Adjuvant chemotherapy decisions in breast cancer are increasingly based on the pathologist's assessment of tumor proliferation. The Swiss Working Group of Gyneco- and Breast Pathologists has surveyed inter- and intraobserver consistency of Ki-67-based proliferative fraction in breast carcinomas.MethodsFive pathologists evaluated MIB-1-labeling index (LI) in ten breast carcinomas (G1, G2, G3) by counting and eyeballing. In the same way, 15 pathologists all over Switzerland then assessed MIB-1-LI on three G2 carcinomas, in self-selected or pre-defined areas of the tumors, comparing centrally immunostained slides with slides immunostained in the different laboratoires. To study intra-observer variability, the same tumors were re-examined 4 months later.ResultsThe Kappa values for the first series of ten carcinomas of various degrees of differentiation showed good to very good agreement for MIB-1-LI (Kappa 0.56–0.72). However, we found very high inter-observer variabilities (Kappa 0.04–0.14) in the read-outs of the G2 carcinomas. It was not possible to explain the inconsistencies exclusively by any of the following factors: (i) pathologists' divergent definitions of what counts as a positive nucleus (ii) the mode of assessment (counting vs. eyeballing), (iii) immunostaining technique, and (iv) the selection of the tumor area in which to count. Despite intensive confrontation of all participating pathologists with the problem, inter-observer agreement did not improve when the same slides were re-examined 4 months later (Kappa 0.01–0.04) and intra-observer agreement was likewise poor (Kappa 0.00–0.35).ConclusionAssessment of mid-range Ki-67-LI suffers from high inter- and intra-observer variability. Oncologists should be aware of this caveat when using Ki-67-LI as a basis for treatment decisions in moderately differentiated breast carcinomas.

SummaryThe mechanisms of sustained overproduction of eosinophils in the idiopathic hypereosinophilic syndrome and in some human immunodeficiency virus (HIV)-l-infected individuals are largely unknown. We hypothesized that T cells may release soluble products that regulate eosinophi]ia in these patients, as has been previously shown in bronchial asthma. We identified one patient with idiopathic hypereosinophilic syndrome and one HIV-l-infected individual with associated hypereosinophilia who demonstrated high numbers of CD4-CD8-T cells in peripheral blood. CD4-CD8-T cells from both patients, although highly activated, did not express functional Fas receptors. In one case, the lack of functional Fas receptors was associated with failure ofFas mR.NA and protein expression, and in another, expression of a soluble form of the Fas molecule that may have antagonized normal signaling ofFas ligand. In contrast to the recently described lymphoproliferative/autoimmune syndrome, which is characterized by accumulation of CD4-CD8-T cells and mutations within the Fas gene, this study suggests somatic variations in Fas expression and function quite late in life. Both genetic and somatic abnormalities in regulation of the Fas gene are therefore associated with failures to undergo T cell apoptosis. Furthermore, the expanded population of CD4-CD8-T cells from both patients elaborated cytokines with antiapoptotic properties for eosinophils, indicating a major role of these T ceils in the development of eosinophilia. Thus, this study demonstrates a sequential dysregulation ofapoptosis in different cell types.

Plasma cell myelomas (PMs) have a poor prognosis. Cancer-testis (CT) antigens are immunogenic proteins, representing potential targets for tumor vaccination strategies. The expression of the CT antigens GAGE, MAGE-A4, MAGE-C1/CT-7, and NY-ESO-1 was investigated on paraffin-embedded bone marrow biopsies from 219 PM and 8 monoclonal gammopathy of undetermined significance (MGUS) patients. The frequency and prognostic impact of these CT antigens were compared with known morphological prognostic markers (i.e. Mib1 labeling index) and the presence of the translocations t(4;14)(p16.3; q32) and t(11;14)(q13;q32). We show that MAGE-C1/CT-7 is the most prevalent CT antigen, expressed in 57% of PMs in a high percentage of tumor cells. While MAGE-C1/CT-7 was absent in non-malignant plasma cells, plasma cells of patients with MGUS did express MAGE-C1/CT-7, but no other CT antigens. MAGE-C1/CT-7 was more frequently expressed in PMs with an elevated proliferation rate (Mib1 > > > >10%) compared to PMs with a low proliferation rate (Mib1 ≤ ≤ ≤ ≤10%, 71% versus 29%, P < < < < 0.001) and correlated with overall survival, depending on its subcellular distribution. PMs with pure cytoplasmic MAGE-C1/CT-7 expression showed a better prognosis (48 months versus 33 months, P < < < < 0.05) than PMs with combined nuclear-cytoplasmic or nuclear expression only. Thus, expression of MAGE-C1/CT-7 in patients with monoclonal gammopathies represents a predictor of outcome and overt malignant transformation. (Cancer Sci 2008; 99: 720-725)

Sclerosing angiomatoid nodular transformation (SANT) is a recently recognized benign vascular lesion of the spleen. There is limited information regarding its imaging findings of this condition. Until now, the diagnosis was based on histopathologic examination of splenectomy specimens. We report the sonographic findings in a case of SANT of the spleen confirmed by ultrasound-guided core needle biopsy.

Objectives: Intravascular accumulations of atypical large lymphoid cells are a rare finding in skin biopsy specimens and raise the suspicion for intravascular lymphoma. The intravascular accumulation of atypical large CD30+ T cells, however, as a reactive process is very uncommon in the skin, with only four cases documented so far in the literature. This condition, referred to as benign intravascular atypical CD30+ T-cell proliferation, has been associated with chronic inflammation after trauma. Methods: We report on a case of atypical intravascular CD30+ T-cell proliferation in a patient with ulcerated lichen sclerosus on the foreskin, discuss the differential diagnoses, propose diagnostic criteria, and review the literature on this uncommon reactive intralymphatic CD30+ T-cell lymphoproliferation. Results: The atypical intravascular CD30+ T-cell proliferation is characterized by the accumulation of large CD30+ polyclonal T cells within lymphatics in close vicinity to ulceration or an inflammatory skin disease. There is no association with Epstein-Barr virus infection. Conclusions: This benign cutaneous lymphoproliferation needs to be distinguished from intravascular T-cell lymphoma, particularly from the intravascular variant of anaplastic large cell lymphoma. Obstruction of lymphatics due to lichen sclerosus with disrupted immune cell trafficking may result in the accumulation of activated CD30+ lymphocytes.