Special Articles
In Compressed Lung Tissue Microscopic Sections of Adenocarcinoma In Situ May Mimic Papillary Adenocarcinoma Erik Thunnissen, MD, PhD; Jeroen A. M. Belien, ¨ PhD; Keith M. Kerr, MD; Jin-Haeng Chung, MD, PhD; Douglas B. Flieder, MD; Masayuki Noguchi, MD; Yasushi Yatabe, MD, PhD; David M. Hwang, MD, PhD; Rutger J. Lely, MD; Koen J. Hartemink, MD, PhD; Lorine B. Meijer-Jorna, MD, PhD; Ming-Sound Tsao, MD, PhD
Context.—Surgical removal and pathologic handling of lung tissue has a compressive effect upon its architecture. The effect of surgical atelectasis on morphology has not been examined in depth, especially with respect to lung adenocarcinomas. Objective.—To examine the influence of surgical atelectasis on morphologic lepidic growth pattern, mimicking papillary adenocarcinoma pattern. Design.—In 2 cases serial sections of resected pulmonary adenocarcinoma were used, as was a 3-dimensional reconstruction. Elastin stains were performed on primary and metastatic adenocarcinomas. Results.—Perfusion fixation of another case showed marked morphologic differences of less compressed
peripheral lung tissue, emphasizing the preexisting alveolar structure. An elastic stain may help identify true lesional architecture. Conclusions.—We demonstrate that microscopic sections of adenocarcinoma in situ in compressed/collapsed tissue may give rise to a pseudopapillary pattern mimicking invasive adenocarcinoma. Accurate appreciation of different tumor architecture in lung adenocarcinoma has important biologic and clinical implications. Pathologists should be aware of the possibility of misclassification of adenocarcinoma pattern due to tissue artifacts caused by lung tissue handling. (Arch Pathol Lab Med. 2013;137:1792–1797; doi: 10.5858/arpa.2012-0613-SA)
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lobectomy, and pneumonectomy. Especially during videoassisted thoracoscopic surgery procedures, visualization of the surgical field is seriously hampered by a ventilated lung.1,2 Deflation of the surgical lung is achieved by doublelumen endotracheal intubation, allowing selective ventilation of the nonsurgical lung. Such surgical atelectasis of the peripheral lung results in narrow air spaces between compressed alveolar walls. To reduce this effect, perfusion fixation in the pathology laboratory may be used to reexpand the alveoli, thereby restoring the lung volume of the resection specimen. The effect of surgical atelectasis on morphology has not been examined in depth, especially with respect to lung adenocarcinomas. The World Health Organization classification of lung cancer is based on resection specimen examination.3 The preoperative diagnosis of lung cancer is, however, made using cytology and small biopsy samples obtained by various means.4 The recent multidisciplinary classification of lung adenocarcinoma extends the classification to such small samples, but this addresses cellular phenotype rather than tumor architecture.5 In the morphologic classification, primarily of surgically resected tumors, 5 invasive tumor patterns are recognized: adenocarcinoma with lepidic growth pattern, acinar pattern, papillary pattern, micropapillary pattern, and solid pattern with mucin. In general, reproducibility is good, but in some areas discrepancies may exist.6 When the lesion is purely lepidic and 3 cm or less in diameter, a diagnosis of adenocarcinoma in situ (AIS) is
urgical removal and pathologic handing of resected lung tissue may have a compressive effect on the alveolar lung tissue, distorting its architecture. To facilitate a pulmonary resection and improve access in the thoracic cavity, the lung is usually deflated during segmentectomy,
Accepted for publication March 9, 2013. Supplemental digital content is available for this article at www. archivesofpathology.org in the December 2013 Table of Contents. From the Departments of Pathology (Drs Thunnissen and Belie¨ n), Radiology (Dr Lely), and Surgery (Dr Hartemink), VU University Medical Center, Amsterdam, the Netherlands; the Department of Pathology, Aberdeen Royal Infirmary, Aberdeen University Medical School, Aberdeen, Scotland (Dr Kerr); the Department of Pathology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea (Dr Chung); the Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania (Dr Flieder); the Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan (Dr Noguchi); the Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan (Dr Yatabe); the Department of Pathology, University Health Network-Princess Margaret Hospital and University of Toronto, Toronto, Ontario, Canada (Drs Hwang and Tsao); and the Department of Pathology, Symbiant/Medical Center Alkmaar, Alkmaar, the Netherlands (Dr Meijer-Jorna). The authors have no relevant financial interest in the products or companies described in this article. Corresponding author: Erik Thunnissen, MD, PhD, Department of Pathology, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands (e-mail: e.thunnissen@ vumc.nl). 1792 Arch Pathol Lab Med—Vol 137, December 2013
AIS Mimics Lung Papillary Adenocarcinoma—Thunnissen et al
given. Such a lesion is now considered a noninvasive carcinoma with a 100% 5-year survival rate. Morphologic distinctions therefore carry great clinical relevance. We present 2 cases with lepidic growth, mimicking papillary pattern, and use a 3-dimensional (3D) reconstruction and serial sections to arrive at the correct diagnosis. MATERIALS AND METHODS Two cases with lepidic pattern and showing elastin in the fibrovascular cores are described. The effect of surgical resection on morphology of peripheral lung tissue is investigated in an additional case with perfusion fixation. Because conceptually elastin fibers are not the consequence of neoplastic papillary carcinoma, metastases of papillary lung carcinomas were examined for the presence of elastin fibers. All samples were used in compliance with the respective institutional ethics regulations.
