Case 1 -

Adenocarcinoma of Mixed Histologic Type (pT1a) Arising in Usual Interstitial Pneumonia Jeffrey L. Myers University of Michigan Ann Arbor, MI

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Clinical History: A 79-year-old man presented for evaluation of a lung nodule. He had a history of idiopathic pulmonary fibrosis, a diagnosis established 5 months prior to admission on the basis of clinical and radiological abnormalities. He had experienced the insidious onset of shortness of breath over the 4 months prior to his initial evaluation. At that time high resolution CT scan showed not only diffuse abnormalities but also a 1.5 mass in the superior segment of his right lower lobe that enlarged to 2 cms over a 5 month interval (see CT scan image). Other significant past medical history included coronary artery disease for which he underwent bypass grafting three and a half years prior to admission. He had smoked 1 pack of cigarettes per day for 13 years, but quit about 4 years prior to developing respiratory symptoms. Pulmonary function studies showed a mild restrictive defect (FVC 68% of the predicted value) with moderate impairment in gas exchange (DLCO 55% of the predicted value). He underwent video-assisted thoracoscopic surgery and wedge biopsy of his right lower lobe. Case 1 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 1 - Figure 1 Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: At low magnification there is an adenocarcinoma with a variety of growth patterns including areas with bronchioloalveolar, acinar, solid and micropapillary architecture. In some ares the adenocarcinoma merges with zones of honeycomb change in which cystic air spaces are lined by non-neoplastic, ciliated respiratory epithelium. On closer inspection there are foci in which there is an abrupt transition from non-neoplastic to neoplastic epithelium. Away from the tumor there is patchy fibrosis that includes the aforementioned honeycomb change. Combined with the patchy fibrosis this is strong evidence in support of usual interstitial pneumonia (UIP). Differential Diagnoses: The wedge biopsy and completion lobectomy of his right lower lobe showed a peripheral tumor measuring 1.1 x 0.9 x 0.9 cms that abutted but did not invade visceral pleura. All sampled N1 and N2 lymph nodes were free of tumor. Histologically his tumor shows a mixed pattern typical of primary pulmonary adenocarcinomas comprising areas of bronchioloalveolar, acinar, micropapillary and solid growth. While the diagnosis of adenocarcinoma is not challenging in this example, the diagnosis of UIP is. He had a history of IPF but no definite diagnosis had been established. His preoperative CT scan was described as showing, "lower lung predominant interstitial lung disease with interlobular septal thickening, mild traction bronchiectasis and minimal groundglass opacities likely nonspecific interstitial pneumonia (NSIP)." His wedge biopsy and subsequent lobectomy show a pattern of fibrosis more typical of usual interstitial pneumonia (UIP). In the section available for your review the fibrotic changes are overshadowed by the carcinoma, but demonstrate a patchy, subpleural and paraseptal distribution characteristic of UIP. Elsewhere the "patchwork" distribution is combined with peripheral architectural distortion in the form of subpleural honeycomb change and scarring. Rare subepithelial, interstitial foci of proliferating fibroblasts and myofibroblasts (fibroblast foci) typical of UIP are also present. This combination of findings establishes a diagnosis of UIP in a patient with the syndrome of IPF. Final Diagnosis: Adenocarcinoma of mixed histologic type (pT1a) arising in usual interstitial pneumonia. Case Discussion: Carcinoma is a well recognized complication of UIP and accounts for around 20% of IPF-associated deaths. [1, 2, 3, 4, 5, 6, 7, 8, 9, 10] The preponderance of evidence indicates that patients with UIP are at increased risk of developing lung carcinoma and that the risk may be confounded by the prevalence of cigarette smoking. [5, 6] Men account for about 90% of patients in retrospective observational