Atilla Omeroglu

Stromal gene expression predicts clinical outcome in breast cancer

Although it is increasingly evident that cancer is influenced by signals emanating from tumor stroma, little is known regarding how changes in stromal gene expression affect epithelial tumor progression. We used laser capture microdissection to compare gene expression profiles of tumor stroma from 53 primary breast tumors and derived signatures strongly associated with clinical outcome. We present a new stroma-derived prognostic predictor (SDPP) that stratifies disease outcome independently of standard clinical prognostic factors and published expression-based predictors. The SDPP predicts outcome in several published whole tumor–derived expression data sets, identifies poor-outcome individuals from multiple clinical subtypes, including lymph node–negative tumors, and shows increased accuracy with respect to previously published predictors, especially for HER2-positive tumors. Prognostic power increases substantially when the predictor is combined with existing outcome predictors. Genes represented in the SDPP reveal the strong prognostic capacity of differential immune responses as well as angiogenic and hypoxic responses, highlighting the importance of stromal biology in tumor progression.

Adrenocortical Adenoma and Carcinoma: Histopathological and Molecular Comparative Analysis

We compared histomorphological features and molecular expression profiles of adrenocortical adenomas (ACAd) and carcinomas (ACCa). A critical histopathological review (mean, 11 slides per patient) was conducted of 37 ACAd and 67 ACCa. Paraffin-embedded tissue cores of ACAd (n = 33) and ACCa (n = 38) were arrayed in triplicate on tissue microarrays. Expression profiles of p53, mdm-2, p21, Bcl-2, cyclin D1, p27, and Ki-67 were investigated by immunohistochemistry and correlated with histopathology and patient outcome using standard statistical methodology. Median follow-up period was 5 years. Tumor necrosis, atypical mitoses, and >1 mitosis per 50 high-power fields were factors that were highly specific for ACCa (P < .001). Number (0 to 4) of unfavorable markers [Ki-67 (+), p21 (+), p27 (+), mdm-2(−)] expressed was significantly associated with mitotic activity and morphologic index (i.e., number of adverse morphologic features) and highly predictive of malignancy (P < .001). Ki-67 overexpression occurred in 0 ACAd and 36% ACCa (P < .001) and was significantly associated with mitotic rate and unfavorable morphologic index (P < .001). Tumor necrosis, atypical mitoses, >5 mitoses per 50 high-power fields, sinusoidal invasion, histologic index of >5, and presence of more than two unfavorable molecular markers were associated significantly with metastasis in ACCa. Well-established histopathologic criteria and Ki-67 can specifically distinguish ACCAd from ACCa. Tumor cell proliferation (Ki-67) correlates with mitotic activity and morphologic index. Tumor morphology is a better predictor of metastatic risk in ACCa than current immunohistochemistry-detected cell cycle regulatory and proliferation–associated proteins.

Atypical ductal hyperplasia diagnosed at sonographically guided core needle biopsy: frequency, final surgical outcome, and factors associated with underestimation.

OBJECTIVE The purposes of this article were to review the mammographic and sonographic features of breast masses yielding atypical ductal hyperplasia (ADH) at sonographically guided biopsy, evaluate the surgical pathology outcome of these lesions, and determine whether clinical or imaging features can be used to predict upgrade to malignancy. MATERIALS AND METHODS Among 6325 sonographically guided biopsies (2003- 2010) (14-gauge cores), 56 yielded the diagnosis of ADH (0.9%). Six patients were excluded (lost to follow-up). Fifty lesions were surgically excised in 45 patients. Mammographic and sonographic features were analyzed in consensus by two radiologists using the BI-RADS lexicon. RESULTS Forty-five patients (mean age, 56 years; 12 < 50 years; six with synchronous breast carcinoma) had 50 ADH lesions (median size, 0.6 cm). Surgical excision yielded malignancy in 28 cases (56% underestimation rate). Among 42 mammograms (47 lesions), 30 lesions were identified (30/47, 64%) as masses (12/30, 40%), asymmetric densities (10/30, 33%), microcalcifications (4/30, 13%), and architectural distortions (4/30, 13%). Sonographically, most lesions appeared as hypoechoic masses (64%, 30/47) with irregular shape (51%, 24/47), microlobulated margins (49%, 23/47), no posterior acoustic feature (25/47, 53%), abrupt interface (70%, 33/47), and parallel orientation (57%, 27/47). No mammographic and sonographic features were associated with malignant outcome, whereas age less than 50 years (p = 0.03) and synchronous malignancy (p = 0.03) were associated with malignant outcome. CONCLUSION ADH diagnosed at sonographically guided 14-gauge core needle biopsy shows a high underestimation rate. Synchronous carcinoma or age less than 50 years is associated with malignant outcome.

Value of pre-operative breast MRI for the size assessment of ductal carcinoma in situ.