Case 1 A female patient age 57 years with a smoking history of more than 20 pack-years was treated for breast cancer in 2005. She presented with cough and right lower lobe pneumonia. Computed tomography (CT) scan showed a 1.2-cm, semisolid lesion (Figure 1). The positron emission tomography scan result was negative for FDG uptake. Repeat CT scan after 3 months revealed growth of the lesion, and a transthoracic needle biopsy was performed, from which a diagnosis of nonmucinous adenocarcinoma in situ (AIS, formerly bronchioloalveolar carcinoma2) was made. Subsequently, a right lower lobectomy and a mediastinal lymph node dissection were performed. Gross examination of the 11 3 6 3 5 cm uninflated right lower lobe demonstrated a 1.1-cm tumor 1.5 cm from overlying visceral pleura. After formalin fixation and paraffin embedding, sections were cut and stained with hematoxylin-eosin (H&E) and elastic (Elastic Van Gieson) stains. Morphologic assessment revealed compressed peripheral lung tissue occupied by an apparent papillary pattern adenocarcinoma with peripheral lepidic growth. The carcinoma was positive for thyroid transcription factor-1 but negative for mucin. For preparation of a 3D reconstruction a total of 60 serial sections of 4-lm thickness were cut from the case 1 resection specimen. Every other slide was stained with H&E. The H&E slides were digitized (320 objective) with the Mirax Scan system (3DHISTECH, Budapest, Hungary). The panoramic viewer software in combination with the 3D module (3DHISTECH) was used to make a 3D reconstruction (Jeroen A. M. Belien). ¨
Case 2 An 82-year-old man with a past medical history of emphysema and remote myocardial infarction underwent thoracoscopic left apical segmentectomy for resection of a spiculated left upper lobe mass. At gross examination, the uninflated 19 3 7 3 4.5 cm segment of lung showed moderate emphysema and contained a 4.5 3 4.0 3 3.0 cm tumor. Histologic examination confirmed this tumor to be a squamous cell carcinoma. Following formalin fixation, an ill-defined firm area was noted 2.5 cm from the tumor. Initial H&E sections from this lesion documented the presence of an adenocarcinoma demonstrating extensive lepidic growth as well as areas demonstrating apparent papillary pattern growth. Serial 4lm sections of this lesion were cut and stained in an alternating manner with H&E, elastic trichrome, and cytokeratin 7 (1:200; OVTL12/30 mouse monoclonal antibody, Dako, Burlington, Ontario, Canada), using the Ventana BenchMark Autostainer (Tucson, Arizona).
RESULTS The high-resolution CT scan of case 1 showed a partly solid nodule with prominent ground-glass opacity (Figure 1). A retrospective review of the CT scan from case 2 Arch Pathol Lab Med—Vol 137, December 2013
Figure 1. High-resolution computed tomography scan at 2 levels (approximately 10–20% of the normal size) shows a 1.2-cm tumor in the right lower lobe, with more ground-glass opacity in a lower section (A) and a more solid aspect in a higher section (B).
revealed a similar abnormality adjacent to the dominant squamous cell carcinoma. In case 1, the lobectomy specimen revealed compressed alveolar tissue and a 0.9-cm tumor with an apparent papillary pattern on histology (Figure 2, A through D). Alveolar airspaces were difficult to identify. The content of the tumor stroma component resembled that of the adjacent peripheral lung tissue, except for the lining of tumor cells. At the edge of the tumor the stroma component merged imperceptibly with the preexisting alveolar walls. Elastin fibers were present in a discontinuous fashion with a distribution in the tumor similar to that in the adjacent peripheral lung tissue. In 3D reconstruction, ‘‘papillae’’ appeared to be continuous in space, with thin walls (movie with series of still images; Figure 3 ¼ Video, Supplemental Digital Content [found at www.archivesofpathology.org in the December 2013 table of contents]). Moreover, this architecture was AIS Mimics Lung Papillary Adenocarcinoma—Thunnissen et al 1793
Figure 2. Histologic image of resection specimen shows hematoxylin-eosin (H&E) stain of center (A) and periphery (B), and elastic stain of center (C) and periphery (D). Gross cut sections of deflated lobectomy specimen (E) with a width of approximately 4 cm (, 30% compared with the in vivo situation). An H&E image of compressed peripheral lung tissue (F), and from the same lung, infusion fixed part (G). An elastic stain of papillary lung carcinoma metastasis from another patient showing fibrovascular core without elastin fibers (H). The inset shows a small artery with elastin fibers (original magnifications 35 [A, B, F, and G], 310 [C, H, and inset in H], and 340 [D]). 1794 Arch Pathol Lab Med—Vol 137, December 2013
AIS Mimics Lung Papillary Adenocarcinoma—Thunnissen et al
Figure 4. Pseudopapillary structures in nonneoplastic lung parenchyma damaged by emphysematous process and in adenocarcinoma in situ arising in lung with preexisting parenchymal remodeling. Low-magnification view of tumor and adjacent remodeled nonneoplastic lung parenchyma (hematoxylin-eosin [A], elastic trichrome [B], and cytokeratin 7 [C], original magnifications 32.5).
similar to that of the adjacent lung. Because the distance between H&E sections was 8 lm, the seemingly papillary structures that could be followed through different levels were continuous. For more than 6 levels, this amounts to more than 48 lm demonstrating a thin fibrovascular layer (alveolar wall) on 2 sides covered with epithelial cells. True papillae were not found in any of the sections. Thus, the 2D ‘‘papillary’’ pattern seen on the H&E section was created by sectioning of markedly compressed alveolar walls covered with monotonous tumor cells. This artifact in the lesion architecture led to an erroneous diagnosis of papillary adenocarcinoma rather than lepidic pattern disease. The entire resection specimen was examined, and no invasive tumor was identified. To provide further evidence that AIS may give rise to pseudopapillary appearances in lung parenchyma with emphysematous damage and remodelling, digital images of areas of apparent papillary growth in serial sections of tumor from case 2 were aligned by visual inspection (Figures 4 and 5), following alternate staining by H&E, elastic trichrome, and cytokeratin 7 immunohistochemistry. In the tumor area, apparent papillary structures were noted to contain elastic fibers and to connect with alveolar septa, confirming that these are pseudopapillae rather than true papillae. This likely resulted from tumor cells growing lepidically along collapsed and damaged emphysematous alveolar septa. Alveolar septa in adjacent nonneoplastic emphysematous lung also featured this ‘‘pseudopapillary’’ appearance. To further investigate this apparent morphologic difference, the effect of surgical atelectasis was explored. A typical deflated lobectomy specimen has a width of less than 30% compared with an in vivo situation (Figure 2, E). A deflated lobectomy specimen from another patient with lung cancer was studied. Neutral-buffered formalin solution was injected transpleurally, using a 50-mL syringe and a 15-gauge needle. This procedure expanded a segment of lung within the lobectomy specimen. Subsequently, the whole specimen was immersed in neutral-buffered formalin for 24 hours, then sectioned according to usual practice. The architectural Arch Pathol Lab Med—Vol 137, December 2013
