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Anatomic Pathology Selected Abstracts, 5/13

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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; Rouzan Karabakhtsian, MD, attending pathologist, Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY; and Thomas Cibull, MD, dermatopathologist, Evanston Hospital, NorthShore University HealthSystem, Evanston, Ill.

Pseudomyxoma peritonei of appendiceal origin treated with cytoreductive surgery and chemotherapy

Pseudomyxoma peritonei originating from an appendiceal mucinous neoplasm remains a biologically heterogeneous disease. The authors conducted a study to evaluate outcome and long-term survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) consolidated through an international registry study. A retrospective multi-institutional registry was established through the collaborative efforts of units affiliated with the Peritoneal Surface Oncology Group International. A total of 2,298 patients from 16 specialized units underwent CRS for pseudomyxoma peritonei. Treatment-related mortality was two percent, and major operative complications occurred in 24 percent of patients. The median survival rate was 196 months (16.3 years), and the median progression-free survival rate was 98 months (8.2 years), with 10- and 15-year survival rates of 63 percent and 59 percent, respectively. Multivariate analysis identified the following as independent predictors of a poorer progression-free survival: prior chemotherapy treatment (P<.001), peritoneal mucinous carcinomatosis (PMCA) histopathologic subtype (P<.001), major postoperative complications (P=.008), high peritoneal cancer index (P=.013), debulking surgery (completeness of cytoreduction [CCR], two or three; P<.001), and not using HIPEC (P=.030). Independent predictors of poorer overall survival were older age (P=.006), major postoperative complications (P<.001), debulking surgery (CCR, two or three; P<.001), prior chemotherapy treatment (P=.001), and PMCA histopathologic subtype (P<.001). The authors concluded that the combined modality strategy for pseudomyxoma peritonei may be performed safely, with acceptable morbidity and mortality, in a specialized unit setting, with 63 percent of patients surviving beyond 10 years. Minimizing nondefinitive operative and systemic chemotherapy treatments before definitive cytoreduction may improve outcomes with this therapy and boost long-term survival. Optimal cytoreduction generates the best outcomes.

Chua TC, Moran BJ, Sugarbaker PH, et al. Early- and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Clin Oncol. 2012;30:2449–2456.

Correspondence: Terence Chua at terence.chua@unsw.edu.au

An audit of dermatopathology requisitions: handwritten vs. EMR data-entry accuracy

Dermatopathology case requisitions are sent to the authors’ institution in handwritten form or via electronic medical record. Requisition data entry can be divided into the categories of patient demographics, physician name, and procedure site/date. Systematic data-entry problems potentially cause considerable documentation error, propagate inaccurate patient information, and potentially delay billing/revenue collection. The authors conducted a study in which they compared dermatopathology data-entry errors on handwritten requisitions to data-entry errors using an electronic medical record (EMR). A total of 11,475 requisitions (8,545 handwritten and 2,930 via EMR) were included in the study, which ran from April through September 2011. The authors found that the handwritten requisitions generated 258 data-entry errors on 8,545 specimens (three percent), while the requisitions entered via the EMR generated 113 errors on 2,930 specimens (3.9 percent). Container labeling, which is a handwritten process for both requisition methods, was the most common source of error. The authors concluded that even with an EMR, containers are at least partially hand labeled, and 96 percent of EMR errors occurred during the hand-labeling process. Other EMR data-entry errors are extremely uncommon (four of 2,930 cases). These findings suggest that introducing a labeling process entirely linked to EMR data entry could nearly eliminate data-entry errors. Although this study focused solely on dermatopathology cases, the findings can be extrapolated to all types of specimens.

Kinonen CL, Watkin WG, Gleason BC, et al. An audit of dermatopathology requisitions: hand written vs. electronic medical record data entry accuracy. J Cutan Pathol. 2012;39(9):850–852.

