Subsequent Development Of Invasive Carcinoma Research Articles

Expression pattern and methylation of estrogen receptor α in breast intraductal proliferative lesions

Intraductal proliferative lesions of the breast including usual ductal hyperplasia (UDH), atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) are associated with increased risk, albeit of greatly different magnitudes, for the subsequent development of invasive carcinoma. Estrogen receptor α (ERα) has been widely accepted as a prognostic marker and a predictor for endocrine therapy response of breast cancer. To investigate the ERα expression and methylation in breast intraductal proliferative lesions, we analyzed ERα expression in breast intraductal proliferative lesions including pure UDH (N=98), ADH without DCIS (N=160), DCIS without invasive breast cancer (N=149) by immunohistochemistry. Furthermore, the methylation status of ERα by methylation-specific PCR (MSP) was defined in 217 cases of breast intraductal proliferative lesions. Immunohistochemistry showed that 98/98 (100%) of the UDH cases were positive for ERα expression. ERα protein expression in ADH (132/160) (92.5%) was higher than in DCIS (101/149) (67.8%). But the ERα expression pattern was different with histological diversity of breast intraductal proliferative lesions. The average percent cells staining positive for ERα was 35.33% in UDH, 87.75% in ADH and 71.45% in DCIS. ERα methylation in 32/60 (53.3%) UDH, 11/77 (10.2%) ADH and 32/80 (40.0%) DCIS. Our results demonstrated a strong negative correlation between the percent of cells staining positive for ERα and ERα methylation (r=−0.831, p<0.001). Taken together, our results underlined that ERα expression or methylation may be involved in the breast carcinogenesis and advancement, thus it is not parallel to breast cancer risk in breast intraductal proliferative lesions. No obvious watershed between ERα-positive and -negative breast carcinogenesis was established. Estrogen receptor (ER) methylation or expression is a reversible signal in breast carcinogenesis which affected biological behavior of cells.

The Practical Use of Molecular Profiling

Molecular profiling is used in three stages of breast cancer development: cacinoma in situ, primary, and metastatic. The treatment of in situ carcinoma of the breast is controversial. In the molecular progression from normal tissue to invasion, in situ carcinoma is a late-occurring step associated with an increased risk of the subsequent development of invasive carcinoma [Bombonati A, Sgroi DC. J Pathol 2011]. This article discusses data on molecular profiling of in situ carcinoma of the breast, an overview of molecular profiling of breast cancer, and the current use of genomic and molecular tests in routine practice and clinical research in metastatic breast cancer.

Multistep mouse mammary tumorigenesis through preneoplasia to neoplasia and acquisition of metastatic potential

Human breast tissue can give rise to hyperplasias, atypical hyperplasias, and in situ carcinomas originating in a terminal duct-lobular unit (TDLU). These entities are associated with increased risk of subsequent development of invasive carcinoma. Human breast carcinomas arise via intermediate steps known as precursor or premalignant lesions. However, it is difficult to perform stepwise observation of the progression of human breast cancer. Mouse mammary tissue can give rise to several characteristic types of premalignant hyperplasia and tumor, originating in a duct or acinus, that progress to carcinoma. Three specific types of mouse mammary lesion with premalignant potential have been identified: hyperplastic alveolar nodule (HAN), plaque (PLQ), and ductal hyperplasia (DH). These lesions partially resemble human precursor lesions, and clarification of similarities and differences between the human and mouse lesions could improve our understanding of human breast carcinogenesis. Some invasive breast carcinomas acquire metastatic potential and may cause the death of the patient. Because the most malignant aspect of neoplasia is metastasis, recognition of metastatic phenotypes is particularly important. Mouse mammary carcinomas rarely metastasize, but there exist mouse models of metastasis of mammary carcinoma. In the present review article, we describe morphological, biological, and molecular aspects of premalignant lesions of mice, and we discuss their metastatic phenotypes.

