Artifactual Displacement of Ductal Carcinoma In Situ (ADDCIS) (Toothpaste Effect): A Mimicker of Invasive Ductal Carcinoma.

Needle tract displacement is a recognized mimicker of invasive ductal carcinoma (IDC). Artifactual displacement of ductal carcinoma in situ (ADDCIS) unassociated with needle tracts may occur secondary to mechanical compression of breast specimens but has not been systematically studied. We identified 16 cases of ADDCIS unassociated with needle tract changes; the majority (75%) were internal referrals to the breast pathology service to rule out IDC, 19% were received as external diagnostic consultations to rule out IDC, and 6% were routine second review cases originally diagnosed as IDC at an outside hospital. The majority (62.5%) of ADDCIS occurred in lumpectomies, whereas 25% occurred in mastectomies and 12.5% in core biopsies. ADDCIS foci ranged from <1 to 5 mm; however, all ADDCIS spanning >4 mm demonstrated a linear pattern of displacement. In all cases, ADDCIS involved mammary stroma in a nonlobular distribution; in half, ADDCIS extended between benign lobules. Immunohistochemistry revealed no myoepithelial cells around the ADDCIS (n=7), adding to the concern for IDC. However, in contrast to most IDC, ADDCIS lacked stromal reaction and showed degenerative, smudged chromatin. None of the 9 patients with significant follow-up (mean, 7 y) developed metastasis. All received further local therapy for DCIS (5 radiation, 4 completion mastectomy); 1 received adjuvant systemic therapy (hormone therapy for contralateral IDC). In conclusion, ADDCIS mimics IDC, particularly given its permeative pattern and absence of myoepithelial cells. ADDCIS is most common in lumpectomies but can occur in mastectomies or core biopsies. Diagnostic clues include smudged nuclear chromatin, lack of stromal response, and linear pattern of displacement in larger lesions. The benign follow-up without systemic therapy supports our view that ADDCIS does not represent true IDC.

Liposarcomatous differentiation in malignant phyllodes tumours is unassociated with MDM2 or CDK4 amplification.

AIMS: Breast sarcomas are rare, usually occurring in the setting of malignant phyllodes tumour (MPT). Heterologous differentiation commonly resembles well-differentiated or pleomorphic liposarcoma. In extramammary sites, these subtypes have different biological behaviours and distinct genetic alterations: MDM2 and CDK4 amplification in well-differentiated liposarcoma, and polyploidy with complex structural rearrangements in pleomorphic liposarcoma. The aim of this study was to investigate foci resembling well-differentiated liposarcoma in MPT for MDM2 and CDK4 amplification. METHODS AND RESULTS: We evaluated the clinicopathological characteristics of MPTs received by the Vanderbilt Breast Consultation Service containing components resembling well-differentiated or pleomorphic liposarcoma. Cases with available tissue blocks were subjected to fluorescence in-situ hybridization with MDM2 and CDK4 probes. Thirty-eight MPTs with liposarcomatous components were available for review. The mean patient age was 49.8 years (range 26-84 years). In addition to well-differentiated liposarcoma, the following components were also present: high-grade undifferentiated sarcoma (n = 9; 23.7%), pleomorphic liposarcoma (n = 4; 10.5%), non-high-grade sarcoma not otherwise specified (n = 22; 57.9%), and malignant peripheral nerve sheath tumour-like (n = 2; 5.2%). Among 10 cases tested, none showed amplification of MDM2 or CDK4. CONCLUSIONS: This study examined molecular changes in the well-differentiated liposarcomatous components of MPT. Despite histological similarity to well-differentiated liposarcoma of soft tissues, liposarcomatous differentiation in MPT lacks the molecular phenotype characteristic of extramammary well-differentiated liposarcoma.

Continued observation of the natural history of low-grade ductal carcinoma in situ reaffirms proclivity for local recurrence even after more than 30 years of follow-up.

