouse explants results in dysplasia, metaplasia, and, possibly, anaplasia. The molecular pathogenesis appears to center around the activation of canonical and, perhaps more importantly, noncanonical NFκB. Further, COX-2 and IL-6 are important downstream effectors of embryopathology. At the cellular level, there appears to be a consequential interplay between the transformed SMG cells and the surrounding extracellular matrix, resulting in the nuclear translocation of β-catenin. From these studies, a tentative framework has emerged within which additional studies may be planned and performed.

Clinical course of laryngeal papillomatosis

Laryngeal papillomatosis (LP) can have various clinical courses. Malignant transformation is rare. The purpose of the present study was to correlate the clinical course of the disease with the histopathologic findings of the surgically removed papillomas. In the series of 123 patients, abnormal or atypical epithelial hyperplasia of the papillomas removed at the first surgical procedure appeared to be the most frequent histopathologic finding associated with the recurrent disease. Malignant transformation was detected in three patients with adult type of recurrent LP. Laryngeal carcinoma appeared five times more often in the adult patients with atypical hyperplasia than in the adults without it.

Large-needle core biopsy in atypical intraductal epithelial hyperplasia including immunohistochemical expression of high molecular weight cytokeratin: analysis of results of a single institution.

The diagnosis of atypical intraductal epithelial hyperplasia (AIDH) constitutes 6.3% of the breast core biopsies performed at our institution. Seventy-nine cases that were diagnosed as AIDH on core biopsy and went through excisional biopsy were included. Sixty-four biopsies were performed by an image-guided 11-gauge vacuum device, 11 under sonographic guidance using 14-gauge needles and 4 by a sonographically guided 11-gauge vacuum device. The histopathology of the core biopsies and the surgical excisions were reviewed. Immunohistochemistry was performed on the consecutive sections of core biopsy specimens using high molecular weight cytokeratin (HMW-CK) (DAKO-Cytokeratin, 34betaE12). At interpretation of the stain, intensity and percentage of positive cells were taken into account. The immunoprofiles of AIDH were categorized into four groups showing negative (i.e., no staining) or low-, moderate-, high-, and very high-intensity staining. Surgical excision of the 79 lesions revealed carcinoma in only 3 cases (4%)-two infiltrating carcinomas and one intraductal carcinoma-residual AIDH in 44 cases (56%), and epithelial hyperplasia or other benign lesions without atypia in 32 cases (40%). The HMW-CK stain was performed retrospectively on all of the core biopsies and 66 of them contained residual areas with AIDH for staining. Forty-nine (74%) were CK negative or stained with low intensity, but 17 cases (26%) had a moderate- to high-intensity stain. Our study showed a lower incidence of carcinoma on surgical excision following core biopsy for AIDH than other studies. The HMW-CK stain helped to characterize the nature of the intraductal proliferation and to confirm the presence of atypia, as has been previously reported, but frequently was inconclusive. The low incidence of carcinoma brings into question the need for surgical excision of all cases of AIDH diagnosed by core biopsy.

Pathologic quiz case: a 41-year-old woman with bilateral nodular breasts.

