Histological correlation of mammographically detected microcalcifications in stereotactic core biopsies

The aims of this study were to assess the value of specimen radiographs of stereotactic core biopsy, the usefulness of measuring size of calcifications on tissue sections, whether demonstration of calcifications in tissue sections alters the pathological diagnosis when specimen radiograph demonstrates calcifications, and to correlate these assessments with diagnostic outcome. A total of 301 core biopsies from 266 women with 274 mammographically suspicious areas of calcifications were examined. Core biopsies (five cores per procedure) were obtained stereotactically using a 14-gauge needle in an automated Biopty gun. Prior to processing of the tissue, 214 core biopsy specimens from 193 women with 197 lesions were radiographed. Of the 301 core biopsies, 56 (19%) were diagnosed as malignant, 15 (5%) were diagnosed as atypical ductal hyperplasia and 230 (76%) contained benign breast tissue. Of the core biopsies diagnosed as benign, 160 (70%) had specimen radiography prior to processing. Of these, 109 (69%) core biopsies showed calcifications on specimen radiographs. In 96 (88%) of these core biopsies, calcifications measuring > 100 microm were found on the initial tissue sections. In 11 (10%) further deeper sections were required to detect calcifications > 100 microm; however, this did not result in a change of the pathological diagnosis. Two of the 109 (1.8%) "benign" core biopsies, which contained tissue calcifications > 100 microm and at that time were considered representative of the mammographic lesion, have had a malignant outcome on clinical and mammographic follow-up ranging from 2.4 to 7.5 years. Of the 51 (31%) core biopsies where calcifications were not seen on specimen radiographs, histological calcifications were not found in 34 (67%) core biopsies, whereas in 17 (33%) core biopsies, calcifications measuring < 100 microm were found. All of these core biopsies were considered non-diagnostic and therefore not representative of the lesion targeted. Five (9.8%) of these cases had a malignant outcome with either immediate rebiopsy or excision. Accurate diagnosis of all mammographic lesions requires radiological-pathological correlation. This study shows that the presence of calcifications on the specimen radiograph and the demonstration of tissue calcifications > 100 microm are an essential and highly reliable part of core biopsy assessment for mammographically "suspicious" calcifications. Nevertheless, lesions with "highly suspicious" calcifications on mammography should be considered for excision even if the core biopsy diagnosis is benign and calcifications > 100 microm are present.     

Predictors of invasive breast cancer in mammographically detected microcalcification in patients with a core biopsy diagnosis of flat epithelial atypia, atypical ductal hyperplasia or ductal carcinoma in situ and recommendations for a selective approach to sentinel lymph node biopsy

15±30% of malignancies detected through screening programs are ductal carcinoma in situ (DCIS), and the majority of DCIS cases present in the form of mammographic microcalcification. This study was performed in order to determine the value of features in predicting invasive disease in patients with mammographic calcification and to help determine which patients (with, Core Needle Biopsy-diagnosed DCIS) are the most appropriate candidates for Sentinel Lymph Node (SLN) biopsy. The original aspect of this study was to select patients with mammographic microcalcification but without an associated mass. The factor that we identified to be associated with invasive disease at final surgical excision was the presence of necrosis at core histology. SLN biopsy or complete axillary lymph node dissection was performed in 22 (40%) patients of whom only one (4.5%) had a micrometastasis. Further larger studies are needed to see if it would be interesting to propose a SLN biopsy in case of necrosis on CNB-diagnosed DCIS with microcalcifications but not associated with a mass.     