Opportunities to study the natural history of ductal carcinoma in situ are rare. A few studies of incompletely excised lesions in the premammographic era, retrospectively recognized as ductal carcinoma in situ, have demonstrated a proclivity for local recurrence in the original site. The authors report a follow-up study of 45 women with low-grade ductal carcinoma in situ treated by biopsy only, recognized retrospectively during a larger review of surgical pathology diagnoses and original histological slides for 26 539 consecutive breast biopsies performed at Vanderbilt, Baptist and St Thomas Hospitals in Nashville, TN from 1950 to 1989. Long-term follow-up was previously reported on 28 of these women. Sixteen women (36%) developed invasive breast carcinoma, all in the same breast and quadrant as their incident ductal carcinoma in situ. Eleven invasive breast carcinomas were diagnosed within 10 years of the ductal carcinoma in situ biopsy. Subsequent cases were diagnosed at 12, 23, 25, 29 and 42 years. Seven women, including one who developed invasive breast cancer 29 years after her ductal carcinoma in situ biopsy, developed distant metastasis, resulting in death 1-7 years postdiagnosis of invasive breast carcinoma. The natural history of low-grade ductal carcinoma in situ may extend more than four decades, with invasive breast cancer developing at the same site as the index lesion. This protracted natural history differs markedly from that of patients with high-grade ductal carcinoma in situ or any completely delimited ductal carcinoma in situ excised to negative margins. This study reaffirms the importance of complete margin evaluation in women treated with breast conservation for ductal carcinoma in situ as well as balancing recurrence risk with possible treatment-related morbidity for older women.

Intranodal papillary epithelial proliferations: a local process with a spectrum of morphologies and frequent association with papillomas in the breast.

Lymph nodes, particularly those draining in major anatomic sites like axilla, pelvis, and neck are potential sites for the occasional presence of ectopic tissue, usually representative of the organ being drained. Owing to the uncertainty surrounding the processes causing such findings, and particularly in the setting of lymph node dissection and sampling for cancer staging, intranodal epithelial inclusions, rare as they may be, might be fertile soil for overdiagnosis of metastatic disease. Intranodal papillary inclusions are particularly problematic and challenging because of their complex architecture that may easily mimic a metastasis. From the files of the Breast Consultation Service, Department of Pathology at the Vanderbilt University Medical Center in Nashville, we identified 6 cases in which histopathologic examination of axillary lymph nodes revealed intranodal papillary inclusions (papillary epithelial proliferations). One case showed atypical ductal hyperplasia, 1 showed low-grade ductal carcinoma in situ, and 1 showed usual ductal hyperplasia. The corresponding breast lesions were papillomas in 5 of 6 cases, 2 of which displayed atypical ductal hyperplasia, whereas 3 showed low-grade ductal carcinoma in situ. One case showed intermediate-grade invasive ductal carcinoma, and the associated intranodal papilloma lacked atypia. Our findings suggest that intranodal papillary proliferations are often, although not exclusively, associated with papillary and noninvasive breast neoplasms, hence highlighting the origin of these intranodal lesions as independent de novo nodal processes rather than metastatic deposits.

Clinicopathologic characteristics of carcinomas that develop after a biopsy containing columnar cell lesions: evidence against a precursor role.

BACKGROUND: Columnar cell lesions are frequently associated with atypical ductal hyperplasia, lobular neoplasia, and tubular carcinoma, and have been suggested as a precursor lesion for low-grade carcinomas. However, in long-term follow-up studies, columnar cell lesions are associated with only a slight increase in later breast cancer development. If columnar cell lesions are precursor lesions, one would expect subsequent cancers to develop at the same site as the biopsy and to be preferentially of low grade. The goal of this article is to review the clinical and pathologic features of carcinomas that develop after a diagnosis of columnar cell lesion to try to establish whether these lesions are precursors to low-grade invasive carcinoma. METHODS: The authors reviewed biopsies containing columnar cell lesions, using the criteria of Schnitt and Vincent-Salomon, from 77 women in the Nashville Breast Cohort who developed subsequent breast carcinoma. Clinicopathologic features including laterality, type, and grade of the subsequent cancer were recorded. RESULTS: Breast cancer developed a median of 11 years after initial biopsy. The median age at diagnosis was 60 years. The majority of invasive carcinomas were of no special type and of intermediate grade. Moreover, the carcinomas were as likely to occur in the contralateral breast as in the breast that was originally diagnosed with columnar cell lesion, regardless of columnar cell lesion subtype (P = .48). CONCLUSIONS: Carcinoma subsequent to columnar cell lesions may occur in either breast and tends to show a similar grade and type distribution as sporadic breast cancer. These findings argue against columnar cell lesions being a true precursor for low-grade invasive carcinoma.

