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ABSTRACT: The presence and distribution of mitotic figures is an important discriminatory parameter in the assessment of melanocytic lesions. We evaluated the number and distribution of mitotic figures in 353 randomly collected melanocytic nevi of various subtypes by hematoxylin and eosin (H&E) staining and immunohistochemically with the 2 mitotic markers Phospho-Histone H3 Ser28 (PHH3) and MPM2. At least 1 mitotic figure was present in 19.5%, 31.3%, and 42.8% of H&E-, PHH3-, and MPM2-stained lesions, respectively. In common compound nevi, the mean number of dermal mitoses amounted to 0.024/mm dermal surface area in the H&E staining (PHH3: 0.061; MPM2: 0.087) and to 0.175/mm in Spitz nevi (PHH3: 0.325; MPM2: 0.45). Nevi exhibiting mitotic figures were significantly more frequent in the youngest age group (0-20 years) than in patients older than 50 years (P < 0.0001). In the upper half of the dermis, mitotic activity was roughly 3 times as frequent as compared with the lower half. Clusters of mitotic figures within the dermis were not observed. Mitotic activity in obviously benign melanocytic nevi is not rare even in the deep dermal part. More than 2 mitotic figures per lesion can usually be explained either by the nevus subtype, young patient age, traumatization, or inflammation. PHH3 and MPM2 are a valuable diagnostic adjunct in the evaluation of melanocytic tumors allowing more sensitive and faster recognition of mitotic figures and their distribution.
The American Journal of dermatopathology 10/2010; 32(7):643-9. · 1.30 Impact Factor
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ABSTRACT: Visceral pleural invasion (VPI) increases the T category of non-small cell lung carcinomas (NSCLCs) that otherwise only meet T1 criteria to T2. The American Joint Committee on Cancer provides no guidelines on what constitutes VPI. Penetration beyond the visceral pleural elastic layer (VPEL) has been proposed as the minimum criterion but is not internationally accepted. The purposes of this study were to elucidate current international practices regarding assessment of VPI and identify histologic features pathologists consider necessary for VPI. We examined responses to an online quiz consisting of 15 NSCLCs adjacent to or involving the visceral pleura. Of 103 participants from 22 countries, 84.5% were in academic practice; 42.7% had a subspecialty interest in pulmonary pathology. Interobserver percentage agreement about whether VPI was present, absent, or indeterminate ranged from 36.9% to 93.2% (mean, 73.0%). The K for participants for all quiz cases was 0.35. There was considerable diagnostic variability in cases with extensive pleural elastosis and when tumor cells were intermingled with the VPEL. It seems that the majority of participants consider penetration of the VPEL necessary and also sufficient to categorize VPI as present. However, the formation of internationally recognized guidelines for assessing VPI by NSCLC is likely to improve diagnostic consensus.
American Journal of Clinical Pathology 11/2007; 128(4):638-47. · 2.60 Impact Factor
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ABSTRACT: This Internet-based quiz (http://kathrin.unibas.ch/polyp/) tested the diagnostic variability of 168 pathologists in the diagnosis of 20 colorectal polyps on 3 representative images, including hyperplastic polyps (HPs), traditional serrated adenomas (TSAs), sessile serrated adenomas (SSAs), and tubulovillous adenomas (TVAs). Interobserver variability for each of the 20 lesions was significant and was most pronounced for SSAs. Correct answers were independent of the participant's experience with TVAs, HPs, and TSAs. Participants with gastrointestinal subspecialty training and those who had read a reference article on serrated polyps gave a significantly higher percentage of correct answers for SSAs. The nomenclature used for serrated polyps was generally inconsistent. Our results suggest significant shortcomings in the routine H&E diagnosis of serrated colorectal polyps. A diagnostically unifying concept for lesions of the serrated neoplasia pathway, standardization of nomenclature, training of pathologists, and possibly development of ancillary techniques are of paramount importance for accurate patient management.
