College of American Pathologists
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  Anatomic Abstracts





October 2008

Michael Cibull, MD
Melissa Kesler, MD

Galectin-3-expression analysis in the surgical selection of follicular thyroid nodules with indeterminate FNA cytology
Actinin-4 expression in ovarian cancer
Phosphohistone H3 expression and classical prognosticators in invasive lymph node-negative breast cancer
Clinicopathologic analysis of primary angiosarcoma of the breast
Spectrum of endometrial pathology induced by the drugs progesterone receptor modulators
Distinct clinical and prognostic features of infiltrating lobular carcinoma of the breast
Prevalence and characteristics of neuroendocrine tumors

Galectin-3-expression analysis in the surgical selection of follicular thyroid nodules with indeterminate FNA cytology Galectin-3-expression analysis in the surgical selection of follicular thyroid nodules with indeterminate FNA cytology

Approximately 30,200 well-differentiated thyroid carcinomas were diagnosed in the United States in 2007, but the prevalence of thyroid nodules is much higher, at about five percent of the adult population. The preoperative characterization of follicular thyroid nodules is still a challenge, and many benign lesions, which remain indeterminate after fine-needle aspiration (FNA) cytology, are referred to surgery. About 85 percent of these thyroid nodules are classified as benign at final histology. The authors assessed the diagnostic effect of galectin-3-expression analysis in distinguishing between preoperatively benign and malignant follicular thyroid nodules when FNA findings were indeterminate. They enrolled in their study 544 patients between June 1, 2003 and Aug. 30, 2006. The authors used a purified monoclonal antibody to galectin-3, a biotin-free immunocytohistochemical assay, and a morphological and phenotypic analysis of FNA-derived cell-block preparations. Galectin-3-expression analysis was applied preoperatively to 465 follicular thyroid proliferations that were candidates for surgery, and its diagnostic accuracy was compared with final histology. The authors excluded from the study 31 patients because they had small galectin-3-negative thyroid nodules. Data were not available for 47 patients, and one patient was excluded because of an oncocytic nodule. The authors found that 331 (71 percent) of the assessable 465 preoperative thyroid FNA samples did not express galectin-3. They classified 280 (85 percent) of these galectin-3-negative lesions as benign at final histology. Galectin-3 expression was detected, instead, in 134 of 465 (29 percent) thyroid proliferations, 101 (75 percent) of which were confirmed as malignant. The overall sensitivity of the galectin-3 test was 78 percent (95 percent confidence interval [CI], 74–82), and specificity was 93 percent (95 percent CI, 90–95). Estimated positive predictive value was 82 percent (95 percent CI, 79–86), and negative predictive value was 91 percent (95 percent CI, 88–93). Three hundred eighty-one (88 percent) of 432 patients with follicular thyroid nodules who were referred for thyroidectomy received the correct preoperative classification using the galectin-3 test. How­ever, 29 (22 percent) of 130 cancers were missed by the galectin-3 method. The authors concluded that if the option of surgery were based on galectin-3 expression alone, then, theoretically, only 134 thyroid operations would have been performed in 465 patients. Therefore, a large proportion (71 percent) of unnecessary thyroid surgical procedures could be avoided, although a number of galectin-3-negative cancers potentially could be missed. The galectin-3 test proposed by the authors does not replace conventional FNA cytology but represents a complementary diagnostic method for those follicular nodules that remain indeterminate.

Bartolazzi A, Orlandi F, Saggiorato E, et al. Galectin-3-expression analysis in the surgical selection of follicular thyroid nodules with indeterminate fine-needle aspiration cytology: a prospective multicentre study. Lancet Oncol. 2008;9:543–549.

