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M. Tsuboi

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    MS 01 - How to Treat Multiple GGO's (ID 19)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 5
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      Introduction (ID 2066)

      14:15 - 15:45  |  Author(s): M. Tsuboi

      • Abstract
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      MS01.01 - What Is the Appropriate Diagnostic Technique in the Setting of Multiple GGO's? (ID 1848)

      14:15 - 15:45  |  Author(s): C.A. Powell

      • Abstract
      • Presentation
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      Abstract not provided

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      MS01.02 - What Is the Role of Surgical Resection in the Setting of Multiple GGO's? (ID 1849)

      14:15 - 15:45  |  Author(s): R. Flores

      • Abstract
      • Presentation

      Abstract:
      Main point: Given the nonspecific nature of a GGO or multiple GGOs, a conservative approach to GGOs without a solid component is suggested. Ground glass opacity is a localized nodular lesion which appears as an undetermined finding ‘of hazy lung opacification, without obscuration of the underlying vascular markings’ on a CT scan. Any condition that decreases the air content of the lungs without totally obliterating the alveoli can produce ground glass opacity. GGOs, also known as nonsolid nodules, have been known to decrease or increase in size and/or disappear. There are benign and malignant causes of GGOs. A GGO can be indicative of inflammation, infection and fibrosis that are usually not fatal: pulmonary edema, alveolar proteinosis, many causes of alveolitis or interstitial pneumonitis, including idiopathic pulmonary fibrosis, sarcoidosis, hypersensitivity pneumonitis, early radiation pneumonitis, aspergillus infection, pneumonia, and bronchiectasis. GGOs can also be an early finding of neoplasms such as bronchioalveolar carcinoma (BAC). A recent study has shown that lung cancers appearing as nonsolid nodules were Stage I adenocarcinomas. Analysis of 57,496 participants in the International Early Lung Cancer Action program has shown a 100% survival rate regardless of the time from diagnosis to treatment and tumor size. There are methods to indicate malignancy without surgery: marginal characteristics, the size and development of the solid component or the attenuation on the CT scan, patient’s medical history of cancer, and fine needle aspiration. These are not without some controversy. A solid component is concerning because they are areas of collapsed alveoli or fibroplastic proliferation which signifies more invasive lesions. However, nonsolid nodules can be followed safely by CT screening annually to see if they transition to a part-solid component. Lung cancers diagnosed among nonsolid nodules tend to be slow growing and indolent in nature. The recent I-ELCAP study shows that until the identification of molecular markers, CT imaging can differentiate among different levels of lung cancer sufficiently early so delay in treatment did not change prognosis. A surgeon has to weigh the risks inherent to surgery while leaving the patient with as much lung as possible. Note that a patient’s desire to have the nodule removed may factor in. If feasible, follow the patient and if the GGO’s morphologic characteristics begin to change dramatically, proceed with surgical intervention, preferably VATS. In most cases, with a conservative approach, the patient has enough pulmonary reserve for aggressive action if required. Location of the lesions may make surgical resection challenging. The decision to perform a lobar versus sublobar resection is based on multiple factors and varies from patient to patient. REFERENCES Cho J, Ko SJ, Kim SJ, Lee YJ, Park JS, Cho YJ, Yoon HI, Cho S, Kim K, Jheon S, Lee JH, Lee CT1. Surgical resection of nodular ground-glass opacities without percutaneous needle aspiration or biopsy. BMC Cancer. 2014 Nov 18;14:838. Cho JH, Choi YS, Kim J, Kim HK, Zo JI, Shim YM. Long-term outcomes of wedge resection for pulmonary ground-glass opacity nodules. Ann Thorac Surg. 2015 Jan;99(1):218-22. Engeler CE, Tashjian JH, Trenkner SW, Walsh JW. Ground-glass opacity of the lung parenchyma: a guide to analysis with high-resolution CT. AJR Am J Roentgenol. 1993 Feb;160(2):249-51. Kim HK, Choi YS, Kim J, Shim YM, Lee KS, Kim K. Management of multiple pure ground-glass opacity lesions in patients with bronchioloalveolar carcinoma. J Thorac Oncol. 2010 Feb;5(2):206-10. Miettinen OS, Henschke CI, Smith JP, Yankelevitz DF. Is ground glass descriptive of a type of pulmonary nodule? Radiology. 2014 Jan;270(1):311-2. Mirtcheva RM, Vazquez M, Yankelevitz DF, Henschke CI. Bronchioloalveolar carcinoma and adenocarcinoma with bronchioloalveolar features presenting as ground-glass opacities on CT. Clin Imaging. 2002 Mar-Apr;26(2):95-100. Yankelevitz DF, Yip R, Smith JP, Liang M, Liu Y, Xu DM, Salvatore MM, Wolf AS, Flores RM, Henschke CI; As the Writing Committee for The International Early Lung Cancer Action Program Investigators Group. CT Screening for Lung Cancer: Nonsolid Nodules in Baseline and Annual Repeat Rounds. Radiology. 2015 Jun 23:142554. [Epub ahead of print]