American Journal of Clinical Pathology 07/2007; 127(6):938-45. · 2.60 Impact Factor
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Coya Tapia, Katharina Glatz,
Hedvika Novotny,
Alessandro Lugli,
Milo Horcic,
Christian A Seemayer,
Luigi Tornillo,
Luigi Terracciano,
Hanspeter Spichtin,
Martina Mirlacher,
Ronald Simon,
Guido Sauter
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ABSTRACT: The relationship between HER-2 overexpression and gene amplification is well evaluated in breast cancers but remains unclear or controversial in many other tumor entities. Therefore, we tested the HER-2 status in more than 120 different tumor entities. 5751 tumor samples were analyzed on TMAs by immunohistochemistry (Hercept-Test, DAKO) and fluorescence in situ hybridization (PathVysion, Abbott-Vysis) under highly standardized conditions. HER-2 overexpression (score 2/3+) and amplification occurred most often in breast cancers but was also seen in 18 other tumor entities including cancers of the urinary bladder (amplification in 14.3%, overexpression in 6.7%), stomach (8.3/4.9%), endometrium (6.6/6.8%), lung (2.8/3.1%) and ovary (2.3/1.2%). Remarkably, a strong association between overexpression and amplification was seen in all examined cancer entities. Trastuzumab therapy is highly efficient in HER-2 amplified breast cancer both in metastatic disease and as an adjuvant therapy. A variety of other tumor entities including frequent neoplasms and cancers with often limited therapeutic options have similar patterns of HER-2 alterations as observed in breast cancer (ie high overexpression due to high level gene amplification). Such tumor entities should be carefully evaluated for a possible utility of trastuzumab treatment.
Modern Pathology 03/2007; 20(2):192-8. · 4.79 Impact Factor
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Katharina Glatz,
Spasenija Savic,
Dieter Glatz,
Gilbert Francz,
Audrey Barascud,
Bruno Grilli,
Michelle Herzog,
Peter Dalquen,
Georg Feichter,
Peter Spieler,
Michael Tamm,
Lukas Bubendorf
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ABSTRACT: Equivocal atypia in respiratory cytology can be a diagnostic challenge. In such cases fluorescence in situ hybridization (FISH) may be used for the analysis of chromosomal aberrations and often allows a reliable distinction of benign and malignant cells.
An online picture gallery of 30 respiratory cytologic preparations comprising 23 specimens with equivocal cytology as well as 5 positive and 2 negative controls was prepared (www.unibas.ch/patho/lungenzyto/loesung). The final diagnoses were confirmed by clinical follow-up or biopsy or both. Each of the illustrated cell groups was analyzed by multitarget FISH after PAP image capturing and automatic relocalization.
The online questionnaire was completed by 137 cytomorphologists from all continents. The control cases were assessed accurately to a significantly higher percentage than the equivocal cases. In equivocal cases participants more often made false-positive than false-negative diagnoses. In 2 patients with benign conditions (tuberculosis and pulmonary capillaritis) the rate of false-positive answers was remarkably high (31.4% and 62.8% respectively). The result of the 20 best-performing participants for the 5 cases with the highest percentage of inaccurate answers was not better than if they had chosen their answer by chance.
These data illustrate that single cells or cell clusters of a subgroup of equivocal lung cytology are a diagnostic challenge even for highly experienced morphologists. Internet-based tests are able to reveal limitations of cytomorphology.
Cancer 01/2007; 108(6):480-7. · 4.77 Impact Factor
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Katharina Glatz,
Niels Willi,
Dieter Glatz,
Audrey Barascud,
Bruno Grilli,
Michelle Herzog,
Peter Dalquen,
Georg Feichter,
Thomas C Gasser,
Tullio Sulser,
Lukas Bubendorf
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ABSTRACT: Urinary cytology is limited by high interobserver variability in the evaluation of cells with little atypia. We set up an online quiz on urinary cytology and tested the performance of 246 international participants. The quiz consisted of still images of 42 urinary specimens with equivocal morphologic features and 10 control cases with an unequivocal cytologic diagnosis. The nature of the cells on the 292 quiz images had been verified by multitarget fluorescence in situ hybridization in addition to the information obtained by cystoscopy, clinical follow up, and/or histologic examination. The original quiz cases and the percentage of answers given by the participants can be viewed at: http://kathrin.unibas.ch/urinzyto/. High-grade cancers were diagnosed correctly in 76.0% and low-grade cancers in only 33.9%. Remarkably, 54.5% of all participants misclassified decoy cells as malignant. This study shows that large-scale international online quizzes may be used to find educational deficits in cytopathology.
