Association of computed tomography scan-assessed body composition with immune and PI3K/AKT pathway proteins in distinct breast cancer tumor components.

This hypothesis-generating study aims to examine the extent to which computed tomography-assessed body composition phenotypes are associated with immune and PI3K/AKT signaling pathways in breast tumors. A total of 52 patients with newly diagnosed breast cancer were classified into four body composition types: adequate (lowest two tertiles of total adipose tissue [TAT]) and highest two tertiles of total skeletal muscle [TSM] areas); high adiposity (highest tertile of TAT and highest two tertiles of TSM); low muscle (lowest tertile of TSM and lowest two tertiles of TAT); and high adiposity with low muscle (highest tertile of TAT and lowest tertile of TSM). Immune and PI3K/AKT pathway proteins were profiled in tumor epithelium and the leukocyte-enriched stromal microenvironment using GeoMx (NanoString). Linear mixed models were used to compare log2-transformed protein levels. Compared with the normal type, the low muscle type was associated with higher expression of INPP4B (log2-fold change = 1.14, p = 0.0003, false discovery rate = 0.028). Other significant associations included low muscle type with increased CTLA4 and decreased pan-AKT expression in tumor epithelium, and high adiposity with increased CD3, CD8, CD20, and CD45RO expression in stroma (P<0.05; false discovery rate >0.2). With confirmation, body composition can be associated with signaling pathways in distinct components of breast tumors, highlighting the potential utility of body composition in informing tumor biology and therapy efficacies.

Integrative spatial omics reveals distinct tumor-promoting multicellular niches and immunosuppressive mechanisms in African American and European American patients with TNBC.

Racial disparities in triple-negative breast cancer (TNBC) outcomes have been reported. However, the biological mechanisms underlying these disparities remain unclear. We integrated imaging mass cytometry and spatial transcriptomics, to characterize the tumor microenvironment (TME) of African American (AA) and European American (EA) patients with TNBC. The TME in AA patients was characterized by interactions between endothelial cells, macrophages, and mesenchymal-like cells, which were associated with poor patient survival. In contrast, the EA TNBC-associated niche is enriched in T-cells and neutrophils suggestive of an exhaustion and suppression of otherwise active T cell responses. Ligand-receptor and pathway analyses of race-associated niches found AA TNBC to be immune cold and hence immunotherapy resistant tumors, and EA TNBC as inflamed tumors that evolved a distinctive immunosuppressive mechanism. Our study revealed the presence of racially distinct tumor-promoting and immunosuppressive microenvironments in AA and EA patients with TNBC, which may explain the poor clinical outcomes.

Surgical excision versus clinical follow-up: Outcomes of benign intraductal papillomas diagnosed on core needle biopsy.

OBJECTIVE: To compare outcomes between benign intraductal papillomas diagnosed on core need biopsy that were excised (BIP-E) versus those that were followed-up (BIP-F) at our institution. METHODS: Patients were identified by an electronic data base search from January 2010 to October 2016. After exclusions, clinical, radiological and histologic variables were evaluated and biopsy and excision slides reviewed. RESULTS: 110 BIP from 104 females were analyzed. 84 BIP were excised and 26 BIP were followed up (mean 43.3 months, range 7-93 months).11 patients in BIP-E group had atypia on excision. There were no statistically significant differences between BIP-E with atypia and BIP-E without, except for clinical presentation with pain/discomfort (p â€‹= â€‹0.015) in the former. There were no true upgrades to malignancy in both groups on follow up. One patient from each group developed a new breast cancer distant from IP site after nearly 4 years of uneventful follow-up. CONCLUSION: Clinical follow up is an oncologically safe alternative for radiologically concordant BIP. Excision may be considered if a diagnosis of atypia would impact surveillence and chemoprevention recommendations.

Metastasis of Clear Cell Renal Cell Carcinoma to Uterine Leiomyoma: First Case Report and Review of Literature.