difference in morphologic appearance between the noninflated and the injection-inflated peripheral lung tissue is shown in Figure 2, F and G, respectively. Furthermore, to examine whether elastin fibers are present in papillary adenocarcinoma tumor of the lung, metastases of pulmonary papillary adenocarcinomas that were hematogenic to the brain and skull (n ¼ 2, respectively) and to the regional lymph nodes (n ¼ 4) were stained with elastin (Figure 2, H). Except for elastin in a small artery, elastin fibers are absent in the stromal part of the papillary metastases, suggesting that the formation of elastin is not part of the metastatic tumor process and not an inherent part of the papillary adenocarcinoma structure. COMMENT The 3D reconstruction of a peripheral lung carcinoma showing a semisolid nodule on CT scan and having a seemingly papillary pattern morphologically revealed architectural continuity, indicating folding of preexisting alveolar walls rather than tumoral papillary growth. Therefore, the correct diagnosis for case 1 is adenocarcinoma in situ, nonmucinous type. Limited reconstruction of the incidental case 2 nodule within a background of collapsed emphysematous lung tissue demonstrated similar continuity between apparent papillary structures and adjacent alveolar walls. This lesion therefore also represents an adenocarcinoma in situ of the nonmucinous type. The lack of ‘‘empty space’’ equivalent to air in vivo in the lobectomy specimen can be at least partially explained by the deflation effect from perioperative single-lung ventilation. Furthermore, during video-assisted thoracoscopic surgery procedures, the resection specimen is withdrawn from the thoracic cavity through a 3- to 7-cm incision. Although the plasticity of the lung permits this procedure, a lobe with a diameter greater than 10 cm is greatly compressed, and such lung squeezing gives rise to a ‘‘surgical atelectasis’’ artifact. If the open biopsy or resection specimen is not subsequently perfusion fixed, either through the bronchus or by injection through the visceral pleura, this artifact remains. This gives rise to a misleading morphologic AIS Mimics Lung Papillary Adenocarcinoma—Thunnissen et al 1795
Figure 5. Serial sections (1–9) of the same tumor as shown in Figure 4, alternately stained with hematoxylin-eosin (A, D, and G), elastic trichrome (D, E, and H), and cytokeratin 7 (C, F, and I) immunohistochemistry. Apparent papillary structures were seen to connect with alveolar septae, confirming these to be pseudopapillae rather than true papillae, resulting from tumor cells growing lepidically along collapsed, emphysematously distorted alveolar septae (original magnifications 310).
appearance of a central papillary pattern, whereas at the periphery a lepidic pattern is present. For frozen-section analysis a procedure for injection perfusion has recently been described.7 This deflation artifact may not occur to the same extent during transthoracic biopsy procedures. The radiologic appearance of a papillary tumor on highresolution CT scan may be partly solid, but a ground-glass opacity also is seen,8 depending on the amount of air present within the lesion. Moreover, the solid components may correspond not only to collapse and fibrosis, but also to severe narrowing or reduction of air spaces.8 In vivo, alveolar air volume is at a functional minimum at the end of maximal expiration. Hypothetically, in AIS alveolar wall rigidity may be increased by a compact layer of tall, columnar tumor cells lying upon the alveolar basement membrane. In such lesions the alveolar interstitium may also be thickened. This reduction in tumor lesional tissue compliance may lead to a degree of collapse of the lesion even before there is any additive effect of surgical atelectasis. In AIS, structural collapse of the alveolar network may also be associated with fibroelastosis, further compounding this appearance and possibly giving a ‘‘solid’’ appearance on the CT scan image. Moreover, in comparing radiologic and 1796 Arch Pathol Lab Med—Vol 137, December 2013
pathologic size measurements, these surgical artifacts may lead to the lesional diameter as measured in the surgical resection sample being less than those on the CT scan. This may be compounded by shrinkage artifact after formalin fixation and paraffin embedding. In histologic sections of normal lung, elastin fibers are visible in a discontinuous manner within alveolar walls.9 Elastin fibers are not present in papillary tumors of other organs, nor are they present in metastases of papillary adenocarcinoma of the lung. In papillary tumors of the lung with very thin fibrovascular cores containing elastin fibers, it is highly likely that these cores are part of the preexisting alveolar wall. The alternative option requires a molecular biologic explanation for the formation of elastin fibers only in primary papillary lung carcinomas, but not in papillary pulmonary adenocarcinoma metastases or in papillary tumors of other organs. Published descriptions of pulmonary papillary carcinoma are of interest. In the oft-quoted 1997 publication, a prominent desmoplastic stroma is described in lesions that were clearly destructive to the underlying lung architecture.10 The 2004 World Health Organization classification states, ‘‘The papillary pattern is characterized by papillae AIS Mimics Lung Papillary Adenocarcinoma—Thunnissen et al
with secondary and tertiary papillary structures that replace the underlying architecture. Bronchioloalveolar carcinomas that have simple papillary structures with intact alveolar structures are excluded from this definition.’’ 3 These 2 sentences already suggest some morphologic resemblance between the 2 patterns. In 2011 the International Multidisciplinary Classification Lung Adenocarcinoma Classification added that ‘‘myofibroblastic stroma is not needed to diagnose this pattern.’’ 5 In morphologic terms, the current definition of a papillary pattern has moved a considerable distance from the original publications. The lack of emphasis on the stromal and vascular components of a true tumor papilla risks further confusion between collapsed lepidic tumor and true papillary adenocarcinoma. The description of papillary predominant adenocarcinoma in the new recommended classification states that ‘‘a major component of a growth of glandular cells [is] along central fibrovascular cores. If a tumor has lepidic growth but the alveolar spaces are filled with papillary structures, the tumor is classified as papillary adenocarcinoma. Myofibroblastic stroma is not needed to diagnose this pattern.’’ Although the 2D descriptions of our cases were consistent with this new classification under the heading of papillary carcinoma, 3D reconstruction does not support this definition, and such tumors are, in reality, AIS, nonmucinous type. This is based on the fact that (1) air spaces are reduced, giving rise to collapsed lung with pseudopapillary appearance of the lepidic growth, and (2) elastin stains highlight preexisting alveolar structure.11 The chances of finding numerous true papillary structures with fibrovascular cores extending to the base of each papilla in a single 4-lm section are very remote, given their size and the expectations that the core extends to the base at a single point and there is circumferential lining of tumor cells in 3 dimensions. This is not the first report to recognize that 2 potential patterns fall under the description of papillary carcinoma. Jian and colleagues11 reported 1 subtype closely related to the morphology of bronchioloalveolar carcinoma. The use of 3D reconstruction is not necessary to recognize this pattern, but elastic stain facilitates the recognition of the (2D seemingly discontinuous) elastic fibers of the preexisting lung. It should be recognized that in specimens where the alveolar tissues are compressed or deflated, a pseudopapillary pattern may be evident where tumor cells appear to line central fibrovascular cores. These cores generally lack a myofibroblastic stroma but do show elastic fibers. The lack of abundant rounded ‘‘unattached’’ papillae and an obvious lepidic pattern where the lesion is less compressed are clues to the correct diagnosis of AIS. Adenocarcinoma in situ less than 3 cm is associated with a 100% 5-year survival rate. This tumor is considered pTis. A papillary predominant adenocarcinoma is by definition an invasive carcinoma with a less than 100% 5-year survival rate and is considered pT1 through T3, depending on its size and other parameters. For the patient this difference has important implications, and it serves to emphasize the importance of not overdiagnosing invasive disease. Moreover, a prognostic difference exists between lesions fitting the initial description of papillary carcinoma10—these lesions do worse than those fulfilling criteria laid out in the World Health Organization 2004 classification, which appear to have a better-than-average prognosis.12,13 It is also possible that confusion between papillary and AIS patterns of adenocarcinoma could explain why EGFR mutations are Arch Pathol Lab Med—Vol 137, December 2013
reported by some preferentially in papillary carcinomas,12,14 whereas others find the association (of EGFR mutations) with AIS (formerly bronchioloalveolar carcinoma)15–19 or in both.20 In conclusion, the accurate appreciation of different tumor architecture in lung adenocarcinoma has important biologic and clinical implications. Pathologists should be aware of the possibility of misclassification of adenocarcinoma pattern due to tissue artifacts caused by lung tissue handling and inadequate specimen preparation. The help of Marcia Mentar with cutting serial sections of the paraffin blocks is greatly appreciated. References 1. Wilson WC, Benumof JL. Anesthesia for thoracic surgery. In: Miller RD, ed. Anesthesia. 6th ed. Philadelphia, PA: Elsevier; 2005:1847–1940. 2. Heerdt DM, Triantafillou A, Yao FF. Bronchoscopy, mediastinoscopy, and thoracothomy. In: Yao FF, ed. Anesthesiology: Problem-Oriented Patient Management. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003: 32–49. 3. Travis WD, Brambilla E, Muller-Hermelink KM. Pathology and Genetics: Tumours of the Lung, Pleura, Thymus and Heart. Lyon, France: IARC; 2004. 4. Thunnissen E, Kerr KM, Herth FJ, et al. The challenge of NSCLC diagnosis and predictive analysis on small samples: practical approach of a working group. Lung Cancer. 2012;76(1):1–18. 5. Travis WD, Brambilla E, 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 Thorac Oncol. 2011;6(2):244–285. 6. Thunnissen E, Beasley MB, Borczuk AC, et al. Reproducibility of histopathological subtypes and invasion in pulmonary adenocarcinoma: an international interobserver study. Mod Pathol. 2012;25(12):1574–1583. 7. Xu X, Chung JH, Jheon S, et al. The accuracy of frozen section diagnosis of pulmonary nodules: evaluation of inflation method during intraoperative pathology consultation with cryosection. J Thorac Oncol. 2010;5(1):39–44. 8. Aoki T, Nakata H, Watanabe H, et al. Evolution of peripheral lung adenocarcinomas: CT findings correlated with histology and tumor doubling time. AJR Am J Roentgenol. 2000;174(3):763–768. 9. Borczuk AC. Assessment of invasion in lung adenocarcinoma classification, including adenocarcinoma in situ and minimally invasive adenocarcinoma. Mod Pathol. 2012;25(suppl 1):S1–S10. 10. Silver SA, Askin FB. True papillary carcinoma of the lung: a distinct clinicopathologic entity. Am J Surg Pathol. 1997;21(1):43–51. 11. Jian Z, Tomizawa Y, Yanagitani N, Iijima H, Sano T, Nakajima T. Papillary adenocarcinoma of the lung is a more advanced adenocarcinoma than bronchioloalveolar carcinoma that is composed of two distinct histological subtypes. Pathol Int. 2005;55(10):619–625. 12. Motoi N, Szoke J, Riely GJ, et al. Lung adenocarcinoma: modification of the 2004 WHO mixed subtype to include the major histologic subtype suggests correlations between papillary and micropapillary adenocarcinoma subtypes, EGFR mutations and gene expression analysis. Am J Surg Pathol. 2008;32(6):810– 827. 13. Russell PA, Wainer Z, Wright GM, Daniels M, Conron M, Williams RA. Does lung adenocarcinoma subtype predict patient survival?: a clinicopathologic study based on the new International Association for the Study of Lung Cancer/ American Thoracic Society/European Respiratory Society international multidisciplinary lung adenocarcinoma classification. J Thorac Oncol. 2011;6(9):1496– 1504. 14. Kim YH, Ishii G, Goto K, et al. Dominant papillary subtype is a significant predictor of the response to gefitinib in adenocarcinoma of the lung. Clin Cancer Res. 2004;10(21):7311–7317. 15. Matsumoto S, Iwakawa R, Kohno T, et al. Frequent EGFR mutations in noninvasive bronchioloalveolar carcinoma. Int J Cancer. 2006;118(10):2498– 2504. 16. Chantranuwat C, Sriuranpong V, Huapai N, et al. Histopathologic characteristics of pulmonary adenocarcinomas with and without EGFR mutation. J Med Assoc Thai. 2005;88(suppl 4):S322–S329. 17. Haneda H, Sasaki H, Lindeman N, et al. A correlation between EGFR gene mutation status and bronchioloalveolar carcinoma features in Japanese patients with adenocarcinoma. Jpn J Clin Oncol. 2006;36(2):69–75. 18. Blons H, Cote JF, Le Corre D, et al. Epidermal growth factor receptor mutation in lung cancer are linked to bronchioloalveolar differentiation. Am J Surg Pathol. 2006;30(10):1309–1315. 19. Zakowski MF, Hussain S, Pao W, et al. Morphologic features of adenocarcinoma of the lung predictive of response to the epidermal growth factor receptor kinase inhibitors erlotinib and gefitinib. Arch Pathol Lab Med. 2009;133(3):470–477. 20. Dacic S, Shuai Y, Yousem S, Ohori P, Nikiforova M. Clinicopathological predictors of EGFR/KRAS mutational status in primary lung adenocarcinomas. Mod Pathol. 2010;23(2):159–168.
