Histopathology of Lung
Disease in the Connective
Tissue Diseases
Marina Vivero, MD, Robert F. Padera, MD, PhD*
INTRODUCTION
The pathologic correlates of interstitial lung disease (ILD) secondary to connective
tissue disease (CTD) comprise a diverse group of histologic patterns that can vary
greatly within a given CTD and may in fact display significant overlap between distinct
CTDs.1 Lung biopsies in patients with CTD-associated ILD tend to demonstrate simultaneous involvement of multiple anatomic compartments of the lung, including the
airways, alveolar septa, alveolar spaces, pleura, and vasculature, and often demonstrate acute, subacute, and chronic lesions within the same specimen, indicating an
ongoing pathophysiologic process.1,2 All CTDs can result in nonspecific histologic
The authors have no disclosures to make.
Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA
02115, USA
* Corresponding author.
E-mail address: rpadera@partners.org
KEYWORDS
Pathology Histopathology Interstitial lung disease Connective tissue disease
Rheumatoid arthritis Scleroderma Myositis
KEY POINTS
Although there is substantial histologic overlap among the pulmonary manifestations of
different connective tissue diseases (CTDs), certain patterns may favor 1 CTD over
another; occasionally, distinctive histologic clues may be present.
CTDs may present with acute, subacute, and/or chronic pleuropulmonary manifestations,
often mixed within the same biopsy, representing ongoing disease.
Patients with CTD may be taking immunosuppressive medications and are vulnerable to
certain infections; both of these can result in histologic changes that are similar to direct
pulmonary manifestations of the underlying CTD and can represent diagnostic dilemmas
for the pathologist.
A multidisciplinary approach involving the pathologist, rheumatologist, pulmonologist,
and radiologist allows for correlation of the clinical, radiologic, and pathologic findings
to arrive at the proper diagnosis.
Rheum Dis Clin N Am - (2015) -–-
http://dx.doi.org/10.1016/j.rdc.2014.12.002 rheumatic.theclinics.com
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patterns that are essentially indistinguishable from the idiopathic interstitial pneumonias; however, in the setting of known CTD, the probability that the lung findings are
caused by the patient’s underlying systemic disease must be considered.3,4 Certain
histologic patterns do tend to predominate in each defined CTD, and it is possible
in many cases to confirm connective tissue-associated lung disease and guide patient
management using surgical lung biopsy.
Some pulmonary pathologies seen in patients with CTD may not be a direct manifestation of the effect of CTD on the lung, but may be related to therapy or to other systemic complications of the patient’s CTD. These conditions can result in significant
histologic changes that can make it difficult to determine which findings can be truly
be ascribed to involvement by the patient’s CTD.5–7 For example, a patient with rheumatoid arthritis (RA) treated with methotrexate may develop a cellular nonspecific interstitial pneumonitis (NSIP) secondary to drug toxicity; this may mimic cellular NSIP that
could represent the bona fide onset of RA-associated ILD, or it could mimic the histologic pattern of a viral pneumonia to which the patient would be predisposed secondary to immunosuppression. The recognition and contextualization of these processes
are best accomplished via review by a multidisciplinary team, including pathologists
with specialized training in thoracic pathology or significant experience reading nonneoplastic surgical lung biopsies, rheumatologists, pulmonologists, and radiologists.
This article will cover the pulmonary pathologies seen in RA, systemic sclerosis,
myositis, systemic lupus erythematosus, Sjo ¨ gren syndrome, and mixed CTD.