Atypical ductal hyperplasia diagnosis by directional vacuum-assisted stereotactic biopsy of breast microcalcifications. Considerations for surgical excision

In 824 patients who underwent directional vacuum-assisted biopsies (DVABs) of breast microcalcifications, 61 (7.4%) showed atypical ductal hyperplasia (ADH). The 42 who subsequently underwent excision were the subjects of this study. Cases were evaluated for the mammographic characteristics of the lesion, the percentage of lesion removed according to mammography, and histologic findings (including number of large ducts and/or terminal duct-lobular units involved with ADH) in DVAB specimens. Pathologic findings in the surgical specimens in the area of the biopsy site also were recorded. In the DVAB specimens, ADH was confined to an average of 1.5 large ducts or lobular units and was associated with microcalcifications in all of the patients. Surgical specimens showed ADH in 15 cases, no residual lesion in 24 cases, and ductal carcinoma in situ in 3 cases. We found that microcalcifications that contain ADH in less than 3 lobules or ducts and/or that are removed completely by DVAB do not reveal higher-risk lesions on excision; thus, removal is unnecessary. When assessing microcalcifications with ADH, clinicians should consider the percentage of microcalcifications removed by DVAB and the extent of lobular involvement to better assess the need for excision.     

Atypical breast lesions: a challenging pathological diagnosis and an uncertain malignant potential

Atypical epithelial breast lesions are a heterogeneous group of entities, the diagnosis of which can be challenging. In this review, we discuss the wide spectrum of atypical epithelial breast proliferations including atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), flat epithelial atypia (FEA), atypia in a papilloma, atypical microglandular adenosis, apocrine atypia and post neo-adjuvant chemotherapy associated atypia. We aim to review the histologic diagnostic criteria for these entities, with an emphasis on the salient morphologic features and differential diagnoses to consider, in order to provide a comprehensive and practical guide to their diagnosis.     

Atypical ductal hyperplasia and ductal carcinoma in situ of the breast associated with perineural invasion

Perineural invasion is a histologic feature usually diagnostic of invasion in malignancies. In the breast, however, it has been associated with benign lesions such as sclerosing adenosis (SA), complex sclerosing lesion/radial scar (CSL/RS), and ductal carcinoma in situ (DCIS). This article describes perineural invasion associated with atypical ductal hyperplasia (ADH), florid hyperplasia without atypia (FH), and DCIS. All cases with a diagnosis of perineural invasion were selected from a series of 10,000 breast consult cases. Invasive mammary carcinomas were excluded. Fourteen cases of perineural invasion were found and associated with the following diagnoses: ADH (5), DCIS (3), FH (5), and ductal adenoma (1). Nine cases developed in CSL/RS, 4 cases in SA, and 1 case in a previous biopsy site of ductal adenoma; lesions were all less than 3 mm. The glands involving nerves showed cytologic and architectural features of the adjacent ADH, DCIS, and FH. Immunostaining for protein gene product (PGP) 9.5 marked nerves, and smooth muscle actin antibody highlighted the myoepithelial cells around glands. Perineural invasion seen in association with DCIS and ADH, in a background of CSL/RS and SA, may pose difficulty in diagnosis, especially in small biopsy specimens. It should be assessed with care to avoid misinterpretation as invasive mammary carcinoma.     

Atypical ductal hyperplasia in breast core needle biopsies. Correlation of size of the lesion, complete removal of the lesion, and the incidence of carcinoma in follow-up biopsies.

We reviewed the results of all breast core needle biopsies with a diagnosis of atypical ductal hyperplasia (ADH) or atypia not otherwise specified and subsequent excisional biopsies for a 50-month period and correlated the results. Of 3,026 biopsies, 216 were diagnosed as ADH or atypia not otherwise specified, and subsequent resection was available for 105. After review, 95 qualified as ADH. Subsequent resection showed ductal carcinoma in situ (DCIS) in 13 excisions, ADH in 31, lobular carcinoma in situ in 6, and benign proliferative lesions in the remaining 45. In none of the 8 biopsies in which DCIS was found and radiographs were available for review was the radiographic lesion entirely removed. For comparison, the incidence of carcinoma in resections done for a diagnosis of DCIS, low or intermediate grade (solid, cribriform, or micropapillary type), on core needle biopsy was significantly greater (8 of 10 cases). However, the size of the lesions diagnosed as carcinoma also was significantly greater than that of the lesions diagnosed as ADH, and in none of the 8 biopsies with DCIS at excision was the lesion entirely removed at the time of biopsy. The incidence of carcinoma in excisional biopsies done for a diagnosis of ADH in core needle biopsies in our institution is relatively low, while the incidence of ADH is relatively high. Possible reasons for this include total removal of small lesions at the time of biopsy and use of the diagnostic term ADH for lesions that are not associated with coexistent DCIS.     