American Journal of Clinical Pathology 09/2006; 126(2):294-301. · 2.60 Impact Factor
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ABSTRACT: The category of equivocal respiratory cytology is a common diagnostic dilemma to both cytopathologists and clinicians. Chromosomal alterations are a hallmark of cancer but are rare or absent in benign conditions. The goal of this study was to test the ability of multitarget fluorescence in situ hybridization (FISH) for dissecting equivocal respiratory cytology into reactive and malignant categories. A consecutive series of 54 Papanicolaou-stained cytologic specimens of the lung was analyzed. The Papanicolaou-stained atypical cell groups were photographed, and the exact locations on the specimens were saved using automated stage and relocation software. The specimens were hybridized with a multitarget FISH probe that contains a mixture of fluorescent probes to the centromeric region of chromosome 6 and to the 5p15, 8q24 (site of the MYC gene) and 7p12 (site of the EGFR gene) loci. The hybridized atypical cells were selectively scored after relocation. A final diagnosis was available in 45 patients, revealing lung carcinoma in 55.5% (n = 25), no evidence of malignancy in 37.8% (n = 17), and pulmonary metastasis of another primary carcinoma in 6.7% (n = 3). FISH results were negative in all 17 patients with benign pulmonary disease and positive in 20 of the 25 patients (80%) with lung carcinoma (p < 0.0001). The sensitivity, specificity, and positive and negative predictive values for detection of malignancy were 79%, 100%, 100%, and 74%, respectively. These data suggest that multitarget FISH in conjunction with automated relocation is a powerful approach for the elucidation of equivocal lung cytology.
Chest 06/2006; 129(6):1629-35. · 5.25 Impact Factor
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ABSTRACT: Mitotic figure (MF) counting is important in the evaluation of many tumor types. Inadequate fixation, crush artefacts, the presence of many apoptoses, or the rarity of MFs in a given lesion can make the determination of the mitotic index a very time-consuming or even impossible task, especially for novices. We evaluated the potential of the two commercially available mitotic markers MPM-2 and Phospho-Histone H3 Ser28 (PHH3) for improving mitotic counting. Formalin-fixed tissue of 1 lymphoma, 19 epithelial, 25 mesenchymal, and 10 melanocytic tumors was immunohistochemically stained with both antibodies. Mitotic counts of each tumor sample were determined by a pathologist and three residents in the hematoxylin and eosin and in both immunohistochemical stainings. Because of the higher sensitivity of the immunohistochemical stainings for MFs, average mitotic counts per 10 HPF were higher with MPM-2 (11.0) and PHH3 (10.1) than with hematoxylin and eosin (5.9) staining. The precise distinction of MFs from apoptoses and the visualization of the distribution of MFs uncovering mitotic hotspots, even at low magnification, turned out to be major advantages of both mitotic markers. In addition, the average time needed to establish the mitotic count was reduced by 40.3% with MPM-2 and by 50.4% with PHH3. MPM-2 and PHH3 were subjectively rated by all pathologists involved in this study to be very helpful in mitotic counting, especially in melanocytic and mesenchymal lesions but less so in epithelial tumors. Both markers have hence been successfully introduced in our laboratory for the routine assessment of MFs in melanocytic and mesenchymal tumors.
American Journal of Surgical Pathology 02/2006; 30(1):83-9. · 4.35 Impact Factor
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ABSTRACT: We set out to evaluate alterations of the therapeutic target genes KIT (CD 117), EGFR, and HER-2 in human retinoblastoma.
Ninety-five formalin-fixed, paraffin-embedded retinoblastomas were brought into a tissue microarray (TMA) format. Immunohistochemistry was performed to analyze the expression of CD117, EGFR, and HER-2. Fluorescence in situ hybridization (FISH) was utilized for detection of EGFR amplifications. Three tumors with strong CD117 positivity were sequenced for KIT exon 11 mutations.