Correspondence: Dr. Thomas Cibull at tcibull@northshore.org

Intratumoral heterogeneity of HER2 gene amplification in breast cancer

Intratumoral heterogeneity of human epidermal growth factor receptor 2 gene amplification has been reported to occur with variable frequencies in breast cancers. However, there have been few studies of its clinicopathological significance. The authors used tissue microarrays to evaluate two aspects of intratumoral heterogeneity of HER2 gene amplification: regional heterogeneity and genetic heterogeneity. They examined 96 invasive breast cancers in which HER2 amplification had been diagnosed in whole sections and determined the clinicopathological characteristics of those tumors. HER2 regional heterogeneity, defined as the existence of amplification-negative or amplification-equivocal patterns in different tissue microarray cores of a tumor, was present in 17 (18 percent) of the 96 cases. HER2 genetic heterogeneity, defined as the presence of tumor cells with a HER2/chromosome enumeration probe 17 ratio higher than 2.2 in five to 50 percent of the tumor cells, was found in 11 (11 percent) cases, all of which showed HER2 regional heterogeneity. The cases with intratumoral heterogeneity of HER2 gene amplification were characterized by low-grade or equivocal HER2 amplification and equivocal (2+) HER2 expression in whole sections. The patients with intratumoral heterogeneity of HER2 gene amplification had significantly shorter disease-free survival times than those with homogeneous HER2 gene amplification. This effect was also evident in subgroup analysis by hormone receptor status. In multivariate analysis, intratumoral HER2 heterogeneity retained its status as an independent prognostic factor for disease-free survival. The authors concluded that intratumoral heterogeneity of HER2 gene amplification is present in a subset of HER2-amplified breast cancers, especially in cases with low-grade HER2 amplification and equivocal HER2 expression, indicating a need for HER2 testing on larger, more representative tumor samples to accurately assess HER2 status in such cases. The patients with this heterogeneity have decreased disease-free survival rates, suggesting that genetic instability and hence aberrant HER2 amplification in subclones of such tumors may be associated with breast cancer progression.

Seol H, Lee HJ, Choi Y, et al. Intratumoral heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance. Mod Pathol. 2012;25:938–948.

Correspondence: Dr. S. Y. Park at sypmd@snu.ac.kr

An immunohistochemical and JAZF1 rearrangement study of endometrial sarcomas

The World Health Organization classifies endometrial sarcomas as either low-grade endometrial stromal sarcoma or undifferentiated endometrial sarcoma. Studies suggest that undifferentiated endometrial sarcoma is a heterogeneous group, and a subgroup with uniform nuclei is more akin to low-grade endometrial stromal sarcoma in terms of morphologic, immunohistochemical, and genetic features. The authors classified endometrial sarcomas treated at their institution from 1998 to 2011 into low-grade endometrial stromal sarcoma or undifferentiated endometrial sarcoma as well, the latter being further categorized into a group with either uniform or pleomorphic nuclei. Morphological features, immunoprofile, and fluorescence in situ hybridization rearrangements of JAZF1 and PHF1 genes were correlated with tumor category and outcome. The authors evaluated 40 cases, comprising 23 low-grade endometrial stromal sarcomas, 10 undifferentiated endometrial sarcomas with nuclear uniformity, and seven undifferentiated endometrial sarcomas with nuclear pleomorphism. Low-grade endometrial stromal sarcomas were more often estrogen and progesterone receptor positive (83 percent) compared with undifferentiated endometrial sarcoma with nuclear uniformity (10 percent) or nuclear pleomorphism (none; P<.001). Positivity for p53 was restricted to undifferentiated endometrial sarcomas, with more frequent expression in the group with nuclear pleomorphism (57 percent) than with nuclear uniformity (10 percent; P=.06). Ki-67 proliferation index in more than 10 percent of tumor cells was more frequent in undifferentiated endometrial sarcoma than in low-grade endometrial stromal sarcoma (P<.001). JAZF1 rearrangement was detected in 32 percent of low-grade endometrial stromal sarcomas and none of the undifferentiated sarcomas. Rearrangement of PHF1 was found in two patients, one with JAZF1–PHF1 fusion. No significant differences in clinical behavior were noted between undifferentiated endometrial sarcoma with nuclear uniformity and nuclear pleomorphism. The authors concluded that undifferentiated endometrial sarcoma subtypes and low-grade endometrial stromal sarcoma have distinct immunohistochemical and cytogenetic profiles. The data do not show any difference in clinical behavior between the subgroups of undifferentiated sarcomas.

