My last post was a "Digital Case Challenge" presenting a case of pulmonary adenocarcinoma with non-mucinous bronchioloalveolar (BAC) features.
Here's my synopsis of 3 recent papers on bronchioloalveolar carcinoma that focus on the clinicopathological, histological, and molecular differences between the two subtypes, non-mucinous and mucinous, as well as the practical importance in distinguishing these two subtypes.
1. Wislez et al, in a recently published paper in Lung Cancer (2010;68:185-191), studied 50 cases of non-resectable adenocarcinoma with bronchioloalveolar (ADC-BAC) features who were enrolled in a multicenter study to evaluate gefitinib as a first-line therapy for non-resectable ADC-BAC. Previous trials (SWOG S0126 and IFCT0401) have shown that the mucinous subtype was associated with a lower response rate and was predictive for shorter survival after treatment with gefitinib. The purpose of this study was to identify markers that would better characterize each subtype. They first classified each tumor by routine H&E staining using conventional criteria. They found that three variables enabled segregation of 96% of cases (48/50 patients): diastase-resistant PAS staining, IHC staining for TTF-1, and EGFR mutation/genomic gain.
dr-PAS: 80% non-mucinous ADC-BAC tumors showed <5% positive cells; 83% mucinous ADC-BAC >5%
TTF-1: 95% non-mucinous ADC-BAC express TTF-1 >20% of cells; only 27% mucinous ADC-BAC
EGFR mutations (exons 18-21): only 3/25 (12%) in non-mucinous ADC-BAC but none in mucinous ADC-BAC
The last findings are lower than previously published rates for non-mucinous ADC-BAC in both Asian and U.S./European studies. Moreover, EGFR exon 18-21 mutations have been reported in mucinous ADC-BAC, albeit at a much lower rate compared to non-mucinous subtype. Which leads me to a second recent report I recently reviewed.
2. Casali et al (J Thorac Oncol 2010;5:830:836) presented a single-institution retrospective study from Italy of 40 cases of BAC based on strict application of the 2004 WHO histologic classification of BAC (although 6 cases were not completely sampled for histology due to large size/pneumonic involvement). Their purpose was to compare previous studies of BAC in primarily Japanese/East Asian studies with their exclusively European Caucasian patient population. Their findings are similar but not identical to these previous studies. Non-mucinous BAC presents more frequently as a solitary mass and early stage (cf. mucinous subtype), whilst mucinous BAC more frequently presents as multifocal tumor or a pneumonic pattern of lung involvement and in more advanced stage.
The overall incidence of EGFR mutation was similar to the study by Wislez et al (17%) which is also less frequent than that reported in primarily Japanese reports; they did confirm a strong correlation with never-smoking status and female gender. Also, they found a significant difference in mutation profile between subtypes: 6/14 non-mucinous BAC versus none in mucinous BAC. Conversely, KRAS mutation was found in 12/13 mucinous BAC versus 3/20 non-mucinous BAC.
Although this is a small, single-institution study, there is helpful and interesting survival data that shows significantly increased OS and RFS for non-mucinous versus mucinous/mixed BAC in early stage (IA and IB) tumors. They also note the raw numbers for the small subgroup of patients with multifocal tumor (N=6) and pneumonic involvement (N=7) which suggest a dismal survival for these patterns of involvement. Four out of six patients with multifocal tumor died of disease; 5 of 7 with pneumonic involvement died of disease--all 5 of whom had mucinous BAC type.
Finally, they confirmed by multivariate analysis that stage (p=0.004) and histologic subtype (p=0.035) were independent prognostic factors for overall survival. It would be nice to have this data presented as hazard ratios to assess the relative effect of each of these factors.
3. Finally, Hata et al (J Thorac Oncol 2010;5:1197-1200) recently reported a study of EGFR and KRAS mutations in Japanese patients with mucinous BAC/adenocarcinoma with mucinous BAC subtype features (MBAC/AWBF). They analyzed 20 cases of MBAC/AWBF for EGFR and KRAS mutations and compared them with 24 cases of N-MBAC/AWBF. Briefly, they found in MBAC/AWBF there is a low incidence of EGFR mutations (3/20, 15%) while there is a frequent incidence of KRAS mutations (12/20, 70%). Conversely, in N-MBAC/AWBF there is a higher incidence of EGFR mutations (14/24, 58%) but less frequent incidence of KRAS mutations (7/24, 29%). Note that in contrast to the studies above, these authors did find some EGFR mutations in MBAC/AWBF tumors. Moreover, the authors identified 3 patients with MBAC/AWBF with concomitant EGFR and KRAS mutations--thus showing that these mutations are not always necessarily mutually exclusive. The reasons for these discrepancies may be methodological becasue of different mutation detection techniques or may be due to racial/ethnic differences. Further work to examine differences across populations would definitely be interesting. But, more importantly from a practical standpoint, I think this is significant because it illustrates that we cannot simply use histology as a perfect triage for mutation testing. It would be quite interesting to see if any of the 3 patients with MBAC/AWBF with EGFR mutations were treated with EGFR-TKIs and what the response was in comparison to other histologic types and subtypes.
Bottom line? Pathologists should use the above information to try and differentiate mucinous versus non-mucinous subtypes in BAC/ACA with BAC features, especially in early stage tumors as this has prognostic and, possibly, therapeutic significance. Also, although histological subtype can predict the likelihood of an EGFR mutation being present, it alone should not be used as a criterion for mutational testing, particularly for EGFR mutations.