Shah, Sejal

Abstract Context. —The cytologic distinction between pleomorphic adenoma (PA) and adenoid cystic carcinoma (ACC) can be diagnostically challenging in aspirate smears. Hence a cytologic diagnosis of “atypical cytology” with a differential diagnosis including PA and ACC is occasionally rendered in a subset of salivary gland fine-needle aspirations. Objective. —To evaluate the role of glial fibrillary acidic protein (GFAP) and CD57 expression in cell block material obtained during fine-needle aspiration procedure in differentiating PA from ACC. Design. —We performed GFAP and CD57 immunostains on formalin-fixed, paraffin-embedded cell block sections of 26 salivary gland fine-needle aspiration cases with the following cytologic diagnoses: (1) PA (10 cases); (2) atypical cytology, cannot exclude ACC (8 cases); and (3) ACC (8 cases). Results. —All 10 (100%) cases with cytologic diagnoses of PA were positive for GFAP, and 8 (80%) of 10 cases were positive for CD57; tissue follow-up confirmed the diagnosis of PA in all cases. All 8 (100%) cases with cytologic diagnosis of ACC were negative for both GFAP and CD57; tissue follow-up confirmed the diagnoses of ACC in all cases. Of the 8 cases with diagnoses of atypical cytology, 4 (50%) were negative and 4 (50%) were positive for both GFAP and CD57. Subsequent tissue follow-up in these cases revealed 4 cases of ACC (all negative for GFAP and CD57) and 4 cases of PA (all positive for GFAP and CD57). Conclusions. —Our results show that positive staining for GFAP and CD57 serves as a useful adjunct for the diagnosis of PA and helps to reduce the uncertainty in challenging cases.

Inflammatory breast cancer is a highly aggressive form of breast cancer that forms clusters of tumor emboli in dermal lymphatics and readily metastasizes. These cancers express high levels of E-cadherin, the major mediator of adherens junctions, which enhances formation of tumor emboli. Previous studies suggest that E-cadherin promotes cancer when the balance between apical and basolateral cadherin complexes is disrupted. Here, we used immunohistochemistry of inflammatory breast cancer patient samples and analysis of cell lines to determine the expression of PLEKHA7, an apical adherens junction protein. We used viral transduction to re-express PLEKHA7 in inflammatory breast cancer cells and examined their aggressiveness in 2D and 3D cultures and in vivo. We determined that PLEKHA7 was deregulated in inflammatory breast cancer, demonstrating improper localization or lost expression in most patient samples and very low expression in cell lines. Re-expressing PLEKHA7 suppressed proliferation, anchorage independent growth, spheroid viability, and tumor growth in vivo. The data indicate that PLEKHA7 is frequently deregulated and acts to suppress inflammatory breast cancer. The data also promote the need for future inquiry into the imbalance between apical and basolateral cadherin complexes as driving forces in inflammatory breast cancer.

Abstract Background: Inflammatory breast cancer is a highly aggressive form of breast cancer that robustly forms clusters of tumor emboli in dermal lymphatics and readily metastasizes. Inflammatory breast cancers express high levels of E-cadherin, the major protein of adherens junctions, which may enhance the ability of tumor cells to form such clusters and contribute to metastasis. Seemingly contradictory, E-cadherin has both tumor-suppressing and tumor-promoting roles in cancer; previous studies suggest that this depends on the balance between apical and basolateral cadherin-catenin complexes. Methods: In the present study, we use immunohistochemistry of inflammatory breast cancer patient samples and biochemical analysis of cell lines to determine the expression of PLEKHA7, an apical adherens junction protein. We use viral transduction to ectopically express PLEKHA7 in the SUM149 inflammatory breast cancer cell line. The effect of PLEKHA7 on the aggressiveness of inflammatory breast cancer in 2D, 3D and in-vivo were examined. Results: We determined that PLEKHA7 was deregulated in inflammatory breast cancer, demonstrating improper localization or lost expression in a strong majority of patient samples and very low expression in cell line models. We found that re-expressing PLEKHA7 is sufficient to suppress proliferation, anchorage independent growth, spheroid viability, and tumor growth in-vivo. We also observed a negative-selection pressure within the xenograft tumors to lose PLEKHA7 function or expression.Conclusions: The data indicate that PLEKHA7 is frequently deregulated and acts as a suppressor of inflammatory breast cancer. They also suggest that the resulting imbalance between apical and basolateral cadherin-catenin complexes contributes to growth, survival and emboli-forming capacities of inflammatory breast cancer.

