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  Anatomic Abstracts





November 2010

Michael Cibull, MD
Melissa Kesler, MD
Rouzan Karabakhtsian, MD
Megan Zhang, MD

A study of micropapillary ductal carcinoma in situ of the breast A study of micropapillary ductal carcinoma in situ of the breast

The clinical significance of micropapillary growth pattern in ductal carcinoma in situ is controversial, and the impact of nuclear grading in terms of recurrence of this lesion is yet to be clarified. The authors conducted a study to evaluate, using a series of micropapillary in situ carcinomas, how the histological features correlate with recurrence and whether the micropapillary subtype behaved differently from other nonmicropapillary ductal carcinoma in situ. The authors collected 55 cases of micropapillary in situ carcinomas from four institutions. They reviewed all cases for nuclear grade, extent, necrosis, and microinvasion and tested for estrogen and progesterone receptors, Ki67, HER2, epidermal growth factor receptor, and p53 expression. The authors obtained clinical data, type of surgery, and followup for all patients. The results showed that nuclear grade is crucial in determining the biology of micropapillary carcinoma in situ. They also showed that high nuclear grade micropapillary ductal carcinoma in situ more frequently overexpressed HER2, showed a higher proliferation index, displayed necrosis and microinvasion, and was more extensive than low/intermediate nuclear grade. Logistic regression analysis confirmed high nuclear grade (odds ratio, 6.86; confidence interval, 1.40–33.57) as the only parameter associated with elevated risk of local recurrence after breast-conserving surgery. However, the recurrence rate of 19 micropapillary carcinoma in situ, which were part of a cohort of 338 conse-cutive ductal carcinoma in situ, was significantly higher (log-rank test, P=0.019) than that of nonmicropapillary, independent of nuclear grade. The authors concluded that although nuclear grade may significantly influence the biological behavior of micropapillary ductal carcinoma in situ, micropapillary growth pattern represents a risk factor for local recurrence after breast-conserving surgery.

Castellano I, Marchiò C, Tomatis M, et al. Micropapillary ductal carcinoma in situ of the breast: an inter-institutional study. Mod Pathol. 2010;23:260–269.

Correspondence: Dr. A. Sapino at
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Subtypes in epidermal growth factor receptor 2-positive breast cancer Subtypes in epidermal growth factor receptor 2-positive breast cancer

Human epidermal growth factor receptor 2 gene amplification or protein overexpression (HER2 positivity) defines a clinically challenging subgroup of patients with breast cancer who have a variable prognosis and response to therapy. The authors investigated the heterogeneous biologic appearance and clinical behavior of HER2-positive tumors using molecular profiling. They used hierarchical clustering of gene expression data from 58 HER2-amplified tumors of various stages and histologic grades and estrogen receptor status to construct a HER2-derived prognostic predictor that would be further evaluated in several large independent breast cancer data sets. Unsupervised analysis identified three subtypes of HER2-positive tumors with mixed stage, histologic grade, and estrogen receptor status. One subtype had a significantly worse clinical outcome. The authors created a prognostic predictor based on differentially expressed genes between the subtype with worse outcome and the other subtypes. The predictor was able to define patient groups with better and worse outcome in HER2-positive breast cancer across multiple independent breast cancer data sets and identify a sizable HER2-positive group with a long disease-free survival period and low mortality rate. Significant correlation to prognosis was also observed in basal-like, estrogen receptor-negative, lymph node-positive, and high-grade tumors, irrespective of HER2 status. The predictor included genes associated with immune response, tumor invasion, and metastasis. The authors concluded that the HER2-derived prognostic predictor provides additional insight into the heterogeneous biology of HER2-positive tumors and may become useful for improving the selection of patients who need additional treatment with new drugs targeting the HER2 pathway.

Staaf J, Ringnér M, Vallon-Christersson J. Identification of subtypes in human epidermal growth factor receptor 2-positive breast cancer reveals a gene signature prognostic of outcome. J Clin Oncol. 2010;28(11):1813–1820.

Correspondence: Dr. Ake Borg at
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Effect of a minimum lymph node policy in radical cystectomy and pelvic lymphadenectomy Effect of a minimum lymph node policy in radical cystectomy and pelvic lymphadenectomy

Extended pelvic lymphadenectomy during radical cystectomy reportedly improves bladder cancer-specific survival. Lymph node counts are often a proxy for the extensiveness of a dissection. The authors conducted a study in which they assessed the impact of an institutional policy requiring a minimum number of lymph nodes. They retrospectively reviewed patients undergoing radical cystectomy and pelvic lymphadenectomy (PLND) for invasive bladder cancer between March 2000 and February 2008. Beginning March 1, 2004, a policy was established at the study institution that at least 16 lymph nodes had to be examined. Specimens with fewer than 16 lymph nodes (including any fat) were resubmitted to detect additional lymph nodes. The authors compared lymph node yields, lymph node positivity, lymph node density, and survivorship before and after policy implementation. A total of 147 patients underwent surgery four years before policy implementation, and 202 underwent surgery four years after. The authors found that the median number of lymph nodes increased from 15 to 20 after policy implementation. The percentage of cases with 16 or more lymph nodes increased from 42.9 to 69.3 percent (P<0.01). The lymph node positivity rates did not change significantly, but the proportion of patients with lymph node density of less than 20 percent increased from 43.9 to 65.5 percent (P=0.04). Overall survival increased from 41.5 to 72.3 percent (P<0.01). Univariate and multivariate regression demonstrated that policy implementation and subsequent increase in median lymph node yield decreased mortality risk by 30 percent (hazard ratio, 0.70; P=0.04) and 48 percent (hazard ratio, 0.52; P=0.01), respectively. The authors concluded that evaluation of PLND specimens obtained at radical cystectomy can be influenced by an institutional policy mandating a minimum number of lymph nodes. This could lead to greater confidence in pathologic staging and in the reliability of lymph node density as a predictor of prognosis. Survival can improve due to increased awareness of the need to perform a more thorough PLND.