Detectable CD117 expression was seen in 19% of all interpretable cases. Sequence analysis of the three tumors with the strongest CD117 expression revealed no mutations. EGFR was positive in 14% of all cases. No EGFR amplification was observed by FISH, however. All tumors were negative for HER-2 expression.
Our data suggest that selected cases of retinoblastoma may be candidates for anti-EGFR and imatinib mesylate (STI571) therapy.
Albrecht von Graæes Archiv für Ophthalmologie 03/2005; 243(2):156-62. · 2.17 Impact Factor
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Mona Pache, Katharina Glatz,
Doris Bösch,
Stephan Dirnhofer,
Martina Mirlacher,
Ronald Simon,
Peter Schraml,
Alex Rufle,
Josef Flammer,
Guido Sauter,
Peter Meyer
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ABSTRACT: We aimed to immunohistochemically examine the expression of KIT (CD 117) in human posterior uveal melanoma and to analyze KIT-positive tumors for gene mutations. Brought into a tissue microarray (TMA) format were 101 formalin-fixed, paraffin-embedded posterior uveal melanomas. Immunohistochemistry was performed using the polyclonal anti-CD117 antibody from Dako (A4502). In ten selected KIT-positive tumors, exons 2, 8, 9, 11, 13 and 17 were sequenced. Of the 101 cases, 89 (88%) could be evaluated on the TMAs. Immunohistochemistry for CD 117 was weakly positive in 5 cases (6%), moderately positive in 10 cases (12%) and strongly positive in 57 cases (69%). No KIT mutations were detected in the analyzed exons. In conclusion, human posterior uveal melanoma frequently expresses CD117 at high levels. Although KIT mutations could not be found, it appears justified to investigate the utility of imatinib mesylate in the treatment of these patients.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 01/2004; 443(6):741-4. · 2.49 Impact Factor
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Gabriele Mild,
Felix Bachmann,
Jean-Louis Boulay, Katharina Glatz,
Urban Laffer,
Adam Lowy,
Urs Metzger,
Jürgen Reuter,
Luigi Terracciano,
Richard Herrmann,
Christoph Rochlitz
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ABSTRACT: Adjuvant chemotherapy reduces the incidence of distant metastasis and increases survival of patients with colorectal cancer. However, predictive markers are needed to define subsets of patients with stage II and III disease that may benefit from adjuvant treatment. A secreted member of the TNF receptor superfamily, the decoy receptor 3 (DcR3), was reported to be amplified in colorectal cancer as a negative regulator of Fas-mediated apoptosis. We analyzed DcR3 gene copy number and protein expression in a large series of tumors from a randomized multicenter trial of 5-fluorouracil/mitomycin C (FU/MMC) adjuvant chemotherapy of the Swiss Group for Clinical Cancer Research (SAKK 40/81), using real-time quantitative PCR and immunohistochemistry on tumor microarrays. Results of gene status and protein expression of DcR3 were correlated with disease-free and overall survival of patients. We observed amplification of the DcR3 gene in 185/294 (63%) and overexpression of the DcR3 protein in 163/223 (73%) of colorectal tumors. Multivariate analysis showed no prognostic effect of DcR3 gene amplification and protein overexpression. However, adjuvant chemotherapy was significantly more beneficial in patients with normal DcR3 gene copy number than in patients with amplification (DFS: HR 2.84, 95% CI 1.16-6.98, p = 0.02; OS: HR 3.15, 95% CI 1.19-8.32, p = 0.02), whereas DcR3 protein overexpression did not influence the effect of adjuvant chemotherapy (DFS: HR 1.02, 95% CI 0.65-1.60, p = 0.95; OS: HR 0.95, 95% CI 0.61-1.49, p = 0.83). We conclude that amplification of the 20q13 locus is a predictive marker for adjuvant chemotherapy in colorectal cancer.
International Journal of Cancer 12/2002; 102(3):254-7. · 5.44 Impact Factor