ABSTRACT Objectives Albumin messenger RNA (mRNA) expression is a marker of hepatocellular differentiation. Most published data are from review of tissue microarrays, and albumin in situ hybridization (ISH) expression across several tumor types is incompletely characterized. Methods Sections from 221 tumors were evaluated for albumin mRNA. Immunohistochemistry was used to confirm diagnoses. Albumin ISH was performed according to manufacturer-provided instructions. Fifty-nine cases were evaluated with both commercial ISH assays. Results Albumin mRNA was detected in all hepatocellular carcinomas (HCCs) and 81% of intrahepatic cholangiocarcinomas. Lung (20%), gallbladder (39%), hepatoid pancreatic (n = 1 of 1) adenocarcinoma, breast invasive ductal carcinoma (18%), yolk sac tumor (25%), and acinar cell carcinoma (29%) showed expression. Both assays were concordant in 93% of cases. Conclusions Albumin ISH was expressed in all HCCs studied. It was also positive in intrahepatic cholangiocarcinoma and patchy positive in gallbladder adenocarcinoma and a subset of other neoplasms, which can be a potential pitfall.

Aims To examine copper deposition in focal nodular hyperplasia (FNH) and inflammatory hepatocellular adenoma (IHA) and to determine if it can play a role in their differentiation. Methods 28 FNHs and 19 IHAs from surgical resections showing typical morphological and immunohistochemical features were stained with rhodanine to evaluate for copper deposition. Histological features such as nodularity, fibrous bands, ductular proliferation, steatosis, ballooned hepatocytes and lymphocytic inflammation were also scored. Results Copper deposition was detected in 96% (27/28) of FNHs and 37% (7/19) of IHAs, P<0.001. In all cases, copper was seen within the hepatocytes only around the pseudo-portal tracts or areas of fibrosis. Copper deposition in IHA was significantly associated with presence of lymphocytic inflammation (P=0.04) but not associated with features like nodularity, fibrous bands, ductular proliferation, ballooned hepatocytes and steatosis (P>0.05, for all). In FNH, the presence and degree of copper deposition was not significantly associated with any histological features (P>0.05, for all). Conclusions Copper deposition occurs more frequently in FNH (96%) than IHA (37%), P<0.001. However, the presence of copper alone cannot be used as a feature to differentiate between FNH and IHA.

Background and ObjectivesAdenoid cystic carcinoma (ACC) is a rare, typically triple‐negative, breast cancer reported to have a favorable prognosis and low rate of nodal metastasis. No consensus guidelines exist for axillary staging and treatment.MethodsWe identified all patients with ACC evaluated at our institution from January 1994 to August 2016. Patient, tumor, and treatment variables were abstracted and analyzed.ResultsWe identified 20 pure ACCs (0.13% of all invasive breast cancers) with size range 0.2‐4.8 cm, in 19 women, median age 59 years. Preoperative axillary ultrasound was normal in 10/13 women and suspicious in 3/13 who had a subsequent negative lymph node fine needle aspiration (FNA). Fifteen patients (75%) had sentinel lymph node surgery and were pathologically node‐negative, while the remaining five had no axillary surgery. With 3.6 years median follow‐up (range 0.2‐38.6 years), three patients experienced an in‐breast recurrence at 2, 16, and 17 years, respectively, while none recurred in regional nodes.ConclusionsWe observed no cases of nodal metastasis in 20 consecutive cases of ACC of the breast. Preoperative axillary ultrasound with FNA of suspicious nodes accurately predicted pathologic nodal stage. These data suggest axillary surgery might be omitted safely in patients with pure ACC and a clinically negative axilla.

