Amy L. Adams

Solid pseudopapillary tumor of the pancreas: a review of salient clinical and pathologic features.

Solid pseudopapillary tumor (SPT) of the pancreas is a rare tumor of uncertain histogenesis characterized, as the name suggests, by a cystic and solid pattern of growth with formation of pseudopapillae. Accounting for only a small percentage of pancreatic neoplasms, SPT occurs primarily in young women, although cases in older patients and men have been reported. The tumor is thought to have low-grade malignant potential, as the majority of the cases are cured by simple but complete surgical resection. Knowledge of the unique morphologic and demographic characteristics of this neoplasm is essential for accurate diagnosis. Herein, we review the clinical and pathologic features, which can help separate SPTs from other primary pancreatic tumors.

Mucoepidermoid carcinoma of the bronchus: a review.

Although mucoepidermoid carcinoma of the salivary gland is relatively common, mucoepidermoid carcinoma arising from the mucous glands of the bronchus is rare. Bronchial mucoepidermoid carcinoma usually presents as an intraluminal mass producing luminal occlusion. Symptoms are airway obstruction and recurrent pneumonia. Macroscopically, mucoepidermoid carcinoma appears as an exophytic intrabronchial mass with intact or ulcerated bronchial mucosa. Microscopically, the tumors are located in the submucosa of the large bronchi. The tumors are usually well differentiated and contain a combination of mucus-secreting, squamous, and intermediate cells. The increased frequency of this tumor in the pediatric population suggests a genetic abnormality. Recent genetic studies have demonstrated reciprocal chromosomal translocations including t(1;11)(p22;q13), t(11;19)(q14-21;p12), and t(11; 19)(q21;p13). Chromosome 11 in the first translocation appears to have been altered resulting in up-regulation of the cyclin D1 gene and overexpression of cyclin D1. The t(11;19)(q21;p13) encodes a novel fusion product capable of disrupting the Notch signaling pathway.

Combinatorial Effects of Lapatinib and Rapamycin in Triple-Negative Breast Cancer Cells

Triple-negative breast cancers, which lack estrogen receptor, progesterone receptor, and HER2/neu overexpression, account for approximately 15% of breast cancers, but occur more commonly in African Americans. The poor survival outcomes seen with triple-negative breast cancers patients are, in part, due to a lack of therapeutic targets. Epidermal growth factor receptor (EGFR) is overexpressed in 50% of triple-negative breast cancers, but EGFR inhibitors have not been effective in patients with metastatic breast cancers. However, mTOR inhibition has been shown to reverse resistance to EGFR inhibitors. We examined the combination effects of mTOR inhibition with EGFR inhibition in triple-negative breast cancer in vitro and in vivo. The combination of EGFR inhibition by using lapatinib and mTOR inhibition with rapamycin resulted in significantly greater cytotoxicity than the single agents alone and these effects were synergistic in vitro. The combination of rapamycin and lapatinib significantly decreased growth of triple-negative breast cancers in vivo compared with either agent alone. EGFR inhibition abrogated the expression of rapamycin-induced activated Akt in triple-negative breast cancer cells in vitro. The combination of EGFR and mTOR inhibition resulted in increased apoptosis in some, but not all, triple-negative cell lines, and these apoptotic effects correlated with a decrease in activated eukaryotic translation initiation factor (eIF4E). These results suggest that mTOR inhibitors could sensitize a subset of triple-negative breast cancers to EGFR inhibitors. Given the paucity of effective targeted agents in triple-negative breast cancers, these results warrant further evaluation. Mol Cancer Ther; 10(8); 1460–9. ©2011 AACR.

Breast Arterial Calcification: A Marker of Medial Vascular Calcification in Chronic Kidney Disease

BACKGROUND AND OBJECTIVES Because previous studies have not distinguished between intimal (atherosclerotic) and medial vascular calcification, the prevalence and clinical significance of either condition in chronic or end-stage kidney disease (CKD or ESKD) are unknown. We hypothesized that breast arterial calcification (BAC) is exclusively medial and that mammography can serve as a useful marker of generalized medial calcification in CKD and ESKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Arterial calcification was identified histologically in breast tissue or visually in mammograms and radiographs of extremities from patients with CKD or ESKD. RESULTS Medial calcification but no intimal calcification was present in all 16 specimens from patients with CKD or ESKD. In 71 women with ESKD, BAC was present on mammograms in 63% compared with 17% in women without renal insufficiency matched for age, race, and diabetes (P<0.001). Age and ESKD duration were significant, independent predictors of BAC. BAC was also present in 36% of mammograms from the same patients performed 5.5±0.7 years before the onset of ESKD (P<0.05 versus control) but in only 14% of patients with stage 3 CKD. Comparison of mammograms and extremity radiographs revealed that BAC was present in over 90% of patients with peripheral arterial calcification (PAC), and PAC was observed in less than 6% of patients without BAC. CONCLUSIONS BAC is a specific and useful marker of medial vascular calcification in CKD, and its prevalence is markedly increased in ESKD and advanced CKD.

Proliferation (Ki-67 and phosphohistone H3) and oncotype DX recurrence score in estrogen receptor-positive breast cancer.

