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Background: Breast cancer, the most common cancer type among women, was recently found to contain a specific tumor microbiome, but its impact on host biology remains unclear. CD8 + tumor-infiltrating lymphocytes (TILs) are pivotal effectors of anti-tumor immunity that influence cancer prognosis and response to therapy. This study aims to elucidate interactions between CD8 + TILs and the breast tumor microbiome and metabolites, as well as how the breast tumor microbiome may affect the tumor metabolome., Methods: We investigated the interplay among CD8 + TILs, the tumor microbiome, and the metabolome in a cohort of 46 breast cancer patients with mixed subtypes (Cohort A). We characterized the tumor metabolome by mass spectrometry and CD8 + TILs by immunohistochemistry. Microbiome composition and T cell gene transcript levels were obtained from data from our previous study, which utilized 16S rRNA gene sequencing and a targeted mRNA expression panel. To examine interactions between intratumoral Staphylococcus and specific breast cancer subtypes, we analyzed RNA sequencing data from an independent cohort of 370 breast cancer patients (Cohort B). We explored the functions of the tumor microbiome using mouse models of triple-negative breast cancer (TNBC)., Results: In tumors from Cohort A, the relative abundance of Staphylococcus positively correlated with the expression of T cell activation genes. The abundances of multiple metabolites exhibited significant correlations with CD8 + TILs, of which NADH, γ-glutamyltryptophan, and γ-glutamylglutamate displayed differential abundance in Staphylococcus -positive versus Staphylococcus -negative breast tumors. In a larger breast cancer cohort (Cohort B), we observed positive correlations between tumoral Staphylococcus and CD8 + TIL activity exclusively in TNBC. Preclinical experiments demonstrated that intratumoral administration of S. aureus , the predominant species of Staphylococcus in human breast tumors, resulted in a depletion of total NAD metabolites, and reduced the growth of TNBC tumors by activating CD8 + TILs., Conclusions: We identified specific metabolites and microbial taxa associated with CD8 + TILs, delineated interactions between the breast tumor microbiome and metabolome, and demonstrated that intratumoral Staphylococcus influences anti-tumor immunity and TIL-associated metabolites. These findings highlight the role of low-biomass microbes in tumor tissues and provide potential biomarkers and therapeutic agents for breast cancer immunotherapy that merit further investigation., Competing Interests: Competing interests The authors declare that they have no competing interests.

Introduction: Solitary fibrous tumor (SFT) is a fibroblastic tumor with malignant potential that is underpinned by a recurrent inv12(q13q13)-derived NAB2::STAT6 fusion. Breast and axilla are uncommon locations for this entity. Methods: Records of two academic institutions were electronically searched for breast and axillary SFTs. Clinical and pathologic data were reviewed. Literature review for breast or axillary SFTs was performed. Present study and previously reported tumors were stratified using five SFT risk models: original and modified Demicco metastatic risk, Salas local recurrence risk, Salas metastatic risk, and Thompson local recurrence risk. Results: Five patients with breast or axillary SFT were identified. Median age was 49 years, and median follow-up (available for four patients) was 82 months. Three patients showed no evidence of disease, and one developed recurrence. Literature review identified 58 patients with breast or axillary SFT. Median age was 54 years, and median follow-up (available for 35 patients) was 24 months. Thirty-one patients showed no evidence of disease, three developed recurrence, and one developed metastasis. Original and modified Demicco models and Thompson model showed the highest sensitivity; original and modified Demicco models and Salas metastatic risk model demonstrated the highest specificity. Kaplan-Meier models were used to assess recurrence-free probability (RFP). Original and modified Demicco models predicted RFP when stratified by "low risk" and "moderate/intermediate and high risk" tumor, though sample size was small. Conclusions: While many SFTs of breast and axilla remain indolent, a subset may develop recurrence and rarely metastasize. The modified Demicco risk model demonstrated optimal performance characteristics., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Neoadjuvant chemotherapy is often administered for high-grade serous ovarian carcinoma (HGSC) prior to cytoreductive surgery. We evaluated treatment response by CT (simplified peritoneal carcinomatosis index [S-PCI]), pathology (chemotherapy response score [CRS]), laboratory markers (serum CA-125), and surgical outcomes, to identify predictors of disease-free survival., Methods: For this retrospective, HIPAA-compliant, IRB-approved study, we identified 396 women with HGSC receiving neoadjuvant chemotherapy between 2010 and 2019. Two hundred and ninety-nine patients were excluded (surgery not performed; imaging/pathology unavailable). Pre- and post-treatment abdominopelvic CTs were assigned CT S-PCI scores 0-24 (higher score indicating more tumor). Specimens were assigned CRS of 1-3 (minimal to complete response). Clinical data were obtained via chart review. Univariate, multivariate, and survival analyses were performed., Results: Ninety-seven women were studied, with mean age of 65 years ± 10. Interreader agreement was good to excellent for CT S-PCI scores (ICC 0.64-0.77). Despite a significant decrease in CT S-PCI scores after treatment (p < 0.001), mean decrease in CT S-PCI did not differ significantly among CRS categories (p = 0.20) or between patients who were optimally versus suboptimally debulked (p = 0.29). In a survival analysis, lower CRS (more viable tumor) was associated with shorter time to progression (p < 0.001). A joint Cox proportional-hazard models showed that only residual pathologic disease (CRS 1/2) (HR 4.19; p < 0.001) and change in CA-125 (HR 1.79; p = 0.01) predicted progression., Conclusion: HGSC response to neoadjuvant therapy by CT S-PCI did not predict pathologic CRS score, optimal debulking, or progression, revealing discordance between imaging, pathologic, biochemical, and surgical assessments of tumor response., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Nipple adenoma (NA) is a rare, benign proliferation of the nipple ducts. It may be clinically mistaken for Paget disease or squamous cell carcinoma; thus, microscopic evaluation is paramount. A large case series of NA has not been undertaken since the 1980s. Therefore, we undertook this study to evaluate the clinicopathologic characteristics of NA, emphasizing differential diagnoses and follow-up data. We retrieved 50 cases from our in-house archives or consultation files between 2003 and 2022. Available slides were reviewed, and clinical data and follow-up information were obtained. Cases must have exhibited a dense ductal proliferation in the breast tissue with proximity to the nipple epidermis. All patients were women; median age was 56 years. In all, 68% of patients were symptomatic; 53% demonstrated a skin growth. Overall, 67% were excised completely, either primarily (33%) or via re-excision after biopsy (33%). Four histologic patterns were noted: adenosis (dense proliferation of small-to-medium ducts); large duct (medium-to-large caliber ducts); papillary-like (frond-like architecture with branching, slit-like lumens); and pseudoinfiltrative (ducts squished and distorted by dense stromal fibrosis). Follow-up in 44 patients (88%) with a median time of 66 months showed no evidence of recurrence. NA demonstrates a wide spectrum of histopathologic variation. Subtyping of this entity is unlikely to be clinically relevant. Differentiation from invasive carcinoma or other histologic mimics (syringocystadenoma papilliferum, syringomatous adenoma) may be difficult. Simple excision is curative, and recurrence is rare. A definitive link to invasive carcinoma has not been established., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

