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  1. 1. Anatomic Pathology / Micropapillary Adenocarcinoma of LungMicropapillary Lung AdenocarcinomaEGFR, K-ras, and BRAF Mutational ProfileRosane De Oliveira Duarte Achcar, MD, Marina N. Nikiforova, MD, and Samuel A. Yousem, MDKey Words: Micropapillary adenocarcinoma; Papillary adenocarcinoma; Bronchioloalveolar adenocarcinomaDOI: 10.1309/AJCPBS85VJEOBPDOAbstract Lung adenocarcinomas are histologically heterogeneous, Micropapillary lung adenocarcinoma (MPA) which led the World Health Organization to highlight thathas been reported as an aggressive variant of most adenocarcinomas had a mixed growth pattern, withadenocarcinoma, frequently manifesting at high characteristic patterns being solid, acinar, papillary, and le-stage with a poor prognosis. We analyzed the clinical pidic.1 Lung adenocarcinomas with papillary growth show 2and molecular profile of 15 primary MPAs for types of papillary architecture: true papillary structures withK-ras, EGFR, and BRAF mutations and performed papillae containing a layered glandular epithelium surround-fluorescence in situ hybridization for EGFR ing a fibrovascular core and micropapillary growth in whichamplification. In our study, 11 (73%) of 15 MPAs the papillary tufts lack a central fibrovascular core and exten-harbored mutually exclusive mutations: 5 (33%) K-ras, sively shed within alveolar spaces.2,3 Micropapillary growth3 (20%) EGFR, and 3 (20%) BRAF. Mutations in all 3 patterns have been associated with an aggressive clinicalgenes occurred in patients with a smoking history and course compared with traditional papillary adenocarcinomatumors with mucinous differentiation and secondary and bronchioloalveolar carcinoma.2-10 Micropapillary adeno-lepidic, acinar, and solid growth, suggesting that in carcinoma (MPA) often manifests at a high stage in nonsmok-a Western population, cytomorphologic correlation ers, with intralobar satellites, and frequently metastasizes towith genetic mutations is more unpredictable than the contralateral lung, mediastinal lymph nodes, bone, andin Japanese cohorts. We conclude that K-ras, adrenal glands, with high mortality.4-12EGFR, and BRAF mutations are disproportionately Because MPA represents a unique form of lung adeno-seen in adenocarcinomas of lung with a dominant carcinoma, we analyzed 15 MPA cases for the commonmicropapillary growth pattern compared with genetic mutations in lung adenocarcinoma to determineconventional adenocarcinoma in our institutional whether a distinct genetic profile was associated with thisexperience. histopathologic growth pattern. To our knowledge, no study comparing K-ras, EGFR, and BRAF mutations in micropapil- lary adenocarcinoma has been reported. Materials and Methods The 1997-2008 pathology files of the University of Pittsburgh Medical Center, Pittsburgh, PA, were searched for lung adenocarcinomas showing micropapillary growth. The study was approved by the institutional review board of the University of Pittsburgh Medical Center. Histologic694 Am J Clin Pathol 2009;131:694-700 © American Society for Clinical Pathology694 DOI: 10.1309/AJCPBS85VJEOBPDO
  2. 2. Anatomic Pathology / Original Articleclassification was according to the revised World Health second, annealing at 55°C for 20 seconds, and extension atOrganization classification of lung malignancies of 2004, 72°C for 10 seconds. Postamplification fluorescence meltingwith micropapillary adenocarcinoma defined according to the curve analysis was performed by gradual heating of samplescriteria of Silver and Askin13 for papillary adenocarcinoma, at a rate of 0.2°C/s from 45°C to 95°C. All PCR products thatin which greater than or equal to 75% of the adenocarcinoma showed deviation from the wild-type (placental DNA) melt-manifested a micropapillary growth pattern with primary and ing peak