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Postgraduate Education Corner: Chest Imaging and Pathology for Clinicians |

Recurrent Pneumonia, Persistent Cough, and Dyspnea in a 41-Year-Old ManRecurrent Pneumonia, Persistent Cough, and Dyspnea FREE TO VIEW

Jinghong Li, MD, PhD; Andrew Yen, MD; Grace Y. Lin, MD, PhD
Author and Funding Information

From the Division of Pulmonary and Critical Care Medicine (Dr Li), Department of Medicine; the Department of Radiology (Dr Yen); and the Department of Pathology (Dr Lin), University of California San Diego Health System, San Diego, CA.

Correspondence to: Grace Y. Lin, MD, PhD, University of California San Diego Health System, Department of Pathology, 200 W Arbor Dr, MC 8720, San Diego, CA 92103-8720; e-mail: g4lin@ucsd.edu


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2012;142(5):1338-1342. doi:10.1378/chest.11-2026
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A 41-year-old man with a history of bronchiectasis, recurrent pneumonia, persistent dyspnea, and cough presented to the hospital for a second opinion. He had an unknown chest radiograph abnormality as a young adult and multiple episodes of pneumonia, including four episodes of pneumonia within the previous 3 years for which he was hospitalized twice. The patient had been followed by a pulmonologist for the previous 3 years. Since his most recent hospitalization for pneumonia, the patient had persistent cough with production of abundant clear secretions.

The patient denied fevers, chills, fatigue, hemoptysis, chest pain, night sweats, and weight loss. He denied ever smoking. The patient had no exposure to farming, birds, hot tubs, or chemicals. Family history was significant for paternal death from colon cancer, but no lung disease. Physical examination was significant for left lower posterior rales and right midposterior rhonchi. He had no evidence of heart failure. Genetic screening was negative for cystic fibrosis. Repeated respiratory cultures were negative.

A chest CT scan from an outside institution 2 years previously showed nodular and lobular ground-glass lung opacities, variably involving all lobes, with confluence and consolidation in the basal left upper lobe, lingula, and posterobasal segment of the left lower lobe. Air bronchograms were present in the lingula. There was no evidence of bronchiectasis, despite the reported history. An air cyst was noted in the left upper lobe (Figs 1A, 1B). Chest radiography at the time of presentation to our institute showed patchy opacities in both midlung zones and at the left lung base (Figs 1C, 1D). A repeat chest CT scan demonstrated the increased extent of previously seen ground glass and consolidation in all lobes, although some lingular consolidation had improved (Figs 1E, 1F). Mediastinal lymph nodes were generally increased in size, measuring up to 1.3 cm.

Figure Jump LinkFigure 1. A and B, Axial images (5-mm-thick sections) from an outside chest CT scan 2 years previously demonstrate focal and diffuse mixed ground-glass and consolidative lung opacities, variably seen in the basal upper lobes, right middle lobe, and lingula; an air cyst is noted in the left upper lobe (arrow). C and D, Posterior-anterior and lateral chest radiographs obtained at presentation show a mix of nodular, patchy, and consolidative lung opacities in the basal upper lobes, lingula, and left lower lobe, and, to a lesser extent, in the right middle lobe. E and F, Axial images (1.25-mm-thick sections) from the chest CT scan acquired at presentation show worsening ground glass and consolidation in the basal upper lobes, slight clearing of consolidation in the lingula (double arrow head), and development of focal centrilobular ground-glass opacities in both lower lobes; an air cyst is again noted in the left upper lobe (arrow).Grahic Jump Location

Diagnostic bronchoscopy with BAL and transbronchial biopsies were nondiagnostic. Bacterial, mycobacterial, and fungal culture results were negative. Given the progression on CT scanning and despite the relative absence of new symptoms, the patient underwent video-assisted thoracoscopic surgery with lingular wedge biopsy. Sections showed multiple foci of columnar cells lining the alveolar septa (Fig 2A). There was a background of acute inflammation involving the alveolar septa, with columnar cells lining the alveolar septa and within the alveolar space (Fig 2B). Intraalveolar plugs of fibroblasts were also present (Fig 2C). Some of the columnar cells contained apical mucin droplets, which were confirmed by periodic acid-Schiff staining with diastase (Fig 2D). Immunohistochemical staining was performed on one of the areas with prominent columnar cells. The columnar cells were positive for cytokeratin (CK) 7 but negative for CK20, thyroid transcription factor (TTF)-1, CDX-2, p53, and MIB-1.