Metastasis of clear cell renal cell carcinoma (clear cell RCC) to the gynecologic tract is infrequent, and involvement of the uterus is extremely rare. A review of the literature identified a total of 12 reported examples with metastasis to the uterine serosa (1), endometrium (5), cervix (5) and only one with metastasis to the myometrium. This report represents the first case of tumor-to-tumor metastasis involving a clear cell RCC with metastasis to a uterine leiomyoma. The patient was a 50-year-old woman status post-radical nephrectomy for newly diagnosed unilateral clear cell RCC (stage pT3a) with negative margins, who subsequently underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy for the incidental finding of multiple uterine masses measuring up to 14.5 cm suggestive of fibroid on pelvic ultrasound. The pathologic exam of the specimen was consistent with metastatic clear cell RCC (1.2 cm) to uterine leiomyoma, confirmed with keratin, vimentin, CD10, CA9, and PAX8 immunohistochemistry. The patient's postoperative course was uneventful, and no new lesions were identified at follow-up during the past 6 months.

Proteogenomic Approaches for the Identification of NF1/Neurofibromin-depleted Estrogen Receptor-positive Breast Cancers for Targeted Treatment.

NF1 is a key tumor suppressor that represses both RAS and estrogen receptor-α (ER) signaling in breast cancer. Blocking both pathways by fulvestrant (F), a selective ER degrader, together with binimetinib (B), a MEK inhibitor, promotes tumor regression in NF1-depleted ER+ models. We aimed to establish approaches to determine how NF1 protein levels impact B+F treatment response to improve our ability to identify B+F sensitive tumors. We examined a panel of ER+ patient-derived xenograft (PDX) models by DNA and mRNA sequencing and found that more than half of these models carried an NF1 shallow deletion and generally have low mRNA levels. Consistent with RAS and ER activation, RET and MEK levels in NF1-depleted tumors were elevated when profiled by mass spectrometry (MS) after kinase inhibitor bead pulldown. MS showed that NF1 can also directly and selectively bind to palbociclib-conjugated beads, aiding quantification. An IHC assay was also established to measure NF1, but the MS-based approach was more quantitative. Combined IHC and MS analysis defined a threshold of NF1 protein loss in ER+ breast PDX, below which tumors regressed upon treatment with B+F. These results suggest that we now have a MS-verified NF1 IHC assay that can be used for patient selection as a complement to somatic genomic analysis. Significance: A major challenge for targeting the consequence of tumor suppressor disruption is the accurate assessment of protein functional inactivation. NF1 can repress both RAS and ER signaling, and a ComboMATCH trial is underway to treat the patients with binimetinib and fulvestrant. Herein we report a MS-verified NF1 IHC assay that can determine a threshold for NF1 loss to predict treatment response. These approaches may be used to identify and expand the eligible patient population.

Heterotopic Hepatic Tissue in the Placenta: A Case Report.

Heterotopic hepatic tissue in placenta or umbilical cord is rare. The exact mechanism by which this heterotopia occurs has not been fully understood but is thought to be related to yolk sac primordia. To date, a handful of such cases have been reported. We present a case of heterotopic liver tissue within a chorionic stem villus of a 37 week-growth restricted neonate and describe the tissue morphology and its immunohistochemistry workup.

Melanoma in the Breast: A Diagnostic Challenge.

Although rare, breast metastases can mimic primary tumors, both clinically, radiologically, and histopathologically. Melanoma is a highly metastasizing tumor, and it is known as a great mimicker of tumors. Metastatic melanoma in the breast can mimic primary breast cancer and pose a diagnostic challenge. In most cases, it is associated with disseminated disease and a poor prognosis, therefore, histologic, immunohistochemical and clinical correlation is crucial in diagnosing these cases. In this case report, we discuss a 63-year-old female who presented with clinical features of probable breast cancer, describe immunohistochemistry workup, and discuss pitfalls in interpretation.

Endocervicosis in an Intramammary Lymph Node.