Jakate K, Azimi F, Ali RH, et al. Endometrial sarcomas: an immunohistochemical and JAZF1 re-arrangement study in low-grade and undifferentiated tumors. Mod Pathol. 2013;26:95–105.

Correspondence: Dr. M. Rouzbahman at marjan.rouzbahman@uhn.on.ca

Grading system combining architectural features and mitotic count predicts recurrence in lung adenocarcinoma

The International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society has proposed a new lung adenocarcinoma classification. The authors investigated whether nuclear features can stratify prognostic subsets. They reviewed slides of 485 stage I lung adenocarcinoma patients. They also evaluated nuclear diameter, nuclear atypia, nuclear/cytoplasmic ratio, chromatin pattern, prominence of nucleoli, intranuclear inclusions, mitotic count per 10 high-power fields (HPFs) or 2.4 mm2, and atypical mitoses. Tumors were classified into histologic subtypes according to the IASLC/ATS/ERS classification and grouped by architectural grade into the categories of low (adenocarcinoma in situ, minimally invasive adenocarcinoma, or lepidic predominant), intermediate (papillary or acinar), and high (micropapillary or solid). Log-rank tests and Cox regression models evaluated the ability of clinicopathologic factors to predict recurrence-free probability. In univariate analyses, nuclear diameter (P=.007), nuclear atypia (P=.006), mitotic count (P<.001), and atypical mitoses (P<.001) were significant predictors of recurrence. The recurrence-free probability was the lowest for patients with a high mitotic count (five or more per 10 HPFs; n=175; five-year recurrence-free probability, 73 percent), followed by an intermediate count (two to four per 10 HPFs; n=106; 80 percent), and a low count (zero to one per 10 HPFs; n=204; 91 percent; P<.001). A combined architectural/mitotic grading system stratified patient outcomes (P<.001) into low grade (low architectural grade with any mitotic count and intermediate architectural grade with low mitotic count: n=201; five-year recurrence-free probability, 92 percent), intermediate grade (intermediate architectural grade with intermediate-high mitotic count: n=206; 78 percent), and high grade (high architectural grade with any mitotic count: n=78; 68 percent). Adding mitotic count to architectural grade is an advantage in stratifying patients with intermediate architectural grade into two prognostically distinct categories (P=.001). After adjusting for clinicopathologic factors, including gender, stage, pleural/lymphovascular invasion, and necrosis, mitotic count was not an independent predictor of recurrence (P=.178). However, patients with a high architectural/mitotic grade remained at significantly increased risk of recurrence (high versus low: P=.005) after adjusting for clinical factors. The authors proposed this combined architectural/mitotic grade for lung adenocarcinoma as a practical method that can be applied in routine practice.

Kadota K, Suzuki K, Kachala SS, et al. A grading system combining architectural features and mitotic count predicts recurrence in stage I lung adenocarcinoma. Mod Pathol. 2012;25(8):1117–1127.

Correspondence: Dr. W. D. Travis at travisw@mskcc.org

A clinicopathological study of solitary fibrous tumor and a proposed risk-assessment model

