Low-grade DCIS Research Articles

The low nuclear grade breast neoplasia family

Breast cancer is a heterogeneous disease with varied morphological and molecular features and clinical behaviour. Recently a group of invasive tumours and precursor lesions was reported to exhibit strikingly similar low-grade nuclear features, immunophenotypic and molecular profiles and coexist at frequencies that could not be justified by chance alone. These lesions are grouped together into a single class termed low-grade breast neoplasia family (LGBNF) to differentiate them from high-grade neoplasms, which are thought to develop through different evolutionary pathways. Precursor lesions in this family include columnar cell lesions (CCLs), flat epithelial atypia (FEA), atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), lobular carcinoma in-situ (LCIS) and low-grade DCIS. Invasive LGBNF tumours include invasive tubular and cribriform carcinomas, invasive lobular carcinoma, low-grade invasive mucinous and low-grade ductal no special type (NST) carcinomas. These lesions are characterized by strong uniform expression of hormone receptors, lack of HER2 expression and HER2 gene amplification, and exhibit a unique pattern of genetic aberrations mainly deletions of 16q and gains of 1q. In this review, we present the concept of LGBNF with emphasis on their characteristic phenotypic, genotypic and molecular profiles and their impact on BC management strategies and discuss a hypothetical model of breast cancer evolution and progression.

Atypical Ductal Hyperplasia at the Margin of Lumpectomy Performed for Early Stage Breast Cancer: Is there Enough Evidence to Formulate Guidelines?

Background. Negative margins are associated with a reduced risk of ipsilateral breast tumor recurrence (IBTR) in women with early stage breast cancer treated with breast conserving surgery (BCS). Not infrequently, atypical ductal hyperplasia (ADH) is reported as involving the margin of a BCS specimen, and there is no consensus among surgeons or pathologists on how to approach this diagnosis resulting in varied reexcision practices among breast surgeons. The purpose of this paper is to establish a reasonable approach to guide the treatment of ADH involving the margin after BCS for early stage breast cancer. Methods. the published literature was reviewed using the PubMed site from the US National Library of Medicine. Conclusions. ADH at the margin of a BCS specimen performed for early stage breast cancer is a controversial pathological diagnosis subject to large interobserver variability. There is not enough data evaluating this diagnosis to change current practice patterns; however, it is reasonable to consider reexcision for ADH involving a surgical margin, especially if it coexists with low grade DCIS. Further studies with longer followup and closer attention to ADH at the margin are needed to formulate treatment guidelines.

Significance of AgNOR analysis and the expression of Ki-67 in the precursor lesions of the breast carcinoma

Objective To study the diagnostic and differential diagnostic significance of argyrophilic nucleolar organizer region (AgNOR) and cellular proliferation index ( PlKi-67 ) in the precursor lesions of the breast carcinoma. Methods Image quantitative analysis of AgNOR and immunostains of Ki-67 in tissue microarray sections from 76 biopsies of the precursor lesions of the breast carcinoma. Results There were some differences in granulae sizes and shapes of AgNOR among the precursor lesions of the breast carcinoma. The number of AgNORs per nucleu, total area of AgNORs, mean area of a single AgNOR, PIKi-67 were increasing from ADH to high-grade DCIS, and there was statistical difference between ADH, low-grade DCIS,respectively and high-grade DCIS. The number of AgNORs per nucleu was statistically different between ADH and low-grade DCIS. Conclusion AgNOR and Ki-67 could be regarded as assistant indicators in the diagnosis and differential diagnosis of the precursor lesions of the breast carcinoma. Key words: Breast neoplasia; Atypical ductal hyperplasia; Ductal carcinoma in situ; Argyrophilic nucleolar organizer regions; Ki-67; Tissue microarray