Benign müllerian inclusions are frequently encountered within infra-diaphragmatic locations such as pelvic lymph nodes, bladder, cervix and vagina. Supra-diaphragmatic müllerian inclusions, especially endocervicosis, are exceedingly rare. We report a case of endocervicosis within an intramammary lymph node in a 49-year-old woman. To the best of our knowledge, this is the second reported case.

How Do Pathologists in Academic Institutions Across the United States and Canada Evaluate Sentinel Lymph Nodes in Breast Cancer? A Practice Survey.

OBJECTIVES: There are little data on how changes in the clinical management of axillary lymph nodes in breast cancer have influenced pathologist evaluation of sentinel lymph nodes. METHODS: A 14-question survey was sent to Canadian and US breast pathologists at academic institutions (AIs). RESULTS: Pathologists from 23 AIs responded. Intraoperative evaluation (IOE) is performed for selected cases in 9 AIs, for almost all in 10, and not performed in 4. Thirteen use frozen sections (FSs) alone. During IOE, perinodal fat is completely trimmed in 8, not trimmed in 9, and variable in 2. For FS, in 12 the entire node is submitted at 2-mm intervals. Preferred plane of sectioning is parallel to the long axis in 8 and perpendicular in 12. In 11, a single H&E slide is obtained, whereas 12 opt for multiple levels. In 11, cytokeratin is obtained if necessary, and immunostains are routine in 10. Thirteen consider tumor cells in pericapsular lymphatics as lymphovascular invasion (LVI), and 10 consider it isolated tumor cells (ITCs). CONCLUSIONS: There is dichotomy in practice with near-equal support for routine vs case-by-case multilevel/immunostain evaluation, perpendicular vs parallel sectioning, complete vs incomplete fat removal, and tumor in pericapsular lymphatics as LVI vs ITCs.

HER-2/neu-positive breast cancer neoadjuvant chemotherapy response after implementation of 2018 ASCO/CAP focused update.

Human Epidermal Growth Factor Receptor 2 (HER2), a routinely tested breast cancer marker, is associated with worse prognosis yet increased sensitivity to targeted neoadjuvant therapy (NAT) in breast cancer patients. The presence of HER2 in breast carcinoma can be detected with either immunohistochemistry (IHC) or in situ hybridization (ISH). In this study, we examine the relationship between clinicopathological features, HER2 detection method (IHC vs ISH), and prognostic outcomes in NAT-treated HER2-positive breast cancer patients. We included 99 HER2-positive patients from three academic institutions following 2018 HER2 testing updates and conducted a retrospective correlational study. Seventy-one (72%) were HER2-positive by IHC and 28 (28%) were positive following reflexive ISH. Multivariate analysis showed biomarker status to be significantly associated with pathologic complete response (pCR) (p = 0.003), Residual Cancer Burden (RCB) (p = 0.007), and tumor size downstaging (p = 0.002) and HER2 detection method of IHC to be significantly associated with pCR (p = 0.05), RCB (p = 0.004), and nodal downstaging (p= 0.03). In conclusion, HER2 detection method and biomarker subtype allow for further prognostic stratification of HER2-positive patients when 2018 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline updates are applied.

Microbiota composition in bilateral healthy breast tissue and breast tumors.

