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K. Shibuya



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    MS 07 - Neuroendocrine Tumors other than SCLC: Pathology to Patient Management (ID 529)

    • Event: WCLC 2017
    • Type: Mini Symposium
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      MS 07.04 - Surgical Treatment for Neuroendocrine Tumors other than SCLC (ID 7672)

      15:45 - 17:30  |  Author(s): K. Shibuya

      • Abstract
      • Presentation
      • Slides

      Abstract:
      In the 1970s, pulmonary neuroendocrine tumors were classified into three histologically defined categories: typical carcinoid (TC), atypical carcinoid (AC) and small cell lung carcinoma (SCLC) [1]. In 1999, the World Health Organization (WHO) classified large cell neuroendocrine carcinoma (LCNEC) as a fourth neuroendocrine tumor of the lung. Although LCNEC was classified as a variant of large cell carcinoma in 1999 [2], it was classified as a neuroendocrine tumor in 2015. To date, for neuroendocrine tumors of the lung, the major categories of morphologically identifiable neuroendocrine tumors are TC, AC, LCNEC, and SCLC. Analyses of molecular markers revealed that low-grade TC and intermediate-grade AC exhibit a low proliferative rate compared with high-grade LCNEC and SCLC [3], and TC and AC have different genetic alterations from high-grade LCNEC and SCLC [4]. Analyses of their genetic alterations show that neuroendocrine lung tumors may represent a spectrum ranging from low-grade TC and intermediate-grade AC to highly malignant LCNEC and SCLC tumors [4]. TC is classified as a malignant epithelial tumor of the lung [2, 5]. However, the overall survival rate is better for TC than for AC [5, 6], and the frequency of lymph node metastases in TC is lower than in high-grade LCNEC and SCLC [6]. Therefore, some investigators have advocated limited resection in patients with TC [7]. Some reports revealed that sublobar resection was noninferior to lobectomy for survival in patients with TC tumor [7]. However, other reports advised that radical oncologic surgery with radical node dissection was needed, and segmental and other limited procedures had to be avoided because of the high frequency of lymph node involvement and multicentric forms [8]. Moreover, preoperative diagnoses and/or diagnoses from intraoperative frozen sections are often difficult for differentiating AC from TC, because small amounts of necrosis or few mitoses are sometimes unclear in those specimens. A randomized controlled trial is the best method to compare surgical efficacy. However, it may be impractical due to the rarity of carcinoid tumors. Moreover, AC has a poorer prognosis and a higher frequency of lymph node metastases than TC. Therefore, sublobar resection for TC might be the optimal surgical method because of lung preservation and lower mortality than lobectomy; however, limited resection for TC remains an area of controversy. Several reports [9] revealed that the clinical behavior, morphology, and prognosis of LCNEC were similar to those of SCLC, even though there might be several clinicopathological differences between SCLC and LCNEC in peripheral, small-sized, and high-grade neuroendocrine tumors [10]. Because it is difficult to diagnose patients with LCNEC pre-operatively, and most cases have been diagnosed postoperatively from surgically resected specimens, many reports on LCNEC have referred to surgical cases, of which the majority [9] revealed that patients with LCNEC had poor prognoses. Even patients with pathological stage I LCNEC have had poor prognoses, with five-year survival rates of 27-67% [9]. In patients with LCNEC who underwent radical surgery and complete resection, many recurrent tumors were observed as distant metastases [10]. Therefore, surgery alone is not sufficient to treat patients with LCNEC, and subsequent adjuvant therapy may be necessary [10]. Although there were high response rates with platinum-based and SCLC-based chemotherapies in patients with LCNEC, almost all patients had only partial responses [9, 10]. Patients with LCNEC may not be able to expect complete responses with platinum-based and SCLC-based chemotherapies compared with patients with SCLC, even though these chemotherapies are as effective as adjuvant treatment. Therefore, patients with advanced-stage LCNEC had a poor prognosis because they could not always achieve a complete response. Although the indication for surgery is limited to stage I in patients with SCLC, surgery and adjuvant chemotherapy may achieve satisfactory results in terms of survival for patients with LCNEC with not only stage I but also stage II/III [10]. Therefore, surgical indications for patients with LCNEC may not be limited to clinical stage I cases, and surgery with adjuvant chemotherapy should be attempted for resectable LCNEC. References [1] Arrigoni MG, Woolner LB, Bernatz PE. Atypical carcinoid tumors of the lung. J Thorac Cardiovasc Surg. 1972;64:413-21. [2] Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E, editors. Histological Typing of Lung and Pleural Tumours. World Health Organization International Histological Classification of Tumors, XIII, 3rd ed. Berlin/Heidelberg: Springer-Verlag; 1999. [3] Rusch VW, Klimstra DS, Venkatraman ES. Molecular markers help characterize neuroendocrine lung tumors. Ann Thorac Surg. 1996;62:798-810. [4] Onuki N, Wistuba II, Travis WD, Virmani AK, Yashima K, Brambilla E, Hasleton P, Gazdar AF. Genetic changes in the spectrum of neuroendocrine lung tumors. Cancer. 1999;85:600-7. [5] Travis W.D, Brambilla E, Müller-Hermelink H.K, Harris C.C (Eds.): World Health Organization Classification of Tumours. Pathology and Genetics of Tumors of the Lung, Pleura, Thymus and Heart. IARC Press:Lyon 2004. [6] Iyoda A, Hiroshima K, Baba M, Saitoh Y, Ohwada H, Fujisawa T. Pulmonary large cell carcinomas with neuroendocrine features are high grade neuroendocrine tumors. Ann Thorac Surg. 2002;73:1049-54. [7] Fox M, Van Berkel V, Bousamra M II, Sloan S, Martin RC II. Surgical management of pulmonary carcinoid tumors: sublobar resection versus lobectomy. Am J Surg. 2013;205:200-8. [8] Daddi N, Ferolla P, Urbani M, Semeraro A, Avenia N, Ribacchi R, Puma F, Daddi G. Surgical treatment of neuroendocrine tumors of the lung. Eur J Cardiothorac Surg. 2004;26:813-7. [9] Iyoda A, Hiroshima K, Nakatani Y, Fujisawa T. Pulmonary large cell neuroendocrine carcinoma- its place in the spectrum of pulmonary carcinoma. Ann Thorac Surg. 2007;84:702-7. [10] Iyoda A, Makino T, Koezuka S, Otsuka H, Hata Y. Treatment options for patients with large cell neuroendocrine carcinoma of the lung. Gen Thorac Cardiovasc Surg. 2014;62:351-6.