Figure Jump LinkFigure 2. A, Tumor cells lining alveolar septa in a predominantly lepidic growth pattern (hematoxylin and eosin stain, original magnification ×100). B, Acute inflammation involving the alveolar septa, tumor cells, and alveolar space (hematoxylin and eosin stain, original magnification ×200). C, Intraalveolar plugs of fibroblasts (hematoxylin and eosin stain, original magnification ×100). D, Periodic acid-Schiff with diastase stain confirming the presence of intracellular mucin (Periodic acid-Schiff with diastase stain, original magnification ×200).Grahic Jump Location
What is the diagnosis?
Diagnosis: Invasive mucinous adenocarcinoma (formerly mucinous bronchioloalveolar carcinoma) with concomitant cryptogenic organizing pneumonia
Clinical Discussion

We report the case of a 41-year-old man with a presumptive diagnosis of bronchiectasis and a history of recurrent pneumonia. The clinical differential diagnosis included chronic infections; however, repeated culture test results were negative. The patient was not at risk of chronic aspiration or lipoid pneumonia. Other entities including malignancy, cryptogenic organizing pneumonia (COP), and inflammatory pseudotumor or plasma cell granuloma, remained on the differential diagnosis.

In 2011, the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society recommended that lesions previously termed “mucinous bronchioloalveolar carcinoma”1 be called “invasive mucinous adenocarcinoma.”2 Invasive mucinous adenocarcinomas consist of tumor cells with goblet or columnar morphology and abundant intracytoplasmic mucin. The tendency is for multifocal, multilobar, and bilateral lung involvement, perhaps from aerogenous spread. Distinction from the rare mucinous forms of adenocarcinoma in situ and minimally invasive adenocarcinoma may be made by a size >3 cm, a focus of invasion >0.5 cm, the presence of multiple nodules, or the absence of a circumscribed border with miliary spread into adjacent lung parenchyma.2 Small (≤3 cm) solitary tumors with pure lepidic growth are termed “mucinous adenocarcinoma in situ,”2 whereas small (≤3 cm) solitary tumors with a predominantly lepidic growth with ≤5 mm of invasion are termed “mucinous minimally invasive adenocarcinoma.”2 Despite predominantly lepidic growth seen in the lingular wedge resection in our case, the multifocality of the tumor and the presence of columnar cells with apical mucin droplets led to the diagnosis of invasive mucinous adenocarcinoma.

Nearly one-half of patients with invasive mucinous adenocarcinoma are asymptomatic at presentation. Cough, chest pain, and weight loss are the most common symptoms. Invasive mucinous adenocarcinoma may cause a productive cough with abundant mucoid secretions called bronchorrhea, as noted in the patient on presentation. Invasive mucinous adenocarcinoma portends a poorer prognosis than nonmucinous adenocarcinoma with a lepidic component.3,4

Organizing pneumonia (OP) is a pattern of lung injury that, if idiopathic, has been referred to as “COP” or idiopathic bronchiolitis obliterans organizing pneumonia (BOOP).5,6 However, OP is also secondary to many causes, including infection, collagen vascular diseases, drug reactions, and radiation. OP may also be a nonspecific reaction adjacent to lesions such as abscesses, infarcts, or neoplasms.6,7 One-half of patients with COP present clinically with suspected pneumonia.8

We suspect that the patient had at least a component of COP. He had long-standing abnormal CT scan lung findings dating back to 2004 that never completely resolved but rather appeared to progress slowly over time; only some consolidation in the lingula improved by the time of presentation. The generally poor prognosis of invasive mucinous adenocarcinoma made it unlikely that he had cancer all along. A review of the literature revealed one case report of concomitant BOOP and bronchioloalveolar carcinoma.9

