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Morphologic features of adenocarcinoma of the lung predictive of response to the epidermal growth factor receptor kinase inhibitors erlotinib and gefitinibMaureen F Zakowski et al. Arch Pathol Lab Med. 2009 Mar.
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AbstractContext: A subset of lung adenocarcinomas appears preferentially sensitive to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). EGFR-activating mutations and never smoking are associated with response to TKIs.
Objectives: To describe the morphology of adenocarcinomas responsive to TKIs, compare it to tumors in nonresponding patients, and correlate findings with EGFR mutations, gene copy number, and protein expression.
Design: Material from 52 EGFR TKI-treated patients was studied: 29 responders and 23 nonresponders. Adenocarcinoma subtypes and morphologic features were defined in histologic and cytologic material. EGFR mutations were detected by sequencing, copy number by chromogenic in situ hybridization, and expression by immunohistochemistry.
Results: Tumors from TKI responders tended to be better-differentiated adenocarcinomas with bronchioloalveolar carcinoma components. Nonresponders showed more heterogeneous morphology, higher grade, and more subtypes, and were more likely to show solid growth. In nonresponders, the only pure bronchioloalveolar carcinoma was mucinous, a subtype known to be negative for EGFR mutations. Using World Health Organization criteria, all tumors in both groups other than pure bronchioloalveolar carcinomas would be classified as adenocarcinomas, mixed subtype, thereby obscuring some of these distinctions. EGFR mutations were significantly more common in responders (22/29 vs 0/23; P < .001). Immunohistochemistry and chromogenic in situ hybridization results were not significantly correlated with EGFR mutations or response to TKIs in this study.
Conclusions: Overall, histologic differences exist between tumors that respond to TKIs and those that do not, although sampling affects classification, and there is significant histologic overlap between the 2 groups. Response is strongly associated with EGFR mutations.
FiguresFigure 1
A, An area of bronchioloalveolar…
Figure 1
A, An area of bronchioloalveolar carcinoma (BAC) in a responder. This tumor was…
Figure 1A, An area of bronchioloalveolar carcinoma (BAC) in a responder. This tumor was from a lobectomy specimen (hematoxylin-eosin, original magnification ×40). B, A focus of adenocarcinoma interpreted as BAC in a small biopsy specimen from a responder. The inset shows the intranuclear inclusions frequently found in BAC (hematoxylin-eosin, original magnifications ×4 and ×100 [inset]).
Figure 2
A focus of micropapillary carcinoma…
Figure 2
A focus of micropapillary carcinoma seen in a nonresponder. This morphology was not…
Figure 2A focus of micropapillary carcinoma seen in a nonresponder. This morphology was not seen in responders (hematoxylin-eosin, original magnification ×100).
Figure 3
Mixed subtype adenocarcinoma can be…
Figure 3
Mixed subtype adenocarcinoma can be found in both responders and nonresponders. This is…
Figure 3Mixed subtype adenocarcinoma can be found in both responders and nonresponders. This is from a nonresponder who underwent a wedge resection (hematoxylin-eosin, original magnification ×40).
Figure 4
Increased epidermal growth factor receptor…
Figure 4
Increased epidermal growth factor receptor (EGFR) copy number by chromogenic in situ hybridization…
Figure 4Increased epidermal growth factor receptor (EGFR) copy number by chromogenic in situ hybridization in a responder. EGFR copy number was high (more than 6), and the specimen was from a wedge resection (original magnification ×40).
Figure 5
Epidermal growth factor receptor immunohistochemical…
Figure 5
Epidermal growth factor receptor immunohistochemical stain scored as 3+ in a responder. The…
Figure 5Epidermal growth factor receptor immunohistochemical stain scored as 3+ in a responder. The specimen was from a lobectomy (original magnification ×40).
Figure 6
Chromogenic in situ hybridization showing…
Figure 6
Chromogenic in situ hybridization showing epidermal growth factor receptor amplification in case 3,…
Figure 6Chromogenic in situ hybridization showing epidermal growth factor receptor amplification in case 3, a gefitinib nonresponder. The copy number in this case was 6 (original magnification ×100).
Figure 7
Mucinous bronchioloalveolar carcinoma (BAC) (case…
Figure 7
Mucinous bronchioloalveolar carcinoma (BAC) (case 22) from an erlotinib nonresponder. This tumor was…
Figure 7Mucinous bronchioloalveolar carcinoma (BAC) (case 22) from an erlotinib nonresponder. This tumor was homogeneous in appearance. Areas of nonmucinous BAC were not identified (hematoxylin-eosin, original magnification ×40).
Figure 8
Papillary component in adenocarcinoma from…
Figure 8
Papillary component in adenocarcinoma from patient 13, an erlotinib nonresponder (hematoxylin-eosin, original magnification…
Figure 8Papillary component in adenocarcinoma from patient 13, an erlotinib nonresponder (hematoxylin-eosin, original magnification ×40).
Figure 9
Necrosis seen in patient 1,…
Figure 9
Necrosis seen in patient 1, a gefitinib nonresponder. Necrosis was seen in 3…
Figure 9Necrosis seen in patient 1, a gefitinib nonresponder. Necrosis was seen in 3 nonresponders (hematoxylin-eosin, original magnification ×40).
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