were sequenced to verify the presence of mutation.secondary budding from papillary stalks.1 Our internal study of more than 350 primary adenocar- In this series, micropapillary growth was always inti- cinomas (exclusive of micropapillary adenocarcinoma) of themately admixed with a lesser component of papillary growth. lung revealed the following overall general rates of mutationBecause the two were nonseparable, we used dominant micro- in lung adenocarcinoma at our institution: EGFR (exons 19papillary growth, in a background of simple papillae, as part and 21), 10%; K-ras, 23%; and BRAF, 5.5% (S. Dacic et al,of the histologic definition of MPA. Of the 37 cases identified, 2009, unpublished data).15 adenocarcinomas conformed to these criteria. There was The χ2 and Fisher exact tests were used for categoricalan average of 5 tumor sections (range, 2-11 sections) of each data. Two-tailed P values of less than .05 were consideredadenocarcinoma available for review. The adenocarcinomas significant.were analyzed by patient age, sex, and smoking history and bytumor location and stage. Tumors were also evaluated for thefollowing morphologic features: tumor size, grade, second- Resultsary architectural growth patterns, and predominant cell type(hobnail vs columnar); goblet, clear cell, and signet-ring cell The clinicohistopathologic and molecular profiles of thedifferentiation; mucin production; psammoma bodies; host 15 cases of MPA are summarized in zTable 1z. The male/inflammatory response; presence of necrosis; and visceral- female ratio was 8:7 (1.1), and ages ranged from 50 to 80pleural and angiolymphatic invasion. years (mean and median, 68 years). Of the 15 patients, 13 Fluorescence in situ hybridization analysis for EGFR (87%) were 60 years or older at diagnosis. All patients cur-gene amplification was performed with the dual-color EGFR rently smoked or had a history of smoking cigarettes. TumorSpectrumOrange/CEP7 SpectrumGreen probe and paraffin sizes ranged from 0.5 to 6.5 cm (mean, 3.4 cm; median, 3.0pretreatment kit (Vysis, Downers Grove, IL) using previously cm), and 10 (67%) of the tumors were 3 cm or larger.described methods.14 Amplification was determined by the Micropapillary growth constituted 75% to 100% of theratio of the number of EGFR signals per cell to the number of tumors zImage 1z and zImage 2z. In 13 cases, secondarychromosome 7 centromere signals per cell. Amplification was minor growth patterns included a lepidic pattern in 7 (54%),defined as a ratio of 2.0 or greater. Direct DNA sequencing of codons 12 and 13 of exon2 of the K-ras gene and exons 19 and 21 of the EGFR genewas performed as previously described and according to themanufacturer’s instructions using the BigDye Terminator v3.1cycle sequencing kit on an ABI 3130 (Applied Biosystems,Foster City, CA).14-16 All polymerase chain reaction (PCR)products were sequenced in sense and antisense directions.The sequences were analyzed by using Mutation Surveyorsoftware (SoftGenetics, State College, PA). Each case wasclassified as positive or negative for the K-ras and EGFRmutations based on the sequencing results. Detection of the BRAF V600E mutation was performedusing real-time PCR and post-PCR fluorescence meltingcurve analysis on a LightCycler (Roche Applied Science,Indianapolis, IN), as previously reported.16 Briefly, a pairof oligonucleotide primers flanking the mutation site wasdesigned, together with 2 fluorescent probes, with the sensorprobe spanning the nucleotide position 1799. Amplificationwas performed in a glass capillary using 50 ng of DNA in zImage 1z Micropapillary lung adenocarcinoma. At lowa 20-µL volume. The reaction mixture was subjected to 40 magnification, a nodular growth pattern with prominentcycles of rapid PCR consisting of denaturation at 94°C for 1 desmoplastic stroma is shown (H&E, ×40).© American Society for Clinical Pathology Am J Clin Pathol 2009;131:694-700 695 695 DOI: 10.1309/AJCPBS85VJEOBPDO 695