Mucin extravasation in breast core biopsies – clinical significance and outcome correlation

Aims:  To document the spectrum of lesions associated with mucin extravasation (ME) in breast core biopsy specimens, and to correlate with open surgical excisions.
Methods and results:  Thirty-nine lesions in 37 women with ME on core biopsies constituted the study group. Fibrocystic change (FC), atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) were found in 21 (53.8%), 13 (33.3%) and four (10.3%) core biopsy specimens, respectively, with one (2.6%) consisting only of mucin pools. Except for the latter, all disclosed mucocoele-like lesions (MLL) accompanying ME. Columnar cell lesions (CCL) were frequently observed (84.6%). On open biopsy, three cases underdiagnosed on core biopsy included FC that later disclosed ADH; one ADH lesion on core later upgraded to DCIS; and a case of mucin pools that revealed mucinous carcinoma on excision. The extent of CCL on core biopsy appeared to predict sinister lesions on open excision. For calcified lesions that were completely removed on core biopsy, there were no malignant lesions discovered on open excision that had not already been diagnosed preoperatively.
Conclusions:  ME and MLL on core biopsy warrant close radiological–pathological correlation. When the entire radiological abnormality has been removed with large core mammotome biopsy specimens, surgery may potentially be avoided in histologically benign lesions, although such an approach requires further validation.     

Improved reporting methods for atypia and atypical ductal hyperplasia in breast core needle biopsy specimens. Potential for interlaboratory comparisons.

The incidence of atypia and atypical ductal hyperplasia (ADH) in breast core needle biopsies varies widely (900%). I sought to identify methods to reduce the dependence of this measure on variability in the patient population. The results of all breast core needle biopsies with a diagnosis of ADH or atypia not otherwise specified for a 50-month period were reviewed. These were separated into different groups by age, and the variability of different reporting methods was compared. Of 3,026 cases, 216 were diagnosed as ADH or atypia not otherwise specified. The overall incidence of atypia by age group varied significantly from 0.029 to 0.10. The variability was reduced when atypia was expressed in relation to ductal carcinoma in situ (range, 1.0-2.1) or fibrocystic changes (range, 0.15-0.28). However, variability by age was the least when atypia was expressed in relation to the number of cases performed for calcifications (range, 0.13-0.17). Variability in atypia rates associated with age is reduced significantly when atypia is expressed in relation to the number of biopsies done for calcifications. This method of reporting atypia may allow interlaboratory comparisons with less dependence on the characteristics of the patient population.     

A comparative analysis of core needle biopsy and fine-needle aspiration cytology in the evaluation of palpable and mammographically detected suspicious breast lesions

The present study was undertaken to compare the efficacy of needle core biopsy (NCB) of the breast with fine-needle aspiration cytology (FNAC) in breast lesions (palpable and non-palpable) in the Indian set-up, along with the assessment of tumor grading with both the techniques. Fifty patients with suspicious breast lesions were subjected to simultaneous FNAC and ultrasound-guided NCB following an initial mammographic evaluation. Cases were categorized into benign, benign with atypia, suspicious and malignant groups. In cases of infiltrating duct carcinomas, grading was performed on cytological smears as well as on NCB specimens. Both the techniques were compared, and findings were correlated with radiological and excision findings. Out of 50 cases, 18 were found to be benign and 32 malignant on final pathological diagnosis. Maximum number of patients with benign diagnosis was in the fourth decade (42.11%) and malignant diagnosis in the fourth as well as fifth decade (35.48% each). Sensitivity and specificity of mammography for the diagnosis of malignancy was 84.37% and 83.33%, respectively. Sensitivity and specificity of FNAC for malignant diagnosis was 78.15% and 94.44%, respectively, and of NCB was 96.5% and 100%, respectively. But NCB had a slightly higher specimen inadequacy rate (8%). NCB improved diagnostic categorization over FNAC by 18%. Tumor grading in cases of IDC showed high concordance rate between NCB and subsequent excision biopsy (94.44%) but low concordance rate between NCB and FNAC (59.1%). NCB is superior to FNAC in the diagnosis of breast lesions in terms of sensitivity, specificity, correct histological categorization of the lesions as well as tumor grading.     

