Detection of Occult Micrometastases in Patients With Clinical Stage I Non-Small-Cell Lung Cancer: A Prospective Analysis of Mature Results of CALGB 9761 (Alliance).

PURPOSE: Outcomes after resection of stage I non-small-cell lung cancer (NSCLC) are variable, potentially due to undetected occult micrometastases (OM). Cancer and Leukemia Group B 9761 was a prospectively designed study aimed at determining the prognostic significance of OM. MATERIALS AND METHODS: Between 1997 and 2002, 502 patients with suspected clinical stage I (T1-2N0M0) NSCLC were prospectively enrolled at 11 institutions. Primary tumor and lymph nodes (LNs) were collected and sent to a central site for molecular analysis. Both were assayed for OM using immunohistochemistry (IHC) for cytokeratin (AE1/AE3) and real-time reverse transcriptase polymerase chain reaction (RT-PCR) for carcinoembryonic antigen. RESULTS: Four hundred eighty-nine of the 502 enrolled patients underwent complete surgical staging. Three hundred four patients (61%) had pathologic stage I NSCLC (T1, 58%; T2, 42%) and were included in the final analysis. Fifty-six percent had adenocarcinomas, 34% had squamous cell carcinomas, and 10% had another histology. LNs from 298 patients were analyzed by IHC; 41 (14%) were IHC-positive (42% in N1 position, 58% in N2 position). Neither overall survival (OS) nor disease-free survival was associated with IHC positivity; however, patients who had IHC-positive N2 LNs had statistically significantly worse survival rates (hazard ratio, 2.04, P = .017). LNs from 256 patients were analyzed by RT-PCR; 176 (69%) were PCR-positive (52% in N1 position, 48% in N2 position). Neither OS nor disease-free survival was associated with PCR positivity. CONCLUSION: NSCLC tumor markers can be detected in histologically negative LNs by AE1/AE3 IHC and carcinoembryonic antigen RT-PCR. In this prospective, multi-institutional trial, the presence of OM by IHC staining in N2 LNs of patients with NSCLC correlated with decreased OS. The clinical significance of this warrants further investigation.

Unexplained bone marrow granulomas: is amiodarone the culprit? A report of 2 cases.

Granulomas in the bone marrow are usually caused by infectious or hematological diseases, and drugs are only rarely implicated as causative agents. Recent reports have drawn attention to the role of amiodarone in the etiology of bone marrow granulomas. We report two cases of amiodarone-induced bone marrow granulomas in patients being investigated for refractory anemia and pancytopenia, respectively. Since both patients had life-threatening arrhythmias, discontinuation of the drug followed by rechallenge was not possible. Both patients did well in spite of continued amiodarone therapy, indicating that the underlying hematological illnesses were unrelated to the granulomas. Amiodarone should be considered as a possible cause of bone marrow granulomas after the exclusion of other causes. Continued use of amiodarone after granuloma formation must be dictated by the underlying cardiac condition.

Carcinosarcoma of the urinary bladder following cyclophosphamide therapy: evidence for monoclonal origin and chromosome 9p allelic loss.

We report a case involving a 45-year-old man with a 12-year history of Wegener granulomatosis, who developed a carcinosarcoma of the urinary bladder after long-term cyclophosphamide therapy. Cyclophosphamide is well recognized as an etiologic agent for urothelial carcinoma of the urinary bladder. However, only 5 cases of carcinosarcoma of the urinary bladder following cyclophosphamide therapy have been reported. We used loss of heterozygosity studies and microsatellite markers to define the molecular basis of this rare neoplasm. These studies revealed evidence supporting a monoclonal origin for the 2 components of this tumor. We also demonstrated allelic loss of chromosome 9p. This loss associated with carcinosarcoma of the urinary bladder is in agreement with previous studies, suggesting a possible role for the tumor suppressor gene p16 in the pathogenesis of this tumor.

Immunohistochemical detection of occult lymph node metastases in non-small cell lung cancer: anatomical pathology results from Cancer and Leukemia Group B Trial 9761.

PURPOSE: Our purpose was to study the detection of occult metastases (OM) in regional lymph nodes using immunohistochemical stain for cytokeratin, and for this study we targeted clinical stage I patients with non-small cell lung cancer. EXPERIMENTAL DESIGN: The study comprised the first 193 patients entered onto Cancer and Leukemia Group B protocol 9761. All had clinically staged T(1-2)N(0)M(0) non-small cell lung cancer, and all underwent curative resections of their primary tumors. Samples of the primary tumor and lymph nodes were taken from lymph node stations 2-12 and shipped to a central laboratory, where each lymph node was histologically processed and stained with H&E as well as with immunohistochemical stain using antibodies to cytokeratin (AE1/3). RESULTS: Altogether, we examined 825 lymph nodes. Whereas routine H&E staining allowed us to detect 18 positive lymph nodes, immunohistochemical staining allowed us to detect 45 positive lymph nodes (P < 0.0001). There were 28 OM [i.e., those detectable only by immunohistochemistry (IHC)], and there was 1 metastasis detected only by H&E staining. The OM included 9 OM in N1 stations and 19 OM in N2 stations. Twelve patients with OM had skip metastases. Routine H&E staining upstaged six patients to N1, and IHC added another five. Routine H&E upstaged 9 patients to N2, and IHC added another 11. We also uncovered new details about the way in which H&E detection depends on metastatic tumor burden. Specifically, for the probability of detecting metastases by H&E to exceed 0.50, the maximum diameter of the metastasis must be greater than 0.23 mm. CONCLUSIONS: IHC detects greater than twice as many positive regional lymph nodes as does H&E staining, and the foci of tumor it detects are significantly smaller than those detected by H&E staining.

Impact of tumor size on survival in stage IA non-small cell lung cancer: a case for subdividing stage IA disease.

PURPOSE: Stage IA (T1N0M0) non-small cell lung cancer (NSCLC) includes all lesions up to 3 cm in diameter. With the use of advanced imaging techniques, smaller pulmonary lesions can be identified. A greater proportion of patients with NSCLC will likely have smaller tumors at presentation in the future. The purpose of this study was to determine the relationship between tumor size, and survival in patients with pathologic stage IA NSCLC. METHODS: We conducted a retrospective review of 246 consecutive, surgically treated patients with pathologic stage IA NSCLC. Eligible patients were identified from the tumor registries and pathology records. Follow-up was obtained from the surgical database and primary physicians' records. RESULTS: Eighty six patients had tumors