Moderators: Dr. Elizabeth Brambilla, Dr. John English and Dr. Donald Guinee
Case 5 -
Squamous Cell Carcinoma Arising in Idiopathic
Dr. Sylvie Lantuejoul
Department of Pathology, CHU Albert Michallon
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
Case 5 - Slide 2
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
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
Squamous cell carcinoma arising on idiopathic pulmonary fibrosis
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 . 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  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
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 .
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 .
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 .
On the histological point of view, lung cancers arising on UIP are frequently multiple (22% versus
3.4% without UIP)
, with a significant higher incidence of small cell
carcinoma combined with squamous cell carcinoma or adenocarcinoma .
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 . According to Nagai et al, there is no
relationship between the severity of fibrosis and the incidence of lung cancer .
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
. 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 . 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
Atypia in honeycombing areas are found in nearly 20% of the UIP, perhaps more frequently when a
carcinoma is found concomitantly , 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
A P53 immunohistochemical expression and p53
mutations were demonstrated in 60% and 40% of squamous metaplasia in UIP, respectively 
. 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
. 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.
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