Abstract P4-06-07: PI3K Mutations Are More Common in Low Grade DCIS

Abstract Background: DCIS is a non-obligate precursor to invasive breast cancer yet it remains difficult to predict which lesions will progress or over what time interval. Factors associated with a higher risk of progression include high histologic grade and HER2 amplification. HER2 signaling via the PI3K pathway is associated with accelerated invasiveness in laboratory models and mutations in the helical domain of PI3K have been associated with a worse prognosis in invasive cancer. We hypothesized that PI3K pathway mutations are associated with higher risk of progression in DCIS and therefore would be more common in high grade DCIS. Methods: 195 cases of pure DCIS were identified from the MSKCC breast service database (1999-2003). All cases were reviewed by a single pathologist to assign histologic grade. Sections were obtained from archived formalin-fixed paraffin embedded (FFPE) blocks for manual microdissection to isolate pure DCIS lesions for DNA extraction. Multiplex array (Sequenom®) genotyping for PIK3CA was performed on prePCR amplified DNA. Comparisons were made between high and low grade DCIS using Fisher's exact test. Results: Among 195 pure DCIS cases, 89 were classified as high grade and 106 as low grade. Sequenom® analysis was informative in all cases. PIK3CA mutations were identified in 4/89 (4%) cases of high grade DCIS and in 24/106 (23%) cases of low grade DCIS (p=0.000). All 4 mutations in high grade DCIS were located in the kinase domain, whereas in low grade DCIS, 9/24 (37%) mutations were in the kinase domain (H1047R) and 15/24 (67%) mutations were in the helical domain (E542K, E545K, N345K). Conclusion: PI3K mutations were relatively uncommon in pure high grade DCIS as compared to low grade DCIS. PI3K mutations in low grade DCIS were observed in both the kinase and helical domain. These findings support the hypothesis that breast tumorigenesis differs by grade and PI3K mutations may be more prominent in low grade carcinogenesis. The significance of helical domain mutations in low grade lesions requires further investigation. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-06-07.

The ever-changing face of breast advocacy

My personal journey into breast cancer advocacy resulted from a diagnosis of low grade DCIS. I joined with others throughout the world in turning adversity into advocacy to support endeavors which further public and professional education, political change and scientific research. This path took me from a mere one woman networking effort to addressing national panels of experts in Washington, D.C. charged with improving quality of breast care. It often became more than a full time job but the rewards were worth it. My family also supported my mission and the potential impact that advocacy could make on both a personal and community level. So I follow in the footsteps of other tenacious advocates and always keep in mind the singular focus of improving standards for quality breast care now and in the future. This paper describes the ever-changing face of advocacy from my viewpoint as a breast cancer survivor.

In newly diagnosed breast cancer, is a contralateral prophylactic mastectomy necessary following a negative MRI?

627 Background: With more centers using MRI to aid in initial staging, there is apprehension that the highly sensitive MRI exam may lead to “unnecessary” mastectomies. We evaluated whether a negative contralateral MRI could be used to rule out a synchronous contralateral carcinoma and hence avoid a prophylactic contralateral mastectomy (CPM) at initial breast cancer diagnosis. Methods: Data of women with a new diagnosis of breast cancer (invasive or DCIS) from February 2003-November 2007 at our institution were reviewed. Women who had a negative MRI of the contralateral breast and who subsequently underwent CPM were included. A CPM was one in which there was no histological confirmation of cancer in the contralateral breast before surgery. All mastectomy specimens were analyzed pathologically. True negatives were mastectomy samples which contained no cancer following pathologic examination. False negatives were mastectomy samples which were found to have cancer after pathologic review. Results: 538 women were identified. 51 women met the study criteria. Median patient age was 56 years (range, 33–77). Of the 51 women who underwent a CPM, 2 were found to have pathologic confirmation of cancer. One occult cancer was a 0.3 cm grade 1, invasive lobular carcinoma; the second a 0.5 cm, low grade DCIS. The overall prevalence of synchronous occult contralateral cancer after a negative MRI was 3.9% (95% CI 0.5 - 13.5%). The negative predictive value of MRI was 96.1% (95% CI 86.5 - 99.5%). Conclusions: This study provides pathologic data regarding the utility of a negative contralateral breast MRI in women with newly diagnosed breast cancer. The prevalence of a synchronous occult contralateral cancer after a negative MRI in women with newly diagnosed breast cancer is very low. Physicians and patients can be assured that the risk of occult cancer is low in the setting of a normal contralateral MRI, an important fact when considering CPM after a diagnosis of unilateral breast cancer. No significant financial relationships to disclose.

