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BackgroundFew data are available on the prevalence and clinicopathological meaning of CD99, the transmembrane product of the pseudoautosomal MIC2 gene, in pulmonary neuroendocrine tumors.MethodsWe evaluated CD99 immunoreactivity in lung tissues, pulmonary neuroendocrine hyperplasias, and 136 consecutive pulmonary neuroendocrine tumors of diverse histological types.ResultsBy immunohistochemistry, a membranous and/or cytoplasmic immunoreactivity was seen in 60 of 136 (44%) tumors, whereas both normal and hyperplastic neuroendocrine cells of the lung were consistently nonreactive. A steady decrease of the CD99 labeling index was observed from better to poorly differentiated tumors, with a prevalence of the membranous pattern in typical carcinoids (TCs), and of the cytoplasmic pattern in atypical carcinoids (ACs) and large cell neuroendocrine carcinoma/small cell lung carcinoma (P < 0.0001), independent of tumor stage. In TCs/ACs, increased levels of CD99 labeling index or the membranous pattern were associated with low proliferative fraction (P = 0.0011) and smaller tumor size (P = 0.0054) and with lack of regional lymph node metastases (P = 0.0078). Moreover, CD99 expression decreased according to the pN0-2 classes (P = 0.0016), with an inverse relationship between the number of positive lymph nodes, the labeling index (P = 0.013) and the nonmembranous pattern (P = 0.016). At multivariate analysis, both the decreased CD99 labeling index and the negative/cytoplasmic staining were independent risk indicators for lymph node metastases in the subset of TC/AC patients. No relevant relationships were found in large cell neuroendocrine carcinoma/small cell lung carcinoma.ConclusionCD99 is especially present in low- to intermediate-grade neuroendocrine tumors of the lung, and loss of the marker correlates with the occurrence of nodal metastases in TC/AC patients.

Summary Occasionally, breast cancer relapses in the subclavicular region. In patients with failed multimodal treatment, or in those who develop an isolated recurrence, surgical resection may be useful to remove all macroscopically evident diseases. However, the procedure may be technically demanding and there are no published data regarding its benefits. The aim of the present study was to evaluate the feasibility and safety of subclavicular resection in breast cancer and provide indications as to whether it can contribute to disease control. We used a transpectoral approach to surgically remove isolated breast cancer recurrence in the subclavicular region in seven consecutive patients presenting over 2 years; in the eighth case a transmanubrial approach was necessary. We found that the surgical approach proposed is feasible and safe, with a 75% rate of complete resection; however, the series was characterised by a high rate of local and distant relapse. We conclude that the technique may be useful, in selected cases, for palliation only.

High levels of serum carcinoembryonic antigen (S-CEA) are considered a negative prognostic factor in non-small-cell lung cancer (NSCLC), while the prognostic value of tumour CEA (T-CEA) is unknown. We investigated the prognostic role of T-CEA in radically resected early stage NSCLC. We measured preoperative S-CEA levels and T-CEA in 146 patients with stage 1-2 NSCLC, and analysed their influence on survival. In patients positive for T-CEA, 3-year survival was 80%, compared to 65% in T-CEA-negative patients (p=0.03). After stratification by histology, T-CEA positivity was prognostic of better survival in squamous cell carcinoma (SCC) (p=0.024) but not in adenocarcinomas (ADK) (p=0.87). Multiple Cox regression analysis showed that T-CEA positivity was an independent predictor of better survival in patients with early stage NSCLC (p=0.02). In SCC patients, the magnitude of the hazard ratio was confirmed even if the precision of the estimate is decreased (p=0.06). In conclusion, T-CEA expression appears to be an important prognostic factor in early stage SSC of the lung.

Purpose To determine whether epidermal growth factor receptor (EGFR) expression in non–small-cell lung cancer (NSCLC) is modulated by chemotherapy and to assess the agreement of EGFR status between mediastinal nodes and the primary tumor after chemotherapy. Patients and Methods Patients with NSCLC stage IIIa/b pN2/3 confirmed by mediastinoscopy or mediastinostomy were treated with at least three cycles of chemotherapy before undergoing surgery. EGFR expression was evaluated on mediastinal nodes at the time of initial diagnosis and on both the primary tumor and residual metastatic nodes after treatment. Results EGFR expression determined on 138 of 164 patients who underwent mediastinoscopy or mediastinostomy was 0 (22 patients), 1+ (27 patients), 2+ (28 patients), and 3+ (61 patients). Fifty-four patients of 164 received chemotherapy followed by surgery. Of the 89 of 138 patients with EGFR score of 2+/3+ at the time of diagnosis, 34 patients underwent surgery after induction chemotherapy. None changed to zero EGFR immunoreactivity, with 29 patients (88%) maintaining a score of 2+/3+. Of the 22 of 138 patients with no EGFR expression at the time of diagnosis, six underwent surgical resection after induction chemotherapy. Of these six patients, four changed their EGFR expression from an EGFR score of 0 to 2+/3+. After treatment, the agreement of EGFR status between tumor and nodes in the subgroup of patients with EGFR score 2+/3+ was 89% to 92%. Conclusion Our data suggest a very good agreement of EGFR status before and after chemotherapy in EGFR-positive NSCLC. Induction chemotherapy can induce EGFR expression in occasional EGFR-negative tumors.