HISTOLOGY OF LUNG DISEASE IN RHEUMATOID ARTHRITIS
Perhaps more so than any of the other CTDs, lung disease in patients with RA exhibits
a wide variety of histopathologic patterns that can affect all of the major compartments
of the lung. Pleural effusion and pleuritis are common initial pleuropulmonary manifestations of RA and may be appreciated grossly and microscopically as acute fibrinous
pleuritis, fibrous pleural thickening, and/or pleural adhesions.8–10 Cytologic preparations of pleural fluid may have characteristic aggregates of amorphous debris and
degenerated neutrophils.11 Single or multiple rheumatoid nodules (Fig. 1) may be
Fig. 1. Rheumatoid nodule in a patient with RA. Rheumatoid nodules possess a central area
of amorphous, eosinophilic necrobiosis surrounded by a rim of epithelioid histiocytes and
occasional giant cells. A mixed inflammatory infiltrate including occasional neutrophils
may line the inner perimeter of the histiocyte rim, and there may be finely granular basophilic material within areas of necrobiosis, imparting a dirty appearance at low power.
100 original magnification.
2 Vivero & Padera
found in the pleura, interlobular septa, or alveolar interstitium; although not the most
common manifestation, they are considered the most specific finding of RA-ILD.
These nodules, which can measure up to 2 to 3 cm, are identical to those seen in
the subcutaneous tissues, consisting of sterile central necrobiosis surrounded by
epithelioid histiocytes.5,8,9
The most frequent histologic patterns of ILD among RA patients are NSIP (Fig. 2), followed closely by usual interstitial pneumonia (UIP) (Figs. 3 and 4), accounting for 30%
to 67% and 13% to 57% of RA-associated ILD, respectively.2,3,12–17 Some studies have
noted an equal or greater incidence of UIP histology in RA-ILD, although smaller sample
sizes and the high frequency of both ILD patterns among this patient population may
account for the discrepancy.14,18 The histologic appearance of RA-associated NSIP
(RA-NSIP) or UIP (RA-UIP) is identical to that seen in idiopathic NSIP and UIP, although
the occurrence of more prominent interstitial lymphoid aggregates, either within alveolar septal walls or associated with small airways, has been noted in several studies.5,9
Indeed, the presence of lymphoid aggregates, and specifically germinal centers, has
been reported to be significantly greater in RA-UIP than in UIP, and has been suggested
to be a distinguishing feature of RA-ILD.12,15,16,19 Similarly, the frequency of fibroblast
foci has been reported to be lesser in RA-UIP than in idiopathic UIP.3,16
Various types of inflammatory airway disease including bronchiectasis, chronic
bronchitis, and follicular bronchiolitis are often seen as a secondary finding in a background of NSIP or UIP.17,20,21 Acute and subacute processes such as diffuse alveolar
damage (DAD) and organizing pneumonia (OP) can be seen in patients with established RA-ILD, often in the clinical setting of an acute exacerbation, but they can occasionally represent the initial pulmonary manifestation of RA.5,14,18,22 Vasculitis,
capillaritis, and pulmonary hemorrhage are rare acute manifestations of RA-ILD;
chronic vascular manifestations, when present, are usually a result of underlying
fibrotic lung disease.23
HISTOLOGY OF LUNG DISEASE IN SYSTEMIC SCLEROSIS (SCLERODERMA)
ILD occurs in up to 80% of patients with systemic sclerosis (SSc), making ILD more
prevalent in SSc than in any other CTD. The most characteristic histologic features
Fig. 2. Cellular NSIP in a patient with RA. Cellular NSIP is characterized by uniform expansion of the alveolar septal interstitium by a chronic inflammatory infiltrate composed primarily of small lymphocytes intermixed with occasional plasma cells and histiocytes.
Prominent lymphoid aggregates and germinal centers are characteristic of RA. 20 original
magnification.