It is possible that invasive mucinous adenocarcinoma developed in response to COP. Lung carcinomas have been reported to arise from inflammatory conditions such as cavitary TB.10 Alternatively, OP could have arisen as a host immune response to neoplasm or because of obstructive pneumonia secondary to tumor.7 BOOP has also been described as coexisting with adenocarcinoma separately within the lungs.11

Corticosteroids have been used for the treatment of COP. Most patients show a rapid response. Reports suggest that erythromycin can be used instead of corticosteroids for treatment of COP as a corticosteroid-sparing agent.12 The hypothesis is that either the antiinflammatory effect of erythromycin is beneficial or, in some instances, the cause of COP may be an unidentified infectious agent. Hence, antibiotics could explain the patient’s clinical improvement and mild clearing in the lingula on imaging.

Radiologic Discussion

Chest CT scans from outside institutions spanning a 5-year period demonstrated bilateral nodular, lobular, and confluent ground-glass lung opacities intermixed with consolidation and air bronchograms, slowly progressing over time in both conspicuity and extent. The absence of complete resolution or change in distribution suggested an indolent rather than a recurrent process.

The differential diagnosis based on these findings included invasive mucinous or nonmucinous adenocarcinoma, OP, lymphoma, and the increasingly recognized entity of IgG4-related sclerosing disease.13 An indolent infection such as Mycobacterium avium complex or actinomycosis was not supported by the prolonged duration and progressive nature over 5 years. The addition of clinical history decreased the likelihood of aspiration.

Lung adenocarcinoma may appear on imaging as a solitary lesion, segmental/lobar opacity, or multifocal/diffuse disease. Lesions may be purely ground glass, solid/consolidated, or mixed. Air bronchograms are a frequent association. Invasive mucinous adenocarcinoma, as in our case, typically manifests as multifocal and multilobar disease, with the mucoid component creating a solid or consolidated appearance. Aerogenous spread is a reported association. Of note, the imaging features of invasive mucinous and nonmucinous adenocarcinoma overlap.2,4

In immunocompetent patients, COP most commonly presents with subpleural and peribronchovascular areas of consolidation. These may be intermixed with ground-glass opacification and/or nodules.14

The fact that both COP and adenocarcinoma may demonstrate chronic consolidation and areas of ground glass complicated the treatment and follow-up for the patient. Specifically, we were not able to stage his cancer accurately because we could not identify tumor boundaries on imaging. Difficulty separating the two processes was compounded by the relative lack of imaging response to both corticosteroids and chemotherapy.

Pathologic Discussion

Invasive mucinous adenocarcinomas of the lung frequently have a different immunohistochemical staining pattern from nonmucinous primary pulmonary adenocarcinomas. This staining pattern is similar to GI primaries and may raise the possibility of metastatic colorectal mucinous adenocarcinoma. Typically, nonmucinous primary pulmonary adenocarcinomas are positive for CK7 and negative for CK20.2 Invasive mucinous adenocarcinomas are positive for CK7 in 83% to 100% of cases but also positive for CK20 in 25% to 89% of cases.15,16

Nonmucinous pulmonary adenocarcinomas are positive for TTF-1 in 75% to 94% of cases,16 whereas invasive mucinous adenocarcinomas are positive for TTF-1 in only 0% to 27.5% of cases.15,16 CDX-2 is typically positive in mucinous colorectal carcinomas and negative in pulmonary nonmucinous adenocarcinomas,17,18 but all cases of mucinous adenocarcinomas of the lung were found to be positive for CDX-2.18 In this case, the tumor was positive for CK7 and negative for CK20, TTF-1, and CDX-2.

The differential diagnosis for this case included reactive type 2 pneumocyte hyperplasia, especially with the presence of neutrophils in the epithelium and the background of OP. Type 2 pneumocytes are typically positive for TTF-1, so for this case and in cases of invasive mucinous adenocarcinoma, negative TTF-1 immunostain may be useful for differentiating between reactive type 2 pneumocyte hyperplasia and involvement by tumor, especially on small biopsies.

