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New techniques and treatments in medicine occasionally take on a life of their own. Sometimes, an idea's use is inherently obvious from the outset, sometimes not, in which case it becomes technology in search of an application. Identification of sentinel lymph nodes in breast cancer is a combination of these two options: to some extent the technique has been overused and its results overinterpreted. 10 years after the procedure's introduction and general acceptance, a few issues still deserve further discussion despite much published work on this topic. Use of sentinel-lymph-node identification has been extended to other organ systems, yet not all the lessons learned in the breast might apply to other sites. Review of the theory behind the technique and breast cancer experience to date is important. Many of the published controversies about sentinel lymph nodes in breast cancer can be resolved by consideration of the basic ideas underlying the procedure, which is the aim of this Essay. [ABSTRACT FROM AUTHOR]

Purpose: The COVID-19 pandemic has posed significant pressures on healthcare systems, raising concern that related care delays will result in excess cancer-related deaths. Because data regarding the impact on patients with breast cancer are urgently needed, we aimed to provide a preliminary estimate of the impact of COVID-19 on time to treatment initiation (TTI) for patients newly diagnosed with breast cancer cared for at a large academic center., Methods: We conducted a retrospective study of patients with newly diagnosed early-stage breast cancer between January 1, 2020, and May 15, 2020, a time period during which care was affected by COVID-19, and an unaffected cohort diagnosed between January 1, 2018 and May 15, 2018. Outcomes included patient volume, TTI, and initial treatment modality. Adjusted TTI was compared using multivariable linear regression., Results: Three hundred sixty-six patients were included. There was an 18.8% decrease in patient volume in 2020 (n = 164) versus 2018 (n = 202). There was no association between time of diagnosis (pre-COVID-19 or during COVID-19) and adjusted TTI ( P = .926). There were fewer in situ diagnoses in the 2020 cohort ( P = .040). There was increased use of preoperative systemic therapy in 2020 (43.9% overall, 20.7% chemotherapy, and 23.2% hormonal therapy) versus 2018 (16.4% overall, 12.4% chemotherapy, and 4.0% hormonal therapy) ( P < .001)., Conclusion: TTI was maintained among patients diagnosed and treated for breast cancer during the COVID-19 pandemic at a single large academic center. There was a decrease in patient volume, specifically in patients with in situ disease and a shift in initial therapy toward the use of preoperative hormonal therapy., Competing Interests: Lawrence N. ShulmanResearch Funding: Celgene Ira J. BleiweissHonoraria: Bard BiopsySpeakers' Bureau: Bard Biopsy, Philips Digital Imaging Rachel C. JankowitzHonoraria: EisaiConsulting or Advisory Role: MerckNo other potential conflicts of interest were reported.

Modern breast imaging techniques include digital mammography, 3-dimensional tomography, high-resolution ultrasound, and magnetic resonance imaging. Each of these has enabled the diagnosis of ever smaller, largely non-palpable lesions, not all of which require surgery. As these techniques evolved, so too did methods of accurately targeting and sampling the lesions, necessitating methods to mark the areas should surgical localization be needed. These methods have introduced heretofore unseen histologic changes to both breast tissue and lymph nodes, especially sentinel lymph nodes. These changes are the topic of this review., (© 2020 Wiley Periodicals, Inc.)

Microglandular adenosis (MGA) of the breast is exceedingly rare, with only a few case reports and series published to date. Previous studies have elegantly demonstrated the progression of benign MGA to atypical MGA to MGA-in situ carcinoma to invasive carcinoma and therefore suggest MGA as a possible non-obligate precursor lesion to a subset of breast carcinomas. Immunohistochemically, MGA is negative for estrogen receptor (ER), progesterone receptor (PR), and HER2-neu oncoprotein expression, and carcinomas arising in the setting of MGA are often reported to be triple negative. In this article, we present a unique case of an ER+/PR+/HER2- invasive carcinoma associated with MGA and atypical MGA. Our case highlights the diagnostic pitfall of MGA and suggests that MGA is a heterogeneous group of lesions with potential for either luminal-type or basal-type differentiation during progression to breast carcinoma.

Adenomyoepitheliomas (AME) of the breast and epithelial-myoepithelial carcinomas (EMCs) of salivary gland are morphologically similar tumors defined by the presence of a biphasic population of ductal epithelial elements mixed with myoepithelial cells. We sought to explore the molecular profile of AMEs and determine whether they might also share the PLAG1, HMGA2, and HRAS alterations seen in EMCs. Tumor tissue from 19 AMEs was sequenced and analyzed using Ion AmpliSeq Cancer Hotspot Panel v2 covering ∼2800 COSMIC mutations across 50 cancer-related genes. Cases were additionally screened by FISH for PLAG1 and HMGA2 rearrangements. Of 19 AMEs (12 benign; 7 malignant), 2 cases failed the DNA extraction. Of the remaining 17 cases, 14 had at least one nonsynonymous mutation identified. The most common mutations were in PIK3CA (6/17) and AKT1 (5/17), which were mutually exclusive. Two tumors demonstrated mutations in APC, while 1 demonstrated an STK11 mutation. Mutations in ATM, EGFR, FGFR3 or GNAS were identified in 4 cases with concurrent AKT1 mutations. HRAS mutation co-occurring with PIK3CA mutation was noted in 1 case of ER-negative malignant AME. While 2 cases harbored alterations in HMGA2, none was positive for PLAG1 rearrangement. Our findings confirm that breast AMEs are genetically heterogeneous exhibiting recurrent mutually exclusive mutations of PIK3CA and AKT1 in a majority of cases. HRAS mutations co-occur with PIK3CA mutations in ER-negative AMEs and may possibly be linked to clinically aggressive behavior. We identified hotspot mutations in additional genes (APC, STK11, ATM, EGFR, FGFR3, and GNAS). We report the presence of HMGA2 alterations in 2/16 AMEs, supporting their relationship with EMC of salivary glands in at least a subset of cases. PIK3CA, AKT1 and HRAS may serve as potential actionable therapeutic targets in clinically aggressive AMEs.