Correspondence: Dr. Armando Bartolazzi at
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Actinin-4 expression in ovarian cancer Actinin-4 expression in ovarian cancer

Actinin-4 is an isoform of nonmuscular α-actinin and actin-bundling protein. By enhancing cell motility, actinin-4 exhibits biological properties that differ from those of another isoform of nonmuscular actinin, actinin-1. Variable clinicopathological implications of actinin-4 have been demonstrated in some human malignancies, such as breast, lung, and colorectal cancers. The authors conducted a study in which they described the clinicopathological and prognostic significance of actinin-4 expression in ovarian cancers. They analyzed actinin-4 expression immunohistochemically in 265 primary ovarian carcinomas: 116 serous, 71 clear cell, 43 endometrioid, and 35 mucinous adenocarcinomas. With reference to endothelial immunoreactivity, cytoplasmic expression of actinin-4 was classified as either low (including negative) or high. The authors then compared various parameters, such as patient characteristics, histopathological findings, including E-cadherin and β-catenin immunoreactivity, and clinical outcome, between groups showing differences in the intensity or intracellular distribution of actinin-4 immunoreactivity. The authors found that high expression of actinin-4 was demonstrated in 137 (57 percent) cases and was associated with serous histology (P=.0075), high histological grade (P<.0001), advanced disease stage (P=.036), high degree of residual disease after initial surgery (P=.0047), poor patient outcome (five-year survival, 52.4 percent in the high-expression group versus 71.9 percent in the low expression group; P=.0043 by log-rank test), and reduced E-cadherin and preserved β-catenin expressions (P=.0097 and P=.017, respectively). Nuclear immunoreactivity for actinin-4 was detected in 20 (7.5 percent) cases and was associated with low histological grade (P=.0079) but not with other variables. Multivariate analysis showed that high actinin-4 expression was an independent prognostic factor for overall survival as well as a high degree of residual disease and clear-cell histology. The authors concluded that the accumulation of actinin-4 in cytoplasm may be related to a higher propensity for tumor invasiveness and metastasis, probably by enhancing cell motility, and could be a novel prognostic indicator for patients with ovarian carcinomas.

Yamamoto S, Tsuda H, Honda K, et al. Actinin-4 expression in ovarian cancer: a novel prognostic indicator independent of clinical stage and histological type. Mod Pathol. 2007;20:1278–1285.

Correspondence: Dr. H. Tsuda at
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Phosphohistone H3 expression and classical prognosticators in invasive lymph node-negative breast cancer Phosphohistone H3 expression and classical prognosticators in invasive lymph node-negative breast cancer

The proliferation factor mitotic activity index is the strongest prognostic factor in early breast cancer, but it may lack reproducibility. The authors analyzed the prognostic value of phosphohistone H3, a marker of cells in late G(2) and M phase. They measured highly standardized immunohistochemical nuclear phosphohistone H3 expression by subjective counts and digital image analysis. Expression was compared with classical clinicopathologic prognostic variables and the mitotic activity index in 119 node-negative invasive breast cancers in patients up to 55 years of age who were treated with adjuvant systemic chemotherapy with long-term followup (median, 168 months). Nineteen patients (16 percent) developed distant metastases and 16 (13 percent) died. Strong phosphohistone H3 expression occurred preferentially in the peripheral growing front; counts were highly reproducible between observers (r=0.92) and highly consistent with digital image analysis (r=0.96). Phosphohistone H3 correlated (P<.05) with tumor diameter, estrogen receptor, carcinoma grade, and mitotic activity index. Phosphohistone H3 values were systematically (80 percent) higher than the mitotic activity index. Receiver operating characteristic curve analysis ob­jectively showed that a phosphohistone H3 value of less than 13 (n=53; 45 percent of all cases) versus a phosphohistone H3 value of 13 or greater (n=66; 55 percent of all cases) was the strongest prognostic threshold, with 20-year recurrence-free survival of distant metastases of 96 percent and 58 percent, respectively (P=.0002; HR=9.6). Mitotic activity index was the second strongest prognostic variable (P=.003; HR=3.9). In multivariate analysis, a phosphohistone H3 value of less than 13 versus 13 or greater exceeded the prognostic value of the mitotic activity index. None of the other classical prognostic factors examined offered prognostic value additional to phosphohistone H3. The authors concluded that phosphohistone H3 is by far the strongest prognostic variable in early invasive node-negative breast cancer patients younger than 55 years of age who are receiving long-term followup.

Skaland I, Janssen EA, Gudlaugsson E, et al. Phosphohistone H3 expression has much stronger prognostic value than classical prognosticators in invasive lymph node-negative breast cancer patients less than 55 years of age. Mod Pathol. 2007; 20: 1307– 1315.