Lobular in situ neoplasia and columnar cell lesions: diagnosis in breast core biopsies and implications for management

Histopathologists are encountering intra-lobular epithelial proliferations more frequently in core biopsies taken from lesions identified in mammographic breast screening programmes. In particular, columnar cell lesions are increasingly being seen in core biopsies taken for the histological assessment of mammographically detected microcalcifications. The morphological features of lobular neoplasia are relatively well known, but columnar cell lesions, particularly forms with atypical features, are less widely recognised. The biological and clinical significance of both of these intra-lobular processes is controversial, (1) as indicators of adjacent malignancy when encountered in core biopsy, (2) the relative risk conferred of development of subsequent malignancy, and (3) their precursor behaviour. For this reason, the optimal clinical management of these lesions, particularly when encountered on core biopsy, is unclear. This review provides an update on the histological diagnosis of lobular neoplasia and columnar cell lesions and outlines recent clinico-pathological and molecular findings with discussion on clinical management.     

Comparison of pathological and biological features of symptomatic and mammographically detected ductal carcinoma in situ of the breast.

To determine whether the ductal carcinoma in situ (DCIS) detected mammographically or presenting clinically is the same or differs, pathological and biological (c-erbB-2 and p53 detection) features of 79 cases of pure DCIS, 5 cases with microinvasion and 8 cases with 1 to 2 mm of invasion, all detected by mammography, have been compared with 59 cases of pure DCIS, 8 cases with microinvasion and 7 cases with 1 to 2 mm invasion, all of which presented clinically. Half of the mammographically detected group were smaller than 20 mm, and there was a higher incidence of these being low grade, whereas 30% of the symptomatic cases were smaller than 20 mm, and more of this group were larger than 50 mm. For the pure DCIS, there were less high-grade and more intermediate-grade cases in the mammographically detected group, although the incidence of low grade was similar between the two groups. There were more cases with a micropapillary pattern in the symptomatic group. C-erbB-2 protein was detected in 42% of the mammographically detected cases, whereas 59% of the symptomatic cases had c-erbB-2 reactivity. P53 detection was similar for both groups (33.0% and 37.0%). There were more symptomatic cases with invasion, and these were predominantly high grade, whereas the mammographically detected cases were both high and intermediate grade. Twelve of the 15 symptomatic cases with invasion expressed c-erbB-2, in comparison with 4 of the 13 mammographically detected cases, with half of the high-grade lesions in the latter group being negative. This study has shown that although there is overlap of pathological and biological features between DCIS presenting clinically and that detected mammographically, there can be differences in extent, grade, and invasion. The impact of this, however, can be determined only by clinical follow-up.     

Grading of atypia in nevi: correlation with melanoma risk.

Nevi with architectural disorder and cytologic atypia of melanocytes (NAD), aka "dysplastic nevi," have varying degrees of histologic abnormalities, which can be considered on a spectrum of grades of atypia. Somewhat controversial and subjective criteria have been developed for grading of NAD into three categories "mild," "moderate," and "severe." Grading involves architectural and cytological features, which often correlate with each other. Architectural criteria were intraepidermal junctional extension beyond any dermal component, complex distortion of rete ridges, and dermal fibrosis. Cytological criteria were based on nuclear size, dispersion of chromatin, prominence of nucleoli, hyperchromasia and variation in nuclear staining. Few tests have been made of the relationship between specific grades of atypia and patient risk for melanoma. Retrospective review of pathology reports was performed on 20,275 nevi examined between 1989 and 1996. From the total, 6,275 were diagnosed as NAD, which were in 4,481 patients. These patients were divided into those whose worst NAD was mild (2,504), moderate (1,657), or severe (320). Review of accession data revealed that a personal history of melanoma was present in 5.7% of patients with mild, 8.1% with moderate, and 19.7% with severe atypia. The male/female ratios were similar in each group. In the three groups, the mean ages of men were similar and of women were similar, but the mean age of men tended to be 6-11 yrs. older than women in each group. Family histories of melanoma were not considered. The odds ratio as a measure of association between NAD and personal history of melanoma, shows an odds ratio of 4.08 (2.91-5.7) for NAD-severe versus NAD mild, odds ratio 2.81 (2-3.95) for NAD-severe versus NAD-moderate and odds ratio 1.45 (1.13-1.87) for NAD moderate versus NAD-mild. These data show that the probability of having personal history of melanoma, for any given NAD patient, correlates with the NAD grade. Likewise, the risk of melanoma is greater for persons who tend to make nevi with high grade histological atypia.     