Context.—: The College of American Pathologists guidelines recommend testing additional tumor foci in multifocal invasive breast carcinomas for the biomarkers estrogen receptor (ER), progesterone receptor, and HER2 only if the carcinomas show different morphologies or grades., Objective.—: To assess clinical significance of testing for biomarkers in additional tumor foci in multifocal invasive breast tumors., Design.—: Retrospective analysis of 118 patients diagnosed with ipsilateral synchronous multifocal breast carcinomas from January 2015 through March 2016 at Mount Sinai Hospital (New York, New York)., Results.—: Eighty-six cases were tested for at least 1 of the 3 biomarkers in additional tumor foci. Fifteen cases (17%) showed discordant staining between the 2 foci for at least one biomarker. Of the 7 of 67 ER-discordant cases (10%), 4 (57%) showed major variation from negative to positive expression, including 3 cases in which a smaller tumor focus was strongly positive for ER whereas the index tumor was negative. Similarly, within the 7 of 67 progesterone receptor-discordant cases (10%), 4 (57%) showed major variation from negative to positive, and in 3 cases with major discordance, the index tumor was negative for progesterone receptor, whereas a smaller focus was positive. A difference in HER2 expression was noted in 5 of 86 cases (6%). In only 5 of the 15 patients (33%) with discordant results, biomarker testing on additional foci would have been offered per the College of American Pathologists recommendations because of differences in histology or grading. Of the remaining 10 patients, 7 (70%) with positive results on smaller foci would have been deprived of appropriate adjuvant systemic treatment if the smaller focus had not been tested., Conclusions.—: We propose that negative values expressed in the primary tumor be repeated routinely on additional ipsilateral synchronous tumors.

Aims: Adenomyoepithelioma (AME) and adenoid cystic carcinoma (ACC) of the breast have been noted to occur simultaneously, raising the possibility that AME may represent a related or precursor lesion to ACC. ACC frequently harbours genetic rearrangement of the MYB gene. We sought to clarify the relationship between AME and ACC by comparing their rates of MYB expression by IHC and MYB rearrangement by FISH., Methods and Results: IHC and FISH for MYB rearrangement were performed on paraffin-embedded sections of 11 breast ACCs, 11 non-breast ACCs and 11 breast-AMEs. Using FISH, five of eight (63%) interpretable breast ACCs demonstrated MYB gene rearrangement. Nine of 11 (81%) breast ACCs demonstrated MYB expression (range = 20-95%). Of the three FISH-negative breast ACCs, two were solid variant and demonstrated strong MYB expression by IHC. Of the 10 interpretable non-breast ACCs, six showed MYB rearrangement, all of which were conventional type. Nine of these 11 (81%) cases showed MYB immunoexpression (range = 10-90%), including three solid-variant cases which were negative by FISH. No MYB rearrangements were detected by FISH in 10 interpretable AMEs. However, three of 11 cases (27%) showed weak to moderate MYB expression by IHC (range = 10-40%)., Conclusions: Our results indicate that AMEs do not harbour MYB gene rearrangement. IHC for MYB may be helpful in diagnosing FISH-negative cases of ACC, particularly the diagnostically more difficult solid variants. However, weak to moderate MYB expression in a subset of AMEs highlights not only a potential diagnostic pitfall, but also shared pathophysiology with ACC worth investigating further at the genomic level., (© 2018 John Wiley & Sons Ltd.)

Primary mucinous cystadenocarcinoma (MCA) of breast is an exceedingly rare tumor with histologic resemblance to MCA arising in ovary, pancreas, and gastrointestinal tract. In this article, we present 2 additional cases of MCA of breast, one highlighting the diagnostic challenges of a rare entity that may potentially lead to unnecessary chemotherapy and the second case presenting with recurrence after 8 years of primary surgical excision defying the indolent behavior reported in the literature. To our knowledge, this is the first reported instance of such behavior.

With the introduction of sentinel lymph node (SLN) biopsy as a standard procedure for staging clinically node negative breast cancer patients, meticulous pathologic evaluation of SLNs by serial sections and/or immunohistochemistry for cytokeratins has become commonplace in order to detect small volume metastases (isolated tumor cells and micrometastases). This practice has also brought to the fore the concept of iatrogenically false positive sentinel nodes secondary to epithelial displacement produced largely by preoperative needling procedures. While this concept is well described in the clinical and pathologic literature, it is, in our experience, still under-recognized, with such lymph nodes frequently incorrectly diagnosed as harboring true metastases, possibly resulting in unwarranted further surgery and/or chemotherapy. This review discusses the concept of displaced epithelium in the histologic evaluation of breast surgical specimens and provides a stepwise approach to the correct identification of iatrogenically transported displaced epithelial cells in sentinel lymph nodes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

A 53-year-old woman presented with an apocrine cystadenoma of the right upper eyelid. Histologic examination revealed proliferating epithelial cells with apocrine snouts and occasional mitotic figures. Immunohistochemical analysis revealed a Ki-67 index of 15% and positive staining for synaptophysin, chromogranin, estrogen receptor, progesterone receptor, gross cystic disease fluid protein (GCDFP)-15, and mammoglobin. The complement of positive immunomarkers in this case reinforces the importance of total excision and careful histologic assessment.

Oncotype Dx is used to determine the recurrence risk (RR) in patients with estrogen receptor positive (ER+) and lymph node negative (LN-) breast cancer. The RR is divided into low (0-17), intermediate (18-30), and high (31) to predict chemotherapy benefit. Our goal was to determine the association between histomorphology, immunohistochemistry, and RR. We retrospectively identified 536 patients with ER+ and LN- breast cancers that underwent Oncotype testing from 2006 to 2013. Tumor size ranged from 0.2 cm to 6.5 cm (mean = 1.3 cm) and was uniform in all 3 categories. The carcinomas were as follows: ductal = 63.2%, lobular = 11.1%, and mixed = 35.7%. The RR correlated with the Nottingham grade. Increasing RR was inversely related to PR positivity but directly to Her2 positivity. Of the morphologic parameters, a tubular(lobular) morphology correlated only with low-intermediate scores and anaplastic type with intermediate-high scores. Other morphologies like micropapillary and mucinous were uniformly distributed in each category. Carcinomas with comedo intraductal carcinoma were more likely associated with high RR. Forty-four patients with either isolated tumor cells or micrometastases were evenly distributed amongst the 3 RR. While there was only 1 ER discrepancy between our immunohistochemistry (3+ 80%) and Oncotype, up to 8% of PR+ cases (mean = 15%, median = 5%) and 2% of HER2+ cases were undervalued by Oncotype., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this paper.

Phyllodes tumours constitute an uncommon but complex group of mammary fibroepithelial lesions. Accurate and reproducible grading of these tumours has long been challenging, owing to the need to assess multiple stratified histological parameters, which may be weighted differently by individual pathologists. Distinction of benign phyllodes tumours from cellular fibroadenomas is fraught with difficulty, due to overlapping microscopic features. Similarly, separation of the malignant phyllodes tumour from spindle cell metaplastic carcinoma and primary breast sarcoma can be problematic. Phyllodes tumours are treated by surgical excision. However, there is no consensus on the definition of an appropriate surgical margin to ensure completeness of excision and reduction of recurrence risk. Interpretive subjectivity, overlapping histological diagnostic criteria, suboptimal correlation between histological classification and clinical behaviour and the lack of robust molecular predictors of outcome make further investigation of the pathogenesis of these fascinating tumours a matter of active research. This review consolidates the current understanding of their pathobiology and clinical behaviour, and includes proposals for a rational approach to the classification and management of phyllodes tumours., Competing Interests: The authors declare no conflicts of interest with respect to the authorship, research and/or publication of this article, (© 2015 John Wiley & Sons Ltd.)

