Stromal MED12 exon 2 mutations in complex fibroadenomas of the breast.

AIMS: Here we explore the presence of mediator complex subunit 12 (MED12) exon 2 and telomerase reverse transcriptase (TERT) promoter hotspot mutations in complex fibroadenomas (CFAs) of the breast. METHODS: The stromal components from 18 CFAs were subjected to Sanger sequencing of MED12 exon 2 and the TERT promoter hotspot loci. The epithelial and stromal components of two MED12 mutated CFAs were subjected to laser capture microdissection, and Sanger sequencing of MED12 exon 2, TERT promoter and PIK3CA exons 9 and 20, separately. RESULTS: MED12 exon 2 mutations were identified in the stroma of 17% of CFAs. The analyses of epithelial and stromal components, microdissected separately, revealed that MED12 mutations were restricted to the stroma. No TERT promoter or PIK3CA mutations in exons 9 and 20 were detected in analysed CFAs. CONCLUSIONS: Like conventional fibroadenomas, MED12 exon 2 mutations appear to be restricted to the stromal component of CFAs, supporting the notion that CFAs are stromal neoplasms.

Morphologic subtypes of lobular carcinoma in situ diagnosed on core needle biopsy: clinicopathologic features and findings at follow-up excision.

Lobular carcinoma in situ (LCIS) is currently classified as classic (CLCIS), florid (FLCIS), and pleomorphic (PLCIS). Given the rarity of FLCIS and PLCIS, information on their clinico-pathologic features and biologic potential remains limited. We evaluated the upgrade rates at excision of FLCIS and PLCIS diagnosed on inhouse core needle biopsy (CNB) and their clinical presentation and follow-up. Over a period of 11 and a half years, there were a total of 36 inhouse CNBs with pure PLCIS (n = 8), FLCIS (n = 24), or LCIS with pleomorphic features (LCIS-PF) (n = 4). The upgrade rates to invasive carcinoma or ductal carcinoma in situ (DCIS) were 25% for PLCIS (2/8), 17% for FLCIS (4/24), and 0% for LCIS-PF (0/4). The overall upgrade rate of PLCIS and FLCIS combined was 19% (6/32). All but one case (not upgraded at excision) were radiologic-pathologic concordant. Apocrine features, previously reported only in PLCIS, were also noted in FLCIS. HER2 overexpression was seen in 13% of cases. This study highlights the more aggressive biologic features of PLCIS and FLCIS compared to CLCIS and supports surgical management for these lesions.

Interobserver Variation of PD-L1 SP142 Immunohistochemistry Interpretation in Breast Carcinoma: A Study of 79 Cases Using Whole Slide Imaging.

CONTEXT.­: The Ventana programmed death ligand-1 (PD-L1) SP142 immunohistochemical assay (IHC) is approved by the US Food and Drug Administration as the companion diagnostic assay to identify patients with locally advanced or metastatic triple-negative breast cancer for immunotherapy with atezolizumab, a monoclonal antibody targeting PD-L1. OBJECTIVE.­: To determine interobserver variability in PD-L1 SP142 IHC interpretation in invasive breast carcinoma. DESIGN.­: The pathology database was interrogated for all patients diagnosed with primary invasive, locally recurrent, or metastatic breast carcinoma on which PD-L1 SP142 IHC was performed from November 2018 to June 2019 at our institution. A subset of cases was selected using a computerized random-number generator. PD-L1 IHC was evaluated in stromal tumor-infiltrating immune cells using the IMpassion130 trial criteria, with positive cases defined as immunoreactivity in immune cells in 1% or more of the tumor area. IHC was interpreted on whole slide images by staff pathologists with breast pathology expertise. Interobserver variability was calculated using unweighted κ. RESULTS.­: A total of 79 cases were assessed by 8 pathologists. Interobserver agreement was substantial (κ = 0.727). There was complete agreement among all 8 pathologists in 62% (49 of 79) of cases, 7 pathologists or more in 84% (66 of 79) of cases, and 6 pathologists or more in 92% (73 of 79) of cases. In 4% (3 of 79) of cases, all of which were small biopsies, pathologists' interpretations were evenly split between scores of positive and negative. CONCLUSIONS.­: The findings show substantial agreement in PD-L1 SP142 IHC assessment of breast carcinoma cases among 8 pathologists at a single institution. Further study is warranted to define the basis for discrepant results.