Solitary fibrous tumor represents a spectrum of mesenchymal tumors encompassing tumors previously termed hemangiopericytoma, which are classified as having intermediate biological potential (rarely metastasizing) in the 2002 World Health Organization classification scheme. Few series have reported on clinicopathological predictors with outcome data and formal statistical analysis in a large series of primary tumors as a single unified entity. For this study, institutional pathology records were reviewed to identify primary solitary fibrous tumor cases. Histological sections and clinical records were also reviewed for canonical prognostic indicators, including patient age, tumor size, mitotic index, tumor cellularity, nuclear pleomorphism, and tumor necrosis. Patients (n=103) with resected primary solitary fibrous tumor (excluding meningeal tumors) were identified. The most common sites of occurrence were abdomen and pleura. These tumors were larger than those occurring in the extremities, head, and neck or trunk but did not demonstrate significant outcome differences. Overall five- and 10-year metastasis-free rates were 74 percent and 55 percent, respectively, while five- and 10-year disease-specific survival rates were 89 percent and 73 percent, respectively. Patient age, tumor size, and mitotic index predicted time to metastasis and disease-specific mortality, while necrosis predicted metastasis only. A risk-stratification model based on age, size, and mitotic index clearly delineated patients at high risk for poor outcomes. While small tumors with low mitotic rates are highly unlikely to metastasize, tumors of 15 cm or greater that occur in patients who are 55 years or older, with mitotic figures greater than or equal to four per 10 high-power fields, require close followup and are linked to a high risk of metastasis and death.

Demicco EG, Park MS, Araujo DM, et al. Solitary fibrous tumor: a clinicopathological study of 110 cases and proposed risk assessment model. Mod Pathol. 2012;25:1298–1306.

Correspondence: Dr. W. L. Wang at wlwang@mdanderson.org

Expression of thyroid transcription factor-1 in normal endometrium and risk of endometrial cancer

Thyroid transcription factor-1 is a DNA-binding protein that is primarily expressed in thyroid and lung tissue, but it has also been found in gynecologic tissue. Recent studies have suggested that thyroid transcription factor-1 (TTF-1) has tumor-suppressor function in lung adenocarcinoma models. The authors conducted a study in which they examined whether expression of TTF-1 in benign endometrium and endometrial hyperplasia might impact the risk of developing endometrial cancer. They used formalin-fixed, paraffin-embedded endometrial tissues obtained from 535 cases to construct an endometrial tissue microarray. One hundred fifty of 207 patients had multiple serial endometrial specimens, including 46 patients who progressed to endometrial cancer. The tissue microarray included a range of histopathologies, among them benign endometrium (n=231), simple hyperplasia (n=105), complex hyperplasia (n=36), simple atypical hyperplasia (n=10), complex atypical hyperplasia (n=44), and endometrial carcinoma (n=109). Expression of TTF-1 by immunohistochemistry in benign endometrium and endometrial hyperplasia was correlated with progression to cancer and clinical features known to be associated with increased risk of developing endometrial cancer. Carcinoma specimens showed a significantly greater expression of TTF-1 compared with benign endometrium and nonatypical hyperplasia (P=.0007 and P=.05). Presence of TTF-1 expression in benign endometrium was associated with a significantly decreased risk of cancer development (P=.003; hazards ratio, 0.104; 95 percent confidence interval, 0.024–0.455). TTF-1 expression in hyperplasia did not significantly correlate with progression to cancer. The study data indicated that TTF-1 expression in normal endometrium is associated with a reduced risk of developing endometrial cancer. This observation suggests that TTF-1 might function as a tumor suppressor in endometrial tissue. TTF-1 expression in normal endometrium could potentially provide clinically useful information as a biomarker for risk of endometrial cancer.

Sullivan PS, Maresh EL, Seligson DB, et al. Expression of thyroid transcription factor-1 in normal endometrium is associated with risk of endometrial cancer development. Mod Pathol. 2012;25(8):1140–1148.

Correspondence: Dr. P. S. Sullivan at psullivan@mednet.ucla.edu

Use of four immunohistochemistry panels versus gene-expression analysis to classify breast tumors