  3. 3. Achcar et al / Micropapillary Adenocarcinoma of LungzImage 2z Micropapillary lung adenocarcinoma. Dyscohesive zImage 3z Micropapillary lung adenocarcinoma (MPA).papillary clusters of cytologically malignant cells “float” within While MPA frequently shows “hobnail” cytologic andair spaces and are focally associated with lepidic growth bronchioloalveolar features, acinar and tubular architectures(H&E, ×120). are common, as are columnar and polygonal cell cytologic features with abundant intracellular and extracellular mucin production (H&E, ×100).an acinar growth pattern in 5 (38%), and solid growth in 1 pure hobnail or terminal reserve differentiation, 2 had K-ras(8%); 2 cases showed micropapillary growth exclusively. mutations, 1 an EGFR mutation, and 1 a BRAF mutation.Cytologically, the tumors were extremely heterogeneous, Of the tumors with pure columnar or polygonal cell change,although we attempted to separate out nonmucinous hobnail 2 had EGFR mutations, 1 a K-ras mutation, and 1 a BRAFand terminal reserve unit–type micropapillary adenocarci- mutation. Of the 15 adenocarcinomas, 5 showed clear cellnoma (n = 4) from tumors having a predominant columnar or differentiation, whereas only 1 showed signet-ring change.polygonal cell configuration (n = 8), with the remainder hav- Intracellular and extracellular mucin production with diastase-ing mixed cell populations (n = 3) zImage 3z.7,17 Of the 4 with predigested periodic acid–Schiff and mucicarmine stains waszTable 1zComplete Clinicopathologic Data for 15 Cases of MicropapillaryLung Adenocarcinoma* Cytologic FeaturesCase No./ Tumor Tumor Mucin Psammoma Angiolymphatic Sex/Age (y) Location Size (cm) Differentiation Hobnail Columnar Production Bodies Host Response Necrosis Invasion 1/M/67 RML 3.3 Moderate No Yes Yes No Moderate Yes Yes 2/M/74 LUL 4.0 Well Yes No No No Mild Yes Yes 3/F/80 LUL 1.3 Moderate Yes Yes No Yes Mild No No 4/M/64 LUL 6.0 Moderate Yes No No No Moderate Yes Yes 5/M/79 LLL 2.0 Moderate No Yes Yes No Mild Yes No 6/F/71 LUL 3.5 Moderate Yes No No No Mild Yes Yes 7/F/73 LUL 3.0 Moderate No Yes Yes No Moderate Yes Yes 8/F/68 RUL 2.0 Moderate No Yes No No Minimal Yes Yes 9/F/60 LUL 1.5 Well Yes Yes No No Mild Yes Yes 10/M/58 RLL 6.0 Moderate No Yes Yes No Mild Yes Yes 11/F/80 RUL 6.5 Moderate Yes Yes Yes No Mild Yes Yes 12/M/64 LUL 3.0 Moderate Yes No Yes Yes Mild Yes Yes 13/F/50 RLL 0.5 Moderate No Yes Yes Yes Minimal Yes No 14/M/68 LLL 4.0 Moderate No Yes Yes No Mild Yes Yes 15/F/70 LLL 4.5 Moderate No Yes No Yes Moderate Yes Yes LLL, left lower lobe; LUL, left upper lobe; RLL, right lower lobe; RML, right middle lobe; RUL, right upper lobe.* Hobnail, cells with Clara and type II pneumocyte differentiation, often called terminal reserved unit cells; columnar, columnar or polygonal cells resembling bronchiolar epithelium.696 Am J Clin Pathol 2009;131:694-700 © American Society for Clinical Pathology696 DOI: 10.1309/AJCPBS85VJEOBPDO
  4. 4. Anatomic Pathology / Original Articleseen in 8 (53%) of 15 cases. Psammoma bodies were noted in micropapillary adenocarcinoma; articles reporting on micro-4 (27%) of 15 cases. papillary growth have indicated its presence in between 5% Of 7 cases associated with secondary lepidic growth, 6 and 100% of their study populations.2-10 In our study of 15demonstrated the following mutations: 3 (43%) of 7, K-ras; 2 cases of primary MPA, we used an original definition sug-(29%) of 7, EGFR; and 1 (14%) of 7, BRAF V600E. Among the gested by Silver and Askin13 that a papillary adenocarcinomaMPAs showing mucin production with histochemical stains, 4 be composed of greater than or equal to 75% papillary growth.