Monomorphic Epithelial Proliferations: Characterization and Evidence
Monomorphic Epithelial Proliferations: Characterization and Evidence
We studied whether precursor lesions (monomorphic epithelial proliferations [MEPs]) contributed to ipsilateral breast failures (IBFs; local recurrences). Margin status and MEPs near (within 4.2 mm) of the initial excision margin in 70 carcinoma patients with IBFs and allelic imbalance clonality data were recorded. Of the IBFs, 46 (66%) were clonal and 24 (34%) were second primary carcinomas. Control cases were 2 matching non-IBF cases for each study case. MEP lesions were predominantly single-cell layered, slightly overcrowded, monomorphic, clonal-like luminal cell proliferations that unfolded terminal duct lobular units (TDLUs) in an overgrowth extension pattern. MEPs often extended into TDLUs involved by hyperplasia of usual type. Clonal IBF cases had a mean of 6.24 MEPs near the initial excision margin compared with 3.85 MEPs in matched non-IBF control samples (P < .001). In the negative-margin subset, clonal IBF cases had mean of 7.82 MEPs near the margin, which was significantly greater than 4.26 in the distinct IBF group (P = .012) and 2.85 in the non-IBF matched control group (P < .001). MEPs seem to be the pool of partially transformed precursor lesions for most invasive carcinomas. Radiation therapy may reduce the IBF rate by eradicating these precursor lesions and preventing new carcinomas from emerging rather than eradicating microscopic residual disease.
Radiation after breast-conserving surgery significantly reduces local recurrences, or ipsilateral breast failures (IBFs), in patients with invasive breast carcinoma treated with breast conserving surgery. The reduction in IBF rate from radiation is proportionally similar across all patient groups. Despite the efforts of many, the subset of patients unlikely to benefit from radiation therapy has not been identified. Inconsistent margin assessment, inadequate resection, and carcinoma multicentricity are generally accepted to be the key responsible factors. Although plausible when first considered, this explanation has inconsistencies if taken to its conclusion. Given the strength and breadth of the radiation–IBF risk reduction association, invoking this explanation would mean the overwhelming majority of patients following breast-conserving surgery have a sufficiently large volume of residual carcinoma in the adjacent breast parenchyma. Because "negative" margin status has been the standard of practice, it raises the question of what is radiation eradicating in the unexcised parenchyma to produce such a significant statistical reduction in IBF rate?
The allelic imbalance (AI) assay is a well-established method for determining the clonality of 2 carcinomas, including initial and IBF breast carcinomas. Approximately 70% of IBFs are clonally related to the initial carcinoma, and 30% are clonally distinct, second primary carcinomas. The factors related to the development of IBFs are poorly understood. Similar to radiation's association with reduction of IBF risk, residual carcinoma, owing to inadequate resection or incomplete eradication by radiation, is generally held responsible. Although residual carcinoma is clearly behind some IBFs, the majority of patients in whom clonal IBFs develop have negative final margins on the initial excision specimen, which leads to the question: What results in the IBF in the latter cases?
These 2 questions focused our investigation toward possible alternative factors, specifically, whether a precursor lesion less than atypical ductal hyperplasia (ADH) or ductal carcinoma in situ (DCIS) was a contributing factor in IBFs in some cases.
Most invasive breast carcinomas are high-grade molecular group neoplasms. Hyperplasia of the usual type (HUT) was previously thought to be the precursor lesion for these carcinomas. It is currently considered a marker of increased carcinoma risk. A precursor lesion less than ADH has not been identified for these neoplasms. This is not the case for invasive tubular carcinomas. The precursor, termed columnar cell lesion (CCL), has a variety of cytologic and architectural alterations, each of which is associated with distinct and progressively greater molecular alterations. Studies have elegantly shown they form a biologic continuum that merges into ADH/low-grade DCIS.
The key features that draw CCLs together into a single entity are monomorphism, slight hypercellularity, and an overgrowth replacement growth pattern, in our opinion. With CCLs as the prototype, we wondered if there were similar precursor lesions with these 3 key morphologic features for most invasive carcinomas. We termed these lesions, regardless of the cytologic features, monomorphic epithelial proliferations (MEPs) to divest ourselves of any presumed risk associations and sidestep the terminology morass associated with CCLs, flat epithelial atypia, and flat and clinging DCIS.
The goals of this study were to characterize MEPs from the perspective of the potential precursor lesion to most invasive carcinomas and evaluate whether there was a relationship between MEPs and initial or IBF carcinomas. To facilitate our study of MEPs, we used the rim of tissue near the margin of initial excision specimens in patients in whom IBF developed, concentrating on the subset of patients with negative margins.