Clinicopathological characteristics of subsequent breast cancers in patients with benign breast disease

1061 Background: Benign breast disease (BBD) is a significant risk factor for breast cancer (BC); however little is known about the aggressiveness of the BCs these patients develop. Shared features between select atypias and low-grade DCIS have led some to speculate that a history of BBD portends the development of well-differentiated BCs. Methods: The Mayo BBD cohort includes 9,376 women who had benign breast biopsies from 1967–1991. Data on BC events were obtained from medical records and questionnaires. Tissue from the BCs was reviewed by a single breast pathologist (DWV). Results: Our cohort included 6,244 patients with nonproliferative disease (NP), 2,801 women with proliferative disease without atypia (PDWA), and 331 with atypical hyperplasias (AH). With a median of 18 years of follow-up, 799 patients with BBD have developed breast cancer, 416 initially had NP, 313 had PDWA, and 70 AH. BC tissue was available for 703 of the women. The cancers were invasive ductal in 76.1% (n = 535), invasive lobular in 9.4% (n = 66), and DCIS alone in 14.5% (n = 102) patients. Grade is currently available for 500 women, and is well differentiated in 29.4% (n = 150), moderately differentiated in 42.7% (n = 218) and poorly differentiated in 27.8% (n = 142). In 537 cases the malignant tissue had a concurrent benign component consisting of NP in 24% (n = 129), PDWA in 25.1% (n = 135), and AH in 50.8% (n = 273). In regards to tumor size, 69.6% had T1 tumors, 24.9% T2 tumors, and 5.5% T3 disease. Metastasis to lymph nodes occurred in 25% of patients. Median time to BC was 12.3 years and did not differ across the different benign entities. Breast cancer developed within 5 years from the initial BBD in 163 women (20%). In this group, tumor size was greater (p = 0.02), and there were more poorly differentiated tumors (p = 0.006) than in those who later developed BC. Conclusions: In the BCs that have developed in our BBD cohort, we do not see a preponderance of well-differentiated, good-risk BCs. Patients diagnosed within 5 years of BBD appear to have BCs with more aggressive features. No significant financial relationships to disclose.

The assessment of angiogenesis and fibroblastic stromagenesis in hyperplastic and pre-invasive breast lesions

BackgroundTo investigate the changes of the neoplastic microenvironment during the different morphological alterations of hyperplastic and pre-invasive breast lesions.Methods78 in situ ductal carcinomas of all degrees of differentiation, 22 atypical ductal hyperplasias, 25 in situ lobular carcinomas, 18 atypical lobular hyperplasias, 32 ductal epithelial hyperplasias of usual type and 8 flat atypias were immunohistochemically investigated for the expression of vascular endothelial growth factor (VEGF), smooth muscle actin (SMA) and CD34, while microvessel density (MVD) was counted using the anti-CD31 antibody.ResultsVEGF expression was strongly correlated with MVD in all hyperplastic and pre-invasive breast lesions (p < 0.05). Stromagenesis, as characterized by an increase in SMA and a decrease in CD34 positive myofibroblasts was observed mostly around ducts harboring high grade in situ carcinoma and to a lesser extent around moderately differentiated DCIS. In these two groups of in situ carcinomas, a positive correlation between MVD and SMA (p < 0.05) was observed. On the contrary, CD34 was found to be inversely related to MVD (p < 0.05). No statistically significant changes of the stromal fibroblasts were observed in low grade DCIS neither in any of the other lesions under investigation as compared to normal mammary intra- and interlobular stroma.ConclusionAngiogenesis is observed before any significant fibroblastic stromagenesis in pre-invasive breast lesions. A composite phenotype characterized by VEGF positive epithelial cells and SMA positive/CD34 negative stromal cells, is identified mostly in intermediate and high grade DCIS. These findings might imply for new therapeutic strategies using both anti-angiogenic factors and factors selectively targeting tumor stroma in order to prevent the progression of DCIS to invasive carcinoma.