Whenever possible, tumor should be assessed for the presence of an epidermal growth factor receptor (EGFR) mutation, given the clinical benefit from oral EGFR tyrosine kinase inhibitors. Mutations in EGFR have been described as being present in 47% to 78% of nonmucinous adenocarcinoma with lepidic growth pattern but in only 0% to 22% of invasive mucinous adenocarcinoma.19,20 In contrast, mutations in the k-ras oncogene are reported in only 2% to 17% of nonmucinous adenocarcinoma with lepidic growth pattern but in 67% to 86% of invasive mucinous adenocarcinoma.19,20 The patient showed k-ras mutation with Gly12QAsp deletion but no EGFR mutation. Thus, he was not a candidate for tyrosine kinase inhibitors.

In summary, we describe a case of concomitant invasive mucinous adenocarcinoma and COP in a young nonsmoking man, indistinguishable by imaging. With multifocal disease, the extent of invasive mucinous adenocarcinoma was never clear because of coexisting COP. He received the “standard” cytotoxic doublet containing carboplatin and pemetrexed. He finished six cycles of doublet and continued on maintenance pemetrexed. He is currently doing well. This is a rare entity with difficulties of staging, treatment, and follow-up.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Colby TV, Noguchi M, Henschke C, et al;. Adenocarcinoma.. In:Travis WD, Brambilia E, Muller-Hermelink HK, Harris CC., eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus, and Heart. Lyon, France: IARC Press; 2004:35-44.
 
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. [CrossRef] [PubMed]
 
West HL, Garfield DH. Bronchioloalveolar carcinoma: not as easy as “BAC.”. J Thorac Oncol. 2009;4(9):1047-1048. [CrossRef] [PubMed]
 
Lee KS, Kim Y, Han J, Ko EJ, Park CK, Primack SL. Bronchioloalveolar carcinoma: clinical, histopathologic, and radiologic findings. Radiographics. 1997;17(6):1345-1357. [PubMed]
 
Epler GR, Colby TV, McLoud TC, Carrington CB, Gaensler EA. Bronchiolitis obliterans organizing pneumonia. N Engl J Med. 1985;312(3):152-158. [CrossRef] [PubMed]
 
Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Muller NL, King TE. Idiopathic interstitial pneumonia and other diffuse parenchymal lung disease.. In:King DW., ed. Atlas of Nontumor Pathology: Non-Neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology; 2002:82-89.
 
Romero S, Barroso E, Rodriguez-Paniagua M, Aranda FI. Organizing pneumonia adjacent to lung cancer: frequency and clinico-pathologic features. Lung Cancer. 2002;35(2):195-201. [CrossRef] [PubMed]
 
Cordier JF. Cryptogenic organising pneumonia. Eur Respir J. 2006;28(2):422-446. [CrossRef] [PubMed]
 
Song J, Gorgan L, Corkey R, Kwa SL. An unusual case of bronchiolitis obliterans organizing pneumonia concomitant with bronchioloalveolar carcinoma. Respiration. 2004;71(1):95-97. [CrossRef] [PubMed]
 
Gezer S, Kilicgün A, Tosun S. An adenocarcinoma developed in tuberculosis cavity. Eur J Cardiothorac Surg. 2011;39(1):139. [CrossRef] [PubMed]
 
Arrabal Sánchez R, Mongil Poce R, Benítez Doménech A, Fernández de Rota Avecilla A, Fernández Bermúdez JL. Bronchiolitis obliterans organizing pneumonia and bronchogenic carcinoma coexisting in different parts of the lungs [in Spanish]. Arch Bronconeumol. 2004;40(3):141-143. [PubMed]
 
Stover DE, Mangino D. Macrolides: a treatment alternative for bronchiolitis obliterans organizing pneumonia?. Chest. 2005;128(5):3611-3617. [CrossRef] [PubMed]
 
Inoue D, Zen Y, Abo H, et al. Immunoglobulin G4-related lung disease: CT findings with pathologic correlations. Radiology. 2009;251(1):260-270. [CrossRef] [PubMed]
 
Lee KS, Kullnig P, Hartman TE, Müller NL. Cryptogenic organizing pneumonia: CT findings in 43 patients. AJR Am J Roentgenol. 1994;162(3):543-546. [PubMed]
 
Goldstein NS, Thomas M. Mucinous and nonmucinous bronchioloalveolar adenocarcinomas have distinct staining patterns with thyroid transcription factor and cytokeratin 20 antibodies. Am J Clin Pathol. 2001;116(3):319-325. [CrossRef] [PubMed]
 