This report describes 3 cases of ovarian tumors with unusual glandular proliferations co-expressing estrogen receptor and CDX-2 by immunohistochemistry set in cystadenofibromatous background. Targeted next-generation sequencing was performed on the cyst lining epithelium and glandular proliferations for all cases; CTNNB1 mutations were detected in the glandular proliferations of all neoplasms. The cyst lining of case 1 demonstrated a different CTNNB1 mutation from the matched glandular proliferation. No mutations were detected in the cyst lining from case 2. The cyst lining and glandular proliferation for case 3 harbored identical ATM and PIK3CA mutations with an additional CTNNB1 mutation in the glandular proliferation. To our knowledge, this is the first reported series of endometrioid proliferations with co-expression of estrogen receptor and CDX-2 in cystadenofibromatous background., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 by the International Society of Gynecological Pathologists.)

Background and Objectives: Given the significant benefit of targeted therapies for HER2+ breast cancer patients in both the neoadjuvant and adjuvant settings, it is critical to identify all eligible patients for these treatments. We sought to investigate cT1cN0 HER2+ patients to determine the rate of postsurgical nodal positivity, and to identify presurgical factors associated with nodal positivity. We hypothesize there is a subset of underdiagnosed HER2+ patients who would benefit from preoperative axillary imaging and inclusion in neoadjuvant chemotherapy regimens., Methods: We performed a 10-year retrospective analysis of T1 HER2+ breast cancer patients. Clinicopathologic characteristics were evaluated based on surgical nodal data., Results: We identified 38 patients with cT1cN0 HER2+ cancer. Of this cohort, 24% had positive lymph nodes on final pathology. High tumor grade (p = 0.035) on core needle biopsy and the presence of lymphovascular invasion (p = 0.0036) were associated with an increased likelihood of lymph node positivity. The majority (66%) of lymph node positive patients were clinically T1c., Conclusions: We identified a 24% nodal positivity rate in clinically node negative T1 HER2+ breast cancer patients. In particular, HER2+ patients with high-grade T1c cancers should undergo preoperative diagnostic axillary imaging to expand potential benefit from targeted therapies., (© 2022 Wiley Periodicals LLC.)

Aims: As gender-affirming surgery is becoming more common, it is important for pathologists to recognize potential benign findings to avoid misinterpretation. Cervical transitional cell metaplasia and superficial clusters of small basophilic cells have been described in the context of gender-affirming testosterone therapy; these findings may be misdiagnosed as high-grade squamous intraepithelial lesions or endometrial cells on Pap smears. Prostatic metaplasia has been reported in the surface squamous epithelium of the vagina and the uterine cervix in individuals undergoing gender-affirming androgen therapy; this finding is often associated with NKX3.1-positive basal keratinocytes. The aim of this study was to assess the morphological and immunohistochemical features of the uterine cervix in gender-affirming hysterectomies in comparison with benign hysterectomies from cisgender women., Methods and Results: We assessed the morphological and immunohistochemical features of the uterine cervix in 49 gender-affirming hysterectomies as compared with 57 hysterectomies from cisgender patients to establish the relative prevalences of surface prostatic metaplasia, NKX3.1-positive basal keratinocytes, transitional cell metaplasia, and small basophilic cells in the cervical squamous epithelium. The cervical tissue from the gender-affirming therapy cohort showed significantly higher prevalences of NKX3.1-positive basal keratinocytes (86% versus 1.8%), transitional cell metaplasia (80% versus 3.5%), superficial clusters of small basophilic cells (67% versus 7%), and surface prostatic metaplasia (43% versus 3.5%)., Conclusion: NKX3.1-positive basal keratinocytes, transitional cell metaplasia, small basophilic cells and surface prostatic metaplasia are all more prevalent in the cervices of individuals receiving gender-affirming testosterone therapy; awareness of this fact allows pathologists to avoid the overdiagnosis of dysplasia or the recommendation of unnecessary follow-up procedures., (© 2022 John Wiley & Sons Ltd.)

