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M.S. Tsao

Moderator of

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    E04 - Lung Cancer Pathology Classification (ID 4)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Pathology
    • Presentations: 4
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      E04.1 - Adenocarcinoma (ID 387)

      14:05 - 14:25  |  Author(s): M. Noguchi

      • Abstract
      • Presentation
      • Slides

      Abstract
      In 2011, an international multidisciplinary classification of adenocarcinoma was published (2011 IASLC classification) (1) (Table). Pathologists, oncologists, radiologists, and basic scientists in the field of lung cancer are involved in this project. The new concepts of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) in this classification are based on the multistep carcinogenesis of adenocarcinoma (2). Pulmonary adenocarcinoma develops to invasive adenocarcinoma through atypical adenomatous hyperplasia (AAH), AIS, and MIA. The diagnostic criteria for AIS and MIA were first defined in this new classification. AAH is a localized proliferation of mildly to moderately atypical cells lining involved alveoli and, sometimes, respiratory bronchioles. AAH is usually less than 5 mm in diameter and lacks any underlying interstitial inflammation or fibrosis. Before, AAH was detected as incidental findings in the adjacent lung parenchyma in resected lung adenocarcinoma, but recently it is found by thin-slice CT scan examination and shows characteristic ground glass opacity (GGO), similar to AIS. AAH shows positivity for TTF-1 antigen and is a preinvasive lesion of peripheral-type adenocarcinoma, especially the terminal respiratory unit (TRU) type (3). Adenocarcinoma with pure lepidic growth is a special subtype, because it mimics AAH, which is a preinvasive form of adenocarcinoma and has an extremely favorable prognosis. Among the pure lepidic adenocarcinomas, “adenocarcinoma in situ” is defined as localized small (< 3 cm) adenocarcinoma with growth restricted to neoplastic cells along preexisting alveolar structures (lepidic growth), lacking stromal, vascular, or pleural invasion. Differential diagnosis between AAH and AIS is sometimes very difficult. AIS corresponds to type A and B adenocarcinoma according to the 1995 Noguchi classification (4). AIS is usually nonmucinous but rarely may be mucinous. MIA is a small, solitary adenocarcinoma (< 3 cm), with a predominantly lepidic pattern and < 5 mm invasion in greatest dimension in any one focus. By definition, the invasive component is composed of histological subtypes other than the lepidic pattern (i.e. acinar, papillary, micropapillary, and/or solid) or tumor cells infiltrating myofibroblastic stroma (malignant stroma). MIA is excluded if the tumor invades lymphatics, blood vessels, or pleura, or contains tumor necrosis. If the tumor is larger than 2 cm, diagnosis should be done with caution, and the tumor needs to be extensively sampled, especially the solid component. On thin-slice CT examination, MIA reveals pure GGO or a partly solid appearance. MIA corresponds to type C’ adenocarcinoma according to the modified Noguchi classification (5). We believe that the 5-year survival of patients with localized resected MIA is more than 95%, but there are no actual data on the clinical outcome of MIA. In Japan, leading radiologists and pathologists have just started a joint project to clarify the natural history of MIA, supported by the Ministry of Health, Labor and Welfare. First, they are defining the radiological diagnostic criteria for MIA. Then, based on the criteria, they will follow up cases for more than 5 years. In the course of follow-up, the growing cases will be surgically resected and examined histologically. Finally we will understand the radiological and biological characteristics of MIA in more detail. Invasive adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic, acinar, papillary, micropapillary, and solid patterns. Among the subtypes, lepidic growth represents in situ growth or spreading of invasive adenocarcinoma and the region showing lepidic growth does not influence the patient’s outcome. Therefore, it is very important to report the percentage of the lepidic subtype in the invasive adenocarcinoma. In order to verify the utility of invasive adenocarcinoma classification, interobserver agreement (kappa value) of the diagnostic criteria was assessed (6). Eight Japanese pathologists used the 2011 IASLC classification to independently evaluate the histologic grade of 122 adenocarcinoma cases resected in the National Cancer Center Hospital (Tokyo). The mean (±SD) value of the kappa statistic for the 2011 IASLC classification was 0.46±0.09 (range: 0.24 to 0.61) and the value was not enough for practical use. But, if we modified the classification into low grade (lepidic, acinar, and papillary) and high grade (solid and micropapillary), the mean (±SD) value rose to 0.66±0.09 (range: 0.47 to 0.85) reaching the level of practical use (Figure). Therefore, the modified 2011 IASLC classification shows the clinical outcome of the invasive adenocarcinoma. References (1) Travis WD, Elisabeth B, Noguchi M, et al. International association for the study of lung cancer/American thoracic society/European respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thoracic Oncol 6:244-285, 2011. (2) Noguchi M. Stepwise progression of pulmonary adenocarcinoma. Clinical and molecular implications. Cancer Metastasis Rev 29:15-21, 2010. (3) Yatabe Y, Kosaka T, Takaashi T, et al. EGFR mutation is specific for terminal respiratory unit type adenocarcinoma. Am J Surg Pathol 29:633-9, 2005. (4) Noguchi M, Morikawa A, Kawasaki M, et al. Small adenocarcinoma of the lung. Histologic characteristics and prognosis. Cancer 75:2844-2852, 1995. (5) Minami Y, Matsuno Y, Iijima T, et al. Prognistication of small-sized primary pulmonary adenocarcinomas by hitopathlogical and karyometric analyasis. Lung Cancer 48:339-348, 2005. (6) Nakazato Y, Maeshima AM, Ishikawa Y, et al. Interobserver agreement in the nuclear grading of primary pulmonary adenocarcinoma. J Thoracic Oncol 8:736-743, 2013