Dysplasia as a predictive marker for invasive carcinoma in Barrett esophagus: A follow-up study based on 138 cases from a diagnostic variability study

The objective of endoscopic surveillance in Barrett esophagus (BE) is to assess the risk of subsequent development of invasive carcinoma. Criteria for morphologic evaluation of dysplasia, the presumed precursor lesion, have been established, although there are surprisingly few data in the literature correlating biopsy diagnosis of dysplasia with outcome. We collected follow-up information on 138 patients with BE whose initial endoscopic biopsy specimens had been selected for submission in an interobserver variability study performed by 12 pathologists with special interest in gastrointestinal pathology and reviewed blindly twice each by all the participants. Cases were scored as BE with no dysplasia, atypia indefinite for dysplasia (IND), low-grade dysplasia (LGD), high-grade dysplasia (HGD), intramucosal carcinoma, and frankly invasive carcinoma, thus generating 24 scores on each biopsy specimen. Clinical follow-up was obtained and correlated with both the submitting diagnoses and majority diagnoses. Kaplan-Meier statistics were used to compare both the submitting and majority diagnoses with outcome using detection or documentation of invasive carcinoma as the endpoint. Using the submitting diagnoses, no invasive carcinomas were detected in 44 cases diagnosed as BE (median follow-up, 38.5 months). Carcinomas were detected in 4 of 22 (18%) cases submitted as IND (median progression-free survival of 62 months), in 4 of 25 (15%) cases of LGD (median progression-free survival of 60 months), in 20 of 33 cases of HGD (median progression-free survival, 8 months), and all 13 (100%) cases submitted as adenocarcinoma. Grade on initial biopsy correlated significantly with progression to invasive carcinoma (log-rank P =.0001). Majority diagnosis was achieved in 99 of the cases. Using the majority diagnoses, no invasive carcinomas were found in 50 cases of BE (median follow-up, 48 months), and carcinomas were detected in 1 of 7 (14%) IND cases (80% progression-free survival at 2 months), 3 of 15 (20%) LGD (median progression-free survival, 60 months), 9 of 15 (60%) HGD (median progression-free survival, 7 months), and all 12 (100%) carcinoma. Initial grading again correlated significantly with progression to invasive carcinoma (log-rank P =.0001). However, there were 39 cases without a majority diagnosis. Among these, no carcinomas developed in 8 cases with an average score between BE and IND. Carcinomas were detected in 9 of 21 (43%) cases with an average score between IND and LGD, and 7 of 10 (70%) cases with an average score between LGD and HGD. There were ulcers in 8 of 39 cases (20%) of the “no-majority” group and in 13 of 99 (13%) of the majority cases. Of 21 total ulcerated cases, cancer was demonstrated in 15 (71%) of these on follow-up. These data support combining the IND and LGD categories for surveillance purposes. Cases without dysplasia may be followed up conservatively. The data obtained from submitted diagnoses as opposed to those from blind review suggest that knowledge of the clinical findings aids in diagnosis. The data also support the assertion that HGD is strongly associated with invasive carcinoma. Rebiopsy of ulcerated areas should be considered because they may harbor malignancy. Histologic grading of dysplasia using established criteria is a powerful prognosticator in BE. HUM PATHOL 32:379-388. Copyright © 2001 by W.B. Saunders Company

The role of alcohol in non-smokers and tobacco in non-drinkers in the aetiology of oral epithelial dysplasia

Oral epithelial dysplasia (OED) is an important risk factor in predicting subsequent development of invasive carcinoma. Despite the malignant potential of OED, the current state of knowledge regarding aetiological risk factors associated with OED is limited. The aim of our study was to evaluate the aetiological role of alcohol consumption in non-tobacco smokers and smoking behaviour in non-drinkers, in patients presenting with OED. Data from a hospital-based case-control study of OED were used to analyse the risk associated with alcohol in non-smokers and with tobacco in non-drinkers. A total of 140 cases and 236 controls were included. In the non-drinkers, the risks of OED increased with tobacco smoking of more than 20 cigarettes per day, particularly non-filter cigarettes. The risk of OED declined following smoking cessation, with ex-smokers of 10 or more years demonstrating no excess risk relative to non-smokers. In the nonsmokers, consumption of alcohol was not a significant predictor of OED. However, there was a synergistic effect of alcohol when combined with some aspects of tobacco smoking. Our results confirm that tobacco has an independent role in the aetiology of OED. The role of alcohol, however, is principally only important in conjunction with tobacco use.