3 Background: Atypical ductal hyperplasia (ADH) is a high-risk breast lesion usually diagnosed with core needle biopsy. Although upgraded to cancer at surgical excision in ~15 to 25% of cases, routine excision is questioned due to cost and overtreatment. We evaluated clinical, imaging, and histologic features associated with cancer upgrade and developed a multivariate model to predict risk of upgrade. Methods: With IRB approval a single institution retrospective review was performed of patients who underwent surgical excision of ADH diagnosed by core biopsy from 06/2005 to 06/2013. Review was performed of electronic records, breast imagin,g and biopsy slides. Multiple imputations were used for missing data. Association of cancer upgrade with various features was assessed with logistic regression. Results: 409 biopsies with ADH on core biopsy, with later surgical excision, were included. The overall upgrade rate was (16.1%, 95% CI:12.9-20.0%); 10 patients had invasive cancer at excision and 56 DCIS only. Features on core biopsy most strongly associated with upgrade were imaging estimated percent of lesion removed (upgrade 9% for 90% removed, 14% for 50 to 75%, and 27% for < 50% removed), individual cell necrosis (upgrade 34% with necrosis vs. 9.5% without), and # foci of ADH (22% for >1 focus vs 8% for 1 focus). A multivariate predictive model (see Table) showed an average C-statistic of 0.77. Women with no necrosis and either 1 focus with ≥ 50% removal or >1 focus with 90% removal (36% of the sample) have low risk of upgrade (5.0%, 95% CI:1.3-8.7%). Conclusions: ADH on core biopsy with low risk of upgrade to cancer is defined by percent of imaging lesion removed, # of foci of ADH, and lack of individual cell necrosis. If findings are validated, women whose biopsies meet low-risk criteria might be considered for chemoprevention and surveillance rather than surgical excision.[Table: see text]

98 Background: Concomitant with widespread adoption of axillary ultrasound (AUS) with ultrasound-guided needle biopsy (USNB) of suspicious lymph nodes (LN) for preoperative nodal staging of breast cancer patients, utilization of breast MRI, which includes axillary imaging, has increased. Little is known about the added value of MRI imaging of the axilla in this context. We undertook this study to assess the role of breast MRI in preoperative axillary nodal staging. Methods: We studied 988 consecutive invasive breast cancers in patients undergoing primary operation including axillary surgery, without neoadjuvant therapy, from 2010-2011. Results: 505 patients (51%) underwent MRI of which 168 (33%) demonstrated suspicious findings in the axilla. Abnormal axillary MRI findings included cortical thickening, edema, enhancement, hilar effacement, and/or altered shape and size. 114 patients had findings concordant with AUS. 54 patients had suspicious LNs on MRI either without a preceding AUS (33 cases) or after an initially negative AUS (21 cases). Second look AUS was performed in 29 of these cases and was abnormal in 3 (10%) in whom USNB confirmed metastatic adenopathy. Of the 54 cases with MRI-detected suspicious LNs 20 (37%) were node positive at operation with a pN stage of N0 (63%), N0i+ (5%), N1mic (4%), N1 (20%), N2 (6%), N3 (2%); extranodal extension was seen in 7 of 20 node-positive patients (35%). Conclusions: Second look AUS, when performed secondary to suspicious axillary MRI findings, identified LN metastasis preoperatively in 10% of patients. When MRI is done to evaluate the breast in newly diagnosed breast cancer patients, axillary findings can enhance the accuracy of preoperative nodal staging. We recommend second look AUS when MRI demonstrates suspicious axillary LN findings. [Table: see text]