A woman with no family history of breast cancer, but with a long history of bilateral nodular breasts, complained of increasing breast size. Three previous breast biopsies (the right breast in 1973 and 1983 and the left in 1992) were all reported as benign fibrocystic changes. Physical examination showed pendulous but symmetrical breasts with no noted skin changes. Palpation revealed multiple, discrete, large, firm, and mobile breast masses bilaterally. No axillary adenopathy was detected. Mammography revealed multiple homogeneously dense well-circumscribed masses present in both breasts (Figure 1), which were compatible with giant fibroadenomata or multiple phyllodes tumors. Ultrasonography showed multiple well-demarcated masses with focal cystic change. Ultrasound-guided 14-gauge needle core biopsy of the right and left breast was performed, and microscopic examination of the biopsied tissue revealed dense stromal fibrosis and a few epithelial ducts. The fibrotic areas showed thick bundles of dense collagen admixed with a complex arrangement of cleftlike spaces resembling lymphovascular structures lined by flattened spindle cells, but without red blood cells in the spaces. No atypical epithelial hyperplasia or carcinoma was identified. A diagnosis was suggested. Two weeks later, resection of the bilateral masses along with reduction mammoplasty of both breasts was performed. On the right side, 13 white-pink well-circumscribed nodules with a total weight of 748 g (range: 4 to 382 g) were resected. The nodules had a smooth external surface and ranged in size from 3 to 17 cm in greatest dimension (Figure 2). On the left side, 10 white-pink wellcircumscribed nodules with a total weight of 214 g (range: 2 to 84 g) were resected. Morphologically, the nodules were similar to those seen in the right breast and ranged in size from 1.5 to 11 cm in greatest dimension. The cut surfaces of the nodules showed a generally homogeneous white fibrous parenchyma with occasional cystic spaces. No hemorrhage or necrosis was noted grossly. Microscopically, the breast nodules showed histopathologic changes similar to those seen in the needle core biopsies, showing large areas of dense stromal fibrosis containing numerous cleftlike spaces, often in a complex arrangement (Figure 3). In some areas, the cleftlike spaces and flattened spindle cells were concentrically arranged around breast lobules. The cleftlike spaces did not contain red blood cells. The adjacent breast parenchyma showed focal fibrocystic changes (sclerosing

Dietary energy restriction inhibits estrogen-induced mammary, but not pituitary, tumorigenesis in the ACI rat

Because of the suggested role of energy consumption and the well-documented role of estrogens in the etiology of breast cancer, we have examined the effect of a 40% restriction of dietary energy consumption on the ability of administered 17beta-estradiol (E2) to induce mammary tumorigenesis in female ACI rats. Experiments herein test the hypothesis that at least part of the inhibitory effect of energy restriction on mammary tumorigenesis is exerted downstream of potential effects of dietary manipulation on the production of estrogens by the ovaries. Ovary-intact ACI rats were fed a control or a 40% energy-restricted diet and were either treated continuously with E2 from subcutaneous Silastic tubing implants or received no hormone treatment. Mammary cancers rapidly developed in E2-treated rats fed the control diet; within 216 days of initiation of E2 treatment 100% of the population at risk exhibited palpable mammary tumors. Dietary energy restriction markedly inhibited E2-induced mammary tumorigenesis, as evidenced by significant reductions in cancer incidence and tumor burden as well as a significant increase in the latency to the appearance of the first palpable cancer. The inhibitory actions of dietary energy restriction on E2-induced mammary tumorigenesis were associated with an inhibition of E2-stimulated mammary cell proliferation. However, this inhibition was insufficient to block induction of lobuloalveolar hyperplasia or appearance of focal regions of atypical epithelial hyperplasia. These data suggest that dietary energy restriction inhibits E2-induced mammary cancer by attenuating or retarding the progression of atypical hyperplasia to carcinoma. Expression of progesterone receptor (PR) was up-regulated within the focal regions of atypical hyperplasia and the carcinomas induced by E2, regardless of whether the rats were fed the control or energy-restricted diet. However, circulating progesterone was reduced by dietary energy restriction, suggesting a possible mechanism for inhibition of mammary tumorigenesis. Dietary energy restriction did not inhibit the ability of administered E2 to induce prolactin (PRL)-producing pituitary tumors and associated hyperprolactinemia, indicating that the inhibitory effects of dietary energy restriction on mammary tumorigenesis are tissue specific and independent of circulating E2 and PRL.

3. FIXED AND MODIFIABLE RISK FACTORS FOR BREAST CANCER

SUMMARYLikely pathogenesis of breast cancer is in two phases, initiation and promotion. Initiating factors include ionising irradiation, dietary factors and possibly alcohol consumption causing DNA mutations uncorrected by repair mechanisms. Subsequent promotional factors include exposure to oestrogens, reduced by late menarche, early pregnancy and lactation and increased by nulliparity, oral contraceptive use and hormone replacement therapy. Only 5% of breast cancers result from inherited genetic mutations of BRCA1 and BRCA2, but individuals with such mutations have a high risk (66–80%) of developing the disease. Most patients with benign breast problems are not at increased risk of breast cancer, but those with atypical epithelial hyperplasia have an increased risk and should be kept under surveillance or asked to participate in trials of prevention.