Breast Carcinoma Arising in Microglandular Adenosis: A Tumor Expressing S-100 Immunoreactivity. Report of Five Cases

Abstract: Five cases of breast carcinomas arising in microglandular adenosis (MGA) are described. This type of carcinoma is rare and due to 5–100 protein positivity of the tumor cells might be misinterpreted as malignant melanoma, especially when poorly differentiated or displaying a prominent clear cell change. The distinct presence of MGA with transition through areas of atypical MGA around the carcinoma, and the cytokeratin positivity of tumor cells assist in establishing the correct diagnosis. This study also supports the observation that MGA may be associated with an increased risk for subsequent development of invasive carcinoma.

A comparison of the results of long-term follow-up for atypical intraductal hyperplasia and intraductal hyperplasia of the breast

Follow-up information was obtained on 199 women with breast biopsy specimens containing intraductal epithelial proliferation. The proliferations were divided into regular or ordinary intraductal hyperplasia (IDH) (117 cases) and atypical intraductal hyperplasia (AIDH) (82 cases). The average length of follow-up was 14 years for the patients with IDH and 12.4 years for the patients with AIDH. Of the 117 patients with ordinary IDH, carcinoma subsequently developed in six (5%); three of these were invasive carcinomas (2.6%). All three invasive carcinomas were in the ipsilateral breast, but of the three intraductal carcinomas (IDCa), two were in the contralateral breast. Of the 82 patients with AIDH, invasive carcinoma subsequently developed in eight (9.8%); six of these were located in the ipsilateral breast and two in the contralateral breast. One of these six patients died of disseminated carcinoma. The average interval to the subsequent carcinoma (intraductal and invasive carcinoma) was about the same in the two groups (8.3 years for AIDH and 8.8 years for IDH lacking atypia). When considering only subsequent invasive carcinomas, the interval was 8.3 years for the AIDH and 14.3 years for the IDH lacking atypia. Of the 14 patients with IDH and a family history of breast carcinoma, invasive carcinoma subsequently developed in one (7%) as compared with two (2%) of the 91 with a negative family history. Among patients with AIDH, invasive carcinoma subsequently developed in two of the 13 (15%) of those with a family history of breast carcinoma as compared with one of 57 (1.8%) of the women with a negative family history. The presence of atypia in epithelial hyperplasia is a significant factor in increasing the likelihood of the development of subsequent invasive carcinoma (P = 0.03; two-tailed test). Of women with AIDH, invasive carcinoma subsequently developed in 17% of those with sclerosing adenosis (SA) as compared with 4.2% of those without it. Therefore, SA may be a contributing factor to increased risk. A positive family history also appears to increase the likelihood of the subsequent development of invasive carcinoma, particularly in patients with AIDH.

Epithelial alterations in proximity to invasive squamous carcinoma of the vulva.

The histologic changes within epithelium adjacent to invasive carcinomas theoretically may include the specific lesions that precede the development of the invasive neoplasm, or may reflect the response of host epithelium to the carcinoma or to nonspecific inflammatory stimuli related to ulceration and tissue necrosis. We have studied the vulvar epithelium surrounding squamous carcinomas of 60 women undergoing vulvectomy to determine the frequency and type of potential precursor lesions and their relationship to various biologic parameters. Using modified criteria and nomenclature of the International Society for the Study of Vulvar Disease, we identified some degree of nuclear atypia (either atypical hyperplastic dystrophy or carcinoma in situ) in 72% of patients; in only 3% was there a direct transition from normal epithelium to invasive carcinoma. There was no apparent relationship between the presence of atypia and histologic grade, depth of invasion, size or stage of tumor, or frequency of nodal metastasis. Although direct evidence is lacking, these atypical lesions may serve to identify a population at increased risk for subsequent development of invasive carcinoma.