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    P3.15 - SCLC/Neuroendocrine Tumors (ID 731)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      P3.15-016a - Prediction of Potential Biomarkers for Personalized Treatment in Pulmonary Large-Cell Neuroendocrine Carcinoma (ID 8869)

      09:30 - 16:00  |  Author(s): K. Shibuya

      • Abstract
      • Slides

      Background:
      The prognosis for patients with large-cell neuroendocrine carcinoma (LCNEC) of the lung is extremely poor, and optimal treatment strategies have not yet been established. To improve prognoses in patients with LCNEC, we analyzed immunohistochemical expression and gene mutations of several known molecular targets in LCNECs and compared the expression levels of these targets with those in lung adenocarcinomas.

      Method:
      Twenty-six patients with primary LCNEC and 40 patients with adenocarcinoma were analyzed. Topoisomerase II, epidermal growth factor receptor (EGFR)-L858R, and somatostatin receptor expression were evaluated by immunohistochemistry, and EGFR mutations were evaluated using direct DNA sequencing and the Scorpion-amplified refractory mutation system.

      Result:
      There was no significant difference between patients with LCNEC and adenocarcinoma in relation to age, gender, smoking status, pathological stage (8[th]), performance status, and pulmonary function. In patients with LCNEC and adenocarcinoma, positive rates of topoisomerase II, EGFR-L858R, and somatostatin were 65.4% and 15.0% (p < 0.0001), 0.0% and 20.0% (p = 0.0182), and 50.0% and 5.0% (p < 0.0001), respectively. The frequencies of EGFR mutations were 0.0% and 37.5% in LCNEC and adenocarcinoma (p = 0.0002), respectively.

      Conclusion:
      LCNEC showed overexpression of topoisomerase II, somatostatin, suggesting it was possible to have good response to treatment with etoposide and octreotide compared with adenocarcinoma. EGFR mutations were not observed in LCNEC. These results may indicate a favorable response to adjuvant treatments that are not typically prescribed for non-small cell lung cancer.

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    P3.16 - Surgery (ID 732)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Surgery
    • Presentations: 1
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      P3.16-004 - Surgery for Patients with Lung Cancer Associated with Interstitial Pneumonia (ID 9361)

      09:30 - 16:00  |  Author(s): K. Shibuya

      • Abstract
      • Slides

      Background:
      Treatment of patients with lung cancer associated with interstitial pneumonia (IP) is difficult because of post-operative complications or treatment-related deaths. Indeed, post-operative acute exacerbation of IP in patients with lung cancer and IP is associated with a high mortality rate. In our institute, we have unified surgical methods and improved peri-operative management of such patients since 2013. In the current study, we retrospectively studied the clinical features, surgical methods, and peri-operative management, and analyzed the clinicopathologic features of patients with lung cancer associated with IP.

      Method:
      We selected patients with lung cancer associated with IP who underwent surgery from January 2004 to May 2017. A presumptive diagnosis of IP or an IP pattern on computed tomography (CT) was confirmed histologically by examination of resected specimens and/or the presence of the clinical diagnostic criteria. Acute exacerbation of IP was defined according to the guidelines of the Japanese Respiratory Society when the following criteria were fulfilled within 1 month: (1) increased respiratory distress; (2) fibrosis, newly developed ground glass opacity and infiltrative shadow on high-resolution computed tomography (HRCT); and (3) > 10 Torr decrease in PaO~2~ under the same oxygenation conditions. (4) no evidence of pulmonary infection, heart failure, pneumothorax, and pulmonary embolism. We studied the following clinicopathologic features in patients with lung cancer associated with IP: gender, age, surgical methods, pathologic stages, mortality rate, and post-operative complications, including acute exacerbation of IP.

      Result:
      Fifty-three patients underwent surgery. The mean age was 70.8 years (50 males and 3 females). Forty-three, 1, and 9 patients underwent lobectomies, a segmentectomy, and partial resections, respectively. Twenty-three, 17, and 13 patients were stage I, II, and III, respectively. Eight patients had post-operative acute exacerbations of IP and there were three in-hospital deaths caused by acute exacerbations. Of note, there have been no in-hospital deaths since 2013.

      Conclusion:
      It is possible to prevent severe post-operative complications in patients with lung cancer associated with IP with the aid of intra-operatively and optimal peri-operative management.

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