Fang AC, Ahmad AE, Whitson JM, et al. Effect of a minimum lymph node policy in radical cystectomy and pelvic lymphadenectomy on lymph node yields, lymph node positivity rates, lymph node density, and survivorship in patients with bladder cancer. Cancer. 2010;116:1901–1908.

Correspondence: Dr. Badrinath R. Konety at
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Cyclin D1 immunoreactivity in normal endocervix and its diagnostic value in endocervical lesions Cyclin D1 immunoreactivity in normal endocervix and its diagnostic value in endocervical lesions

It may be difficult to distinguish reactive glandular lesions from adenocarcinoma in situ of the uterine cervix. Although several immunohistochemical markers have established value in this diagnostic setting, none is completely reliable. The authors noted that neoplastic endocervical lesions often show loss of nuclear cyclin D1 expression, in contrast to benign glandular cells. Therefore, they investigated cyclin D1 staining in a series of 64 cervical biopsy specimens, including normal and reactive endocervical epithelium, adenocarcinoma in situ, stratified mucinproducing intraepithelial lesions, and invasive adenocarcinoma. Thirteen specimens also included a component of high-grade cervical squamous intraepithelial neoplasia. Normal endocervical epithelium usually expressed cyclin D1, although staining was typically focal, and there was increased immunoreactivity in reactive and metaplastic glandular cells, including tubo-endometrioid metaplasia. In contrast, most cases of adenocarcinoma in situ were completely negative. Therefore, cyclin D1 staining distinguished benign from neoplastic epithelial cells. Although focal cyclin D1 expression was observed in five of 19 cases of adenocarcinoma in situ, the staining was associated with more marked cytological atypia, precluding confusion with a reactive process. The invasive adenocarcinomas were primarily negative for cyclin D1. However, focal staining was observed in 10 of 19 cases and was mainly restricted to cells at the deep tumor margin or to small infiltrative glands and detached cell clusters within the stroma. The authors concluded that cyclin D1 can be included within an immunohistochemical panel to aid in distinguishing between reactive cervical glandular lesions and adenocarcinoma in situ. The localized distribution of staining within invasive lesions suggests that cyclin D1 upregulation plays a specific role during the progression of some endocervical adenocarcinomas.

Little L, Stewart CJ. Cyclin D1 immunoreactivity in normal endocervix and diagnostic value in reactive and neoplastic endocervical lesions. Mod Pathol. 2010;23:611–618.

Correspondence: C. J. Stewart at
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Histologic assessment to differentiate multiple NSCLC from metastases Histologic assessment to differentiate multiple NSCLC from metastases

Lung adenocarcinoma is morphologically heterogeneous, with mixtures of acinar, papillary, bronchioloalveolar, and solid patterns in more than 80 percent of cases. With synchronous or metachronous multiple nonsmall cell lung cancer (NSCLC), distinguishing intrapulmonary metastases from independent primary tumors is of great clinical importance because it influences staging and, potentially, therapeutic strategy. The authors undertook a study in which they assessed a cohort of 20 patients with 42 multiple NSCLC tumors (24 potential pair comparisons) that were annotated molecularly using genomic and mutational profiling to evaluate the value of comprehensive histologic assessment in this setting. Using the Martini-Melamed criteria, paired tumors were characterized as multiple primary NSCLCs in 21 cases and intrapulmonary metastases in three cases. Genomic and mutational data led to a diagnosis of multiple primaries in 14 cases and metastases in eight cases; two cases could not be assessed. This molecular characterization contradicted the Martini-Melamed diagnosis in seven of the 22 (32 percent) assessable com-parisons. Adenocarcinoma was found in 32 of the 42 (76 percent) tumors. Review in a blinded fashion found semiquantitative comprehensive histologic assessment of paired tumors to be different in 16 of the paired tumors and similar in eight. The authors determined that comparing adenocarcinomas is a complex issue that requires assessing not only percentages of histologic subtypes, but also the recording of additional histologic details, such as cytologic features, patterns of stroma, necrosis, discrete nodularity versus miliary growth, and variants such as clear cell, signet ring, mucinous, and fetal patterns. The authors found that paired squamous cell carcinomas could be compared based on histologic subtyping, in addition to cytologic and stromal characteristics. Considering tumors that differ histologically as multiple primaries and similar tumors as metastases, comprehensive histologic subtyping was consistent with molecular characterization in 20 of the 22 (91 percent) pairs comparisons. The authors concluded that histologic assessment seems to be a powerful tool for determining whether multiple lung adenocarcinomas or squamous cell carcinomas are metastatic or multiple primaries. This has great clinical implications for staging and therapeutic management of lung cancer patients with multiple tumors.

Girard N, Deshpande C, Lau C, et al. Comprehensive histologic assessment helps to differentiate multiple lung primary nonsmall cell carcinomas from metastases. Am J Surg Pathol. 2009;33(12):1752–1764.

Correspondence Dr. William D. Travis at
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Anatomic pathology abstracts editors: Michael Cibull, MD, professor and vice chair, Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington; Melissa Kesler, MD, and Rouzan Karabakhtsian, MD, assistant professors of pathology and laboratory medicine, University of Kentucky College of Medicine; and Megan Zhang, MD, visiting fellow, Division of Dermatopathology, University of California, San Francisco.