—  SPECIALTY CONFERENCE  —

Pulmonary Pathology

Case 2 - Squamous Cell Carcinoma Arising in Usual Interstitial Pneumonia

Marie-Christine Aubry
Mayo Clinic
Rochester, MN


Click on each slide thumbnail image for an enlarged view
Clinical History
A 68 year-old man was investigated for persistent chest pain. He also complained of progressive shortness of breath and dry cough for several months. He had no significant past medical or familial history. He was a current smoker of 90 pack-years. His pulmonary function test showed mild restriction. Chest X-ray and CT Scan were performed and showed a spiculated peripheral mass in the left lower lobe. Bilateral fibrotic infiltrates were also noted. He underwent a left lower lobectomy, which was complicated by prolonged ventilator dependence, bronchopleural fistula and infection of muscle flap. He was eventually dismissed to hospice care and died 6 months following his surgery.


Case 2 - Figure 1 - Usual interstitial pneumonia. Interstitial pneumonia with heterogeneous appearance at low magnification, with alternating areas of normal lung, fibrosis and honeycomb change (H&E, 20x).
Case 2 - Figure 2 - Usual interstitial pneumonia. Interstitial inflammation and fibrosis is patchy, with fibrosis mainly comprised of collagen deposition (H&E, 100x).
Case 2 - Figure 3 - Usual interstitial pneumonia. Scattered foci comprised of proliferating fibroblasts in a myxoid background can also be seen (H&E, 200x).


Case 2 - Figure 4 - Usual interstitial pneumonia. Areas of honeycomb change are comprised of dilated airspaces, filled with mucin, and surrounded by fibrosis resulting in architectural distortion (H&E, 40x).
Case 2 - Figure 5 - Usual interstitial pneumonia. The dilated airspaces are frequently lined by bronchiolar epithelium but squamous metaplasia can also be seen (H&E, 200x).


Case 2 - Figure 6 - Squamous cell carcinoma. The mass is comprised of large anastomosing nests of cells with central necrosis, embedded in a fibrotic stroma (H&E, 40x).
Case 2 - Figure 7 - Squamous cell carcinoma. At high power, dyskeratosis and intercellular bridges are seen (H&E, 400x).

Diagnosis
Squamous cell carcinoma arising in usual interstitial pneumonia

Discussion

Usual interstitial pneumonia/ Idiopathic pulmonary fibrosis.
Usual interstitial pneumonia (UIP) is the most common idiopathic interstitial pneumonia and is the histologic correlate of idiopathic pulmonary fibrosis (IPF), also referred to as cryptogenic fibrosing alveolitis. Patients are usually men in their 5th or 6th decade complaining of shortness of breath and cough. Onset is commonly insidious and symptoms present for more than 6 months. Physical exam reveals end-inspiratory rales described as Velcro-type. Digital clubbing is present in up to half of patients. Restrictive pattern with decreased diffusion capacity and low resting oxygen saturation are common findings on pulmonary function tests. Although no consistent risk factor has been described, patients often have a history of smoking and in one study, ever smokers had a 60% increased risk of developing IPF. Chest radiographs show decreased lung volumes with bilateral interstitial reticular or linear infiltrates. Typical high-resolution CT scans show peripheral, subpleural, bibasilar reticular opacities associated with architectural distortion such as honeycomb change and traction bronchiectasis. Prognosis is poor with reported mortality rates of 55-70% and median survival as low as 2.8 years from time of diagnosis. Although most patients succumb to respiratory failure, death by lung cancer occurs in 10 to 17% of patients with IPF.

Histologically, UIP is characterized by a heterogeneous appearance due to alternating areas of normal lung, interstitial chronic inflammation and fibrosis, and honeycomb change. The peripheral and subpleural parenchyma is most severely involved. The interstitial inflammation is usually mild and patchy, comprised of lymphocytes, plasma cells and histiocytes within alveolar septa. The fibrosis shows temporal heterogeneity with mostly dense acellular collagen deposition and scattered small foci of fibroblast proliferation. Smooth muscle hyperplasia is commonly seen in areas of fibrosis and honeycomb change. Transition between abnormal areas is usually abrupt. Areas of honeycomb change are characterized by dilated airspaces, commonly lined by bronchiolar epithelium and filled with inspissated mucus. Epithelial abnormalities accompanying interstitial changes include alveolar hyperplasia, bronchiolar and squamous metaplasia, with varying degrees of cytologic atypia. Although the cytologic atypia is usually considered reactive, the increased number of genetic abnormalities demonstrated in some studies suggests that it potentially represents pre-neoplastic epithelium and therefore site of induction for invasive carcinoma.