The clinical significance of IMLN metastases in breast cancer is controversial. Although IMLN status is an integral part of current AJCC staging of breast cancer, the elective sampling of IMLN is not part of routine surgery for breast cancer. The purpose of this study was to determine the incidence of IMLN metastases, associated risk factors if any, and its impact on further management and outcome. We retrospectively studied 470 cases that underwent autologous reconstruction surgery between 2002 and 2014. Of 470 cases, 157 breast cancer cases had histology-confirmed IMLN removal during the reconstruction. Only 9 patients (6 %) showed IMLN metastases as compared to 45 (34 %) that showed axillary nodal metastases (p < 0.01). Interestingly, 4 patients had metastases limited to IMLN without any metastases to axillary nodes. IMLN metastasis was significantly associated with age <40 years, lymphovascular invasion, and negative PR status. IMLN metastasis resulted in upstaging of 2 patients from stage I to III, and 1 from stage II to III. Five patients received additional chest wall radiation to target the positive IMLNs. Nine of 157 (6 %) patients with IMLN removal during reconstruction had loco-regional recurrence/metastasis as compared to 20 of 293 (7 %) patients without IMLN removal (p > 0.05) (follow-up, 1-134 months). The overall rate of IMLN metastases (6 %) is much lower than the rate of axillary node metastases. Selective biopsy of IMLNs in patients with breast cancer, especially if younger than 40 years, and with lymphovascular invasion and negative PR status, may guide adjuvant treatment.

Aims: It is known that sentinel lymph nodes (SLN) may be falsely positive due to displaced epithelial cells, particularly in cases with an underlying intraductal papilloma. Given the low metastatic rate in pT1a carcinomas, we aimed to investigate the effect of this phenomenon on staging., Methods and Results: Using morphology and immunohistochemistry, we classified the epithelial cells in the SLN in 39 cases of pT1a carcinoma as positive for carcinoma in six, negative in 26 and undetermined in seven. Comparative morphology and immunohistochemistry (using oestrogen receptor, ER) showed complete concordance between the primary carcinoma and SLN in the positive cases, and discordance in the negative cases. The primary tumours in the negative cases were ER-positive except one, in contrast to the SLN cytokeratin-positive (CK(+) ) cells, which were ER-negative. The exception was a case with a Her2-positive primary, in which the SLN CK(+) cells did not stain for Her2. In these cases considered SLN-negative, either displacement (19 cases) or an intraductal papilloma (20 cases) was identified. Two cases showed displacement of benign and malignant cells in the biopsy. Seven cases were indeterminate due to the small number of SLN CK(+) cells, precluding comparison with the primary., Conclusion: Given the low rate of metastases in pT1a carcinomas, the significance of SLN CK(+) cells should be resolved by comparative morphology and immunohistochemistry to prevent erroneous upstaging., (© 2014 John Wiley & Sons Ltd.)

Sentinel lymph node biopsy (SLNB) was introduced 2 decades ago and thereafter validated for routine surgical management of breast cancer, including cases treated with neoadjuvant chemotherapy. As the number of lymph nodes for staging has decreased, pathologists have scrutinized SLN with a combination of standard hematoxylin and eosin, levels, immunohistochemistry (IHC), and molecular methods. An epidemic of small-volume metastases thereby arose, leading to modifications in the American Joint Committee on Cancer staging to accommodate findings such as isolated tumor cells (ITC) and micrometastases. With the goal of determining the significance of these findings, retrospective followed by prospective trials were performed, showing mixed results. The ACOSOG Z10 and NSABP B-32 trials both independently showed that ITC and micrometastases were not significant and thus discouraged the use of levels and IHC for detecting them. However, the Surveillance Epidemiology and End Results database showed that patients with micrometastases had an overall decreased survival. In addition, the MIRROR (Micrometastases and ITC: Relevant and Robust or Rubbish?) trial, showed that patients with ITC and micrometastases treated with adjuvant therapy had lower hazard ratios compared with untreated patients. Subsequently, the ACOSOG Z0011 trial randomized patients with up to 2 positive SLN to axillary lymph node dissection (ALND) or not, all treated with radiation and chemotherapy, showing no difference in survival or recurrence rates between the 2 groups and causing a shift from ALND. As the rate of ALND has declined, the necessity of performing levels, IHC, frozen section, and molecular studies on SLN needs to be revisited.

The role of sentinel lymph node biopsy in microinvasive breast carcinoma is unclear. We examined the incidence of lymph node metastasis in patients with microinvasive carcinoma who underwent surgery at our institution. Retrospective review of our pathology database was performed (1994-2012). Of 7000 patients surgically treated for invasive breast carcinoma, 99 (1%) were classified as microinvasive carcinoma. Axillary staging was performed in 81 patients (64, sentinel lymph node biopsy; 17, axillary lymph node excision). Seven cases (9%) showed isolated tumor/epithelial cells in sentinel nodes. Three of these seven cases showed reactive changes in lymph nodes, papillary lesions in the breast with or without displaced epithelial cells within biopsy site tract, or immunohistochemical (estrogen receptor, progesterone receptor, and HER2) discordance between the primary tumor in the breast and epithelial cells in the lymph node, consistent with iatrogenically transported epithelial cells rather than true metastasis. The remaining four cases included two cases, each with a single cytokeratin-positive cell in the subcapsular sinus detected by immunohistochemistry only, and two cases with isolated tumor cells singly and in small clusters (<20 cells per cross-section) by hematoxylin and eosin and immunohistochemistry. The exact nature of cytokeratin-positive cells in the former two cases could not be determined and might still have represented iatrogenically displaced cells. In the final analysis, only two cases (3%) had isolated tumor cells. Three of these four cases had additional axillary lymph nodes excised, which were all negative for tumor cells. At a median follow-up of 37 months (range 6-199 months), none of these patients had axillary recurrences. Our results show very low incidence of sentinel lymph node involvement (3%), only as isolated tumor cells, in microinvasive carcinoma patients. None of our cases showed micrometastases or macrometastasis. We recommend reassessment of the routine practice of sentinel lymph node biopsy in patients with microinvasive carcinoma.