Secretory carcinoma of the breast: clinicopathologic profile of 14 cases emphasising distant metastatic potential.

AIMS: Secretory carcinoma of the breast (SCB) is a rare histological type of breast carcinoma with a generally indolent clinical behaviour. We aim to elucidate the clinical, pathological and molecular findings of SCB cases and identify characteristics associated with aggressive clinical courses. METHODS AND RESULTS: Fourteen patients with SCB were identified, including 12 women and two men, with a median age of 56 years (range = 8-81 years). Clinical data, histological diagnosis, molecular findings and follow-up were reviewed. Eight patients presented with palpable masses and four patients with radiographic abnormalities. All cases were unilateral. Surgical procedures included excisional biopsies and ipsilateral mastectomies. In 10 cases, oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) results were obtained, with six cases positive for ER and three positive for PR. All cases lacked HER2 overexpression. Sentinel lymph node biopsy was performed in 10 cases, and two patients had axillary lymph node metastasis. Follow-up ranged from 21 to 212 months (median = 70 months). Two patients developed distant metastasis of SCB. Molecular analysis of these aggressive tumours revealed amplification of the 16p13.3 locus, a TERT promotor mutation and loss of 9p21.3 locus. Review of the literature for SCB cases with distant metastasis was performed. CONCLUSIONS: Although SCBs are generally associated with a favourable prognosis, our study and review demonstrate that a subset of SCBs may develop distant metastases. Further studies are warranted to identify markers predictive of more aggressive clinical behaviour in this rare breast cancer subtype.

Long-Term Outcomes After Surgical Treatment of Malignant/Borderline Phyllodes Tumors of the Breast.

BACKGROUND: Malignant/borderline phyllodes tumors (PTs) are rare, and little is known about their long-term prognosis. This study sought to evaluate recurrence rates and identify factors associated with local and distant failure. METHODS: From 1957 to 2017, we identified 124 patients with 125 PTs (86 malignant and 39 borderline). Recurrence rates and survival were assessed using the Kaplan-Meier method, and correlated with clinicopathologic factors using the log-rank test. RESULTS: The median age of the patients was 44 years, and the median tumor size was 5 cm. Breast-conserving surgery was performed for 57% of the patients. At a median follow-up of 7.1 years, 14 patients experienced a locoregional recurrence (LRR), with a 10-year cumulative LRR incidence of 12%. On univariable analysis, age younger than 40 years (p = 0.02) and close/positive margins (p = 0.001) were associated with increased risk of LRR. Seven patients developed distant disease, all occurring in malignant PTs. The 10-year distant recurrence-free survival was 94%. Uniformly poor pathologic features consisting of marked stromal cellularity, stromal overgrowth, infiltrative borders, and 10 or more mitoses per 10 high-power fields (hpf) were identified in 25 PTs (20%), and all distant recurrences occurred in this group. For the patients who did not have uniformly poor features, the 10-year disease-specific survival was 100%, and the overall survival was 94% compared with 66% and 57%, respectively, among those with poor features. CONCLUSION: Malignant/borderline PTs without uniformly poor histologic features have an excellent prognosis after surgical resection, with a 10-year disease-specific survival of 100%. The presence of uniformly poor pathologic features predicts a poor prognosis. Efforts should be directed toward new treatment approaches for these tumors.

Recurrent MED12 exon 2 mutations in benign breast fibroepithelial lesions in adolescents and young adults.

AIMS: Most benign breast fibroepithelial lesions (FEL) in adults harbour recurrent somatic MED12 exon 2 mutations and rare TERT promoter hotspot mutations. We sought to determine the frequency of MED12 exon 2 and TERT promoter hotspot mutations in fibroadenomas (FA) and benign phyllodes tumours (BePT) in adolescents and young adults. METHODS: DNA from 21 consecutive FAs and eight consecutive BePTs in adolescents and young adults was subjected to Sanger sequencing of the exon 2 of MED12 and the TERT promoter hotspot locus. RESULTS: We identified MED12 exon 2 mutations in 62% and 88% of FAs and BePTs, respectively, and no TERT promoter hotspot mutations. The majority of the MED12 exon 2 mutations identified were in-frame deletions (60%). CONCLUSIONS: As in adults, benign FELs in juvenile patients harbour recurrent MED12 exon 2 mutations.