(50%) of 8 showed the following mutations: 2 (25%) of 8, BRAF By using this definition for MPA, we confirmed the generalV600E; 1 (13%) of 8, K-ras; and 1 (13%) of 8, EGFR. observations of other studies having a less stringent defini- Molecular studies demonstrated that 11 (73%) of 15 tion. In particular, micropapillary adenocarcinoma is typicallycases had mutations involving the 3 genes investigated: 5 a malignancy of older people, with an equal sex distribution,(33%) showed K-ras mutations, 3 (20%) demonstrated EGFR that manifests more often at a late stage with intrapulmonarymutations, and 3 (20%) showed BRAF V600E mutations zFig- and extrapulmonary metastases. Our study is unique in focus-ure 1z. Of the 3 EGFR mutations, 2 were deletions in exon 19 ing on the 3 major oncogenes reported in lung adenocarci-and 1 was a point mutation in exon 21. EGFR amplification noma, although we recognize that between 30% and 70% ofwas detected in 2 (13%) of 15 cases, with 1 of these 2 cases lung adenocarcinomas have complex genetic mutations notassociated with EGFR mutations. All K-ras mutations were at tied to EGFR, K-ras, and BRAF.18 Still, in our study group,codon 12 leading to substitution of glycine with phenylalanine 73% of the cases demonstrated mutations of K-ras (33%),(n = 1), cysteine (n = 3), or alanine (n = 1). Gly12Phe is a rare EGFR (20%), and BRAF (20%), making MPA unusual in itstype of K-ras mutation in which 2 nucleotides are substituted frequency of involvement of these 3 genes compared withat codon 12 (GGT to TTT) instead of the usual 1-nucleotide our institutional percentages in lung adenocarcinoma: EGFR,substitution. We attempted to correlate the mutations of these 10%; K-ras, 23%; and BRAF, 5.5% (see the “Materials and3 genes with morphologic findings. No clear association of Methods” section). This percentage far outweighs the cumu-mutations with the morphologic or clinical features shown in lative percentages of 40% usually associated with primaryTable 1 was noted (P > .05). conventional lung adenocarcinoma.18-20 Most studies on micropapillary growth and lung adeno- carcinomas have focused on a higher than usual incidence ofDiscussion EGFR mutations in papillary and micropapillary adenocarci- Micropapillary growth in pulmonary adenocarcinomas nomas of lung.7,11 Our study, in fact, confirmed that EGFRreflects an aggressive subset of lung adenocarcinomas with mutations are twice as common in MPA as reported in thea poor prognosis.2,3,5,6,8-10 In analyzing the relevant stud- Western literature. However, our study also highlights thaties, one problem is achieving agreement on a definition for EGFR is not the only gene associated with MPA, with K-ras and BRAF mutations present in more than 50% of our study population. Furthermore, while the association of EGFR mutations with an absence of smoking has been emphasized in Far Eastern and Western populations, our study also shows that EGFR mutations in MPA also occur in cigarette smok- Mutation ers.11,17,21,22 In our study, we defined a history of cigaretteVisceral-Pleural Pathologic EGFR EGFR K-ras BRAF smoking in absolute terms—any patient with a history ofInvasion Stage Exon 19 Exon 21 Exon 2 V600E cigarette smoking was considered as having a risk of develop- ing adenocarcinoma, in contrast with other studies, such as aYes T2 N0 M0 No No No NoYes T2 N0 M0 Yes No No No study by Motoi et al,11 who defined nonsmokers as patientsNo T1 NX M0 No No Yes No having less than a 15-pack-year history of smoking.Yes T2 N1 M0 No No Yes NoNo T1 NX M0 No No No No EGFR mutations have also been reported primarily inNo T2 N0 M0 No No Yes No adenocarcinomas having type II alveolar pneumocyte dif-Yes T2 N1 M1 Yes No No No ferentiation, variously reported as “hobnail configuration”No T1 N0 M0 No Yes No NoYes T4 N2 M0 No No Yes No or “terminal reserve unit” cytologic features.7,11,17 AlthoughYes T2 N2 M0 No No Yes No EGFR mutations were certainly seen in cells with theseYes T4 N0 M0 No No No YesYes T4 N2 M0 No No No Yes differentiation characteristics, EGFR mutations were alsoNo T4 N0 M0 No No No No observed in MPAs with columnar and polygonal cell dif-Yes T2 N0 M0 No No No NoYes T2 N0 M0 No No No Yes ferentiation, whereas K-ras and BRAF mutations were seen in adenocarcinomas with hobnail or terminal reserve unit cell differentiation. Furthermore, although it has been emphasized© American Society for Clinical Pathology Am J Clin Pathol 2009;131:694-700 697 697 DOI: 10.1309/AJCPBS85VJEOBPDO 697