Correspondence: Dr. J. P. Baak at
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Clinicopathologic analysis of primary angiosarcoma of the breast Clinicopathologic analysis of primary angiosarcoma of the breast

Mammary angiosarcoma is a rare neoplasm, accounting for about 0.05 percent of all primary malignancies of the breast. Histologic grading of mammary angiosarcomas is believed to play an important role in prognostication. The authors conducted an analysis in which they reviewed 49 cases of primary angiosarcoma of the breast. Clinical details and follow-up information were obtained from referring pathologists and other clinicians and by chart review. All statistics were performed using Fisher exact test, and only P<.05 was considered significant. Recurrence-free survival and overall survival curves were established using Statistica software version 5.5 from StatSoft. All patients were female and ranged in age from 15 to 74 years (mean, 41.5 years; median, 40 years). Peak incidence was between 30 and 50 years of age. All tumors examined were located within breast parenchyma with or without minor cutaneous involvement. The right side was more commonly affected than the left side (66 percent versus 29.5 percent). Tumor was bilateral at presentation in two cases (4.5 percent). Tumor size varied from 0.7 to 25 cm (mean, 6.7 cm; median, 5 cm). Most patients presented with a palpable, painless mass. Two patients had a history of prior radiation treatment for breast carcinoma. Primary tumors were graded histologically using Rosen’s three-tier system: 17 tumors (35.4 percent) as low grade, 17 (35.4 percent) as intermediate grade, and 14 (29.2 percent) as high grade. Forty-six patients were treated surgically; 11 underwent chemotherapy; and 12 received radiotherapy. Followup was available for 41 patients (83.7 percent; median duration, 29 months). Ten patients (24.4 percent) showed evidence of local recurrence within 11 to 60 months (median, 36 months) after diagnosis. Twenty-four patients (58.5 percent) had developed metastases by the time the study was published. The metastases were most commonly found in lung, liver, skin, and bone. Time interval between diagnosis and metastasis ranged from two to 144 months (median, 34 months). Eighteen patients (44 percent) died of disease and one presumably died of disseminated breast carcinoma. Five patients (12.2 percent) were alive with disease, and 15 patients (36.6 percent) were alive with no evidence of disease. Statistical analysis evaluating correlation between tumor grade and size and rate of local recurrence, metastasis, and death owing to disease showed no significant difference among tumors of different grades. The median recurrence-free and overall survival rates for the entire cohort were 2.8 and 5.7 years, respectively. The authors concluded that mammary angiosarcoma seems to have an overall clinical course similar to other types of angiosarcoma arising in skin or soft tissue. It carries a moderate risk of local recurrence and a high risk of metastasis and death. The authors found no correlation between histologic grade and patient outcome, which is more in line with angiosarcomas at other sites.

Nascimento AF, Raut CP, Fletcher CD. Primary angiosarcoma of the breast: clinicopathologic analysis of 49 cases, suggesting that grade is not prognostic [published online ahead of print September 19, 2008]. Am J Surg Pathol. doi: 10. 1097/ PAS. 0b013e31876dbc7.

Correspondence: Dr. Christopher D. Fletcher, Dept. of Pathology, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115
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Spectrum of endometrial pathology induced by the drugs progesterone receptor modulators Spectrum of endometrial pathology induced by the drugs progesterone receptor modulators

Progesterone receptor modulators are hormonally active drugs effective in managing endometriosis and uterine leiomyomata. The endometrial effects of progestin blockade by progesterone receptor modulators (PRMs) in premeno­pausal women are being evaluated in several clinical trials, but few pathologists have had access to these materials, and published information about the histological changes is scanty. Eighty-four endometrial specimens from women receiving one of four different PRMs were reviewed by a panel of seven experienced gynecologic pathologists to develop consensus observations and interpretive recommendations as part of a National Institutes of Health-sponsored workshop. Although the pathologists were blinded to agent, dose, and exposure interval, the analysis was intended to provide an overview of the breadth of possible findings and a conduit for describing unique features. Endometrial histology included inactive and normal-appearing cycling endometrium. Overtly premalignant lesions (atypical hyperplasia or endometrial intraepithelial neoplasia) were not seen. In a subset of cases, asymmetry of stromal and epithelial growth resulted in prominent cystically dilated glands with admixed estrogen (mitotic) and progestin (secretory) epithelial effects of a type not encountered in contemporary clinical practice. The variety of endometrial appearances suggested that findings might differ by agent and dose over time according to relationships that must be specified for each agent. The constellation of changes seen in those endometria with cystically dilated glands was so novel that new terminology and diagnostic criteria are required for pathologists to recognize them. The panel has designated these changes as PRM-associated endometrial changes (PAEC). Additional follow-up studies are needed to fully define their natural history and relationship to specific agents and administration regimens.