In patients with DCIS: is it sufficient to histologically examine only those tissue specimens that contain microcalcifications?

The purpose was to investigate in patients with histologically proven DCIS to what extent there is agreement between radiographically proven microcalcifications of specimens obtained by vacuum-assisted biopsy and the histologic diagnosis of microcalcifications and DCIS, and second, to assess the accuracy of biopsy in relation to the number of specimens obtained in patients with high-grade and low-grade DCIS. Four hundred twenty specimens from 35 patients who were diagnosed with DCIS were examined radiographically and histologically for the presence of microcalcifications. The results were analyzed using the McNemar-test. In addition, the average numbers of biopsy specimens necessary for diagnosing low-grade DCIS and high-grade DCIS were compared using the t-test. Specimen radiography had a PPV of 0.50 and a NPV of 0.85 for the demonstration of DCIS. Differences in localization between radiographically proven microcalcifications and DCIS were statistically significant (p<0.01). The difference between the mean numbers of specimens required per patient for correctly diagnosing high-grade or low-grade DCIS was statistically significant (p<0.01). Specimen radiography is very limited in identifying those specimens that are crucial for diagnosing DCIS. The rate of underestimation is expected to be higher for low-grade than for high-grade DCIS. The findings suggest that all samples obtained by vacuum-assisted breast biopsy should be histologically examined.

Matriptase and Survivin Expression Associated with Tumor Progression and Malignant Potential in Breast Cancer of Chinese Women: Tissue Microarray Analysis of Immunostaining Scores with Clinicopathological Parameters

Objective: The aim of this study was to examine the expression of matriptase and survivin in breast carcinoma and correlate with clinicopathological parameters. Methods: Immunohistochemical analysis of matriptase and survivin were performed in tissue microarray slides of 290 cases, including 11 normal breast tissue; 27 fibrocystic disease; 17 fibroadenoma; 6 atypical ductal hyperplasia; 39 ductal carcinoma in situ, low grade (DCIS, low grade); 39 ductal carcinoma in situ, high grade (DCIS, high grade); 27 invasive ductal carcinoma, grade I (IDC, grade I); 78 invasive ductal carcinoma, grade II (IDC, grade II); and 46 invasive ductal carcinoma, grade III (IDC, grade III). Results: The average immunostaining scores of matriptase were 44.1 in normal breast tissue, 52.7 in fibrocystic disease, 76.5 in fibroadenoma, 81.7 in atypical ductal hyperplasia, 133.7 in low-grade DCIS, and 155.8 in high-grade DCIS. Among 151 breast IDC cases, the average immunostaining scores of matriptase were 172.7 in grade I, 211.7 in grade II, and 221.2 in grade III. Additionally, the average immunostaining scores of surviving also correlate with tumor grades and stages. Conclusions: Higher expressions of matriptase and survivin correlate significantly with clinicopathological parameters in breast cancer and the malignant potential in premalignant lesions. In addition, higher survivin expression had poorer prognosis of breast IDC cases.