To evaluate the feasibility and toxicity of three-times-daily radiotherapy (3tdRT), preceded by induction chemotherapy (iCT), in stage IIIA–IIIB non-small cell lung cancer (NSCLC). iCT consisted of three cycles of cisplatin and gemcitabine. Surgery was considered for stage IIIA patients responsive to iCT; definitive or postoperative 3tdRT was planned. Doses of 54.4 Gy and 64.6 Gy in postoperative and definitive treatments, respectively, were delivered in three daily fractions. From February 1998 to October 2000, 37 patients received 3tdRT as definitive (n = 18) or postoperative treatment (n = 19). Toxicity was limited to RTOG grade 2 (25 patients, 67.6%) and grade 3 (four patients, 10.8%) acute esophagitis; no grade 3 late esophagitis occurred. Late lung toxicity was represented by one grade 3 pneumonitis. No correlation emerged between acute esophageal toxicity and irradiated esophageal volume or disease- and treatment-related factors. A significant correlation was found for stage (IIIA vs. IIIB; p = 0.03) and a trend for the N-class (N2 vs. N3; p = 0.08). In this experience of 3tdRT preceded by iCT, the low toxicity profile confirmed the feasibility of this combination. The limited statistical power does not permit a definition of predictors for radiation-induced esophagitis incidence and severity; additional studies are required to clarify the impact of volumetric and dosimetric parameters. Failure patterns and survival results are warranted to confirm the efficacy of this approach in locally advanced NSCLC.

CD117, a trans-membrane tyrosine kinase receptor, has been immunolocalized in a large variety of human neoplasms. Little, however, is known about the prevalence and clinical implications of CD117 in stage I adenocarcinoma and squamous cell carcinoma of the lung. We evaluated 201 consecutive stage I adenocarcinoma and squamous cell carcinoma of the lung for CD117 immunoreactivity (dichotomized as negative or positive if containing less than 5% or >/=5% immunoreactive neoplastic cells, respectively), also taking into account the pattern (either membranous or cytoplasmic), and the intensity of immunostaining in comparison with intratumoral mast cells. The immunostaining results were then correlated with tumor biopathological characteristics and patients' survival. Membranous CD117 immunoreactivity was documented in 19 (22%) of 88 adenocarcinomas and 15 (13%) of 113 squamous cell carcinomas, whereas cytoplasmic labelling was seen in 28 (32%) adenocarcinomas and eight (7%) squamous cell carcinomas. In both tumor types, membranous or cytoplasmic CD117 immunoreactivity was associated with higher proliferative fraction and with features of more aggressive tumor behavior, including higher stage, size and grade, occurrence of clinical symptoms, high microvessel density and neuroendocrine differentiation. Furthermore, immunoreactive tumors exhibited increased levels of bcl-2, cyclin-E, Her-2, p27(Kip1) and fascin, the latter being a marker of tumor cell metastatization in lung cancer. Membranous but not cytoplasmic labelling emerged as an independent risk factor for death and reduced time to progression in adenocarcinoma but not in squamous cell carcinoma patients, when singly adjusted for confounding factors. CD117 immunoreactivity identifies a peculiar subset of stage I adenocarcinoma and squamous cell carcinoma of the lung with highly proliferative tumors and may have prognostic relevance in adenocarcinoma patients. Targeting the CD117 pathway could be a novel therapeutic strategy in a subset of pulmonary carcinomas.

