A 59-year old white woman presented to the clinic for evaluation of dyspnea and an abnormal chest computed tomography (CT). Three years ago, she was diagnosed with breast cancer. One of twenty-nine axillary lymph nodes were positive for tumor, which was estrogen receptor positive. She was treated with surgery, radiation, and chemotherapy that included doxirubicin, cyclophosphamide,paclitaxel, and gemcitabine. She was then given anastrozole. She was followed closely over the next two years and had no evidence of recurrence.

Before developing breast cancer, the patient was physically active, walking 3 to 4 miles daily. However, over the last two years she had increasing dyspnea on exertion and was able to walk only 1 mile. Just prior to the visit a chest radiograph revealed hilar and mediastinal lymphadenopathy. A chest CT confirmed bilateral hilar and mediastinal lymphadenopathy as well as perilymphatic nodules less than a centimeter in diameter throughout the lungs. In addition, a positron emission tomography (PET) scan revealed uptake in several mediastinal lymph nodes with a standard uptake value of 8. The patient denied any cough, weight loss, night sweats, fevers, or occupational or travel-related exposures. A repeat mammogram and breast ultrasound were both negative.

Multinodular lung parenchymal disease can be characterized by lobar distribution and by diffuse versus focal disease. However, in order to develop a useful differential diagnosis, characterizing nodular disease by its relationship to secondary lobar anatomy is the most useful (1). The three most commonly used distributions are: random, centrilobular, and perilymphatic.

Randomly distributed nodules are by definition diffuse in nature with no obvious pattern. Diseases that are spread via a hematogenous route commonly cause a random distribution of nodules. Although diffuse, these nodules may show a predominance in the lung bases due to the higher perfusion there (2). Metastatic disease, such as carcinomatosis, is the most common cause of random nodules. Miliary infections, such as tuberculosis, Mycobacterium avium complex, or fungal disease can also cause this pattern, but are usually seen in a centrilobular distribution (see below).

Nodular disease can also be found clustered around the fissures, along the interlobular septae, and along the pleura. These regions are where the lymphatics are extensive, and this pattern is termed a perilymphatic distribution (2). Sarcoidosis is the classic disease that fits this distribution. Sarcoidosis can also occur in the lymphatics of the bronchovascular bundle.  Silicosis and coal-workers’ pneumoconiosis can also appear in this distribution. Importantly, lymphangitic carcinomatosis occasionally fits a perilymphatic distribution, but it is usually associated with lymphadenopathy, pleural effusions, and septal thickening.

The third category involves nodules that do not touch the pleura and are not along the fissures. These nodules are found around the centrilobular bronchioles and their pulmonary artery branches, hence the label centrilobular nodules (3). The differential of this category is broader than the other two, and breaking it down further into nodules with a “tree-in-bud” appearance versus those with a more “ground-glass” appearance can be helpful. Tree-in-bud refers to branches that can come off the nodules, giving them this appearance (4). This appearance usually fits with an infection such as Mycobacterium avium complex, Mycobacterium tuberculosis, fungal, or other bacterial infection.

Hypersensitivity pneumonitis and respiratory bronchiolitis are the most common diseases that present as ground-glass centrilobular nodules (2). Other, less common diseases such as lymphocytic interstitial pnuemonitis and Langerhans’ histiocytosis can present this way as well.

In our case, the nodules were in a perilymphatic pattern. Given the patient’s history of cancer, recurrence was high on the differential and needed to be thoroughly evaluated. However, no malignant cells were seen in the mediastinoscopy samples or the trans-bronchial biopsy samples. Also, little septal thickening and no effusions were seen. Pathology instead revealed granulomatous lymphadenitis in the lymph node samples and multiple non-necrotizing granulomas in the trans-bronchial samples. While clubbing is rare in sarcoid, given these findings and the perilymphatic distribution, sarcoidosis is the most likely diagnosis. However, the diagnosis of a sarcoid-like reaction to tumor antigens released from a recurrence cannot be completely ruled out (see below). Given the large number of biopsies with no evidence of recurrence, this is somewhat less likely.

Given the patient’s lack of significant symptoms and relatively normal pulmonary function testing, therapy should initially be withheld until the course of the disease is established. This is especially true in light of her malignancy history, as any treatment has the potential to increase the risk of recurrence or development of a secondary malignancy.