Comparison of fine needle aspiration cytology and needle core biopsy in the diagnosis of radiologically detected abdominal lesions

AIMS: To compare the sensitivity and specificity of percutaneous fine needle aspiration (FNA) cytology and needle core biopsy (NCB) in the diagnosis of suspected intra-abdominal tumours. METHODS: One hundred and forty one consecutive patients who underwent radiologically guided combined FNA/NCB of abdominal lesions over a four year period were reviewed. The diagnostic accuracy of both techniques and the value of rapid staining and assessment of cytological preparations were assessed. RESULTS: FNA cytology and NCB identified 111 of 129 (86%) and 104 of 129 (80.6%) malignant lesions, respectively; in combination, the sensitivity increased to 90.7%. The diagnostic specificity was 100% for both methods, although one case of phaeochromocytoma was misinterpreted as undifferentiated carcinoma on biopsy. More accurate tumour subtying was possible in two cases with FNA and four cases on NCB. The series included 12 benign lesions, of which 11 and nine were accurately identified on FNA and NCB, respectively. Two specific benign diagnoses (Budd-Chiari syndrome and hepatic infarct) were made only on biopsy. The use of rapid assessment cytology preparations ensured that appropriate samples were submitted for microbiology in three liver abscesses, and provided an accurate cytological diagnosis at the time of the procedure in 103 of 141 (73%) cases. None of the patients suffered biopsy related complications. CONCLUSIONS: FNA cytology is more sensitive and accurate than NCB in the diagnosis of abdominal lesions, and also offers more rapid diagnosis. However, the combination of these sampling techniques increases diagnostic sensitivity and occasionally provides more accurate classification of tumours and benign lesions. The techniques should be considered complementary in the investigation of abdominal lesions.     

Atypical ductal hyperplasia of the breast: clonal proliferation with loss of heterozygosity on chromosomes 16q and 17p.

AIMS--To determine if allelic loss on chromosomes 16q and 17p, commonly encountered in in situ and invasive ductal carcinomas, is present in atypical ductal hyperplasia (ADH); to determine whether ADH is a neoplastic (clonal) or hyperplastic (polyclonal) proliferation. METHODS--Fourteen cases of ADH were examined for allele loss at loci on chromosome 16q and 17p using a microdissection technique, polymorphic DNA markers and the polymerase chain reaction (PCR). RESULTS--Loss of heterozygosity (LOH) was detected in five of nine informative cases on chromosome 16q at the microsatellite D16S413 and two of eight informative cases on chromosome 17p at D17S796. CONCLUSIONS--The incidence of LOH at these loci is similar to that previously observed in ductal carcinoma in situ and in invasive ductal carcinoma. Because of the nature of the technique used, our findings also demonstrate that ADH is a monoclonal, and hence, neoplastic proliferation rather than a hyperplastic (polyclonal) condition as its name suggests. There is thus a case for including ADH, as presently defined, within the spectrum of ductal carcinoma in situ.     

