Case 2 -
Squamous Cell Carcinoma Arising in Usual Interstitial Pneumonia
Click on each slide thumbnail image for an enlarged view
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).
Squamous cell carcinoma arising in usual interstitial pneumonia
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
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
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
*Summary of studies by Aubry, Hironaka, Kawasaki, Kumar, Lee, Park, Qunn, and Takahashi.
| ||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, %|
|Tumor type, %|
|Post-operative morbidity ||32 || ||9|
|Post-operative mortality ||12 ||- ||2|
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.
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.|
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