Spontaneous Mammary Intraepithelial Lesions in Dogs—A Model of Breast Cancer

Mammary intraepithelial lesions (IEL) are nowadays frequently diagnosed as a result of the success of mammographic screening, education programs, and awareness by women. Establishment of an animal model for these lesions to test treatment or preventive modalities is a prerequisite for human clinical trials. A model for spontaneous IELs, especially for estrogen receptor (ER)-negative lesions, does not exist. This study describes the histologic and immunohistochemical similarity between human and canine mammary IELs. Mammary tumors from 200 dogs were classified and histologic sections of the excisional specimens were evaluated for IELs. IELs, found in specimens from 60 dogs, were categorized as adenosis, sclerosing adenosis, intraductal papilloma, sclerosing papilloma, ductal hyperplasia, atypical ductal hyperplasia (ADH), and ductal carcinoma in situ (DCIS; high, intermediate, and low grade). Most proliferative IELs without atypia were associated with benign tumors, whereas IELs with atypia (ADH and DCIS) were generally associated with mammary cancer. ER-alpha expression was significantly low or absent in most ADH and DCIS lesions as well as in their associated tumors. Ki67 expression was significantly higher in high-grade DCIS than in hyperplasia or low-grade DCIS. Two thirds of high-grade DCIS lesions were positive for HER-2. Canine mammary IELs were strikingly similar to those of the human breast. The frequency of IELs in the dog, their association with spontaneous mammary cancer, their pattern of ER-alpha and HER-2 expression, and their histologic resemblance to human IELs may make the dog an ideal model to study human ER-negative (both HER-2 positive and negative) breast cancer progression as well as prevention and treatment.

Clinicopathologic study of breast cancer with features of endocrine ductal carcinoma-in-situ

To study the clinicopathologic features and differential diagnosis of 18 cases of endocrine ductal carcinoma-in-situ (E-DCIS). Eighteen cases of breast cancer with features of E-DCIS were studied by light microscopy, histochemistry and immunohistochemistry. E-DCIS was diagnosed if the histologic patterns were compatible with those described in the literature and at least 50% of the tumor cells expressing two of the three neuroendocrine markers employed (chromogranin, synaptophysin and neuron-specific enolase). E-DCIS tended to occur in older women. All the patients were over 61 years old (mean age=71 years). The presenting symptoms were either palpable breast mass or had nipple discharge. Histologically, E-DCIS demonstrated an expansile intraductal growth pattern. Intraductal papilloma was not uncommon at the peripheral area of the tumor. The tumor cells were polygonal, oval or spindle in shape and contained abundant eosinophilic to granular cytoplasm and mildly to moderately pleomorphic nuclei. Intracellular or extracellular mucin was highlighted by periodic acid-Schiff (with diastase digestion) or alcian blue stains. Some tumor cells assumed a signet-ring configuration. All the three neuroendocrine markers were expressed by more than 50% of the E-DCIS cells. The neuroendocrine differentiation was further confirmed in some cases by CD57 and CD56 immunostaining. Pagetoid spread into adjacent ductolobular units was frequently seen in E-DCIS, and the expanded lobules were often not rimmed by myoepithelial cells. These two features helped to distinguish E-DCIS from usual ductal hyperplasia. E-DCIS represents a subgroup of low-grade DCIS, which carries characteristic morphologic features and immunophenotype. Conventional light microscopy usually permits a correct diagnosis. Ancillary histochemical and immunohistochemical studies can be helpful in doubtful cases.

Immunophenotype similarity and high frequency of co-existence of columnar cell lesions, lobular neoplasia, and low grade DCIS with invasive tubular carcinoma and invasive lobular carcinoma

The increasing availability of emerging non-combusted tobacco products (snus, dissolvables, and electronic nicotine delivery systems or ENDS) may have implications for pregnant women and women of reproductive age. We conducted 15 focus groups to explore how women perceive emerging non-combusted tobacco products and nicotine replacement therapy (NRT) in general, and during pregnancy. Sessions were held in 2013 in four U.S. cities. Participants were 18–40 years old and were pregnant smokers, pregnant quitters, or smokers planning a pregnancy. Responses were coded and analyzed to identify key themes using NVivo 10.0 qualitative software (QSR).Several themes emerged from focus groups. Participants generally found snus unappealing, but viewed dissolvables as a discreet and stigma-free way to use tobacco during pregnancy. Participants perceived NRT as ineffective and having undesired side effects. ENDS were thought to offer advantages over cigarettes, including use in smoke-free areas, lower cost, appealing flavors, and fewer health effects, and were seen by some as a potential quit aid. Some participants, however, worried that the lack of natural stopping point could lead to excessive use. Many participants felt that the use of any tobacco or NRT product is harmful during pregnancy.Women seeking to reduce health risks or stigma related to smoking during pregnancy may perceive advantages of using some emerging products over cigarettes. These findings can inform future public health efforts to reduce risks associated with tobacco product use among women of reproductive age.