Accurate diagnosis of differentiated vulvar intraepithelial neoplasia (dVIN) is challenging, in part due to the sometimes subtle nature of its atypia. Many dVIN lesions demonstrate aberrant p53 staining; however, staining patterns overlap between dVIN and benign/reactive entities. We evaluate a p53/CK17 dual stain in an initial cohort of dVIN (n=30), benign vulvar skin (n=5), lichen sclerosus (LS, n=10), lichen simplex chronicus (LSC, n=10), and pseudoepitheliomatous hyperplasia (PEH, n=10). In the initial cohort, aberrant p53 staining was seen only in dVIN (50%, 15/30). Equivocal p53 staining patterns were seen in dVIN (37%, 11/30), LS (50%, 5/10), LSC (40%, 4/10), and PEH (40%, 4/10). All 30 dVIN cases were positive for CK17 (strong partial-thickness or full-thickness staining), but positive CK17 staining was also seen in LS (70%, 7/10), LSC (50%, 5/10), and PEH (100%, 10/10). In the initial cohort, the combination of aberrant p53 and positive CK17 was seen only for dVIN (50%, 15/30). Forty cases of LS with known follow-up (20 with progression to dVIN, 20 without) were stained to assess prognostic value. Three LS cases showed aberrant p53 staining with CK17 positivity; all progressed to dVIN. Equivocal p53 staining and CK17 positivity were seen in cases with and without progression. The p53/CK17 dual stain is more diagnostically useful than either stain alone. Negative/focal staining for CK17 argues against a diagnosis of dVIN, while aberrant p53 staining with CK17 positivity strongly supports the diagnosis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 by the International Society of Gynecological Pathologists.)

Aims: Atypical polypoid adenomyoma (APAM) is an uncommon uterine lesion composed of complex endometrioid glands with frequent squamous morular metaplasia and fibromuscular stroma. On endometrial curettage, biopsy or polypectomy specimens, the admixture of endometrioid glands and smooth muscle raises the differential diagnosis of myoinvasive endometrioid carcinoma. Reproductive-age APAM patients may opt for fertility preservation, whereas myoinvasive carcinoma is treated surgically. One previous study reported an incidental finding that the stroma of APAM, in contrast to that of other polypoid lesions, was SATB2-positive. APAM has also been reported to show increased stromal p16 staining. We aimed to assess whether SATB2 and p16 are useful stains for the distinction of APAM from myoinvasive carcinoma and benign adenomyomatous polyps., Methods and Results: Cases of 'atypical polypoid adenomyoma' (n = 32), 'adenomyomatous polyp' (n = 39) and 'myoinvasive endometrioid carcinoma' (n = 30) were identified. Morphological features were assessed, along with the intensity and extent of SATB2 and p16 staining in the stromal component of each lesion. SATB2 expression was seen in the stromal components of 30 of 32 (94%) APAMs, versus none of 39 (0%) benign adenomyomatous polyps and five of 30 (17%) myoinvasive endometrioid carcinomas. Stromal p16 expression was seen in 31 of 31 (100%) APAMs, versus 20 of 39 (51%) benign adenomyomatous polyps and 12 of 30 (40%) myoinvasive endometrioid carcinomas., Conclusions: Patchy to diffuse SATB2 and block-type p16 staining of fibromuscular stroma separating atypical endometrioid glands is more consistent with APAM than with myoinvasive endometrioid carcinoma. These stains are potentially useful adjuncts to careful morphological evaluation of endometrial biopsies/curettings., (© 2021 John Wiley & Sons Ltd.)

Purpose: To examine radiologic-histopathologic correlation and the diagnostic performance of transvaginal US prior to risk-reducing salpingo-oophorectomy (RRSO) in women at high risk for tubo-ovarian carcinoma (TOC)., Materials and Methods: This retrospective study included 147 women (mean age, 49 years; age range, 28-75 years) at high risk for TOC who underwent transvaginal US within 6 months of planned RRSO between May 1, 2007, and March 14, 2018. Histopathologic results were reviewed. Fellowship-trained abdominal radiologists reinterpreted transvaginal US findings by using standardized descriptors. Descriptive statistical analysis and multiple logistic regression were performed., Results: Of the 147 women, 136 had mutations in BRCA1 , BRCA2 , Lynch syndrome, BRIP1 , and RAD51D genes, and 11 had a family history of TOC. Histopathologic reports showed 130 (88.4%) benign nonneoplastic results, 10 (6.8%) benign neoplasms, five (3.4%) malignant neoplasms, and two (1.4%) isolated p53 signature lesions. Transvaginal US results showed benign findings in 95 (64.6%) women and abnormal findings in 11 (7.5%) women; one or both ovaries were not visualized in 41 (27.9%) women. Hydrosalpinx was absent in all TOC and p53 signature lesions at transvaginal US. Transvaginal US had 20% sensitivity (one of five), 93% specificity (132 of 142), 9% positive predictive value (one of 11), and 97% negative predictive value (132 of 136) for TOC. Cancer was detected in one of five women at transvaginal US, and three of five false-negative lesions were microscopic or very small., Conclusion: Preoperative transvaginal US had low sensitivity for detecting TOC in women at high risk for TOC. Clinically relevant precursors and early cancers were too small to be detected. Keywords: Genital/Reproductive, Ultrasound Supplemental material is available for this article. © RSNA, 2020., Competing Interests: Disclosures of Conflicts of Interest: M.D.S. disclosed no relevant relationships. N.E.C. disclosed no relevant relationships. W.R.M. disclosed no relevant relationships. M.M.L. disclosed no relevant relationships. E.B.S. disclosed no relevant relationships. A.P.W. disclosed no relevant relationships. A.P.S. disclosed no relevant relationships. S.U. disclosed no relevant relationships. M.D.P. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: payment from Davies McFarland & Carroll for expert testimony in a trial. Other relationships: disclosed no relevant relationships. K.E.M. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: paid royalties from Elsevier and Wolters Kluwer for educational publishing. Other relationships: disclosed no relevant relationships., (2020 by the Radiological Society of North America, Inc.)