Phyllodes tumors with and without fibroadenoma-like areas display distinct genomic features and may evolve through distinct pathways.

Breast fibroepithelial lesions (fibroadenomas and phyllodes tumors) are underpinned by recurrent MED12 exon 2 mutations, which are more common in fibroadenomas and benign phyllodes tumors. TERT promoter hotspot mutations have been documented in phyllodes tumors, and found to be more frequent in borderline and malignant lesions. Several lines of evidence suggest that a subset of phyllodes tumors might arise from fibroadenomas. Here we sought to investigate the genetic differences between phyllodes tumors with fibroadenoma-like areas vs. those without. We retrieved data for 16 borderline/ malignant phyllodes tumors, including seven phyllodes tumors with fibroadenoma-like areas and nine phyllodes tumors without fibroadenoma-like areas, which had been previously subjected to targeted capture massively parallel sequencing. Whilst MED12 exon 2 mutations were significantly more frequent in tumors with fibroadenoma-like areas (71 vs. 11%), an enrichment in genetic alterations targeting bona fide cancer genes was found in those without fibroadenoma-like areas, in particular in EGFR mutations and amplifications (78 vs. 14%). No significant difference in the frequency of TERT genetic alterations was observed (71% in cases with fibroadenoma-like areas vs 56% in those without fibroadenoma-like areas). Our data suggest that the development of phyllodes tumors might follow two different evolutionary pathways: a MED12-mutant pathway that involves the progression from a fibroadenoma to a malignant phyllodes tumor; and a MED12-wild-type pathway, where malignant phyllodes tumors arise de novo through the acquisition of genetic alterations targeting cancer genes. Additional studies are warranted to confirm our observations and define whether the outcome differs between both pathways.

Breast MR imaging for the assessment of residual disease following initial surgery for breast cancer with positive margins.

OBJECTIVES: To determine the accuracy of post-operative MR in predicting residual disease in women with positive margins, emphasizing the size thresholds at which residual disease can be confidently identified. METHODS: This IRB-approved HIPAA-compliant retrospective study included 175 patients with MR after positive margins following initial surgery for breast cancer. Two expert readers independently re-evaluated MR images for evidence of residual disease at the surgical cavity and multifocal/multicentric disease. All patients underwent definitive surgery and MR findings were correlated to histopathology. RESULTS: 139/175 (79.4%) patients had residual disease at surgery. Average overall sensitivity, specificity, PPV and NPV for residual disease at the surgical cavity were 73%, 72%, 91% and 45%, respectively. The readers identified 42/45 (93%, reader 1) and 43/45 (95%, reader 2) patients with residual invasive disease at the cavity of ≥5 mm and 22/22 (100%, both readers) patients with disease ≥10 mm. Average sensitivity, specificity, PPV and NPV for unknown multifocal/multicentric disease were 90%, 96%, 93% and 86%, respectively. CONCLUSIONS: Post-operative breast MR can accurately depict ≥5-mm residual disease at the surgical cavity and unsuspected multifocal/multicentric disease. These findings have the potential to lead to more appropriate selection of second surgical procedures in women with positive margins. KEY POINTS: • Post-operative breast MRI accurately defines residual disease of ≥5 mm. • Surgical cavity sensitivities were high for both invasive carcinoma and DCIS. • Post-surgical changes and very small residual disease (<5 mm) may overlap. • Post-operative breast MRI may help planning an accurate re-resection.

Benign vascular lesions of the breast diagnosed by core needle biopsy do not require excision.

