Two diseases were present in this case. One was expected and the other was not. Diffuse interstitial pulmonary fibrosis/usual interstitial pneumonia was identified. This had been diagnosed clinically here at the University of Pittsburgh Medical Center, but microscopic findings of usual interstitial pneumonia with numerous fibroblast foci and areas of honeycomb change, multifocal acute and subacute organizing pneumonia, and multifocal pulmonary hemorrhage and hemosiderosis confirmed the diagnosis histopathologically.
However, what was unexpected to see microscopically was diffusely infiltrating, moderately differentiated adenocarcinoma in the peripheral and central left upper and lower lobes as well as the central right middle and lower lobes. It was also metastatic to multiple left pulmonary hilar lymph nodes.
Immunostain of the adenocarcinoma for CK7 and TTF-1 were strongly positive, and CK20 and CDX2 were negative. The immunostaining pattern of CK7 positivity and CK20 negativity helped to support the diagnosis of primary lung adenocarcinoma. Additionally, TTF-1 positivity also supported a lung primary, whereas CDX2 negativity helped to exclude a metastatic colon cancer.
UIP is more common in males than females, and has prevalence upwards of 55,000 in the United States. The majority of patients with UIP are over age 60. The primary symptom is dyspnea, commonly associated with a non-productive cough. Symptoms generally begin insidiously and progress slowly over months to years. Signs include dry inspiratory crackles and, later, clubbing of the digits. Patients may have secondary pneumonias that can confound the clinical picture. Additionally, while ANA and rheumatoid factor can be slightly elevated in UIP, a significant elevation should sway the differential diagnosis towards a systemic connective tissue disease. Radiologic findings on high-resolution computed tomographic scanning include reticular opacities at the lung bases, ground-glass opacities, subpleural cysts representing honeycombing, and traction bronchiectasis. "Skip" areas representing intervening areas of relatively normal lung parenchyma are common. Microscopically, the peripheral areas of the lung are commonly involved. The classic findings are described as having "temporal heterogeneity," for which "THORN" is an excellent pneumonic: Temporal heterogeneity, Honeycombing, Old fibrosis, Recent fibrosis, and Normal lung. Temporal heterogeneity refers to the simultaneous presence of old fibrosed lesions, fibroblastic foci of subacute disease, and areas of new inflammation. Honeycombing refers to microscopic cystic changes, much smaller than the honeycombing seen on imaging. These cysts are usually irregular, subpleural, lined by columnar ciliated epithelium, and filled with mucus and inflammatory cells and debris. Old fibrosis is seen microscopically usually as pink, dense sheets of collagen. Recent fibrosis refers to fibroblastic foci representing active disease; these areas are often located next to normal lung parenchyma. All of these criteria are necessary to assign a diagnosis of UIP - and even then other diseases can contribute to causing UIP-like changes, as opposed to true idiopathic UIP. Fibrosis in and of itself is not UIP - it is only fibrosis; many pulmonary diseases cause fibrosis as an end-stage feature, so it's important to be strict with the diagnostic criteria.
The old expression of "once you identify your first diagnosis, keep your eyes and mind open for the second" truly was important in this case. This patient had unsuspected metastatic adenocarcinoma diagnosed at autopsy. In light of his clinical diagnosis of diffuse interstitial fibrosis, pleural effusion cytology negative for malignancy, and biopsies directed at radiologically solid areas negative for malignancy, his deteriorating status was attributed solely to his UIP. Primary lung adenocarcinoma is a malignant epithelial neoplasm that has glandular differentiation. This lesion can be graded from well-differentiated, which forms easily recognizable infiltrating glands, to poorly-differentiated, which grow and invade as solid sheets of tumor with hardly any recognizable glands. As a first approximation, if it is difficult to tell whether the glandular neoplasm is malignant, it is well differentiated. With moderately differentiated adenocarcinoma of the lung, the glands are more irregularly arranged, and there are an increased number of mitoses and cellular atypia along with a prominent stromal reaction and inflammation. If it is difficult to tell whether the obviously malignant neoplasm is glandular, it is poorly differentiated. Other common findings include pleomorphic nuclei with enlarged, prominent nucleoli. This patient had all the features of a moderately differentiated primary lung adenocarcinoma. While there is an increased risk of developing carcinoma with idiopathic pulmonary fibrosis, there has been no method of showing causality. Needless to say, this case illustrates the potential value of autopsy in providing feedback and quality assurance for cytology and surgical pathology.
Contributed by Jay S Raval, MD and Larry Nichols, MD