Histology of Pulmonary and Bronchiolar Disorders in Connective Tissue Diseases

Cecilia Brambilla, MD; Alexandra Rice, FRCPath; Andrew G. Nicholson, FRCPath


Semin Respir Crit Care Med. 2019;40(2):147-158. 

In This Article

Abstract and Introduction


Connective tissue diseases (CTDs) are a heterogeneous group of disorders, acquired or hereditary, involving an autoimmune-mediated inflammation of connective tissues in the whole body. Lung involvement is common with CTDs, and associated with significant morbidity and mortality. Each compartment of the lung may be affected, often simultaneously, depending on the type of CTD. In addition, the lung may show pathological changes related to treatment, such as infection, drug reaction, and neoplasia. A multidisciplinary approach to diagnose these patients is essential and incorporates radiological and clinical as well as pathological data. In this review we describe the patterns of lung disease associated with common CTDs, lung disease in pediatric CTD patients, and newly recognized conditions.


Connective tissue diseases (CTDs) are a heterogeneous group of disorders that share similar pathogenetic mechanisms. Different levels of systemic autoimmune-mediated inflammation involve connective tissues in organs throughout the body, including the lungs and the pleura to varying extents. There are several difficulties for pathologists in the assessment of biopsies from these patients.

  • CTDs show variably strong associations with different histological patterns of lung disease, but these histological patterns can both overlap across CTDs and also show diversity within any particular CTD.

  • Although the interstitium is often the compartment upon which clinical interest is centered, there is a greater propensity for CTDs to involve multiple pulmonary compartments such as large and small airways, pleura, and pulmonary vasculature. Therefore a combination of patterns, either across compartments or even within the same one (e.g., both organizing pneumonia [OP] and nonspecific interstitial pneumonia [NSIP]), or the presence of lymphoid hyperplasia and/or eosinophilia, should prompt consideration of an underlying CTD. Pathologists should report cases as such, rather than using the fall back of "unclassifiable."

  • Patients with a known CTD may be on various drugs including immunomodulatory and cytotoxic agents, which can also be associated with pulmonary toxicity and a variety of pathological changes. Many are immunosuppressed, predisposing them to developing lung infections and neoplasia.

  • Many of the pathologic entities associated with CTD can be diagnosed by noninvasive methods, especially high-resolution computed tomography (HRCT), obviating the need for biopsy, so undertaking biopsy is often quite rare when patients are known to have CTDs. Conversely, biopsy may be the first pointer toward a disease in patient thought to be presenting in an idiopathic setting. Indeed, the lung may be the first organ to be involved, with the CTD manifesting systemically at a later date.

The diagnosis of CTD-related interstitial lung disease (ILD) therefore relies on a multidisciplinary approach, within which the role of the pathologist is often critical. As well as identifying or confirming the presence of CTD-related lung disease, the pathologist may identify patients with an occult CTD, or be called upon to confirm or exclude manifestations of systemic therapy, infection, or a secondary effect of CTD such as aspiration or malignancy (e.g. mucosa-associated lymphoid tissue [MALT] lymphoma in patients with Sjogren's syndrome [SS]). This review will first assess the anatomic compartments of the lung (Table 1) and then review some rare entities.