The Oncotype DX Recurrence Score (RS) is often used in lymph node-negative, estrogen receptor-positive breast cancer to refine prognosis and direct therapy. Its utility is limited by its cost, proprietary nature, and turnaround time. Markers of proliferation factor heavily into determination of RS. Our aim is to correlate expression of proliferation markers Ki-67 and phosphohistone H3 (PPH3) with RS and other prognostic indicators. Estrogen receptor-positive invasive breast carcinomas from 133 patients with Oncotype DX testing were selected. Representative tumor sections were stained with MIB1, a monoclonal antibody that reacts against Ki-67, and antibody to PPH3. Nuclear staining was quantitated through an automated imaging system. The percentage of positive cells was scored as low (<10%), intermediate (10% to 20%), or high (>20%) for Ki-67, and low (<2%), intermediate (2% to 5%), or high (>5%) for PPH3. Expression of both markers was compared with RS and clinicopathologic parameters including grade, tumor size, lymph node metastasis, and angiolymphatic invasion. Ki-67 and PPH3 expression were both significantly associated with RS (P=0.02 and P=0.027, respectively) and grade (P<0.001 and P=0.002, respectively). Ki-67 expression correlated with angiolymphatic invasion (P=0.01) but not with tumor size or lymph node metastasis; PPH3 expression showed no association with any of these 3 parameters. Expression of proliferation markers Ki-67 and PPH3 by immunohistochemistry is significantly correlated with RS and tumor grade. This observation suggests that immunohistochemical assessment of markers of proliferation may provide useful prognostic information, at lower cost than RS testing.

The Effect of Neoadjuvant Chemotherapy on Histologic Grade, Hormone Receptor Status, and Her2/neu Status in Breast Carcinoma

Abstract:  The use of neoadjuvant chemotherapy prior to surgical resection for breast cancer is no longer restricted to patients with locally advanced disease. As preoperative treatment becomes more common, the question arises whether or not such therapy changes important tumor characteristics. The objective of our study is to compare histological grade, hormone receptor status, and HER2/neu expression pre‐ and post‐therapy patients receiving preoperative neo‐adjuvant chemotherapy. Forty patients status post‐neoadjuvant treatment who had available archived pathologic material pre‐ and post‐therapy were identified. Glass slides were reviewed retrospectively, and tumor grade, hormone receptor status, and HER2/neu expression were compared between the pre‐ and post‐therapy specimens. No significant differences were noted between the pre‐ and post‐specimens for two of the three parameters comprising the modified Bloom–Richardson grade, including degree of tubule formation (p = 0.062) and nuclear pleomorphism (p = 0.086). For mitotic activity, a decrease in score was observed between pre‐ and post‐therapy specimens which was statistically significant (p = 0.021). However, there was no significant difference in the overall modified Bloom–Richardson grade (p = 0.118). Information was available regarding hormone receptor and HER2/neu status in 26 patients (65%). There was no significant difference between pre‐ and post‐treatment specimens for hormone receptor status. However, there were more patients with HER2/neu overexpression after receiving neoadjuvant therapy (p = 0.027). Neoadjuvant therapy resulted in a significant decrease in mitotic count and an increase in the proportion of patients with Her2/neu overexpression. No significant changes were noted for the degree of tubule formation, nuclear pleomorphism, overall Bloom–Richardson score, and hormone receptor status. However, small sample size may be a limitation of these results.

Breast arterial calcification in chronic kidney disease: absence of smooth muscle apoptosis and osteogenic transdifferentiation

The pathophysiology of medial arterial calcification in chronic kidney disease (CKD) is unclear but has been ascribed to phenotypic changes in vascular smooth muscle, possibly in conjunction with intimal proliferation and atherosclerosis. As the prevalence of calcification in breast arteries is increased in women with CKD and end-stage renal disease (ESRD), this was examined histologically in mastectomy specimens from 19 women with CKD or ESRD. Arterial calcification was present in 18, was exclusively medial, and occurred in vessels as small as arterioles. Intimal thickening was common but unrelated to calcification. There was no evidence of atherosclerosis. The earliest calcification presented as small punctate lesions scattered throughout the media, often with calcification of the internal elastic lamina. Arterial calcification was present in all samples from an age- and diabetes-matched cohort without CKD but was much milder. While smooth muscle cell density was reduced one-third in arteries from patients with ESRD, the cells appeared normal, expressed SM22α, and exhibited no apoptosis. Staining for the bone-specific protein osteocalcin, the osteoblastic transcription factors Runx2 or osterix, or the chondrocytic transcription factor SOX9 was absent in regions of early calcification. Thus, medial calcification in breast arteries of patients with CKD can occur in the absence of smooth muscle cell apoptosis and/or osteogenic transdifferentiation. This suggests that the pathologic mineralization process may differ from one arterial type to the other.