Mutter GL, Bergeron C, Deligdisch L, et al. The spectrum of endometrial pathology induced by progesterone receptor modulators. Mod Pathol. 2008;21:591–598.

Correspondence: Dr. G. L. Mutter at
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Distinct clinical and prognostic features of infiltrating lobular carcinoma of the breast Distinct clinical and prognostic features of infiltrating lobular carcinoma of the breast

The authors conducted a study to determine how patients with infiltrating lobular carcinoma (ILC) differ from patients with the more common infiltrating ductal carcinoma (IDC) with regard to patient and tumor factors, local treatment, and patterns of recurrence. For the study, 12,206 breast cancer patients who were entered into 15 International Breast Cancer Study Group trials between 1978 and 2002 were categorized as having ILC, IDC, or other/mixed types. From this group, 767 tumors (6.2 percent) were classified as ILC, 8,607 (70.5 percent) as IDC, and 2,832 (23.2 percent) as other. The authors analyzed only the 9,374 patients categorized as pure IDC or ILC. The median follow-up time was 13 years. Compared with IDC, ILC was associated with older age; larger, better differentiated, and estrogen receptor-positive tumors; and less vessel invasion. Mastectomy was performed more frequently for ILC (P<.01). There was a significant (P<.01) early advantage in disease-free survival and overall survival for the ILC cohort followed by a significant (P<.01) late advantage for the IDC cohort after six and 10 years, respectively. Similar patterns were observed in cohorts defined by estrogen receptor status. ILC was associated with an increased incidence of bone events but a decrease in regional and lung events (all, P<.01). The authors concluded that ILC is more than a histologic variant of breast cancer. The diagnosis of ILC carries distinct prognostic and biologic implications.

Pestalozzi BC, Zahrieh D, Mallon E, et al. Distinct clinical and prognostic features of infiltrating lobular carcinoma of the breast: combined results of 15 International Breast Cancer Study Group clinical trials. J Clin Oncol. 2008;26:3006–3014.

Correspondence: Dr. Bernhard C. Pestalozzi at
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Prevalence and characteristics of neuroendocrine tumors Prevalence and characteristics of neuroendocrine tumors

Neuroendocrine tumors are considered to be rare and can produce a variety of hormones. The authors examined the epidemiology of and prognostic factors for neuroendocrine tumors (NETs) because neither had been thoroughly examined. They searched the Surveillance, Epidemiology, and End Results (SEER) Program registries to identify NET cases from 1973 to 2004. Associated population data were used for incidence and prevalence analyses. The authors identified 35,618 patients with NETs. They observed a significant increase in the reported annual age-adjusted incidence of NETs from 1973 (1.09/100,000) to 2004 (5.25/100,000). Using SEER 9 registry data, the authors estimated the 29-year limited-duration prevalence of NETs on Jan. 1, 2004 to be 9,263. The estimat­ed 29-year limited-duration prevalence in the United States on that date was 103,312 cases (35/100,000). The most common primary tumor site varied by race, with the lung being the most common in white patients and the rectum in Asian/Pacific Islander, American Indian/Alaska native, and African-American patients. Furthermore, survival duration varied by histologic grade. In multivariate analyses of patients with well-differentiated to moderately differentiated NETs, disease stage, primary tumor site, histologic grade, gender, race, age, and year of diagnosis were predictors of outcome (P<.001). The authors concluded that there was an increased reported incidence of NETs and increased survival durations over time, suggesting that NETs are more prevalent than previously reported. Clinicians need to become familiar with the natural history and patterns of disease progression, which are characteristic of these tumors.

Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063–3072.

Correspondence: Dr. James C. Yao at
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Dr. Cibull is professor of pathology and laboratory medicine and direct of surgical pathology, University of Kentucky Medical Center, Lexington. Dr. Kesler is hematopathology fellow, University of Texas Southwestern Medical Center at Dallas.