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      MS01.03 - Is There a Role for Targeted Therapy or Conventional Chemotherapy in Patients with Multiple GGO's? (ID 1850)

      14:15 - 15:45  |  Author(s): B.P. Levy

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Recent advances in diagnostic imaging and the use of low dose screening CT scans for high risk individuals has increased detection of ground-glass opacities (GGOs). These lesions are defined as hazy lung opacities on CT with preservation of bronchial and vascular markings, and are typically classified as pure, without a solid component, or mixed,with a solid component[1, 2]. While GGOs have historically been characterized by slow growth and indolent tumor biology, their pathogenesis is poorly understood, and progression can be variable. It remains unclear whether these lesions represent dissemination of malignant cells from a single primary tumor (intrapulmonary spread) or synchronous development of multifocal independent clones [3]. In addition, depending on their size and solid component, GGOs can exist anywhere along the histological spectrum from adenomatous hyperplasia (AAH) to invasive adenocarcinoma (AC). Histologic heterogeneity can be reflected in uncertain growth rates, making therapeutic decision making challenging. While historically GGOs have been managed surgically or with close surveillance, chemotherapeutic strategies have been employed. In addition, recent identification of relevant, driver mutations within GGOs has allowed for consideration of targeted therapies including tyrosine kinase inhibitors (TKIs). Given that GGOs frequently represent bronchioloaveolar carcinoma (BAC) (recently reclassified as adenocarcinoma in situ, lepidic predominant adenocarcinoma or mucinous adenocarcinoma), an overview of chemotherapeutic and targeted strategies for such lesions would require extrapolation from the BAC literature. Despite longstanding recognition of BAC as a distinct subclass of lung adenocarcinoma, few completed prospective trials are available to inform on therapy decisions. To date, only two, small phase II prospective studies evaluating cytotoxic chemotherapy for treatment naïve patients with multi-focal BAC have been published. Both trials evaluated single agent paclitaxel and resulted in disappointing response rates (RR) of 11% and 15%, respectively [4, 5]. Post hoc analysis from the sentinel ECOG 1594 study demonstrated a response rate of only 6% to platinum chemotherapy in patients with BAC [6]. In contrast, the French IFCT-0401 trial demonstrated a RR of 21% and PFS of 3 months in 43 patients with BAC who received chemotherapy (platinum doublet; N=38) after disease progression on first line gefitnib[7]. Experience with third-generation agents such as pemetrexed or gemcitabine has been described only in case reports or retrospective series; however, these agents have demonstrated acceptable outcomes and may be considered in systemic treatment plans Subgroup analysis of early studies evaluating the role of EGFR TKIs in NSCLC demonstrated disproportionate and often dramatic responses in those tumors formally classified as BAC. This observation led to several trials exploiting gefitinb or erlotinib as initial therapy for patients with BAC. While overall responses rates in these studies were similar to studies evaluating chemotherapy (RR: 15 to 25%) patients with EGFR mutations derived greater benefit. For example, in a study evaluating erlotinib as initial therapy for patients with advanced BAC, the RR for those with EGFR mutations was 87% compared to 7% for those without EGFR mutations [8]. The association of EGFR mutations with GGOs and the non-mucinous subtype of BAC is supported by multiple studies including a recent comprehensive analysis evaluating genetic alterations in 217 resected GGOs from 215 lung cancer patients[9]. In this study, EGFR mutations were detected in 119 (54.8%). Other relevant driver mutations, including ALK mutations (2.8% in the aforementioned study evaluating resected GGOs) and KRAS mutations in mucinous subtype of AIS, have also been identified. This allows for consideration of other targeted therapies including ALK directed therapies (crizotinib, certinib, alectinib) and those targeting KRAS (selumetinib). Despite the well-established paradigm of offering targeted therapy to molecularly characterized subgroups, the clinical scenarios for patients with multiple GGO’s can be unique in several ways. Should these patients, if confirmed to have EGFR mutations, be treated with TKIs if lesions are slow growing or not growing at all? Or, should the indolent biology of such lesions trump the actionable mutation when making a therapeutic decision? In addition, the notion that a mutation discovered on a biopsied or resected GGOs is representative of all GGOs within a patient may be incorrect. A recent analysis evaluating 72 resected GGO lesions from 35 patients, all with more than one GGO, demonstrated a high rate of mutation discrepancy. In this study, 80% of patients (24/30) who harbored at least one genetic alteration had a driver mutation discrepancy within another GGO supporting the hypothesis that multiple GGOs seem to arise from different primary clones [10]. Given that patients with GGOs represent a spectrum of tumor biology and clinical behavior, an individualized approach that affords flexibility should be employed when implementing treatment strategies (Figure 1). Management decisions need to factor in the potential for indolent disease with consideration of a watch and wait approach for stable or slow growing lesions. If the clinician identifies progressive disease, systemic options should be entertained and include both chemotherapy and TKIs for patients who harbor actionable mutations. Further studies are needed to better define the clonal relationship of GGOs in an effort to optimize targeted approaches for such patients.Figure 1 References: 1. Hansell, D.M., et al., Fleischner Society: glossary of terms for thoracic imaging. Radiology, 2008. 246(3): p. 697-722. 2. Godoy, M.C. and D.P. Naidich, Subsolid pulmonary nodules and the spectrum of peripheral adenocarcinomas of the lung: recommended interim guidelines for assessment and management. Radiology, 2009. 253(3): p. 606-22. 3. Chung, J.H., et al., Epidermal growth factor receptor mutation and pathologic-radiologic correlation between multiple lung nodules with ground-glass opacity differentiates multicentric origin from intrapulmonary spread. J Thorac Oncol, 2009. 4(12): p. 1490-5. 4. West, H.L., et al., Advanced bronchioloalveolar carcinoma: a phase II trial of paclitaxel by 96-hour infusion (SWOG 9714): a Southwest Oncology Group study. Ann Oncol, 2005. 16(7): p. 1076-80. 5. Scagliotti, G.V., et al., A phase II study of paclitaxel in advanced bronchioloalveolar carcinoma (EORTC trial 08956). Lung Cancer, 2005. 50(1): p. 91-6. 6. Schiller, J.H., et al., Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med, 2002. 346(2): p. 92-8. 7. Duruisseaux, M., et al., Chemotherapy effectiveness after first-line gefitinib treatment for advanced lepidic predominant adenocarcinoma (formerly advanced bronchioloalveolar carcinoma): exploratory analysis of the IFCT-0401 trial. J Thorac Oncol, 2012. 7(9): p. 1423-31. 8. Miller, V.A., et al., Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J Clin Oncol, 2008. 26(9): p. 1472-8. 9. Ko, S.J., et al., Epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangements in lung cancer with nodular ground-glass opacity. BMC Cancer, 2014. 14: p. 312. 10. Wu, C., et al., High Discrepancy of Driver Mutations in Patients with NSCLC and Synchronous Multiple Lung Ground-Glass Nodules. J Thorac Oncol, 2015. 10(5): p. 778-83.



