A European interlaboratory testing of three well‐known procedures for immunocytochemical detection of epithelial cells in bone marrow. Results from analysis of normal bone marrow

Borgen, Elin; Pantel, Klaus; Schlimok, Günter; Müller, Peter E.; Otte, Marcus; Renolen, Anne; Ehnle, Susanne; Coith, Cornelia; Nesland, Jahn M.; Naume, Bjørn

doi:10.1002/cyto.b.20114

Cited by 33 publications

(29 citation statements)

References 42 publications

(59 reference statements)

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“…An important step into this direction has been thus far made for the immunocytochemical detection of DTC using anticytokeratin antibodies. 17,[20][21][22] Currently, most data on the prognostic value of DTC are available for breast cancer. In other tumor entities, the database is not as solid and the results are more controversial as in breast cancer, but several single institution studies including patients with colon, lung and prostate cancer have documented a link between the presence of DTC at primary surgery and subsequent metastatic relapse.…”

Section: Discussionmentioning

confidence: 99%

“…[17][18][19] Criteria to evaluate morphology and staining results after automatic microscopic screening using sophisticated imaging approaches have also been defined to avoid false-positive and false-negative results. 17,[20][21][22] Flow cytometry-based methods have been used for the detection of CTC/DTC. However, very few studies have been conducted on larger patient cohorts.…”

Section: Detection Of Dtcmentioning

confidence: 99%

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Review: Biological relevance of disseminated tumor cells in cancer patients

Riethdorf

Wikman

Pantel

2008

Intl Journal of Cancer

289

236

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The prognosis of cancer patients is largely determined by the occurrence of distant metastases. In patients with primary tumors, this relapse is mainly due to clinically occult micrometastasis present in secondary organs at primary diagnosis but not detectable even with high resolution imaging procedures. Sensitive and specific immunocytochemical and molecular assays enable the detection and characterization of disseminated tumor cells (DTC) at the single cell level in bone marrow (BM) as the common homing site of DTC and circulating tumor cells (CTC) in peripheral blood. Because of the high variability of results in DTC and CTC detection, there is an urgent need for standardized methods. In this review, we will focus on BM and present currently available methods for the detection and characterization of DTC. Furthermore, we will discuss data on the biology of DTC and the clinical relevance of DTC detection. While the prognostic impact of DTC in BM has clearly been shown for primary breast cancer patients, less is known about the clinical relevance of DTC in patients with other carcinomas. Current findings suggest that DTC are capable to survive chemotherapy and persist in a dormant nonproliferating state over years. To what extent these DTC have stem cell properties is subject of ongoing investigations. Further characterization is required to understand the biology of DTC and to identify new targets for improved risk prevention and tailoring of therapy. Our review will focus on breast, colon, lung, and prostate cancer as the main tumor entities in Europe and the United States.

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Section: Discussionmentioning

confidence: 99%

Section: Detection Of Dtcmentioning

confidence: 99%

Review: Biological relevance of disseminated tumor cells in cancer patients

Riethdorf

Wikman

Pantel

2008

Intl Journal of Cancer

289

236

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“…CK form the cytoskeleton of epithelial cells, and their main function is to maintain the epithelial cell integrity. The most commonly used broad spectrum anti-CK antibodies, A45-B/B3 and AE1/AE3 (hereafter referred to as ''A45'' and ''AE''), have been shown to be specific for DTC detection as shown by analysis of large cohorts of noncancer control patients [12][13][14][15]. Although both, A45 and AE1/AE3, are broad spectrum anti-CK monoclonal antibodies, difference in the antibody epitope binding might potentially give different DTC results in individual cases because CK expression varies considerably in breast cancer cells during tumor progression.…”

Section: Introductionmentioning

confidence: 99%

Detection and clinical relevance of early disseminated breast cancer cells depend on their cytokeratin expression pattern