Abstract and Introduction
Abstract
We studied whether precursor lesions (monomorphic epithelial proliferations [MEPs]) contributed to ipsilateral breast failures (IBFs; local recurrences). Margin status and MEPs near (within 4.2 mm) of the initial excision margin in 70 carcinoma patients with IBFs and allelic imbalance clonality data were recorded. Of the IBFs, 46 (66%) were clonal and 24 (34%) were second primary carcinomas. Control cases were 2 matching non-IBF cases for each study case. MEP lesions were predominantly single-cell layered, slightly overcrowded, monomorphic, clonal-like luminal cell proliferations that unfolded terminal duct lobular units (TDLUs) in an overgrowth extension pattern. MEPs often extended into TDLUs involved by hyperplasia of usual type. Clonal IBF cases had a mean of 6.24 MEPs near the initial excision margin compared with 3.85 MEPs in matched non-IBF control samples (P < .001). In the negative-margin subset, clonal IBF cases had mean of 7.82 MEPs near the margin, which was significantly greater than 4.26 in the distinct IBF group (P = .012) and 2.85 in the non-IBF matched control group (P < .001). MEPs seem to be the pool of partially transformed precursor lesions for most invasive carcinomas. Radiation therapy may reduce the IBF rate by eradicating these precursor lesions and preventing new carcinomas from emerging rather than eradicating microscopic residual disease.
Introduction
Radiation after breast-conserving surgery significantly reduces local recurrences, or ipsilateral breast failures (IBFs), in patients with invasive breast carcinoma treated with breast conserving surgery. The reduction in IBF rate from radiation is proportionally similar across all patient groups. Despite the efforts of many, the subset of patients unlikely to benefit from radiation therapy has not been identified. Inconsistent margin assessment, inadequate resection, and carcinoma multicentricity are generally accepted to be the key responsible factors. Although plausible when first considered, this explanation has inconsistencies if taken to its conclusion. Given the strength and breadth of the radiation–IBF risk reduction association, invoking this explanation would mean the overwhelming majority of patients following breast-conserving surgery have a sufficiently large volume of residual carcinoma in the adjacent breast parenchyma. Because "negative" margin status has been the standard of practice, it raises the question of what is radiation eradicating in the unexcised parenchyma to produce such a significant statistical reduction in IBF rate?
The allelic imbalance (AI) assay is a well-established method for determining the clonality of 2 carcinomas, including initial and IBF breast carcinomas. Approximately 70% of IBFs are clonally related to the initial carcinoma, and 30% are clonally distinct, second primary carcinomas. The factors related to the development of IBFs are poorly understood. Similar to radiation's association with reduction of IBF risk, residual carcinoma, owing to inadequate resection or incomplete eradication by radiation, is generally held responsible. Although residual carcinoma is clearly behind some IBFs, the majority of patients in whom clonal IBFs develop have negative final margins on the initial excision specimen, which leads to the question: What results in the IBF in the latter cases?
These 2 questions focused our investigation toward possible alternative factors, specifically, whether a precursor lesion less than atypical ductal hyperplasia (ADH) or ductal carcinoma in situ (DCIS) was a contributing factor in IBFs in some cases.
Most invasive breast carcinomas are high-grade molecular group neoplasms. Hyperplasia of the usual type (HUT) was previously thought to be the precursor lesion for these carcinomas. It is currently considered a marker of increased carcinoma risk. A precursor lesion less than ADH has not been identified for these neoplasms. This is not the case for invasive tubular carcinomas. The precursor, termed columnar cell lesion (CCL), has a variety of cytologic and architectural alterations, each of which is associated with distinct and progressively greater molecular alterations. Studies have elegantly shown they form a biologic continuum that merges into ADH/low-grade DCIS.
The key features that draw CCLs together into a single entity are monomorphism, slight hypercellularity, and an overgrowth replacement growth pattern, in our opinion. With CCLs as the prototype, we wondered if there were similar precursor lesions with these 3 key morphologic features for most invasive carcinomas. We termed these lesions, regardless of the cytologic features, monomorphic epithelial proliferations (MEPs) to divest ourselves of any presumed risk associations and sidestep the terminology morass associated with CCLs, flat epithelial atypia, and flat and clinging DCIS.
The goals of this study were to characterize MEPs from the perspective of the potential precursor lesion to most invasive carcinomas and evaluate whether there was a relationship between MEPs and initial or IBF carcinomas. To facilitate our study of MEPs, we used the rim of tissue near the margin of initial excision specimens in patients in whom IBF developed, concentrating on the subset of patients with negative margins.