Histopathology of Lung Disease 3
of ILD in SSc are dense interstitial fibrosis and pulmonary hypertensive vascular
changes.24,25 The most common pattern of interstitial fibrosis in SSc is fibrotic NSIP
(Fig. 5), manifesting as dense, paucicellular interstitial fibrosis that maintains the underlying lung architecture and often spares the immediate subpleural area.26–28 As
the lung disease progresses, the areas of fibrosis may become confluent and appear
as honeycomb or end-stage lung. Patients with SSc may also manifest their ILD as a
typical UIP pattern with temporal and spatial heterogeneity, in contrast to the diffusely
uniform fibrosis of NSIP. The pulmonary hypertensive vascular changes (Fig. 6) are
manifested as concentric intimal thickening by fibromyxoid tissue and mild medial hypertrophy leading to thickened and stenotic pulmonary arterioles. The degree of pulmonary hypertensive changes is often more severe and out of proportion to the degree
of interstitial fibrosis.29 Although true vasculitis and pulmonary hemorrhage can occasionally be seen, it is a fairly uncommon feature in this disease.30 Patients with SSc
often have esophageal dysmotility with associated gastrointestinal reflux; this can
Fig. 3. UIP in a patient with RA. The UIP pattern is characterized by patchy, predominantly
subpleural interstitial fibrosis. Interstitial fibrosis in UIP, unlike NSIP, appears temporally
heterogenous, with some areas of dense eosinophilic or elastotic mature interstitial
collagen and other areas of looser, immature myxoid collagenous matrix with discrete,
lens-shaped nodes of fibroblastic proliferation (fibroblast foci). These areas of involvement
often demonstrate a characteristic, sharply demarcated interface with completely uninvolved lung parenchyma. As in RA-NSIP, an increased number of lymphoid aggregates
and germinal centers are present in RA-UIP. 1 original magnification.
Fig. 4. UIP in a patient with RA. A fibroblastic focus is seen at the interface between dense
fibrosis and normal lung. 100 original magnification.
4 Vivero & Padera
lead to superimposed aspiration pneumonia that may or may not be clinically apparent
but can complicate the interpretation of the surgical lung biopsy.
HISTOLOGY OF LUNG DISEASE IN MYOSITIS
Chronic pulmonary disease in polymyositis and dermatomyositis (PM-DM) consists of
varying degrees of cellular interstitial pneumonitis that are best characterized as NSIP
(Fig. 7).2,6,22,31–35 Most case series have described varying degrees of fibrosis accompanying the cellular interstitial infiltrates of PM-DM, including 1 study indicating
approximately a 40% prevalence of cellular NSIP and 53% prevalence of mixed
cellular and fibrotic NSIP in myositis patients, with only rare cases of pure fibrotic
NSIP.33 The OP pattern (Fig. 8) can be seen in PM-DM patients, either as an isolated
manifestation or superimposed on a background of NSIP, and it has been histologically confirmed to resolve with steroid treatment.32,34,36 UIP pattern histology has been
Fig. 5. Fibrotic NSIP in a patient with SSc. Fibrotic NSIP is characterized by dense, paucicellular interstitial fibrosis that largely maintains the underlying lung architecture and is
spatially and temporally homogeneous. 40 original magnification.
Fig. 6. Pulmonary hypertensive vascular disease in a patient with SSc. The arteriolar wall is
thickened and the lumen narrowed by a fibrointimal proliferation with no significant
inflammation. 200 original magnification.
Histopathology of Lung Disease 5
described in PM-DM and, similar to RA-UIP, it often contains at least moderately
cellular areas consisting of lymphoplasmacytic or mononuclear infiltrates.2,16,31,34,36
The UIP pattern may arise more frequently in patients with the antisynthetase antibody
Jo-1. DAD is occasionally seen as a more acute manifestation of PM-DM lung disease
in the clinical setting of acute exacerbation of underlying chronic lung disease, and it
typically carries a poor prognosis similar to DAD associated with the clinical entity of
acute respiratory distress syndrome.22,33,36,37 Other more florid cellular manifestations
of ILD, such as follicular bronchiolitis and lymphoid interstitial pneumonia (LIP) are rare
in PM-DM.1,7,34 Other rare manifestations of ILD associated with PM-DM include
diffuse alveolar hemorrhage (DAH), pleuritis, airway involvement, and vasculitis.1,38
Fig. 7. Cellular NSIP in a patient with PM. There is a dense lymphocytic infiltrate that expands the alveolar walls but does not distort the underlying lung architecture. In this
case, intra-alveolar macrophages are abundant as well. 100 original magnification.
