Surgical excision of radial scars diagnosed by core biopsy may help predict future risk of breast cancer.

Radial scars (RS's) are benign breast lesions known to be associated with carcinomas and other high-risk lesions (HRL's). The upgrade rate to carcinoma after core biopsy revealing RS is 0-40 %. We sought to determine the outcomes of RS with and without HRL diagnosed by core biopsy. Patients who underwent core biopsy revealing RS without carcinoma at our institution between 1/1996 and 11/2012 were identified from a surgical pathology database. Retrospective chart review was utilized to classify patients as RS-no HRL or RS-HRL. HRL was defined as ADH, LCIS, and/or ALH. We determined upgrade rate to carcinoma at surgical excision, and upgrade to HRL for RS-no HRL patients. Univariate analysis was performed to identify risk factors for upgrade in RS-no HRL patients. 156 patients underwent core biopsy revealing RS, 131 RS-no HRL (84 %), and 25 RS-HRL (16 %). The overall rate of upgrade to invasive carcinoma was 0.8 % (1/124). 1.0 % (1/102) of RS-no HRL and 13.6 % (3/22) of RS-HRL patients were upgraded to DCIS (P = 0.0023). The upgrade of RS-no HRL to HRL at excision was 21.6 % (22/102). By univariate analysis, RS-no HRL with radiologic appearance of a mass/architectural distortion had a significantly higher rate of upgrade to HRL or carcinoma compared with calcifications (P = 0.03). Excision of RS to rule out associated invasive carcinoma is not warranted, given a <1 % rate of upgrade at excision. However, excision to evaluate for non-invasive cancer or HRL may be considered to help guide clinical decision-making about use of chemoprevention.

A pilot study evaluating shaved cavity margins with micro-computed tomography: a novel method for predicting lumpectomy margin status intraoperatively.

Microscopically clear lumpectomy margins are essential in breast conservation, as involved margins increase local recurrence. Currently, 18-50% of lumpectomies have close or positive margins that require re-excision. We assessed the ability of micro-computed tomography (micro-CT) to evaluate lumpectomy shaved cavity margins (SCM) intraoperatively to determine if this technology could rapidly identify margin involvement by tumor and reduce re-excision rates. Twenty-five SCM from six lumpectomies were evaluated with a Skyscan 1173 table top micro-CT scanner (Skyscan, Belgium). Micro-CT results were compared to histopathological results. We scanned three SCM at once with a 7-minute scanning protocol, and studied a total of 25 SCM from six lumpectomies. Images of the SCM were evaluated for radiographic signs of breast cancer including clustered microcalcifications and spiculated masses. SCM were negative by micro-CT in 19/25 (76%) and negative (≥2 mm) by histopathology in 19/25 (76%). Margin status by micro-CT was concordant with histopathology in 23/25 (92%). Micro-CT overestimated margin involvement in 1/25 and underestimated margin involvement in 1/25. Micro-CT had an 83.3% positive predictive value, a 94.7% negative predictive value, 83.3% sensitivity, and 94.7% specificity for evaluation of SCM. Evaluation of SCM by micro-CT is an accurate and promising method of intraoperative margin assessment in breast cancer patients. The scanning time required is short enough to permit real-time feedback to the operating surgeon, allowing immediate directed re-excision.

Nipple-sparing mastectomy: lessons from ex vivo procedures.

Moderate size series have reported successful nipple-sparing mastectomy using a variety of surgical techniques. This study aimed to understand which aspects of these techniques are safe, necessary, and successful. Eight skin-sacrificing mastectomy specimens were used as ex vivo models of nipple-sparing mastectomy. After inking the resection margins of the specimen, the skin ellipse was elevated in the subcutaneous plane using a scalpel. The retroareolar breast tissue was taken as a margin specimen. The nipple was inverted and the nipple core removed. The hollowed-out nipple remnant (which would have remained with the patient in a true nipple-sparing mastectomy) was submitted for confirmatory histopathologic analysis. Precise identification of the duct margin directly beneath the nipple proved difficult once the duct bundle had been divided. Successful retroareolar margin identification was achieved by grasping the duct bundle with atraumatic forceps as soon as it became exposed. A cut made below and above the forceps resulted in a full cross-section of the duct bundle. Nipple core tissue was difficult to excise in one piece and cannot be oriented, thus complete evaluation of the specimen required examination of multiple levels. Histologic artifacts caused by freezing may be present in frozen sections of nipple core and retroareolar margin specimens; the impact of such changes must be considered when developing institutional protocols for this procedure. Evaluation of the hollowed-out nipple revealed that the inverted nipple must be substantially thinned to remove all ducts. Modification of technique resulted in more complete excision of duct tissue. This series of ex vivo procedures provides information that can be used to modify surgical and pathologic techniques for nipple-sparing mastectomy. When performing nipple-sparing mastectomy for breast cancer, these measures may be advisable as complements to careful patient selection.