Background: Breast pathology is a challenging field, and previous work has shown discrepancies in diagnoses, even among experts. We set out to determine whether mandatory pathology review changes the diagnosis or surgical management of breast disease., Methods: Cases were referred for pathology review after patients presented for surgical opinion to the Dubin Breast Center at Mount Sinai Medical Center over the course of 2 years. Surgical pathologists with expertise in breast disease reviewed slides submitted from the primary institution and rendered a second opinion diagnosis. Comparison of these reports was performed for evaluation of major changes in diagnosis and definitive surgical management., Results: A total of 306 patients with 430 biopsy specimens were reviewed. Change in diagnosis was documented in 72 (17 %) of 430 cases and change in surgical management in 41 (10 %). A change in diagnosis was more likely to occur in patients originally diagnosed with benign rather than malignant disease (31 vs. 7 %, p < 0.001). Twelve (7 %) of 169 specimens initially diagnosed as benign were reclassified as malignant. A malignant diagnosis was changed to benign in 4 (2 %) of 261 cases. Change in diagnosis was less common in specimens originating from commercial laboratories than community hospitals or university hospitals (8, 19, 21 %, p = 0.023). Change in management was not dependent on initial institution. Type of biopsy specimen (surgical or core) did not influence diagnostic or management changes., Conclusions: We recommend considering breast pathology review based on the individual clinical scenario, regardless of initial pathologic diagnosis or originating institution.

Background: In the past decade, sentinel lymph node biopsy (SLNB) has become standard for patients with early-stage clinically node-negative breast carcinoma (BC). Despite high overall surgical identification success rates with introduction of the dual-tracer techniques (dye and radiolabeled probe), false-negative rates remained unchanged in most recent meta-analyses., Patients and Methods: We analyzed cases with false-negative SLN biopsy results over a 12-year period in a single institution to evaluate their clinicopathologic characteristics. Sixty-three false-negative cases (3.1%) were found in 2043 successful SLN mapping procedures, all of which were followed by varying amounts of additional axillary sampling., Results: There was a higher proportion of invasive lobular carcinomas (ILCs; 23 cases [37%]) when compared with this lesion's overall reported frequency (5%-15%). The majority of invasive ductal carcinoma (IDC) cases (31 of 40) were poorly differentiated. In 80% of the ductal-type cases, 1 or more nonsentinel nodes (NSLNs) were completely or partially replaced by tumor, as opposed to less than half of such cases of the lobular type. Twenty-two cases had multiple positive NSLN metastases, which were significantly associated with larger tumor size (≥ 1.0 cm) and tumor replacement of NSLNs. Eighty-two percent of the cases with known hormone receptor status were positive for estrogen or progesterone receptors, or both., Conclusion: False-negative SLN biopsy results were more often associated with a primary BC characterized by a lobular or poorly differentiated ductal histologic type or partial to complete replacement of NSLNs with tumor, or both., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Most authors recommend excision of intraductal papillomas diagnosed on core needle biopsy. This leads to the question of whether or not excision is necessary for incidental intraductal papillomas on core needle biopsy as opposed to those corresponding to imaging findings. Using the pathology computerized data base we retrospectively identified 46 incidental intraductal papillomas diagnosed on core needle biopsy from 1/2000 to 12/2008. Clinical, radiologic, and pathologic information was gathered and correlated. All core needle biopsies were reviewed to confirm the diagnosis of incidental intraductal papillomas, and excision specimens reviewed when available. Of the 46 patients, follow-up information was available in only 38. The age of the patients ranged from 39 to 82 years (mean = 48 years). Most incidental intraductal papillomas were diagnosed by mammotome core needle biopsy (36 cases). A total of 33 cases were performed for calcifications with the following indications: clustered = 21, new = 4, pleomorphic = 3, increasing = 3, indeterminant = 2. The correlating diagnoses included the following: fibrocystic changes with calcium phosphate = 18 or calcium oxalate = 10, fibroadenoma with calcifications = 5. The three masses were: two cases of cystic papillary apocrine metaplasia (I Ultrasound and 1 MRI) and 1 fibroadenoma (Ultrasound). In all cases, the intraductal papillomas were ≤0.2 cm, were not associated with calcifications, and were incidental to them or the underlying mass. A total of 14 patients underwent excision, whereas the remaining 24 have remained radiologically stable for over 12 months. The excision specimen findings were: fibrocystic changes = 8 and intraductal papilloma = 6. With the exception of one case, all the intraductal papilloma remained incidental to imaging findings. In this solitary case, the calcifications were described as pleomorphic and corresponded to fibrocystic changes calcifications on core needle biopsy. However, on excision, residual pleomorphic calcifications on mammogram correlated with both fibrocystic changes and intraductal papilloma. No cases were upstaged on excision to atypical duct hyperplasia or intraductal or invasive carcinoma. With the exception of one case, all incidental intraductal papillomas diagnosed on core needle biopsy were either completely excised or remained incidental. The exception occurred due to sampling error and accounted for the change from an incidental intraductal papillomas on core needle biopsy to one that was associated with calcifications on excision. Given the complete lack of upstaging, it is difficult to recommend excision of incidental intraductal papillomas diagnosed on core needle biopsy provided the index lesion has been adequately sampled and radiologic follow-up is maintained., (© 2013 Wiley Periodicals, Inc.)

Purpose: p53 as a prognostic and predictive factor in early-stage breast cancer has had mixed results. We studied p53 protein expression, by immunohistochemistry, in a randomized clinical trial of stage II patients treated with adjuvant doxorubicin and cyclophosphamide with or without paclitaxel [Cancer and Leukemia Group B (CALGB) 9344, INT0148]., Patients and Methods: Epithelial p53 expression was evaluated using two immunohistochemical antibodies (DO7 and 1801) in formalin-fixed, paraffin-embedded tissue from patients with node-positive breast cancer who were randomized to four cycles of cyclophosphamide and one of three doses of doxorubicin (60, 75, or 90 mg/m(2); AC) and to receive four subsequent cycles of paclitaxel (T) or not. Prognostic and predictive value of p53 protein expression was assessed, independent of treatment assignment, for escalating doses of doxorubicin or addition of T with endpoints of relapse-free (RFS) and overall survival (OS)., Results: Of 3,121 patients, 1,887 patient specimens treated on C9344 were obtained, passed quality control, and evaluated for p53 expression. Expression was 23% and 27% for mAbs 1801 and D07, respectively, with 92% concordance. In univariate analysis, p53 positivity was associated with worse OS with either antibody, but only p53 staining with monoclonal antibody 1801 had significantly worse RFS. In multivariate analysis, p53 was not predictive of RFS or OS from either doxorubicin dose escalation or addition of paclitaxel regardless of the antibody., Conclusion: Nuclear staining of p53 by immunohistochemistry is associated with worse prognosis in node-positive patients treated with adjuvant doxorubicin-based chemotherapy but is not a useful predictor of benefit from doxorubicin dose escalation or the addition of paclitaxel., (©2011 AACR.)

