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ABSTRACT: The Ki67 labeling index is known to correlate with survival in patients with neuroendocrine tumors (NETs). A grading scheme recently endorsed by the World Health Organization for gastroenteropancreatic NETs classifies well-differentiated NETs into 2 categories based on the Ki67 labeling index: low (G1) and intermediate grades (G2). Tumor heterogeneity is a common finding in many tumors including NETs. Metastatic NETs to the liver are often diagnosed by radiographically guided needle core biopsy from which the Ki67 index is determined, which randomly samples the lesion without being targeted to regions that may show a higher proliferative rate. Whether the Ki67 index obtained from this type of limited material represents the whole tumor has been questioned. Forty-five surgically resected liver metastases of well-differentiated NETs were retrieved. A 9 core (3 core-triplets) tissue microarray (TMA) was constructed from the paraffin blocks of each tumor, each triplet considered to represent a virtual biopsy. Immunohistochemical staining for Ki67 was performed on TMA and whole slides, and the Ki67 labeling indices were determined by digital image analysis. Correlation of the Ki67 index with patient survival was analyzed. Forty-seven percent of cases showed intratumoral heterogeneity in Ki67 index that translated into discrepant grades among subsections on the whole slide. A similar trend was recapitulated on the virtual biopsies, although to a lesser degree. When the definitive grade of the tumor was based on the highest Ki67 index identified on the whole slide, the virtual biopsies perfectly predicted G1 cases (100%), but were much less accurate for G2 cases (47.8% with 3 biopsies and 34.8% with single biopsy). Accordingly, the predictive value for G1 on the virtual biopsies was low (64.7% and 59.5% for 3 and 1 biopsy, respectively), but was perfect for G2 (100%). By Kaplan-Meier survival analysis, there was a statistically significant difference between G1 and G2 in terms of overall survival, disease-free survival, and progression-free survival when graded on either whole-slide subsections or virtual biopsies. On the whole slides, the highest Ki67 grade showed a better correlation with overall survival than the mean Ki67 grade. In summary, by image analysis, we found that about half of the NETs metastatic to the liver show intratumoral heterogeneity resulting in discrepant Ki67 grade. In most cases, in particular G1, the virtual biopsy is representative of the whole slide, but for G2 the representation is <50%. Nevertheless, grades based on virtual biopsy had statistically significant prognostic values on patient survival, and there is no clear difference between the 3 and single virtual biopsy. Ki67 staining of core biopsies usually provides an adequately reliable method of proliferation assessment for prognosis of metastatic NETs to the liver, although the choice of treatment may be affected by intratumoral grade heterogeneity.
The American journal of surgical pathology 06/2011; 35(6):853-60. · 4.06 Impact Factor
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ABSTRACT: Although podoplanin expression in breast myoepithelial (ME) cells has been reported to be readily distinguishable from that of lymphatic endothelium (LE), we recently encountered a case in which attenuated expression led to an incorrect interpretation of lymphatic invasion. This prompted us to further analyze the pattern and intensity of podoplanin expression in LE and in ME cells surrounding both non-neoplastic and neoplastic breast epithelium in 42 cases of breast carcinoma. In addition, cases with presumed lymphatic invasion (tumor cells within podoplanin-positive lymphatic-like structures) were further characterized on the basis of histologic review and results of additional endothelial (CD31 and/or CD34) and ME (p63+/-calponin) immunostains. Normal LE always displayed a strong (3+) linear podoplanin expression pattern, whereas ME cells surrounding non-neoplastic breast epithelium had a granular, branching membranous staining pattern that was either moderate (2+) or strong (3+) in 13 (34%) and 25 (66%) foci, respectively. ME cells surrounding ductal carcinoma in situ (DCIS) displayed weaker (1+ to 2+) podoplanin expression with 26 (72%) foci showing only a residual thin/discontinuous pattern of expression, whereas the other 10 (28%) foci showed a pattern similar to that around non-neoplastic epithelium. Further evaluation of 10 foci of presumed lymphatic invasion confirmed the presence of lymphatic invasion in 6 (60%) cases, whereas 4 displayed surrounding ME cells and were thus interpreted as DCIS. One case, in which both DCIS and lymphatic invasion were unequivocally present, displayed a few nests of tumor cells surrounded by both podoplanin-positive and p63-positive cells in different areas of the periphery and could not be readily classified. These findings represent an important caveat in the diagnosis of lymphatic invasion and, accordingly, one should always interpret results of podoplanin staining in the context of the histologic appearance and/or consider evaluation of additional endothelial or ME immunostains, especially when the characteristically strong linear pattern of expression of LE is not evident.
Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 05/2009; 17(5):425-30. · 1.63 Impact Factor
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Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 03/2009; 8(1):A24. · 5.64 Impact Factor
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ABSTRACT: Hemoglobin (Hb) A2 electrophoresis has been used for prenatal screening for the beta-thalassemia trait (betaTT). We retrospectively reviewed Hb capillary electrophoresis performed in our laboratory. We found that of the 122 cases showing elevated HbA2 levels, 79 cases were due to hemoglobinopathies, mostly HbS. Review of the RBC indices suggested that 3 of 36 cases with elevation of HbA2 in the HbAA-pregnancy group had betaTT and 29 had normal RBC indices; data were not available for 4 patients. Among 7 cases with elevation of HbA2 in the HbAA-other group, 5 had betaTT and 2 were normal. The number of patients without betaTT but with HbA2 elevation in the pregnant group was significantly higher than that in the nonpregnant group. When a higher HbA2 cutoff (3.5%) was used, only 3 pregnant patients without betaTT had HbA2 elevation, similar to the nonpregnant group. We found that a significant number of pregnant women with mild HbA2 elevation had no evidence of betaTT, compared with the nonpregnant group.
American Journal of Clinical Pathology 02/2009; 131(1):42-8. · 2.60 Impact Factor
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ABSTRACT: Clostridium septicum infection is a rare cause of aortic dissection, and the mortality rate for the condition is high. Only 26 cases of C. septicum aortitis have been reported; all of those patients were elderly, and 20 of them had an associated colonic neoplasm. Herein, we present the case of a 22-year-old man whose C. septicum aortitis resulted in aortic dissection that involved the entire length of the aorta. Upon autopsy, no neoplasm or other predisposing condition was identified in this patient. To the best of our knowledge, this is the 1st report of C. septicum aortitis, fatal or otherwise, in a young individual.
Texas Heart Institute journal / from the Texas Heart Institute of St. Luke's Episcopal Hospital, Texas Children's Hospital 02/2009; 36(4):334-6. · 0.65 Impact Factor
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ABSTRACT: We evaluated the performance of the CAPILLARYS 2 (Sebia, Norcross, GA) capillary electrophoresis system for detection and identification of monoclonal proteins in serum samples. We analyzed 104 serum specimens by Sebia Hydragel serum protein electrophoresis (agarose gel electrophoresis [AGE]/immunofixation electrophoresis [IFE]) and CAPILLARYS 2 capillary zone electrophoresis (CZE)/immunosubtraction. AGE and CZE had sensitivities of 90% and 81%, respectively, based on IFE as the "gold standard," and all bands detected were confirmed by IFE (100% specificity). AGE and CZE had an overall agreement of 91% on serum protein electrophoresis. In the population tested, IgG was detected in 29% of samples by IFE and 30% using immunosubtraction. Similarly IgA was detected in 9% of cases by IFE and 8% by immunosubtraction. IgM and light chains were detected in 6% and 3% of cases, respectively, by IFE, whereas CZE/immunosubtraction did not detect any IgM or light chains. In our hands, AGE and CZE had the same specificity for detection of monoclonal proteins; however, CZE/immunosubtraction seems to be less sensitive than IFE for the detection of IgM and, possibly, serum light chains.
American Journal of Clinical Pathology 09/2007; 128(2):293-9. · 2.60 Impact Factor