Histopathology of primary breast cancer 2005

Major efforts have been recently devoted to a better definition of intraductal proliferative lesions with atypia. The new WHO classification of tumors of the breast highlights the morphological features of flat epithelial atypia (DIN 1A) and atypical duct hyperplasia (DIN 1B). Flat epithelial atypia now encompasses lesions previously designated as clinging carcinoma (monomorphous type) and atypical columnar changes. Atypical ductal hyperplasia (ADH) is characterized by the same cytological changes as low-grade DCIS, involving a very small portion of the ductal tree. Minimal lymph node involvement includes true micrometastases (from 0.2 to 2 mm in size) and isolated tumor cells (ITC). ITC have been defined as individual tumor cells or small clusters of cells, not more than 0.2 mm in size, that do not typically show evidence of metastatic activity or penetration of vascular or lymphatic sinus walls. The biological and clinical implications of ITC remain to be elucidated.

Cytologic Findings with Histologic Correlation in 43 Cases of Mammary Intraductal Adenocarcinoma Diagnosed by Aspiration Biopsy

To review the cytologic and subsequent histologic findings in intraductal mammary adenocarcinoma (ductal adenocarcinoma in situ) (DCIS) to evaluate the role of aspiration biopsy (AB) in identifying and grading the disease. AB smears and tissue sections from 43 women with pure DCIS who underwent preoperative AB were reviewed. Smears were assessed for cellularity, cellular arrangement (including dissociation, nuclear size and pleomorphism), and presence of nucleoli and necrosis. Of the 43 cases, 22 were high grade (HG) DCIS, 7 cases were intermediate grade (IG), and 14 cases were low grade (LG). Cytologic findings of HG DCIS was as follows: high cellularity (22/22), clusters of pleomorphic cells with large nuclei and increased nuclear/cytoplasmic ratios (22/22), single cells (20/22), prominent nucleoli (22/22) and necrosis (diffuse in 15/22, focal in 7/22). All LG cases had moderately to highly cellular smears with cohesive, 3-dimensional sheets of uniform, small cells with inconspicuous nucleoli arranged around a central lumen, forming "punched-out" spaces. Single cells were prominent in 2 of 14 cases. IG DCIS showed intermediate features between LG and HG DCIS: 3-dimensional sheets with punched-out spaces, abundant single cells, moderate pleomorphism and focal necrosis. HG DCIS is easily identifiable on AB smears; however, distinction from invasive carcinoma may not be possible. The cytologic diagnosis of LG DCIS is difficult, and 50% of our cases were called atypical on AB. Recognition of cohesive cellular arrangements with crowding and punched-out spaces is crucial as single cells and prominent atypia are often lacking.

Probleme der intraoperativen Schnellschnittdiagnostik von Mammaläsionen — Analyse von 5479 konsekutiven Fällen

Background: Until recently intraductal carcinomas (DCIS) were thought to be a single entity of disease. In order to examine this theory we examined DCIS with respect to several morphological parameters. Methods: 88 DCIS were investigated by steroid hormone receptors, p53 and cellular proliferation determined by MIB1. DCIS were classified according to the new suggestion by EORTC. This classification is based mainly on nuclear pleomorphism and architectural pattern. Results: All prognostic factors showed direct or inverse correlation, respectively, with subclassification of DCIS. There existed a significant correlation between steroid hormone receptor positivity and low proliferative activity in low grade DCIS subgroup compared to high grade DCIS. In contrast p53 expression was high in high grade DCIS and showed only little positivity in low grade DCIS. Conclusions: It is concluded that DCIS classification based on nuclear pleomorphism may become an important prognosticator in the future.

