Section 1 -

Bronchioloalveolar Carcinoma Maureen F. Zakowski MD Memorial Sloan-Kettering Cancer Center New York, NY, USA

Case History: The patient is a 67-year-old white man who presented to his local emergency room with shortness of breath. His past medical history was non-contributory and he had a remote 10 pack-year history of smoking; he stopped 32 years ago. He was found to have a left upper lobe lung mass on chest X-ray and follow up CT demonstrated a 2 cm lobulated left upper lobe mass and a right upper lobe ground glass opacity. PET can revealed uptake in the left upper lobe with SUV of 3.9 and negative uptake in the right upper lobe opacity. Case 1 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer He underwent a right upper lung lobectomy that found two similar appearing lung adenocarcinomas, both with acinar and non-mucinous bronchioloalveolar patterns. BAC made up 30 and 50% of the tumor types. A month later he underwent a left upper lobectomy where two adenocarcinomas both with BAC growth patterns in addition to acinar growth. Both tumors had approximately 10% BAC. Material from both sides of the lung was found to have a EGFR mutation consisting of an exon 19 deletion. There has been considerable change in the recent WHO classification of lung cancer of 1999 and 2004. In 1999 the category of adenocarcinoma with mixed subtypes was added to the subtypes of the 1981 classification (acinar, papillary, BAC and solid carcinoma with mucus formation). BAC underwent a major change as well with the requirement that all BAC demonstrate pure lepidic growth without invasion of stroma, blood vessels or pleura [1, 2, 3]. The basis for the narrow definition of BAC was the 1995 publication by Noguchi and Shimosato who showed that small peripheral carcinomas, with a pure BAC pattern had a 100% 5 year survival. [4] They also showed that mixed subtype adenocarcinoma with a BAC component (check amt) had 75% survival and purely invasive had a 52% survival at 5 years. The term adenocarcinoma, mixed subtype is used for tumors that have a BAC and invasive component by this classification system. Three types of BAC were recognized: mucinous, non-mucinous and mixed mucinous and non-mucinous. Most BAC in North America and Europe occurs in the setting of mixed subtype; pure, solitary, peripheral BAC as defined by the 2004 WHO Classification is much more common in Japan than in Western Europe and North America. Interestingly, Liebow, who coined the term "bronchioloalveolar carcinoma" in 1960 defined it as a "generally well-differentiated adenocarcinoma primarily in the periphery of the lung beyond a grossly recognizable bronchus, with a tendency to spread chiefly within the confines of the lung by aerogenous and lymphatic routes, the walls of the distal air spaces often acting as supporting stroma for the neoplastic cells". He also stated that "to expect classic appearance of entirely intact parenchyma throughout as the sole support of BAC cells is imaginary" and "to insist that the tumor called BAC grows on the unaltered walls of alveoli without destruction (invasion) of pulmonary architecture is to add confusion". This definition was adopted at that time by the WHO and AJCC [5, 6]. Recent data indicate that there are molecular differences according to lung carcinoma subtype. Among non small cell lung cancers (NSCLC), adenocarcinomas, and interestingly, the subtype of adenocarcinoma with a bronchioloalveolar component, appears susceptible to the effects of tyrosine kinase inhibitors (TKI) gefitinib and erlotinib [7]. The epidermal growth factor receptor (EGFR) is a member of a family of transmembrane glycoproteins that includes HER-2,3 and 4, that possess tyrosine kinase activity and is present on most NSCLC and is over expressed in about a quarter of the cancers. Agents such as erlotinib and gefitinib that interfere with phosphorylation of critical tyrosine residues can block signal transduction through EGFR [7]. Recently reported [8, 9] identification of specific activating mutations in the EGFR TK domain are thought to underlie the responsiveness of NSCLC to gefitinib and erlotinib. The most common mutations found in lung cancer are deletions of exon 19 and point mutations of exon 21. Mutations are more frequently present in non-smokers, women and Asians. Mutations of EGFR are not found in association with KRAS, which is more commonly found in smokers. Mutations are also not seen in pure mucinous BAC, and KRAS mutations may be more common in these tumors. Patients with EGFR mutations are more likely to respond to TKIs than those without mutations, although responses have been seen in patients without mutations. When response is seen it can be dramatic, both clinically and radiographically. Unfortunately, response is usually not durable and relapse may be due to acquired resistance to the drugs. Morphologic differences were seen in lung tumors from 28 patients who responded to TKIs compared to the tumors in 25 patients who did not respond to drug. Although the differences were sometimes subtle, they indicated that, in general, responders appeared to have better differentiated adenocarcinomas with significant amounts of BAC and less overall tumor heterogeneity that non-responders. Necrosis and solid growth patterns were more frequent among nonresponders. Correlation between response or presence of mutations and either EGFR over expression by IHC or EGFR amplification detected by CISH, if present, appeared to be weak in this study. These techniques should not be used instead of mutation analysis to select therapy. More studies are needed to define and describe the tumors that respond to TKI therapy so that pathologists may be better able to interpret the histologic features of prognostic importance in lung cancer. References Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E. Histological Typing of Lung and Pleural Tumors. Third Edition ed. Berlin: Springer; 1999. Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC Press; 2004. World Health Organization. Histologic typing of lung tumors. 2 ed. ed. Geneva; 1981. Noguchi M, Morikawa A, Kawasaki M, Matsuno Y, Yamada T, Hirohashi S, et al. Small adenocarcinoma of the lung. Histologic characteristics and prognosis. Cancer 1995;75(12):2844-52. Hajdu SI. The story of bronchioloalveolar carcinoma. Ann Clin Lab Sci 2005;35(3):336-338 Liebow AA. Bronchiolo-alveolar carcinoma. Adv Intern Med 1960;10:329-58. Miller VA, Johnson DH, Krug LM, Pizzo B, Tyson L, Perez W, et al. Pilot trial of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib plus carboplatin and paclitaxel in patients with stage IIIB or IV non-small-cell lung cancer. J Clin Oncol 2003;21(11):2094-100. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350(21):2129-39. Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004;101(36):13306-11.