      IASLC/ATS/ERS Classification of Lung Adenocarcinoma
      Preinvasive lesions Atypical adenomatous hyperplasia (AAH) Adenocarcinoma in situ (<3cm formerly BAC)
      Minimally invasive adenocarcinoma (MIA) (<3cm lepidic predominant tumor with <5mm invasion)
      Invasive adenocarcinoma Lepidic predominant Acinar predominant Papillary predominant Micropapillary predominant Solid predominant with mucin production
      Variants (Invasive mucinous ad., Collid, Fetal, Enteric
      Figure 1Figure 2

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      E04.2 - Squamous Cell Carcinoma (ID 388)

      14:25 - 14:45  |  Author(s): A.G. Nicholson

      • Abstract
      • Presentation
      • Slides

      Abstract
      Squamous cell carcinoma is one of the four common types of lung cancer, and is defined as a malignant epithelial tumour showing evidence of squamous differentiation in the form of keratinisation, intercellular bridging or both. The main purpose of a pathological classification is to produce clinically relevant subgroups, in addition being reproducible, thorough, dynamic, and globally applicable, and this talk summarises the current WHO classification and potential new parameters. Current morphological classification: Since the 1999 classification, the recognised variants have been being papillary, clear cell, small cell and basaloid. Pure primary basaloid carcinomas of the lung are rare and the current WHO (2004) classification classifies basaloid carcinomas as variants of large cell carcinoma when they lack evidence of squamous differentiation. When squamous differentiation is present, they are classified as basaloid variants of squamous cell carcinoma. Basaloid morphology has been shown to carry a poorer prognosis than poorly differentiated squamous cell carcinomas for stage I and II disease. Papillary squamous cell carcinomas tend to be endobronchial and most are staged as T1N0 with a 5‑year survival of over 60 percent, which may be due to early presentation at this location rather than the architectural pattern itself. With regard to small cell and clear cell variants, the last decade has seen virtually no publications. Indeed, the primary reason for recognising these variants is to avoid misdiagnosis as metastases or other subtypes of lung carcinoma. Therefore, with the exception of the basaloid variant that appears to carry a worse prognosis, especially given small cell and clear cell variants are cytological parameters, consideration should be given to their removal from the next WHO classification, as well as the papillary variant. Also, given the increased knowledge in relation to immunophenotyping, basaloid and basaloid variant of squamous cell carcinoma could potentially be collapsed into a single subgroup of squamous cell carcinoma. Potential new morphological subgroups: The last decade has seen publications suggesting an architectural classification termed "alveolar filling" pattern. One paper has shown 100% survival when this pattern is present, although the number of cases showing this as a pure pattern is very low, around 1-2%. A more recent paper has suggested that the percentage of alveolar filling (greater than 70%) was significantly associated with a better prognosis, arguing that in tumours less than 30 mm in maximum diameter, a minimally invasive category might be appropriate. Tumours with this predominance would likely be sufficiently frequent (near 25%) to be clinically useful, and more data are required to support its inclusion. Other histological parameters such as extent of background of lymphocytic infiltration and keratinisation do not seem to carry prognostic significance. Classification according to presentation and/or aetiological factors: Publications in the last decade have suggested that the frequency of peripheral squamous cell carcinomas is increasing, with a greater number of stage 1 patients having peripheral presentation, although there was no difference in survival in N0 disease when compared to central tumours in one paper (Funai K et al Am J Surg Pathol 2003:27;978-984) . Indeed, survival was better in N1 disease in central presenting tumours. The alveolar pattern of growth was seen within the peripheral group only. However, unlike adenocarcinomas where those that present peripherally may be never-smokers, nearly all peripheral squamous carcinomas appear to be either current or ex-smokers. The frequency of HPV being present in squamous cell carcinoma of the lung varies extensively in the literature. The same ‘high-risk’ subtypes of HPV for cervical carcinoma are found in invasive bronchial carcinomas. However, although data from oropharyngeal squamous cell carcinomas suggest HPV infection is associated with better prognosis, data in the lung are conflicting. There is also likely synergism between smoking and infection as the preferred site of entry for HPV is at squamo-columnar junctions, and the presence or absence of HPV is unlikely to be recommended as a parameter for subclassification. Pre-invasive lesions: Squamous lesions arising in the airways have been regarded as progenitors of squamous carcinoma for decades and basal cell hyperplasia and squamous metaplasia also likely represent earlier phases in the development of squamous carcinomas. The current WHO/IASLC classification tabulates methodology for such gradation, and the system is sufficiently reproducible for diagnostic usage. The sequence progresses from basal cell hyperplasia through squamous metaplasia and squamous dysplasia to carcinoma-in-situ. Immunohistochemistry and small biopsies: The past decade has seen increasing usage of immunohistochemistry to refine the diagnosis of non-small cell carcinoma, driven by the needs for more accurate subclassification in relation to chemotherapeutic agents. This is not part of the current (WHO 2004) classification, although is recommended for use in biopsies by the IASLC as well as the ATS and ERS in relation subclassifying biopsies hitherto called non-small cell carcinoma, not otherwise specified (NSCLC-NOS) (Travis et al. J. Thor. Oncol. 2011;6:244-85). Therefore, any biopsy with NSCLC showing keratinisation and/or intercellular bridges should be classified as squamous cell carcinoma and, in NSCLCs lacking these or other disciminating morphological features on biopsy, but showing immunohistochemical evidence of squamous differentiation (one or two of CK 5/6, P63, and P40 being the most commonly used antibodies for this purpose) should be classified as NSCLC, favouring squamous cell carcinoma on immunohistochemistry. Similar investigation should also be considered in resected large cell undifferentiated carcinomas. Molecular subtypes: There is a vast literature on the carcinogenesis of squamous carcinoma, in particular preinvasive lesions. However none have yet become part of pathology classification. In relation to targeted therapy for invasive squamous cell carcinoma, data are still primarily related to clinical trials, with low frequencies of identification. Therefore, although targets such as DDR2 show some promise, at present, there is insufficient data to warrant pathological classification of invasive squamous carcinoma in relation to specific genetic abnormalities. Conclusion: Unlike adenocarcinomas, there has not been much advance in the morphogical subtyping of squamous cell carcinoma. There has however been advance in immunophenotyping, especially in relation to NSCLC-NOS, and it is hoped that molecular classification may have a role to play in the next decade.