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      MS01.04 - The Pathologic Classification of GGO's - Clinical Pathologic Correlation (ID 1851)

      14:15 - 15:45  |  Author(s): E. Thunnissen

      • Abstract
      • Slides

      Abstract:
      Definition. Ground glass opacity (GGO) is a finding on thin-section CT that is defined as “hazy increased attenuation of the lung with preservation of bronchial and vascular margins”.[1]This is in contrast to consolidation that is defined as a “homogeneous increase in pulmonary parenchymal attenuation that obscures the margins of vessels and airway walls” (also called ‘solid´ component). Introduction. The resolution of the CT differs few orders of magnitude from the resolution of the microscope. Therefore, GGO is not one disease: pathological examination reveals several different diseases. The radiological GGO change is actually due to a reduction of air, while a certain amount of air remains present. At the microscopic level this may be caused by either i) partial filling of the alveolar airspaces, ii) thickening of the parenchymal interstitium and alveolar walls, iii) relative increase in perfusion, or iv) any combination of these factors.[1,2]Alveolar spaces may become partially filled by several ways, such as transudative fluid, blood, inflammatory cells or debris, or amorphous material as seen in cardiogenic pulmonary edema, diffuse alveolar hemorrhage, pneumonia, and pulmonary alveolar proteinosis. Alveolar walls and septal interstitium may become thickened secondary to edema, neoplastic proliferation, fibrosis, and noncaseating granulomatous deposition as seen in cardiogenic pulmonary edema, nonspecific interstitial pneumonia, and sarcoidosis. Partial alveolar filling and interstitial thickening coexist in many disease entities. Thus GGO is a non-specific finding that may be caused by various disorders, including inflammatory disease, pulmonary fibrosis, alveolar haemorrhage or neoplasms. GGO may be either (multi)focal (=localised GGO) or diffuse (present bilaterally in most of the lobes, nicely reviewed by El-Sherief et al.[1]), usually associated with inflammatory diseases. Localized GGO may be pure associated with a solid component (mixed GGO) or without (pure GGO). Localized GGO may contain benign[3,4](organising pneumonia, non-specific fibrosis, atypical adenomatous hyperplasia: AAH; aspergillosis) premalignant (adenocarcinoma in situ: AIS, formerly also called BAC)[5]and malignant diseases[3]((minimal) invasive adenocarcinoma with prominent lepidic component[4,5]). The clinical significance of localized GGO is its high incidence of malignancy compared with solid nodules. The reported range varies from 10-90%.[6–8] CT-guided thoracic needle biopsy is a useful tool for tissue diagnosis and may support the patient management with GGO lesions.[9]Fluoroscopic or image guidance has been studied as well.[10–12] The core biopsy procedure is preferred over aspiration.[13]As usual with biopsies underestimation/ underdiagnosis due to sampling variation is not excluded.[11,14]As GGO contains many diseases the term “Natural history of GGO” is a misnomer.[15,16] Radiology To distinguish GGOs with growth from those without growth, a 3-year follow-up observation period is a reasonable benchmark based on the data that the volume-doubling time (VDT) of pure GGOs ranges from approximately 600 to 900 days and that of part-solid GGOs ranges from 300 to 450 days.[7,8,17] AAH is often associated with malignancy and is shown on CT as persistent well-defined oval or round nodular GGOs without solid components, and it does not change on the follow-up CT.[18] Clinicoradiological characteristics of a benign course are smaller size (< 10 mm.), round/oval shape, lack of consolidation[18,19]or scattered consolidation.[20] Clinicoradiological characteristics of a progressive course are smoking history[21]and initial lesion diameter (> 1 cm) [5,19,22,23], lobulated or speculated margin,[4]growth[16], increase in attenuation,[24]greater irregularity of pixel texture (entropy).