OBJECTIVE To retrospectively evaluate the accuracy of pre-operative breast MRI and mammography in determining the size of ductal carcinoma in situ (DCIS) compared with the histopathological results. METHODS 79 patients [mean age: 56.5 (standard deviation 10.2) years] with pathologically proven DCIS (79 lesions) obtained a bilateral mammogram and a pre-operative contrast-enhanced MRI. The accuracy of MRI and mammography to detect tumour size were estimated and compared, using histopathological size as the gold standard, on the subjects with measurements with both modalities (n = 60). RESULTS MRI detected 67 (85%) lesions, mammography detected 72 (91%) and both modalities detected 60 (76%). Median DCIS size detected by mammography vs MRI was smaller (1.55 vs 1.65 cm). Out of these 60 cases, compared with the histopathological size, the accuracy of MRI and mammography was 0.66 and 0.56, respectively (p = 0.045). MRI showed better accuracy than mammography for younger patients (age ≤ 50 years, p = 0.003). For tumour nuclear grade, there was a statistically significant difference for the intermediate level, with higher accuracy for MRI (p = 0.03). CONCLUSION MRI was more accurate than mammography in DCIS size assessment when visible, particularly in lesions of intermediate grade and in patients less than 50 years of age. ADVANCES IN KNOWLEDGE Breast MRI may help in management of DCIS of intermediate grade and in females less than 50 years of age.

A carcinosarcoma/sarcomatoid carcinoma arising in a urinary bladder diverticulum

We describe an invasive polypoid carcinosarcoma/sarcomatoid carcinoma arising within a urinary bladder diverticulum in a 65-year-old patient with synchronous, moderately differentiated prostatic adenocarcinoma. Histologically, the diverticular tumor exhibits an admixture of different morphologic components, including invasive high-grade urothelial carcinoma, malignant glandular structures in a cellular background of malignant spindle cells, and areas formed exclusively by spindle and pleomorphic cells. There was full-thickness involvement of the diverticulum with extension of the tumor into the perivesical fat and ipsilateral seminal vesicle. In view of the early invasive behavior of carcinosarcoma/sarcomatoid carcinoma combined with the paucity of the muscular layer in the diverticulum wall, a graver prognosis was expected for this aggressive tumor that occurred in this unusual site.

Imaging features and conspicuity of invasive lobular carcinomas on digital breast tomosynthesis

OBJECTIVE To review the imaging features of invasive lobular carcinoma (ILC) seen on digital breast tomosynthesis (DBT) in comparison with invasive ductal carcinoma (IDC), and to evaluate whether DBT could improve conspicuity and tumour size assessment of ILC in comparison with digital mammography (DM). METHODS Institutional review board with waiver of informed consent was obtained for this retrospective study. Patients with ILC or IDC who underwent DBT and DM at the time of diagnosis were included. DM and DBT images were reviewed in consensus by two breast radiologists in order to assess imaging features, conspicuity and maximum tumour diameter of ILC and IDC. Pathology on the surgical specimen was considered the standard of reference for assessment of tumour size. RESULTS 43 patients (20 patients with ILC and 23 patients with IDC) were included. On DBT, compared with IDC, ILC presented less frequently as masses (40% vs 78%) (p = 0.01) and more frequently as isolated distortion (20% vs 0%) (p = 0.03). ILC presented more often as asymmetries (60%) than masses (20%) on DM (p = 0.02) but not on DBT (35% vs 40%; p = 1.00). Conspicuity of ILC was significantly higher on DBT than on DM (p = 0.002), while the difference between the two techniques was not significant for IDC (p = 0.2). Regarding ILC, concordance in tumour size measurement between DBT and pathology was fair (intraclass correlation coefficient = 0.24). CONCLUSION ILC rarely presented as dense masses but frequently demonstrated architectural distortion on DBT. DBT increased lesion conspicuity but failed to accurately assess tumour size of ILC. Advances in knowledge: (1) This study describes specific features of ILC on DBT. (2) It shows that DBT can improve conspicuity of ILC.

Imaging Features Associated With Posttraumatic Breast Neuromas

OBJECTIVE The aim of this study is to review the clinical and imaging features of patients with a histopathologic diagnosis of posttraumatic breast neuromas. MATERIALS AND METHODS We report eight biopsy-proven posttraumatic neuromas in six patients with a history of breast surgery. Mammographic, sonographic, and breast MRI examinations were reviewed according to the BI-RADS lexicon. In addition, the tail sign, a specific sign known to be associated with neuromas in other parts of the body, was assessed. RESULTS Mammographic, MRI, and sonographic examinations were performed in three, four and all six patients, respectively. The neuromas were occult on the three mammograms performed but all of them were identified on ultrasound as hypoechoic masses with parallel orientation; seven of the eight neuromas (87.5%) had an oval shape with circumscribed margins. Strain elastography performed for two patients (three neuromas) showed benign features (benign elasticity scores and fat-to-lesion ratio). Half of the masses showed a tail sign (focal thickening of the nerve adjacent to posttraumatic neuroma, similar to the dural tail sign). Of five lesions investigated by MRI, two were occult on MRI. The remaining three were visible as isointense foci on T1-weighted images, with a benign type 1 enhancement curve. CONCLUSION In patients who underwent breast surgery, a mass with benign features raises the possibility of a neuroma. Although the tail sign was present in half of the posttraumatic neuromas, imaging-guided biopsy remains the standard of care.