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      E04.3 - Large Cell and Sarcomatoid Carcinoma (ID 389)

      14:45 - 15:05  |  Author(s): K.M. Kerr

      • Abstract
      • Presentation
      • Slides

      Abstract
      Large cell and sarcomatoid carcinomas account for approximately 10% of all lung cancers. For all practical purposes, each of these diagnoses can only be made with accuracy in surgically resected cases since tumour definitions mandate a feature be excluded from or present in at least 10% of the whole lesion. Although features suggesting a large cell variant or sarcomatoid tumour may be recognised in a small biopsy or cytology sample, these diagnoses are inappropriate in such samples. Large cell carcinoma (LCC) is morphologically defined as comprising large undifferentiated tumour cells lacking any evidence of squamous, glandular or small cell carcinoma (SCLC). Epidemiologically these cases are no different from most other non-small cell carcinomas (NSCLC). They favour a more peripheral location in the lung and necrosis is common. Cells are generally large, with open nuclei, prominent nucleoli and abundant cytoplasm, but some cases show hyperchromatic, granular nuclei, inconspicuous nucleoli and less cytoplasm. In the classical case, the cells show no organisation, just sheets of cells with little intervening vascular stroma, but some cases show cellular stratification with more abundant fibrous stroma. Several variants of large cell carcinoma are described. Large cell neuroendocrine carcinoma (LCNEC) additionally requires demonstration of neuroendocrine differentiation, usually by immunohistochemistry. These are often large, necrotic tumours and share many epidemiological and molecular features with small cell lung carcinoma. Organoid morphology with trabeculae and rosettes are common. A significant proportion of LCNEC are combined with other tumour types in the same lesion, most often adenocarcinoma. These cases would more logically reside in a separate category with other NE tumours. The basaloid variant of LCC largely meets the above definition, but tends to have rather smaller cells, peripheral nuclear palisading around discrete nests/sheets of cells, frequent intercellular basement membrane material, like basaloid carcinomas at other sites. An infrequent and unusual form of small keratin pearl may be seen but basaloid carcinomas lack the larger cells with eosinophilic cytoplasm and intercellular bridges of squamous cell carcinomas (SCC). They share immunohistochemical features (p63, p40, CK5/6, desmocollin3) with SCC and could represent de-differentiated SCC. Defining basaloid carcinoma apart from SCC remains a controversial issue. Lymphoepithelioma-like lung carcinoma (LELC) comprises a syncytium of large undifferentiated cells with indistinct cell borders and a heavy lymphoplasmacytic infiltrate. Commoner in East Asian countries, this tumour is still rare and is closely associated with EBV genome. Distinction from other poorly differentiated carcinomas with a heavy immune cell infiltrate may be impossible in the absence of evidence of EBV infection and the latter should, perhaps, be incorporated into the tumour definition. Clear cell carcinoma of the lung features large cells with clear cytoplasm. This histological feature is, however, seen in a range of other NSCLC and as such, serves little useful purpose, apart from awareness of potential confusion with metastatic renal cell carcinoma. This would be better used as a descriptor rather than defining a separate tumour category. Large cell carcinoma with rhabdoid phenotype is rather ill-defined and extremely rare. A few cases reports or small series reflect the heterogeneity of so-called cases with no clear definition. One common impression is that of an aggressive tumour but again, this terminology is better used as a descriptor rather than defining a separate subtype. Emerging immunohistochemical and molecular data have questioned the nature of large cell carcinoma and our current classification. Many cases share a molecular and/or immunohistochemical phenotype with either squamous cell or adenocarcinoma, suggesting that they should be classified by their molecular profile, effectively deleting the LCC category. This approach has several problems including the following: (a) Not all cases can be so re-classified as squamous cell or adenocarcinoma, (b) these immune/molecular profiles are not specific for either diagnosis, and (c) the definition of these differentiated tumours is based on H&E morphology, not immune/molecular findings. Further confusion stems from the inappropriate use of the term ‘large cell carcinoma’ in the small biopsy/cytology setting. Any sample containing large undifferentiated cells lacking features of small cell carcinoma should be referred to as NSCLC, not otherwise specified (NOS) and not ‘large cell carcinoma’. Most of these cases, if resected, derived from differentiated adeno- or squamous cell carcinomas. The legitimate, recommended use of IHC to predict tumour subtype in small samples is neither validated nor justified in resected tumours under the current classification. However, it may be useful to characterise resected LCC cases by immunophenotype since this may correlate with some targetable mutations but it should not lead to a major change in diagnosis. Mutations of EGFR or KRAS are rarer than in adenocarcinoma but correlate with TTF1 positivity. Sarcomatoid carcinomas show pleomorphic, spindle or giant cells comprising at least 10% of the tumour. Usually all three cell types are seen. They account for 3-4% of resected tumours and are usually large, invasive, necrotic tumours. They are clinically aggressive and frequently chemorefractory, justifying their separation in our classification. Most lesions also show differentiated squamous cell or adenocarcinoma components. As for LCC, this diagnosis should not be made in the small biopsy/cytology setting but if these cell types are present in the sample they should be described in the report. Immunohistochemical and/or molecular studies are few. Most cases show an immunoprofile in the sarcomatoid component consistent with the differentiated tumour also present. Pure sarcomatoid cases may also show a ‘differentiation-associated’ immunoprofile but often it is inconclusive or IHC is negative. KRAS mutations have been consistently reported in a few case series. Carcinosarcoma is an exceptionally rare tumour, defined in the lung as a lesion showing carcinoma plus differentiated, heterologous sarcomatous elements, such as rhabdomyo, osteo or chondrosarcoma. Pulmonary Blastoma is a biphasic lesion combining primitive mesenchymal tumour and well-differentiated adenocarcinoma, the latter described as endometrioid or ‘fetal’ in pattern. Regarding the more typical cases of LCC, sarcomatoid and basaloid carcinoma, the molecular evidence supports the concept that these tumours may represent dedifferentiated carcinomas of the lung. How this emerging concept is reflected in our classification is a matter of ongoing debate.

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      E04.4 - Neuroendocrine Tumours (ID 390)