[5]Growth of localised GGO may be slow: for one case progression was reported within 10 years.[25] Biomarkers EGFR mutations may be present in pure and mixed GGO lesions, representing preinvasive and invasive cancer.[26–28]Interestingly, for p53 immunohistochemistry positive staining was seen in a small group (n=6) associated with growth or a solid component.[26]MIB1 (ki67) is higher in mixed GGO than in pure GGO.[29]CEA not relevant for the distinction of the progressive GGO.[30] Remarkably, with laborious cytogenetic analysis spontaneous metaphases appeared after 24-48 h. in 9 cases of pure GGO. Abnormal FISH was associated with poor outcome.[15] In case of multiple GGO synchronous BAC and/or ADC can have different EGFR or K-ras mutational profiles suggesting these lesions arise as independent events rather than intrapulmonary spread or systemic metastasis.[31] Management Surgical handling is hampered since AAH not or much less well easy palpable than AIS.[30] Since GGO may contain only AIS or minimal invasive adenocarcinoma partial resection may be the method of choice.[30]and systematic lymph node dissection may be avoided.[32] For multiple localized GGO wait and see is an option[33] Prognosis of mixed GGO invasive adenocarcinomas better for solid size than size including the GGO.[34,35]A larger solid component is worse than less solid component.[36] References 1. El-Sherief, A. H. et al. Clear Vision Through the Haze: A Practical Approach to Ground-Glass Opacity. Curr. Probl. Diagn. Radiol. 43, 140–158 (2014). 2. Hewitt, M. G., Miller, W. T., Reilly, T. J. & Simpson, S. The relative frequencies of causes of widespread ground-glass opacity: A retrospective cohort. Eur. J. Radiol. 83, 1970–1976 (2014). 3. Lee, H. J. et al. Nodular ground-glass opacities on thin-section CT: size change during follow-up and pathological results. Korean J. Radiol. 8, 22–31 4. Kim, H. Y. et al. Persistent Pulmonary Nodular Ground-Glass Opacity at Thin-Section CT: Histopathologic Comparisons 1. Radiology 245, 267–275 (2007). 5. Son, J. Y. et al. Quantitative CT Analysis of Pulmonary Ground-Glass Opacity Nodules for the Distinction of Invasive Adenocarcinoma from Pre-Invasive or Minimally Invasive Adenocarcinoma. PLoS One 9, e104066 (2014). 6. Ichinose, J. et al. Invasiveness and malignant potential of pulmonary lesions presenting as pure ground-glass opacities. Ann. Thorac. Cardiovasc. Surg. 20, 347–52 (2014). 7. Lee, H. Y. & Lee, K. S. Ground-glass Opacity Nodules. J. Thorac. Imaging 26, 106–118 (2011). 8. Kobayashi, Y. & Mitsudomi, T. Management of ground-glass opacities : should all pulmonary lesions with ground-glass opacity be surgically resected ? 2, 354–363 (2013). 9. Yang, J.-S. et al. Meta-analysis of CT-guided transthoracic needle biopsy for the evaluation of the ground-glass opacity pulmonary lesions. Br. J. Radiol. 87, 20140276 (2014). 10. Hur, J. et al. Diagnostic Accuracy of CT Fluoroscopy–Guided Needle Aspiration Biopsy of Ground-Glass Opacity Pulmonary Lesions. Am. J. Roentgenol. 192, 629–634 (2009). 11. Yamagami, T. et al. Diagnostic performance of percutaneous lung biopsy using automated biopsy needles under CT-fluoroscopic guidance for ground-glass opacity lesions. Br. J. Radiol. 86, 20120447 (2013). 12. Chavez, C. et al. Image-guided bronchoscopy for histopathologic diagnosis of pure ground glass opacity: a case report. J. Thorac. Dis. 6, E81–4 (2014). 13. Choi, S. H. et al. Percutaneous CT-guided aspiration and core biopsy of pulmonary nodules smaller than 1 cm: analysis of outcomes of 305 procedures from a tertiary referral center. AJR. Am. J. Roentgenol. 201, 964–70 (2013). 14. Lu, C.-H. et al. Percutaneous Computed Tomography-Guided Coaxial Core Biopsy for Small Pulmonary Lesions with Ground-Glass Attenuation. J. Thorac. Oncol. 7, 143–150 (2012). 15. Bettio, D., Venci, A., Cariboni, U., Di Rocco, M. & Infante, M. Fluorescent in situ hybridization (FISH) in the differential diagnosis of ground-glass opacities in the lung. Lung Cancer 71, 319–322 (2011). 