Lobulocentricity of breast hypersecretory hyperplasia with cytologic atypia: infrequent association with carcinoma in situ

Intracytoplasmic and extracytoplasmic features of secretion, similar to lactational changes, occasionally are seen in the nonparous human breast, usually are lobulocentric, and often have aberrant cytologic and nuclear changes. In these "hypersecretory hyperplasias" (HHs; 38 women) there is bubbly cytoplasm with irregular apical cytoplasmic and/or nuclear protrusions. In a review of 138 HH cases the following additional associated changes were found: nuclear atypia (HHA, 22 women), atypical ductal hyperplasia (ADH-HH, 24 women), and ductal carcinoma in situ (DCIS-HH, 54 women). A diagnosis of DCIS-HH requires involvement of true duct(s) and of several contiguous lobular units, emphasizing the importance of extent and overall size and similar cytology and histologic arrangement of intercellular spaces indicating a homogeneous cell population. Cases of HH regularly are characterized as having adjacent and nearby lobular units with quite diverse cytologic patterns. The major impact of this study is to recognize that HHA may be regarded as having uncertain significance when found alone in the usual presentation in a single unit, but that formally defined ADH and/or DCIS may be locally present.     

Tubular carcinoma and grade 1 (well-differentiated) invasive ductal carcinoma: comparison of flat epithelial atypia and other intra-epithelial lesions

The distinction between tubular carcinomas (TC) and invasive well-differentiated (grade 1) ductal carcinoma (IDC) is important given treatment and prognostic differences. Studies have described a strong association between flat epithelial atypia (FEA) and TC. The incidence of FEA associated with grade 1 IDC is not well established. The aim of the present study was to assess morphology and intra-epithelial lesions between 14 TC and 18 grade 1 IDC matched for size. Of 14 TC, eight (57%) had associated FEA, seven (50%) had micropapillary atypical ductal hyperplasia (ADH), three (21%) had low nuclear grade ductal carcinoma in situ (DCIS), and four (29%) had lobular neoplasia. Notably, only two of 18 (11%) grade 1 IDC had associated FEA. Three of 18 (16%) grade 1 IDC had ADH, two (11%) had lobular neoplasia, and seven (39%) had DCIS. All tubular carcinomas were estrogen receptor (ER) positive and negative for Her-2/neu overexpression. All grade 1 IDC were ER positive but 5% also overexpressed Her-2/neu. Axillary lymph node metastasis was present in 11% of grade 1 IDC and absent in TC. A strong association was found between TC, FEA, and micropapillary ADH, which may reflect a biological progression. Despite matching for tumor size, grade 1 IDC have a higher incidence of lymph node metastasis and may have Her-2-neu overexpression compared to TC.     

Arteriolar lesions in renal transplant biopsies: prevalence, progression, and clinical significance

Arteriolar hyalinosis in kidney transplants is considered the histopathologic hallmark of chronic calcineurin inhibitor (CNI) toxicity. However, the lesion is not specific. We assessed prevalence, progression, and clinical significance of arteriolar lesions in 1239 renal transplant sequential protocol biopsy samples and 408 biopsy for cause samples in 526 patients. Associations between arteriolar lesions and presumed risk factors, concomitant histopathologic lesions, demographic factors, and graft function were evaluated. The frequency of arteriolar lesions was stable during the first 2 years after transplantation, and increased thereafter (14.8% at 6 months versus 48.6% at >2 years; P < 0.0001). We were unable to find associations with diabetes, hypertension, or CNI therapy. However, patients with early arteriolar lesions received grafts from older donors (mean ± SD age, 54.4 ± 13.4 years versus 43.1 ± 16.6 years; P < 0.0001), and had inferior graft function (estimated glomerular filtration rate 55 ± 21 mL/min versus 63 ± 24 mL/min at 6 weeks, 53 ± 19 mL/min versus 60 ± 23 mL/min at 1 year, and 49 ± 19 mL/min versus 59 ± 22 mL/min at 2 years; P < 0.05). Evaluation of late biopsy samples from patients not receiving CNI therapy revealed a high prevalence of AH without clear-cut identifiable underlying cause. Reproducibility of arteriolar lesions was at best moderate (κ ≤ 0.62). Sampling error in sequential biopsy samples was frequent. In conclusion, in samples from sequential protocol biopsies and biopsies for cause in individual patients, arteriolar lesions in renal transplants not only increase over time without being specific for CNI toxicity but are affected by sampling error and limited reproducibility.