      15:05 - 15:25  |  Author(s): W.D. Travis

      • Abstract
      • Presentation
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      Abstract
      TUMORLETS AND DIFFUSE IDIOPATHIC PULMONARY NE CELL HYPERPLASIA (DIPNECH) Tumorlets are defined as nodular proliferations of NE cells that measure less than 0.5 cm in greatest diameter. Tumorlets typically represent incidental histologic findings found in lung tissues with inflammatory and/or fibrotic lesions such as bronchiectasis, interstitial fibrosis, or infections. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) consists of widespread peripheral airway NE cell hyperplasia and/or multiple tumorlets. These patients are thought to represent a preinvasive lesion for carcinoid tumors because a subset of these patients has one or more carcinoid tumors.[1] DIPNECH may present as multiple pulmonary nodules often mistaken for metastatic cancer or as a form of interstitial lung disease with airway obstruction. Histologically DIPNECH is characterized by prominent NE cell hyperplasia and tumorlets. Some patients also have carcinoid tumors. Tumorlets may cause airway narrowing and/or obliteration. The surrounding lung parenchyma is generally normal.CARCINOID TUMORS Carcinoid tumors most commonly show an organoid growth pattern. The tumor cells show uniform cytologic features with a moderate amount of eosinophilic cytoplasm and finely granular nuclear chromatin. AC are separated from TC by the presence of mitoses between 2 and 10 per 2mm[2] area or the presence of necrosis. Necrosis is usually in the form small punctate foci. Other histologic features such as pleomorphism, vascular invasion and increased cellularity are not as helpful in separating TC from AC. Chromogranin, CD56 and synaptophysin are the most helpful NE immunohistochemical markers. A clear role for Ki-67 in separating TC from AC is not established. However, a low proliferation rate (≤5%) is typically seen in TC compared to AC where it is usually between 5 and 20%. Ki-67 is most useful in addressing the problem of over diagnosis of a high grade tumor in carcinoid tumors where diagnostic criteria are obscured in small crushed biopsies. In this setting a high proliferation rate (>59%) will be found in the high grade LCNEC or SCLC where TC or AC show a much lower proliferation rate.LARGE CELL NEUROENDOCRINE CARCINOMA LCNEC is a high grade NE carcinoma with cytologic features of a non-small cell carcinoma. It was classified as a variant of large cell carcinoma in the 2004 WHO classification.[1] LCNEC are diagnosed according to the following criteria: 1) NE morphology with organoid nesting, palisading or rosette-like structures, 2) high mitotic rate greater than 10 mitoses per 2 mm[2] (average 60-80 mitoses per 2 mm[2]), 3) non-small cell cytologic features including large cell size, low nuclear/cytoplasmic ratio, nucleoli, or vesicular chromatin, and 4) NE differentiation by immunohistochemistry with antibodies such as chromogranin, CD56 or synaptophysin or electron microscopy. The diagnosis of LCNEC is difficult to establish based on small biopsies or cytology. This is because the NE pattern is difficult to see morphologically in small tissue samples or cytology. Also NE differentiation can be difficult to demonstrate by immunohistochemistry in small pieces of tissue. For these reasons the diagnosis of LCNEC requires a surgical lung biopsy. When a LCNEC has components of adenocarcinoma, squamous cell carcinoma, giant cell carcinoma and/or spindle cell carcinoma it is called combined LCNEC. The most common component is adenocarcinoma, but squamous cell, giant cell or spindle cell carcinoma can also occur. If the second component is SCLC the tumor becomes a combined SCLC and LCNEC. NE differentiation must be demonstrated by immunohistochemistry