Fig. 8. OP in a patient with PM. OP is a subacute manifestation of lung injury that has been
described as a manifestation of all connective tissue diseases. Histologically, OP has been
characterized by rounded to elongated plugs of fibroblasts embedded in a blue-tinted
immature collagenous matrix within alveolar spaces, alveolar ducts, and occasionally the
terminal airways. An associated interstitial lymphocytic infiltrate often accompanies the
fibroblastic proliferation and may be brisk. 100 original magnification.
6 Vivero & Padera
HISTOLOGY OF LUNG DISEASE IN SYSTEMIC LUPUS ERYTHEMATOSUS
Pleuritis is the most frequent pleuropulmonary manifestation of systemic lupus erythematosus (SLE), and it appears histologically as nonspecific inflammation, fibrin deposition, and pleural fibrosis (Fig. 9).39–43 Cytologic preparations of pleural fluid from SLE
patients may show pathognomonic lupus erythematosis cells consisting of neutrophils
or macrophages with intracytoplasmic remnants of degenerated nuclei.
Pulmonary involvement in SLE is usually acute in nature and presents clinically as
acute lupus pneumonitis (ALP), which correlates to a variety of nonspecific acute and
organizing lung injury patterns (Fig. 10) in surgical lung biopsies.44 Acute and organizing diffuse alveolar damage, with fibrin microthrombi, hemorrhage, and hyaline
membranes in various stages of fibroblastic organization, is the most frequently reported manifestation of lupus lung disease.43,45–47 OP also seems to be a common
finding among studies of lupus pneumonitis.48–50 Finally, DAH is a potentially fatal
acute complication of SLE, possibly as a result of capillary immune complex
deposition, and can be seen as fresh hemorrhage or aggregates of hemosiderin
laden (Fig. 11) within alveolar spaces and alveolar septa, with or without
capillaritis.39–41,43,51–53
Chronic lung disease is also seen in patients with SLE. Most studies describe mononuclear or lymphoplasmacytic interstitial and peribronchiolar infiltrates of variable intensity in a cellular NSIP pattern with lesser degrees of fibrosis.1,40,42,48,53,54
Pulmonary vascular disease leading to pulmonary hypertension can occur in SLE,
possibly secondary to chronic thromboembolic disease or repeated episodes of
vasculitis with healing. The morphology of the vascular disease can range from active
vasculitis to chronic intimal thickening to plexiform lesions. Other patterns of chronic
lung disease such as UIP, diffuse interstitial fibrosis, LIP, and amyloidosis have been
reported, but these are rare.2,39,40,48,50,52–54
HISTOLOGY OF LUNG DISEASE IN SJO ¨ GREN SYNDROME
Sjo ¨ gren syndrome (SjS)-associated ILD (SjS-ILD) presents with a spectrum of cellular
chronic interstitial pneumonia and airway disease that ranges from a minimally cellular
NSIP pattern to more florid patterns of lymphoplasmacytic infiltration such as follicular
Fig. 9. Pleuritis in a patient with SLE. Acute fibrinous pleuritis manifests as a layer of hypereosinophilic fibrin on the pleural surface, usually with chronic inflammation in the visceral
pleura underneath. Over time, the pleura may become fibrotic with diminished active
inflammation. 100 original magnification.
Histopathology of Lung Disease 7
bronchiolitis, lymphoid interstitial hyperplasia, and LIP. NSIP as a cellular, fibrotic, or
mixed pattern is the more commonly reported histologic pattern of SjS-ILD in recent
studies.22,55,56 LIP (Fig. 12) lies on the other end of the spectrum of cellular chronic
interstitial pneumonitis seen in SjS-ILD and is characterized by a florid peribronchiolar
and interstitial lymphoplasmacytic infiltrate that significantly expands the alveolar
septa, is usually associated with germinal centers, and may occasionally contain
rare poorly formed non-necrotizing granulomas. Among the CTDs, LIP is most often
associated with SjS and may represent a precursor lesion that is associated with
Fig. 10. ALP in a patient with SLE. The histology of ALP involves a lung injury pattern with
diffuse interstitial inflammation, reactive pneumocyte hyperplasia, and alveolar fibrin present either as hyaline membranes or as acute fibrinous pneumonia. There may be variable
degrees of organization of this process depending on when the biopsy was performed relative to the onset of symptoms. 100 original magnification.