Practice-changing evidence requires confirmation, preferably in multi-institutional clinical trials. The collection of tissue within such trials has enabled biomarker studies and evaluation of companion diagnostic tests. Tissue microarrays (TMAs) have become a standard approach in many cooperative oncology groups. A principal goal is to maximize the number of assays with this precious tissue. However, production strategies for these arrays have not been standardized, possibly decreasing the value of the study. In this article, members of the Cancer and Leukemia Group B Pathology Committee relay our experiences as array facility directors and propose guidelines regarding the production of high-quality TMAs for cooperative group studies. We also discuss statistical issues arising from having a proportion of patients available for TMAs and the possibility that patients with TMAs fail to represent the greater study population.

Mucocele-like lesions of the breast are ruptured ducts that discharge their contents into the stroma. They constitute a spectrum from benign to atypical to malignant. The current management of these lesions diagnosed on core biopsy is excision. The goal of our study was to evaluate the necessity of this practice for benign mucocele-like lesions. Retrospective review of the pathology database from 1 January 2000 to 1 June 2008 identified 61 cases, with follow-up information available in 50 cases. Clinical, radiological, and pathological information was correlated. Core biopsies were reviewed to confirm the diagnosis and verify previous biopsy site. In all, 45 patients underwent surgery, whereas 5 patients were followed for >1 year and remained stable. Patient's ages ranged from 44 to 76 years. Most benign mucoceles were diagnosed stereotactically while targeting calcifications (93.3%); rarely, the lesion was a sonographically detected mass. Most excisions had no residual mucocele (37/45=82%). In seven cases (15.6%), atypical duct hyperplasia was present, three with residual mucocele. In one case, the residual mucocele showed a continuum from florid to atypical duct hyperplasia at the core biopsy site. The other six cases showed atypical duct hyperplasia adjacent to but not directly at the core biopsy site. The sizes of the benign mucoceles ranged from incipient to 0.6 cm, all containing calcifications except one, which was incidental. Radiological-pathological correlation was concordant in all cases except one with suspicious calcification, which was ductal carcinoma in situ on excision. In this series, the largest of its kind, the upstage rate of benign mucoceles diagnosed on core biopsy was 17.8%. With the exception of the ductal carcinoma in situ case, no radiological or morphological features were predictive of atypia. Thus, because of associated atypical duct hyperplasia, sampling reasons, and intralesional heterogeneity, we continue to recommend excision of benign mucocele-like lesions diagnosed on core biopsy.

Background: Although it has been accepted that intraductal papillomas with atypia or malignancy diagnosed on core needle biopsy require surgical excision, the management of pure intraductal papillomas has been controversial. Because some series reported a small but definite incidence of atypia or malignancy, whereas others claimed that radiologic follow-up was adequate, this study evaluated results of excision of all pure intraductal papillomas diagnosed on core needle biopsy at this institution., Methods: By using computerized pathology files from January of 2000 to December of 2004, 200 cases of intraductal papillomas on core needle biopsy were identified. Information regarding excision was available in 104 cases. All specimens were reviewed to confirm both the diagnoses as well as the presence of biopsy site changes in excision specimens, and the findings were correlated with radiologic data., Results: The age of the patients ranged from 25 to 82 years (mean, 55.5). The diagnoses on excision were as follows: intraductal papillomas = 71 cases (68.3%), no residual intraductal papillomas = 16 (15.3%), atypical duct hyperplasia = 8 (7.7%), ductal carcinoma in situ = 6 (5.8%), and invasive carcinoma = 3 (2.9%). In cases with atypia or malignancy, these findings were adjacent to but not in the biopsy site. In cases with atypical duct hyperplasia or ductal carcinoma in situ, a spectrum of histologic changes ranging from florid to atypical duct hyperplasia (14 cases), to ductal carcinoma in situ (6 cases) were present, all involving intraductal papillomas., Conclusions: The upstage rate of pure intraductal papillomas on core needle biopsy to atypia or malignancy on excision was 16.4%. Because of sampling error and the close proximity of atypia or malignancy to the intraductal papillomas (suggesting precancerous potential), excision was recommended of these lesions diagnosed on core needle biopsy. Close radiologic-pathologic correlation was important in the evaluation of these lesions.

Background: Lobular neoplasia (LN), encompassing atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS), is often an incidental finding on core needle biopsies (CNBs) performed in instances of radiologic densities and/or calcifications. Because LN is generally considered a risk factor for breast carcinoma, the utility of subsequent excision is controversial., Methods: The authors' database yielded 98 cases of LCIS and/or ALH. Cases containing LN accompanied by a second lesion mandating excision (eg, radial scar, atypical ductal hyperplasia [ADH]) and those failing to meet strict diagnostic criteria for LN (eg, atypical cells, mitoses, single-cell necrosis) were excluded. Radiographic calcifications were correlated with their histologic counterparts in terms of size, number, and pattern., Results: Ninety-one biopsies were performed for calcifications and 7 were performed for mass lesions. The ages of the patients ranged from 35 to 82 years. Fifty-three patients were followed radiologically without excision, 42 of whom had available clinicoradiologic information. The 45 patients who underwent excision were without disease at follow-up periods ranging from 1 to 8 years. Of these 45 patients, 42 (93%) had biopsy results demonstrating only LN. The remaining 3 patients had biopsies with the following findings: ADH in 1 biopsy, residual LCIS and a separate minute focus of infiltrating lobular carcinoma (clearly an incidental finding) in the second biopsy, and ductal carcinoma in situ admixed with LCIS in the third biopsy (a retrospective examination performed by 2 blinded breast pathologists revealed foci of atypical cells and mitoses)., Conclusions: Excision of LN is unnecessary provided that: 1) careful radiographic-pathologic correlation is performed; and 2) strict histologic criteria are adhered to when making the diagnosis. Close radiologic and clinical follow-up is adequate., ((c) 2008 American Cancer Society.)

Objective: To evaluate the prevalence of occult malignancy with screening breast ultrasound., Methods: All ultrasound-guided core needle breast biopsies performed between January 1, 1999, and June 30, 2001, were retrospectively reviewed. Lesions were identified during screening breast ultrasound in high-risk women with no mammographic or palpable abnormality in either breast, a unilateral mammographic or palpable abnormality in the contralateral breast, or a unilateral mammographic or palpable abnormality in a different quadrant of the same breast. All ultrasound-detected lesions were histologically verified., Results: Six hundred and fifty-two women with a mean age of 49 years underwent 698 biopsies during the study period. Three hundred and forty-nine of these lesions were detected at screening breast ultrasound. Out of 349, 11 (3.2%) had a mammographically and clinically occult malignancy. Nine cancers were found in women with no mammographic or palpable abnormality. Two cancers were found in the same breast as the mammographic or palpable abnormality. None were found in the breast contralateral to a palpable or mammographic abnormality., Conclusion: Screening breast ultrasound of high-risk women has a similar detection rate for occult carcinoma as screening mammography, but has a low positive predictive value in cases where biopsy is performed.