Can we know what to do when DCIS is diagnosed?

Utilizing routine histopathologic parameters obtained from appropriately handled lumpectomy and mastectomy specimens, a rational therapeutic plan based on epidemiologic and outcome-based data can be devised for any patient diagnosed with ductal carcinoma in situ (DCIS). In order to make a sound decision when weighing the current treatment options for DCIS--which include excision alone, excision plus radiation, and mastectomy--the following are mandatory: 1) assurance of an accurate diagnosis, 2) assessment of DCIS size and grade, and 3) careful margin evaluation. Accurate grading of DCIS is critical, since high nuclear grade and the presence of necrosis are highly predictive of the inability to achieve adequate margins, of local recurrence, and of the probability of missed areas of invasion. Margin status is the single most important determinant of local control following breast conservation for DCIS; numerous studies have shown that as the margin width increases, the risk of local failure decreases. The pros and cons of irradiating conservatively treated patients with DCIS should be carefully weighed on a case-by-case basis. Despite the 20-year-old dogma that all patients treated with breast conservation should receive postoperative radiation, a subset of patients who can be successfully treated by excision alone has been identified.

Definitive diagnosis for high-risk breast lesions without open surgical excision: the Intact Percutaneous Excision Trial (IPET).

BACKGROUND: Open surgical excision (OSE) is generally recommended when image-guided core-needle breast biopsy demonstrates a high-risk lesion (HRL). We evaluated intact percutaneous excision (IPEX) with standard radiologic and histologic criteria for definitive diagnosis of HRL, particularly atypical ductal hyperplasia (ADH). The primary aim is to confirm criteria associated with <2% risk for upgrade to carcinoma, equivalent to risk associated with Breast Imaging Reporting and Data System (BI-RADS) 3 lesions, for which imaging surveillance is considered sufficient. METHODS: In a prospective trial, 1,170 patients recommended for breast biopsy at 25 institutions received IPEX with a vacuum- and radiofrequency-assisted device. ADH patients in whom the imaged lesion had been removed and the lesion adequately centered for definitive characterization were designated as the potential surgical avoidance population (PSAP) before OSE. Subsequent OSE specimen pathology was compared with IPEX findings. RESULTS: In 1,170 patients, 191 carcinomas and 83 (7%) HRL, including 32 ADH (3%), were diagnosed via IPEX. None of the 51 non-ADH HRL were upgraded to carcinoma on OSE (n = 24) or, if OSE was declined, on radiologic follow-up (n = 27). No ADH lesions meeting PSAP criteria (n = 10) were upgraded to carcinoma on OSE; 3 (14%) of 22 non-PSAP ADH lesions were upgraded to carcinoma on OSE. In summary, no upgrades to carcinoma were made in patients with non-ADH lesions who underwent IPEX or in ADH patients who had IPEX, met histologic and radiologic criteria, and underwent OSE or follow-up. CONCLUSION: IPEX combined with straightforward histologic and radiologic criteria and imaging surveillance constitutes acceptable management of image-detected HRL, including ADH.

Foamy cell angiosarcoma: a rare and deceptively bland variant of cutaneous angiosarcoma.

Cutaneous angiosarcoma can sometimes mimic other benign and malignant lesions, thereby presenting a difficult differential diagnosis. In the two cases of cutaneous angiosarcoma presented herein, extensive foamy cell alteration of tumor cells resembled a reactive xanthogranulomatous process. Foamy cell angiosarcoma is an unusual and deceptively benign morphologic variant of cutaneous angiosarcoma. Critical features for diagnosis include the presence of a deep, permeative, sometimes 'scaffolding' growth pattern and subtle areas of vascular formation.