Solid papillary ductal carcinoma in situ versus usual ductal hyperplasia in the breast: a potentially difficult distinction resolved by cytokeratin 5/6.

The solid papillary variant of ductal carcinoma in situ is an uncommon entity, which usually presents in the seventh or eighth decade and may be associated with invasive mucinous carcinoma. Solid papillary ductal carcinoma in situ (SP-DCIS) shares many morphological features with usual ductal hyperplasia (UDH) involving a papilloma: papillary architecture, solid growth, cellular streaming, and low-grade nuclear features. These similarities can make the distinction between these 2 entities challenging. Recent studies have demonstrated that immunohistochemical staining for cytokeratin 5/6 can distinguish UDH from conventional forms of ductal carcinoma in situ. Most of the epithelial cells of UDH express cytokeratin 5/6, but the tumor cells of ductal carcinoma in situ do not. We tested the hypothesis that the results of staining for cytokeratin 5/6 can distinguish UDH from the solid papillary variant of ductal carcinoma in situ. Immunohistochemical staining of 14 cases of SP-DCIS and 9 cases of UDH (4 involving papillomas) was performed using cytokeratin 5/6 antibody clone D5/16 B4. Strong cytoplasmic or membrane staining was considered positive. The hyperplastic cells in all cases of UDH showed strong staining for cytokeratin 5/6. The percentage of positive cells ranged from 50% to 80%. None of the SP-DCIS tumor cells stained for cytokeratin 5/6; however, many cases did show staining of occasional entrapped, benign epithelial, and myoepithelial cells. We conclude that the absence of strong cytokeratin 5/6 expression by SP-DCIS distinguishes it from its morphological mimic, UDH. Pathologists must guard against misinterpreting SP-DCIS as UDH in those cases in which the carcinoma cells engulf cytokeratin 5/6-expressing residual, native epithelial cells.

A brief historical perspective on the pathology of the breast: from Cheatle to Azzopardi and beyond.

The modem pathological study of disorders of the breast begins with the intraoperative macroscopical examinations of such late-nineteenth-century American and British surgeons as Drs. John Collins Warren, Joseph Colt Bloodgood, and Sir George Lenthal Cheatle. Technical advances in the fields of microscopy and histology led to a shift in the nature and conduct of pathological studies in the first part of the twentieth century. Microscopical examination became the primary method of study, and pathologists assumed the leading role in this line of research. With the studies of Drs. Frank W. Foote, Fred W. Stewart, and Arthur Purdy Stout, pathologists began to explore the territory of breast pathology in detail, describing the microscopical features of breast lesions and developing theories regarding their pathogenesis. The spread of the use of biopsy procedures to establish diagnoses led pathologists of the mid-twentieth century to assume the new role of clinical diagnostician. Exemplified by the work of Dr. John G. Azzopardi, pathological research of the latter half of the twentieth century came to emphasize microscopical diagnostic criteria and differential diagnosis. With ever more sophistication and increasingly powerful techniques, this trend continues to this day.

Epithelial proliferations of ductal type.