Lung cancer associated with usual interstitial pneumonia/ idiopathic pulmonary fibrosis.
The association of pulmonary fibrosis and carcinoma has been recognized since 1939 when Friedrich first described peripheral carcinomas arising in focal scarring. Beaver and Spain subsequently suggested and association between bronchioloalveolar carcinoma and diffuse interstitial fibrosis of various etiologies, speculating that the epithelial hyperplasia observed in areas of fibrosis may progress to lung carcinoma. In 1965, Meyer and Liebow showed that carcinomas arose from atypical hyperplasia within areas of honeycomb change. They identified underlying honeycomb change in 32 (21%) of 153 consecutive surgical resections for lung carcinoma. All were male smokers, the majority over 60 years of age, who developed peripheral carcinomas, mostly squamous cell carcinomas, with a predilection for the upper lobes. Areas of transition between atypical non-neoplastic epithelium and carcinoma were histologically demonstrated, foresight to the hyperplasia-dysplasia-neoplasia sequence now well accepted in carcinogenesis.

Subsequent investigators have described carcinoma arising in diffuse pulmonary fibrosis of various etiologies and in IPF, however often without histologic confirmation of UIP. Thus the reported frequency of lung cancer in IPF has varied anywhere between 4.8- 48.2%. In series with histologic confirmation, the frequency is closer to 7%. These data suggest an excess risk of lung cancer in patients with IPF. Patients with lung carcinoma arising in IPF are most commonly men, with reported ratios of more than 10:1, exceeding ratios observed in IPF or primary lung carcinoma alone. Some studies even suggest that male gender is an independent risk factor for developing lung cancer in IPF.

Debates still exist regarding the role of cigarette smoking in the development of lung cancer in patients with IPF. Some studies support cigarette smoking as an independent risk factor, with significant increase in the proportion of smokers and pack-years or smoking index in patients with IPF and carcinoma, in comparison to patients with IPF or carcinoma alone. However, this is not supported by other studies which argue that cigarette smoking is a confounding factor, demonstrating that non-smokers with IPF are also at increased risk of developing lung cancer, findings which would suggest other involved risk factors, including potential role of fibrosis in carcinogenesis. Indeed the majority of cancers arising in IPF are peripheral, commonly in the lower lobes, in areas of fibrosis. In recent series, squamous cell carcinoma has been the most common histologic tumor type, despite its peripheral lower lobe location. In contrast, lung carcinoma not in association with IPF usually arises in the upper lobes. Adenocarcinoma is the predominant subtype in current lung cancer series and squamous cell carcinoma most commonly presents as a central mass.

In the Mayo Clinic series, discovery of lung cancer in patients with IPF was incidental in nearly half of the patients. This is most likely attributable to the fact that these patients underwent more frequent chest radiographs in the course of follow-up for IPF or other medical conditions. In several studies, the degree of restriction on PFT in patients who developed cancer was often less severe than patients with IPF alone, in part due to the presence of combined obstruction in this greater smoking population.

The diagnosis of IPF is commonly made during investigation of pulmonary symptoms related to lung cancer or at the time of surgery for lung cancer. In the Mayo Clinic series, only 21% of patients had an established diagnosis of IPF, for an average of 5.5 years. The majority (67%) had IPF and lung carcinoma diagnosed within 4 months of one another. IPF was diagnosed after lung carcinoma in 25%. However, all patients had symptoms or radiologic findings suggesting the diagnosis of IPF. Similarly, in another study, nearly half of patients had a diagnosis of pulmonary fibrosis made at the time of surgery for lung cancer, emphasizing the role of pathologist in the evaluation of these patients. Patients with IPF undergoing surgical resection, mostly lobectomy or pneumonectomy, for lung carcinoma have greater operative morbidity, particularly for pulmonary events, and mortality than patients with lung carcinoma alone. Some series show a worse prognosis

Table* Contrasting Clinical and Histologic Features Between Patients with IPF and carcinoma, IPF without carcinoma and carcinoma without IPF

  IPF-ca IPF only Ca only
Men % 72-97 52-79 58-65
Mean age (years) 67.8 62.7 64.9
Smokers % 88.3 60.2 74.9
Tumor location, %
Upper lobes
Lower lobes
Peripheral 		 
40
54
81 		 
-
-
- 		 
53
34
48
Tumor type, %
Squamous cell
Adenocarcinoma
Small cell 		 
44
28
20 		 
-
-
- 		 
34
46
14
Stage
I
II
IIIa
IIIb-IV 		 
55
10
29
12 		 
-
-
-
- 		 
39
17
38
13
Post-operative morbidity 32   9
Post-operative mortality 12 - 2
*Summary of studies by Aubry, Hironaka, Kawasaki, Kumar, Lee, Park, Qunn, and Takahashi.

with decreased survival for patients with IPF and lung cancer, despite similar stage. However, in the Mayo Clinic series the prognosis was equally poor for patients with IPF alone, cancer alone and IPF and cancer. Patients with IPF and lung cancer most commonly die of respiratory failure rather than recurrent/metastatic lung cancer, in contrast to patients with lung cancer alone.