Papillary microcarcinoma of the thyroid comprises 10-20% of all thyroid malignancies. Most microcarcinomas are slow growing and have a favorable prognosis. Lymph node metastasis caused by thyroid microcarcinoma is uncommon, and distant metastasis to lung or bone is even rarer. Thyroid microcarcinoma with metastasis to a thymic lymph node was not previously reported. We describe a case of incidental 1 mm micropapillary thyroid cancer identified within a thymic lymph node following total parathyroidectomy for secondary hyperparathyroidism.

Purpose: Immunohistochemical (IHC) staining for cytokeratins (CK) is common practice in evaluating sentinel lymph nodes (SLNs) in patients with breast carcinoma. IHC positivity typically indicates metastasis. SLN procedures are increasingly common in patients with pure intraductal carcinoma (DCIS). Iatrogenic epithelial cell displacement and benign transport of breast epithelial cells into axillary lymph nodes are recently described phenomena. We report 25 cases in which these factors probably resulted in benign epithelial cells in axillary SLNs (ie, false positivity)., Methods: We reviewed 25 cases of CK-positive SLNs in which the epithelial cells had histologic and IHC characteristics different from their respective patients' underlying breast carcinomas., Results: In all cases, the cytologic features of the epithelial cells in the SLNs were benign, and 22 matched those of corresponding intraductal papillomas that were involved by or were separate from the DCIS in the original cores or surgical biopsies. Fifteen cases were pure DCIS; most invasive tumors were smaller than 1.0 cm. In six carcinomas (DCIS) showing strong Her-2/neu staining, the corresponding epithelial cells in the SLNs were negative. In 13 tumors that were strongly and uniformly positive for estrogen receptor (ER), the cytokeratin-positive cells in the SLNs were negative for ER. Nineteen cases showed benign epithelial cell displacement at the biopsy site., Conclusion: Epithelial cells in SLNs may result from transport of displaced cells, usually originating in intraductal papillomas. Positive immunohistochemical results in SLNs should be interpreted with extreme caution to avoid automatically concluding that such cells represent metastasis. Sentinel lymph nodes in breast carcinoma can be falsely positive.

The United States National Cancer Institute Breast/Ovarian Cancer Family Registry is the largest international Registry of this type; over 37 724 individuals have been enrolled to date. One activity of this Registry is the semicentralized pathologic review of tumors from all probands. Given the semicentralized nature of the review, this study was undertaken to determine the reproducibility, source(s) of classification discrepancies and stratagems to circumvent discrepancies for histologic subtyping and grading of invasive breast cancer among the reviewing pathologists. A total of 13 pathologists reviewed 35 invasive breast cancers and classified them by primary and secondary histologic type, Nottingham grade and score. Lymph-vascular space invasion, circumscribed margins, syncytial growth and lymphocytic infiltrate were also evaluated. A training session using a separate set of slides was conducted prior to the study. General agreement, in terms of category-specific kappa's and percent agreement, and accuracy of classification relative to a reference standard were determined. Classification of histologic subtype was most consistent (and accurate) for mucinous carcinoma (kappa=1.0), followed by tubular (kappa=0.8) and lobular subtypes (kappa=0.8). Classification of medullary subtype was moderate (kappa=0.4), but additional evaluation of degree of lymphocytic infiltrate, syncytial growth and circumscribed margins identified most cases. Category-specific kappa's were moderate to good for Nottingham grade (kappa=0.5-0.7), with the greatest agreement obtained in categorizing grade I (kappa=0.7), and grade III tumors (kappa=0.7). A flexible classification strategy that employs individual and combined criteria provides good interobserver agreement for invasive breast cancers with uniform, unambiguous histology and compensates for classification discrepancies in the more histologically ambiguous or heterogeneous cancers.

Upregulation of N-cadherin in epithelial tumor cells has been shown to contribute to the invasive/metastatic phenotype. It remains however to be determined whether N-cadherin is increased in human breast cancers with enhanced malignant potential. We examined a large number of invasive breast cancer specimens (n = 114) for N- and E-cadherin. These specimens compared invasive duct carcinomas (IDCs) of varying histologic grades with an aggressive subtype, invasive micropapillary carcinoma of the breast (MPAP), which has a high propensity for lymphatic invasion and lymph node metastasis. Staining scores for N- and E-cadherin were compared between non-MPAP and MPAP IDCs, and between the invasive and ductal carcinoma in situ (DCIS) of each IDC using statistical analysis. We found that N-cadherin was expressed in 76% of MPAP and 52% of non-MPAP carcinomas, and E-cadherin in 57% of MPAP and 36% of non-MPAP tumors. More MPAP (25%) compared to non-MPAP (5%) tumors expressed both cadherins. Of the two cadherins, N-cadherin was significantly associated with MPAP tumors (p = 0.033) compared to E-cad (p = 0.171). Moreover, in the majority of tumors that were positive for N-cadherin, the staining scores were increased in the IDC relative to intraductal components, and this effect was more dramatic in the MPAP carcinomas. This difference for N-cadherin was greater than the corresponding difference for E-cadherin in the MPAP group (p = 0.005), whereas such changes were not significant in the non-MPAP group (p = 0.10). Thus, N-cadherin is associated with tumor aggressiveness and metastatic potential and may contribute to tumor progression.

Necrosis in the breast is more frequently associated with malignancies than benign conditions. In the latter, it may be diffuse as seen in infarcts, postpartum changes, and after anticoagulant therapy, or focal as in florid adenosis and juvenile papillomatosis. The goal of this study was to find other benign entities associated with necrosis. Using our pathology database from January 1994 to March 2003, we identified 10 cases of florid duct hyperplasia associated with luminal necrosis. Clinical information was collected and all slides were reviewed. The age of the patients ranged from 36 to 94 years (mean, 53.2 years). All patients underwent an initial excisional biopsy except for one who had a core biopsy. Patients presented with a palpable mass (6 cases) a radiographic density (3 cases), or nipple discharge (1 case). Findings correlated with the presence of an intraductal papilloma with adjacent or associated florid duct hyperplasia. Within the central luminal spaces of the florid duct hyperplasia, cellular debris associated with necrosis was present and was morphologically identical to that seen in comedo intraductal carcinoma. In fact, in two of the four consultation cases, these lesions were initially diagnosed as comedo carcinoma. Re-excision performed in three cases showed no atypia or malignancy. It is important to recognize the presence of comedo-like necrosis in florid duct hyperplasia associated with or adjacent to intraductal papillomas of the breast and not to misinterpret these findings as intraductal carcinoma. The necrosis may be secondary to reactive changes within the intraductal papilloma.

Solid and cystic papillary carcinoma is typically a localized indolent, low-nuclear-grade form of intraductal carcinoma of the breast that occurs in a cystically dilated duct and predominantly affects elderly women in the sixth to the eighth decade of life (mean age, 57 to 75 years). We describe two such lesions, both of high nuclear grade, of larger than average size, that occurred in women in their second decade, one of whom was pregnant.