The diagnosis of ductal proliferations requires analysis of both architectural and cytological features. Architectural characteristics of conventional ductal hyperplasia include persistence of the duct lumen as peripheral, crescent shaped spaces; streaming of cells; formation of irregular, slit-like fenestrations; and "maturation." Hyperplastic ductal cells exhibit indistinct cell borders, irregular placement of nuclei, irregular nuclear shapes, granular chromatin, and uniform small nucleoli. The cells do not show polarization or dishesion. Low-grade ductal carcinoma in-situ exhibits both architectural and cytological atypicality. The architectural atypicality takes two forms: the formation of cribriform spaces or their variants and the regular arrangement of cells. The former reflects the polarization of the carcinoma cells and the latter their dishesion. Cytological atypicality includes distinct cell borders; smoothly contoured, oval or round nuclei; homogeneous chromatin; and inconspicuous nucleoli. Atypical ductal hyperplasia shows low-grade cytological atypicality but lacks the architectural atypicality of ductal carcinoma in situ. Proliferations lacking cytological atypicality do not merit the diagnosis of atypical ductal hyperplasia whatever their architectural characteristics. Although not usually necessary, immunohistochemical staining for high molecular weight keratin can help resolve difficult cases. Current evidence does not support the belief that conventional ductal hyperplasia represents an obligate precursor to ductal carcinoma in situ.

Noninvasive papillary proliferations.

The diagnosis of noninvasive papillary tumors begins with categorization of the lesions as macropapillary or micropapillary. Macropapillary lesions include papilloma, papillary carcinoma, and papilloma harboring carcinoma. Papillomas consist of a few broad fronds, abundant stroma, and an epithelium containing both luminal and myoepithelial cells. Papillary carcinomas have many irregular fronds, small amounts of stroma, and a uniform population of malignant glandular cells. Papillomas can give rise to both conventional ductal hyperplasia and carcinomas. One analyzes proliferations on the surface of a papilloma as one would analyze those in a duct. Proliferations within the stalk of a papilloma require especially careful attention; one must observe large masses of cells demonstrating both cytological and architectural atypicality and devoid of intervening stroma to make the diagnosis of low-grade ductal carcinoma in-situ involving the stalk of a papilloma. Micropapillary proliferations represent either ductal hyperplasia or ductal carcinoma in situ. The former shows slight dilatation of ducts, micropapillae of similar size and shape, maturation of cells, lack of dishesion and necrosis, and lack of cytological atypicality. Micropapillary ductal carcinoma in situ exhibits extreme dilatation of ducts and lobules, micropapillae varying in size and shape, lack of maturation, dishesion and necrosis, and cytological atypicality.

Pathologic response and long-term follow-up in breast cancer patients treated with neoadjuvant chemotherapy: a comparison between classifications and their practical application.

CONTEXT: Breast cancer is increasingly treated with neoadjuvant chemotherapy to improve surgical resectability and evaluate tumor response, which is assessed histopathologically. Several histopathologic classification systems have been previously described for assessment of treatment response. OBJECTIVES: To test performance in a side-by-side comparison of several histopathologic classification systems after neoadjuvant chemotherapy with clinical outcome. DESIGN: Sixty-two patients were enrolled in a randomized trial receiving sequential neoadjuvant chemotherapy with doxorubicin and paclitaxel. Histologic sections from the patients' tumors sampled before (core biopsy) and after treatment (excision or mastectomy) were reviewed. Histologic response was assessed following National Surgical Adjuvant Breast and Bowel Project protocol B18, Miller-Payne grading, Sataloff tumor and nodes, Residual Cancer Burden (RCB), and Residual Disease in Breast and Nodes (RDBN). Pathologic classification results were correlated with survival using Kaplan-Meier and Cox hazards regression with a median follow-up of 93 months. RESULTS: RDBN was associated with distant disease-free survival by univariate and multivariate analysis (P = .01 and .004, respectively), as were lymph node metastases (P = .02 and .01, respectively). Five patients (8%) had complete pathologic response after neoadjuvant chemotherapy, and none of them relapsed during the study period. Survival was shorter among patients with higher Residual Cancer Burden scores, but the associations were not significant. Miller-Payne grading and Sataloff tumor scores were not correlated with survival. CONCLUSIONS: Evaluation of breast specimens after neoadjuvant chemotherapy by the composite index RDBN correlates with long-term outcome. The residual disease in breast and nodes system is suitable for routinely processed pathology cases. This study confirms the importance of lymph node status after neoadjuvant chemotherapy and favorable outcome in patients with pathologic complete response.

Occult nipple involvement in breast cancer: clinicopathologic findings in 316 consecutive mastectomy specimens.

