Bhuvanesh Singh

Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). We found from sequencing the EGFR TK domain that 7 of 10 gefitinib-sensitive tumors had similar types of alterations; no mutations were found in eight gefitinib-refractory tumors (P = 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is undocumented, had analogous somatic mutations, as opposed to none of 10 erlotinib-refractory tumors (P = 0.003). Because most mutation-positive tumors were adenocarcinomas from patients who smoked <100 cigarettes in a lifetime ("never smokers"), we screened EGFR exons 2-28 in 15 adenocarcinomas resected from untreated never smokers. Seven tumors had TK domain mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (P = 0.0001). Immunoblotting of lysates from cells transiently transfected with various EGFR constructs demonstrated that, compared to wild-type protein, an exon 19 deletion mutant induced diminished levels of phosphotyrosine, whereas the phosphorylation at tyrosine 1092 of an exon 21 point mutant was inhibited at 10-fold lower concentrations of drug. Collectively, these data show that adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity.

Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA cross-linking agents and cancer predisposition. Recent evidence for the interactions of ataxia-telangiectasia mutated protein ATM and breast cancer susceptibility proteins BRCA1 and BRCA2 (identified as FANCD1) with other known FA proteins suggests that FA proteins have a significant role in DNA repair/recombination and cell cycle control. The International Fanconi Anemia Registry (IFAR), a prospectively collected database of FA patients, allows us the unique opportunity to analyze the natural history of this rare, clinically heterogeneous disorder in a large number of patients. Of the 754 subjects in this study, 601 (80%) experienced the onset of bone marrow failure (BMF), and 173 (23%) had a total of 199 neoplasms. Of these neoplasms, 120 (60%) were hematologic and 79 (40%) were nonhematologic. The risk of developing BMF and hematologic and nonhematologic neoplasms increased with advancing age with a 90%, 33%, and 28% cumulative incidence, respectively, by 40 years of age. Univariate analysis revealed a significantly earlier onset of BMF and poorer survival for complementation group C compared with groups A and G; however, there was no significant difference in the time to hematologic or nonhematologic neoplasm development between these groups. Multivariate analysis of overall survival time shows that FANCC mutations (P =.007) and hematopoietic stem cell transplantation (P = <.0001) define a poor-risk subgroup. The results of this study of patients registered in the IFAR over a 20-year period provide information that will enable better prediction of outcome and aid clinicians with decisions regarding major therapeutic modalities.

INTRODUCTION: The relative rarity of mucosal melanomas of the head and neck (MMHN) has made analysis of treatment approaches difficult. Advances in diagnostic techniques and treatment interventions have had obvious impact on outcomes in cutaneous melanoma, but the effects on outcome in MMHN remain undefined. This study aims to assess the outcome and identify clinical and histologic prognostic indicators in a recent cohort of patients with MMHN treated at a single institution. METHODS: The clinical records of 59 patients with the diagnosis of MMHN treated at Memorial Sloan-Kettering Cancer Center (MSKCC) between 1978 and 1998 were retrospectively reviewed. Pathologic material on each of these patients was prospectively reviewed by at least two pathologists (MP, KB, or AH) for confirmation of diagnosis and assessment of histologic variables. Survival was calculated by the Kaplan-Meier method. Clinical (patient demographics, tumor characteristics, and treatment) and histologic data (tumor thickness, melanosis, melanoma in situ, vascular invasion, and multifocality) were analyzed for impact on outcome by both univariate and multivariate analyses. RESULTS: Thirty-five patients (59%) had sinonasal tumors (SNMM), whereas 24 (41%) had oral (ORMM) tumors. Forty-seven patients (79.6%) were staged as stage I, 8 (13.6%) as stage II, and 4 (6.8%) were classified as stage III. Regional lymphatic metastases at presentation were more frequent in ORMM compared with SNMM (25% vs 6%, p =.05). Surgery was used in all patients. Adjuvant radiation therapy was used more frequently in the SNMM group compared with the ORMM group (40% vs 17%, p =.04). The rates of local failure for ORMM and SNMM were 51% and 50%, nodal failure rates were 42% and 20%, and distant failure rates were 67% and 40%, respectively (p = NS). With a median follow-up of 20 months, the 5-year disease-specific survival rate was 44% (40% for ORMM vs 47% for SNMM, p = NS). Significant prognostic factors for disease-specific survival on univariate analysis included advanced clinical stage at presentation, tumor thickness greater than 5 mm, presence of vascular invasion, and development of nodal and distant metastases. On multivariate analysis, however, regional nodal failure lost significance. CONCLUSIONS: Clinical stage at presentation, tumor thickness greater than 5 mm, vascular invasion on histologic studies, and development of distant failure are the only independent predictors of outcome in MMHN.

BACKGROUND: There is continuous debate regarding the optimal classification, prognosis, and treatment of the follicular variant of papillary thyroid carcinoma (FVPTC). The objective of this study was to assess the behavior of FVPTC, especially its encapsulated form, and shed more light on its true position in the classification scheme of well differentiated thyroid carcinoma. METHODS: All patients with FVPTC, follicular thyroid adenoma (FTA), and follicular thyroid carcinoma (FTC) who were diagnosed between 1980 and 1995 were reviewed and reclassified according to the currently accepted definition of FVPTC. The tumors were separated into encapsulated and nonencapsulated (infiltrative/diffuse) types. Encapsulated tumors were subdivided further into tumors with or without capsular/vascular invasion. These different subtypes of FVPTC were correlated with outcome and with other clinicopathologic parameters. RESULTS: After review by 4 pathologists, 78 patients were included in the study. Sixty-one of 78 patients (78%) had encapsulated tumors (18 invasive, 43 noninvasive), and 17 patients had nonencapsulated tumors (infiltrative/diffuse). The gender distribution, age at presentation, and tumor size did not differ between patients with encapsulated and nonencapsulated FVPTC. Patients who had encapsulated FVPTC had a significantly lower rate of marked intratumor fibrosis (18%), extrathyroid extension (5%), and positive margins (2%) compared with patients who had nonencapsulated tumors (88%, 65%, and 50% respectively; P < .0001). Regional lymph node metastases were present in 14 of 78 patients (18%), and no patients had distant metastases. The lymph node metastatic rate was significantly higher in patients who had nonencapsulated tumors (11 of 17 patients; 65%) compared with patients who had encapsulated neoplasms (3 of 61 patients; 5%; P < .0001). In addition, lymph node metastases were not detected in any noninvasive, encapsulated FVPTCs. With a median follow-up of 10.8 years, only 1 patient developed a recurrence, which occurred in an encapsulated FVPTC that had numerous invasive foci. None of the patients with noninvasive, encapsulated FVPTCs developed recurrences, including 31 patients who underwent lobectomy alone, with a median follow-up of 11.1 years. CONCLUSIONS: FVPTC appeared to be a heterogeneous disease composed of 2 distinct groups: an infiltrative/diffuse (nonencapsulated) subvariant, which resembles classic papillary carcinoma in its metastatic lymph node pattern and invasive growth, and an encapsulated form, which behaves more like FTA/FTC. Patients who had noninvasive, encapsulated FVPTCs did not develop lymph node metastases or recurrences and could be treated by lobectomy alone. If the current findings are confirmed, then strong consideration should be given to reclassifying encapsulated FVPTC as an entity that is close to the FTA/FTC class of tumors.