AIMS: Surgical excision of all benign vascular lesions of the breast identified by core needle biopsy has been recommended in the past to rule out a more serious lesion. In this study we investigated the clinical, radiological and pathological findings in patients diagnosed with a benign vascular lesion at our institution to assess whether excision may be spared for lesions without atypia. METHODS AND RESULTS: We searched the electronic medical record for patients with a vascular lesion of the breast diagnosed between 2000 and 2015. The study population consisted of 84 patients, 83 females and one male. The index diagnoses included 76 benign vascular lesions, five vascular lesions with cytological atypia and three angiosarcomas. A radiologist reviewed all pre- and post-biopsy imaging studies; all cases had concordant radiological and pathological findings. Based on radiological and histological correlation, the vascular lesion accounted for the radiological target in 40 (48%) cases and was deemed an incidental finding in 44 (52%). Seven of 32 (22%) targeted and 10 of 44 (23%) incidental benign vascular lesions underwent surgical excision; there were no upgrades at excision. No recurrences or clinical events were observed in patients with a targeted or incidental benign vascular lesion with a median follow-up of 39 months and 40.6 months, respectively. CONCLUSION: Our data suggest that benign vascular lesions diagnosed on core biopsy with concordant radiological and pathological findings do not warrant surgical excision.

Myxoid fibroadenomas differ from conventional fibroadenomas: a hypothesis-generating study.

AIMS: Breast myxoid fibroadenomas (MFAs) are characterized by a distinctive hypocellular myxoid stroma, and occur sporadically or in the context of Carney complex, an inheritable condition caused by PRKAR1A-inactivating germline mutations. Conventional fibroadenomas (FAs) are underpinned by recurrent MED12 mutations in the stromal components of the lesions. The aim of this study was to investigate the genomic landscape of MFAs and compare it with that of conventional FAs. METHODS AND RESULTS: Eleven MFAs from patients without clinical and/or genetic evidence of Carney complex were retrieved. DNA samples of tumour and matching normal tissue were subjected to massively parallel sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay, an assay targeting 410 cancer genes. Genetic alterations detected by MSK-IMPACT were tested in samples in which the stromal and epithelial components were separately laser capture-microdissected. Sequencing revealed no germline PRKAR1A mutations and non-synonymous mutations in six MFAs. Interestingly, in three of the MFAs in which the stromal and epithelial components were separately microdissected, the mutations were found to be restricted to the epithelial rather than the stromal component. The sole exception was a lesion harbouring a somatic truncating PRKAR1A mutation. Upon histological re-review, this case was reclassified as a breast myxoma, consistent with the spectrum of tumous observed in Carney complex patients. In this case, the PRKAR1A somatic mutation was restricted to the stromal component. CONCLUSION: MFAs lack MED12 mutations, and their stromal components seem not to harbour mutations in the 410 cancer genes tested. Whole-exome and/or whole-genome analyses of MFAs are required to elucidate their genetic drivers.

Cytologic assessment of estrogen receptor, progesterone receptor, and HER2 status in metastatic breast carcinoma.

BACKGROUND: Discordance in the receptor status between primary breast carcinomas (PBC) and corresponding metastasis is well documented. Interrogation of the receptor status of metastatic breast carcinoma (MBC) in cytology material is common practice; however, its utility has not been thoroughly validated. We studied patients with MBC, and evaluated the concordance rates of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) between PBC surgical specimens and corresponding MBC cell blocks (CBs). We correlated the findings with clinicopathologic variables and with the fixation methods used. METHODS: We searched for patients with MBC diagnosed on cytology from 2007 to 2009 and selected those with ER, PR and HER2 tested in both the PBC surgical specimens and the MBC CBs. We included CBs fixed in formalin and methanol based solution (CytoLyt®). All slides were reevaluated by cytopathologists. Clinical information was retrieved from the medical records. RESULTS: We studied 65 patients with PBC and MBC paired specimens. The concordance rates between PBC and MBC were 78.5%, 58.5% and 96.9%, for ER, PR and HER2, respectively. When discordant, PR status switched from positive (PBC) to negative (MBC) in most cases (23/27). The PR concordance rate was 45.2% for CBs fixed in formalin and 70.6% for those fixed with CytoLyt® (p=0.047). CONCLUSION: The ER, PR and HER2 concordance rates between the PBC and MBC CBs are similar to those reported in paired surgical specimens. PR status was the most prevalent discordance and was not accompanied by a switch in ER.