studies. [1, 9, 11, 12, 13] Affected patients are also likely to be older, with an average age at carcinoma diagnosis of 65 to 75 years, and over 90% have a smoking history. [1, 9, 11] A substantial number of patients may not be known to have IPF at the time that they undergo lung cancer surgery, a finding emphasized by several authors including an abstract presented in poster form by Schmidt and associates at this year's annual USCAP meeting. [1, 12] Squamous cell carcinoma is over represented in patients with UIP-associated lung carcinomas. In surgical series published since 2000, squamous cell carcinoma accounts for just over 47% of tumors. [1, 9, 11, 12] UIP-associated carcinomas are more likely to be peripherally located and are frequently situated within areas of lung fibrosis. In an abstract presented at this year's USCAP meeting Dr. Lunardi and colleagues suggest that squamous cell carcinoma antigens (SCCA)-1/2 (SERPIN B3/B4) may play a role in modulating both lung fibrosis and aberrant epithelial proliferation. [14] Review of the Literature/Treatment Options (if applicable): Patients with UIP who undergo surgical resection for lung carcinomas experience higher rates of post-operative complications and hospital mortality. [1, 11, 13] There is no single factor that predicts which UIP patients are at greatest risk for developing postoperative respiratory failure. Overall survival in UIP patients with early stage carcinoma is worse than patients with comparable stage lung cancer who lack UIP. [1, 11, 13] Conclusion(s): Carcinoma is an important and frequently fatal complication in patients with UIP. Having carcinoma with underlying UIP is an important risk factor that predicts not only a poor prognosis but also higher morbidity from various treatment strategies. It is important to identify UIP in non- neoplastic lung, something that may be more common than previously understood especially in older men. References: Aubry M-C, Myers JL, Douglas WW, et al. Primary Pulmonary Carcinoma in Patients With Idiopathic Pulmonary Fibrosis. Mayo Clin Proc 2002; 77: 763-70. Fox B, Risdon RA. Carcinoma of the lung and diffuse interstitial pulmonary fibrosis. J Clin Pathol 1968; 21: 486-91. Fraire AE, Greenberg SD. Carcinoma and diffuse interstitial fibrosis of lung. Cancer 1973; 31: 1078-86. Haddad R, Massaro D. Idiopathic diffuse interstitial pulmonary fibrosis (fibrosing alveolitis), atypical epithelial proliferation and lung cancer. Am J Med 1968; 45: 211-9. Harris JM, Johnston IDA, Rudd R, Taylor AJN, Cullinan P. Cryptogenic fibrosing alveolitis and lung cancer: the BTS study. Thorax 2010; 65: 70-6. Hubbard R, Venn A, Lewis S, Britton J. Lung Cancer and Cryptogenic Fibrosing Alveolitis . A Population-based Cohort Study. Am J Respir Crit Care Med 2000; 161: 5-8. Meyer EC, Liebow AA. Relationship of interstitial pneumonia honeycombing and atypical epithelial proliferation to cancer of the lung. Cancer 1965; 18: 322- 51. Olson AL, Swigris JJ, Lezotte DC, Norris JM, Wilson CG, Brown KK. Mortality from pulmonary fibrosis increased in the United States from 1992 to 2003. Am J Respir Crit Care Med 2007; 176: 277-84. Park J, Kim DS, Shim TS, et al. Lung cancer in patients with idiopathic pulmonary fibrosis. Eur Respir J 2001; 17: 1216-9. Turner-Warwick M, Lebowitz M, Burrows B, Johnson A. Cryptogenic fibrosing alveolitis and lung cancer. Thorax 1980; 35: 496-9. Kawasaki H, Nagai K, Yoshida J, Nishimura M, Nishiwaki Y. Postoperative morbidity, mortality, and survival in lung cancer associated with idiopathic pulmonary fibrosis. J Surg Oncol 2002; 81: 33-7. Schmidt L, Medina E, Flaherty K, Myers JL. Usual interstitial pneumonia in lungs resected for carcinoma. 2010 USCAP Poster #1842. Watanabe A, Higami T, Ohori S, Koyanagi T, Nakashima S, Mawatari T. Is lung cancer resection indicated in patients with idiopathic pulmonary fibrosis? J Thorac CV Surg 2008; 136: 1357-63e2. Lundardi F, Loy M, Balestro E, et al. Squamous cell carcinoma antigen (SCCA)-2 is overexpressed in end-stage idiopathic pulmonary fibrosis and correlates with epithelial proliferation. 2010 USCAP Poster #1823.