16. Chang, B. et al. Natural History of Pure Ground-Glass Opacity Lung Nodules Detected by Low-Dose CT Scan. CHEST J. 143, 172 (2013). 17. Oda, S. et al. Volume-Doubling Time of Pulmonary Nodules with Ground Glass Opacity at Multidetector CT. Acad. Radiol. 18, 63–69 (2011). 18. Park, C. M. et al. CT findings of atypical adenomatous hyperplasia in the lung. Korean J. Radiol. 7, 80–6 19. Lee, S. M. et al. Invasive Pulmonary Adenocarcinomas versus Preinvasive Lesions Appearing as Ground-Glass Nodules: Differentiation by Using CT Features. Radiology 268, 265–273 (2013). 20. Matsunaga, T. et al. Lung cancer with scattered consolidation: detection of new independent radiological category of peripheral lung cancer on thin-section computed tomography. Interact. Cardiovasc. Thorac. Surg. 16, 445–449 (2012). 21. Kobayashi, Y. et al. The association between baseline clinical-radiological characteristics and growth of pulmonary nodules with ground-glass opacity. Lung Cancer 83, 61–66 (2014). 22. Kitami, A. et al. One-dimensional mean computed tomography value evaluation of ground-glass opacity on high-resolution images. Gen. Thorac. Cardiovasc. Surg. 60, 425–430 (2012). 23. Fan, L., Liu, S. Y., Li, Q. C., Yu, H. & Xiao, X. S. Multidetector CT features of pulmonary focal ground-glass opacity: Differences between benign and malignant. Br. J. Radiol. 85, 897–904 (2012). 24. Eguchi, T. et al. Tumor Size and Computed Tomography Attenuation of Pulmonary Pure Ground-Glass Nodules Are Useful for Predicting Pathological Invasiveness. PLoS One 9, e97867 (2014). 25. Min, J. H. et al. Stepwise evolution from a focal pure pulmonary ground-glass opacity nodule into an invasive lung adenocarcinoma: An observation for more than 10 years. Lung Cancer 69, 123–126 (2010). 26. Aoki, T. et al. Adenocarcinomas with Predominant Ground-Glass Opacity: Correlation of Morphology and Molecular Biomarkers. Radiology 264, 590–596 (2012). 27. Usuda, K. et al. Relationships between EGFR mutation status of lung cancer and preoperative factors - are they predictive? Asian Pac. J. Cancer Prev. 15, 657–62 (2014). 28. Yoshida, Y. et al. Molecular Markers and Changes of Computed Tomography Appearance in Lung Adenocarcinoma with Ground-glass Opacity. Jpn. J. Clin. Oncol. 37, 907–912 (2007). 29. Ohta, Y. et al. Pathologic and Biological Assessment of Lung Tumors Showing Ground-Glass Opacity. Ann. Thorac. Surg. 81, 1194–1197 (2006). 30. OHTSUKA, T., WATANABE, K., KAJI, M., NARUKE, T. & SUEMASU, K. A clinicopathological study of resected pulmonary nodules with focal pure ground-glass opacity. Eur. J. Cardio-Thoracic Surg. 30, 160–163 (2006). 31. Chung, J.-H. et al. Epidermal Growth Factor Receptor Mutation and Pathologic-Radiologic Correlation Between Multiple Lung Nodules with Ground-Glass Opacity Differentiates Multicentric Origin from Intrapulmonary Spread. J. Thorac. Oncol. 4, 1490–1495 (2009). 32. Ye, B. et al. Factors that predict lymph node status in clinical stage T1aN0M0 lung adenocarcinomas. World J. Surg. Oncol. 12, 42 (2014). 33. Kim, H. K. et al. Management of Multiple Pure Ground-Glass Opacity Lesions in Patients with Bronchioloalveolar Carcinoma. J. Thorac. Oncol. 5, 206–210 (2010). 34. Nakamura, S. et al. Prognostic impact of tumor size eliminating the ground glass opacity component: modified clinical T descriptors of the tumor, node, metastasis classification of lung cancer. J. Thorac. Oncol. 8, 1551–7 (2013). 35. Tsutani, Y. et al. Prognostic significance of using solid versus whole tumor size on high-resolution computed tomography for predicting pathologic malignant grade of tumors in clinical stage IA lung adenocarcinoma: A multicenter study. J. Thorac. Cardiovasc. Surg. 143, 607–612 (2012). 36. Shimada, Y. et al. Survival of a surgical series of lung cancer patients with synchronous multiple ground-glass opacities, and the management of their residual lesions. Lung Cancer 88, 174–180 (2015).