or electron microscopy to diagnose LCNEC. NE immunohistochemical markers are usually best performed as a panel of chromogranin, CD56/NCAM, and synaptophysin. In 41-75% of cases, TTF-1 will be positive. The proliferation index by Ki-67 staining is very with staining of 50-100% of tumor cells .SMALL CELL CARCINOMA The diagnosis of SCLC is established based on small specimens such as bronchoscopic biopsies, fine needle aspirates, core biopsies, and cytology in most all cases, because of the presentation in advanced stages. Fortunately these specimens are diagnostic in most all cases. The diagnosis is based primarily based on light microscopy. Tumor cells appear round to fusiform, growing in sheets and nests. Necrosis is common and is often extensive. Tumor cell cytoplasm is scant and nuclear chromatin is finely granular. Tumor cell size is usually less than the diameter of three small resting lymphocytes. Nucleoli are inconspicuous or absent. A high mitotic rate averages 60-80 per 2 mm[2], however, mitoses can difficult to identify in small biopsy specimens. Combined SCLC is diagnosed when there is also a component of NSCLC such as adenocarcinoma, squamous cell carcinoma, large cell carcinoma, spindle cell carcinoma and giant cell carcinoma. In this setting each of the non-small cell components should be mentioned in the diagnosis. Combined SCLC can be seen in 25% of surgically resected tumors. At least 10% large cells should be present for the diagnosis of combined SCLC/large cell carcinoma; however, for the components of adenocarcinoma, squamous cell or spindle cell carcinoma the amount does not matter. Diagnostic challenges occur in the settings of crush artifact and surgically resected specimens. Crush artifact is common in small biopsy specimens. This can create a problem in separating SCLC from a variety of tumors including non-small cell lung cancer (NSCLC), lymphoma, carcinoid and chronic inflammation. Immunohistochemistry can be very helpful in this setting. In well fixed specimens such as resected specimens the tumor cells of SCLC appear larger than in small biopsies. This often results in over diagnosis of LCNEC. The most important special stain for the diagnosis of SCLC is a good quality H&E stain. However, a panel of immunohistochemical stains is often helpful in the diagnosis. The most common cause of problems in interpretation of biopsies for the diagnosis of SCLC result from sections that are too thick or poorly stained. If the histologic features are classic, it may not be needed. The stains that are useful for the diagnosis of SCLC include a pancytokeratin antibody such as AE1/AE3, CD56, chromogranin and synaptophysin, TTF-1 and Ki-67. If keratin is negative, In 70-80% of SCLC TTF-1 is positive. The main role of Ki-67 is to distinguish SCLC from carcinoids because the proliferation is very high (50-100%) in SCLC.

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Author of

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    MO12 - Prognostic and Predictive Biomarkers III (ID 96)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO12.04 - Biomarker Analysis of NCIC Clinical Trials Group IND.196, a Phase I study of erlotinib plus foretinib in advanced pretreated non-small cell lung cancer patients (ID 3148)

      10:45 - 10:50  |  Author(s): M.S. Tsao

      • Abstract
      • Presentation
      • Slides

      Background
      Upregulation of MET and more recently AXL have been described as potential mechanisms of resistance to EGFR tyrosine kinase inhibitors in NSCLC. We explored the impact of baseline MET and AXL tumour expression and circulating hepatocyte growth factor levels, (HGF), in advanced NSCLC patients receiving erlotinib plus foretinib, an oral multi-targeted kinase inhibitor of MET, RON, AXL, TIE-2 and VEGFR.

