Amy S. Joehlin-Price

Mismatch repair protein expression in 1049 endometrial carcinomas, associations with body mass index, and other clinicopathologic variables

OBJECTIVE Links between obesity, with its attendant estrogen abnormalities, and the endometrial carcinoma (EC) DNA Mismatch Repair Protein (MMR) system have recently been proposed. We investigated relationships between body mass index (BMI) and clinicopathological correlates including MMR expression in a large single institution EC cohort. METHODS Clinical and pathological databases from 2007 to 2012 were used to identify consecutive hysterectomy specimens with EC. Univariate and multivariate analyses were used to explore relationships between BMI, age, stage, tumor type and immunohistochemical results for MLH1, PMS2, MSH2 and MSH6. RESULTS 1049 EC were identified. Overall, BMI was higher amongst women with normal MMR (p=0.002). However, when stratified by age and specific MMR, statistically significant differences localized exclusively to women <50years old with loss of MSH2 and/or MSH6 (p=0.003 and p=0.005 respectively). Higher BMI correlated with endometrioid FIGO 1 and 2 tumors (p<0.001) and with stage 1a (p<0.001). Conversely, MMR abnormalities did not show significant associations with stage (p=0.302) or histologic grade (p=0.097). CONCLUSIONS BMI showed statistically significant associations with MMR expression, tumor grade and stage amongst 1049 consecutive EC. Obesity correlates with lower grade and stage EC. A link between BMI and maintenance of the MMR system is not supported by our data because the only statistically significant association occurred in women <50years old with MSH2 and/or MSH6 abnormalities where Lynch syndrome related cases are expected to cluster.

Classification of follicular lymphoma: the effect of computer aid on pathologists grading

BackgroundFollicular lymphoma (FL) is one of the most common lymphoid malignancies in the western world. FL cases are stratified into three histological grades based on the average centroblast count per high power field (HPF). The centroblast count is performed manually by the pathologist using an optical microscope and hematoxylin and eosin (H&E) stained tissue section. Although this is the current clinical practice, it suffers from high inter- and intra-observer variability and is vulnerable to sampling bias.MethodsIn this paper, we present a system, called Follicular Lymphoma Grading System (FLAGS), to assist the pathologist in grading FL cases. We also assess the effect of FLAGS on accuracy of expert and inexperienced readers. FLAGS automatically identifies possible HPFs for examination by analyzing H&E and CD20 stains, before classifying them into low or high risk categories. The pathologist is first asked to review the slides according to the current routine clinical practice, before being presented with FLAGS classification via color-coded map. The accuracy of the readers with and without FLAGS assistance is measured.ResultsFLAGS was used by four experts (board-certified hematopathologists) and seven pathology residents on 20 FL slides. Access to FLAGS improved overall reader accuracy with the biggest improvement seen among residents. An average AUC value of 0.75 was observed which generally indicates “acceptable” diagnostic performance.ConclusionsThe results of this study show that FLAGS can be useful in increasing the pathologists’ accuracy in grading the tissue. To the best of our knowledge, this study measure, for the first time, the effect of computerized image analysis on pathologists’ grading of follicular lymphoma. When fully developed, such systems have the potential to reduce sampling bias by examining an increased proportion of HPFs within follicle regions, as well as to reduce inter- and intra-reader variability.

The Microcystic, Elongated, and Fragmented (MELF) Pattern of Invasion: A Single Institution Report of 464 Consecutive FIGO Grade 1 Endometrial Endometrioid Adenocarcinomas.

MELF invasion has been associated with nonvaginal recurrences and lymph node (LN) metastases in multi-institutional case control studies but has not been well examined in large single-institution cohorts. Hysterectomy specimens with FIGO 1 endometrioid endometrial carcinoma and lymphadenectomies from 2007 to 2012 were identified. Electronic medical records and histologic slides were reviewed. Of 464 identified cases, 163 (35.1%) were noninvasive, 60 (12.9%) had MELF, 222 (47.8%) had a component of the infiltrative invasion pattern without MELF, 13 (2.8%) had pure pushing borders of invasion, 5 (1.1%) had pure adenomyosis-like invasion, and 1 (0.2%) had pure adenoma malignum-like invasion. Sixteen cases had LN metastases. Significantly more MELF cases had positive LNs than non-MELF cases overall (18.3% vs. 1.2%, P<0.001). The results were almost identical when invasive infiltrative cases with and without MELF were compared (18.3% vs. 1.8%, P<0.001). The maximum number of MELF glands per slide did not differ between cases with and without LN metastases, P=0.137. A majority of positive LNs, even in MELF cases, demonstrated nonhistiocyte-like metastases. Only 5 cases (all with MELF invasion) demonstrated micrometastatic lesions or isolated tumor cells only. MELF cases demonstrated a nonsignificant decrease in time to extravaginal recurrence (P=0.082, log-rank test), for which analysis was limited by low recurrence rates. In summary, MELF is associated with LN metastases, even when compared with other infiltrative cases and shows multiple patterns of growth in positive LNs. MELF cases additionally trended toward decreased time to extravaginal recurrence.