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Author of

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    MINI 19 - Surgical Topics in Localized NSCLC (ID 138)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 1
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      MINI19.02 - Mediastinal Nodal Involvement in Patients with Clinical Stage I Non-Small-Cell Lung Cancer - Possibility of Rational Lymph Node Dissection - (ID 2320)

      16:45 - 18:15  |  Author(s): M. Tsuboi

      • Abstract
      • Presentation
      • Slides

      Background:
      Recent developments of radiological examinations have been able to bring more accurate information about the biological malignancy of primary tumors in non-small cell lung cancer (NSCLC). The aim of this study is to elucidate the optimal candidate of lobe-specific selective lymph node dissection (LND) that reduces the extent of mediastinal LND according to clinical information including radiological evaluation of primary tumor on thin-section computed tomography (TSCT) and tumor location in clinical(c)-stage I NSCLC patients.

      Methods:
      Eight hundred and seventy-six patients with c-stage I NSCLC (adenocarcinoma and squamous cell carcinoma), who underwent complete surgical resection between January 2003 and December 2009 were included in this study. For all tumors, we obtained the maximum dimension of the tumor (tumor) and solid component (consolidation) using a lung window level setting from the TSCT scan images, and estimated the consolidation-to-tumor ratio (C/T ratio) for each tumor. We elucidated the lymph node metastatic incidence and distribution according to the primary tumor lobe location and extracted the associated clinicopathological factors with mediastinal lymph node involvement.

      Results:
      The patients included 490 men and 386 women, with a median age of 66 years old. The radiological findings were ground glass opacity (GGO)-predominant (C/T ratio ≤ 0.5) in 134 patients and solid-predominant (C/T ratio > 0.5) in 742 patients. There were 744 adenocarcinoma cases and 132 squamous cell carcinoma cases, and the incidences of mediastinal lymph node metastasis were 9.9% in adenocarcinoma cases and 4.5% in squamous cell carcinoma cases, respectively. There were no cases with hilar and mediastinal lymph node metastasis in GGO-predominant tumors. There was no significant association of clinical factors with subcarinal lymph node metastasis in right upper-lobe and left upper-division lung adenocarcinoma. In 257 bilateral lower-lobe lung adenocarcinomas, a total of 32 cases (12.5%) were positive for mediastinal lymph node metastasis, and seven cases (2.7%) were negative for subcarinal lymph node metastasis but positive for upper mediastinal lymph node metastasis (mediastinal skip metastasis). An elevated preoperative serum carcinoembryonic antigen (CEA) level (p < 0.001) showed only a significant association with upper mediastinal lymph node metastasis in the patients with bilateral lower-lobe primary lung adenocarcinoma.