Lau SK, Desrochers MJ, Luthringer DJ. Expression of thyroid transcription factor-1, cytokeratin 7, and cytokeratin 20 in bronchioloalveolar carcinomas: an immunohistochemical evaluation of 67 cases. Mod Pathol. 2002;15(5):538-542. [CrossRef] [PubMed]
 
Tsuta K, Ishii G, Nitadori J, et al. Comparison of the immunophenotypes of signet-ring cell carcinoma, solid adenocarcinoma with mucin production, and mucinous bronchioloalveolar carcinoma of the lung characterized by the presence of cytoplasmic mucin. J Pathol. 2006;209(1):78-87. [CrossRef] [PubMed]
 
Rossi G, Murer B, Cavazza A, et al. Primary mucinous (so-called colloid) carcinomas of the lung: a clinicopathologic and immunohistochemical study with special reference to CDX-2 homeobox gene and MUC2 expression. Am J Surg Pathol. 2004;28(4):442-452. [CrossRef] [PubMed]
 
Finberg KE, Sequist LV, Joshi VA, et al. Mucinous differentiation correlates with absence of EGFR mutation and presence of KRAS mutation in lung adenocarcinomas with bronchioloalveolar features. J Mol Diagn. 2007;9(3):320-326. [CrossRef] [PubMed]
 
Sakuma Y, Matsukuma S, Yoshihara M, et al. Distinctive evaluation of nonmucinous and mucinous subtypes of bronchioloalveolar carcinomas in EGFR and K-ras gene-mutation analyses for Japanese lung adenocarcinomas: confirmation of the correlations with histologic subtypes and gene mutations. Am J Clin Pathol. 2007;128(1):100-108. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. A and B, Axial images (5-mm-thick sections) from an outside chest CT scan 2 years previously demonstrate focal and diffuse mixed ground-glass and consolidative lung opacities, variably seen in the basal upper lobes, right middle lobe, and lingula; an air cyst is noted in the left upper lobe (arrow). C and D, Posterior-anterior and lateral chest radiographs obtained at presentation show a mix of nodular, patchy, and consolidative lung opacities in the basal upper lobes, lingula, and left lower lobe, and, to a lesser extent, in the right middle lobe. E and F, Axial images (1.25-mm-thick sections) from the chest CT scan acquired at presentation show worsening ground glass and consolidation in the basal upper lobes, slight clearing of consolidation in the lingula (double arrow head), and development of focal centrilobular ground-glass opacities in both lower lobes; an air cyst is again noted in the left upper lobe (arrow).Grahic Jump Location
Figure Jump LinkFigure 2. A, Tumor cells lining alveolar septa in a predominantly lepidic growth pattern (hematoxylin and eosin stain, original magnification ×100). B, Acute inflammation involving the alveolar septa, tumor cells, and alveolar space (hematoxylin and eosin stain, original magnification ×200). C, Intraalveolar plugs of fibroblasts (hematoxylin and eosin stain, original magnification ×100). D, Periodic acid-Schiff with diastase stain confirming the presence of intracellular mucin (Periodic acid-Schiff with diastase stain, original magnification ×200).Grahic Jump Location

Tables

References

Colby TV, Noguchi M, Henschke C, et al;. Adenocarcinoma.. In:Travis WD, Brambilia E, Muller-Hermelink HK, Harris CC., eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus, and Heart. Lyon, France: IARC Press; 2004:35-44.
 
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. [CrossRef] [PubMed]
 
West HL, Garfield DH. Bronchioloalveolar carcinoma: not as easy as “BAC.”. J Thorac Oncol. 2009;4(9):1047-1048. [CrossRef] [PubMed]
 
Lee KS, Kim Y, Han J, Ko EJ, Park CK, Primack SL. Bronchioloalveolar carcinoma: clinical, histopathologic, and radiologic findings. Radiographics. 1997;17(6):1345-1357. [PubMed]
 
Epler GR, Colby TV, McLoud TC, Carrington CB, Gaensler EA. Bronchiolitis obliterans organizing pneumonia. N Engl J Med. 1985;312(3):152-158. [CrossRef] [PubMed]
 
Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Muller NL, King TE. Idiopathic interstitial pneumonia and other diffuse parenchymal lung disease.. In:King DW., ed. Atlas of Nontumor Pathology: Non-Neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology; 2002:82-89.
 