Genetic analysis of uterine adenosarcomas and phyllodes tumors of the breast.

Uterine adenosarcomas and breast phyllodes tumors (PTs) are morphologically similar, being composed of stromal projections in a leaf-like fashion lined by epithelial cells. Here, we investigated whether their histologic similarities would be mirrored at the genetic level. The previously reported repertoires of somatic genetic alterations found in 19 adenosarcomas and 22 PTs (six benign, six borderline, and 10 malignant) were compared. PTs significantly more frequently displayed mutations affecting MED12, the TERT gene promoter and bona fide cancer genes, whereas adenosarcomas harbored a higher rate of MDM2/CDK4 and TERT gene amplifications. Pathway analyses based on the genes affected by somatic genetic alterations in these tumors indicated that Wnt signaling likely plays a role in the biology of adenosarcomas and benign/borderline PTs. In conclusion, despite the differences at the gene level, PTs and adenosarcomas share remarkable morphologic similarities and enrichment for somatic genetic alterations affecting Wnt pathway-related genes.

Evaluation of breast tissue with confocal strip-mosaicking microscopy: a test approach emulating pathology-like examination.

Confocal microscopy is an emerging technology for rapid imaging of freshly excised tissue without the need for frozen- or fixed-section processing. Initial studies have described imaging of breast tissue using fluorescence confocal microscopy with small regions of interest, typically 750 × 750 ?? ? m 2 . We present exploration with a microscope, termed confocal strip-mosaicking microscope (CSM microscope), which images an area of 2 × 2 ?? cm 2 of tissue with cellular-level resolution in 10 min of excision. Using the CSM microscope, we imaged 34 fresh, human, large breast tissue specimens from 18 patients, blindly analyzed by a board-certified pathologist and subsequently correlated with the corresponding standard fixed histopathology. Invasive tumors and benign tissue were clearly identified in CSM strip-mosaic images. Thirty specimens were concordant for image-to-histopathology correlation while four were discordant.

How Often Is Treatment Effect Identified in Axillary Nodes with a Pathologic Complete Response After Neoadjuvant Chemotherapy?

BACKGROUND: False-negative rates (FNR) of sentinel node biopsy (SNB) after neoadjuvant chemotherapy (NAC) in node-positive (N+) breast cancer patients are <10 % when ≥3 negative SNs are obtained. Marking positive nodes has been suggested to reduce FNR. Identification of treatment effect in the nodes post-NAC is an alternative to decrease FNR. We evaluated the frequency of treatment effect in N+ patients after a pathologic complete response (pCR) with NAC. METHODS: Biopsy-proven N+ patients receiving NAC were identified. Patients with nodal pCR after axillary lymph node dissection (ALND) or SNB with dual mapping and ≥3 SNs removed were evaluated for treatment effect; ALND and SNB patients were compared. RESULTS: From January 2009 to December 2015, 528 N+ patients received NAC. Of these, 204 had a nodal pCR, 135 had an ALND, and 69 had SNB. Median age was 49 years, 15 % were hormone receptor positive (HR+)/HER2-, 27 % triple negative, and 58 % HER2+. The median number of nodes removed in ALND patients was 17 versus 4 in SNB patients. Treatment effect in nodes was identified in 192 patients (94 %) and was more common in ALND versus SNB patients (97 vs 88 %; p = .02). HR+ patients and patients without a breast pCR were less likely to have treatment effect in the nodes (p = .05). Other characteristics did not differ. CONCLUSIONS: Following NAC, SNs with treatment effect were retrieved in 88 % of patients without marking nodes, suggesting that nodal clipping may not be necessary to achieve an acceptable FNR. Longer follow-up is needed to determine regional recurrence rates in the SN-only cohort.

Breast intraductal papillomas without atypia in radiologic-pathologic concordant core-needle biopsies: Rate of upgrade to carcinoma at excision.