      Conclusion:
      It would be acceptable to perform selective LND in patients with c-stage I NSCLC with GGO-predominant tumor. Elevated serum CEA was associated with upper mediastinal lymph node involvement in lower-lobe primary lung adenocarcinoma with radiologically solid-predominant tumor. We should be careful when applying selective LND to patients with solid-predominant tumor, especially located in the lower lobe.

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    MINI 36 - Imaging and Diagnostic Workup (ID 163)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Screening and Early Detection
    • Presentations: 1
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      MINI36.01 - Three-Dimensional Quantitative Computed Tomography Evaluation of Pulmonary Adenocarcinoma Using Image-Analysis Software (ID 772)

      18:30 - 20:00  |  Author(s): M. Tsuboi

      • Abstract
      • Slides

      Background:
      Several 2-dimensional computed tomography (CT)-based evaluation methods of small-sized lung adenocarcinomas have been reported as predictors of the disease invasiveness. They include the ratio of the maximum diameter of consolidation to the maximum entire tumor diameter (C/T ratio), tumor shadow disappearance rate on mediastinal window images (TDR), and visual estimation of the ratio of ground-glass opacity area (GGO-R). However, these measurements can be poorly reproducible due to possible inter-observer discrepancy, and can be unrepresentative because measuring is done only on one section of a lesion. We have developed a 3-dimensional quantitative entire-nodule evaluation method using novel image-analysis software. The aim of this study is to compare the new method to these 2-dimensional evaluation methods as a predictor of small-sized invasive lung adenocarcinomas.

      Methods:
      There were 101 consecutive patients with clinical stage IA adenocarcinoma of the lung who underwent complete resection between 2002 and 2005 at our institution, excluding patients undergoing preoperative treatment and those with multiple lung nodules or with a past history of other cancers. Of them, 75 had a nodule separated from the chest wall and mediastinum depicted on preoperative thin section CT scan without contrast enhancement, and they were the subject of this study. The reconstruction interval of the CT scans was 0.2mm and the reconstructed slice thickness was 0.5mm. The image analysis software recognizes a nodule as a collection of cubic voxels. Ground glass opacity (GGO) was defined as the area of increased attenuation in the lung with preservation of the bronchial and vascular margins. As the average CT value of pulmonary arteries on non-contrast-enhanced CT was 50 Hounsfield Unit (HU), we measured the percentage of the voxels over 50 HU in a nodule to identify voxels representing solid component, and the percentage was defined as R-50. Invasive cancer was defined as a nodule with pathological lymphatic permeation, vascular invasion or node involvement. The correlation between invasive lung cancer and clinicopathological factors, including the image findings (C/T ratio, TDR, GGO-R and R-50) was evaluated using multivariate analysis. The areas under the curve (AUC) of receiver operating characteristics curves were compared among the image evaluation methods.

      Results:
      There were 17 invasive cancers. C/T Ratio, TDR, GGO-R and R-50 were independent predictors of invasive lung cancers (p<0.01). R-50 was equivalent in AUC to the other evaluation methods (AUC: R-50, 0.807; C/T Ratio, 0.800; TDR, 0.809; GGO-R, 0.792, respectively).

      Conclusion:
      Our new 3-dimensional quantitative evaluation method using image-analysis software had invasive cancer predictability similar to the other 2-dimensional evaluation methods. As this method enables entire-tumor evaluation quantitatively and objectively, it should be more reproducible and reliable than the conventional methods.

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    MS 01 - How to Treat Multiple GGO's (ID 19)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 1
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      Introduction (ID 2066)

      14:15 - 15:45  |  Author(s): M. Tsuboi

      • Abstract
      • Slides

      Abstract not provided

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    P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P1.04-009 - Max Collapse and Fibrosis below 5 cm Predict the Prognosis of pT1 Lepidic Predominant Adenocarcinoma (ID 2605)

      09:30 - 17:00  |  Author(s): M. Tsuboi

      • Abstract

      Background:
      According to the International Association for the Study of Lung Cancer , American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) classification, lepidic predominant pattern in pT1 lung adenocarcinoma is divided into adenocarcinoma in situ　(AIS),　minimally invasive adenocarcinoma (MIA), and lepidic predominant invasive adenocarcinoma (LPIA) by using new diagnostic criteria. However the new criteria have many item to diagnose MIA. So we simply classified the pT1 lepidic predominant adenocarcinoma by using only collapse and fibrosis below 5cm as invasive component, and we evaluated prognosis of MIA.