Fig. 11. DAH in a patient with SLE. DAH is a rare complication of connective tissue disease
and is most commonly seen in SLE. The predominant histologic findings in DAH are
numerous intra-alveolar and interstitial aggregates of hemosiderin-laden macrophages (as
seen in the image), with or without evidence of fresh hemorrhage. Capillaritis may be an
associated finding in DAH, but may be subtle or entirely absent, and is characterized by
neutrophilic alveolar septal infiltrates accompanied by fibrinoid necrosis and basophilic
neutrophil nuclear dust. 10 original magnification.
8 Vivero & Padera
the significantly higher incidence of lymphoma in SjS patients.22,56–59 Although the
prevalence of LIP in SjS patients is estimated to be 0.9%, approximately 25% of patients with LIP histology are thought to have SjS.59
Involvement of the large and small airways in SjS is common. Airway involvement is
thought to be analogous to the inflammatory findings in the salivary glands and upper
respiratory tract, and it manifests as lymphoplasmacytic infiltrates of varying intensity
ranging from mild chronic bronchiolitis to follicular bronchiolitis, which is characterized
by nodular lymphocytic infiltrates with reactive germinal centers in an exquisitely bronchiolocentric distribution (Fig. 13).56,59,60
Fig. 12. LIP in a patient with SjS. LIP constitutes the extreme end of the spectrum of chronic
cellular interstitial pneumonitis that can be seen in SjS and is characterized by florid airwaycentered and alveolar interstitial chronic inflammatory infiltrates. Germinal centers and occasional poorly formed non-necrotizing granulomas or histiocytic aggregates can be seen.
Destructive or aggressively infiltrative lymphoid populations are not typical of LIP and
should raise the possibility of lymphoma. 20 original magnification.
Fig. 13. Follicular bronchiolitis (FB) in a patient with SjS. FB is most commonly seen in connective tissue associated lung disease as part of the spectrum of chronic cellular interstitial
pneumonitis that typifies SjS. Histologically, FB consists of a bronchiolocentric proliferation
of lymphoid tissue with occasional germinal centers. The lymphoid infiltrates may or may
not extend into the alveolar septal interstitium immediately surrounding the small airways.
20 original magnification.
Histopathology of Lung Disease 9
Other histologic patterns of interstitial lung disease, such as UIP, DAD, OP, and
pleuritis, are much less common in patients with SjS. The acute and subacute patterns
are most often superimposed on a background of chronic ILD in the setting of an acute
exacerbation.
HISTOLOGY OF LUNG DISEASE IN MIXED CONNECTIVE TISSUE DISEASE
Patients who have anti-(U1)snRNP antibodies manifesting some features of DM, PM,
SLE, or SSc (but not meeting formal diagnostic criteria) are labeled as having mixed
CTD (MCTD). Many of these patients will develop additional clinical and laboratory
findings and eventually declare themselves as having one of the specific CTDs.
Consistent with the clinical phenotype, the pulmonary manifestations of MCTD in
any given patient may reflect any of the patterns discussed previously for the specific
CTDs.