  5. 5. Achcar et al / Micropapillary Adenocarcinoma of LungA B EGFR exon 21 EGFR exon 19 L858R mutation 15 bp deletion G G G C T G G C C A A A T C G C T A T C A A GG A A T T AA G GC D 0.078 –(d/dt) Fluorescence (705/530) K-ras codon 12 BRAF V600E Gly12Cys mutation 0.073 0.069 WT G G A G C TG G T G G C G T A 0.065 0.063 T 0.058 0.053 0.048 40 45 50 55 60 65 70 75 80 Temperature (°C)zFigure 1z Examples of mutations found in micropapillary lung adenocarcinoma. A, Direct nucleotide sequencing shows a15-base-pair (bp) deletion in exon 19 of the EGFR gene. B, Point mutation (CTG to CGG) at codon 858 exon 21 of the EGFRgene detected by sequencing. C, K-ras codon 12 mutation (GGT to TGT) detected by sequencing leads to glycine to cysteineamino acid change. D, BRAF V600E mutation detected by real-time polymerase chain reaction (PCR) and post-PCR meltingcurve analysis demonstrates the mutant peak at a melting temperature of 58ºC in addition to the wild-type (WT) peak.that mucin-producing, goblet cell–type bronchioloalveolar Japanese cohort: EGFR mutations in 4 exons occurred in 59%adenocarcinomas are unassociated with EGFR mutations, our of cases; patients were usually nonsmoking women, and theremicropapillary adenocarcinomas produced mucin and had was a strong association with a bronchioloalveolar and papil-EGFR mutations, as well as K-ras and BRAF mutations. lary growth pattern. Our study in a Western population, using The majority of our MPA cases demonstrated secondary more rigorous criteria for the definition of MPA, suggests thatlepidic and acinar growth patterns ranging from 1% to 25% of this tumor has a wider demographic and molecular spectrum.the tumor. There was no strong correlation between second- Motoi et al11 did not define MPA by absolute percentages ofary growth pattern and molecular profile, although overall, micropapillary growth, the result being the inclusion of con-K-ras mutations were more frequent in tumors with lepidic ventional adenocarcinomas and papillary adenocarcinomas inand papillary growth, whereas BRAF mutations were slightly the analysis, in which micropapillary architecture representedmore frequent in tumors with acinar growth. Nevertheless, in only the major component in relative terms but not necessarilythis group of MPAs, it is important to emphasize that in con- in percentages greater than 75%. We confirmed their observa-trast with the findings of other studies, lepidic growth in these tion that EGFR mutations are more common in MPA than inadenocarcinomas did not exclude EGFR mutations.11 conventional adenocarcinoma, but we also noted that MPA To date, only 2 studies7,11 have looked specifically at is present in smokers, displays mucinous differentiation, andthe molecular alterations in MPAs, and neither used the is associated with K-ras and BRAF mutations, as noted bydefinitions of Silver and Askin.13 In the study by Ninomiya others.23,24et al,7 MPA was defined as an adenocarcinoma with 25% In the literature, EGFR mutations have largely beenof the tumor having micropapillary growth. By using this associated with bronchioloalveolar adenocarcinoma, inva-definition, the authors showed that MPA closely resembled sive adenocarcinomas with prominent lepidic growth,their EGFR+ adenocarcinomas in their demographics in this and papillary adenocarcinoma.7,11,20,23,24 Micropapillary698 Am J Clin Pathol 2009;131:694-700 © American Society for Clinical Pathology698 DOI: 10.1309/AJCPBS85VJEOBPDO