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In Compressed Lung Tissue Microscopic Sections of Adenocarcinoma In Situ May Mimic Papillary Adenocarcinoma Erik Thunnissen, MD, PhD; Jeroen A. M. Belien, ¨ PhD; Keith M. Kerr, MD; Jin-Haeng Chung, MD, PhD; Douglas B. Flieder, MD; Masayuki Noguchi, MD; Yasushi Yatabe, MD, PhD; David M. Hwang, MD, PhD; Rutger J. Lely, MD; Koen J. Hartemink, MD, PhD; Lorine B. Meijer-Jorna, MD, PhD; Ming-Sound Tsao, MD, PhD
Context.—Surgical removal and pathologic handling of lung tissue has a compressive effect upon its architecture. The effect of surgical atelectasis on morphology has not been examined in depth, especially with respect to lung adenocarcinomas. Objective.—To examine the influence of surgical atelectasis on morphologic lepidic growth pattern, mimicking papillary adenocarcinoma pattern. Design.—In 2 cases serial sections of resected pulmonary adenocarcinoma were used, as was a 3-dimensional reconstruction. Elastin stains were performed on primary and metastatic adenocarcinomas. Results.—Perfusion fixation of another case showed marked morphologic differences of less compressed
peripheral lung tissue, emphasizing the preexisting alveolar structure. An elastic stain may help identify true lesional architecture. Conclusions.—We demonstrate that microscopic sections of adenocarcinoma in situ in compressed/collapsed tissue may give rise to a pseudopapillary pattern mimicking invasive adenocarcinoma. Accurate appreciation of different tumor architecture in lung adenocarcinoma has important biologic and clinical implications. Pathologists should be aware of the possibility of misclassification of adenocarcinoma pattern due to tissue artifacts caused by lung tissue handling. (Arch Pathol Lab Med. 2013;137:1792–1797; doi: 10.5858/arpa.2012-0613-SA)
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lobectomy, and pneumonectomy. Especially during videoassisted thoracoscopic surgery procedures, visualization of the surgical field is seriously hampered by a ventilated lung.1,2 Deflation of the surgical lung is achieved by doublelumen endotracheal intubation, allowing selective ventilation of the nonsurgical lung. Such surgical atelectasis of the peripheral lung results in narrow air spaces between compressed alveolar walls. To reduce this effect, perfusion fixation in the pathology laboratory may be used to reexpand the alveoli, thereby restoring the lung volume of the resection specimen. The effect of surgical atelectasis on morphology has not been examined in depth, especially with respect to lung adenocarcinomas. The World Health Organization classification of lung cancer is based on resection specimen examination.3 The preoperative diagnosis of lung cancer is, however, made using cytology and small biopsy samples obtained by various means.4 The recent multidisciplinary classification of lung adenocarcinoma extends the classification to such small samples, but this addresses cellular phenotype rather than tumor architecture.5 In the morphologic classification, primarily of surgically resected tumors, 5 invasive tumor patterns are recognized: adenocarcinoma with lepidic growth pattern, acinar pattern, papillary pattern, micropapillary pattern, and solid pattern with mucin. In general, reproducibility is good, but in some areas discrepancies may exist.6 When the lesion is purely lepidic and 3 cm or less in diameter, a diagnosis of adenocarcinoma in situ (AIS) is
urgical removal and pathologic handing of resected lung tissue may have a compressive effect on the alveolar lung tissue, distorting its architecture. To facilitate a pulmonary resection and improve access in the thoracic cavity, the lung is usually deflated during segmentectomy,
Accepted for publication March 9, 2013. Supplemental digital content is available for this article at www. archivesofpathology.org in the December 2013 Table of Contents. From the Departments of Pathology (Drs Thunnissen and Belie¨ n), Radiology (Dr Lely), and Surgery (Dr Hartemink), VU University Medical Center, Amsterdam, the Netherlands; the Department of Pathology, Aberdeen Royal Infirmary, Aberdeen University Medical School, Aberdeen, Scotland (Dr Kerr); the Department of Pathology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea (Dr Chung); the Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania (Dr Flieder); the Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan (Dr Noguchi); the Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan (Dr Yatabe); the Department of Pathology, University Health Network-Princess Margaret Hospital and University of Toronto, Toronto, Ontario, Canada (Drs Hwang and Tsao); and the Department of Pathology, Symbiant/Medical Center Alkmaar, Alkmaar, the Netherlands (Dr Meijer-Jorna). The authors have no relevant financial interest in the products or companies described in this article. Corresponding author: Erik Thunnissen, MD, PhD, Department of Pathology, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands (e-mail: e.thunnissen@ vumc.nl). 1792 Arch Pathol Lab Med—Vol 137, December 2013
AIS Mimics Lung Papillary Adenocarcinoma—Thunnissen et al
given. Such a lesion is now considered a noninvasive carcinoma with a 100% 5-year survival rate. Morphologic distinctions therefore carry great clinical relevance. We present 2 cases with lepidic growth, mimicking papillary pattern, and use a 3-dimensional (3D) reconstruction and serial sections to arrive at the correct diagnosis. MATERIALS AND METHODS Two cases with lepidic pattern and showing elastin in the fibrovascular cores are described. The effect of surgical resection on morphology of peripheral lung tissue is investigated in an additional case with perfusion fixation. Because conceptually elastin fibers are not the consequence of neoplastic papillary carcinoma, metastases of papillary lung carcinomas were examined for the presence of elastin fibers. All samples were used in compliance with the respective institutional ethics regulations.