Acute fibrinous and chronic organizing pleuritis with pleural adhesions is a common
finding in MCTD and appears similar to pleural disease related to other causes.61
Organizing pneumonia and diffuse alveolar damage have been occasionally described
in MCTD patients and have been suggested to represent acute exacerbations of underlying pulmonary disease.49,62 Although pulmonary fibrosis with radiologic features
of both NSIP and UIP has been described, histologic descriptions of chronic ILD in
MCTD are scarce, limited to case reports or small series, and usually lack definitive
histologic classification.62–64
Pulmonary vascular disease is a prominent and often predominant feature of
MCTD-associated lung involvement, correlating with the clinical manifestations of severe and sometimes fatal pulmonary hypertension. The histologic changes include
medial muscular hypertrophy, intimal fibromyxoid hyperplasia, and endothelial hyperplasia.63,65 Plexiform arteriopathy can occasionally be seen in advanced cases. The
sequelae of thromboembolic disease in the form of eccentric intimal proliferation
have been reported in lung biopsies of patients with MCTD as a manifestation of
CTD-associated hypercoagulability.61 These vascular findings can be seen as an isolated finding or with concomitant interstitial fibrosis; however, when fibrosis is present,
it is usually not extensive enough to explain the degree of vasculopathy, and the
vascular findings are therefore considered to be a separate primary process.65
HISTOLOGIC DIFFERENTIAL DIAGNOSIS OF LUNG DISEASE IN CONNECTIVE TISSUE
DISEASES
The histologic differential diagnosis in cases of suspected pulmonary involvement by
CTD can be broad and is compounded by the significant histologic overlap among pulmonary manifestations of CTD, by the immunosuppressed nature of the patients, and
by various treatments that may induce histologic changes in the lung.5,66 Each of the
patterns of lung disease (ie, UIP, NSIP, OP, LIP) mentioned previously carries its own
differential diagnosis that includes pulmonary involvement by one or more of the CTDs.
There are several nonconnective tissue etiologies that cut across many of these patterns that should be considered. Various infections can mimic many of these patterns:
viral infection can produce a cellular NSIP pattern, resolving bacterial pneumonia can
produce an OP pattern, and invasive fungal or mycobacterial infection can produce
necrotizing granulomas resembling those seen in granulomatosis with polyangiitis.67
Pulmonary toxicity from certain medications can produce many of these injury patterns, particularly OP, cellular NSIP, and DAD. Many therapies for CTD including
immunosuppressive agents such as methotrexate, cyclophosphamide, and possibly
tumor necrosis factor (TNF)-a inhibitors can give rise to pulmonary pathologies and
10 Vivero & Padera
can present years after the offending drug has been discontinued.4,66,68 Vasculitis and
lupus-like syndromes are also potential pulmonary complications of immunosuppressive drugs.66 Pulmonary injury caused by inhaled or aspirated material, either from one
or multiple exposures, can lead to bronchiolitis and bronchiectasis that can enter into
the differential of UIP, OP, DAD, or DAH. Chronic hypersensitivity pneumonitis is in the
differential diagnosis of UIP and NSIP. Lymphoproliferative disorders, which can arise
in the setting of certain CTDs such as SjS, can mimic cellular NSIP and LIP histologically, radiologically, and clinically, and need to be ruled out when the inflammatory infiltrate is unusually florid.22,55,69–72 Of course, most of the histologic patterns, particularly
UIP, have idiopathic forms that occur in the absence of CTD. On the other hand, it is
also the case that any of these patterns can be the initial manifestation of a patient’s
yet to be clinically diagnosed CTD.19
SUMMARY
ILD is common in patients with CTDs. Many of the histologic patterns of the idiopathic
interstitial pneumonidites such as UIP, cellular and/or fibrotic NSIP, LIP, DAD, and OP
can also be seen in patients with CTD; occasionally, the pulmonary manifestations of
CTD may precede formal diagnosis of the underlying CTD. The pulmonary manifestations of CTD can result from the direct involvement of the CTD on the lung, from drug
reactions from the patient’s medications, or from infections to which the patient is predisposed from his or her autoimmune disease and treatment thereof. The histologic
changes seen in a given patient’s surgical lung biopsy may result from any or all of these,
and correlation with the clinical scenario is critical in arriving at the proper diagnosis.
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