Update on atypical epithelial hyperplasia and ductal carcinoma in situ.

Atypical ductal hyperplasia (ADH) as an indicator of increased risk for developing breast cancer is well established. Refinement in its molecular characterisation, especially as it relates to risk, continues to be challenging, largely because of its small and very focal nature. Also a challenge is appropriate management of ADH when present on core biopsy. Additional support for ductal carcinoma in situ (DCIS) as a precursor to invasive cancer, as well as recent molecular characterisation of DCIS are presented. The importance of margin assessment in cases of DCIS and the limited role for sentinel lymph node biopsy in this setting are reviewed.

Differential Diagnosis of Proliferative Breast Lesions.

The correct diagnosis of proliferations within the mammary terminal duct-lobular unit has paramount prognostic and therapeutic implications. Occasionally, the differential diagnosis of compact florid hyperplasia, atypical ductal hyperplasia, and low-grade ductal carcinoma in situ can be quite challenging, with seeming morphologic overlap. This article presents s conceptual and practical understanding of these processes and their impact on subsequent cancer risk, with the intention of assisting the practicing pathologist render accurate and clinically relevant diagnoses for this frequently encountered set of mammary epithelial lesions.

Histologic associations and long-term cancer risk in columnar cell lesions of the breast: a retrospective cohort and a nested case-control study.

BACKGROUND: Mammary columnar cell lesions with atypia have been receiving increased scrutiny in view of their association with atypical hyperplasia (AH) and carcinoma. However, the few retrospective outcome studies performed have failed to establish an increased risk for recurrence or carcinoma on long-term follow-up. METHODS: The authors evaluated the overall cancer risk for 1261 biopsies with columnar cell lesions (CCL) in 4569 women from the Nashville Breast Cohort who were biopsied between 1969 and 1988. On the basis of Schnitt and Vincent-Salomon's classification, they also classified 229 biopsies with CCL into 3 categories: without hyperplasia or atypia, with hyperplasia lacking atypia, and with atypia. By using a nested case-control design, they compared the risks of invasive cancer associated with these 3 categories. RESULTS: A 2- to 3-fold increase in the occurrence of AH in the presence of CCL versus in their absence (P< .005) was observed. Relative risk of invasive breast cancer for women with both AH and CCL compared with those with AH alone did not differ significantly (risk ratio [RR]=1.55; P= .29). The presence of CCL alone was associated with a mild increase in the overall cancer risk (RR=1.47; P= .05). In the nested case-control study, no significant risk difference was observed among the 3 categories of CCL. CONCLUSIONS: The authors observed a positive association between CCL and AH. The possibility that CCL by themselves significantly elevate breast cancer risk is not well supported. However, a finding of CCL on benign breast biopsy may indicate the presence of AH, a more worrisome lesion.

Excellent survival, cancer type, and Nottingham grade after atypical lobular hyperplasia on initial breast biopsy.

BACKGROUND: Atypical lobular hyperplasia (ALH) is associated with a 10% to 20% risk of subsequent invasive carcinoma, primarily in the ipsilateral breast. Nottingham grading, special tumor types, and survival after invasive cancer diagnosis were analyzed consistently for the first time. METHODS: A longitudinal follow-up study of 252 women who underwent 261 benign surgical biopsies between 1950 and 1985 with a diagnosis of ALH was undertaken. Subsequent invasive breast cancers were graded and subtyped based on histologic features and the cohort assessed for cancer survival. RESULTS: Forty-eight (19%) women developed invasive breast cancer at an average of 15.1 years. Twenty (42%) of the tumors were special subtype tumors with good prognosis. By an average of 13 years after invasive cancer diagnosis, 2 (10%) of 20 women with special type and variant tumors had died of breast cancer, compared with 9 (32%) of 28 women with tumors of no special type (24 tumors) or an unknown type (4 tumors). Only 1 patient with a tumor of low Nottingham grade died of breast cancer. CONCLUSIONS: ALH is a nonobligate cancer precursor associated with a moderate risk of breast cancer and predicts that later cancers are associated with overall excellent survival. Nearly half of the subsequent cancers show classic or variant patterns of special types with a good prognosis and the majority are of low or intermediate combined histologic grade. Treatment of women with ALH should be influenced by their modest elevation in breast cancer risk and the good prognosis and low mortality of many of these cancers.