Ovarian germ cell tumors, including yolk sac tumors, are most commonly diagnosed in children and young women. Most so-called yolk sac tumors reported in women >35 years old have been associated with an epithelial proliferation (endometriosis or carcinoma). Here, we describe eight cases clinically diagnosed as uterine or ovarian germ cell tumors in women >35 years old. In addition to routine morphologic examination and immunohistochemical evaluation, we present data from targeted next-generation sequencing (NGS) and isochromosome (12p) fluorescence in situ hybridization (FISH). We identified two groups of tumors with mixed germ cell and epithelial features: (1) tumors with background endometriosis and endometrioid carcinoma-like mutations (PTEN, PIK3CA, FGFR2, and CTNNB1), and (2) high-grade morphology, presumptive presence of isochromosome (12p) by FISH, and TP53 or PIK3CA mutations. These findings support the notion that the "germ cell tumor" component of these tumors is often somatically derived. Two tumors in our cohort were from premenopausal women; one showed no detectable mutations by NGS (suggestive of germ cell derivation), whereas the other showed PIK3CA, PTEN, and CTNNB1 mutations (suggestive of somatic derivation). Accurate classification of these tumors is likely important for selection of appropriate chemotherapy.

Context.—: Cellular spindled histiocytic pseudotumor (CSHPT) is an exuberant, dense histiocytic proliferation seen in the setting of mammary fat necrosis. CSHPT has a broad histologic differential diagnosis, including benign, malignant, and inflammatory etiologies., Objectives.—: To highlight the most important histologic and immunohistochemical findings of CSHPT and provide comparisons to entities within the broad differential diagnosis., Data Sources.—: Recently published literature regarding CSHPT and other diagnostic considerations., Conclusions.—: CSHPT is a benign histiocytic proliferation with a broad differential diagnosis, for which comprehensive ancillary studies may be required to exclude malignant and infectious entities.

The molecular events driving low-grade endometrioid endometrial carcinoma (LGEC) development-like in many cancers-are incompletely understood. Hence, here we performed multiregion, comprehensive somatic molecular profiling of routinely processed formalin-fixed, paraffin-embedded (FFPE) material from 13 cases of LGEC totaling 64 minute, spatially defined cell populations ranging from presumed precursor lesions through invasive LGEC. Shared driving PTEN, PIK3R1 , or PIK3CA mutations support clonal origin of the samples in each case, except for two cases with two clonally distinct neoplastic populations, consistent with unexpected multiclonality in LGEC development. Although substantial heterogeneity in driving somatic alterations was present across populations in nearly all cases, these alterations were usually clonal in a given population, supporting continued selection and clonal sweeping of driving alterations in populations with both precursor and LGEC histology. Importantly, CTNNB1 mutational status, which has been proposed as both prognostic and predictive in LGEC, was frequently heterogeneous and subclonal, occurring both exclusively in precursor or cancer populations in different cases. Whole-transcriptome profiling of coisolated RNA from 12 lesions (from 5 cases) was robust and confirmed histologic and molecular heterogeneity, including activated Wnt signaling in CTNNB1 -mutant versus wild-type populations. Taken together, we demonstrate clinically relevant multiclonality and intratumoral heterogeneity during LGEC development with important implications for diagnosis, prognosis, and therapeutic prediction. More broadly, our methodology is broadly scalable to enable high-throughput genomic and transcriptomic characterization of precursor and invasive cancer populations from routine FFPE specimens. IMPLICATIONS: Multiregion profiling of LGEC populations using a highly scalable approach demonstrates clinically relevant multiclonality and intratumoral heterogeneity., (©2019 American Association for Cancer Research.)

There are many ovarian cancer subtypes, giving rise to a range of appearances at gross pathology and magnetic resonance (MR) imaging. Certain fundamental concepts at MR, arising from underlying tissue characteristics, can provide guidance to radiologists in suggesting a diagnosis. The ability of multiparametric MR to risk stratify ovarian masses can contribute substantially to clinical decision making and patient management., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Mechanisms by which NPM-ALK signaling regulates cell migration, invasion and contributes to the oncogenesis of anaplastic large cell lymphoma (ALCL) are not completely understood. In an attempt to identify novel actin signaling pathways regulated by NPM-ALK, a comprehensive phosphoproteome analysis of ALCL cell lines was performed in the presence or absence of NPM-ALK activity. Numerous phosphoproteins involved in actin dynamics including Wiskott-Aldrich syndrome protein (WASp) were regulated by NPM-ALK. Network analysis revealed that WASp is a central component of the NPM-ALK-dependent actin signaling pathway. Here we show that NPM-ALK phosphorylates WASp at its known activation site (Y290) as well as at a novel residue (Y102). Phosphorylation of WASp at Y102 negatively regulates its interaction with Wiskott-Aldrich interacting protein and decreases its protein stability. Phosphorylation of WASp at Y102 enhances anchorage-independent growth and tumor growth in an in vivo xenograft model and enhances invasive properties of ALCL. We show that knock-down of WASp or expression of Y102F mutant of WASp decreases colony formation and in vivo tumor growth. Our results show that WASp is a novel substrate of ALK and has a critical role in regulating invasiveness and oncogenesis of ALCL.