Effenberger¹,

Borgen²,

Eulenburg³

et al. 2010

Breast Cancer Res Treat

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The factors determining the clinical relevance of disseminated tumor cells (DTC) in breast cancer patients are largely unknown. Here we compared the specificity and clinical performance of two antibodies frequently used for DTC detection. Reactivities of antibodies A45-B/B3 (A45) and AE1/AE3 (AE) for selected cytokeratins (CK) were assessed by 2-DE Western Blot analysis. Using these antibodies bone marrow aspirates from 391 breast cancer patients (M(0), pT1-3, pN0-3) were screened for the presence of DTC. To obtain prognostic information, patients were followed up over a median of 83 months for time to relapse and 99 months for time to death. Among the analyzed CK, AE detected CK5, CK7, CK8, and CK19, whereas A45 recognized CK7 and CK18. In total, 24 of 391 patients (6.1%) were DTC-positive for A45, and 41 (10.5%) for AE. Although concordance between the two antibodies was 84.4%, overlap among positive cases was only 3.2%. DTC-positivity with AE and A45 was more frequent in patients of higher nodal status (P=0.019 and P=0.036, respectively). Nearly all patients with A45-positive DTC had hormone receptor-positive tumors (23/24), while detection of AE-positive DTC was more frequent among hormone receptor negative patients (P=0.006). Survival analyses of all patients revealed shorter distant disease-free survival (P=0.039) for patients with A45-positive DTC, whereas the prognostic relevance of AE-positive DTC was restricted to node-positive patients. The clinical utility of immunocytochemical (ICC) DTC detection depends on the anti-CK antibody used, which may reflect the complex CK composition of DTC.

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“…Microscopic screening of large amounts of immunostained cytological preparations is accomplished by automatic microscopes using sophisticated imaging approaches. Criteria to evaluate morphology and staining results have also been defined to avoid false-positive and false-negative results [23][24][25][26] . Despite existing recommendations for standard operation procedures, however, there are still limitations to the standardization of immunocytochemical methods with respect to reproducibility of the staining procedure itself as well as microscopic interpretations.…”

Section: Detection Of Dtcs In Bone Marrowmentioning

confidence: 99%

“…Despite existing recommendations for standard operation procedures, however, there are still limitations to the standardization of immunocytochemical methods with respect to reproducibility of the staining procedure itself as well as microscopic interpretations. Therefore, both intraand interlaboratory evaluation of the methods is required to ensure reliability of the results [26] .…”

Section: Detection Of Dtcs In Bone Marrowmentioning

confidence: 99%

Disseminated Tumor Cells in Bone Marrow and Circulating Tumor Cells in Blood of Breast Cancer Patients: Current State of Detection and Characterization

Riethdorf

Pantel²

2008

Pathobiology

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Despite the progress resulting from early detection and improved adjuvant therapy, the prognosis of breast cancer patients is still limited by the occurrence of distant metastases largely due to clinically occult micrometastases that remain undetected at primary diagnosis even by high-resolution imaging approaches. Recent research efforts have concentrated on the identification of additional parameters allowing individual risk assessment and stratification of patients for targeted therapies, since traditional prognostic factors are not sufficient to predict metastatic relapse and treatment decisions are still mainly based on statistical risk parameters. Highly sensitive and specific immunocytochemical and molecular assays now enable the detection and characterization of disseminated and circulating tumor cells (DTCs and CTCs, respectively) at the single cell level in bone marrow (BM) and peripheral blood, providing insights into the first crucial steps of the metastatic cascade. However, because of the still high variability of results in DTC/CTC detection, the necessity of standardized approaches will be discussed. A large number of studies showed that the presence of DTCs in BM has prognostic impact for primary breast cancer patients. DTCs are likely to escape from chemotherapy by maintaining a dormant nonproliferating state. There is also evidence for a stem cell-like phenotype of DTCs, probably contributing to the opportunity to escape from dormancy control and to start expansion to manifest metastases. Blood would also be an ideal source for the detection and monitoring of CTCs because of an easy noninvasive sampling procedure enabling repeated analyses. While prognostic significance of CTCs could be reliably demonstrated for metastatic breast cancer, studies to analyze the impact of CTCs in primary breast cancer patients and the potential to replace or supplement BM analysis are still ongoing. Furthermore, molecular characterization of CTCs might contribute to improving targeted and more individualized cancer therapies.

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A European interlaboratory testing of three well‐known procedures for immunocytochemical detection of epithelial cells in bone marrow. Results from analysis of normal bone marrow

Cited by 33 publications

References 42 publications

Review: Biological relevance of disseminated tumor cells in cancer patients

Review: Biological relevance of disseminated tumor cells in cancer patients

Detection and clinical relevance of early disseminated breast cancer cells depend on their cytokeratin expression pattern

Disseminated Tumor Cells in Bone Marrow and Circulating Tumor Cells in Blood of Breast Cancer Patients: Current State of Detection and Characterization

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