Zeta-associated protein-70 (ZAP70) expression measured by flow cytometry has been proposed as a surrogate marker of the somatic mutation status of the immunoglobulin heavy chain variable region genes in chronic lymphocytic leukemia. However, attempts to implement this approach in clinical flow cytometry laboratories have been problematic; many commercially available antibodies give unreliable results. Assessment of ZAP70 protein expression by immunohistochemistry in chronic lymphocytic leukemia tissue sections is an easy, alternative approach, although lack of quantitation and subjective interpretation of results are potential pitfalls. In this study, we correlated ZAP70 protein expression, assessed by immunohistochemistry, with ZAP70 messenger RNA transcript expression, assessed by semi-quantitative real-time reverse transcriptase-polymerase chain reaction assay, with the somatic mutation status of the immunoglobulin heavy chain variable region genes in previously untreated patients with chronic lymphocytic leukemia. Expression of ZAP70 protein and messenger RNA transcripts correlated strongly (p=8.238x10−12). Expression of ZAP70 protein and messenger RNA transcripts also correlated strongly with the somatic mutation status of the immunoglobulin heavy chain variable region genes (p=0.000071 and p=0.00076, respectively). Further, ZAP70 positivity by immunohistochemistry was associated with an increased risk of progression to therapy requirement (3 year risk 83% vs. 31% for ZAP70 negative by immunohistochemistry, p=0.03). These results show that ZAP70 expression assessed by immunohistochemistry is a reliable surrogate marker of the somatic mutation status of the immunoglobulin heavy chain variable region genes, and predicts time to progression.

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Myeloid sarcoma can involve any anatomic site, but involvement of the gynecologic tract is uncommon. We describe 11 women, 17 to 60 years old, with myeloid sarcoma involving the gynecologic tract, including 5 patients in whom myeloid sarcoma presented as an isolated mass. The uterus was the most frequently involved anatomic site, in 8 patients (5 corpus, 3 cervix). Each neoplasm diffusely infiltrated normal structures, and, cytologically 7 tumors were immature, 3 were differentiated, and 1 was blastic. In 9 cases assessed, immunohistochemical stains showed that all neoplasms were positive for myeloperoxidase and lysozyme; CD117 was positive in 7 of 8 cases, and cytochemical staining for naphthol AS-D chloroacetate was positive in all 6 neoplasms analyzed. Following chemotherapy, complete remission and long-term survival were achieved in a subset of patients, as was particularly true for 2 patients (cases 8 and 10), with complete remission 12.5 and 31 years after diagnosis, respectively.

BACKGROUND: Oncogenic AKT/mammalian target of rapamycin (mTOR) signaling has recently been shown to contribute to tumor survival and proliferation in mantle cell lymphoma (MCL) through its downstream effector eukaryotic initiation factor 4E (eIF4E), which may control cyclin D1 protein levels. However, the clinical significance of eIF4E expression in MCL is unknown. METHODS: The authors investigated the prognostic significance of eIF4E expression in 70 MCL patients uniformly treated with hyper-CVAD and rituximab, alternating with the rituximab, high-dose methotrexate, and cytarabine regimen (R-hyper-CVAD). eIF4E expression was assessed using tissue biopsy specimens obtained before treatment, immunohistochemical methods, and a highly specific monoclonal antibody. Failure-free (FFS) and overall (OS) survival were used as endpoints in univariate and multivariate survival analysis. RESULTS: High eIF4E expression was found in 28 (40%) MCL tumors. After a median follow-up of 51 months for survivors, the 5-year FFS was 20.6% for patients with high eIF4E expression, compared with 63.5% for patients with low or no eIF4E expression (P ¼ .01, log-rank). Similarly, the 5-year OS was 40.1% for patients with high eIF4E expression, compared with 73.8% for patients with low or no eIF4E expression (P ¼ .018, log-rank). In multivariate analysis, eIF4E expression was associated with poorer FFS and OS, along with age >60 years and high b 2 -microglobulin in the final prognostic model. CONCLUSIONS: In summary, eIF4E, which seems to recapitulate most of the biologic effects of mTOR signaling in MCL, is an independent predictor of clinical outcome in MCL patients uniformly treated with the R-hyper-CVAD regimen.

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