Case 1 A female patient age 57 years with a smoking history of more than 20 pack-years was treated for breast cancer in 2005. She presented with cough and right lower lobe pneumonia. Computed tomography (CT) scan showed a 1.2-cm, semisolid lesion (Figure 1). The positron emission tomography scan result was negative for FDG uptake. Repeat CT scan after 3 months revealed growth of the lesion, and a transthoracic needle biopsy was performed, from which a diagnosis of nonmucinous adenocarcinoma in situ (AIS, formerly bronchioloalveolar carcinoma2) was made. Subsequently, a right lower lobectomy and a mediastinal lymph node dissection were performed. Gross examination of the 11 3 6 3 5 cm uninflated right lower lobe demonstrated a 1.1-cm tumor 1.5 cm from overlying visceral pleura. After formalin fixation and paraffin embedding, sections were cut and stained with hematoxylin-eosin (H&E) and elastic (Elastic Van Gieson) stains. Morphologic assessment revealed compressed peripheral lung tissue occupied by an apparent papillary pattern adenocarcinoma with peripheral lepidic growth. The carcinoma was positive for thyroid transcription factor-1 but negative for mucin. For preparation of a 3D reconstruction a total of 60 serial sections of 4-lm thickness were cut from the case 1 resection specimen. Every other slide was stained with H&E. The H&E slides were digitized (320 objective) with the Mirax Scan system (3DHISTECH, Budapest, Hungary). The panoramic viewer software in combination with the 3D module (3DHISTECH) was used to make a 3D reconstruction (Jeroen A. M. Belien). ¨
Case 2 An 82-year-old man with a past medical history of emphysema and remote myocardial infarction underwent thoracoscopic left apical segmentectomy for resection of a spiculated left upper lobe mass. At gross examination, the uninflated 19 3 7 3 4.5 cm segment of lung showed moderate emphysema and contained a 4.5 3 4.0 3 3.0 cm tumor. Histologic examination confirmed this tumor to be a squamous cell carcinoma. Following formalin fixation, an ill-defined firm area was noted 2.5 cm from the tumor. Initial H&E sections from this lesion documented the presence of an adenocarcinoma demonstrating extensive lepidic growth as well as areas demonstrating apparent papillary pattern growth. Serial 4lm sections of this lesion were cut and stained in an alternating manner with H&E, elastic trichrome, and cytokeratin 7 (1:200; OVTL12/30 mouse monoclonal antibody, Dako, Burlington, Ontario, Canada), using the Ventana BenchMark Autostainer (Tucson, Arizona).
RESULTS The high-resolution CT scan of case 1 showed a partly solid nodule with prominent ground-glass opacity (Figure 1). A retrospective review of the CT scan from case 2 Arch Pathol Lab Med—Vol 137, December 2013
Figure 1. High-resolution computed tomography scan at 2 levels (approximately 10–20% of the normal size) shows a 1.2-cm tumor in the right lower lobe, with more ground-glass opacity in a lower section (A) and a more solid aspect in a higher section (B).
revealed a similar abnormality adjacent to the dominant squamous cell carcinoma. In case 1, the lobectomy specimen revealed compressed alveolar tissue and a 0.9-cm tumor with an apparent papillary pattern on histology (Figure 2, A through D). Alveolar airspaces were difficult to identify. The content of the tumor stroma component resembled that of the adjacent peripheral lung tissue, except for the lining of tumor cells. At the edge of the tumor the stroma component merged imperceptibly with the preexisting alveolar walls. Elastin fibers were present in a discontinuous fashion with a distribution in the tumor similar to that in the adjacent peripheral lung tissue. In 3D reconstruction, ‘‘papillae’’ appeared to be continuous in space, with thin walls (movie with series of still images; Figure 3 ¼ Video, Supplemental Digital Content [found at www.archivesofpathology.org in the December 2013 table of contents]). Moreover, this architecture was AIS Mimics Lung Papillary Adenocarcinoma—Thunnissen et al 1793
Figure 2. Histologic image of resection specimen shows hematoxylin-eosin (H&E) stain of center (A) and periphery (B), and elastic stain of center (C) and periphery (D). Gross cut sections of deflated lobectomy specimen (E) with a width of approximately 4 cm (, 30% compared with the in vivo situation). An H&E image of compressed peripheral lung tissue (F), and from the same lung, infusion fixed part (G). An elastic stain of papillary lung carcinoma metastasis from another patient showing fibrovascular core without elastin fibers (H). The inset shows a small artery with elastin fibers (original magnifications 35 [A, B, F, and G], 310 [C, H, and inset in H], and 340 [D]). 1794 Arch Pathol Lab Med—Vol 137, December 2013
AIS Mimics Lung Papillary Adenocarcinoma—Thunnissen et al
Figure 4. Pseudopapillary structures in nonneoplastic lung parenchyma damaged by emphysematous process and in adenocarcinoma in situ arising in lung with preexisting parenchymal remodeling. Low-magnification view of tumor and adjacent remodeled nonneoplastic lung parenchyma (hematoxylin-eosin [A], elastic trichrome [B], and cytokeratin 7 [C], original magnifications 32.5).
similar to that of the adjacent lung. Because the distance between H&E sections was 8 lm, the seemingly papillary structures that could be followed through different levels were continuous. For more than 6 levels, this amounts to more than 48 lm demonstrating a thin fibrovascular layer (alveolar wall) on 2 sides covered with epithelial cells. True papillae were not found in any of the sections. Thus, the 2D ‘‘papillary’’ pattern seen on the H&E section was created by sectioning of markedly compressed alveolar walls covered with monotonous tumor cells. This artifact in the lesion architecture led to an erroneous diagnosis of papillary adenocarcinoma rather than lepidic pattern disease. The entire resection specimen was examined, and no invasive tumor was identified. To provide further evidence that AIS may give rise to pseudopapillary appearances in lung parenchyma with emphysematous damage and remodelling, digital images of areas of apparent papillary growth in serial sections of tumor from case 2 were aligned by visual inspection (Figures 4 and 5), following alternate staining by H&E, elastic trichrome, and cytokeratin 7 immunohistochemistry. In the tumor area, apparent papillary structures were noted to contain elastic fibers and to connect with alveolar septa, confirming that these are pseudopapillae rather than true papillae. This likely resulted from tumor cells growing lepidically along collapsed and damaged emphysematous alveolar septa. Alveolar septa in adjacent nonneoplastic emphysematous lung also featured this ‘‘pseudopapillary’’ appearance. To further investigate this apparent morphologic difference, the effect of surgical atelectasis was explored. A typical deflated lobectomy specimen has a width of less than 30% compared with an in vivo situation (Figure 2, E). A deflated lobectomy specimen from another patient with lung cancer was studied. Neutral-buffered formalin solution was injected transpleurally, using a 50-mL syringe and a 15-gauge needle. This procedure expanded a segment of lung within the lobectomy specimen. Subsequently, the whole specimen was immersed in neutral-buffered formalin for 24 hours, then sectioned according to usual practice. The architectural Arch Pathol Lab Med—Vol 137, December 2013