Thus far, a causal relationship between lung cancer and fibrosis has been mostly based on epidemiologic data. A few genetic and molecular studies have tried to provide clues to the mechanism of development of lung cancer in IPF but results have been contradictory. Although morphologically the amount of squamous metaplasia and length of hyperplasia appear greater in patients with IPF and carcinoma vs IPF alone, there are no significant differences in the presence of atypia/dysplasia and mutation of p53 in areas of fibrosis between both groups. However, the rate of p53 mutation and the proliferation index (Ki67) have both been shown to be greater in areas of fibrosis associated with IPF than fibrosis associated with other etiologies such as connective tissue disease. Similarly, microsatellite instability and loss of heterozygosity in genes commonly associated with lung cancer are greater in the sputum of patients with IPF vs normal controls, even smokers.

Differential diagnosis
The main differential diagnosis is distinguishing carcinoma from reactive non-neoplastic epithelial changes in areas of fibrosis/honeycomb change. Radiologic findings can be helpful in this specific setting since over 90% of patients will have a nodule/mass or localized consolidation in the background of bilateral reticular opacities, suggestive of an underlying interstitial disease. The gross surgical specimen usually reflects similar findings with a mass identified in or near the area of fibrosis. In the Mayo Clinic series, the tumor size ranged between 0.8-12.0 cm in diameter (mean 4.7 cm). However, for cases with ill-defined consolidation, a cancer might not be suspected yet biopsied along with the infiltrates for the purpose of diagnosing an interstitial lung disease, which was the scenario in one of the cases in the Mayo Clinic series. Recognition of cytologic atypia and obliteration of the architecture due to stromal invasion are key to identifying carcinoma. Reactive atypia is distinguished from neoplastic atypia by maintained nuclear cytoplasmic-ratio with abundant cytoplasm. Nuclei in foci of reactive change can show marked pleomorphism. However, the nuclear contours remain regular and the chromatin although often dark and smudgy, does not show irregular clumping. Finally, in glandular epithelium, the cells remain in a single layer and do not tend to overlap forming tufts or pseudopapilla. For both squamous and glandular epithelium, a distinct basal layer is seen, with the epithelium lining pre-existing air spaces and the underlying architecture although abnormal is retained.

Take home message

1.Patients with UIP/IPF at risk for developing carcinoma are older male smokers.
2.If peripheral squamous cell carcinoma is diagnosed, think about underlying UIP/IPFUIP; it might not be suspected.
3.Increased cytologic atypia and obliteration of the architecture of the underlying fibrotic process are key features to recognizing carcinoma.