High frequency of clonal chromosome abnormalities in prostatic neoplasms sampled by prostatectomy or ultrasound-guided needle biopsy

Cancer of the prostate remains poorly characterized cytogenetically. This is due in part to methodological problems and in part to the paucity of radical prostatectomies, until now the main source of material for cytogenetic analyses. We have improved existing techniques for the culturing of prostatic neoplasms removed by radical prostatectomy or sampled by ultrasound-guided needle biopsy. Successful short-term cultures were obtained from all 10 prostatectomy samples and from all 10 ultrasound-guided needle biopsies, always with a pure epithelial morphology. Of the 19 cases yielding a sufficient number of high-quality metaphases for chromosome banding analysis, the single atypical epithelial hyperplasia had a normal karyotype, whereas both prostatic intraepithelial neoplasias and 12 of 16 (75%) invasive carcinomas were shown to have clonal abnormalities. Ten of the 12 (83%) karyotypically abnormal invasive carcinomas presented structural chromosomal rearrangements. A recurrent deletion, del(10)(p13), was seen in three tumors; in one of them the terminal nature of the deletion was confirmed by two-color FISH. A del(17)(p11) was seen in one PIN lesion, but since the analysis of exons 4-8 of the TP53 tumor suppressor gene revealed no mutations, there probably was no inactivation of the second TP53 allele. Our study thus leads to the following main conclusions. First, better culturing methods allow the detection of abnormal karyotypes in a much higher percentage of prostatic neoplasms than has hitherto been possible. Second, ultrasound-guided needle biopsies of prostatic neoplasms are a sufficient source of material for cytogenetic analysis. Third, a terminal deletion of the short arm of chromosome 10, del(10)(p13), seems to identify a subgroup of prostatic cancer.

Radial scar and carcinoma of the breast: microscopic findings in 32 cases

We retrospectively reviewed the microscopic findings in 32 histologically confirmed radial scars in 31 women diagnosed in our unit during 1994–1998. The median age at diagnosis was 53 years (range 47–63 years). Thirty–one (97%) of 32 lesions presented as screen detected mammographic abnormalities (28 stellate lesions, 2 microcalcifications and only 1 architectural distortion). One lesion presented as a palpable breast mass. Stereotactic or ultrasound-guided fine needle aspiration cytology (FNAC) was performed in 28 cases. Cytological analysis of FNAs revealed malignant cells (C5) in 8 (29%) cases, highly suspicious cells (C4) in 3 (11%) cases, atypical benign cells (C3) in 7 (25%) cases and benign epithelial cells (C2) in 10 (35%) cases.All non-palpable lesions were surgically excised following wire localization. Histological examination of the breast specimens (mean weight = 16 g) demonstrated, in addition to a radial scar, 6 invasive carcinomas (2 infiltrating ductal, 2 tubular, 1 mixed ductal/lobular and 1 secretory carcinoma) and 4 ductal carcinoma in situ lesions (2 high grade, 1 high grade with micro-invasion and 1 low grade) arising in the radial scar. Of the remaining cases the radial scar was associated with atypical epithelial hyperplasia in 2 cases and regular epithelial hyperplasia in 17 cases (4 florid and 13 mild to moderate). In the 10 cases associated with malignancy, 9 had FNAC and was reported as malignant (C5) in 6 (67%) cases, highly suspicious (C4) in 2 (22%) cases and atypical (C3) in 1 (11%). False positive FNAC (C5) occurred in two patients, one of whom presented with pleomorphic microcalcifications suggestive of ductal carcinoma in situ. This patient was treated with a wire guided segmental mastectomy. All invasive tumours were less than 20 mm in size (T1) and of these 4 were grade I and 2 were grade II. Axillary dissection was performed in 4 patients none of whom had axillary node metastases.Our study demonstrates a significant incidence of malignancy associated with radial scars (31%) suggesting that radial scars may be premalignant lesions. This is supported by detecting various stages of mammary carcinogenesis (atypical epithelial hyperplasia, ductal carcinoma in situ, and early invasive malignancy) in these lesions. Fine needle aspiration cytology seems to be unreliable in the diagnosis of radial scar associated malignancy (67% sensitivity and 91% specificity). Stellate lesions, therefore, should be excised to obtain an histological diagnosis regardless of cytological findings. Further studies examining the biology of radial scars are required.