      Methods
      Advanced NSCLC patients that previously received one or two lines of chemotherapy were treated in IND.196, a phase I dose-finding trial with an initial two-week run-in of single agent erlotinib (100-150 mg daily). If erlotinib was well tolerated, foretinib was then added (30-45 mg daily). Submission of tumour samples (archival or fresh) was mandatory, and circulating HGF levels were determined at baseline and on treatment. Tumour samples were genotyped using Sequenom MassARRAY analysis. MET and AXL expression were determined by immunohistochemistry. For AXL, the human Axl affinity purified polyclonal goat IgG antibody (R&D systems, AF154, Minneapolis MN) was scored manually. For MET, the anti-total MET (SP-44) rabbit monoclonal antibody (Ventana Medical Systems, Tucson AZ) was scored using the Benchmark XT autostainer. Staining intensity (0-3+) and percent cells stained were used to calculate the H-score; H-scores >100 were deemed positive for AXL, and >200 positive for MET.

      Results
      Of 31 patients enrolled, 28 were evaluable for response to combination therapy, with a recommended phase II dose of erlotinib 150 mg daily for a 2-week run-in and then foretinib 30 mg daily added. The overall response rate in the intent to treat population (RECIST 1.1) was 16.1% (95% CI 5.5-33.7%), with partial responses (PR) seen in 5/31 patients and a median response duration of 17.9 months (range 3.6-17.9). Stable disease was seen in 42% (13/31), with a median duration of 4.8 months (95% CI 2.4-15.4). Tumour samples were submitted for 25 patients; 15 had sufficient tissue for genotyping, 17 for assessment of MET, and 16 for AXL expression. 2/5 responding patients had confirmed EGFR mutations, (1 wildtype, 2 unknown). Another 5 had KRAS mutations, one with >20% reduction in tumour size but SD by RECIST. Of 17 patients with MET IHC results, 71% (12/17) were positive. PR was seen in 3/12 patients with MET-positive tumours, (2 with EGFR mutations, 1 wildtype). No response was seen in those with MET-negative tumours. Of 16 samples with AXL IHC results, 9 were positive (56%). PR was seen in 2/9 with AXL-positive tumours and 2/6 with AXL-negative tumours. AXL expression was not seen in samples with EGFR mutations, but 3/5 KRAS mutant samples were AXL positive. Assessment of circulating HGF levels will be presented at the 2013 WCLC meeting.

      Conclusion
      Baseline MET expression, uncontrolled for EGFR status, may be associated with response to combination erlotinib/foretinib. No correlation between baseline AXL expression and response was seen although the sample size is small. Further study is needed to control for the impact of EGFR mutation status on response, and to assess whether combination erlotinib/foretinib can overcome resistance to EGFR TKI therapy mediated by MET and AXL.

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    MS11 - Next Generation Technology for Detection and Treatment of Lung Cancer (ID 28)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Biology
    • Presentations: 1
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      MS11.4 - Reporting and Interpreting Molecular Results (ID 509)