Little is known about CD117 prevalence and clinicopathological implications in pulmonary large-cell neuroendocrine carcinoma. We studied CD117 immunoreactivity in surgical specimens from 39 large-cell neuroendocrine carcinomas of stages I-III and 27 limited-disease small-cell carcinomas, 56 typical and atypical carcinoids of the lung, and 10 neuroendocrine tumorlets, including the membrane and cytoplasmic immunostaining patterns. Membrane CD117 immunoreactivity in 5% or more tumor cells was documented in 30 (77%) large-cell neuroendocrine carcinomas and 18 (67%) small-cell carcinomas and 4 (7%) carcinoids, whereas cytoplasmic labeling was seen in 17 (44%) large-cell neuroendocrine carcinomas, 19 (70%) small-cell carcinomas, and 3 (5%) carcinoids. None of the neuroendocrine cells of the normal bronchial epithelium and of 10 tumorlets showed any CD117 immunoreactivity. Cytoplasmic immunostaining was more prevalent in small-cell carcinomas, whereas membrane labeling did not differ between the two types of high-grade carcinomas. Downregulation of CD117 by neoadjuvant chemotherapy was seen in large-cell neuroendocrine carcinomas but not small-cell carcinomas. Multiple linear regression analysis demonstrated a marginal association between cytoplasmic CD117 immunoreactivity and regional lymph node metastasis in small-cell carcinomas but not large-cell neuroendocrine carcinomas. There was no association between CD117 immunoreactivity and survival in either small-cell carcinoma or large-cell neuroendocrine carcinoma patients.

Neoangiogenesis and enhanced glucose metabolism in neoplasms are likely to be activated by the same biochemical stimulus; hypoxia. A correlation between these two parameters has been postulated. The objective of this study was to evaluate the relationship between Fluoro-desoxi-glucose uptake at positron emission tomography scan and angiogenesis in lung metastasis. Fluoro-desoxi-glucose activity, expressed as a standard uptake value, and microvessel intratumoural density, were retrospectively calculated in a series of 43 lung metastasis resected in 19 patients. Primary sites were colorectal cancer in 16 metastases, sarcoma in eight, gynaecological in four and other sites in 15. The correlation between the two parameters was tested by logistic regression and multivariate analysis. Positron emission tomography scan was positive in 17 patients (sensitivity 89%). No correlation was observed between standard uptake value and microvessel intratumoural density in this series of lung metastasis. Positron emission tomography negative and positive nodules presented comparable value of microvessel intratumoural density (12.9 vs 11.3). Standard uptake value was significantly correlated with nodules size and was higher in colon cancer metastasis than in sarcoma ones. Microvessel intratumoural density was independent from nodule size but significantly higher in sarcoma than in colon cancer metastasis. The lack of correlation was confirmed by multivariate analysis after adjustment for tumour type and nodules size. The present study demonstrated that positron emission tomography scan is positive in a high proportion of patients regardless of microvessel density. Glucose uptake and angiogenesis appear to be independent biological features in lung metastasis. This observation may have implications for future antiangiogenic therapies. British Journal of Cancer (2002) 86, 1391–1395. DOI: 10.1038/sj/bjc/6600262 www.bjcancer.com © 2002 Cancer Research UK

Objective: To evaluate if induction chemotherapy, with or without irradiation, represents an additional risk factor for early and late morbidity and perioperative mortality in bronchoplastic procedures for lung cancers. Methods: From January 1998 to January 2001, 27 patients underwent a bronchial sleeve resection after induction treatment at the European Institute of Oncology in Milan. They represent 7% of lung cancer resections (387) and 27% of those performed after neoadjuvant treatment (100 cases). Histology was: 17 epidermoid carcinoma, 8 adenocarcinoma and 2 SCLC. Twenty-four patients (89%) received a preoperative cisplatin based polichemotherapy, and three cases (11%) a chemo-radiation therapy. A right sleeve lobectomy or bilobectomy was undertaken in 21 patients (78%) and a left lobectomy in 6 (22%). A resection of tracheal carina was associated in three cases and a vascular resection in 10 (five vena cava and five pulmonary artery). Twelve patients (44%) received adjuvant mediastinal irradiation. Perioperative morbidity of the study group (group 1) was compared with that of patients submitted to sleeve resection without neoadjuvant treatment (group 2), or standard pneumonectomy after induction treatment (group 3). Results: There were no postoperative deaths. A major perioperative complication occurred in two patients (7%) of group 1, one patient of group 2 (3.5%), and four in group 3 (17%). Among patients of the study group, no anastomotic dehiscence or pleural empyema were observed. Only one late anastomotic stricture occurred after postoperative radiation treatment. No significant difference in early and late complication rate was found between the three groups of patients. High rate of complete resection was achieved (93%) in patients of the study group and extent of nodal dissection was similar between sleeve resections and pneumonectomy patients. Conclusions: Preoperative chemotherapy or combination of chemo-radio therapy is not associated with an additional risk of anastomotic complications in bronco and angioplastic procedures. Parenchyma sparing resection is a valid option for selected patients with locally advanced lung cancer after induction treatment. A longer follow up is necessary to evaluate efficacy of the procedure in term of survival and local control.

http://hdl.handle.net/20.500.11768/96437