The evaluation of high risk and pre-invasive breast lesions and the decision process for follow up and surgical intervention

Atypical epithelial hyperplasia, lobular carcinoma in situ (lobular neoplasia), radial scar, and ductal carcinoma in situ are considered high-risk lesions that predispose toward the future development of non-invasive or invasive breast cancer. Generally, those women with atypical epithelial hyperplasia, radial scar, or lobular carcinoma in situ can be managed conservatively by close surveillance. The minority of women may consider prophylactic mastectomy. Ductal carcinoma in situ can usually be managed by lumpectomy with or without radiation, with some patients requiring mastectomy due to extensive disease.

Langerhans and other Immunocompetent Cells in Vocal Cord Epithelial Hyperplastic Lesions of Patients with Chronic Laryngitis

Ferluga D, Vodovnik A, Luzar B, Cör A, Perkovie. T, Gale N, KambiČ V. Langerhans and other immunocompetent cells in vocal cord epithelial hyperplastic lesions of patients with chronic laryngitis.The aim of the study was to evaluate the intraepithelial and stromal density of Langerhans cells and lymphoid infiltrate in different stages of carcinogenesis in vocal cord biopsies of 24 randomly selected patients with chronic laryngitis. The Langerhans and lymphoid cells were counted using immunolabelling with antibodies against CD1a, S100, CD3, CD20. and CD68 on paraffin-embedded sections of 24 archival laryngeal vocal cord mucosa biopsy specimens, 6 classified as simple, 7 as abnormal, and 11 as atypical epithelial hyperplasia. Results were statistically evaluated using the Kruskal-Wallis and Wilcoxon sign rank tests. The mean number of Langerhans cells and T lymphocytes per mm' of cross-sectioned epithelium was found to increase from simple to atypical hyperplasia. There were statistically significant differences in Langerhans cell density between atypical hyperplasia and each of the other 2 grades, simple and abnormal hyperplasia, with p < 0.05. Our study suggests the involvement of immune mechanisms, particularly cell mediated, during laryngeal carcinogenesis and the possibility that the assessment of Langerhans cell density might be of prognostic significance.

Expression of epitopes of the tumour-associated glycoprotein 72 and clinicopathological correlations in mammary carcinomas

We analysed the immunohistochemical expression pattern of the distinct carbohydrate epitopes of the TAG-72 molecule, defined by the monoclonal antibodies (MAbs) B72.3, CC-49 and CC-83, in 92 breast carcinomas of different histological type, and in other histological components identified in the mammary tissue samples studied. The results were correlated with the clinico-pathological characteristics of the tumours, and with their proliferative activity, assessed by thymidine labelling index (TLI). Expression of the TAG-72 epitopes was detected in all the tumour histotypes analysed, but patterns of immunoreactivity tended to vary in relation to type and level of differentiation. The comparative analysis of the reactivities of the three anti-TAG-72 MAbs revealed differences in their ability to recognise neoplastic lesions. MAb CC-49 reacted with the highest percentage of tumours (82%), and also tended to yield the highest percentages of immunoreactive cancer cells, while B72.3 and CC-83 reacted with lower percentages of tumours (respectively, 55 and 51%), and identified lower percentages of immunoreactive cells. High levels of expression of the three TAG-72 epitopes were detected in areas of in situ ductal carcinoma. Comparatively lower levels of immunohistochemical positivity were found in atypical epithelial hyperplasia, normal mammary epithelium and epithelium with cystic disease. TAG-72 epitope expression was correlated with prognostic parameters. The synchronous expression of the three epitopes significantly correlated with large tumour size (> 2 cm), and with high histological grade. No correlations could be demonstrated between TAG-72 phenotypes and nuclear grade, lymph node status and proliferative activity (high versus low).