Rationale and Objectives: This study aimed to determine whether uterine leiomyoma can be distinguished from uterine leiomyosarcoma on ultrasound (US), computed tomography (CT), and/or magnetic resonance imaging (MRI) without diffusion-weighted imaging., Materials and Methods: Institutional review board approval was obtained and informed consent was waived for this Health Insurance Portability and Accountability Act-compliant retrospective case-control diagnostic accuracy study. All subjects with resected uterine leiomyosarcoma diagnosed over a 17-year period (1998-2014) at a single institution for whom pre-resection US (n = 10), CT (n = 11), or MRI (n = 7) was available were matched by tumor size and imaging modality with 28 subjects with resected uterine leiomyoma. Six blinded radiologists (three attendings, three residents) assigned 5-point Likert scores for the following features: (1) margins, (2) necrosis, (3) hemorrhage, (4) vascularity, (5) calcifications, (6) heterogeneity, and (7) likelihood of malignancy (primary end point). Mean suspicion scores were calculated and receiver operating characteristic curves were generated. The ability of individual morphologic features to predict malignancy was assessed with logistic regression., Results: Mean suspicion scores were 2.5 ± 1.2 (attendings) and 2.4 ± 1.3 (residents) for leiomyoma, and 2.7 ± 1.3 (attendings) and 2.7 ± 1.4 (residents) for leiomyosarcoma. The areas under the receiver operating characteristic curves (range: 0.330-0.685) were not significantly different from chance, either overall (P = .36-.88) or by any modality (P = .28-.96), for any reader. Reader experience had no effect on diagnostic accuracy. No morphologic parameter was significantly predictive of malignancy (P = .10-.97)., Conclusions: Uterine leiomyoma cannot be differentiated accurately from leiomyosarcoma on US, CT, or MRI without diffusion-weighted imaging., (Copyright © 2016 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: Vascular malformations are congenital abnormalities that do not spontaneously regress and may require surgical resection for treatment., Case: A healthy 23-year-old woman presented with a painless, slowly enlarging mass of the mons pubis. Ultrasonography and magnetic resonance imaging demonstrated a cystic mass with minimal Doppler flow. The final pathology showed a combined lymphatic-venous vascular malformation. A meshed advancement flap was used to close the skin after surgical resection. These flaps create a lattice of small cutaneous defects that heal rapidly by secondary intention and optimize wound healing., Conclusion: Lower genital tract vascular malformations are rare but often become symptomatic in adolescents or young women. Larger lesions may warrant surgical resection. Flap closures may aid in proper wound healing.

MDM2 amplification is known to occur in a variety of neoplasms and its detection by fluorescence in situ hybridization is helpful in distinguishing well-differentiated and dedifferentated liposarcoma from classic lipoma. We recently evaluated a mesenteric mass initially diagnosed as dedifferentiated liposarcoma, largely due to the neoplasm's myxoid morphology and MDM2 expression by immunohistochemistry, from a 46-yr-old woman with a history of uterine low-grade endometrial stromal sarcoma (LG-ESS) with a JAZF1 rearrangement. Our workup of the mesenteric mass revealed a JAZF1 rearrangement and a revised diagnosis of metastatic LG-ESS with myxoid change was rendered. Retrospective testing of the mesenteric mass was negative for MDM2 amplification, an uncommon, but known diagnostic pitfall in MDM2 expression by immunohistochemistry. As MDM2 amplification is not specific for the diagnosis of liposarcoma, we investigated its occurrence in 43 cases of endometrial stromal tumors: 14 uterine LG-ESS, 11 metastatic or recurrent uterine LG-ESS, 8 undifferentiated uterine sarcomas, 5 endometrial stromal nodules, and 4 high-grade ESS with YHWAE rearrangement. In addition, 40 of the 43 cases had previously undergone fluorescence in situ hybridization analysis of JAZF1, PHF1, and YHWAE. Two of the 43 cases (5%) had MDM2 amplification: one was a uterine LG-ESS (JAZF1 rearrangement) and the other was a undifferentiated uterine sarcoma (polysomy intact JAZF1, PHF1, and YHWAE), both metastatic to the lung. Both cases positive for MDM2 amplification showed MDM2 expression by immunohistochemistry. At last follow-up, both patients had died of disease (19 and 60 mo). Our study is the first to demonstrate MDM2 amplification in endometrial stromal tumor. Awareness of MDM2 amplification in endometrial stromal tumor is critical; particularly in locations more common to liposarcoma, to avoid diagnostic errors.