      Methods:
      A total of 231 patients treated for pT1 lepidic predominant lung adenocarcinoma by complete resection at National cancer center hospital east, Chiba, Japan from January 2003 to December 2010 were assessed. We excluded multiple tumor and mucinous invasive adenocarcinoma from the analysis. We classified 187 patients into AIS, MIA, LPIA, according to the IASLC/ATS/ERS classification. The MIA was defined as group A. In the LPIA, we defined invasive component as collapse and fibrosis 5 cm below, and reclassified into MIA and LPIA. Reclassified MIA and LPIA were defined as Group B and C respectively. We analyzed the prognosis of these patients retrospectively.

      Results:
      AIS, Group A, Group B, Group C were 52　(22.5%), 29 (12.5%), 39　(16.9), 111 (48.1%) respectively. Positive lymphatic invasion and, or vascular invasion and, or pleural invasion in Group A, Group B, Group C were 0 (0%), 4 (1.2%), 24 (21.6%) respectively. There are significant difference in 5-year recurrence free survival (5y-RFS) between Group A and B (5y-RFS rate 100% versus 88.1%; p = 0.022), and Group A and C (5y-RFS rate 100% versus 88.1%: p = 0.046).

      Conclusion:
      Max collapse and fibrosis below 5 cm correlated with the prognosis of pT1 lepidic predominant adenocarcinoma. Max collapse and fibrosis below 5cm is more simpl and easy method to measure invasive component than the new IASLC/ATS/ERS classification. This method may have potential to diagnose MIA instead of the IASLC/ATS/ERS classification.

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    P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P2.04-064 - Microenvironmental Factor of Primary Lung Adenocarcinoma Which Predicts the Effectiveness of Chemotherapy in Patients with Recurrences (ID 815)

      09:30 - 17:00  |  Author(s): M. Tsuboi

      • Abstract
      • Slides

      Background:
      The influence of microenvironmental factors on the effectiveness of chemotherapy is being increasingly recognized. Stromal cells in cancer tissue, such as tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), have been shown to influence tumor progression. The associations of CD204-positive cells, which represent an M2 phenotype of TAMs, and podoplanin-positive CAFs, which represent a subpopulation of CAFs with a tumor-promoting phenotype, with a poor prognosis have been identified in patients with lung adenocarcinoma, but whether these associations are involved in the response to chemotherapy remains unknown. The purpose of this study was to investigate the relationships between cancer cell and stromal cell phenotypes in primary tumors and the progression-free survival (PFS) of recurrent lung cancer patients who received platinum-based chemotherapy.

      Methods:
      We retrospectively analyzed 87 postoperative recurrent lung adenocarcinoma patients treated with platinum-based chemotherapy. The expressions of drug resistance-related proteins including BCRP, Ezrin and ALDH1 in cancer cells, the number of CD204-positive TAMs, and the presence of podoplanin-positive CAFs in the primary tumor were examined. The relationships between the immunohistochemical staining results of primary tumors and the PFS after receiving chemotherapy were also analyzed.

      Results:
      Among the clinicopathological factors of primary tumors, only an advanced pathological stage was significantly associated with a shorter PFS. As for immunohistochemical staining, no significant relationships were found between the PFS and the expression of BCRP, Ezrin, or ALDH1. The number of CD204-positive TAMs was not associated with the PFS. The presence of podoplanin-positive CAFs, identified in thirty (34%) of 87 samples, was significantly associated with a shorter PFS (median PFS: 5.1 vs. 7.8 months, P=0.028), but was not significantly associated with a shorter overall survival (median survival time: 18.1 vs. 23.7 months, P=0.156). A multivariate analysis revealed a tendency of podoplanin-positive CAFs to be correlated with a shorter PFS (P=0.087).

      Conclusion:
      The presence of podoplanin-positive CAFs in the primary tumor could be a predictor of a shorter PFS in recurrent lung adenocarcinoma patients who received chemotherapy. These findings suggest that stromal-cell derived factors should be incorporated into predictions of the effectiveness of chemotherapy.

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    YIS - Young Investigator Session incl. Q & A with Longstanding IASLC Members (ID 238)

    • Event: WCLC 2015
    • Type: Young Investigator Session
    • Track: Other
    • Presentations: 1
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      YIS.07 - Q & A with Longstanding IASLC Members (ID 3517)

      07:30 - 11:00  |  Author(s): M. Tsuboi

      • Abstract
      • Slides

      Abstract not provided

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