PURPOSE: Previous reports suggest that a complex microbiome exists within the female human breast that might contribute to breast cancer etiology. The purpose of this pilot study was to assess the variation in microbiota composition by breast side (left versus right) within individual women and compare the microbiota of normal and breast tumor tissue between women. We aimed to determine whether microbiota composition differs between these groups and whether certain bacterial taxa may be associated with breast tumors. METHODS: Bilateral normal breast tissue samples (n = 36) were collected from ten women who received routine mammoplasty procedures. Archived breast tumor samples (n = 10) were obtained from a biorepository. DNA was extracted, amplified, and sequenced. Microbiota data were analyzed using QIIME and RStudio. RESULTS: The most abundant phyla in both tumor and normal tissues were Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria. There were statistically significant differences in the relative abundance of various bacterial taxa between groups. Alpha diversity (Simpson's index) was significantly higher in normal compared to tumor samples (0.968 vs. 0.957, p = 0.022). Based on unweighted UniFrac measures, breast tumor samples clustered distinctly from normal samples (R2 = 0.130; p = 0.01). Microbiota composition in normal samples clustered within women (R2 = 0.394; p = 0.01) and by breast side (left or right) within a woman (R2 = 0.189; p = 0.03). CONCLUSION: Significant differences in diversity between tumor and normal tissue and in composition between women and between breasts of the same woman were identified. These results warrant further research to investigate the relationship between microbiota and breast cancer.

Synovial Biopsy in the Diagnosis of Crystal-Associated Arthropathies.

BACKGROUND/ OBJECTIVE: This study seeks to assess the utility of synovial biopsy in the diagnosis of crystal-associated arthropathies (CAAs) in a clinical setting. METHODS: In this retrospective study, we reviewed biopsy reports involving synovial tissue between 1988 and 2015. We then reviewed the records of patients where the biopsy was performed for a clinical suspicion of CAA-the clinical group-and calculated the frequency of a positive diagnosis. The t test, Mann-Whitney-Wilcoxon test, and Fisher test were used to compare clinical characteristics of patients with and without a tissue diagnosis of CAA. We also reviewed cases of unexpected detection of crystalline disease involving synovial tissue-the incidental group. RESULTS: Among 2786 biopsies involving the synovium, we identified 65 cases in the clinical group and 33 cases in the incidental group. In the clinical group, a relevant diagnosis was obtained from synovial tissue in 36.9%, and a CAA was diagnosed in 20%. Restricting analysis to clinical biopsies performed for a primary suspicion of CAA, a relevant diagnosis was obtained in 61.3%, and a CAA was diagnosed in 38.7%. The incidental group comprised 1.2% of all synovial biopsies and included 7 mass lesions. Basic calcium phosphate was not reported on any biopsy in the study period. CONCLUSIONS: Synovial biopsy is a diagnostic option when suspected CAA is resistant to conventional modes of diagnosis. Crystalline diseases should be considered in the differential diagnosis of musculoskeletal mass lesions mimicking neoplasms.

Invasive Lobular Carcinoma With Extensive Clear Cells: A Pitfall in Diagnosis.

Carcinomas in the breast with a predominantly clear cytoplasm are rare. In this article, we review the differential diagnosis of clear cell breast neoplasms and report a case of invasive lobular carcinoma with extensive clear cell morphology that was diagnosed as invasive ductal carcinoma, not otherwise specified, on ultrasound-guided biopsy. Lobular carcinomas with extensive clear cell change are unusual, but must be considered when evaluating a clear cell neoplasm in the breast.

Myxoid Myofibroblastoma of the Breast With Atypical Cells.

The differential diagnosis of myxoid lesions in the breast is broad and includes both benign and malignant entities. Assessment is particularly challenging on core biopsy specimens. Myofibroblastoma, initially thought to be more common in the adult male breast, is being recognized with increasing frequency in the female breast. The wider anatomic distribution of mammary-type myofibroblastoma has also become known, and many new morphological variants have been described. Though focal myxoid stroma may be noted in myofibroblastomas and occasional myofibroblastomas may contain atypical cells, there have been only 3 reports in the literature of myofibroblastomas with exclusive or predominantly myxoid stroma, and 2 of these contained atypical cells. We report another case of mammary myxoid myofibroblastoma with atypical cells in a 40-year-old woman and discuss the differential diagnoses of myxoid lesions in the breast.

Outcomes of benign intraductal papillomas diagnosed on core biopsy: a review of 104 cases with subsequent excision from a single institution.