Endometrial Cancer Insulin-Like Growth Factor 1 Receptor (IGF1R) Expression Increases with Body Mass Index and Is Associated with Pathologic Extent and Prognosis

Background: Obesity is a main risk factor for endometrial carcinoma (EC). Insulin-like growth factor 1 receptor (IGF1R) expression may influence this association. Methods: IGF1R IHC was performed on a tissue microarray with 894 EC and scored according to the percentage and intensity of staining to create immunoreactivity scores, which were dichotomized into low and high IGF1R expression groups. Logistic regression modeling assessed associations with body mass index (BMI), age, histology, pathologic extent of disease (pT), and lymph node metastasis (pN). Overall survival (OS) and disease-free survival (DFS) were compared between IGF1R expression groups using Kaplan–Meier curves and log-rank tests. Results: The proportion of patients with high IGF1R expression increased as BMI (<30, 30–39, and 40+ kg/m2) increased (P = 0.002). The adjusted odds of having high IGF1R expression was 1.49 [95% confidence interval (CI), 1.05–2.10, P = 0.024] for patients with BMI 30 to 39 kg/m2 compared with <30 kg/m2 and 1.62 (95% CI, 1.13–2.33, P = 0.009) for patients with BMI 40+ kg/m2 compared with <30 kg/m2. High IGF1R expression was associated with pT and pN univariately and with pT after adjusting for BMI, pN, age, and histologic subtype. DFS and OS were better with high IGF1R expression, P = 0.020 and P = 0.002, respectively, but DFS was not significant after adjusting for pT, pN, and histologic subtype of the tumor. Conclusions: There is an association between BMI and EC IGF1R expression. Higher IGF1R expression is associated with lower pT and better DFS and OS. Impact: These findings suggest a link between IGF1R EC expression and obesity, as well as IGF1R expression and survival. Cancer Epidemiol Biomarkers Prev; 25(3); 438–45. ©2015 AACR.

Does the Renal Parenchyma Adjacent to the Tumor Contribute to Kidney Function? A Critical Analysis of Glomerular Viability in Partial Nephrectomy Specimens

OBJECTIVE To evaluate the viability of glomeruli in the peritumor parenchyma of partial nephrectomy specimens removed for renal cell carcinoma (RCC) and relate it to kidney function, to better understand the contribution of peritumor parenchyma to renal function. MATERIALS AND METHODS A retrospective analysis of 53 partial nephrectomies containing RCC was performed. Glomeruli within 0.25-cm increments from the tumor were quantified and histologically assessed for viability. Tumor size, minimum and maximum margin size, and pre- and postoperative estimated glomerular filtration rate (eGFR) were obtained. RESULTS Glomerular viability positively correlated with distance from tumor with mean viable glomeruli in successive 0.25-cm increments of 0-0.25 cm, 58%; 0.25-0.5 cm, 80%; 0.5-0.75 cm, 90%; and 0.75-1.0 cm, 92%. Glomerular viability near the tumor did not correlate with preoperative eGFR, whereas decreased viability further from the tumor did correlate with worse preoperative eGFR. Tumor size showed a nonstatistically significant positive trend with minimum (median 0.15 cm) and maximum margin (median 0.7 cm) sizes. Percent change of glomerular filtration rate did not correlate with margin size (P = .190). CONCLUSION Renal parenchyma immediately adjacent to RCC contains fewer viable glomeruli compared with the parenchyma further from the tumor. Based on this information, attempts to preserve all non-neoplastic renal parenchyma via a surgical margin approaching zero may not necessarily result in clinically relevant differences in the amount of viable glomeruli remaining or the renal function preserved.

