Case 5 -

Squamous Cell Carcinoma Arising in Idiopathic Pulmonary Fibrosis Dr. Sylvie Lantuejoul Department of Pathology, CHU Albert Michallon Grenoble, France

Clinical history: 70 year-old smoker (40 pack/year) with a past history of lung fibrosis with honeycombing diagnosed three years ago. The patient had a severe restrictive pulmonary function testing and CT scan showed honeycombing predominating in both bases. He was found to present a left lower lobe mass increasing in size. A lobectomy was performed. Case 5 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 5 - Slide 2 Click to view with ImageScope Click to view with a Web-Based Viewer Slide A: mass; slide B: non-tumoral lung. Description of the slides: Slide A illustrates a peripheral moderately differentiated squamous cell carcinoma of 30 mm of great diameter, pT1N2; Slide B, performed away from the tumour in another subpleural area, shows an interstitial lung disease of Usual Interstitial Pneumonia (UIP) pattern, with numerous foci of alveolar squamous metaplasia and bronchiolar metaplasia. Diagnosis : Squamous cell carcinoma arising on idiopathic pulmonary fibrosis Discussion : Idiopathic pulmonary fibrosis is the most frequent and the most serious idiopathic interstitial pneumonia. It represents a clinicopathological entity based on HRCT findings, such as reticular pattern and honeycombing predominantly in subpleural regions, and on a histological pattern of Usual Interstitial Pneumonia (UIP). It affects predominantly men, frequently smokers, with an age at time of diagnosis between 50 and 70 [1]. Clinically, patients present with progressive shortening of breath, non-productive cough and abnormal respiratory function tests including restriction and impaired gas exchange. The prognosis remains very poor despite aggressive immunosuppressive and cytotoxic treatments, and the mean survival from the onset of dyspnea varies from 3 to 6 years. Histologically, the UIP pattern is characterised by localised fibrotic areas of various ages, namely of temporal heterogeneity, with a predominant subpleural and paraseptal distribution, alternating with normal lung. These fibrotic zones correspond at higher power of dense scarring and honeycombing, with collapsed alveolar spaces and newly formed cystic spaces lined by bronchiolar metaplasia. At the edge of these dense scars, fibroblastic foci composed of spindle cells in a loose connective tissue are found underlying alveolar epithelial cells. Additional findings are a mild to moderate interstitial inflammation, smooth muscle proliferation and secondary vascular changes. Occasionally, alveolar cells in close vicinity with fibroblastic foci exhibit squamous metaplasia, sometimes with frank atypia. Meyer and Liebow [2] have reported in 1965, 32 cases out of 153 surgical resections of lung carcinoma associated with underlying honeycombing changes, with the demonstration of transitional changes from alveolar atypia to truly malignant areas, suggesting that atypical cells observed in UIP could represent carcinoma precursors. More recent studies based on clinical and histopathological findings have investigated the features of lung cancer in the setting of UIP [3, 4, 5, 6]. The incidence of lung cancer associated with idiopathic pulmonary fibrosis ranges from 9 to 38% and the relative risk is 14.2 for male smokers and 6.7 for female smokers [5]. There a high male preponderance, and the mean age for patients with lung cancer on UIP is slightly higher (63 yrs) than for UIP patients without cancer (58yrs). The prognosis of lung cancer on UIP is poor, with a shorter survival of 1.6 year, in contrast with 2.3 years for UIP patients without cancer [4]. Nearly two third of them are heavy smokers (more than 40 pack/year), suggesting that the association between UIP and cancer may be due to confounding by smoking. However, the relationship between UIP and cancer seems stronger than that between UIP and smoking [7]. On the histological point of view, lung cancers arising on UIP are frequently multiple (22% versus 3.4% without UIP) [3], with a significant higher incidence of small cell carcinoma combined with squamous cell carcinoma or adenocarcinoma [8]. However, the distribution of histological subtypes varies according to series but seems to be for the majority of them similar to that of lung cancer without UIP. Lung carcinomas in UIP predominate in lower lobes and in peripheral locations [4]. According to Nagai et al, there is no relationship between the severity of fibrosis and the incidence of lung cancer [9]. Differential diagnosis: The main differential diagnosis is represented by a carcinoma associated with an extensive and inflammatory background, mimicking an inflammatory lung disease with honeycombing at histology [10, 11, 12] . Carcinoma are able to induce fibrosis and inflammation, questioning the the so- called "scar carcinoma" concept where carcinoma arise preferentially on a preexisting scaring tissue. Other fibrotic lung diseases are said to increase the risk of lung cancer including asbestosis, silicosis and a past history of tuberculosis [13]. In case of carcinoma with fibrosis, the clinical history and the CT findings are essential to assert the diagnosis of an underlying idiopathic pulmonary fibrosis. Another dilemma is represented by the distinction between carcinoma and alveolar cell metaplasia. Squamous cell carcinoma differs from squamous metaplasia by the presence of stromal invasion. Cells are more atypical, forming solid lobules and mitoses are not rare. Adenocarcinoma differs from bronchiolar metaplasia by the presence of monotonous atypical cuboidal or columnar cells, frequently mucus secreting, and responsible for papillary projection formations and a crowded growth. Pathogenesis : Atypia in honeycombing areas are found in nearly 20% of the UIP, perhaps more frequently when a carcinoma is found concomitantly [3], suggesting that these atypia could represent carcinoma precursors. Microsatellite instability and LOH at loci of tumour suppressor genes, such as p53, Rb, FHIT and p16INK4, have been reported in cytologic sputum samples from patients with UIP [14, 15]. A P53 immunohistochemical expression and p53 mutations were demonstrated in 60% and 40% of squamous metaplasia in UIP, respectively [16] . However, other authors have suggested that P53 expression, along with P21 expression and presence of DNA breaks, is related to a response to DNA damage due to tobacco carcinogens [17]. Diffuse inflammatory process may also increase the risk of lung cancer development, and further analyses are required to assess the clinical significance and the prognostic value of these molecular and genetic abnormalities for the development of lung cancer on UIP. References American Thoracic Society, European Respiratory Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. Am J Respir Crit Care Med 2000, 161: 646- 664 Meyer EC, Liebow AA. Relationship of interstitial pneumonia honeycombing and atypical epithelial proliferation to cancer of the lung. Cancer 1965, 18: 322- 351 Hironaka M, Fukayama M. Pulomonary fibrosis and lung carcinoma: a comparative study of metaplastic epithelia in honeycombed areas of usual interstitial pneumonia with or without lung carcinoma. Pathol Int 19999, '9: 1060- 1066 Aubry MC, Myers JL, Douglas WW, Tazelaar HD, Washington Stephens TL, Hartman TE, Deschamps C, Pankratz S. Primary pulmonary carcinoma in patients with idiopathic pulmonary fibrosis. Mayo Clin Proc 2002, 77: 763- 770 Turner-Warwick M, Lebowitz M, Burrows B, Johnson A. Cryptogenic fibrosing alveolitis and lung cancer. Thorax 1980, 35: 496- 499 Kawai T, Yakumaru K, Suzuki M, Kageyama K. Diffuse interstitial fibrosis and lung cancer. Acta Pathol Jpn 1987, 37: 11- 19 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 Nagai A, Chiyotani A, Nakadate T, Konno K. Lung cancer in patients with idiopathic pulmonary fibrosis. Tohoku J Exp Med 1992, 167: 231- 7. Mizushima Y, Kobayashi M. Clinical characteristic of synchronous multiple lung cancer associated with idiopathic pulmonary fibrosis: a review of Japanses cases. Chest 1995, 108: 1272- 1277 Colby TV. Malignancies in the lung and pleura mimicking benign process. Semin Diagn Pathol 1995, 12: 30- 44 Colby TV, Koss MN, Travis WD. Atlas of Tumor Pathology: Tumors of the Lower Respiratory Tract. Washington DC, AFIP 1995, p 179- 201 Lantuejoul S, Colby TV, Ferretti GR, Brichon PY, Brambilla C, Brambilla E. Adenocarcinoma of the lung mimicking inflammatory lung disease with honeycombing. Eur Respir J. 2004, 24:502-5 Tockman MS. Other host factors and lung cancer susceptibility. In JM Samet, editor. Epidemiology of lung cancer. Marcel Dekker New York, 1994, 397- 412 Vassilakis DA, Sourvinos G, Spandidos DA, Siafakas NM, Bouris D. Frequent genetic alterations at the microsatellite level in cytologic sputum samples of patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care 2000, 162: 1115- 1119 Demopoulos K, Arvanitis DA, Vassilakis DA, Siafakas NM, Spandidos DA. MYCL1, FHIT, SPARC, p16INK4 and TP53 genes associated to lung cancer in idiopathic pulmonary fibrosis. 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