difference in morphologic appearance between the noninflated and the injection-inflated peripheral lung tissue is shown in Figure 2, F and G, respectively. Furthermore, to examine whether elastin fibers are present in papillary adenocarcinoma tumor of the lung, metastases of pulmonary papillary adenocarcinomas that were hematogenic to the brain and skull (n ¼ 2, respectively) and to the regional lymph nodes (n ¼ 4) were stained with elastin (Figure 2, H). Except for elastin in a small artery, elastin fibers are absent in the stromal part of the papillary metastases, suggesting that the formation of elastin is not part of the metastatic tumor process and not an inherent part of the papillary adenocarcinoma structure. COMMENT The 3D reconstruction of a peripheral lung carcinoma showing a semisolid nodule on CT scan and having a seemingly papillary pattern morphologically revealed architectural continuity, indicating folding of preexisting alveolar walls rather than tumoral papillary growth. Therefore, the correct diagnosis for case 1 is adenocarcinoma in situ, nonmucinous type. Limited reconstruction of the incidental case 2 nodule within a background of collapsed emphysematous lung tissue demonstrated similar continuity between apparent papillary structures and adjacent alveolar walls. This lesion therefore also represents an adenocarcinoma in situ of the nonmucinous type. The lack of ‘‘empty space’’ equivalent to air in vivo in the lobectomy specimen can be at least partially explained by the deflation effect from perioperative single-lung ventilation. Furthermore, during video-assisted thoracoscopic surgery procedures, the resection specimen is withdrawn from the thoracic cavity through a 3- to 7-cm incision. Although the plasticity of the lung permits this procedure, a lobe with a diameter greater than 10 cm is greatly compressed, and such lung squeezing gives rise to a ‘‘surgical atelectasis’’ artifact. If the open biopsy or resection specimen is not subsequently perfusion fixed, either through the bronchus or by injection through the visceral pleura, this artifact remains. This gives rise to a misleading morphologic AIS Mimics Lung Papillary Adenocarcinoma—Thunnissen et al 1795
Figure 5. Serial sections (1–9) of the same tumor as shown in Figure 4, alternately stained with hematoxylin-eosin (A, D, and G), elastic trichrome (D, E, and H), and cytokeratin 7 (C, F, and I) immunohistochemistry. Apparent papillary structures were seen to connect with alveolar septae, confirming these to be pseudopapillae rather than true papillae, resulting from tumor cells growing lepidically along collapsed, emphysematously distorted alveolar septae (original magnifications 310).
appearance of a central papillary pattern, whereas at the periphery a lepidic pattern is present. For frozen-section analysis a procedure for injection perfusion has recently been described.7 This deflation artifact may not occur to the same extent during transthoracic biopsy procedures. The radiologic appearance of a papillary tumor on highresolution CT scan may be partly solid, but a ground-glass opacity also is seen,8 depending on the amount of air present within the lesion. Moreover, the solid components may correspond not only to collapse and fibrosis, but also to severe narrowing or reduction of air spaces.8 In vivo, alveolar air volume is at a functional minimum at the end of maximal expiration. Hypothetically, in AIS alveolar wall rigidity may be increased by a compact layer of tall, columnar tumor cells lying upon the alveolar basement membrane. In such lesions the alveolar interstitium may also be thickened. This reduction in tumor lesional tissue compliance may lead to a degree of collapse of the lesion even before there is any additive effect of surgical atelectasis. In AIS, structural collapse of the alveolar network may also be associated with fibroelastosis, further compounding this appearance and possibly giving a ‘‘solid’’ appearance on the CT scan image. Moreover, in comparing radiologic and 1796 Arch Pathol Lab Med—Vol 137, December 2013
pathologic size measurements, these surgical artifacts may lead to the lesional diameter as measured in the surgical resection sample being less than those on the CT scan. This may be compounded by shrinkage artifact after formalin fixation and paraffin embedding. In histologic sections of normal lung, elastin fibers are visible in a discontinuous manner within alveolar walls.9 Elastin fibers are not present in papillary tumors of other organs, nor are they present in metastases of papillary adenocarcinoma of the lung. In papillary tumors of the lung with very thin fibrovascular cores containing elastin fibers, it is highly likely that these cores are part of the preexisting alveolar wall. The alternative option requires a molecular biologic explanation for the formation of elastin fibers only in primary papillary lung carcinomas, but not in papillary pulmonary adenocarcinoma metastases or in papillary tumors of other organs. Published descriptions of pulmonary papillary carcinoma are of interest. In the oft-quoted 1997 publication, a prominent desmoplastic stroma is described in lesions that were clearly destructive to the underlying lung architecture.10 The 2004 World Health Organization classification states, ‘‘The papillary pattern is characterized by papillae AIS Mimics Lung Papillary Adenocarcinoma—Thunnissen et al
with secondary and tertiary papillary structures that replace the underlying architecture. Bronchioloalveolar carcinomas that have simple papillary structures with intact alveolar structures are excluded from this definition.’’ 3 These 2 sentences already suggest some morphologic resemblance between the 2 patterns. In 2011 the International Multidisciplinary Classification Lung Adenocarcinoma Classification added that ‘‘myofibroblastic stroma is not needed to diagnose this pattern.’’ 5 In morphologic terms, the current definition of a papillary pattern has moved a considerable distance from the original publications. The lack of emphasis on the stromal and vascular components of a true tumor papilla risks further confusion between collapsed lepidic tumor and true papillary adenocarcinoma. The description of papillary predominant adenocarcinoma in the new recommended classification states that ‘‘a major component of a growth of glandular cells [is] along central fibrovascular cores. If a tumor has lepidic growth but the alveolar spaces are filled with papillary structures, the tumor is classified as papillary adenocarcinoma. Myofibroblastic stroma is not needed to diagnose this pattern.’’ Although the 2D descriptions of our cases were consistent with this new classification under the heading of papillary carcinoma, 3D reconstruction does not support this definition, and such tumors are, in reality, AIS, nonmucinous type. This is based on the fact that (1) air spaces are reduced, giving rise to collapsed lung with pseudopapillary appearance of the lepidic growth, and (2) elastin stains highlight preexisting alveolar structure.11 The chances of finding numerous true papillary structures with fibrovascular cores extending to the base of each papilla in a single 4-lm section are very remote, given their size and the expectations that the core extends to the base at a single point and there is circumferential lining of tumor cells in 3 dimensions. This is not the first report to recognize that 2 potential patterns fall under the description of papillary carcinoma. Jian and colleagues11 reported 1 subtype closely related to the morphology of bronchioloalveolar carcinoma. The use of 3D reconstruction is not necessary to recognize this pattern, but elastic stain facilitates the recognition of the (2D seemingly discontinuous) elastic fibers of the preexisting lung. It should be recognized that in specimens where the alveolar tissues are compressed or deflated, a pseudopapillary pattern may be evident where tumor cells appear to line central fibrovascular cores. These cores generally lack a myofibroblastic stroma but do show elastic fibers. The lack of abundant rounded ‘‘unattached’’ papillae and an obvious lepidic pattern where the lesion is less compressed are clues to the correct diagnosis of AIS. Adenocarcinoma in situ less than 3 cm is associated with a 100% 5-year survival rate. This tumor is considered pTis. A papillary predominant adenocarcinoma is by definition an invasive carcinoma with a less than 100% 5-year survival rate and is considered pT1 through T3, depending on its size and other parameters. For the patient this difference has important implications, and it serves to emphasize the importance of not overdiagnosing invasive disease. Moreover, a prognostic difference exists between lesions fitting the initial description of papillary carcinoma10—these lesions do worse than those fulfilling criteria laid out in the World Health Organization 2004 classification, which appear to have a better-than-average prognosis.12,13 It is also possible that confusion between papillary and AIS patterns of adenocarcinoma could explain why EGFR mutations are Arch Pathol Lab Med—Vol 137, December 2013
reported by some preferentially in papillary carcinomas,12,14 whereas others find the association (of EGFR mutations) with AIS (formerly bronchioloalveolar carcinoma)15–19 or in both.20 In conclusion, the accurate appreciation of different tumor architecture in lung adenocarcinoma has important biologic and clinical implications. Pathologists should be aware of the possibility of misclassification of adenocarcinoma pattern due to tissue artifacts caused by lung tissue handling and inadequate specimen preparation. The help of Marcia Mentar with cutting serial sections of the paraffin blocks is greatly appreciated. References 1. Wilson WC, Benumof JL. Anesthesia for thoracic surgery. In: Miller RD, ed. Anesthesia. 6th ed. Philadelphia, PA: Elsevier; 2005:1847–1940. 2. Heerdt DM, Triantafillou A, Yao FF. Bronchoscopy, mediastinoscopy, and thoracothomy. In: Yao FF, ed. Anesthesiology: Problem-Oriented Patient Management. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003: 32–49. 3. Travis WD, Brambilla E, Muller-Hermelink KM. Pathology and Genetics: Tumours of the Lung, Pleura, Thymus and Heart. Lyon, France: IARC; 2004. 4. Thunnissen E, Kerr KM, Herth FJ, et al. The challenge of NSCLC diagnosis and predictive analysis on small samples: practical approach of a working group. Lung Cancer. 2012;76(1):1–18. 5. Travis WD, Brambilla E, 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 Thorac Oncol. 2011;6(2):244–285. 6. Thunnissen E, Beasley MB, Borczuk AC, et al. Reproducibility of histopathological subtypes and invasion in pulmonary adenocarcinoma: an international interobserver study. Mod Pathol. 2012;25(12):1574–1583. 7. Xu X, Chung JH, Jheon S, et al. The accuracy of frozen section diagnosis of pulmonary nodules: evaluation of inflation method during intraoperative pathology consultation with cryosection. J Thorac Oncol. 2010;5(1):39–44. 8. Aoki T, Nakata H, Watanabe H, et al. Evolution of peripheral lung adenocarcinomas: CT findings correlated with histology and tumor doubling time. AJR Am J Roentgenol. 2000;174(3):763–768. 9. Borczuk AC. Assessment of invasion in lung adenocarcinoma classification, including adenocarcinoma in situ and minimally invasive adenocarcinoma. Mod Pathol. 2012;25(suppl 1):S1–S10. 10. Silver SA, Askin FB. True papillary carcinoma of the lung: a distinct clinicopathologic entity. Am J Surg Pathol. 1997;21(1):43–51. 11. Jian Z, Tomizawa Y, Yanagitani N, Iijima H, Sano T, Nakajima T. Papillary adenocarcinoma of the lung is a more advanced adenocarcinoma than bronchioloalveolar carcinoma that is composed of two distinct histological subtypes. Pathol Int. 2005;55(10):619–625. 12. Motoi N, Szoke J, Riely GJ, et al. Lung adenocarcinoma: modification of the 2004 WHO mixed subtype to include the major histologic subtype suggests correlations between papillary and micropapillary adenocarcinoma subtypes, EGFR mutations and gene expression analysis. Am J Surg Pathol. 2008;32(6):810– 827. 13. Russell PA, Wainer Z, Wright GM, Daniels M, Conron M, Williams RA. Does lung adenocarcinoma subtype predict patient survival?: a clinicopathologic study based on the new International Association for the Study of Lung Cancer/ American Thoracic Society/European Respiratory Society international multidisciplinary lung adenocarcinoma classification. J Thorac Oncol. 2011;6(9):1496– 1504. 14. Kim YH, Ishii G, Goto K, et al. Dominant papillary subtype is a significant predictor of the response to gefitinib in adenocarcinoma of the lung. Clin Cancer Res. 2004;10(21):7311–7317. 15. Matsumoto S, Iwakawa R, Kohno T, et al. Frequent EGFR mutations in noninvasive bronchioloalveolar carcinoma. Int J Cancer. 2006;118(10):2498– 2504. 16. Chantranuwat C, Sriuranpong V, Huapai N, et al. Histopathologic characteristics of pulmonary adenocarcinomas with and without EGFR mutation. J Med Assoc Thai. 2005;88(suppl 4):S322–S329. 17. Haneda H, Sasaki H, Lindeman N, et al. A correlation between EGFR gene mutation status and bronchioloalveolar carcinoma features in Japanese patients with adenocarcinoma. Jpn J Clin Oncol. 2006;36(2):69–75. 18. Blons H, Cote JF, Le Corre D, et al. Epidermal growth factor receptor mutation in lung cancer are linked to bronchioloalveolar differentiation. Am J Surg Pathol. 2006;30(10):1309–1315. 19. Zakowski MF, Hussain S, Pao W, et al. Morphologic features of adenocarcinoma of the lung predictive of response to the epidermal growth factor receptor kinase inhibitors erlotinib and gefitinib. Arch Pathol Lab Med. 2009;133(3):470–477. 20. Dacic S, Shuai Y, Yousem S, Ohori P, Nikiforova M. Clinicopathological predictors of EGFR/KRAS mutational status in primary lung adenocarcinomas. Mod Pathol. 2010;23(2):159–168.
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