BACKGROUND: The surgical management of mammary intraductal papilloma without atypia (IDP) identified at core-needle biopsy (CNB) is controversial. This study assessed the rate of upgrade to carcinoma at surgical excision (EXC). METHODS: This study identified women with a CNB diagnosis of intraductal papilloma without atypia or carcinoma at a cancer center between 2003 and 2013. Radiologic-pathologic concordance was assessed for all cases, and discordant cases were excluded. The radiologic and clinicopathologic features of patients with a CNB diagnosis of IDP were correlated with an upgrade to carcinoma at EXC. RESULTS: The study population consists of 189 women with 196 IDPs; 166 women (171 IDPs) underwent EXC. The upgrade rate was 2.3% (4 of 171). The upgraded lesions were 2 invasive lobular carcinomas and 2 cases of ductal carcinoma in situ (DCIS). One case of DCIS involved the residual IDP, whereas the other 3 carcinomas were ≥ 8 mm away. Twenty-four women (25 IDPs) did not undergo EXC and had stable imaging on follow-up (median, 23.5 months). CONCLUSIONS: The upgrade rate at EXC for IDPs diagnosed at CNB with radiologic-pathologic concordance was 2.3%. These findings suggest that observation is appropriate for patients with radiologic-pathologic concordant CNB yielding IDP, regardless of its size. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2819-2827. © 2016 American Cancer Society.

The Genomic Landscape of Male Breast Cancers.

PURPOSE: Male breast cancer is rare, and its genomic landscape has yet to be fully characterized. Lacking studies in men, treatment of males with breast cancer is extrapolated from results in females with breast cancer. We sought to define whether male breast cancers harbor somatic genetic alterations in genes frequently altered in female breast cancers. EXPERIMENTAL DESIGN: All male breast cancers were estrogen receptor-positive, and all but two were HER2-negative. Fifty-nine male breast cancers were subtyped by immunohistochemistry, and tumor-normal pairs were microdissected and subjected to massively parallel sequencing targeting all exons of 241 genes frequently mutated in female breast cancers or DNA-repair related. The repertoires of somatic mutations and copy number alterations of male breast cancers were compared with that of subtype-matched female breast cancers. RESULTS: Twenty-nine percent and 71% of male breast cancers were immunohistochemically classified as luminal A-like or luminal B-like, respectively. Male breast cancers displayed a heterogeneous repertoire of somatic genetic alterations that to some extent recapitulated that of estrogen receptor (ER)-positive/HER2-negative female breast cancers, including recurrent mutations affecting PIK3CA (20%) and GATA3 (15%). ER-positive/HER2-negative male breast cancers, however, less frequently harbored 16q losses, and PIK3CA and TP53 mutations than ER-positive/HER2-negative female breast cancers. In addition, male breast cancers were found to be significantly enriched for mutations affecting DNA repair-related genes. CONCLUSIONS: Male breast cancers less frequently harbor somatic genetic alterations typical of ER-positive/HER2-negative female breast cancers, such as PIK3CA and TP53 mutations and losses of 16q, suggesting that at least a subset of male breast cancers are driven by a distinct repertoire of somatic changes. Given the genomic differences, caution may be needed in the application of biologic and therapeutic findings from studies of female breast cancers to male breast cancers. Clin Cancer Res; 22(16); 4045-56. ©2016 AACR.

Morphological and Immunohistochemical Reevaluation of Tumors Initially Diagnosed as Ovarian Endometrioid Carcinoma With Emphasis on High-grade Tumors.