References

  1. Araki T, Katsura H, Sawabe M, et al. A clinical study of idiopathic pulmonary fibrosis based on autopsy studies in elderly patients. Internal Medicine 2003; 42(6): 483-9.
  2. Aubry MC, Myers JL, Douglas WW, et al. Primary pulmonary carcinoma in patients with idiopathic pulmonary fibrosis. Mayo Clinic Proceedings 2002; 77(8): 763-70.
  3. Baumgartner KB, Samet JM, Stidley CA, et al. Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis. American Journal of Respiratory & Critical Care Medicine 1997; 155(1): 242-8.
  4. Beaumont F, Jansen H, Elema J, et al. Simultaneous occurrence of pulmonary interstitial fibrosis and alveolar cell carcinoma in one family. Thorax 1981; 36: 252-258.
  5. Beaver D, Shapiro J. A consideration of chronic parenchymal inflammation and alveolar cell carcinoma with regard to a possible etiologic relationship. Am J Med 1956; 21: 879-887.
  6. Bjoraker J, Ryu J, Edwin M, et al. Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998; 157: 199-203.
  7. Bouros D, Hatzakis K, Labrakis H, et al. Association of malignancy with diseases causing interstitial pulmonary changes. Chest 2002; 121(4): 1278-89.
  8. Demopoulos K, Arvanitis DA, Vassilakis DA, et al. MYCL1, FHIT, SPARC, p16(INK4) and TP53 genes associated to lung cancer in idiopathic pulmonary fibrosis. Journal of Cellular & Molecular Medicine 2002; 6(2): 215-22.
  9. Deslauriers J, Ginsberg RJ, Dubois P, et al.Current operative morbidity associated with elective surgical resection for lung cancer. Can J Surg 1989; 32(5): 335-9.
  10. Duque JL, Ramos G, Castrodeza J, et al. Early complications in surgical treatment of lung cancer: a prospective, multicenter study. Grupo Cooperativo de Carcinoma Broncogenico de la Sociedad Espanola de Neumologia y Cirugia Toracica. Ann Thorac Surg 1997; 63(4): 944-50.
  11. Fox B, Ridson R. Carcinoma of the lung and diffuse interstitial pulmonary fibrosis. J Clin Path 1968; 21: 486-91.
  12. Fraire A, Greenberg S. Carcinoma and diffuse interstitial fibrosis of lung. Cancer 1973; 31: 1078-86.
  13. Friedrich G. Periphere Lungenkrebse auf dem Boden pleuranacher. Virch Arch Path Anat 1939; 204: 230-47.
  14. Ginsberg RJ, Hill LD, Eagan RT, et al. Modern thirty-day operative mortality for surgical resections in lung cancer. J Thorac Cardiovasc Surg 1983; 86(5): 654-8.
  15. Haddad R, Massaro D. Idiopathic diffuse interstitial pulmonary fibrosis (fibrosing alveolitis), atypical epithelial proliferation and lung cancer. Am J Med 1968; 45: 211-9.
  16. Hironaka M, Fukayama M. Pulmonary fibrosis and lung carcinoma: a comparative study of metaplastic epithelia in honeycombed areas of usual interstitial pneumonia with or without lung carcinoma. Pathology International 1999; 49(12): 1060-6.
  17. Honma K, Chiyotani K, Kimura K. Silicosis, mixed dust pneumoconiosis, and lung cancer. American Journal of Industrial Medicine 1997; 32(6): 595-9.
  18. Hubbard R, Venn A, Lewis S, et al. Lung cancer and cryptogenic fibrosing alveolitis: A population-based cohort study. Am J Respir Crit Care Med 2000; 161: 5-8.
  19. Jones A. Alveolar cell carcinoma occurring in idiopathic interstitial pulmonary fibrosis. Brit J Chest 1970; 64: 78-84.
  20. Jones RN, Hughes JM, Weill H. Asbestos exposure, asbestosis, and asbestos-attributable lung cancer.[comment]. Thorax 1996; 51 Suppl 2: S9-15.
  21. Jover J, Aranda C. An 80-year-old man with idiopathic pulmonary fibrosis and new bilateral lung densities. Chest 1998; 114: 1210-12.
  22. Katabami M, Dosaka-Akita H, Honma K, et al. Pneumoconiosis-related lung cancers: preferential occurrence from diffuse interstitial fibrosis-type pneumoconiosis. American Journal of Respiratory & Critical Care Medicine 2000; 162(1): 295-300.
  23. Katzenstein A, Myers J. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med 1998; 157: 1301-15.
  24. Katzenstein AL, Zisman DA, Litzky LA, et al. Usual interstitial pneumonia: histologic study of biopsy and explant specimens. American Journal of Surgical Pathology 2002; 26(12): 1567-77.
  25. Kawai T, Yakumaru K, Suzuki M, et al. Diffuse interstitial pulmonary fibrosis and lung cancer. Acta Pathol Jpn 1987; 37: 11-19.
  26. Kawasaki H, Nagai K, Yokose T, et al. Clinicopathological characteristics of surgically resected lung cancer associated with idiopathic pulmonary fibrosis. Journal of Surgical Oncology 2001; 76(1): 53-7.