GATA-3 expression in male and female breast cancers: comparison of clinicopathologic parameters and prognostic relevance

Expression of GATA-3 in female breast cancers has been linked to estrogen receptor (ER) expression and, in turn, to improved outcomes. However, GATA-3 has not been studied in male breast cancers. Nineteen male breast carcinomas (average age: 63 years) and 164 female breast carcinomas (average age: 57 years) were immunostained for GATA-3. Results were compared to age, tumor size, tumor grade, lymph node status, distant metastases, survival, and positivity for ER, progesterone receptor (PR), and HER2/neu. Six of 19 (31.6%) male and 135 of 164 (82.3%) female breast carcinomas were GATA-3 positive (P < .001). In women, 82.1% of GATA-3-positive cancers were grade 1 or 2, whereas 75.9% of GATA-3-negative cancers were grade 3 (P < .001); no such significant correlation was seen in men. Unlike female cancers, male cancers showed no correlation between GATA-3 positivity and ER positivity, PR positivity, or distant metastases. Nodal metastasis and HER2 status were not linked to GATA-3 in either sex. Seventeen (89.5%) men were alive at follow-up (average: 61 months); only 1 died of disease. Most women (159/164, 97.0%) were also alive at follow-up (average: 41 months), with a higher proportion of GATA-3-negative women dead than GATA-3-positive women (3/29 [10.3%] vs. 2/135 [1.5%], P = .039). GATA-3 is expressed less often in male than female breast cancers. Male cancers show no correlation between GATA-3 positivity and ER/PR positivity or distant metastases, unlike female cancers. There appears to be no link between GATA-3 positivity and survival in men, whereas in women, GATA-3-positive tumors are typically lower grade with a better prognosis.

Nottingham-defined mitotic score: comparison with visual and image cytometric phosphohistone H3 labeling indices and correlation with Oncotype DX recurrence score.

Prognosis of breast cancer patients has been determined traditionally by lymph node status, tumor size, and histologic grade. In recent years the Oncotype DX recurrence score (RS) assay has emerged as an expensive adjunct prognostic tool. Markers of proliferation play a large role in determination of RS, and we have shown previously that immunohistochemical expression of proliferation markers Ki-67 and phosphohistone H3 (PPH3) correlates with RS. Our current goal is comparison of the hematoxylin and eosin (H&E) mitotic score, defined by the Nottingham grading system, with anti-PPH3 mitotic figure labeling assessed by both visual and automated image analysis and correlation of mitotic score results with RS. Estrogen receptor-positive breast carcinomas from 137 patients with Oncotype DX testing were selected. A representative H&E-stained tumor section was evaluated. Mitoses were counted per 10 high-power fields and tumors graded using the Nottingham criteria by 1 pathologist in accordance with College of American Pathologists-recommended mitotic count cutoffs for a field diameter of 0.55 mm. An additional section was immunostained with PPH3 antibody. PPH3 mitotic scores were determined visually and by automated imaging system. Statistical analysis was performed using univariate tests and Spearman coefficient. There was a statistically significant positive correlation among the 3 methods of mitotic score assessment. Specifically, correlation of tumor grades obtained using visual and automated methods of assessment of mitotic activity with PPH3 stain was the strongest and most statistically significant (weighted &kgr; value 0.84, P<0.001; Spearman coefficient 0.89, P<0.001). There was a statistically significant positive correlation between H&E mitosis score and RS (P<0.001, Spearman coefficient 0.30) and between visual PPH3 mitotic score and RS (P<0.001, Spearman coefficient 0.28). In conclusion, mitotic score by any of the 3 methods studied may be useful in assessing tumor grade, proliferation, and prognosis.

Luminal cytokeratin expression profiles of breast papillomas and papillary carcinomas and the utility of a cytokeratin 5/p63/cytokeratin 8/18 antibody cocktail in their distinction

Luminal cytokeratin (CK) expression in breast papillary lesions, and its potential diagnostic utility among other markers in distinguishing between papillomas and papillary carcinomas, has not been previously evaluated. Such expression was determined in 42 papillary lesions (18 papillary carcinomas and 24 papillomas) by immunostaining with a CK5/p63/CK8/18 antibody cocktail. The mean CK8/18 intensity score and percentage of positive cells were significantly higher in papillary carcinomas (227 and 95%, respectively, vs 86 and 42% in papillomas; both P-values <0.0001), whereas the mean CK5 intensity score and percentage of positive cells were significantly lower (7 and 5%, respectively, vs 107 and 58% in papillomas; both P-values <0.0001). Half (9/18) of the papillary carcinomas expressed p63 vs all (24/24) of the papillomas (P=0.0001). P63 expression in papillary carcinoma was always (9/9; 100%) focal/limited in nature (expression in <10% of cells), whereas focal expression was seen in only four (17%) papillomas (P<0.0001). Both differential CK (CK8/18 and CK5) expression and p63 were equally sensitive (100%) for the diagnosis of papillary carcinoma, but differential CK expression was more specific (96 vs 83%), resulting in a greater accuracy. However, the best discriminatory power in the distinction from papilloma was achieved when all three markers were used in combination, resulting in 100% sensitivity and specificity values. It is concluded that breast papillary lesions have differential CK expression profiles that, especially in combination with p63, can be useful for their stratification, potentially also in needle biopsy material, in which more accurate and reproducible characterization is needed.