Ovarian endometrioid carcinomas (OEC) of low grade have characteristic morphologic features, but high-grade tumors can mimic high-grade serous and undifferentiated carcinomas. We reviewed tumors initially diagnosed as OEC to determine whether a combination of pathologic and immunohistochemical features can improve histologic subclassification. Tumors initially diagnosed as OEC were reviewed using World Health Organization criteria. We also noted the presence of associated confirmatory endometrioid features (CEFs): (i) squamous metaplasia; (ii) endometriosis; (iii) adenofibromatous background; and (iv) borderline endometrioid or mixed Mullerian component. A tissue microarray was constructed from 27 representative tumors with CEF and 14 without CEF, and sections were stained for WT-1, p16, and p53. Of 109 tumors initially diagnosed as OEC, 76 (70%) tumors were classified as OEC. The median patient age was 55 years, and 75% of patients were younger than 60 years. Ninety-two percent presented with disease confined to the pelvis, and 87% of tumors were unilateral. The median tumor size was 11.8 cm. Only 3% of tumors were high grade (grade 3of 3). Eighty percent of cases had at least 1 CEF, and 59% had at least 2 CEFs. Eleven percent overexpressed p16, 0% overexpressed p53, and 3% expressed WT-1. Only 10% of patients died of disease at last follow-up. Thirty-three (33) tumors, or 30% of tumors originally classified as endometrioid, were reclassified as serous carcinoma (OSC). The median patient age was 54.5 years, and 59% of patients were younger than 60 years of age. Only 27% had disease confined to the pelvis at presentation, 52% of tumors were unilateral, and the median tumor size was 8 cm. Associated squamous differentiation, endometrioid adenofibroma, and endometrioid or mixed Mullerian borderline tumor (CEFs) were not present in any case, but 6% of patients had endometriosis. Approximately one half of the reclassified OSC demonstrated SET-pattern morphology (combinations of glandular, cribriform, solid, and transitional cell-like architecture) and were immunophenotypically indistinguishable from OSCs with papillary architecture. Sixty percent of OSC overexpressed p16, 50% overexpressed p53, and 82% expressed WT-1. At last follow-up, 52% had died of disease. Compared with OSC, OEC patients more frequently presented below 60 years of age (P=0.046), had low-stage tumors (P<0.001), were more frequently unilateral (P<0.001), more frequently had synchronous endometrial endometrioid carcinomas (P<0.001); and had no evidence of disease at last follow-up (P<0.001). Their tumors were of lower grade (P<0.001), had more CEFs (P<0.001), and less frequently overexpressed p16 and p53 (P=0.003 and P<0.001, respectively) and less frequently expressed WT-1 (P<0.001). This analysis emphasizes the diagnostic value of CEFs, the presence of a low-grade gland-forming endometrioid component, and WT-1 negativity, as valid, clinically relevant criteria for a diagnosis of OEC. Glandular and/or cribriform architecture alone may be seen in both OECs and OSCs and are therefore not informative of diagnosis. Further study is needed to elaborate the characteristics of the exceedingly rare high-grade OEC.

Massively parallel sequencing analysis of synchronous fibroepithelial lesions supports the concept of progression from fibroadenoma to phyllodes tumor.

Phyllodes tumors (PTs) and fibroadenomas (FAs) are fibroepithelial lesions (FELs) of the breast. Although mutations affecting exon 2 of MED12 are highly recurrent in FAs and PTs, TERT promoter hotspot mutations are frequently found in PTs but are vanishingly rare in FAs. Malignant transformation of benign PTs is well-documented, but the progression from FA to PT remains a matter of contention. Here we report on the somatic genetic alterations in multiple ipsilateral synchronous FELs (three FAs, one benign PT, and one malignant PT) occurring in the same patient. DNA samples extracted from each tumor and matched normal tissue were subjected to targeted massively parallel sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay. This analysis revealed MED12 mutations in all lesions. One FA and the benign PT harbored a MED12Gly44Val mutation, whereas another FA and the malignant PT displayed a MED12Gly44Asp mutation. The remaining FA had an independent distinct MED12Gly44Cys mutation. A formal clonality analysis suggested a clonal relationship between the FELs with identical MED12 mutations (P<0.05). A clonal TERT promoter hotspot mutation was identified exclusively in the malignant PT. The identification of distinct MED12 mutations in multifocal ipsilateral and synchronous FELs supports the notion that co-existing mammary fibroepithelial tumors can arise independently. Conversely, the co-existence of identical MED12 mutations indicates clonal relatedness among FAs and PTs, corroborating the hypothesis that FAs may constitute the substrate from which PTs develop. Our findings also support the notion that acquisition of TERT promoter mutations may drive the progression of FELs.

Classic lobular carcinoma in situ and atypical lobular hyperplasia at percutaneous breast core biopsy: outcomes of prospective excision.

