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E. Duhig

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
      • Slides

      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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    MTE04 - Submit Your Challenging Cases for Discussion & Debate! (ID 48)

    • Event: WCLC 2013
    • Type: Meet the Expert (ticketed session)
    • Track: Pathology
    • Presentations: 3
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      Cases (ID 5658)

      08:00 - 08:20  |  Author(s): E. Duhig

      • Abstract
      • Slides

      Abstract not provided

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      MTE04.1 - Submit Your Challenging Cases for Discussion & Debate! (ID 596)

      07:00 - 07:30  |  Author(s): A.G. Nicholson

      • Abstract
      • Presentation
      • Slides

      Abstract
      The purpose of this session is to allow delegates to bring cases for discussion in relation to unusual thoracic tumours, primarily related to the pathology but also in relation to clinical management of complex pathological cases. Respiratory medicine does not provide a huge volume of material for the diagnostic pathologist, but much of this is related to thoracic cancers and their differential diagnoses. This sometimes leads to a lack of experience in managing rare and complex cases and most pathologists will have an, albeit informal, link for specialist opinion to help in this instance. Indeed, it is now a recommendation in the United Kingdom that a pathway of referral is part of the multidisciplinary management of lung cancer patients. In the speaker’s experience, around 60% of referrals for complex cases relate to tumour pathology, and this is perhaps increasing with the relative decrease in biopsy for non-neoplastic diseases and increased interest in the subtyping of more common tumours. Cases referred for specialist opinion tend to breakdown into small lung biopsies, in particular asking the question, "is there enough evidence to call the biopsy definitively malignant?" This is, in particular, in relation to adenocarcinoma. Another common area is the differential diagnosis of mesothelioma, in particular in relation to spindle cell rather than epithelioid proliferations in the pleura. The third common area for referral is the "rare" tumour, where cases will often be sent because the referring pathologist has been no previous experience of the particular neoplasm. This process is not only of benefit to the referrer but also for the specialist as it allows accrual of potential new entities, an example being primary pulmonary myxoid sarcomas with EWSR1-CREB1 fusion where cases were collected over a period of 12 years from first sighting. Even within these groups, the pattern of referral has changed over the last two decades. Between 1995 and 2000, there were frequent referrals in relation to the differential diagnosis of pulmonary marginal zone lymphoma of MALT origin and reactive pulmonary lymphoid hyperplasia. Now that distinguishing criteria are much more established, these referrals are much rarer. However the last two years has seen an increase in referrals of non-small cell carcinoma, in relation to the need for further subtyping, with many of the cases being those with diverging immunophenotype. Little has been done to assess the value of specialist referral. However a review of personal experience of 50 cases affirmed diagnoses in 26/50 (52%) cases, revised in 16/50 (32%) and favoured diagnoses in 8/50. 80% of reports were deemed to have major clinical significance. Average (laboratory and pathologist) coast was £130.47 respectively (in 2009), excluding lymphoma investigations and corporate costs and current charges in the UK vary between £150 and £250 per case for slide/block reviews. The author would argue that the cost of referral appears is offset by a high level of definitive diagnosis, negating further investigation. Average turnaround time was 5 days, excluding those over holidays, with 80% reported within 7 days. Prolonged reporting times were mainly due to those referring not sending blocks or unstained slides, necessitating further despatch of material. There is also additional delay when cases require molecular analysis. With the advance of digital pathology, this has potential to facilitate and speed up external opinions, although is still in its infancy. This is because referrals often comprise numerous slides which are still quicker to send and review via the microscope than scan and then go through remotely. However, for single or small numbers of slides, the technology has greater potential. Finally, the question is often asked what happens when the putative specialists are unable to make a diagnosis. In the author’s experience, some are undiagnosable for practical reasons, such as poor fixation, whilst some are sufficiently complex and unusual that a further collective opinion from fellow specialists is obtained and fed back to the referring pathologist. This is often after much emailing and debate!

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      MTE04.2 - Submit Your Challenging Cases for Discussion & Debate! (ID 597)

      07:30 - 08:00  |  Author(s): K. Jones

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    MTE04 - Submit Your Challenging Cases for Discussion & Debate! (ID 48)

    • Event: WCLC 2013
    • Type: Meet the Expert (ticketed session)
    • Track: Pathology
    • Presentations: 1
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      Cases (ID 5658)

      08:00 - 08:20  |  Author(s): E. Duhig

      • Abstract
      • Slides

      Abstract not provided

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    P3.01 - Poster Session 3 - Cancer Biology (ID 147)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.01-011 - Heterogeneity in tumour content and necrosis in primary lung cancers: Implications for molecular analysis (ID 3326)

      09:30 - 09:30  |  Author(s): E. Duhig

      • Abstract

      Background
      Lung adenocarcinoma (AC) and squamous cell carcinoma (SCC) tumours have a large variance in tumour cell content. This heterogeneity is a concern for genomic studies, as it is difficult to distinguish mutational differences between tumour and non-tumour if low percentage tumour is used for analysis. In addition to this, tumour samples are affected by the amount of necrosis present, as the overall number of viable cells is decreased. We assessed tumour and necrotic content in lung tumour specimens from AC and SCC patients and aimed to identify possible implications for the suitability of these samples in molecular characterisation studies using next generation sequencing technology.

      Methods
      Lung tissue specimens were collected during the period of 1990 to 2013 from patients at The Prince Charles Hospital who consented to donate their surgically resected lung tissues for research. Tissues were macroscopically dissected, snap frozen in liquid nitrogen and stored at -80°C. A tissue section was taken and stained with haematoxylin and eosin (H&E) for two pathologists to independently assess tumour cell and necrotic content. Tumour cell content (TC) in each specimen was scored as percentage of viable cells as seen on the H&E slide, where necrotic content (NC) was recorded as a percentage of the whole slide section. Statistics were calculated using SPSS v21 software. Tumour specimens screened for eligibility to The Cancer Genome Atlas sequencing project are presented here.

      Results
      Tumours from 62 AC and 104 SCC subjects were scored (specimen characteristics in Table 1). Scoring between the two pathologists was highly correlated, with a high intraclass reliability (0.94 and 0.96 for TC and NC respectively).

      Table 1: Clinical and Pathological Characteristics of Specimens
      AC SCC
      Number of Specimens 384 609
      Number of Males/Females 36/26 84/20
      Median Specimens per Subject 4 4
      Range of Specimens per Subject 1-25 1-27
      Median TC 35% 30%
      Range of TC 0-88% 0-90%
      Median NC 0% 6%
      Range of NC 0-90% 0-100%
      Median Age 62 yrs 68 yrs
      Range of Age 45-85 yrs 46-91 yrs
      Median Smoking Pack Years 40 56
      Range of Smoking Pack Years 0-115 0-158
      TC varied from 0-~90% for both subtypes. Comparing AC and SCC, the median TC was higher in AC than SCC (35% vs 30% respectively, p<0.05). NC varied from 0-~100%, but was generally low. The median NC was statistically significantly different between AC and SCC (0% and 6% respectively, p<0.001). TC was weakly correlated with NC (Spearman Rank r = 0.32, p<0.01). There were no clinically important correlations between smoking pack years, gender or age with TC and NC of specimens.

      Conclusion
      Lung AC and SCC specimens are heterogeneous in terms of TC and NC. Therefore, only a small proportion of resected lung cancer specimens meet the criteria required for massively parallel sequencing projects that require high quality tumour DNA and RNA (ie low NC) and relatively low stromal contamination (ie high TC).