In the clinical diagnosis of breast cancer, immunohistochemistry panels with estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki-67 are routinely used. It has been proposed that the panels be used to classify breast tumors into distinct subtypes. Gene-expression analysis with formalin-fixed, paraffin-embedded material has become widely available recently, but the prognostic values of corresponding gene panels compared with these four immunohistochemical panels had not been tested. The authors independently evaluated five-year relapse risk-estimation scores using semiquantitative data from four immunohistochemical panels (Ku-IHC4 score) and compared these with the results of four-gene expression profiling of formalin-fixed, paraffin-embedded specimens (Ku-FFPE4 score) in a consecutive series of 235 primary invasive breast cancer patients. Ku-IHC4 score was revealed to be an independent predictor of recurrence in a multivariate model analyzed by classical clinical parameters (Ku-IHC4 score versus Ku-FFPE4 score: χ2, 14.2 versus 2.5; P=.0002 versus P=.11). When patients were trichotomized into high-, intermediate-, and low-risk groups using the thresholds determined from the approximately calculated five-year relapse rate, Kaplan-Meier analyses showed a significant difference among the three groups in Ku-IHC4 score (log-rank, P<.0001) but not in Ku-FFPE4 score. The high-risk group according to the Ku-FFPE4 score showed contradictory low recurrence rates (Ku-IHC4 score versus Ku-FFPE4 score, 53.1 percent versus 24.8 percent), which might be caused by risk-dependently extended error ranges. The authors showed that the Ku-IHC4 score provides better prognostic information than the corresponding quantitative RNA measurements. Prognostication tools such as the Ku-IHC4 score may be useful in screening to determine which patients should be assessed further using genes other than estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki-67 to determine critical aspects of therapeutic decisionmaking.

Yamamoto-Ibusuki M, Yamamoto Y, Yamamoto S, et al. Comparison of prognostic values between combined immunohistochemical score of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, Ki-67 and the corresponding gene expression score in breast cancer. Mod Pathol. 2013;26:79–86.

Correspondence: Dr. H. Iwase at hiwase@kumamoto-u.ac.jp

Partial p16 staining in oropharyngeal squamous cell carcinoma and human papilloma virus RNA status

Human papillomavirus-related oropharyngeal squamous cell carcinoma has a unique biology. P16 immunostaining is used as a surrogate marker for transcriptionally active human papillomavirus (HPV). Although diffuse staining is generally accepted as positive, the significance of partial staining has not been established, nor has the cutoff for extent of p16 staining that should be used to identify a tumor as HPV related. From three other large studies using p16 immunohistochemistry, the authors identified all cases with partial positive staining. The p16-stained slides were reviewed by three study pathologists for staining (nuclear and cytoplasmic) extent (in quartiles) and percentage that was confluent—that is, back-to-back cell staining. Tumors were histologically typed (keratinizing, non-keratinizing, or non-keratinizing with maturation) and tested for high-risk HPV by RNA in situ hybridization and reverse-transcriptase polymerase chain reaction (PCR). Among the 16 cases, two were 4+ (13 percent), five were 3+ (31 percent), six were 2+ (38 percent), and three were 1+ (19 percent) p16 staining tumors. Extent of staining ranged from five percent to 90 percent of cells positive, with 25 percent or more confluent staining in four of 16 (25 percent). Of the 16 (31 percent) cases, five were HPV related on the basis of RNA in situ hybridization and reverse-transcriptase PCR. All of these cases had more than 50 percent p16 staining; four of five cases (80 percent) had more than 25 percent confluent staining; and four of seven cases (57 percent) had non-keratinizing histological features. Only one of the p16 1+/2+ tumors was HPV RNA-positive (by reverse-transcriptase PCR only and low level). All 1+/2+ cases were keratinizing type or undifferentiated. By sensitive detection methods, most partial p16-positive squamous cell carcinoma cases with more than 50 percent staining harbor transcriptionally active HPV, and most HPV+ tumors have significant amounts of confluent staining. Cases with less than 50 percent p16 staining and lacking significant confluent staining rarely harbor HPV. These results indicate that greater than 75 percent p16 staining, or alternatively, more than 50 percent staining combined with more than 25 percent confluent areas, are suitable cutoffs for defining positivity.

Lewis JS Jr., Chernock RD, Ma XJ, et al. Partial p16 staining in oropharyngeal squamous cell carcinoma: extent and pattern correlated with human papillomavirus RNA status. Mod Pathol. 2012;25:1212–1220.

Correspondence: Dr. J. S. Lewis at jlewis@path.wustl.edu


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