Endocrine Ductal Carcinoma in situ (E-DCIS) of the Breast

Endocrine ductal carcinoma in situ (E-DCIS), first characterized by Cross et al. in 1985, is an uncommon entity, and there is little information on its pathobiologic features and natural history in the literature. This report describes the largest series of 34 cases: 14 cases were pure in situ (group A), and 20 were accompanied by an invasive component (group B). All except three patients were over the age of 60 years, with the mean being 69.5 years for group A and 72.6 years for group B. Except for six patients in group A who had nipple discharge, all had a breast mass. On follow-up, one of five group A patients developed local recurrence 5 years after mastectomy, and two of seven group B patients developed another invasive primary in the contralateral breast. Histologically, E-DCIS showed expansile intraductal growths forming solid sheets and festoons traversed by delicate fibrovascular septa. Accumulation of basophilic mucin might be found within the growth and the fibrovascular septa. There were variable degrees of stromal sclerosis. In some cases, the solid intraductal cellular proliferations were focally punctuated by microglandular spaces and rosettes. Comedo necrosis was absent. Intraductal papillomas were found in the immediate vicinity of the tumors in 18 cases and invariably showed pagetoid involvement by E-DCIS. Pagetoid spread into the adjacent ducts and ductules was also a common feature (17 cases). The tumor cells were polygonal, oval, or spindly, often with eccentrically placed, bland-looking, ovoid nuclei and abundant eosinophilic granular cytoplasm. Intracellular mucin was commonly demonstrable. Immunostaining for myoepithelium using muscle-specific actin antibody confirmed the in situ nature of the E-DCIS component. The majority of tumor cells showed strong staining with the neuroendocrine markers chromogranin, synaptophysin, and neuron-specific enolase (monoclonal). Immunostaining also dramatically highlighted the pagetoid spread into the papillomas and ductules by outlining the tumor cells between the negatively stained residual ductal epithelium and myoepithelium. All cases were immunoreactive for estrogen and progesterone receptor, but not p53 and c-erbB2. The Ki-67 index was < 5%. Ultrastructural studies on four cases showed many dense-core neurosecretory granules and larger mucigen granules. In group B cases, the invasive component, which comprised 5-95% of the tumor, included colloid carcinoma, 12; "carcinoid" tumor, 3; mixed "carcinoid"/colloid carcinoma, 4; and small cell neuroendocrine carcinoma, 1. Neuroendocrine markers were also consistently demonstrable in the invasive component. In conclusion, E-DCIS is predominantly a disease of older women that is frequently accompanied by papillomas in the vicinity and may present as nipple discharge (an uncommon presentation in the usual forms of DCIS). It can mimic epitheliosis histologically, but the pagetoid spread is a helpful clue to its neoplastic nature. The bland nuclear morphology, lack of necrosis, and biologic marker profile suggest that E-DCIS is a form of low-grade DCIS despite its solid growth pattern. The invasive carcinomas associated with E-DCIS are also neuroendocrine programmed rather than the usual types of ductal carcinomas, suggesting that E-DCIS represents a biologically distinctive category of DCIS.

613 Ductal carcinoma in situ–prognostic significance of histological types

In a controlled clinical trial 114 patients with biopsy proven ductal carcinoma in situ were treated by breast conserving surgery without postoperative radiatioa Intraductal comedocarcinoma was found in 41%, cribriform and papillary types were found in 22%. The proportion of high-grade lesions and low-grade lesions being 1:0.6. Recurrences were found in 19%. High-grade DCIS was associated with a 15.3%, low-grade DCIS with a 12.2% recurrence rate. The recurrences did not show any correlation with the age of the patient nor the type and size of the lesion within the range of 2–46 mm. Optimal preconditions for mammographic follow-up seems to be of greater importance for the outcome of the patient than the size and type of the DCIS and the age of the patient.