Retinoblastoma (RB) is the most common primary intraocular cancer in children, and the third most common cancer overall in infants. No molecular-targeted therapy for this lethal tumor exists. Since the tumor suppressor RB1, whose genetic inactivation underlies RB, is upstream of the epigenetic regulator EZH2, a pharmacologic target for many solid tumors, we reasoned that EZH2 might regulate human RB tumorigenesis. Histologic and immunohistochemical analyses were performed using an EZH2 antibody in sections from 43 samples of primary, formalin-fixed, paraffin-embedded human RB tissue, cryopreserved mouse retina, and in whole cell lysates from human RB cell lines (Y79 and WERI-Rb1), primary human fetal retinal pigment epithelium (RPE) and fetal and adult retina, mouse retina and embryonic stem (ES) cells. Although enriched during fetal human retinal development, EZH2 protein was not present in the normal postnatal retina. However, EZH2 was detected in all 43 analyzed human RB specimens, indicating that EZH2 is a fetal protein expressed in postnatal human RB. EZH2 expression marked single RB cell invasion into the optic nerve, a site of invasion whose involvement may influence the decision for systemic chemotherapy. To assess the role of EZH2 in RB cell survival, human RB and primary RPE cells were treated with two EZH2 inhibitors (EZH2i), GSK126 and SAH-EZH2 (SAH). EZH2i impaired intracellular adenosine triphosphate (ATP) production, an indicator of cell viability, in a time and dose-dependent manner, but did not affect primary human fetal RPE. Thus, aberrant expression of a histone methyltransferase protein is a feature of human RB. This is the first time this mechanism has been implicated for an eye, adnexal, or orbital tumor. The specificity of EZH2i toward human RB cells, but not RPE, warrants further in vivo testing in animal models of RB, especially those EZH2i currently in clinical trials for solid tumors and lymphoma.

Objectives: In an era of precision medicine, our aim was to determine the frequency and theranostic potential of mutations identified in malignant lymph nodes (LNs) sampled by endoscopic ultrasound fine-needle aspiration (EUS FNA) of patients with rectal cancer by targeted next-generation sequencing (NGS)., Methods: The NGS Ion AmpliSeq Cancer Hotspot Panel v2 (Life Technologies, Carlsbad, CA) and MiSeq (Illumina, San Diego, CA) sequencers were used to sequence and assess for 2,800 or more possible mutations in 50 established cancer-associated genes., Results: Among 102 patients, 89% had 194 pathogenic alterations identified in 19 genes. The identification of KRAS, NRAS, or BRAF mutations suggests that 42% are likely nonresponders to anti-epidermal growth factor receptor therapy. Among KRAS, NRAS, or BRAF wild-type patients, alterations in eight genes linked to alternative therapies were identified in 44%., Conclusions: Our data demonstrate the successful ability to apply a single multiplex test to allow multigene mutation detection from malignant LN cytology specimen DNA collected by EUS FNA., (Copyright© by the American Society for Clinical Pathology.)

Objective: This study aimed to determine the progression-free interval (PFI) for patients with platinum-resistant ovarian cancer on antiestrogen therapy (AET), and to correlate PFI with tumor estrogen receptor (ER) expression status., Materials and Methods: This single-institution retrospective cohort study investigated platinum-resistant epithelial ovarian, fallopian tube, and primary peritoneal cancers treated with tamoxifen or an aromatase inhibitor from January 1999 to January 2012. Median PFI was calculated and a 95% confidence interval was constructed by bootstrapping. Relationships of PFI with disease characteristics were examined using 1-way analysis of variance or Pearson correlation. Estrogen receptor status of tumor specimens was assessed by immunohistochemistry. Progression-free interval was compared between ER groups with the Mann-Whitney test. Kaplan-Meier estimate was used to determine overall survival., Results: Ninety-nine patients met inclusion criteria: 77 (78%) received tamoxifen and 22 (22%) an aromatase inhibitor. Patients had a mean of 4 prior chemotherapy regimens (range, 1-14). Median PFI for any AET was 4.0 months (range, 1-49; 95% confidence interval, 3.0-5.0). Progression-free interval was independent of the number of prior treatments and type of AET, but longer with earlier stage at diagnosis. Estrogen receptor status was obtained for 63 patients, 44 were positive and 19 were negative. Progression-free interval was not statistically significant between ER-positive (median, 4.0 months) and ER-negative (median, 2.0 months) tumor status (P = 0.36)., Conclusions: This is the largest study to date investigating AET in heavily pretreated, platinum-resistant ovarian cancer patients. The median PFI of 4.0 months is comparable to standard cytotoxic therapies, and some patients with PFI greater than this median interval had ER-negative tumors. Given the limited adverse effects of AET, as well as low cost including oral administration, this treatment should be considered in all patients with platinum-resistant ovarian cancer.

Transthoracic fine needle aspiration (TFNA)/core needle biopsy (CNB) under computed tomography (CT) guidance has proved useful in the assessment of pulmonary nodules. We sought to determine the TFNA false-negative (FN) rate at our institution and identify potential causes of FN diagnoses. Medical records were reviewed from 1,043 consecutive patients who underwent CT-guided TFNA with or without CNB of lung nodules over a 5-year time period (2003-2007). Thirty-seven FN cases of "negative" TFNA/CNB with malignant outcome were identified with 36 cases available for review, of which 35 had a corresponding CNB. Cases were reviewed independently (blinded to original diagnosis) by three pathologists with 15 age- and sex-matched positive and negative controls. Diagnosis (i.e., nondiagnostic, negative or positive for malignancy, atypical or suspicious) and qualitative assessments were recorded. Consensus diagnosis was suspicious or positive in 10 (28%) of 36 TFNA cases and suspicious in 1 (3%) of 35 CNB cases, indicating potential interpretive errors. Of the 11 interpretive errors (including both suspicious and positive cases), 8 were adenocarcinomas, 1 squamous cell carcinoma, 1 metastatic renal cell carcinoma, and 1 lymphoma. The remaining 25 FN cases (69.4%) were considered sampling errors and consisted of 7 adenocarcinomas, 3 nonsmall cell carcinomas, 3 lymphomas, 2 squamous cell carcinomas, and 2 renal cell carcinomas. Interpretive and sampling error cases were more likely to abut the pleura, while histopathologically, they tended to be necrotic and air-dried. The overall FN rate in this patient cohort is 3.5% (1.1% interpretive and 2.4% sampling errors)., (© 2014 Wiley Periodicals, Inc.)