Romero S, Barroso E, Rodriguez-Paniagua M, Aranda FI. Organizing pneumonia adjacent to lung cancer: frequency and clinico-pathologic features. Lung Cancer. 2002;35(2):195-201. [CrossRef] [PubMed]
 
Cordier JF. Cryptogenic organising pneumonia. Eur Respir J. 2006;28(2):422-446. [CrossRef] [PubMed]
 
Song J, Gorgan L, Corkey R, Kwa SL. An unusual case of bronchiolitis obliterans organizing pneumonia concomitant with bronchioloalveolar carcinoma. Respiration. 2004;71(1):95-97. [CrossRef] [PubMed]
 
Gezer S, Kilicgün A, Tosun S. An adenocarcinoma developed in tuberculosis cavity. Eur J Cardiothorac Surg. 2011;39(1):139. [CrossRef] [PubMed]
 
Arrabal Sánchez R, Mongil Poce R, Benítez Doménech A, Fernández de Rota Avecilla A, Fernández Bermúdez JL. Bronchiolitis obliterans organizing pneumonia and bronchogenic carcinoma coexisting in different parts of the lungs [in Spanish]. Arch Bronconeumol. 2004;40(3):141-143. [PubMed]
 
Stover DE, Mangino D. Macrolides: a treatment alternative for bronchiolitis obliterans organizing pneumonia?. Chest. 2005;128(5):3611-3617. [CrossRef] [PubMed]
 
Inoue D, Zen Y, Abo H, et al. Immunoglobulin G4-related lung disease: CT findings with pathologic correlations. Radiology. 2009;251(1):260-270. [CrossRef] [PubMed]
 
Lee KS, Kullnig P, Hartman TE, Müller NL. Cryptogenic organizing pneumonia: CT findings in 43 patients. AJR Am J Roentgenol. 1994;162(3):543-546. [PubMed]
 
Goldstein NS, Thomas M. Mucinous and nonmucinous bronchioloalveolar adenocarcinomas have distinct staining patterns with thyroid transcription factor and cytokeratin 20 antibodies. Am J Clin Pathol. 2001;116(3):319-325. [CrossRef] [PubMed]
 
Lau SK, Desrochers MJ, Luthringer DJ. Expression of thyroid transcription factor-1, cytokeratin 7, and cytokeratin 20 in bronchioloalveolar carcinomas: an immunohistochemical evaluation of 67 cases. Mod Pathol. 2002;15(5):538-542. [CrossRef] [PubMed]
 
Tsuta K, Ishii G, Nitadori J, et al. Comparison of the immunophenotypes of signet-ring cell carcinoma, solid adenocarcinoma with mucin production, and mucinous bronchioloalveolar carcinoma of the lung characterized by the presence of cytoplasmic mucin. J Pathol. 2006;209(1):78-87. [CrossRef] [PubMed]
 
Rossi G, Murer B, Cavazza A, et al. Primary mucinous (so-called colloid) carcinomas of the lung: a clinicopathologic and immunohistochemical study with special reference to CDX-2 homeobox gene and MUC2 expression. Am J Surg Pathol. 2004;28(4):442-452. [CrossRef] [PubMed]
 
Finberg KE, Sequist LV, Joshi VA, et al. Mucinous differentiation correlates with absence of EGFR mutation and presence of KRAS mutation in lung adenocarcinomas with bronchioloalveolar features. J Mol Diagn. 2007;9(3):320-326. [CrossRef] [PubMed]
 
Sakuma Y, Matsukuma S, Yoshihara M, et al. Distinctive evaluation of nonmucinous and mucinous subtypes of bronchioloalveolar carcinomas in EGFR and K-ras gene-mutation analyses for Japanese lung adenocarcinomas: confirmation of the correlations with histologic subtypes and gene mutations. Am J Clin Pathol. 2007;128(1):100-108. [CrossRef] [PubMed]
 
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