Neoadjuvant concurrent paclitaxel and radiation in stage II/III breast cancer.

PURPOSE: The aim of this study was to determine the safety and pathologic response rates following neoadjuvant paclitaxel and radiation in patients with stage II/III breast cancer and to evaluate the use of sequential biopsies to allow an in vivo assessment of biological markers as potential predictive markers of response to this regimen. PATIENTS AND METHODS: Patients with high-risk, operable breast cancer were treated with three cycles of paclitaxel 175 mg/m2 every 3 weeks, followed by twice-weekly paclitaxel 30 mg/m2 and concurrent radiation. Core biopsies were obtained at baseline and 24 to 72 hours after the first cycle of paclitaxel. After completing neoadjuvant treatment, patients underwent definitive surgery. The primary end point was pathologic complete response, which is defined as the absence of any invasive cancer at surgery. Potential markers of therapeutic response were evaluated including markers of proliferation, apoptosis, p21, HER2, estrogen receptor, and progesterone receptor status. RESULTS: Of the 38 patients enrolled, 13 (34%) had a pathologic complete response. There was no significant difference in baseline Ki-67 between responders (35%) and nonresponders (28%; P = 0.45). There was also no significant change in Ki-67 following paclitaxel administration. Despite this lack of immunohistologic change in proliferative activity, baseline mitotic index was higher for patients with pathologic complete response over nonresponders (27 versus 10, P = 0.003). Moreover, the increase in mitotic index following paclitaxel administration was associated with pathologic complete response. CONCLUSIONS: Neoadjuvant paclitaxel/radiation is effective and well tolerated. Tumor proliferation at baseline and response to chemotherapy as measured by mitotic activity may serve as an important indicator of pathologic response to neoadjuvant paclitaxel/radiation.

Interdependence of radial scar and proliferative disease with respect to invasive breast carcinoma risk in patients with benign breast biopsies.

BACKGROUND: Radial scars (RS) are benign breast lesions that have been implicated as independent risk factors for invasive breast carcinoma (IBC). METHODS: A retrospective cohort study of 9556 women who underwent biopsy between 1950-1986 and enrolled in the Nashville Breast Cohort was performed to investigate the association between RS in a benign breast biopsy and the risk of IBC. The risk associated with RS and coexistent proliferative disease (PD) was assessed adjusting for age at biopsy using a Cox hazards regression analysis with time-dependent covariates. RESULTS: RS were identified in 880 women (9.2%). The average follow-up time was 20.4 years. Sixty-two women (7.0%) with RS developed IBC compared with 5.5% of controls. The relative risk of IBC associated with RS was 1.82 (95% confidence interval [95% CI], 1.2-2.7) at 10 years. Restricting the analysis to women age > 49 years increased the risk to 2.14 (95% CI, 0.6-2.8). These risks decreased with increasing years of follow-up. Approximately 92% of women with RS also had PD, but RS were present in only 1.3% of biopsies without PD. Analyses stratifying relative risk with regard to PD found RS to minimally elevate the relative risk of subsequent IBC. CONCLUSIONS: RS in the absence of PD is uncommon. Although the presence of RS in a benign breast biopsy mildly elevates the risk of IBC risk, the current analysis indicated that this risk can be largely attributed to the category of coexistent PD. In women with both RS and atypical hyperplasia, recommendations for interventions beyond biopsy should be based on the extent of atypical hyperplasia.

Selective use of intraoperative touch prep analysis of sentinel nodes in breast cancer.