A diagnosis of papilloma with atypia on core biopsy (CB) requires excision, as the risk of associated malignancy is high (average 36.9%). The management of benign intraductal papillomas (IP) diagnosed on CB is controversial due to varying upgradation rates (0-29%, average 7%) reported on excision. Our aim was to study the clinical, radiological, and pathological features associated with benign IP upgradation at our institution. An electronic data base search (keyword papilloma), from Jan. 2000-Aug. 2015 identified 258 CBs. After exclusions, 104 CBs of benign IPs with subsequent excisions from 101 females were reviewed. The clinical, radiological, and pathological features between IPs that had upgrades (defined as malignancy or atypical ductal hyperplasia) and non-upgraded IPs were compared using descriptive statistics. Studies of benign IP on CB with at least 50 follow-up excisions published between 2008 and 2016 were analyzed. Residual IP was present in 83.6% (87/104) of reviewed excisions. There were six upgrades (5.6%) (4 to malignancy (3.8%) and 2 to atypical ductal hyperplasia).Upgrades were associated with mass on imaging with a trend to significance (p = .05). Two cases with malignant upgrade had a history of contralateral cancer. An analysis of 25 published studies showed an average malignant upgrade of 5.7% (182/3164). The majority of benign IP are not upgraded on excision; thus, not all need to be excised. Those that may warrant excision are those with prior history of carcinoma, those with a mass on imaging, and/or suboptimal or imaging-discordant CB sampling.

Atypical Apocrine Adenosis: Diagnostic Challenges and Pitfalls.

Apocrine change in the breast is an extremely common finding. In most cases, the benign or malignant nature of the lesion is easily recognized. Apocrine adenosis is used to describe sclerosing adenosis with apocrine change. The term apocrine atypia is used when there is significant cytologic atypia in apocrine cells, characterized by a 3-fold nuclear enlargement, prominent/multiple nucleoli, and hyperchromasia. Atypical apocrine adenosis is diagnosed when apocrine adenosis and apocrine atypia are superimposed. However, there are no definite criteria to distinguish atypical apocrine adenosis from apocrine ductal carcinoma in situ. Immunohistochemical markers can be confounding and may lead to erroneous diagnoses. Atypical apocrine features in sclerosing lesions may be misinterpreted as invasive carcinoma if the underlying lesion is not recognized. In the absence of definite features of malignancy, the diagnosis of apocrine ductal carcinoma in situ may be extremely difficult. In the present article, we review atypical apocrine adenosis focusing on diagnostic challenges and their implications on clinical management.

Kikuchi-Fujimoto Disease Masquerading as Metastatic Papillary Carcinoma of the Thyroid.

Kikuchi-Fujimoto disease also known as histiocytic necrotizing lymphadenitis is a rare cervical inflammatory lymphadenitis that is most commonly seen in young Asian women. It is mainly characterized by lymphadenopathy, hepatosplenomegaly, fever, nocturnal sweats, myalgia, weight loss, and arthralgia, and commonly follows a self-limited course. The differential diagnosis is challenging as many other conditions such as malignant lymphoma, metastatic disease, tuberculosis and infectious lymphadenopathies can present in a similar way. We present an unusual case of Kikuchi-Fujimoto disease masquerading as metastatic papillary carcinoma of the thyroid. A 30-year-old young female presented, 2 months post-partum, with complaints of neck pain and fever. A computed tomography scan showed enlarged right-sided lymph nodes and a thyroid nodule. Subsequent biopsy of a thyroid nodule revealed papillary thyroid carcinoma and reactive inflammation in one of the lymph nodes. She underwent an elective total thyroidectomy, central node dissection and a right modified lymph node dissection for enlarged lymph nodes. Her recovery was uneventful and the pathology report was consistent with a papillary carcinoma of the thyroid with one lymph node positive for metastatic disease and several other lymph nodes showing histiocytic necrotizing lymphadenitis. This coexistence of Kikuchi-Fujimoto disease with localized metastatic papillary thyroid cancer is unusual and presents an interesting, challenging, and complex management dilemma.