BRAF-Mutated Pleomorphic Xanthoastrocytoma of the Spinal Cord with Eventual Anaplastic Transformation

BACKGROUND Pleomorphic xanthoastrocytoma (PXA) is an uncommon, primary neoplasm of the central nervous system with a relatively favorable prognosis. Most patients are managed with surgery alone and experience significant long-term survival. PXAs occur most commonly along the superficial surfaces of the temporal lobes. Although these tumors may occur in other regions of the brain, their origin within the spinal cord is rare, and it is unclear whether spinal cord PXAs should be managed differently from their intracranial counterparts. CASE DESCRIPTION We describe a 31-year-old patient with a PXA of spinal cord origin who despite surgery, radiation, and multiple chemotherapy regimens experienced anaplastic transformation of his tumor and died of extensive leptomeningeal progression. CONCLUSIONS To our knowledge, our patient represents the seventh reported case of PXA of the spinal cord but is the first described to have a BRAF mutation. Specifically, both the initial and recurrent tumors of the patient showed the same BRAF V600E mutation, which refutes previous suggestions that BRAF mutations may be limited to intracranial PXAs and also shows that BRAF mutations may occur earlier in PXA tumorigenesis.

Minimal Clinical Impact of Intraoperative Examination of Sentinel Lymph Nodes in Patients With Ductal Carcinoma In SituAn Opportunity for Improved Resource Utilization

Objectives There is little information regarding sentinel lymph node (SLN) frozen-section examination in patients with a history of ductal carcinoma in situ (DCIS). We evaluated the usage, clinical impact, and pathology resources used for SLN cryosectioning in mastectomy cases with a DCIS history. Methods Mastectomies with SLNs submitted from 2012 to 2013 at a tertiary care center were analyzed. Medicare reimbursement was used to estimate pathology health care expenditures of intraoperative frozen sections. Results There was no difference in the rate of SLN frozen-section examination or parts submitted, total blocks frozen, total blocks submitted, or total SLNs identified per case between the DCIS (n = 139) and invasive (n = 369) groups. Nine patients with DCIS had SLN metastases (three macrometastases, two micrometastases, and four isolated tumor cells), all of which were examined by frozen section. Only the macrometastases were identified by cryosectioning, which led to two synchronous axillary lymph node dissections that did not yield any additional positive nodes. A total of

Comprehensive evaluation of caspase-14 in vulvar neoplasia: An opportunity for treatment with black raspberry extract

19,313 was spent for pathology per DCIS patient with surgical management affected, whereas only

Programmed Death Ligand 1 Expression Among 700 Consecutive Endometrial Cancers: Strong Association With Mismatch Repair Protein Deficiency

1,019 was spent per invasive carcinoma patient affected. Conclusions Decreasing SLN frozen-section use in patients with a history of DCIS represents an opportunity for pathology cost containment.

Case report: ACTH-secreting pituitary carcinoma metastatic to the liver in a patient with a history of atypical pituitary adenoma and Cushing’s disease

OBJECTIVE The aim of this study is to determine the expression of caspase-14, a key protein in maturation of squamous epithelia, in archival malignant and premalignant vulvar squamous lesions and examine in-vitro effects of a black raspberry extract (BRB-E) on a vulvar squamous cell carcinoma (VSCC) cell line. METHODS VSCC cell cultures were exposed to different BRB-E concentrations and used to create cell blocks. Immunohistochemistry for caspase-14 was performed on cell block sections, whole tissue sections, and a tissue microarray consisting of normal vulvar skin, lichen sclerosus (LS), classic and differentiated vulvar intraepithelial neoplasia (cVIN and dVIN respectively), and VSCC. RESULTS LS demonstrated abnormal full thickness (5/11) or absent (1/11) caspase-14 staining. dVIN often showed markedly reduced expression (4/7), and cVIN occasionally demonstrated either absent or reduced caspase-14 (6/22). VSCC predominantly had absent or markedly reduced caspase-14 (26/28). VSCC cell cultures demonstrated a significant increase in caspase-14 (p=0.013) after BRB-E treatment: 7.3% (±2.0%) of untreated cells showed caspase-14 positivity, while 21.3% (±8.9%), 21.7% (±4.8%), and 22.6% (±5.3%) of cells were positive for caspase-14 after treatment with 200, 400, and 800 μg/mL BRB-E, respectively. Pair-wise comparisons between the treatment groups and the control demonstrated significant differences between no treatment with BRB-E and each of these treatment concentrations (Dunnetts adjusted p-values: 0.024, 0.021, and 0.014, respectively). CONCLUSIONS Caspase-14 is frequently decreased in premalignant and malignant vulvar squamous lesions, and is upregulated in VSCC cell culture by BRB-E. BRB-E should be further explored and may ultimately be incorporated in topical preparations.