      15:05 - 15:25  |  Author(s): M.S. Tsao

      • Abstract
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      Abstract
      As molecular biomarkers are becoming routine in the clinical management of lung cancer patients, there is an increasing need to establish standards or guidelines for the reporting of molecular results. In the most ideal situation, reporting of tissue based molecular biomarker results should be integrated into the histopathology report of the tissue sample, to provide a more complete genotype-phenotype characterization of the tumor. This is particularly important for lung cancer as molecular profiling to date has clearly shown that many “driver” genomic aberrations are often closely associated with specific tumor histology. In fact, the current CAP/IASLC/AMP guideline on molecular testing in lung cancer recommends the use of histology (adenocarcinoma containing tumors) as a primary criterion to select lung cancer samples for EGFR and ALK testing. However, until reflex molecular testing becomes routine in pathology practice, molecular testing is often conducted at a laboratory that is separate from the one where the original tissue histopathological diagnosis was made. In such cases, it is important that the stand alone molecular report should also include some histopathological data that may be highly relevant to the interpretation of the results, or at the very least, refer to the relevant Pathology report. In the Pathology report, the data should include: (a) type of sample, whether it is paraffin embedded or fresh (e.g. fluid), (b) tumor diagnosis, subtypes and variants when applicable, (c) essential immunohistochemical markers that were assessed to support the diagnosis, (d) use of tissue processing solution or fixative that could adversely affect the quality of DNA for sequencing, e.g. acid and Bouin’s solution, (e) the approximate size of the tissue, (f) whether a tumor cell enrichment strategy was used, and (g) estimated tumor cellularity in the tissue area marked for isolation of DNA for testing. It is of utmost important that molecular reports are written in language that can be understood by the treating physicians and the pathologists, who are the end-users of the report. Typical laboratory reports should include patient identification codes, the date the sample was acquired (biopsy or resection) from the patient, the date the sample is received in the molecular testing laboratory, and the date the report is signed out. All this information provides not only important sample identification information, but also the real turnaround time of the reported results. Aside from a summary of the molecular results themselves, the report should include a concise but reasonable detailed methodological section, which also provides the performance features of the assay platform being used. It should specify the list of genes included in the assay, the type of aberrations that can be reliably detected, e.g. single nucleotide mutations, deletions, insertions, rearrangements, copy number changes, etc, and the sensitivity and specificity of the assay. The methodology section should also include the analytical software used for processing the data and identifying the genomic aberrations and the version of the normal reference sequence used for comparison with the sequence in question. If the methodology used is fairly new or represent emerging technology, such as next generation sequencing (NGS), then information about mutation verification technology or process may also be required (1). While molecular aberrations are integral to the complete pathological diagnosis of a tumor, in lung cancer their main clinical relevance is for their ability to predict patient response to a specific therapeutic agent, or for patient prognosis. In this context, especially if there are a number of genetic changes being reported (as example with NGS); it may be useful if the aberrations (often called variants) are classified into categories, which reflect their clinical utility. Although there is as yet no universally acceptable classification framework for reporting genomic aberrations identified by NGS platforms, broad categories that establish prognostic, biological or treatment relevance to the aberrations have been proposed or used. These variants have been classified into several “Levels” or “Tiers”, depending on the level of evidence for their predictiveness of response to specific drug. These levels have been derived from widely accepted classification schemes, such as those published by the American College of Medial Genetics (ACMG) for use in diseases such as Breast Cancer. The “actionable” aberrations are those demonstrating proven evidence for their association with high response rates to a specific drug or treatment strategy. The “potentially actionable” alterations are those with strong rationale but as yet proven clinical evidence for being associated high response rate to a specific drug. This group also include aberrations that have demonstrated evidence for response to a specific drug in one type of cancer, yet of unproven response pattern in a different tumor being studied. However, as NGS enables the discovery of a large number of genetic aberrations that typically occur in sporadic adult cancers, many aberrations fall into the category of “unknown therapeutic or biological significance”. While some of these could potentially be predictive markers of drugs that are already available for other reasons, most may not even be pharmacologically targetable. An important risk of conducting comprehensive genomic profiling in patient samples is the identification of “incidental” aberrations, which require clinical management that is not originally planned or anticipated (2). These aberrations could involve genes/mutations with known hereditary roles in cancer or non-cancer conditions, with potentially significant implication on patient and/or other family members. For these reasons, the ACMG recently convened a working group of experts to publish recommendations for reporting of incidental findings in clinical exome and genome sequencing. While these recommendations have been provided primarily as educational resources for medical geneticists and other health care providers (and are still quite controversial), the issues discussed should be considered when deciding upon the reporting strategy for profiling cancer samples using NGS technology. References: 1. Rehm HL, Bale SJ, et al. ACMG clinical laboratory standards for next-generation sequencing. Genet Med. 2013 Jul 25. doi: 10.1038/gim.2013.92. [Epub ahead of print] 2. Green RC, Berg JS, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013 Jul;15(7):565-74. doi: 10.1038/gim.2013.73. Epub 2013 Jun 20.

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    O17 - Anatomical Pathology I (ID 128)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      O17.04 - DISCUSSANT (ID 3987)

      11:00 - 11:15  |  Author(s): M.S. Tsao

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    P2.18 - Poster Session 2 - Pathology (ID 176)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P2.18-007 - Correlating Histologic and Molecular Features in the Lung Adenocarcinoma TCGA Project (ID 1698)

      09:30 - 09:30  |  Author(s): M.S. Tsao

      • Abstract

      Background
      Our understanding of the molecular landscape of lung adenocarcinoma (ADC) is evolving rapidly. Furthermore, the IASLC/ATS/ERS lung ADC classification was recently published. The histologic and molecular correlations have not yet been thoroughly explored in this rapidly changing field. We sought to investigate the molecular findings according to the IASLC/ATS/ERS classification. .

      Methods
      Aperio© scanned H&E stained slides were reviewed from 230 tumors according to the 2011 IASLC/ATS/ERS lung adenocarcinoma classification criteria. Molecular profiling was performed on 230 resected, untreated lung adenocarcinomas, using mRNA, miRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. Histologic molecular correlations focused on mRNA and DNA sequencing and TTF-1 proteomic findings.