Imprint cytology (touch prep) is often used for intraoperative examination of sentinel nodes in breast cancer. This allows axillary lymph node dissection (ALND) to be performed immediately for tumor-positive nodes. We evaluated the accuracy of touch prep examination of sentinel nodes and its role in the surgical treatment of breast cancer. We analyzed 169 breast cancer patients who underwent 170 lymphatic mapping procedures with intraoperative touch prep examination. Results from the touch prep were correlated with histopathology and clinical variables. There were 115 true-negative, 35 true-positive, 15 false-negative, and 5 false-positive results. Touch prep had a sensitivity of 70 per cent and specificity of 96 per cent. Positive predictive value, negative predictive value, and diagnostic accuracy were all 88 per cent. The false-negative rate was 30 per cent and correlated with the size of the nodal metastasis and number of involved nodes, but not other patient factors. Touch prep is useful for the evaluation of sentinel nodes in breast cancer, but it has a lower sensitivity than initially reported, particularly in patients with micrometastases. False positive results occur, although they may be reduced after experience with the technique. We recommend that suspicious findings on touch prep should be confirmed by frozen section and that ALND only be performed for histologically documented metastases. We currently perform touch prep only in patients who are at high risk of nodal metastasis or will undergo mastectomy. This improves operative efficiency and limits the impact of false positive and negative results without dramatically increasing the number of patients who require a second surgical procedure.

Molecular diagnosis of necrotizing fasciitis by 16S rRNA gene sequencing and superantigen gene detection.

We report the use of molecular techniques in the diagnosis of a case of culture-negative necrotizing fasciitis occurring in a 32-year-old female with no significant past medical history and who died within 36 hours of admission. Paraffin-embedded tissue sections from the popliteal fossa region obtained at autopsy showed hemorrhage, necrosis, and mild inflammation by hematoxylin and eosin staining. Tissue gram stain showed numerous gram-positive organisms arranged in clusters. The sequences of the first 500 bp of bacterial 16S rRNA gene amplified from the lesion were identical to a Lancefield group A beta-hemolytic Streptococcus pyogenes. Streptococcal pyrogenic exotoxin A and B superantigen genes were detected and an emm type 1 was determined by polymerase chain reaction and sequencing from the lesion. This confirmed the etiology of the patient's rapid deterioration with multisystem organ failure.

Accuracy of intraoperative gross examination of surgical margin status in women undergoing partial mastectomy for breast malignancy.

Margin status is an important prognostic factor for local recurrence after partial mastectomy for breast malignancy. Options for intraoperative evaluation of margin status include gross examination of the specimen, frozen section, and "touch preparation" cytology. This study evaluates the accuracy of gross examination without other intraoperative pathological analysis as a method of determining margin status. Records of 254 consecutive patients undergoing partial mastectomy for 255 breast malignancies (199 invasive, 56 DCIS) over 6 years were analyzed retrospectively. All women underwent en bloc excision of the primary lesion with gross examination of margin status by the surgeon and pathologist. All suspicious areas were reexcised, and the specimen was inked, serially sectioned at 2-3 mm intervals and examined with hematoxylin and eosin (H&E) stains. Specimens with tumor <2 mm from a margin were considered margin-positive and those with all tumor > or =2 mm from the margin were designated margin-negative. One hundred fourteen (45%) of the 255 segmental resections were considered to have grossly tumor-free margins, and intraoperative reexcision was not performed. Ninety-six (84%) of these specimens had histologically negative margins. Gross examination prompted intraoperative reexcision in 141 (55%) cases. Ninety-five (67%) of these 141 resections had tumor-free margins on histopathology. Overall, the final margin was involved in 64 of the 255 partial mastectomies. Seventeen (27%) women with initially margin-positive resections underwent mastectomy, while 46 (72%) underwent reexcision, which was margin-negative in 41 (89%). After a median follow-up of 42 months, there have been eight (3.5%) local recurrences. The initial margin-positive rate was similar in ductal carcinoma in situ (DCIS) (30%) and invasive carcinoma (24%). Margin status was correlated with nodal status; there was no correlation with age, tumor size, grade hormone receptor status, or type of diagnostic biopsy. Gross examination of the resection specimen does not reflect margin status in at least 25 per cent of women undergoing partial mastectomy for breast malignancy. Other techniques for evaluation of margin status should be considered to reduce the need for reexcision of involved margins. We are currently designing a prospective clinical trial to examine the efficacy of new techniques for intraoperative evaluation of margin status.