Immunohistochemistry, a technique that microscopically detects cellular constituents via specific antibodies, has revolutionized the field of surgical pathology by tremendously empowering the hematoxylin and eosin (H&E) slide. In the investigation of the unknown primary, it enables detecting the origin of the tumor by use of tissue- or organ-specific antibodies as well as antibodies associated with minimal histogenetic differentiation. It has almost perfected the pathologist's ability to make specific diagnoses such as those of mesothelioma, melanoma, and neuroendocrine tumors. These diagnoses should be reached by interpreting the immunohistochemical results in the context of a detailed morphological analysis and differential diagnosis based on the H&E. Other important uses include detection of microinvasive and micrometastatic disease. Through the use of prognostic markers, immunohistochemistry can provide valuable information regarding tumor behavior and therapy. Lastly, immunohistochemistry serves a small but valuable role in highlighting microorganisms, particularly viruses.

Background: Because breast cancer survival after breast conservation has proved comparable to mastectomy, contraindications to mastectomy are increasingly being challenged. We treated the majority of our patients with multiple synchronous ipsilateral cancers with breast conservation and we compared them with patients who underwent mastectomy for comparable disease during the same interval., Study Design: Patients with multiple ipsilateral synchronous breast cancers between 1989 and 2002 were identified from prospective databases maintained by us. A comparison was made between 36 patients treated with lumpectomy and 19 patients treated with mastectomy., Results: There were no significant (all p values >0.2) differences between mastectomy and breast conservation patients in age, racial distribution, size of cancers, pathology, tumor differentiation, nodal involvement, or hormone receptor positivity. The majority of patients treated with breast conservation underwent at least one reexcision to obtain clear pathologic margins, and they were more likely to receive postoperative radiotherapy than patients treated with mastectomy. There were no significant differences in the local (97% versus 100%, p = 0.54) or distant (97% versus 95%, p = 0.20) 5-year disease- free survival between the group treated with breast conservation and the group treated with mastectomy. One patient in each group developed distant metastases. One patient in the breast conservation group developed local recurrence at both primary sites simultaneously 39 months after lumpectomies. She is free of disease 78 months after mastectomy. The remaining 52 patients are alive and free of disease., Conclusions: Breast conservation is an effective treatment for patients with synchronous ipsilateral breast cancers.

Microglandular adenosis (MGA) is a well-recognized, if rare and incompletely characterized, entity in which carcinoma is rarely thought to develop. We report 17 cases in which patterns of adenoid cystic carcinoma (ACC) coexisted with MGA. Immunocharacterization with beta-catenin, E-cadherin, cytokeratins (AE1/AE3), epithelial membrane antigen, S-100 protein, smooth muscle actin, and vimentin was also performed. Most cases had areas of invasive ACC characterized by its defining dual-lumen types. Some cases of ACC appeared to have expanded glands intermingled within the MGA, whereas in other cases ACC formed a transition with the characteristic small, gland-like spaces of MGA. MGA and "atypical MGA" stained irregularly and similarly to that seen in myoepithelium with the three markers of myoepithelial cells in breast: S-100 protein, smooth muscle actin, and vimentin. These markers were also positive in the more solid elements of the ACC. Our study suggests that ACC may develop in a background of and in continuity with MGA. Altered myoepithelial cells appear to be the major neoplastic element in both ACC and "atypical MGA." "Atypical MGA" with transition to ACC may show histologic patterns and an immunohistochemical profile similar to that of ACC. These lesions might be best interpreted as ACC in situ. Both MGA and ACC of the breast grow in an expansile and diffusely infiltrative pattern without having significant metastatic capacity. Their unusual interaction with the surrounding stroma may play a role in this benign biologic behavior.

Objective: To examine the cytologic features of infiltrating micropapillary carcinoma (IMPC)., Methods: Using the histopathology files of one of the authors (I.J.B.), we retrospectively identified 20 IMPC cases (pure, 12; partial micropapillary carcinoma differentiation, 8) with corresponding cytology. We evaluated the cases for cellularity, atypia, architecture and background., Results: All cases were diagnostic of malignancy, characterized by atypical cells present predominantly in three-dimensional clusters and single cells, facilitating the diagnosis. The clusters had cell ball and papillarylike arrangements, like the morular growth pattern seen on histopathology. Apocrine cytology was present in 12 cases, focal mucin background in 5 and psamomma bodies in 2. The differential diagnosis includes primary papillary neoplasms of the breast, metastatic ovarian papillary serous carcinoma, apocrine and colloid carcinoma of the breast, and intraductal carcinoma (micropapillary type)., Conclusion: As in histopathology, the cytologic features of IMPC are unique and should be recognized due to its aggressive behavior.

Prior to the current mammographic era, ductal carcinoma in situ (DCIS) usually presented as a large mass, was classified morphologically by architecture, and treated by mastectomy. The introduction of screening mammography led to an increase in the incidence of DCIS, a decrease in the average size of DCIS, and an increased emphasis on its heterogeneous nature. Thus, a reproducible and prognostically relevant classification system for DCIS is necessary. The ultimate goal of this classification is proper selection of patients for whom lumpectomy would suffice rather than mastectomy. Features to evaluate include: extent and size of disease, adequacy of resection margins, and histology. While none of the proposed histological classification systems were endorsed at the recent Consensus Conference on the Classification of DCIS, nuclear grade was the most important feature common to most of them. Architecture was given secondary importance. By definition, DCIS is a non-invasive clonal proliferation of epithelial cells originating in the terminal duct lobular unit, which would be expected to be monomorphic; however, it is the degree of nuclear pleomorphism that is primarily used to separate DCIS into low, intermediate, and high grades. Architecturally, DCIS has been divided into the following types: comedo, solid, cribriform, micropapillary, and papillary. Different architectural patterns and grades may be present in a given particular case; however, some combinations of patterns occur more frequently than others. Interobserver studies have shown nuclear grading to be interpreted with greater consistency than architecture, and nuclear grading methods have correlated with biological and molecular marker studies., (Copyright 2002 Wiley-Liss, Inc.)