      Results
      We found 12 lepidic predominant ADC (5%), 21 papillary predominant (9%), 77 acinar predominant (33%), 33 micropapillary predominant (14%), and 58 solid predominant (25%) as well as, 9 invasive mucinous (4%), and 20 unclassifiable ADCs (9%). EGFR mutation and KRAS mutations were found in 8% and 17% of lepidic ADC, respectively. Nine of 12 lepidic ADC (75%) were of the terminal respiratory unit (TRU) gene expression subtype (GES) and 3 (25%)were in the 19p-depleted transcriptional GES, but none were found in the solid-enriched GES (Figure; p=0.007). Most of the papillary ADC were of the TRU (10/21, 47.6%) and 19p-depleted transcriptional (9/21, 42.9%) GES (p=0.026). 46% (41/89) of acinar ADC tumors were in the TRU-GES compared to the solid enriched (18/78, 23.1%) and 19p-depleted transcriptional (18/63, 28.6%) GES (p=0.005). When the oncogene positive group was defined including KRAS, EGFR, ALK, RET, ROS1, BRAF, ERBB2, HRAS and NRAS, there was a higher percentage of solid ADC in the oncogene negative (30/93, 32.3%) compared to the oncogene positive group (28/137, 20.4%, p=0.046). The highest percentage of solid ADC was found in the solid-enriched GES (47/78, 47.4%) compared to the 19p-depleted transcriptional (17/63, 27%) and TRU GES (4/89, 4.5%) (p<0.001). Invasive mucinous ADC correlated with KRAS (but no EGFR) mutations (67%) compared to other ADC (28%, p=0.02) and also lacked elevation of TTF-1 (p=0.007). GES was associated with histologic grade: high grade with solid-enriched GES and intermediate/low grade with TRU GES (p<0.001). Figure 1

      Conclusion
      Our data reveal multiple correlations between molecular (mutation and GES) and histologic (subtyping and grade) features. This reveals insights into the biology of these tumors in particular genetic characteristics of the high grade tumors which may lead to better understanding of why these are more aggressive tumors.

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    P3.24 - Poster Session 3 - Supportive Care (ID 160)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P3.24-037 - The cost-effectiveness of second-line crizotinib in EML4-ALK rearranged advanced non-small cell lung cancer (ID 2637)

      09:30 - 09:30  |  Author(s): M.S. Tsao

      • Abstract

      Background
      The management of non-small cell lung cancer (NSCLC) has changed markedly over last decade with the discovery of distinct molecular and genetic changes within the lung cancer genome and the availability of new therapeutic agents to target these genetic aberrations. However, the clinical benefits observed are not without significant financial costs. These include diagnostic testing to identify molecular targets and an increasing cost of cancer treatment. Chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) are predictive for clinical response to crizotinib, a first-in-class oral ALK inhibitor. In a recent phase 3 trial, crizotinib was associated with a higher response rate, improved progression-free survival and improved quality of life when compared with docetaxel or pemetrexed as second-line chemotherapy for advanced NSCLC following platinum-based chemotherapy. We performed an analysis to estimate the cost-effectiveness of ALK testing and crizotinib treatment in the second-line setting for patients with stage IV ALK-rearranged NSCLC in the province of Ontario, Canada.

      Methods
      We developed a Markov state-transition model to compare the costs and effectiveness of ALK testing and treatment with crizotinib in positive cases with the current standard of care (docetaxel or pemetrexed chemotherapy). Patients had stage IV NSCLC with non-squamous histology and were previously treated with a platinum-based regimen. The analysis was conducted from the Canadian public health perspective (Ontario) and a “lifetime” time horizon was used. Transition probabilities, mortality rates and costs were calculated from the Ontario Registry, Cancer Care Ontario New Drug Funding Program, Ontario Case Costing Initiative, University Health Network and published literature, including a recent second-line randomized trial of crizotinib versus chemotherapy (Shaw et al. New Engl J Med 2013). Population-based ALK testing included initial immunohistochemical (IHC) staining followed by fluorescent in-situ hybridization (FISH) for positive cases. The outcome of the analysis was incremental cost per quality-adjusted life-years (QALY). The survival impact of crizotinib in ALK-positive NSCLC was derived from a retrospective study (Shaw et al. J Clin Oncol 2012), as the second-line randomized trial of crizotinib versus chemotherapy permitted >80% crossover from the standard chemotherapy arm to crizotinib.

      Results
      The use of crizotinib compared to pemetrexed and docetaxel in ALK-rearranged NSCLC, based on our preliminary model, could yield as much as +0.309 QALY and +0.433 QALY respectively, assuming no crossover from chemotherapy to crizotinib. Incremental costs based on the preliminary model are estimated at CAD $88,446 for pemetrexed and $102,764 for docetaxel, with incremental cost-effectiveness ratios of $286,198/QALY ($162,814/life-year) and $237,575/QALY ($136,707/life-year) gained respectively. Major drivers of cost-effectiveness included the cost of drug therapy and incremental survival. Data on the impact of ALK testing on the overall cost-effectiveness ratio will be presented at the 2013 WCLC meeting, as will refined cost estimates after further model calibration.

      Conclusion
      While crizotinib therapy 2[nd] line for advanced ALK-rearranged NSCLC is clearly superior to chemotherapy, the cost-effectiveness ratio is higher than traditionally accepted thresholds, driven largely by drug cost. Payors and manufacturers should collaborate to ensure that highly effective NSCLC treatments are available and affordable to patients with NSCLC.