The existence of a "high-grade endometrial stromal sarcoma" category of tumors has been a controversial subject owing to, among other things, the difficulty in establishing consistent diagnostic criteria. Currently, the recommended classification for such tumors is undifferentiated uterine/endometrial sarcoma. Interest in this subject has recently increased markedly with the identification of recurrent molecular genetic abnormalities. At Mayo Clinic, a group of neoplasms has been observed that morphologically resemble, either cytologically or architecturally, classic "low-grade" endometrial stromal sarcoma but feature obvious deviations, specifically, 17 tumors with unequivocally high-grade morphology. These high-grade tumors displayed 3 morphologic themes: (1) tumors with a component that is identical to low-grade ESS that transitions abruptly into an obviously higher-grade component; (2) tumors composed exclusively of high-grade cells with uniform nuclear features but with a permeative pattern of infiltration; (3) tumors similar to the second group but with a different, yet characteristic, cytomorphology featuring enlarged round to ovoid cells (larger than those found in low-grade ESS) with smooth nuclear membranes and distinct chromatin clearing but lacking prominent nucleoli. We collected clinicopathologic data, applied immunohistochemical studies, and also tested tumors by fluorescence in situ hybridization for abnormalities in JAZF1, PHF1, YWHAE, and CCND1. Tumors from these 3 groups were found to be immunohistochemically and genetically distinct from one another. Most notable was the fact that category 3 contained all the cases that tested positive for YWHAE rearrangement, did not show any classic translocations for JAZF1, PHF1, or CCND1, often presented at a high stage, and behaved aggressively. This study demonstrates the morphologic, immunophenotypic, and molecular genetic heterogeneity that exists within "undifferentiated endometrial sarcomas" as currently defined and lends credence to the effort of subclassifying some tumors as truly "high-grade endometrial stromal sarcomas." Our study also shows that, in the context of undifferentiated endometrial sarcomas, recognition of cytomorphologic features on routine hematoxylin and eosin-stained sections may be used to select tumors with specific molecular genetic changes-that is, translocations involving YWHAE. Our conclusions will help further efforts towards proper sub-classification of these tumors which will aid in diagnosis and potentially affect clinical management.

Background: Monitoring changes in the thyroid bed (TB) is one of the clinical mainstays for surveillance of recurrent thyroid carcinoma. Fine-needle aspiration (FNA) is a diagnostic tool that is commonly used to aid in the identification of residual or recurrent disease. The aim of our study was to evaluate the efficacy of ultrasound-guided FNA of the TB in detecting recurrent thyroid cancer and to correlate the findings with clinicopathologic parameters to identify predictors of TB recurrence., Methods: We retrieved cases of soft tissue masses within the TB that were evaluated for recurrence between January 1, 2006, and February 1, 2011. All ultrasound-guided FNA biopsies clinically suspected to indicate a lymph node metastasis and specimens with lymphocytes were excluded from the data., Results: Of the 291 patients identified for evaluation of recurrence, 250 had papillary thyroid carcinoma (PTC), 10 had follicular carcinoma, 22 had medullary carcinoma, 7 had Hürthle cell carcinoma, and 2 had a previous thyroidectomy for an unknown type of thyroid carcinoma. For all FNAs that were clinically suspicious or intermediate for recurrence, the rate of positivity was 71.8% (209 patients). All cases diagnosed as "positive for PTC" or "suspicious for PTC" on TB FNA were found to have soft tissue metastasis on follow-up surgical resection. This resulted in a negative predictive value of 88.4% and a positive predictive value of 100%. The average time between thyroidectomy and TB FNA was 73.5 months. Of the patients with a previous diagnosis of PTC, those with suspicious/positive cytology were more likely to be women, to be older at thyroidectomy, to have documented metastasis to other sites as well as extrathyroidal extension and multifocal primary disease as compared with nondiagnostic/negative cytology cases. Patient age ≥45 years, primary tumor size at thyroidectomy, and surgical resection margin status had no statistical significance for predicting risk of TB recurrence., Conclusion: TB recurrence of PTC is most likely to occur in patients who have the following clinicopathologic parameters: documented metastasis to any site, extrathyroidal extension, and increased number of primary cancer foci.