BACKGROUND: No consensus exists on the need to excise breast lesions that yield classic lobular carcinoma in situ (LCIS) or atypical lobular hyperplasia (ALH) (known together as classic lobular neoplasia [LN]) as the highest risk lesion at percutaneous core-needle biopsy (CNB). Here, the authors report findings from 72 consecutive lesions with LN at CNB and prospective surgical excision (EXB). METHODS: Lesions that yielded LN at CNB at the authors' center have been referred for EXB since June 2004, regardless of imaging-histologic concordance. A lesion was "concordant" if histologic findings provided sufficient explanation for imaging. An upgrade consisted of ductal carcinoma in situ and/or invasive carcinoma at EXB. Statistical analysis, including 95% confidence intervals (CIs), was performed. RESULTS: Between June 2004 and May 2009, CNB of 85 consecutive lesions yielded LN without other high-risk histologies. Eighty of 85 lesions (94%) underwent prospective EXB. Seventy-two of 85 lesions (90%; 42 LCIS, 30 ALH) had concordant imaging-histologic findings. EXB yielded low-grade carcinoma in 2 of 72 cases (3%; 95% CI, 0%-9%). In both patients, stereotactic, 11-gauge, vacuum-assisted biopsy of calcifications yielded calcifications in benign parenchyma and ALH. CNB results were discordant in 8 of 80 lesions (10%; 4 LCIS, 4 ALH), and EXB yielded cancer in 3 of those 8 lesions (38%; 95% CI, 9%-76%). The upgrade rate was significantly higher for discordant lesions versus concordant lesions (38% vs 3%; P < .01). CONCLUSIONS: Prospective excision of LN identified carcinoma in 3% (95% CI, 0%-9%) of concordant cases versus 38% (95% CI, 9%-76%) of discordant cases. The current data provide an unbiased assessment of the upgrade rate of LN diagnosed at CNB.

Sentinel lymph node biopsy in the management of early-stage cervical carcinoma.

OBJECTIVES: We aimed to determine the sentinel lymph node detection rates, accuracy in predicting the status of lymph node metastasis, and if pathologic ultrastaging improves the detection of micrometastases and isolated tumor cells at the time of primary surgery for cervical cancer. METHODS: A prospective, non-randomized study of women with early-stage (FIGO stage IA1 with lymphovascular space involvement--IIA) cervical carcinoma was conducted from June 2003 to August 2009. All patients underwent an intraoperative intracervical blue dye injection. Patients who underwent a preoperative lymphoscintigraphy received a 99m Tc sulfur colloid injection in addition. All patients underwent sentinel lymph node (SLN) identification followed by a complete pelvic node and parametrial dissection. SLN were evaluated using our institutional protocol that included pathologic ultrastaging. RESULTS: SLN mapping was successful in 77 (95%) of 81 patients. A total of 316 SLN were identified, with a median of 3 SLN per patient (range, 0-10 SLN). The majority (85%) of SLN were located at three main sites: the external iliac (35%); internal iliac (30%); and obturator (20%). Positive lymph nodes (LN) were identified in 26 (32%) patients, including 21 patients with positive SLN. Fifteen of 21 patients (71%) had SLN metastasis detected on routine processing. SLN ultrastaging detected metastasis in an additional 6/21 patients (29%). Two patients had grossly positive LN at exploration, and mapping was abandoned. Three of 26 (12%) patients had successful SLN mapping; however, the SLN failed to identify the metastatic LN. Of these 3 false negative cases, 2 patients had a metastatic parametrial node as the only positive LN with multiple negative pelvic nodes including negative SLN. One patient with stage IA1 disease and lymphovascular invasion had unilateral SLN mapping and a metastatic common iliac LN identified on completion lymphadenectomy of the contralateral side that did not map. The 4 (5%) patients with unsuccessful mapping included 1 who had grossly positive nodes identified at the time of laparotomy; the remaining 3 occurred during each surgeon's initial SLN mapping learning phase. CONCLUSION: SLN mapping in early-stage cervical carcinoma yields high detection rates. Ultrastaging improves micrometastasis detection. Parametrectomy and side-specific lymphadenectomy (in cases of failed mapping) remain important components of the surgical management of selected cases.