Retinoic acid (RA) receptor (RAR) beta2 has been shown to be underexpressed in human breast cancer cells, including MCF-7 cells, and recent reports have suggested that hypermethylation of the RAR beta2 promoter and 5'-UTR is the underlying cause. Here we show that RAR alpha2 is also underexpressed in MCF-7 breast cancer cells, at both the message and the protein level, relative to normal or nontumorigenic breast epithelial cells. Bisulfite sequencing of the CpG island in the RAR alpha2 promoter revealed highly penetrant and uniform cytosine methylation in MCF-7 cells. Pretreatment with the DNA methyltransferase inhibitor, azacytidine, followed by treatment with RA and a histone deacetylase inhibitor, trichostatin A, resulted in partial promoter demethylation and RAR alpha2 induction, which strongly suggested that promoter hypermethylation is responsible for RAR alpha2 underexpression. We compared the outcome of ectopic expression in MCF-7 cells of matched levels of RAR alpha2 and RAR beta2. On the basis of a clonogenic assay, RAR alpha2 displayed ligand-dependent growth-suppressive activity similar to that of RARb eta2; thus, 10 and 20 nM RA inhibited clonogenic growth by 52 and 80%, respectively, in RAR alpha2-transfected cells compared with 75 and 77%, respectively, in RAR beta2-transfected cells. We conclude that the silencing of the RAR alpha2 promoter by hypermethylation may play a contributory role in the dysregulation of RA signaling in mammary tumorigenesis.

Background and Objectives: Neoadjuvant chemotherapy in locally advanced breast cancers produces histologically evaluable changes and frequently reduces the size of the primary tumor. Local clinical response to neoadjuvant chemotherapy may correlate with response of distant metastases. Therefore, clinical or pathological factors, which predict or assess response to treatment, may predict outcome after consideration for initial extent of disease., Methods: To identify pretreatment characteristics of locally advanced breast cancers which predict clinical and pathologic response to neoadjuvant chemotherapy as well as survival and to assess the utility of postoperative histologic changes, we retrospectively studied one hundred forty-four patients with locally advanced breast cancer treated with neoadjuvant chemotherapy between January 1975 and July 1996. Patients were identified through pathology records of the Mount Sinai Medical Center and via one of the author's clinical databases. Pathologic and clinical responses to neoadjuvant chemotherapy were correlated with survival. Stepwise logistic regression was used to identify variables most significantly related to clinical response and pathologic axillary lymph node involvement., Results: Complete clinical response with no palpable tumor was noted in 7/86 patients (8%) and complete pathologic response was achieved in 18/138 patients (13%). Both clinical (P = 0.038) and pathologic response (P = 0.011) were related to tumor size at the time of diagnosis: smaller tumors were more likely to respond to chemotherapy than larger tumors. Histologic evidence of chemotherapeutic effect, i.e., cytoplasmic vacuolization, change in the number of mitoses and localized fibrosis in lymph nodes did not correlate with clinical or pathologically measured response. Clinical and pathologic response was not associated with age, histology, differentiation, or type of chemotherapy. No residual tumor was found in the axillary nodes of 27% (37) of the patients. Age and complete pathologic response were the only variables significantly related to pathologic nodal status. Eighty-four percent of the 61 patients under 50 years of age had nodal involvement compared to 65% of older patients (P = 0.014). Fifty percent of complete pathologic responders had positive axillary lymph nodes compared to 76% of patients who did not have a complete pathologic response (P = 0.020). Distant disease-free (P = 0.039) and overall survival (P = 0.035) were related to the number of involved axillary lymph nodes. After consideration for pathologic lymph node status, no other variable was significantly related to distant disease-free or overall survival in multivariate analysis. No variable was significantly related to local disease-free survival. Age, clinical tumor size, clinical lymph node status, clinical response, type of chemotherapy, histology, differentiation, chemotherapy effects on primary tumor and lymph nodes, decline in the number of mitoses, and degree of fibrosis in nodes were not predictive of distant recurrence or overall survival., Conclusions: This study of patients treated with neoadjuvant chemotherapy for locally advanced breast cancers found little evidence that measurable clinical or pathologic changes attributable to chemotherapy predicted survival. Axillary lymph node status, associated with young age, was the most important prognostic indicator in these patients., (Copyright 2002 Wiley-Liss, Inc.)

Background: In order to define a future subset of breast cancer patients in whom the axilla may be staged by sentinel lymph node biopsy alone, the conditions under which nonsentinel axillary lymph node metastases occur must be delineated., Methods: A prospective database including 212 breast cancer patients who underwent sentinel lymph node biopsy followed by completion axillary dissection at our institution was reviewed. A multivariate, logistic, stepwise regression was performed to evaluate the relationship between nonsentinel lymph node metastasis and patient age, primary tumor size, presence of lymphatic invasion, use of radioisotope to identify the sentinel node and degree of metastasis in the sentinel node., Results: Tumor size greater than 2 cm, lymphatic invasion of the primary tumor, macrometastasis in the sentinel node, and use of radioisotope all positively correlated independently with metastasis in the nonsentinel lymph node (P = 0.0001, P = 0.0483, P = 0.0008, P = 0.0271, respectively)., Conclusions: Predictors of nonsentinel axillary node metastasis exist and are important in defining those patients in whom a sentinel lymph node biopsy alone may not be adequate.

Objective: To study the relationship of mammographic appearance of nonpalpable breast cancer to the pathologic characteristics., Summary Background Data: The mammographic appearance of nonpalpable breast cancer may be associated with pathologic variables having prognostic significance, which could influence clinical management., Methods: The authors correlated the mammographic appearance and pathologic characteristics of 543 nonpalpable malignancies diagnosed in a single institution between July 1993 and July 1999. Cancers were divided into four groups based on mammographic presentation: mass, calcification, mass with calcification, and architectural distortion., Results: The majority of masses (95%), masses with calcifications (68%), and architectural distortions (79%) were due to invasive cancers, whereas the majority of calcifications (68%) were due to ductal carcinoma in situ (DCIS). Among invasive cancers, calcifications were associated with more extensive intraductal carcinoma, more Her2/neu immunoreactivity, and more necrosis of DCIS. Lymphatic invasion was more common in cancers presenting as a mass with calcifications. Sixty-nine percent of DCIS associated with invasive cancers presenting as calcifications were of high grade according to the European Organization for Research and Treatment of Cancer. Calcifications in noninvasive tumors were associated with necrosis in DCIS. Two thirds of cancers presenting as architectural distortion had positive margins (65%) compared with 35% to 37% of other mammographic presentations. Mammographic presentation was not significantly related to tumor differentiation or estrogen or progesterone receptor status. The ratio of invasive to noninvasive malignancies increased progressively with increasing age from 1:1 in patients younger than 50 years of age to 3:1 in patients older than 70 years, whereas the proportion presenting as calcifications declined from 63% in patients younger than 50 years to 26% in patients older than 70 years., Conclusions: Malignancies presenting as calcifications on mammography are most commonly DCIS. When invasive malignancies presented as calcifications, the calcifications were associated with accompanying high-grade DCIS, and the invasive cancers were often Her2/Neu positive. Mammographic masses with calcifications were associated with lymphatic invasion. Excisional biopsy margins were most commonly positive with architectural distortions. The mammographic appearance of nonpalpable malignancies is related to pathologic characteristics with prognostic value, which varies with patient age and influences clinical management.