Fat necrosis of the breast is a relatively common reactive/reparative process that may be either primary, often after trauma, or secondary to prior surgery or therapeutic irradiation. Mammary fat necrosis may closely mimic breast neoplasia, both clinically and radiographically, and is thus frequently biopsied. In the majority of cases fat necrosis in the breast shows classic morphologic features and is a straightforward diagnosis. However, over the past several years we have seen a number of more challenging cases of mammary fat necrosis complicated by a distinctive cellular, spindled proliferation of macrophages, mimicking various spindle cell neoplasms of the breast. Herein we report our experience with such lesions. A total of 118 cases of fat necrosis involving the breast were retrieved from our institutional and consultation archives for the period 1994 to 2011. The final study group of 20 cases included only (1) consultation cases submitted specifically with concern for a spindle cell neoplasm and (2) institutional cases presenting as a mass lesion and showing an identical spindle cell proliferation. The tumors occurred in 20 women (mean age 58 y; range, 24 to 70 y), involved both breasts (left, 11 cases; right, 9 cases), and ranged in size from 0.8 to 2.5 cm (mean 1.5 cm). Additional clinical information was available for 18 (90%) patients; a history of ipsilateral breast carcinoma and prior therapeutic irradiation were documented in 7 of 18 (39%) and 6 of 18 (33%) patients, respectively. Radiographic reports and/or imaging was available for 17 (85%) patients; radiographic impressions were "suspicious for malignancy" (10 cases, 59%), "indeterminate" (2 cases, 12%), or "benign" (5 cases, 29%). The patients underwent core needle (14 cases, 70%) and excisional (6 cases, 30%) biopsies. The morphologic features of all cases were similar, showing a moderately cellular, fascicular proliferation of mitotically active, normochromatic, lightly eosinophilic spindled cells with mild nuclear variability, folded or grooved nuclei, and indistinct nucleoli. Chronic inflammatory cells and multinucleated giant cells were often admixed with the spindled cells, with more typical features of fat necrosis frequently present at the periphery. Immunohistochemical analysis performed at Mayo Clinic showed the lesional cells to express the histiocyte-associated markers CD163 (8 of 8, 100%), CD11c (8 of 8, 100%), and CD31 (4 of 8, 50%) and to be negative for keratins using the OSCAR monoclonal antibody (0 of 8, 0%). Studies conducted at outside institutions showed absent expression of various keratins, S100 protein, p63, and β-catenin protein. Histochemical staining for mycobacterial and fungal organisms was negative. Follow-up (18 patients, 1 to 120 mo, mean 37 mo) showed all patients to be alive without disease. Additional surgical procedures (6 patients) showed only fat necrosis. We believe that these lesions represent an exaggerated histiocytic reaction to fat necrosis in the breast. Awareness of this distinctive pseudotumor should help to prevent its misdiagnosis as various other mammary spindle cell neoplasms.

CD30-positive T-cell lymphoproliferative disorders are classified as cutaneous (primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis) or systemic. As extent of disease dictates prognosis and treatment, patients with skin involvement need clinical staging to determine whether systemic lymphoma also is present. Similar processes may involve mucosal sites of the head and neck, constituting a spectrum that includes both neoplasms and reactive conditions (eg, traumatic ulcerative granuloma with stromal eosinophilia). However, no standard classification exists for mucosal CD30-positive T-cell lymphoproliferations. To improve our understanding of these processes, we identified 15 such patients and examined clinical presentation, treatment and outcome, morphology, phenotype using immunohistochemistry, and genetics using gene rearrangement studies and fluorescence in situ hybridization. The 15 patients (11 M, 4 F; mean age, 57 years) had disease involving the oral cavity/lip/tongue (9), orbit/conjunctiva (3) or nasal cavity/sinuses (3). Of 14 patients with staging data, 7 had mucosal disease only; 2 had mucocutaneous disease; and 5 had systemic anaplastic large cell lymphoma. Patients with mucosal or mucocutaneous disease only had a favorable prognosis and none developed systemic spread (follow-up, 4-93 months). Three of five patients with systemic disease died of lymphoma after 1-48 months. Morphologic and phenotypic features were similar regardless of extent of disease. One anaplastic lymphoma kinase-positive case was associated with systemic disease. Two cases had rearrangements of the DUSP22-IRF4 locus on chromosome 6p25.3, seen most frequently in primary cutaneous anaplastic large cell lymphoma. Our findings suggest mucosal CD30-positive T-cell lymphoproliferations share features with cutaneous CD30-positive T-cell lymphoproliferative disorders, and require clinical staging for stratification into primary and secondary types. Primary cases have clinicopathologic features closer to primary cutaneous disease than to systemic anaplastic large cell lymphoma, including indolent clinical behavior. Understanding the spectrum of mucosal CD30-positive T-cell lymphoproliferations is important to avoid possible overtreatment resulting from a diagnosis of overt T-cell lymphoma.

Background: Becker nevus is a nevoid melanosis, referred to as Becker nevus syndrome when it is associated with other anomalies. Our objectives were to report the occurrence of a Becker nevus with an underlying desmoid soft-tissue tumor; to review Mayo Clinic's experience with Becker nevi, concentrating on Becker nevi associated with bone, vascular, neural, and other soft-tissue abnormalities; to inform physicians of the Becker nevus syndrome; and finally to alert clinicians to evaluate a Becker nevus with its associations in mind., Observations: A 46-year-old woman had a Becker nevus with an underlying desmoid-type fibromatosis (desmoid tumor) presenting clinically as a "painful dimple" within the nevus. Review of medical records for 1997 through 2006 at Mayo Clinic, Rochester, Minnesota, yielded 52 patients with Becker nevi, 12 of whom had an associated bone, vascular, neural, congenital, or other soft-tissue abnormality, ranging from liposarcoma to an accessory areola., Conclusions: We add to the literature a unique case of desmoid-type fibromatosis immediately beneath a Becker melanosis, which presented as a painful dimple. We hope to raise awareness that a Becker nevus may be associated with other abnormalities, including an infiltrative soft-tissue tumor. We also emphasize the importance of follow-up, including inspection of not only the surface but also the deep tissues underlying the Becker nevus.

A patient with bilateral ovarian adenocarcinomas composed predominantly of ciliated cells incidentally found at autopsy is reported. Although obviously malignant, a majority of the cells expressed well-differentiated cilia with terminal bar formation. In one of the masses, the neoplastic cells seemed to arise from a serous adenofibroma. The tumor was confined to the ovaries without evidence of metastatic spread. Although morphologically resembling an endometrioid-type neoplasm, immunohistochemical and molecular studies were more consistent with a serous phenotype, especially in light of its apparent origination from a serous adenofibroma. We agree with previous observations suggesting that although the neoplasm seems morphologically worrisome, it may actually portend a more benign clinical course.