Serous Microcystic Adenoma of the Pancreas

75-year-old woman presented with a 2-week history of diffuse abdominal pain and emesis. According to the patient, the pain was dull and relieved by vomiting. She was admitted for a possible small bowel obstruction. A computed tomographic (CT) scan revealed a large vascular tumor in the distal pancreas that was inhomogeneous and suggestive of multiple, very small cysts. No other masses were visualized in the abdomen, and no lymphadenopathies were present. The patient’s medical history was significant for diabetes mellitus, atrial fibrillation, and coronary artery disease. Her social history was negative for smoking and drinking. A distal pancreatectomy and splenectomy were performed. The specimen consisted of a portion of distal pancreas and a spleen. Most of the pancreatic tissue received was replaced by a slightly bosselated mass measuring 9 cm in greatest dimension (Figure 1). Only a 1.5-cm segment of normal pancreas was present. The mass appeared to be well circumscribed with no invasion of the splenic vessels or the spleen. The cut sections of the mass showed a central scar with radiating fibrous bands. A closer inspection revealed multiple small cysts ranging in size from less than 0.1 to 0.5 cm. Microscopically, the tumor was composed of multiple cysts containing proteinaceous fluid that were lined by low cuboidal cells with centrally located nuclei and clear cytoplasm (Figure 2). Nuclei were round and had inconspicuous nucleoli. The cells lacked atypia, and there were no mitoses present. Focal areas of intracystic papillary projections were also present. At the periphery and within the fibrous stroma, blood vessels were identified, explaining the vascular appearance of the tumor on CT. The cells contained periodic acid‐Schiff‐positive granules (Figure 3), which were digested by diastase, indicating the presence of intracytoplasmic glycogen. Five peripancreatic lymph nodes showed no evidence of malignancy. A diagnosis of serous microcystic adenoma (SMA) was rendered. Serous microcystic adenomas are benign tumors of the pancreas and are also known as glycogen-rich cystadenomas or serous cystadenoma. 1,2 Two thirds of patients present with symptoms such as abdominal pain, abdominal mass, nausea, vomiting, or weight loss. The remaining one third of the tumors are discovered incidentally on rou

Differentiation of Fibroadenomas and Pure Mucinous Carcinomas on Dynamic Contrast-Enhanced MRI of the Breast Using Volume Segmentation for Kinetic Analysis: A Feasibility Study

OBJECTIVE The objective of this study was to retrospectively evaluate the diagnostic performance of volume-based kinetic analysis in dynamic contrast-enhanced MRI (DCE-MRI) of the breast for the differentiation of fibroadenomas (FAs) with high T2 signal intensity from pure mucinous carcinomas (PMCs). MATERIALS AND METHODS A review of records from 2007 to 2013 that were stored in the pathology department database at our institution identified nine patients with PMCs (defined as tumor cells with a mucinous component ≥ 90%) who underwent preoperative breast MRI. The PMCs were compared with 15 biopsy-proven FAs from 13 patients. Characteristics noted on DCE-MRI were evaluated using computer-assisted diagnosis software. For each mass, the proportion of progressive enhancement in the lesion at the delayed phase was quantified. Both groups of masses were compared using a Wilcoxon signed rank test. A ROC curve was used to define an appropriate cutoff point. RESULTS The median rate of progressive enhancement was 100% (range, 99-100%) for FAs and 97% (range, 87-99%) for PMCs (p = 0.0326). The AUC of the kinetic curve for progressive enhancement was 0.7519 (95% CI, 0.5258-0.9407). A more appropriate cutoff value to maximize sensitivity and specificity was 98.5%. With this cutoff, sensitivity was 66.7% (95% CI, 11.1-100%) and specificity was 80% (95% CI, 39.6-99.8%) for the diagnosis of PMCs. CONCLUSION Volume-based kinetic analysis may aid in differentiating FAs from PMCs on DCE-MRI studies of the breast.

Reflex Testing for Germline BRCA1, BRCA2, PALB2, and ATM Mutations in Pancreatic Cancer: Mutation Prevalence and Clinical Outcomes From Two Canadian Research Registries

PurposeWe investigated the translational value of reflex testing for germline mutations in four homology-directed DNA repair predisposition genes (BRCA1, BRCA2, PALB2, and ATM) in consecutive patients with pancreatic adenocarcinoma.MethodsOne hundred fifty patients with French-Canadian (FC) ancestry were evaluated for founder mutations, and 114 patients were subsequently assessed by full gene sequencing and multiplex ligation-dependent probe amplification for nonfounder mutations. Two hundred thirty-six patients unselected for ancestry were also assessed for mutations by full gene sequencing.ResultsThe FC founder mutation prevalence among the 150 patients was 5.3% (95% CI, 2.6% to 10.3%), and the nonfounder mutation prevalence across the four genes among the 114 patients tested was 2.6% (95% CI, 0.6% to 7.8%). In the case series unselected for ancestry, 10.0% (95% CI, 2.7% to 26.4%) of patients reporting Ashkenazi Jewish (AJ) ancestry carried an AJ founder mutation, with no nonfounder mutations identified...