PURPOSE: Although breast-conserving surgery is a standard approach for patients with breast cancer, mastectomy often becomes necessary. Surgical options now include nipple-sparing mastectomy but its oncological safety is still controversial. This study evaluates frequency and patterns of occult nipple involvement in a large contemporary cohort of patients with the retroareolar margin as possible indicator of nipple involvement. PATIENTS AND METHODS: Three hundred sixteen consecutive mastectomy specimens (232 therapeutic, 84 prophylactic) with grossly unremarkable nipples were evaluated by coronal sections through the entire nipple and subareolar tissue. Extent and location of nipple involvement by carcinoma was assessed with the tissue deep to the skin as potential retroareolar en-face resection margin. RESULTS: Seventy-one percent of nipples from therapeutic mastectomies showed no pathologic abnormality, 21% had ductal carcinoma in situ (DCIS), invasive carcinoma (IC), or lymphovascular invasion (LVI), and 8% lobular neoplasia (lobular carcinoma in situ). Human epidermal growth factor receptor 2 amplification, tumor size, and tumor-nipple distance were associated with nipple involvement by multivariate analysis (P = .0047, .0126, and .0176); histologic grade of both DCIS (P = .002) and IC (P = .03), LVI (P = .03), and lymph node involvement (P = .02) by univariate analysis. Nipple involvement by IC or DCIS was identified in the retroareolar margin with a sensitivity of 0.8 and a negative predictive value of 0.96. None of the 84 prophylactic mastectomies showed nipple involvement by IC or DCIS. CONCLUSION: Nipple-sparing mastectomy may be suitable for selected cases of breast carcinoma with low probability of nipple involvement by carcinoma and prophylactic procedures. A retroareolar en-face margin may be used to test for occult involvement in patients undergoing nipple-sparing mastectomy.

Breast duct anatomy in the human nipple: three-dimensional patterns and clinical implications.

BACKGROUND: The anatomy of the nipple has become clinically relevant. Diagnostic techniques access the breast through nipple ducts and surgeons offer nipple-sparing mastectomy. There is variation in the number of ducts reported and little is known about the spatial location of ducts, their size, and their relationship to orifices on the surface. METHODS: Nipple specimens were taken from 129 consecutive mastectomies. Each was sectioned coronally into 3 mm blocks and one section was prepared from each block. The number of ducts and cross-sectional areas of nipple and duct 'bundle' were recorded. Three nipples were sectioned at 50 mum intervals and digitally reconstructed in three dimensions. RESULTS: The median number of ducts was 23 (interquartile range 19-28). Reconstructions and summary data from 25 nipples show a central duct bundle narrowing to form a 'waist' as the ducts enter breast parenchyma. A three-dimensional reconstruction focusing on one nipple tip demonstrated 29 ducts arising from 15 orifices. Beneath the skin, most ducts are very narrow, gradually becoming larger deeper within the nipple. CONCLUSIONS: This work demonstrates that many ducts share a few common openings onto the surface of the nipple, explaining the observed discrepancy between number of ducts and of orifices. Neither duct diameter nor position predicts whether a duct system will terminate close to the nipple or pass deeper into the breast. These new insights into nipple anatomy will be of use in considering the reliability of a ductal approach to diagnosis and in planning nipple-sparing mastectomy.

George Peters Award. Microscopic anatomy within the nipple: implications for nipple-sparing mastectomy.

BACKGROUND: Precise anatomical relationships between ducts and vasculature within the nipple remain unknown. This study investigated nipple microvessels and their position relative to ducts. METHODS: Nipple and duct bundle cross-sectional areas were measured in 48 specimens. Vessels located within the central duct bundle or within a peripheral rim were counted in 7 non-irradiated and 5 irradiated nipples. RESULTS: Mean nipple diameter was 11.1 mm and duct bundle diameter 5.2 mm. A 2-mm and a 3-mm peripheral rim of nipple tissue would result in complete duct excision in 96% and 87% of sections, respectively. Twenty-nine percent of vessels are located in the duct bundle. A 2-mm rim contains 50%; a 3-mm rim contains 66%. Similar proportions were seen in irradiated nipples. CONCLUSIONS: This study describes a strategy to balance duct removal with vascular preservation. Ducts can be excised leaving a rim of nipple tissue that contains a large proportion of microvessels.