  27. Kawasaki H, Ogura T, Yokose T, et al. p53 gene alteration in atypical epithelial lesions and carcinoma in patients with idiopathic pulmonary fibrosis. Human Pathology 2001; 32(10): 1043-9.
  28. Kawasaki H, Nagai K, Yoshida J, et al. Postoperative morbidity, mortality, and survival in lung cancer associated with idiopathic pulmonary fibrosis. Journal of Surgical Oncology 2002; 81(1): 33-7.
  29. Kirishima K, Satoh H, Yamashita Y, et al. Unilateral metachronous lung cancers in a patient with idiopathic pulmonary fibrosis. Oncology report 1999; 6: 763-765.
  30. Kitamura H, Kitamura H, Tsugu S. Combined epidermoid and adenocarcinoma in diffuse interstitial pulmonary fibrosis. Hum Pathol 1982; 13: 580-3.
  31. Kuhara H, Wakabayashi T, Kishimoto H, et al. Synchronous bilateral double primary lung cancer associated with diffuse interstitial fibrosing pneumonitis (DIFP). Acta Pathol Jpn 1984; 34: 617-29.
  32. Kumar P, Goldstraw P, Yamada K, et al. Pulmonary fibrosis and lung cancer: risk and benefit analysis of pulmonary resection. Journal of Thoracic & Cardiovascular Surgery 2003; 125(6): 1321-7.
  33. Lee H, Im J-G, Ahn J, et al. Lung cancer in patients with idiopathic pulmonary fibrosis: CT findings. J Comput Assisted Tomography 1996; 20: 979-82.
  34. Lesobre R, Oury M, Duflo B. Etude des relations des fibroses pulmonaires diffuses et du cancer (A propos de trois observations). Rev Tuberc et Pneumol 1968; 32: 137-66.
  35. Lutwyche V. Another presentation of fibrosing alveolitis and alveolar cell carcinoma. Chest 1976; 70: 292-3.
  36. Ma Y, Seneviratne CK, Koss M. Idiopathic pulmonary fibrosis and malignancy. Current Opinion in Pulmonary Medicine 2001; 7(5): 278-82.
  37. Matsushita H, Tanaka S, Saiki Y, et al. Lung cancer associated with usual interstitial pneumonia. Pathology International 1995; 45: 925-32.
  38. Meyer E, Liebow A. Relationship of interstitial pneumonia, honeycombing and atypical epithelial proliferation to cancer of the lung. Cancer 1965; 18: 322-51.
  39. Mizushima Y, Kobayashi M. Clinical characteristics of synchronous multiple lung cancer associated with idiopathic pulmonary fibrosis. Chest 1995; 108: 1272-77.
  40. Nagai A, Chiyotani A, Nakadate T, et al. Lung cancer in patients with idiopathic pulmonary fibrosis. Tohoku J Exp Med 1992; 167: 231-7.
  41. Panos R, Mortenson R, Niccoli S, et al. Clinical deterioration in patients with idiopathic pulmonary fibrosis: causes and assessment. Am J Med 1990; 88: 396-404.
  42. Park J, Kim DS, Shim TS, et al. Lung cancer in patients with idiopathic pulmonary fibrosis. European Respiratory Journal 2001; 17(6): 1216-9.
  43. Qunn L, Takemura T, Ikushima S, et al. Hyperplastic epithelial foci in honeycomb lesions in idiopathic pulmonary fibrosis. Virchows Archiv 2002; 441(3): 271-8.
  44. Sakai S, Ono M, Nishio T, et al. Lung cancer associated with diffuse pulmonary fibrosis: CT-pathologic correlation. Journal of Thoracic Imaging 2003; 18(2): 67-71.
  45. Seo J-W, Im J-G, Kim Y-W, et al. Synchronous double primary lung cancers of squamous and neuroendocrine type associated with cryptogenic fibrosing alveolitis. Thorax 1991; 46: 857-58.
  46. Shankar P. Cryptogenic fibrosing alveolitis and carcinoma of he lung. Indian Journal of Medical Sciences 1983; 37: 68-70.
  47. Spain D. The association of terminal bronchiolar carcinoma with chronic interstitial inflammation and fibrosis of the lungs. Am Rev Tuber 1957; 76: 559-67.
  48. Stack B, Choo-Kang Y, Heard B. The prognosis of cryptogenic fibrosing alveolitis. Thorax 1972; 27: 535-42.
  49. Tammemagi CM, Neslund-Dudas C, Simoff M, et al. Impact of comorbidity on lung cancer survival. International Journal of Cancer 2003; 103(6): 792-802.
  50. Tesluk H, Ikeda R. Pulmonary carcinoma originating in chronic diffuse interstitial fibrosis of the lung. Chest 1970; 57: 386-8.
  51. Utz JP, Ryu JH, Douglas WW, et al. High short-term mortality following lung biopsy for usual interstitial pneumonia. Eur Respir J 2001; 17(2): 175-9.
  52. Vassilakis DA, Sourvinos G, Spandidos DA, et al. Frequent genetic alterations at the microsatellite level in cytologic sputum samples of patients with idiopathic pulmonary fibrosis. American Journal of Respiratory & Critical Care Medicine 2000; 162(3 Pt 1): 1115-9.
  53. Wells C, Mannino D. Pulmonary fibrosis and lung cancer in the United States: Analysis of the multiple causes of death mortality data, 1979 through 1991. Southern Medical Journal 1996; 89: 505-10.