  6. 6. Anatomic Pathology / Original Articleadenocarcinoma of the lung needs to be added to this group, 5. Kamiya K, Hayashi Y, Douguchi J, et al. Histopathologicalalthough as emphasized before, mutations in this group are features and prognostic significance of the micropapillary pattern in lung adenocarcinoma. Mod Pathol.not restricted to EGFR, thus warranting a comprehensive 2008;21:992-1001.molecular analysis should personalized therapies be con- 6. Makimoto Y, Nabeshima K, Iwasaki H, et al. Micropapillarytemplated. For example, BRAF mutations occur in approxi- pattern: a distinct pathological marker to subclassify tumoursmately 5% of pulmonary adenocarcinomas, often with a with a significantly poor prognosis within small peripheral lung adenocarcinoma (≤20 mm) with mixed bronchioloalveolar andpapillary architecture, but in the micropapillary subgroup, invasive subtypes (Noguchi’s type C tumours). Histopathology.the incidence rises to approximately 20%, similar to that 2005;46:677-684.seen in thyroid and ovarian papillary adenocarcinoma.16 It 7. Ninomiya H, Hiramatsu M, Inamura K, et al. Correlationmay be worthwhile to add this gene to a molecular panel between morphology and EGFR mutations in lung adenocarcinomas: significance of the micropapillary patternwhen one sees this architectural pattern given that some and the hobnail cell type [published online ahead of print Junepersonalized therapies for BRAF mutation (akin to tyrosine 20, 2008]. Lung Cancer. 2009;63:235-240.kinase inhibitor therapy in EGFR-mutated adenocarcinoma) 8. Roh MS, Lee JI, Choi PJ, et al. Relationship betweenhave been identified.25-30 micropapillary component and micrometastasis in the regional This study represents the first attempt to rigorously lymph nodes of patients with stage I lung adenocarcinoma. Histopathology. 2004;45:580-586.evaluate the molecular alterations in MPAs by using a 9. Sánchez-Mora N, Presmanes MC, Monroy V, et al.uniform definition and to correlate this growth pattern with Micropapillary lung adenocarcinoma: a distinctive histologicK-ras, EGFR, and BRAF mutations. We conclude that subtype with prognostic significance: case series. Hum Pathol.K-ras, EGFR, and BRAF mutations occur at an increased 2008;39:324-330.frequency in lung adenocarcinomas showing greater than 10. Yokose T, Suzuki K, Nagai K, et al. Favorable and unfavorable morphological prognostic factors in peripheral75% micropapillary growth and that these mutations are adenocarcinoma of the lung 3 cm or less in diameter. Lungseen in smokers and in adenocarcinomas with mucin produc- Cancer. 2000;29:179-188.tion. K-ras mutations certainly predominate, but BRAF and 11. Motoi N, Szoke J, Riely GJ, et al. Lung adenocarcinoma:EGFR mutations occur at a higher incidence than in conven- modification of the 2004 WHO mixed subtype to include the major histologic subtype suggests correlations betweentional lung adenocarcinomas reported in the literature and in papillary and micropapillary adenocarcinoma subtypes, EGFRour institutional experience. mutations and gene expression analysis. Am J Surg Pathol. 2008;32:810-827.From the Department of Pathology, University of Pittsburgh 12. Noguchi M, Morikawa A, Kawasaki M, et al. SmallMedical Center, Pittsburgh, PA. adenocarcinoma of the lung: histologic characteristics and prognosis. Cancer. 1995;75:2844-2852. Address reprint requests to Dr Yousem: Dept of Pathology, 13. Silver SA, Askin FB. True papillary carcinoma of theUniversity of Pittsburgh Medical Center, Presbyterian Campus, lung: a distinct clinicopathologic entity. Am J Surg Pathol.Room A610, 200 Lothrop St, Pittsburgh, PA 15213-2582. 1997;21:43-51. 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